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[ "AIMS: In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model.METHODS AND RESULTS: Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva.CONCLUSION: In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.", "BACKGROUND: Diagnosing GABHS (Group A-beta Hemolytic Streptococcus) tonsillopharyngitis by clinical scoring is a recommended approach in developed countries, but there is still much controversy for low resource settings.AIM: We aimed to assess the impact of Centor criteria with the support of practical laboratory tests.METHODS: We prospectively included patients complaining sore throat (N = 282). We evaluated them in terms of Centor scoring and performed white blood cell count (WBC), C-reactive protein (CRP), rapid antigen detecting test, and throat culture.RESULTS: In GABHS cases (N = 32, 11·3%), two of the criteria were observed to be positive in more than half of the cases (N = 19, 59·3%), while 13 (40·7%) cases met three/four criteria. The specificity of having two criteria was found to be 65·5% and increased to 91·5% after including CRP and WBC.CONCLUSION: Centor criteria could be safely used to reduce unnecessary antibiotic usage for tonsillopharyngitis in developing countries.", "MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells.", "SUMMARY: Rtpca is an R package implementing methods for inferring protein-protein interactions (PPIs) based on thermal proteome profiling experiments of a single condition or in a differential setting via an approach called thermal proximity coaggregation. It offers user-friendly tools to explore datasets for their PPI predictive performance and easily integrates with available R packages.AVAILABILITY AND IMPLEMENTATION: Rtpca is available from Bioconductor (https://bioconductor.org/packages/Rtpca).SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Oseltamivir (has known by its brand name 'Tamiflu') is a prodrug, requiring ester hydrolysis for conversion to the active form, Oseltamivir carboxylate. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed by US based Gilead Sciences and is currently marketed by F. Hoffmann-La Roche (Roche). Oseltamivir is an antiviral drug which works by blocking the function of the viral neuraminidase protein. US FDA approved Oseltamivir for prophylaxis of uncomplicated influenza A and B. Currently, Oseltamivir is the only first line defense drug available for the treatment of Swine Flu. Orally Oseltamivir is well tolerated and effective in treatment of influenza in adolescents and adults, including the elderly and patients with chronic cardiac and/or respiratory disease. Many of the pharmaceutical companies targeted Oseltamivir as a block buster molecule. In present review, we have tried to cover chemistry, mode of binding, total synthesis, current patent status, adverse effect and clinical status of Oseltamivir giving emphasis on medicinal chemistry aspect.", "PURPOSE: To analyse the rate of secondary malignancies observed in a series of 675 prostate cancer patients who underwent a permanent implant brachytherapy between 1999 and 2003, and to compare the incidence with the expected rate in a matched general French population.MATERIAL AND METHODS: The cohort included low-risk patients and a selection of \"favourable-intermediate\" risk patients. All patients were homogeneously treated using an intraoperative dynamic planning prostate brachytherapy technique, with loose 125-iodine seeds and a prescription dose of 145Gy. The mean follow-up was 132 months.RESULTS: The 10-year overall survival for the entire cohort was 92% (95% confidence interval [CI]: 90-94). The 10-year relapse-free survival rate was 82% (95% CI: 79-85). Overall, 61 second cancers were registered. When comparing with a matched general French population, the standard incidence ratio (SIR) for bladder cancer was 1.02 (95% CI: 0.46-1.93). For colorectal cancer, the SIR was 0.45 (95% CI: 0.19-0.89). For lung cancer, the SIR was 0.38 (95% CI: 0.17-0.76). The SIR for all cancers was 0.61 (95% CI: 0.47-0.79). When excluding secondary colorectal and lung cancers (both with low SIRs in this series), the SIR for all cancers was 1.06 (95% CI: 0.77-1.29).CONCLUSION: With a mean follow-up of more than 11 years, this series does not detect any excess risk of second cancers associated with permanent implant prostate brachytherapy. However, due to power limitation, a small increase in the risk of secondary malignancies cannot be totally ruled out.", "SADS is defined as sudden death under the age of 40 years old in the absence of structural heart disease. Family screening studies are able to identify a cause in up to 50% of cases-most commonly long QT syndrome (LQTS), Brugada and early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) using standard clinical screening investigations including pharmacological challenge testing. These diagnoses may be supported by genetic testing which can aid cascade screening and may help guide management. In the current era it is possible to undertake molecular autopsy provided suitable samples of DNA can be obtained from the proband. With the evolution of rapid sequencing techniques it is possible to sequence the whole exome for candidate genes. This major advance offers the opportunity to identify novel causes of lethal arrhythmia but also poses the challenge of managing the volume of data generated and evaluating variants of unknown significance (VUS). The emergence of induced pluripotent stem cell technology could enable evaluation of the electrophysiological relevance of specific ion channel mutations in the proband or their relatives and will potentially enable screening of idiopathic ventricular fibrillation survivors combining genetic and electrophysiological studies in derived myocytes. This also could facilitate the assessment of personalized preventative pharmacological therapies. This review will evaluate the current screening strategies in SADS families, the role of molecular autopsy and genetic testing and the potential applications of molecular and cellular diagnostic strategies on the horizon." ]

[ "The aim of this study, using a Fleming single-stage design, was to explore the efficacy and safety of Taxotere 100 x mg x m(-2) docetaxel and FEC 75 cyclophosphamide 500 mg x m(-2), fluorouracil 500 x mg x m(-2) and epirubicin 75 mg x m(-2), in alternating and sequential schedules for the first-line treatment of metastatic breast cancer. One hundred and thirty-six women were randomly allocated, to one of three treatment regimens: DTX 100 plus FEC 75, alternated for eight courses (ALT); four courses of DTX 100 followed by four courses of FEC 75 (SEQ T); or four courses of FEC 75 followed by four courses of DTX 100 (SEQ F). One hundred and thirty-one women were evaluable for tumour response. Although the treatment outcome was equivalent in the two sequential arms and the alternating regimen (P=0.110, not significant), the response rate was less encouraging in the SEQ F arm (52.3%) than in the other two arms (71.1% for ALT and 70.5% for SEQ T), in which docetaxel was administered first. Time to progression was similar in the ALT, SEQ T and SEQ F arms (9.5, 9.3 and 10.4 months respectively). Grade 3-4 neutropenia was observed in nearly all patients; febrile neutropenia occurred in 9% (ALT), 16% (SEQ T) and 2% (SEQ F) of patients. Few patients (< or =9%) developed grade 3-4 non-haematological toxicities. Relative dose intensity was 97-99% for all regimens. All treatment regimens were active and well tolerated.", "A prospective study of 9 patients with plasma cell dyscrasia was performed to evaluate the need of plasma exchange (PE) and its possible effect in the acute and chronic management of hyperviscosity syndrome. The underlying dyscrasia was an IgG myeloma in 5 cases, IgA myeloma in 2 cases, one patient had IgD myeloma and in one patient Waldemström's macroglobulinemia was diagnosed. The main sequelae of circulatory disturbances, caused by increased blood resistance to flow, were fundus alterations (55.6%), neurologic manifestations (88.9%), a tendency to bleeding (44.4%) and renal failure (55.6%). In total, 49 PE procedures were performed. Following PE, hyperviscosity symptoms improved in 88.9% of the treated patients. The improvement in neurologic manifestations and hematologic complications was very fast, within the first PE session. The effect was less evident in ocular fundus alterations. Only one myeloma patient developed chronic renal failure. PE is the most effective method in the treatment of hyperviscosity syndrome often seen with multiple myeloma and Waldenström's macroglobulinemia, and it is therapy of choice for this complication.", "BACKGROUND: Various human cardiovascular pathophysiological conditions associate aberrant expression of microRNAs (miRNAs) and circulating miRNAs are emerging as promising biomarkers. In mice, myocardial miR-21 overexpression is related to cardiac fibrosis elicited by pressure overload. This study was designed to determine the role of myocardial and plasmatic miR-21 in the maladaptive remodeling of the extracellular matrix induced by pressure overload in aortic stenosis (AS) patients and the clinical value of miR-21 as a biomarker for pathological myocardial fibrosis.METHODS: In left ventricular biopsies from 75 AS patients and 32 surgical controls, we quantified the myocardial transcript levels of miR-21, miR-21-targets and ECM- and TGF-β-signaling-related elements. miR-21 plasma levels were determined in 25 healthy volunteers and in AS patients. In situ hybridization of miR-21 was performed in myocardial sections.RESULTS: The myocardial and plasma levels of miR-21 were significantly higher in the AS patients compared with the controls and correlated directly with the echocardiographic mean transvalvular gradients. miR-21 overexpression was confined to interstitial cells and absent in cardiomyocytes. Using bootstrap validated multiple linear regression, the variance in myocardial collagen expression was predicted by myocardial miR-21 (70% of collagen variance) or plasma miR-21 (52% of collagen variance), together with the miR-21 targets RECK and PDCD4, and effectors of TGF-ß signaling.CONCLUSIONS: Our results support the role of miR-21 as a regulator of the fibrotic process that occurs in response to pressure overload in AS patients and underscore the value of circulating miR-21 as a biomarker for myocardial fibrosis.", "The major alpha-amylase in honey was characterized. The optimum pH range and temperature were determined for the enzyme as 4.6 to 5.3 and 55 degrees C, respectively. The enzyme was stable at pH values from 7 to 8. The half-lives of the purified enzyme at different temperatures were determined. The activation energy for heat inactivation of honey amylase was 114.6 kJ/mol. The enzyme exhibited Michaelis-Menten kinetics with soluble starch and gave KM and Vmax values of 0.72 mg/mL and 0.018 units/mL, respectively. The enzyme was inhibited by CuCl (34.3%), MgCl2 (22.4%), and HgCl2 (13.4%), while CaCl2, MnCl2, and ZnSO4 did not have any effect. Starch had a protective effect on thermal stability of honey amylase. Therefore, it might be critical to process or control the amylase in honey before incorporation into starch-containing foods to aid in the preservation of starch functionality. One step could involve heat treating honey with other ingredients, especially those that dilute and acidify the honey environment.", "This study aimed to screen alpha-amylase producing microorganisms from honey as a low water activity medium, a suitable source for selecting stable and cost-beneficial bacterial enzyme production systems. Plackett-Burman method was used to select twelve effective factors including pH, inoculum size, temperature, time, corn starch, KH2PO4, peptone, MgSO4, CaCl2, NaCl, glycerin, and yeast extract concentrations on bacterial alpha-amylases production yield. The Box-Behnken method was utilized to optimize the level of selected significant factors. The stability of bacterial alpha-amylases was also determined in low pH and high-temperature conditions. In addition, in silico study was used to create the alpha-amylase structure and study the stability in high-temperature and low water available condition. Among all isolated and characterized microorganisms, Bacillus megaterium produced the highest amount of alpha-amylases. The in silico data showed the enzyme 3D structure similarity to alpha-amylase from Halothermothrix orenii and highly negative charge amino acids on its surface caused the enzyme activity and stability in low water conditions. Based on Box-Behnken results, the temperature 35 °C, pH 6 and starch 40 g/l were determined as the optimum level of significant factors to achieve the highest alpha-amylases unit (101.44 U/ml). This bacterial alpha-amylases enzyme showed stability at pH 5 and a range of temperatures from 40 to 60 °C that indicates this enzyme may possess the potential for using in industrial processes.", "Tumors of the central nervous system (CNS) are common causes of morbidity and mortality. These tumors can occur sporadically or in individuals with genetic disorders predisposing to cancer development. Such syndromes include neurofibromatosis type 2, neurofibromatosis type 1, Li-Fraumeni syndrome, as well as von Hippel-Lindau disease, tuberous sclerosis, and Turcot syndrome. There may also be familial syndromes resulting in glioma or meningioma alone, but these are not well understood. Development of sporadic gliomas is accompanied by a number of molecular genetic alterations, including activation of dominant oncogenes and inactivation of tumor suppressor genes. Some of these alterations may be associated with progression of gliomas to their most malignant form, glioblastoma multiforme. However, at this time molecular genetic analysis of gliomas does not provide better prognosis than histopathological staging. Recently, experimental treatments of gliomas in rodents, using gene therapy, have been reported. Results of these studies have been promising, and these techniques may represent a future direction for therapy in humans.", "Identification and prediction of patients who are at risk of hospital readmission is a critical step towards the reduction of the potential avoidable costs for healthcare organisations. This research was focused on the evaluation of LACE Index for Readmission - Length of stay (days), Acute (emergent) admission, Charlson Comorbidity Index and number of ED visits within six months (LACE) and Patients At Risk of Hospital Readmission (PARR) using New Zealand hospital admissions. This research estimates the risk for all readmissions rather than only those in a subset of referenced conditions. In total, 213,440 admissions between 1 Jan 2015 and 31 Dec 2016 were selected after appropriate ethics approvals and permissions from the three hospitals. The evaluation method used is the Receiver Operating Characteristics (ROC) analysis to evaluate the accuracy of both the LACE and PARR models. As a result, The LACE index achieved an Area Under the Curve (AUC) score of 0.658 in predicting 30-day readmissions. The optimal cut-off for the LACE index is a score of 7 or more with sensitivity of 0.752 and specificity of 0.564. Whereas, the PARR algorithm achieved an AUC score of 0.628 in predicting 30-day readmissions. The optimal cut-off for the PARR index is a score of 0.34 or more with sensitivity of 0.714 and specificity of 0.542.", "McLeod syndrome, characterized by acanthocytosis and the absence of a red-blood-cell Kell antigen (Kx), is a multisystem disorder involving a late-onset myopathy, splenomegaly, and neurological defects. The locus for this syndrome has been mapped, by deletion analysis, to a region between the loci for Duchenne muscular dystrophy (DMD) and chronic granulomatous disease (CGD). In this study, we describe a new marker, 3BH/R 0.3 (DXS 709), isolated by cloning the deletion breakpoint of a DMD patient. A long-range restriction map of Xp21, encompassing the gene loci for McLeod and CGD, was constructed, and multiple CpG islands were found clustered in a 700-kb region. Using the new marker, we have limited the McLeod syndrome critical region to 150-380-kb. Within this interval, two CpG-rich islands which may represent candidate sites for the McLeod gene were identified.", "A new rapid method for the determination of honey diastase activity using direct potentiometric principles has been proposed. A platinum redox sensor has been used to quantify the amount of free triiodide released from a starch triiodide complex after starch hydrolysis by honey diastase. The method was tested on honey samples with varying diastase activities. The first 5 min of data for each sample were used for linear regression analysis in order to calculate diastase activity. The new method was compared with classical Schade and commercial Phadebas procedures. The results showed good correlations with both methods and offered a simple method for unit conversion to DN units for diastase activity, making the method suitable for routine analysis.", "NELF and DSIF collaborate to inhibit elongation by RNA polymerase IIa in extracts from human cells. A multifaceted approach was taken to investigate the potential role of these factors in promoter proximal pausing on the hsp70 gene in Drosophila. Immunodepletion of DSIF from a Drosophila nuclear extract reduced the level of polymerase that paused in the promoter proximal region of hsp70. Depletion of one NELF subunit in salivary glands using RNA interference also reduced the level of paused polymerase. In vivo protein-DNA cross-linking showed that NELF and DSIF associate with the promoter region before heat shock. Immunofluorescence analysis of polytene chromosomes corroborated the cross-linking result and showed that NELF, DSIF, and RNA polymerase IIa colocalize at the hsp70 genes, small heat shock genes, and many other chromosomal locations. Finally, following heat shock induction, DSIF and polymerase but not NELF were strongly recruited to chromosomal puffs harboring the hsp70 genes. We propose that NELF and DSIF cause polymerase to pause in the promoter proximal region of hsp70. The transcriptional activator, HSF, might cause NELF to dissociate from the elongation complex. DSIF continues to associate with the elongation complex and could serve a positive role in elongation.", "Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations-a phenomenon dubbed \"oncogene addiction.\" Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9-a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo.", "Learning that certain actions lead to risky rewards is critical for biological, social, and economic survival, but the precise neural mechanisms of such reward-guided learning remain unclear. Here, we show that the human nucleus accumbens plays a key role in learning about risks by representing reward value. We recorded electrophysiological activity directly from the nucleus accumbens of five patients undergoing deep brain stimulation for treatment of refractory major depression. Patients engaged in a simple reward-learning task in which they first learned stimulus-outcome associations (learning task), and then were able to choose from among the learned stimuli (choosing task). During the learning task, nucleus accumbens activity reflected potential and received reward values both during the cue stimulus and during the feedback. During the choosing task, there was no nucleus accumbens activity during the cue stimulus, but feedback-related activity was pronounced and similar to that during the learning task. This pattern of results is inconsistent with a prediction error response. Finally, analyses of cross-correlations between the accumbens and simultaneous recordings of medial frontal cortex suggest a dynamic interaction between these structures. The high spatial and temporal resolution of these recordings provides novel insights into the timing of activity in the human nucleus accumbens, its functions during reward-guided learning and decision-making, and its interactions with medial frontal cortex.", "BACKGROUND: Chediak-Higashi syndrome (CHS) is an inherited immunodeficiency disease characterized by giant lysosomes and impaired leukocyte degranulation. CHS results from mutations in the lysosomal trafficking regulator (LYST) gene, which encodes a 425-kD cytoplasmic protein of unknown function. The goal of this study was to identify proteins that interact with LYST as a first step in understanding how LYST modulates lysosomal exocytosis.MATERIALS AND METHODS: Fourteen cDNA fragments, covering the entire coding domain of LYST, were used as baits to screen five human cDNA libraries by a yeast two-hybrid method, modified to allow screening in the activation and the binding domain, three selectable markers, and more stringent confirmation procedures. Five of the interactions were confirmed by an in vitro binding assay.RESULTS: Twenty-one proteins that interact with LYST were identified in yeast two-hybrid screens. Four interactions, confirmed directly, were with proteins important in vesicular transport and signal transduction (the SNARE-complex protein HRS, 14-3-3, and casein kinase II).CONCLUSIONS: On the basis of protein interactions, LYST appears to function as an adapter protein that may juxtapose proteins that mediate intracellular membrane fusion reactions. The pathologic manifestations observed in CHS patients and in mice with the homologous mutation beige suggest that understanding the role of LYST may be relevant to the treatment of not only CHS but also of diseases such as asthma, urticaria, and lupus, as well as to the molecular dissection of the CHS-associated cancer predisposition.", "Previous experiments to separate the amylase and \"invertase\" of honey by chromatography on sephadex-gels were unsuccesful. It was shown that honey-amylase, -like amylases form other sources -- has hydrophobic properties. Therefore it was possible to separate amylase-activity from other activities by means of hydrophobic affinity chromatography on phenyl-butylamine-Sepharose 4B.", "Niemann-Pick type C1 (NPC1) disease arises from a mutation inactivating NPC1 protein that normally moves unesterified cholesterol from the late endosomal/lysosomal complex of cells to the cytosolic compartment for processing. As a result, cholesterol accumulates in every tissue of the body causing liver, lung, and CNS disease. Treatment of the murine model of this disease, the npc1 mouse, s.c. with β-cyclodextrin (4000 mg/kg) one time each week normalized cellular cholesterol metabolism in the liver and most other organs. At the same time, the hepatic dysfunction seen in the untreated npc1 mouse was prevented. The severity of cerebellar neurodegeneration also was ameliorated, although not entirely prevented, and the median lifespan of the animals was doubled. However, in contrast to these other organs, lung showed progressive macrophage infiltration with development of lipoid pneumonitis. These studies demonstrated that weekly cyclodextrin administration overcomes the lysosomal transport defect associated with the NPC1 mutation, nearly normalizes hepatic and whole animal cholesterol pools, and prevents the development of liver disease. Furthermore, this treatment slows cerebellar neurodegeneration but has little or no effect on the development of progressive pulmonary disease.", "BACKGROUND: Oral phosphodiesterase (PDE)4 inhibitors have shown efficacy in chronic obstructive pulmonary disease and psoriasis.OBJECTIVES: To assess the effectiveness, local safety and tolerability, and systemic pharmacokinetics of two topical PDE4 inhibitors, roflumilast and TAK-084, in plaque psoriasis.METHODS: An intraindividual comparison of six topical products was made in 15 patients aged 18-65 years with stable chronic plaque psoriasis in an investigator-blinded, within-subject randomized study. The products evaluated were calcipotriol 0·005% cream; betamethasone valerate 0·1% (both in their marketed formulations); investigational cream formulations of roflumilast 0·5% and TAK-084 0·5% and 5%; and a vehicle cream formulation as a control. Each treatment was applied daily to different test sites located on psoriasis plaques for 3 weeks.RESULTS: The primary end point of (mean) change from baseline in skin infiltrate thickness after 3 weeks of treatment showed statistically significant improvements for all treatments: betamethasone valerate cream (-286·9 μm), the selective PDE4 inhibitors roflumilast 0·5% (-237·1 μm) and TAK-084 (0·5% cream, -153·6 μm; 5% cream, -216·7 μm) and calcipotriol 0·005% (-187·7 μm) when compared with vehicle cream control (all P < 0·001). Both the TAK-084 5% and roflumilast 0·5% formulations performed well overall compared with the potent corticosteroid, betamethasone, and were ranked better than the vitamin D analogue calcipotriol. All adverse events were mild or moderate and none was serious.CONCLUSIONS: Topical treatment with cream formulations of the PDE4 inhibitors roflumilast and TAK-084 reduced inflammation, measured as a change in skin infiltrate thickness, and reduced psoriasis severity. Corticosteroid treatments have known systemic and cutaneous side-effects; PDE4 inhibitors could offer an alternative to these and deserve further study." ]

[ "Apoptosis or programmed cell death is a genetically controlled response of cells to commit suicide and is associated with DNA fragmentation or laddering. The common inducers of apoptosis include Ca2+i and oxygen free radicals/oxidative stress, which are also implicated in the pathogenesis of exercise-induced myopathies. To examine training-induced apoptosis, Thoroughbred horses were subjected to 3 months training programme on a treadmill. At the end of the training programme venous blood samples were taken for a creatine kinase (CK) assay. In addition, muscle biopsy samples were obtained for a membrane lipid peroxidation measurement by malondialdehyde (MDA) assay and for apoptosis detection. Apoptosis was studied by visualising the apoptotic myocytes on the paraffin sections by the modified TUNEL method. DNA laddering was evaluated by subjecting the DNA obtained from the biopsies to 1.5% agarose gel electrophoresis. There was a significant increase (P<0.05) of protein-bound MDA, and a nonsignificant trend (P = 0.14) for the control group to have higher levels of CK compared to the trained group. Under light microscopy, percentage of the TUNEL positive cells was higher (P<0.001) in the training group. This result was corroborated with the findings of DNA fragmentation by gel electrophoresis, which showed higher ladders of DNA band at the same group. In conclusion, these results clearly demonstrate that there is training-induced apoptosis in skeletal muscle. It is probable that apoptosis allows the work/recovery/rebound/supercompensation cycle, when unaccustomed muscle cells activate programmed cell death and are replaced by new and stronger cells, which is the mechanism for training-induced increases in fitness.", "1. Many biological processes that are governed by intracellular calcium signals rely on intracellular stores, which provide a reliable, controlled release of calcium into the cytoplasm. Calcium release through the ryanodine receptor (RyR), the main ion channel in the sarcoplasmic reticulum (the calcium store in muscle) is the key determinant of muscle force. 2. Calsequestrin, the main calcium buffer in the sarcoplasmic reticulum, provides a pool of calcium for release through the RyR and acts as a luminal calcium sensor for the channel via its interactions with triadin and junctin. Until recently, how calsequestrin communicated the store Ca(2+) load to the RyR remained unknown. 3. Calsequestrin 1 (skeletal calsequestrin) has been shown to both inhibit and activate the skeletal RyR1, dependent on whether it's bound to the RyR1 directly or indirectly via anchoring proteins. 4. The phosphorylation status of calsequestrin 1 is deemed important: it influences the Ca(2+) binding capacity of calsequestrin, the way in which calsequestrin 1 regulates the RyR1 and how calsequestrin 1 interacts with the key anchoring protein junctin. 5. In skeletal muscle, junctin plays a more critical role than triadin in the mechanism that controls Ca(2+) release from the sarcoplasmic reticulum. 6. The close relationship between altered expression and dysfunction of calsequestrin in several skeletal and cardiac disorders highlights the critical role that calsequestrin plays in maintaining Ca(2+) homeostasis and regulation of muscle contraction.", "BACKGROUND: In this study, it was aimed to determine whether median nerve epineurectomy is beneficial in the surgical management of carpal tunnel syndrome (CTS).MATERIALS AND METHODS: The study enrolled 72 patients including 34 patients without epineurectomy (Group A) and 38 patients with epineurectomy (Group B). Surgery was performed in patients with severe electrodiagnostic CTS findings, CTS duration >1 year and flattening along with hypervascularization in median nerve. All patients were assessed by visual analog scale, two-point discrimination test as well as subjective and objective findings at baseline and on the months 1, 3, and 6 after surgery.RESULTS: The mean age was 58.3 years (42-75 years) in 38 patients who underwent an epineurectomy, whereas it was 61.5 years (41-82 years) in 34 patients who did not have an epineurectomy. The groups were similar with regard to age, gender, duration of symptoms, and preoperative physical findings. Mean visual analog scale (VAS) scores were 1.7 in Group A and 1.8 in Group B. Again, these differences were not significant, on physical examination, the average two-point discrimination in the distribution of the median nerve was 4.9 mm (range: 3-11 mm) in Group A and 5.3 mm (range: 3-10 mm) in Group B. In postoperative evaluations, there was a better improvement in visual analog scale scores, two-point discrimination test and subjective symptoms including dysesthesia, pain and nocturnal pain within first 3 months; however, there was no marked difference in objective and subjective findings on the 6th month. No complication or recurrence was observed.CONCLUSION: We believe that median nerve epineurectomy is unnecessary in the surgical management of primary CTS since it has no influence on the midterm outcomes.", "BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally every other day (QOD) to females with FD.METHODS: This was an open-label, uncontrolled, Phase 2 study of 12 weeks with extension to 48 weeks in nine females with FD. Doses of 50mg, 150 mg and 250 mg were given QOD. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Each individual GLA mutation was retrospectively categorized as being amenable or not to migalastat HCl based on an in vitro α-Gal A transfection assay developed in human embryonic kidney (HEK)-293 cells.RESULTS: Migalastat HCl was generally well tolerated. Patients with amenable mutations seem to demonstrate greater pharmacodynamic response to migalastat HCl compared to patients with non-amenable mutations. The greatest declines in urine GL-3 were observed in the three patients with amenable GLA mutations that were treated with 150 or 250 mg migalastat HCl QOD. Additionally, these three patients all demonstrated decreases in GL-3 inclusions in kidney peri-tubular capillaries.CONCLUSIONS: Migalastat HCl is a candidate oral pharmacological chaperone that provides a potential novel genotype-specific treatment for FD. Treatment resulted in GL-3 substrate decrease in female patients with amenable GLA mutations. Phase 3 studies are ongoing.", "\"Product sampling\" is an effective marketing strategy which lowers consumer buying resistance by providing a free sample of the product for the consumer to test. We used this strategy to demonstrate the palatability of the prudent diet (30-35% of calories from total fats, less than 10% from saturated fats, less than 3 g sodium, and increased fiber) to physicians attending a 5-day family practice continuing medical education conference. The effect of the intervention was evaluated with pre- and postintervention questionnaires and a 20% random sample of participants was surveyed 1 year later. The proportion of physicians who reported that they considered the diet to be \"very palatable\" rose from 26% before the demonstration to 64% after the demonstration. Only 5% of the physicians did not report a favorable response to the demonstration. Sixty-two percent of the physicians reported that the diet was better than expected, and 82% reported that the demonstration encouraged them to recommend the diet to their patients. One year after the intervention 60% considered the diet \"very palatable\" and 55% reported that the demonstration stimulated them to increase their dietary intervention activities. These data suggest that serving the prudent diet at continuing medical education programs helps to remove prejudices about the diet and encourages physicians to recommend the diet to their patients.", "Sickle-cell anemia results from an A leads to T transversion in the second nucleotide of codon 6 of the beta-globin gene. We now report an uncommon beta-thalassemia gene that contains a deletion of this nucleotide. Thus, one mutation (GAG leads to GTG) produces sickle-cell anemia, while the other (GAG leads to GG) eliminates beta-globin production. These data establish that different alterations affecting one specific nucleotide can produce either an abnormal hemoglobin or beta-thalassemia. Moreover, the nucleotide sequence comprising codons 6-8 of the beta-globin gene appears to be particularly susceptible to mutations affecting nucleotide number.", "Many pharmacogenomic biomarkers (PGBM) were identified and translated into clinical practice, affecting the usage of drugs via label updates. In this context, abacavir is one of the most brilliant examples of pharmacogenetic studies translated into clinical practice. Pharmacogenetic studies have revealed that abacavir HSRs are highly associated with the major histocompatibility complex class I. Large studies established the effectiveness of prospective HLA-B*57:01 screening to prevent HSRs to abacavir. Accordingly to these results the abacavir label has been modified: the European Medicines Agency (EMA) and the FDA recommend/suggested that the administration of abacavir must be preceded by a specific genotyping test. The HLA locus is extremely polymorphic, exhibiting many closely related alleles, making it difficult to discriminate HLA-B*57:01 from other related alleles, and a number of different molecular techniques have been developed recently to detect the presence of HLA-B*57:01. In this review, we provide a summary of the available techniques used by laboratories to genotype HLA-B*57:01, outlining the scientific and pharmacoeconomics pros and cons." ]

[ "Aim: To determine the effectiveness of Centro Nacional de Investigaciones Cardiovasculares (CNIC)-polypill (acetylsalicylic acid 100 mg, ramipril 5/10 mg, simvastatin 40 mg) in achieving blood pressure (BP) goals. Patients & methods: A multicenter, observational, one cohort, prospective study. BP targets were analyzed in patients with cardiovascular disease after 12-months treatment with the CNIC polypill. Results: A total of 572 patients (59.4 ± 13.9 years, 57.3% men) were analyzed. At baseline, BP was 147.1 ± 18.1/88.3 ± 10.6 mmHg, 97.1% of patients were taken renin-angiotensin system inhibitors, 5.4% calcium antagonists, 1.9% diuretics and 13.1% β-blockers. The proportion of patients who achieved BP targets increased from 20.1 to 55.4% (p < 0.001). Conclusion: In routine practice, switching from usual care to the CNIC-polypill in patients with cardiovascular disease could facilitate achieving BP goals.", "Tin mesoporphyrin (SnMP), a competitive heme oxygenase (HO) inhibitor, also induces HO-1 mRNA and protein expression by a mechanism that is not fully understood. We examined whether the induction by SnMP is mediated by a de-repression of Bach1, a transcription factor that suppresses the HO-1 gene. Incubation of NIH3T3-HO-1-luc cells with SnMP attenuated HO activity with a concomitant increase in HO-1 mRNA and protein and a decrease in Bach1 and HO-2 proteins, which was not due to transcriptional down-regulation, but accelerated protein decay. Similarly, HO-1 protein degradation was increased by SnMP, despite of an elevation in HO-1 transcription. Transfection of Bach1 shRNA in Hepa cells raised basal HO-1 expression significantly, and SnMP treatment further increased HO-1 mRNA. In conclusion, SnMP induces HO-1 expression not only by de-repressing the HO-1 promoter by binding Bach1, but also by accelerating Bach1 degradation.", "Focal, small-to-moderate and transient improvement occurred in the muscle strength and function of patients with ALS who received TRH in dose-response and screening studies. In a small pilot study of 12 patients, 3 months administration of TRH at 10 mg per kg on alternate days resulted in localized increased strength of jaw muscles as well as significant improvement in lower extremity function. Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH. Autonomic effects of TRH on heart rate, respiration, and blood pressure were not serious and attenuated slightly over the course of the study.", "Dapagliflozin (SGLT-2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) are two of the drugs of SGLT inhibitor class which have been recommended by the National Institute for Health and Care Excellence (NICE) in people with type 1 diabetes with BMI ≥27 kg/m2 . Dapagliflozin is licensed in the UK for use in the NHS while sotagliflozin may be available in future. These and possibly other SGLT inhibitors may be increasingly used in people with type 1 diabetes as new licences are obtained. These drugs have the potential to improve glycaemic control in people with type 1 diabetes with the added benefit of weight loss, better control of blood pressure and more time in optimal glucose range. However, SGLT inhibitors are associated with a higher incidence of diabetic ketoacidosis without significant hyperglycaemia. The present ABCD/Diabetes UK joint updated position statement is to guide people with type 1 diabetes and clinicians using these drugs help mitigate this risk and other potential complications. Particularly, caution needs to be exercised in people who are at risk of diabetic ketoacidosis due to low calorie diets, illnesses, injuries, starvation, excessive exercise, excessive alcohol consumption and reduced insulin administration among other precipitating factors for diabetic ketoacidosis.", "This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of alteplase for the treatment of acute ischaemic stroke, in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence included several randomised controlled trials indicating that, in highly selected patients, alteplase administered at a licensed dose within 3 hours of the onset of acute ischaemic stroke is associated with a statistically significant reduction in the risk of death or dependency at 3 months compared with placebo, despite a significantly increased risk of symptomatic intracranial haemorrhage within the first 7-10 days. Data from the National Institute of Neurological Disorders and Stroke (NINDS) trial suggest that the benefit of treatment is sustained at 6 and 12 months. However, data from observational studies suggest that few patients with acute ischaemic stroke will be eligible for alteplase therapy under the terms of the current licensing agreement. In particular, many patients will be excluded by virtue of their age, and many more by the restriction of therapy to patients in whom treatment can be initiated within 3 hours of symptom onset. The manufacturer's submission included a state transition model evaluating the impact of treatment with alteplase within 3 hours of onset of stroke symptoms compared to standard treatment reporting that, in the base-case analysis, alteplase was both less costly and more effective than standard treatment. This increased to a maximum of approximately 4000 pounds upon one-way sensitivity analysis of the parameters. The probabilistic sensitivity analysis presented within the submission suggests that the probability that alteplase has a cost-effectiveness ratio greater than 20,000 pounds per quality-adjusted life-year (QALY) gained is close to 1 (0.99). The results of the short-term model demonstrate that alteplase is cost-effective over a 12-month period, with an incremental cost-effectiveness ratio of 14,026 pounds per QALY gained. This increased to a maximum of 50,000 pounds upon one-way sensitivity analysis of the parameters. At 12 months, the probabilistic sensitivity analysis presented within the submission suggests that the probability that alteplase has a cost-effectiveness ratio greater than 20,000 pounds per QALY gained is approximately 0.7. The guidance issued by NICE in April 2007 as a result of the STA states that alteplase is recommended for the treatment of acute ischaemic stroke only when used by physicians trained and experienced in the management of acute stroke and in centres with the required facilities.", "The Philadelphia chromosome found in leukemia cells of chronic myelogenous leukemia (CML) patients is produced by translocation between chromosomes 9 and 22, resulting in expression of a chimera protein of Bcr and Abl kinase in the cytoplasm. Bcr-Abl kinase attracted oncology researchers as a molecular target for CML therapy, and a variety of small Abl kinase inhibitors were synthesized. STI571 (imatinib mesylate) was produced by modification of 2-phenylaminopyrimidine, a core structure of protein kinase C inhibitor, to improve selectivity, stability, solubility, and bioavailability. STI571 competitively binds to the ATP binding site of Bcr-Abl kinase and inhibits Abl tyrosine kinase activity. STI571 showed significant efficacy in the clinical study with CML patients at all stages: chronic phase, accelerated phase, and blast crisis. More than 90% of the patients showed good hematologic response to STI571. STI571 is also a potent inhibitor of a receptor-type c-Kit tyrosine kinase. Therefore, STI571 was examined for therapeutic efficacy against malignant Gastro-Intestinal Stromal Tumors (GIST), which are mainly caused by aberrant expression of a mutated c-Kit that is constitutively active without binding of a ligand, stem cell factor (SCF). More than a half of the metastatic GIST patients enrolled in the clinical study responded to STI571. Thus, STI571 is now used as a therapeutic drug for both CML and GIST in more than 80 countries worldwide. Certain point mutations in the ATP binding site were found to be a cause of resistance to STI571 in both Bcr-Abl and c-Kit kinases. Therefore, it would be better to make a precise therapeutic strategy with STI571 based on the gene analysis data. It is also expected that it will be possible to design an inhibitor to overcome such resistance by using the structural information on the mutants.", "Gastrointestinal stromal tumor (GIST) represents a paradigm for clinically effective targeted inhibition of oncogenic driver mutations in cancer. Five drugs are currently positioned as the standard of care for the treatment of advanced or metastatic GIST patients. This is the result of continuous, deep understanding of KIT and PDGFRA GIST oncogenic drivers as well as the resistance mechanisms associated to tumor progression. However, the complexity of GIST molecular heterogeneity is an evolving field, and critical questions remain open. Specifically, the clinical benefit of approved and/or investigated targeted agents is strikingly modest at advanced stages of the disease when compared with the activity of first-line imatinib. Ripretinib is a novel switch-pocket inhibitor with broad activity against KIT and PDGFRA oncoproteins and has recently demonstrated antitumoral activity across phase I to phase III clinical trials. Therefore, ripretinib has emerged as a new standard of care for advanced, multi-resistant GIST patients. Based on this data, the Food and Drug Administration has granted in 2020 the approval of ripretinib for GIST patients after progression to imatinib, sunitinib and regorafenib. This, in turn, constitutes a major breakthrough in sarcoma drug development, as there have not been new treatment approvals in GIST for nearly a decade. Herein, we provide a critical review on the preclinical and clinical development of ripretinib in GIST. Furthermore, we seek to assess the biological and clinical impact of this new standard of care on the course of the disease, aiming to provide an insight on future treatments strategies for the next coming years.", "INTRODUCTION AND OBJECTIVES: To compare the pharmacodynamics of the CNIC polypill (atorvastatin 40mg/ramipril 10mg/aspirin 100mg) in terms of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP), with the corresponding reference products (atorvastatin and ramipril).METHODS: This was a multicenter, randomized, open-label, and parallel 3-arm study comparing the effect of the CNIC polypill vs ramipril 10mg and atorvastatin 40mg on SBP and LDL-C. The coprimary endpoints were differences in the adjusted mean 24-hour SBP (using ambulatory BP measurement) and LDL-C during the study period estimated using an ANCOVA model.RESULTS: Of the 241 patients included in the per protocol population, 84 received the CNIC polypill (group A), 84 atorvastatin (group B), and 73 ramipril (group C). SBP decreased from 139.3±12.5 to 133.2±12.9mmHg in group A and from 138.1±11.9 to 134.0±12.8mmHg in group C (baseline adjusted mean difference for the decrease in SBP was 1.77mmHg (90%CI, -0.5 to 4.0) in favor of group A, without reaching statistical significance. LDL-C was reduced by 33.9±21.6 and 29.2±25.8mg/dL in groups A and B, respectively (baseline adjusted mean difference for the decrease in LDL-C was 7.0% (90%CI, 1.5-12.4), a significantly greater decrease with the polypill). The 3 treatments were well tolerated.CONCLUSIONS: The results of this study rule out a negative effect on blood pressure of the interaction between the components of the CNIC polypill. The reduction in LDL-C was greater in the CNIC polypill group, suggesting a synergistic effect of the components." ]

[ "Author information:(1)HM Sanchinarro University Hospital-CIBERONC, Madrid, Spain.(2)HM Sanchinarro University Hospital, Madrid, Spain.(3)La Paz University Hospital, Madrid, Spain.(4)Ramon y Cajal University Hospital, IRYCIS and CIBERESP, Madrid, Spain.(5)Germans Trias i Pujol University Hospital, Badalona, Spain.(6)Catalan Institute of Oncology-Germans Trias i Pujol University Hospital, Universitat Autònoma Barcelona (UAB), Badalona-Applied Research Group of Oncology (B-ARGO), Badalona, Spain.(7)General University Hospital-ISABIAL, Alicante, Spain.(8)Institute of Health Research-Jimenez Diaz Foundation-CIBERONC, Madrid, Spain.(9)Institute of Health Research-Jimenez Diaz Foundation, Madrid, Spain.(10)Vall d'Hebron University Hospital, Barcelona, Spain.(11)Quironsalud Hospital, Barcelona, Spain.(12)La Fe University Hospital, Valencia, Spain.(13)Clinico San Carlos University Hospital, Madrid, Spain.(14)Puerta del Mar University Hospital, Cadiz, Spain.(15)Clinico de Santiago University Hospital, Santiago De Compostela, Spain.(16)Insular Materno-Infantil University Hospital Complex, Las Palmas de Gran Canaria, Spain.(17)Clinic Hospital, Barcelona, Spain.(18)Alvaro Cunqueiro Hospital, Vigo, Spain.(19)University of Navarra Clinic, Pamplona, Spain.(20)Marques de Valdecilla University Hospital, Santander, Spain.(21)Hospital del Mar, Barcelona, Spain.(22)Clinico University Hospital, Valencia, Spain.(23)Cruces University Hospital, Baracaldo, Spain.(24)Miguel Servet University Hospital, Zaragoza, Spain.(25)University Hospital of Gran Canaria Doctor Negrin, Las Palmas de Gran Canaria, Spain.(26)12 de Octubre University Hospital, Madrid, Spain.(27)Ramon y Cajal University Hospital, Madrid, Spain.(28)12 de Octubre University Hospital-CIBERONC, Madrid, Spain.(29)Ramon y Cajal University Hospital-CIBERONC, Madrid, Spain.(30)HM Sanchinarro University Hospital-CIBERONC, Madrid, Spain. Electronic address: flopezrios@hmhospitales.com.", "The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence, and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Eμ-tTA/tetO-MYC T-cell acute lymphoblastic leukemia, some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express either transgenic or endogenous Myc, albeit in many cases at levels below those in the original tumor, suggesting that tumors continue to be addicted to MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator, resulting in expression of the MYC transgene even in the presence of doxycycline. Some of the remaining recurring tumors expressed high levels of endogenous Myc, which was associated with a genomic rearrangement of the endogenous Myc locus or activation of Notch1. By gene expression profiling, we confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis, confirming that these tumors remain oncogene addicted. These results suggest that tumors induced by MYC remain addicted to overexpression of this oncogene.", "BACKGROUND: Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine.METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had migraine headaches 8-14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9-12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache-days during weeks 9-12. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at ClinicalTrials.gov, number NCT02025556.FINDINGS: Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9-12 was -3.46 days (SD 5.40) in the placebo group, -6.27 days (5.38) in the 225 mg dose group, and -6.09 days (5.22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was -2.81 days (95% CI -4.07 to -1.55; p<0.0001), whereas the difference between the placebo and 675 mg dose group was -2.64 days (-3.90 to -1.38; p<0.0001). LSM differences in the reduction of headache-days were -2.63 days (-3.91 to -1.34; p<0.0001) between the placebo group and 225 mg dose group and -2.58 days (-3.87 to 1.30; p <0.0001) between the placebo group and the 675 mg dose group. Adverse events occurred in 58 (56%) patients in the placebo group, 44 (46%) patients in the 225 mg dose group, and 57 (59%) patients in the 675 mg dose group; moderate or severe adverse events were reported for 29 (27%) patients, 24 (25%) patients, and 26 (27%) patients, respectively.INTERPRETATION: TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials.FUNDING: Teva Pharmaceuticals.", "The appearance of counterfeit medicines in supply chains is a global public health problem that may seriously affect patients. Counterfeit drugs do not meet quality standards and do not declare their real composition and/or source for the purposes of fraud. They may be generic or innovative, they may contain genuine constituents in a fake packaging, or wrong ingredients, or inactive ingredients, or an incorrect quantity of the active substance. In Croatia, no cases of counterfeit medicines have been detected so far, but the Agency for Medicinal Products and Medical Devices has received 34 samples of medicines and other products for testing from Zagreb City Police. The samples included medicines for erectile dysfunction: sildenafil, tadalafil, and vardenafil. Twenty-three samples of tablets without marketing authorisation in Croatia were tested with high-performance liquid chromatography (HPLC) for the declared sildenafil and tadalafil content. Samples labelled 1 (batch T/33), 3 (batch T/33), 5 (batch 4), 6 (batch M0016J), 10 (batch T-070235), 12 (batch T-070544), 15 (batch 314833201), 16 (batch 832718474), and 17 (batch 504830028) containing sildenafil and samples labelled 20 (batch 070356), 21 (batch 05668), and 22 (batch T 378 5) containing tadalafil did not contain the active substance within the acceptable 95 % to 105 % margin of deviation from the declared content. While most samples cannot be described as fake with a reasonable amount of certainty, there is still a suspicion of counterfeit. A correct conclusion can be drawn only with the assistance of the manufacturers and by conducting additional laboratory tests.", "Author information:(1)Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA.(2)Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA and Department of Otolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.(3)Key Laboratory of Medical Electrophysiology of Education Ministry, School of Pharmacy, Southwest Medical University, China and Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Southern University of Science and Technology, Shenzhen, Guangdong, China.(4)Cell Research Center, Shenzhen Bolun Institute of Biotechnology, Shenzhen, China.(5)Key Laboratory of Medical Electrophysiology of Education Ministry, School of Pharmacy, Southwest Medical University, China and Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Southern University of Science and Technology, Shenzhen, Guangdong, China. zouchang.cuhk@gmail.(6)Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA. chenz@stjohns.edu.", "Author information:(1)University Hospital Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany reiners_c@ukw.de.(2)University Hospital Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany.(3)National Institutes for Quantum and Radiological Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, 263-8555 Chiba, Japan.(4)Department of Internal Medicine, American University of Beirut, Riad-El-Solh 1107 2020, P.O. Box: 11-0236, Beirut, Lebanon.(5)Institut de Radioprotection et de Sûreté Nucléaire, B.P. 17, 92262 Fontenay-aux- Roses, France.(6)Radiation Protection Bureau, Health Canada, 775 Brookfield Rd, Ottawa, Canada K1A 1C1.(7)Division Radioprotection de l'Office Federal de la Santé Publique, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland.(8)Federal Agency for Nuclear Control, Ravensteinstraat 36, B-1000 Brussels, Belgium.(9)Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 8528523, Japan.(10)Leibniz-Institute for Prevention Research and Epidemiology (BIPS), Achterstraße 30, 28359 Bremen, Germany.(11)Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital, Via Paradisa, 2, 56124 Pisa, Italy.(12)Department of Public Health, Environmental and Social Determinants of Health, World Health Organization, 20 avenue Appia, 1211 Geneva-27, Switzerland.", "Migraine is a debilitating neurologic disease. People who experience migraine can have substantial disability, impaired functioning and a decreased quality of life (QoL). Expert recommendations suggest that people with frequent migraine attacks or severe impairment related to attacks may benefit from preventive treatment. Despite these recommendations and the existence of evidence-based guidelines for the use of preventive medication, many people who are candidates for preventive therapies do not receive them. Thus, there is still a substantial unmet need for preventive migraine treatment. Calcitonin gene-related peptide (CGRP) has a demonstrated role in the pathophysiology of migraine. Galcanezumab-gnlm (galcanezumab) is a humanized monoclonal antibody that binds to the CGRP ligand and prevents binding to its receptor. It is administered as a once-monthly subcutaneous injection. The aim of this review is to present a comprehensive overview of the existing short- and long-term efficacy and safety data for galcanezumab in patients with migraine. Data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2 and REGAIN studies show that galcanezumab treatment for 3 or 6 months results in overall reduction in mean monthly migraine headache days in patients with episodic (EVOLVE-1 and EVOLVE-2) and chronic (REGAIN) migraine. Greater proportions of patients with episodic migraine receiving galcanezumab versus placebo demonstrated a ≥ 50%, ≥ 75% and 100% response to therapy and reported a lower level of disability and an improvement in functioning and QoL. Similarly, when compared with placebo, greater proportions of patients with chronic migraine treated with galcanezumab demonstrated a ≥ 50% and ≥ 75% response and reported improved functioning. A 12-month open-label study demonstrated the continued efficacy of galcanezumab for up to 12 months. In all studies galcanezumab was well tolerated. In conclusion, data from pivotal studies show that galcanezumab may fulfill an unmet need in the treatment of patients with migraine who require preventive therapy." ]

[ "Gradenigo's syndrome is a rare but life threatening complication of acute otitis media (AOM), which includes a classic triad of otitis media, deep facial pain and ipsilateral abducens nerve paralysis. The incidence of Fusobacterium necrophorum infections has increased in recent years. We describe two cases of Gradenigo's syndrome caused by F. necrophorum. Additional four cases were identified in a review of the literature. Gradenigo's syndrome as well as other neurologic complications should be considered in cases of complicated acute otitis media. F. necrophorum should be empirically treated while awaiting culture results.", "The authors present a case of an arteriovenous malformation of the central sulcus treated with Gamma Knife surgery. The patient developed perilesional edema 9 months after treatment and experienced severe headache and hemiparesis. Her symptoms were refractory to corticosteroid therapy and pain management. She was subsequently treated with bevacizumab with striking improvement in her symptoms and results of neuroimaging studies. This is the first time that bevacizumab has been used to control severe refractory perilesional edema related to an intracranial arteriovenous malformation.", "In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.", "Tivozanib is a potent and highly specific orally available, tyrosine kinase inhibitor that targets vascular endothelial growth factor (VEGF) receptor-1, VEGF receptor-2, and VEGF receptor-3 at very low concentrations with a long half-life (4 days). After its promising activity in xenograft and preclinical models, tivozanib was evaluated in early phase clinical trials in various solid tumors. The phase III trial (TIVO-1) compared tivozanib with sorafenib in metastatic clear cell renal cell carcinoma (RCC). Because of detrimental overall survival (OS), Oncology Drug Advisory Committee (ODAC) voted against its approval in RCC. Tivozanib is also being evaluated in various other solid tumors like breast, gastrointestinal cancers, hepatocellular cancer, sarcomas, and gynecological cancer. In BATON-CRC trial, low-serum neuropilin-1 (NRP-1) levels were associated with better progression-free survival (PFS) in patients treated with tivozanib. The NRP-1 will be evaluated as a biomarker for tivozanib response in future clinical trials. Ongoing clinical trial will further characterize activity of tivozanib in hepatocellular carcinoma, sarcomas, and gynecologic cancers.", "MOTIVATION: Cellular mRNA levels originate from the combined action of multiple regulatory processes, which can be recapitulated by the rates of pre-mRNA synthesis, pre-mRNA processing and mRNA degradation. Recent experimental and computational advances set the basis to study these intertwined levels of regulation. Nevertheless, software for the comprehensive quantification of RNA dynamics is still lacking.RESULTS: INSPEcT is an R package for the integrative analysis of RNA- and 4sU-seq data to study the dynamics of transcriptional regulation. INSPEcT provides gene-level quantification of these rates, and a modeling framework to identify which of these regulatory processes are most likely to explain the observed mRNA and pre-mRNA concentrations. Software performance is tested on a synthetic dataset, instrumental to guide the choice of the modeling parameters and the experimental design.AVAILABILITY AND IMPLEMENTATION: INSPEcT is submitted to Bioconductor and is currently available as Supplementary Additional File S1.CONTACT: mattia.pelizzola@iit.itSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "Mitomycin C (MMC) induces various types of DNA damages that cause significant cytotoxicity to cells. Accordingly, repair of MMC-induced damages involves multiple repair pathways such as nucleotide excision repair, homologous recombination repair and translesion bypass repair pathways. Nonetheless, repair of the MMC-induced DNA damages in mammals have not been fully delineated. In this study, we investigated potential roles for Xeroderma pigmentosum (XP) proteins in the repair of MMC-induced DNA damages using an assay that detects the ssDNA patches generated following treatment with MMC or 8'-methoxy-psoralen (8-MOP) + UVA (ultraviolet light A). Human wild-type cells formed distinctive ssDNA foci following treatment with MMC or 8-MOP + UVA, but not with those inducing alkylation damage, oxidative damage or strand-break damage, suggesting that the foci represent ssDNA patches formed during the crosslink repair. In contrast to wild-type cells, mutant defective in XPE orXPG did not form the ssDNA foci following MMC treatment, while XPF mutant cells showed a significantly delayed response in forming the foci. A positive role for XPG in the repair of MMC-induced DNA damages was further supported by observations that cells treated with MMC induced a tight association of XPG with chromatin, and a targeted inhibition of XPG abolished MMC-induced ssDNA foci formation, rendering cells hypersensitive to MMC. Together, our results suggest that XPG along with XPE and XPF play unique role(s) in the repair of MMC-induced DNA damages.", "BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety.RESULTS: Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.CONCLUSIONS: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .)." ]

[ "BACKGROUND: CNS metastases-including brain and leptomeningeal metastases-from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) are associated with poor prognosis. AZD3759 is a novel EGFR tyrosine kinase inhibitor with high capability to penetrate the blood-brain barrier. We aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of AZD3759 in patients with EGFR-mutant NSCLC with brain and leptomeningeal metastases.METHODS: This open-label, multicentre, phase 1 study was undertaken at 11 centres and hospitals in Australia, South Korea, Taiwan, and the USA. Eligible patients included those with histologically confirmed, advanced-stage, EGFR-mutant NSCLC. The study was done in two parts, with dose-escalation and dose-expansion phases. In the dose-escalation phase, patients who had progressed after treatment with an EGFR tyrosine kinase inhibitor received AZD3759 at 50 mg, 100 mg, 200 mg, 300 mg, or 500 mg twice a day. In the dose-expansion phase, AZD3759 at 200 mg or 300 mg twice a day was administered to patients with either brain or leptomeningeal metastases who had never received an EGFR tyrosine kinase inhibitor and patients with leptomeningeal metastases who had been pretreated with an EGFR tyrosine kinase inhibitor. The primary objective was safety and tolerability, with severity of adverse events assessed with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03. This trial is registered with ClinicalTrials.gov, number NCT02228369.FINDINGS: Between Nov 18, 2014, and Sept 7, 2016, 67 patients with NSCLC were enrolled into the study, 29 to the dose-escalation phase and 38 to the dose-expansion phase. At data cutoff (Dec 12, 2016), three (10%) patients in the dose-escalation phase and 20 (53%) in the dose-expansion phase were still receiving treatment. Dose-limiting toxic effects occurred in two (67%) of three patients who received 500 mg twice a day in the dose-escalation phase (grade 3 acne [n=1] and intolerable grade 2 mucosal inflammation [n=1]); hence, doses of 200 mg and 300 mg twice a day were selected for further assessment in the dose-expansion phase. Drug-related skin and gastrointestinal disorders of any grade occurred in 35 (92%) and 29 (76%) patients in the dose-expansion phase, respectively, and led to treatment discontinuation in one (4%) patient treated with 200 mg twice a day (grade 3 increase of alanine aminotransferase and aspartate aminotransferase) and two (13%) patients given 300 mg twice a day (grade 3 diarrhoea [n=1] and grade 3 skin rash [n=1]). Grade 3 skin and gastrointestinal disorders occurred in four (17%) and two (9%) patients, respectively, at a dose of 200 mg twice a day, and in six (40%) and four (27%) patients, respectively, at a dose of 300 mg twice a day. No grade 4 disorders arose. Other grade 3 disorders included hepatobiliary and renal disorders (three [13%] at 200 mg twice a day), asthenia (one [7%] at 300 mg twice a day), infections and infestations (one [7%] at 300 mg twice a day), and metabolism and nutrition disorders (one [4%] at 200 mg twice a day and one [7%] at 300 mg twice a day).INTERPRETATION: AZD3759 at a dose of 200 mg twice daily showed a tolerable safety profile in patients with NSCLC and CNS metastases who had either never received a tyrosine kinase inhibitor or who had been pretreated with a tyrosine kinase inhibitor. The good penetration of the blood-brain barrier by AZD3759, and its promising clinical activity, support further assessment of this compound in studies.FUNDING: AstraZeneca.", "Since the discovery of sensitizing EGFR mutations as a predictive marker of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the field of targeted therapy in non-small cell lung cancer (NSCLC) has been revolutionized. Patients harbouring these sensitizing mutations treated with EGFR TKI have derived significant clinical outcome when compared with standard platinum based chemotherapy doublets. However disease progression invariably occurs at a median of about 9-13 months from initiation treatment, if acquired resistance commonly due to the development of EGFR T790M mutation. A novel class of \"third generation\" EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Early phase clinical data suggest the third generation EGFR TKIs such as osimertinib, rociletinib, and HM61713 are highly efficacious and well tolerated. Another promising class of EGFR TKI such as AZD3759 has been designed to penetrate blood brain barrier to treat brain metastases and leptomeningeal disease and has showed promising responses in patients with brain metastases. Acquired resistance to third generation EGFR TKIs has been reported including EGFR C797S. Given its non-invasive nature, plasma ctDNA is being explored as a possible approach to detect T790M mutation and to also inform on novel molecular mechansims of tertiary resistance to third generation EGFR TKIs. An understanding of the mechanisms of acquired resistance to the third-generation EGFR TKIs will greatly aid in the development of the next generation of EGFR TKIs.", "Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes. Both are rare, with TEN and SJS affecting approximately 1or 2/1,000,000 annually, and are considered medical emergencies as they are potentially fatal. They are characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as blisters and areas of denuded skin. Currently, TEN and SJS are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma pneumoniae and Herpes simplex virus infections are well documented causes alongside rare cases in which the aetiology remains unknown. Several drugs are at \"high\" risk of inducing TEN/SJS including: Allopurinol, Trimethoprim-sulfamethoxazole and other sulfonamide-antibiotics, aminopenicillins, cephalosporins, quinolones, carbamazepine, phenytoin, phenobarbital and NSAID's of the oxicam-type. Genetic susceptibility to SJS and TEN is likely as exemplified by the strong association observed in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnosis includes linear IgA dermatosis and paraneoplastic pemphigus, pemphigus vulgaris and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and consideration of immunomodulating agents such as high-dose intravenous immunoglobulin therapy. SJS and TEN are severe and life-threatening. The average reported mortality rate of SJS is 1-5%, and of TEN is 25-35%; it can be even higher in elderly patients and those with a large surface area of epidermal detachment. More than 50% of patients surviving TEN suffer from long-term sequelae of the disease.", "The IL-17 pathway is an established driver of psoriasis pathogenesis. We examined the detailed molecular and cellular effects of blockade of IL-17 signaling in human psoriatic skin before and following treatment with brodalumab, a competitive inhibitor of the IL-17 Receptor A subunit. Thousands of aberrantly expressed genes in lesional skin normalized within 2 weeks following brodalumab treatment, with conversion of the lesional psoriasis transcriptome to resemble that seen in nonlesional skin. Keratinocyte-expressed genes appeared to normalize rapidly, whereas T cell-specific normalization occurred over six weeks. The three IL-17 ligand genes that are upregulated in lesional skin, IL17A, IL17C, and IL17F, were all downregulated in a dose-dependent manner following brodalumab treatment. Cellular measures also showed a similar pattern with dramatic decreases in keratinocyte hyperplasia within one week, and decreases in infiltrating leukocytes occurred over a longer timescale. Individuals with the highest brodalumab exposure showed normalization of both IL-17-responsive genes and the psoriasis transcriptome, whereas subjects with lower exposures showed transient or incomplete molecular responses. Clinical and molecular response appeared dependent on the extent of brodalumab exposure relative to the expression of IL-17 ligand genes, and reduction of IL-17 signaling into the nonlesional range was strongly correlated with normalization of the psoriasis transcriptome. These data indicate that blockade of IL-17 signaling in psoriatic skin leads to rapid transcriptomal changes initially in keratinocyte-expressed genes, followed by normalization in the leukocyte abnormalities, and demonstrates the essential role of the IL-17R on keratinocytes in driving disease pathogenesis.", "Mice expressing the mutant thyroid hormone receptor TRalpha1R384C, which has a 10-fold reduced affinity to the ligand T(3), exhibit hypermetabolism due to an overactivation of the sympathetic nervous system. To define the consequences in the liver, we analyzed hepatic metabolism and the regulation of liver genes in the mutant mice. Our results showed that hepatic phosphoenolpyruvate-carboxykinase was up-regulated and pyruvate kinase mRNA down-regulated, contrary to what observed after T(3) treatment. In contrast, mice expressing a mutant TRalpha1L400R specifically in the liver did not show a dysregulation of these genes; however, when the TRalpha1L400R was expressed ubiquitously, the hepatic phenotype differed from TRalpha1R384C animals, suggesting that the localization of the mutation plays an important role for its consequences on glucose metabolism. Furthermore, we observed that glycogen stores were completely depleted in TRalpha1R384C animals, despite increased gluconeogenesis and decreased glycolysis. Exposure of the mutant mice to high maternal levels of thyroid hormone during fetal development leads to a normal liver phenotype in the adult. Our results show how genetic and maternal factors interact to determine the metabolic setpoint of the offspring and indicate an important role for maternal thyroid hormone in the susceptibility to metabolic disorders in adulthood.", "BACKGROUND: Clinical data showed promising antitumour activity with feasible tolerability for matuzumab plus epirubicin, cisplatin and capecitabine (ECX) chemotherapy in untreated advanced oesophago-gastric (OG) cancer. The aim was to evaluate the efficacy of matuzumab plus ECX versus ECX alone.PATIENTS AND METHODS: In this multicentre, randomised open-label phase II study, 72 patients with metastatic OG cancer were randomly assigned to either 800 mg matuzumab weekly plus epirubicin 50 mg/m², cisplatin 60 mg/m² on day 1 and capecitabine 1250 mg/m² daily in a 21-day cycle (ECX) or the same ECX regimen alone. The primary end point was objective response. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life, safety and tolerability.RESULTS: Following random assignment, 35 patients (median age 59 years) received ECX/matuzumab and 36 patients (median age 64 years) ECX. The addition of matuzumab to ECX did not improve objective response: 31% for ECX/matuzumab [95% confidence interval (CI) 17-49] compared with 58% for the ECX arm (95% CI 41-74) P = 0.994 (one sided). There was no significant difference in median PFS: 4.8 months (95% CI 2.9-8.1) for ECX/matuzumab versus 7.1 months (95% CI 4.4-8.5) for ECX, or in median OS: 9.4 months (95% CI 7.5-16.2), compared with 12.2 months (95% CI 9.8-13.8 months). Grade 3/4 treatment-related toxicity was observed in 27 and 25 patients in the ECX/matuzumab and ECX groups, respectively.CONCLUSION: Matuzumab 800 mg weekly combined with ECX chemotherapy does not increase response or survival for patients with advanced OG cancer. Therefore, ECX/matuzumab should not be examined further in phase III trials.", "Aim: Evaluate the utility of glutamate dehydrogenase (GLDH) and cardiac troponin I as safety biomarkers, and creatine kinase and muscle injury panel as muscle health biomarkers in Duchenne muscular dystrophy. Patients & methods: Data were collected during a Phase II trial of domagrozumab. Results: GLDH was a more specific biomarker for liver injury than alanine aminotransferase. Cardiac troponin I elevations were variable and not sustained, limiting its applicability as a biomarker. Muscle injury panel biomarkers were no more informative than creatine kinase as a muscle health biomarker. Conclusion: Results support the use of GLDH as a specific biomarker for liver injury in patients with Duchenne muscular dystrophy. Clinical trial registration: ClinicalTrials.gov, NCT02310763.", "Recent studies demonstrate that UHRF1 is required for DNA methylation maintenance by targeting DNMT1 to DNA replication foci, presumably through its unique hemi-methylated DNA-binding activity and interaction with DNMT1. UHRF2, another member of the UHRF family proteins, is highly similar to UHRF1 in both sequence and structure, raising questions about its role in DNA methylation. In this study, we demonstrate that, like UHRF1, UHRF2 also binds preferentially to methylated histone H3 lysine 9 (H3K9) through its conserved tudor domain and hemi-methylated DNA through the SET and Ring associated domain. Like UHRF1, UHRF2 is enriched in pericentric heterochromatin. The heterochromatin localization depends to large extent on its methylated H3K9-binding activity and to less extent on its methylated DNA-binding activity. Coimmunoprecipitation experiments demonstrate that both UHRF1 and UHRF2 interact with DNMT1, DNMT3a, DNMT3b and G9a. Despite all these conserved functions, we find that UHRF2 is not able to rescue the DNA methylation defect in Uhrf1 null mouse embryonic stem cells. This can be attributed to the inability for UHRF2 to recruit DNMT1 to replication foci during S phase of the cell cycle. Indeed, we find that while UHRF1 interacts with DNMT1 in an S phase-dependent manner in cells, UHRF2 does not. Thus, our study demonstrates that UHRF2 and UHRF1 are not functionally redundant in DNA methylation maintenance and reveals the cell-cycle-dependent interaction between UHRF1 and DNMT1 as a key regulatory mechanism targeting DNMT1 for DNA methylation.", "Author information:(1)Cell Cycle and Cancer Genetics, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.(2)1] Cell Cycle and Cancer Genetics, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia [2] The Sir Peter MacCallum Department of Oncology, Melbourne, Victoria, Australia.(3)Cell Signaling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.(4)1] The Sir Peter MacCallum Department of Oncology, Melbourne, Victoria, Australia [2] Translational Research Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.(5)1] Cell Cycle and Cancer Genetics, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia [2] The Sir Peter MacCallum Department of Oncology, Melbourne, Victoria, Australia [3] Department of Pathology, University of Melbourne, Parkville, Victoria, Australia [4] Department of Molecular Biology and Biochemistry, University of Melbourne, Parkville, Victoria, Australia.", "The antineutrophil cytoplasmic antibody (ANCA) vasculitides include several closely related, often severe, multisystem autoimmune diseases characterized by antibodies against serine proteinase 3 (PR3) or myeloperoxidase. Loss of tolerance to these antigens triggers a cascade of events, beginning with the priming of neutrophils by proinflammatory cytokines and complement activation, translocation of ANCA-specific antigens to the plasma membrane, neutrophil hyperactivation, and further activation of the alternative complement pathway, leading to tissue damage and the clinical manifestations of ANCA vasculitis. Due to the heterogeneity in presentation of these diseases, diagnosis is often substantially delayed, leading to poor outcomes. The current treatment pathway for most patients involves induction with cyclophosphamide or rituximab in combination with glucocorticoids, followed by a maintenance phase with rituximab, azathioprine, or methotrexate, during which time glucocorticoids are tapered. Current therapies are often effective in inducing and maintaining remission but are associated with a range of toxicities. Several new therapies are in development for ANCA vasculitis. Avacopan, an orally administered inhibitor of the complement fragment 5a (C5a) receptor, has been assessed in a phase 3 clinical trial and may play a role in reducing the cumulative glucocorticoid dose. Preliminary data suggest that cluster of differentiation (CD) 80 and CD86 blockade with abatacept may also have a role in the management of ANCA vasculitis. There is an unmet need for additional therapeutic options for patients with these diseases.", "With the use of EGFR TKIs, patient survival is now prolonged and as a consequence, a higher chance of development of CNS metastases has been observed during the course of the disease. CNS metastases remains a therapeutically challenging subset of patient to treat owing to the blood-brain barrier (BBB). Prior to routine EGFR mutation testing, surgical resection, stereotactic radiosurgery and/or whole brain radiation therapy (WBRT) were the main treatment options whereas treatment options for patients with leptomeningeal metastases (LM) included intra-thecal chemotherapy, WBRT, and ventriculo-peritoneal shunting. Unfortunately outcome for both BM and LM remains poor with median survival between 3 and 6 months. Systemic treatment with EGFR TKIs had been effective in the treatment of intracranial metastases but efficacy of early generation TKIs were hampered by its limited BBB penetration. The next generation EGFR TKIs osimertinib and AZD3759 have improved BBB penetration and the BLOOM study of osimertinib and AZD3759 has reported highly promising intracranial efficacy and may herald a new frontier to treat this therapeutically challenging subset of advanced EGFR mutant patients.", "The prognosis of patients with brain metastasis (BM) is poor. In our study, we demonstrated that AZD3759, an EGFR tyrosine kinase inhibitors (TKIs) with excellent blood-brain barrier (BBB) penetration, combined with radiation enhanced the antitumor efficacy in BM model from EGFR mutant (EGFRm) NSCLC. Besides, the antitumor activity displayed no difference between radiation concurrently with AZD3759 and radiation sequentially with AZD3759. Mechanistically, we found that two factors determined the enhanced efficacy: cells with EGFRm which were sensitive to AZD3759, and a relative high concentration of AZD3759. We have validated mechanisms underlying the radiosensitizing effect of AZD3759, which were involved in decreased cell proliferation and survival, and suppressed repair of DNA damage. Moreover, our study found that AZD3759 inhibited both the non-homologous end joining (NHEJ) and homologous recombination (HR) DNA double-strand breaks (DSBs) repair pathway, and abrogated the G2/M checkpoint to suppress DNA damage repair. We also detected the BBB penetration of AZD3759 when combined with cranial radiation. The results showed the BBB penetration of AZD3759 was decreased within 24 hr after radiation, however, the free concentration of AZD3759 in brain kept at a high level in the context of radiation. In conclusion, our findings suggest that AZD3759 combined with radiation enhances the antitumor activity in BM from EGFRm NSCLC, this combination therapy may be an effective treatment option for BM from EGFRm NSCLC.", "Non-small-cell lung cancer patients with activating mutations in epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitor (TKI) treatment. Nevertheless, patients often develop central nervous system (CNS) metastases during treatment, even when their extracranial tumors are still under control. In the absence of effective options, much higher doses of EGFR TKIs have been attempted clinically, with the goal of achieving high enough drug concentrations within the CNS. Although limited tumor responses have been observed with this approach, the toxicities outside the CNS have been too high to tolerate. We report the discovery and early clinical development of AZD3759, a selective EGFR inhibitor that can fully penetrate the blood-brain barrier (BBB), with equal free concentrations in the blood, cerebrospinal fluid, and brain tissue. Treatment with AZD3759 causes tumor regression in subcutaneous xenograft, leptomeningeal metastasis (LM), and brain metastasis (BM) lung cancer models and prevents the development of BM in nude mice. An early clinical study in patients with BM and LM treated with AZD3759 confirms its BBB-penetrant properties and antitumor activities. Our data demonstrate the potential of AZD3759 for the treatment of BM and LM and support its further clinical evaluation in larger trials.", "Bartter-like syndrome encompasses a set of inherited renal tubular disorders associated with hypokalemic metabolic alkalosis, renal salt wasting, hyperreninemic hyperaldosteronism, and normal blood pressure. Antenatal Bartter syndrome, a subtype of Bartter-like syndrome, is characterized by polyhydramnios, premature delivery, life-threatening episodes of fever and dehydration during the early weeks of life, growth retardation, hypercalciuria, and early-onset nephrocalcinosis. Mutations in the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and ATP-sensitive inwardly rectifying potassium channel (ROMK) of the thick ascending limb of Henle's loop have been identified in the antenatal Bartter syndrome. We report the identification of two heterozygous mutations of the gene for Kir 1.1 (ROMK) from an antenatal Bartter syndrome patient who presented at birth with mild salt wasting and a biochemical findings that mimicked primary pseudohypoaldosteronism type 1, such as hyperkalemia and hyponatremia, and evolved to a relatively benign course. We have identified amino acid exchanges Arg338Stop and Met357Thr in the gene exon 5 for ROMK by PCR and direct sequencing. Both mutations alter the C-terminus of the ROMK protein, and can affect channel function.", "Saccharomyces cerevisiae ergosterol biosynthesis, like cholesterol biosynthesis in mammals, is regulated at the transcriptional level by a sterol feedback mechanism. Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes. The 7-bp consensus SRE is identical to the anaerobic response element, AR1c. Data indicate that Upc2 and Ecm22 function through binding to this SRE site. We now show that it is two novel anaerobic AR1b elements in the UPC2 promoter that direct global ERG gene expression in response to a block in de novo ergosterol biosynthesis, brought about by antifungal drug treatment. The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function. We further demonstrate the direct binding of recombinant expressed S. cerevisiae ScUpc2 and pathogenic Candida albicans CaUpc2 and Candida glabrata CgUpc2 to AR1b and SRE/AR1c elements. Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression. Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place. Thus, the two UPC2-AR1b elements drive expression of all ERG genes necessary for maintaining normal antifungal susceptibility, as wild type cells lacking these elements have increased susceptibility to azole antifungal drugs. Therefore, targeting these specific sites for antifungal therapy represents a novel approach to treat systemic fungal infections.", "The dopaminergic stabilizer pridopidine demonstrates state-dependent effects on locomotor activity, counteracting both hypo- and hyperactivity in rats. Pridopidine has been shown to display both functional dopamine D2 receptor antagonist properties and increase in biomarkers associated with NMDA-mediated glutamate transmission in the frontal cortex. To further characterise the effects of pridopidine on prefrontal cortex (PFC) neurons, a series of in vivo electrophysiological studies were performed in urethane-anaesthetised rats. Pridopidine, administered at doses from 10 to 60 mg/kg (i.v.), dose dependently increased pyramidal cell firing in the majority of the neurons tested. Pridopidine induced a significant increase of 162 % in mean firing activity of PFC neurons, versus initial basal firing activity as the cumulative dose of 30 mg/kg, i.v., was administered. This enhancement of activity was due to increased firing frequency of already spontaneously active neurons, rather than an increase in population activity. The increase was partially reversed or prevented by a sub-threshold dose of the dopamine D1 receptor antagonist SCH23390 (0.5 mg/kg, i.v.). Microiontophoretic application of pridopidine had only moderate activating effects. The selective dopamine D1 receptor agonist A-68930 also had limited effects when administered by microiontophoretic application, but exerted a dose dependent (0.2-3 mg/kg, i.v.) activation of firing in the majority of neurons tested (10/16). However, inhibition of firing by systemic administration of A-68930 was also observed in a subgroup of neurons (6/16). Both activation and inhibition of firing induced by systemic administration of A-68930 were reversed by the systemic administration of SCH23390. The present data suggests that pridopidine enhances pyramidal cell firing via an indirect dopamine D1 receptor-mediated mechanism. These effects of pridopidine may serve to strengthen the cortico-striatal communication and to improve motor control in Huntington's disease for which pridopidine is currently in development.", "In humans, testis development depends on a regulated genetic hierarchy initiated by the Y-linked SRY gene. Failure of testicular determination results in the condition termed 46,XY gonadal dysgenesis (GD). Several components of the testis determining pathway have recently been identified though it has been difficult to articulate a cascade with the known elements of the system. It seems, however, that early gonadal development is the result of a network of interactions instead of the outcome of a linear cascade. Accumulating evidence shows that testis formation in man is sensitive to gene dosage. Haploinsufficiency of SF1, WT1 and SOX9 is responsible for 46,XY gonadal dysgenesis. Besides, data on SRY is consistent with possible dosage anomalies in certain cases of male to female sex reversal. 46,XY GD due to monosomy of distal 9p and 10q might also be associated with an insufficient gene dosage effect. Duplications of the locus DSS can lead to a failure of testicular development and a duplication of the region containing SOX9 has been implicated in XX sex reversal. Transgenic studies in mouse have shown, however, that this mammal is less sensitive to gene dosage than man. Here, we will try to put in place the known pieces of the jigsaw puzzle that is sex determination in mammals, as far as current knowledge obtained from man and animal models allows. We are certain that from this attempt more questions than answers will arise.", "Collaborators: Agnelli G, Buller H, Cohen A, Gallus A, Raskob G, Weitz J, Prins M, Brandjes D, Kolbach D, Limburg M, Mac Gillavry M, Otten JM, Peters R, Roos Y, Segers A, Slagboom T, Bounameaux H, Hirsh J, Samama MM, Wedel H, Curto M, Johnson M, Masiukiewicz U, Pak R, Porcari A, Sanders P, Sisson M, Sullivan B, Thompson J, Auerbach J, Cesario L, Crawford J, Gordon M, Noble M, Pennington A, Reinhold P, Simmons M, Urwin K, Ceresetto J, McRae S, Pabinger I, Pereira AH, Spencer F, Wang C, Zhang J, Gorican K, Husted SE, Mottier D, Harenberg J, Vértes A, Pinjala R, Zeltser D, Prandoni P, Sandset M, Torbicki A, Fijalkowska A, Alvares JP, Kirienko A, Shvarts Y, Sala LA, Jacobson B, Gudz I, Ortel T, Spyropoulos A, Beyer-Westendorf J, Sipos G, Bredikhin R, Della Siega A, Klinke W, Lawall H, Zwettler U, Prasol V, Cannon K, Vasylyuk S, Jin B, Prandoni P, Desai S, Zaichuk A, Katelnitskiy I, De Pellegrin A, Santonastaso M, Skupyy O, Pesant Y, Shvalb P, Spacek R, Visonà A, Alvarez Sala L, Borja V, Gudz I, Noori E, Sereg M, Ortel T, Braester A, Falvo N, Mottier D, Jacobson B, Vöhringer H, Laperna L, Oliven A, Skalicka L, Bolster D, Haidar A, Schellong S, Vértes A, Smith S, Sergeev O, Pullman J, Torp-Pedersen C, Zimlichman R, Elias M, Fourie N, Pernod G, Panchenko E, Pendleton R, van Nieuwenhuizen E, Vinereanu D, Agnelli G, Becattini C, Manina G, Leduc J, Dunaj M, Frost L, Gavish D, Jakobsen T, Lishner M, Morales L, Chochola J, Gubka O, Holaj R, Hussein O, Katona A, Sergeeva E, Bova C, Cepeda J, Cohen K, Sobkowicz B, Grzelakowski P, Husted S, Lupkovics G, Spencer F, Dedek V, Liu C, Puskas A, Ritchie B, Ambrosio G, Parisi R, Heuer H, Livneh A, Podpera I, Stanbro M, Caraco Y, Fulmer J, Ghirarduzzi A, Schmidt-Lucke J, Bergmann J, Cizek V, Leyden M, Stein R, Abramov I, Chong B, Colan D, Jindal R, Liu S, Pereira A, Porreca E, Salem H, Welker J, Yusen R, Dhar A, Gallus A, Podczeck-Schweighofer A, Shtutin O, Vital Durand D, Zeltser D, Zhang J, Balaji V, Correa J, Harenberg J, Kline J, Runyon M, Laszlo Z, Martelet M, Parakh R, Sandset PM, Schmidt J, Yeo E, Bhagavan N, Bura-Riviere A, Cepeda J, Ferrer J, Lacroix P, Lewczuk J, Pilger E, Sokurenko G, Yu H, Nikulnikov P, Pabinger-Fasching I, Sanchez-Diaz C, Schuller D, Shvarts Y, Suresh K, Wang C, Lobo S, Lyons R, Marschang P, Palla A, Schulman S, Spyropoulous A, Fraiz J, Gerasymov V, Lerner R, Llamas Esperón G, Manenti E, Masson J, Moreira R, Poy C, Rodoman G, Bruckner I, Gurghean A, Carrier M, Freire A, Gan E, Gibson K, Herold M, Hudcovic M, Kamath G, Koslow A, Meneveau N, Roos J, Zahn R, Balanda J, Bratsch H, Dolan S, Gould T, Hirschl M, Hoffmann U, Kaatz S, Shah V, Kadapatti K, Kræmmer Nielsen H, Lahav M, Natarajan S, Tuxen C, Tveit A, Alves C, Formiga A, Brudevold R, Cardozo M, Gorican K, Lorch D, Marais H, Mismetti P, Panico M, Pop C, Quist-Paulsen P, Stevens D, Tarleton G, Yoshida W, Cox M, Crispin P, Czekalski P, Ebrahim I, Game M, Ghanima W, Harrington D, Jackson D, Lawall H, Lee A, Matoska P, Meade A, Camargo AC, Nishinari K, Sanchez Llamas F, Tosetto A, Vejby-Christensen H, Basson M, Blombery P, Fu G, Jha V, Keltai K, Le Jeunne C, Lodigiani C, Ma Y, Nagy A, Neumeister A, Pinjala R, Shotan A, Wong T, Ying K, Anderson S, Brenner B, Carnovali M, Cerana S, Cunha C, Diaz-Castañon J, Graham M, Kirenko A, Palareti G, Rodriguez-Cintron W, Nathanson A, Rosenthal S, Sanders D, Scheinberg P, Schjesvold F, Torp R, van Zyl L, Venher I, Xia G, Brockmyre A, Chen Z, Hakki S, Hanefield C, Mügge A, Janczak D, Karpovych D, Lancaster G, Lavigne C, Lugassy G, Melaniuk M, Moran J, Oliver M, Schattner A, Staroverov I, Timi J, Vöhringer F, von Bilderling P, Warr T, White R, Wronski J, Wu C, Almeida C, Blum A, Bono J, Durán M, Erzinger F, Fu W, Jagadesan R, Jurecka W, Korban E, Nguyen D, Raval M, Willms D, Zevin S, Zhu H, Abdullah I, Achkar A, Albuquerque L, Ali M, Bai C, Bloomfield D, Chen J, Fajardo Campos P, Garcia Bragado F, Kobza I, Lindhoff-Last E, Lourenço A, Marchena Yglesias P, Marshall P, Siegel M, Mikhailova O, Oliva M, Pottier P, Pruszczyk P, Sauer M, Baloira A, Cromer M, D'Angelo A, Faucher J, Gutowski P, Hong S, Lissauer M, Lopes A, Lopes R, Maholtz M, Mesquita E, Miekus P, Mohan B, Ng H, Peterson M, Piovella F, Siragusa S, Srinivas R, Tiberio G, Van Bellen B, Arutyunov G, Assi N, Baker R, Blanc F, Curnow J, Fu C, Gonzalez-Porras J, Guijarro Merino R, Gunasingam S, Gupta P, Laule M, Liu Z, Luber J, Masson J, Serifilippi G, Paulson R, Shevela A, Simonneau G, Siu D, Sosa Liprandi M, Takács J, Tay J, Vora K, Witkiewicz W, Zhao L, Aquilanti S, Dabbagh O, Dellas C, Denaro C, Doshi A, Fijalkowska A, Flippo G, Giumelli C, Gomez Cerezo J, Han D, Harris L, Hofmann L Jr, Kamerkar D, Kaminski L, Kazimir M, Kloczko J, Ko Y, Koura F, Lavender R, Maly J, Margolis B, McRae S, Mos L, Sanchez-Escalante L, Solvang A, Soroka V, Szopinski P, Thawani H, Vickars L, Welker J, Yip G, Zangroniz P.", "Activating mutations in the KRAS gene (Kirsten rat sarcoma 2 viral oncogene homolog gene) are commonly seen across the various solid organ and hematolymphoid neoplasms. With the likelihood of the mutation specific KRAS inhibitor entering clinical practice, the present studies profiled the landscape of these mutations in the Indian population to add to databases and posit the clinical utility of its emerging inhibitors. This study included 489 formalin fixed paraffin-embedded (FFPE) tissue samples from consecutive patients during a 5-year period (2015-2019). The clinical records were obtained from the medical record archives of the institution. Library preparation was done using the Oncomine Assay™. Sequencing was performed using the Ion PGM Hi-Q Sequencing Kit on the Ion Torrent Personal Genome Machine (Ion PGM) as well as on Ion Torrent S5 sequencer using the S5 sequencing kit. Ion Torrent Suite™ Browser version 5.10 and Ion Reporter™ version 5.10 were used for data analysis. A total of 50 cases with KRAS mutations were observed occurring most commonly in the codons 12 and 13. The G12D mutation was the most commonly encountered subtype in our cohort (21/50), whereas the G12C mutation was observed in 5 cases, and interestingly, this mutation was only seen in patients with non-small cell lung carcinoma (NSCLC). In the largest cohort from Indian subcontinent reporting spectrum of KRAS mutations in human cancers, an incidence of 11% was observed across all cancer types. Therapies targeting the G12C mutations can benefit up to 20% KRAS-mutated NSCLC. Building databases of spectrum of KRAS mutations in different populations across diverse cancer types is the anticipatory step to this end.", "CONTEXT: Although most primary cancers of the lung carry a heavy mutational load and will potentially present many \"nonself\" antigens to the immune system, there are a wide range of possible mechanisms for tumors to avoid so-called immune surveillance. One such mechanism is the adoption of immune checkpoints to inhibit the host immune response. Immune checkpoint inhibitors show great promise in the treatment of advanced non-small cell lung cancer.OBJECTIVE: To discuss the possibility of biomarker selection of patients for these therapies. This is becoming a much debated issue, and the immunohistochemical detection of Programmed Death Ligand 1 (PD-L1), the ligand for the inhibitory Programmed Death receptor 1 (PD-1) checkpoint, is one possible biomarker. Data so far available show some conflicting results, but PD-L1 immunohistochemistry looks likely to be introduced into clinical use for selecting patients for treatment with anti-PD-1 or anti-PD-L1 therapies. Given that there are 4 such drugs rapidly approaching regulatory approval, each with its own independent PD-L1 immunohistochemistry biomarker test, both oncologists and pathologists face some significant challenges.DATA SOURCES: Peer-reviewed literature and meeting proceedings, especially during the last 12 months, were used.CONCLUSIONS: The biology of PD-1/PD-L1 is complex, the clinical data for these drugs show considerable variation, the selection performance of the PD-L1 biomarker test is not perfect, and the existence of 4 drug/test combinations adds significantly to the problems faced. This article addresses some of the background to this therapeutic problem and discusses some of the issues ahead." ]

[ "BACKGROUND: Charcot-Marie-Tooth (CMT) neuropathy is a heterogeneous group of inherited disorders of the peripheral nervous system. The authors recently mapped an autosomal dominant demyelinating form of CMT type 1 (CMT1C) to chromosome 16p13.1-p12.3.OBJECTIVE: To find the gene mutations underlying CMT1C.METHODS: The authors used a combination of standard positional cloning and candidate gene approaches to identify the causal gene for CMT1C. Western blot analysis was used to determine relative protein levels in patient and control lymphocyte extracts. Northern blotting was used to characterize gene expression in 1) multiple tissues; 2) developing sciatic nerve; and 3) nerve-crush and nerve-transection experiments.RESULTS: The authors identified missense mutations (G112S, T115N, W116G) in the LITAFgene (lipopolysaccharide-induced tumor necrosis factor-alpha factor) in three CMT1C pedigrees. LITAF, which is also referred to as SIMPLE, is a widely expressed gene encoding a 161-amino acid protein that may play a role in protein degradation pathways. The mutations associated with CMT1C were found to cluster, defining a domain of the LITAF protein having a critical role in peripheral nerve function. Western blot analysis suggested that the T115N and W116G mutations do not alter the level of LITAF protein in peripheral blood lymphocytes. The LITAF transcript is expressed in sciatic nerve, but its level of expression is not altered during development or in response to nerve injury. This finding is in stark contrast to that seen for other known genes that cause CMT1.CONCLUSIONS: Mutations in LITAF may account for a significant proportion of CMT1 patients with previously unknown molecular diagnosis and may define a new mechanism of peripheral nerve perturbation leading to demyelinating neuropathy.", "BACKGROUND: The CYP2C19*2 or *3 loss-of-function (LOF) allele is associated with high platelet reactivity (HPR) on clopidogrel treatment. East Asians may benefit from a lower dose of prasugrel due to their more potent platelet inhibitory response. The impact of LOF alleles on the pharmacodynamic response to half-dose prasugrel in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) is unknown.METHODS: Seventy patients with the LOF alleles were assigned to half-dose prasugrel (n = 35, 30-mg load followed by 5 mg daily) or clopidogrel (n = 35, 600-mg load followed by 75 mg daily). The primary endpoint was the rate of HPR, defined as VerifyNow-P2Y12 reaction unit (PRU) >235, at 24 h post loading.RESULTS: Prasugrel achieved a lower PRU compared to clopidogrel after loading (119 [56-175] vs. 245 [189-299]), at 24 h (34 [8-58] vs. 196 [122-244]), and at 30 days (134 [98-189] vs. 203 [144-248]). Prasugrel had a lower rate of HPR after loading (5.7% vs. 57.1%, p <0.001), at 24 h (2.9% vs. 28.6%, p=0.006), and at 30 days (11.4% vs. 34.3%, p=0.004). Prasugrel had a similar rate of optimal platelet reactivity at 30 days (71.4% vs. 60.0%, p=0.450). There was no significant difference in the occurrence of periprocedural myonecrosis within 48 h after PCI with clopidogrel and prasugrel (22.9% vs. 17.1%, p>0.960).CONCLUSIONS: Half-dose prasugrel provided potent platelet inhibition in NSTE-ACS patients that were carriers of the CYP2C19*2 or *3 allele, with a lower rate of HPR. Periprocedural myonecrosis was not significantly different in the 2 groups.", "On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.", "Virological and serological methods were used in examination of 28 patients suffering from subacute thyroiditis de Quervain. Attempts to isolate a presumed viral agent from 8 patients were performed by inoculation of serum, urine, and aspiration biopsies of thyroid glands taken at different stages of the illness, into tissue cultures of different types of human and animal cells. Recovery of a cytopathic viral agent on cells of a rabbit lung continuous line was successful in 5 cases. Serological cross reactions exist between the isolated viruses and patient serum but not with serum of healthy people. Cases with the acquired illness and positive antibodies against the isolated viruses who had been in close and prolonged contact with patients suffering from subacute thyroiditis de Quervain were also investigated.", "Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis. There remains, however, a significant number of patients with non-syndromic craniosynostosis in whom no genetic cause can be identified. We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. The mutation is also present in her mother and her maternal grandfather who have mild facial asymmetry but do not have craniosynostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed that the proband was in persistent breech presentation in utero and was delivered by Caesarean section, at which time compression of the skull was apparent. We propose that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is necessary for craniosynostosis to occur. To our knowledge, this is the first report of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.", "Carpal tunnel syndrome (CTS) is the most common focal entrapment mononeuropathy, comprising medium nerve chronic inflammation and fibrosis. Although carpal tunnel release surgery (CTRS) has demonstrated to be effective, around 3% to 25% of CTRS show recurrence. Amniotic membrane transplantation (AMT) has been used in different pathologies inhibiting inflammation and fibrosis and promoting nerve repair. The aim of this study was to determine the efficacy of AMT in CTRS. The present study comprised a randomized, single-blind controlled trial to compare the 1-year follow-up outcomes of AMT in CTRS (AMT group) or CTRS alone (control group) in patients with CTS. Thirty-five patients with unilateral or bilateral CTS were enrolled, and 47 wrists were randomized into two groups: the AMT group and the control group. To compare the outcomes, three different questionnaires scores (Boston Carpal Tunnel Syndrome Questionnaire, Disabilities of the Arm, Shoulder, and Hand, and Historical-Objective scale) were used. Evaluations were assessed at baseline and at 15 days, 1, 3, 6, and 12 months after surgery. Compared with the control group, the AMT group showed significant (p < 0.05) reductions in all scores from 6 months after surgery until the end of the study. Both AMT and control groups showed significant intragroup differences in all scores, since the first month after surgery until the end of the study in comparison with the baseline scores. Taken together, these results indicate that CTRS in conjunction with AMT is more effective than CTRS alone in patients with CTS at 1-year follow-up. Clinical Trial: NCT04075357; Amniotic Membrane in Carpal Tunnel Syndrome.", "Apoptotic cell death is essential for development and tissue homeostasis. Failure to clear apoptotic cells can ultimately cause inflammation and autoimmunity. Apoptosis has primarily been studied by staining of fixed tissue sections, and a clear understanding of the behavior of apoptotic cells in living tissue has been elusive. Here, we use a newly developed technique to track apoptotic cells in real time as they emerge and are cleared from the zebrafish brain. We find that apoptotic cells are remarkably motile, frequently migrating several cell diameters to the periphery of living tissues. F-actin remodeling occurs in surrounding cells, but also within the apoptotic cells themselves, suggesting a cell-autonomous component of motility. During the first 2 days of development, engulfment is rare, and most apoptotic cells lyse at the brain periphery. By 3 days postfertilization, most cell corpses are rapidly engulfed by macrophages. This engulfment requires the guanine nucleotide exchange factor elmo1. In elmo1-deficient macrophages, engulfment is rare and may occur through macropinocytosis rather than directed engulfment. These findings suggest that clearance of apoptotic cells in living vertebrates is accomplished by the combined actions of apoptotic cell migration and elmo1-dependent macrophage engulfment." ]

[ "DNA replication in eukaryotic cells is tightly regulated to ensure faithful inheritance of the genetic material. While the replicators, replication origins and many replication-initiation proteins in Saccharomyces cerevisiae have been identified and extensively studied, the detailed mechanism that controls the initiation of DNA replication is still not well understood. It is likely that some factors involved in or regulating the initiation of DNA replication have not been discovered. To identify novel DNA replication-initiation proteins and their regulators, we developed a sensitive and comprehensive phenotypic screen by combining several established genetic strategies including plasmid loss assays with plasmids containing a single versus multiple replication origins and colony color sectoring assays. We isolated dozen of mutants in previously known initiation proteins and identified several novel factors, including Ctf1p Ctf3p, Ctf4p, Ctf18p, Adk1p and Cdc60p, whose mutants lose plasmid containing a single replication origin at high rates but lose plasmid carrying multiple replication origins at lower rates. We also show that overexpression of replication initiation proteins causes synthetic dosage lethality or growth defects in ctf1 and ctf18 mutants and that Ctf1p and Ctf18p physically interact with ORC, Cdt1p and MCM proteins. Furthermore, depletion of both Ctf1p and Ctf18p prevents S phase entry, retards S phase progression, and reduces pre-RC formation during the M-to-G₁ transition. These data suggest that Ctf1p and Ctf18p together play important roles in regulating the initiation of DNA replication.", "Transcription-coupled repair (TCR) is a subpathway of nucleotide excision repair (NER) that acts specifically on lesions in the transcribed strand of expressed genes. First reported in mammalian cells, TCR was then documented in Escherichia coli. In this organism, an RNA polymerase arrested at a lesion is displaced by the transcription repair coupling factor, Mfd. This protein recruits the NER lesion-recognition factor UvrA, and then dissociates from the DNA. UvrA binds UvrB, and the assembled UvrAB* complex initiates repair. In mutants lacking active Mfd, TCR is absent. A gene transcribed by the bacteriophage T7 RNA polymerase in E. coli also requires Mfd for TCR. The CSB protein (missing or defective in cells of patients with Cockayne syndrome, complementation group B) is essential for TCR in humans. CSB and its homologs in higher eukaryotes are likely functional equivalents of Mfd.", "Author information:(1)Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.(2)European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.(3)The Jackson Laboratory, Bar Harbor, ME, 4609, USA.(4)Departments of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.(5)Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.(6)Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.(7)The Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, M5T 3H7, Canada.(8)The Centre for Phenogenomics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5T 3H7, Canada.(9)Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK.(10)German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany.(11)Université de Strasbourg, CNRS, INSERM, Institut Clinique de la Souris, PHENOMIN-ICS, 67404, Illkirch, France.(12)Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, 252 50, Prague, Czech Republic.(13)Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.(14)Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764, Neuherberg, Germany.(15)Department of Developmental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85764, Neuherberg, Germany.(16)Deutsches Institut für Neurodegenerative Erkrankungen (DZNE) Site Munich, Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, 80336, Munich, Germany.(17)Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, 00015, Monterotondo Scalo, Italy.(18)Translational Medicine, The Hospital for Sick Children, Toronto, ON, M5T 3H7, Canada.(19)Université de Strasbourg, CNRS, INSERM, Institut de Génétique, Biologie Moléculaire et Cellulaire, Institut Clinique de la Souris, IGBMC, PHENOMIN-ICS, 67404, Illkirch, France.(20)Department of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354, Freising-Weihenstephan, Germany.(21)German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.(22)Mouse Biology Program, University of California, Davis, CA, 95618, USA.(23)Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. d.smedley@qmul.ac.uk.(#)Contributed equally", "Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene rarely diagnosed prenatally and with little fetal description reported. It is mainly characterized by moderate-to-severe intellectual disability, epilepsy, facial dysmorphism and various malformations including Hirschsprung disease and corpus callosum anomalies. Here we report a fetal case of MWS well described, suspected at standard autopsy. The association of a corpus callosum hypoplasia with a histological Hirschsprung disease and a typical facial gestalt allowed the guiding of genetic testing. Classical fetopathological examination still keeps indications in cases of syndromic association in the era of virtual autopsy.", "Aortic aneurysm and dissection cause significant morbidity and mortality. There are several known single gene disorders that predispose to isolated aortic disease and eventually aneurysm and dissection. FBN1 mutations are associated with multiple clinical phenotypes, including Marfan syndrome (MFS), MASS phenotype, and familial ectopia lentis, but rarely with isolated aortic aneurysm and dissection. In this report, we describe three patients who presented with primary descending thoracic aortic dissection and who were found to have an FBN1 mutation. None of the patients fulfilled clinical criteria for the diagnosis of MFS, and all had few or none of the skeletal features typical of the condition. Two patients had a history of long-term hypertension, and such a history was suspected in the third patient. These observations suggest that some individuals with FBN1 mutations have significant aortic disease involvement of other systems that is typical of FBN1 mutation-related syndromes. Superimposed risk factors, such as hypertension, may weaken the aortic wall and eventually lead to aortic dissection. Given that the cost continues to decrease, we suggest that diagnostic DNA sequencing for FBN1 mutations in patients with thoracic aortic aneurysms and dissection may be a practical clinical step in evaluating such patients and at-risk family members.", "In approximately 10-20% of all sudden deaths no structural cardiac abnormalities can be identified. Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada syndrome, long QT syndrome (LQTS), short QT syndrome and catecholaminergic polymorphic ventricular tachyarrhythmias. Each of these cardiac channelopathies is charaterized by unique genetic and clinical features. The resting ECG and the ECG under exercise are pivotal for the diagnosis of ion channel diseases. Molecular genetic screening can reveal underlying mutations in a variable degree among the cardiac ion channel diseases in up to 70% (LQTS) and may identify individuals with incomplete penetration of the disease. In patients with primary electrical diseases specific clinical triggers for arrhythmic events such as syncope or sudden cardiac death have been identified including exercise, strenuous activity, auditory stimuli or increased vagal tone. The significance of programmed ventricular stimulation is at present unclear concerning risk stratification in patients with Brugada syndrome and short QT syndrome and of no significance in long QT syndrome and catecholaminergic polymorphic ventricular tachycardias. The success of medical therapy remains modest for prevention of sudden cardiac death and may necessitate the insertion of an implantable cardioverter. However, side effects with inappropriate therapies in this patient group with often young and active individuals have to be encountered. More insights into the arrhythmogenesis is critical for future development of effective medical treatment strategies.", "BACKGROUND: Primary intestinal lymphangiectasia (Waldmann's disease) is a rare disease characterized by dilated lymphatics in the small bowel leading to an exudative enteropathy with lymphopenia, hypoalbuminemia and hypogammaglobulinemia.CASE PRESENTATION: We report the case of a 23 year-old male who presented with chronic anemia and in whom primary intestinal lymphangiectasia was diagnosed. A low-fat diet along with nutritional therapy with medium-chain triglyceride supplementation improved the protein-losing enteropathy, but did not solve the anemia. Octreotide was also unsuccessful, and after attempting angiographic embolization therapy, limited small bowel resection together with antiplasmin therapy managed to correct the anemia and control the exudative enteropathy.CONCLUSIONS: Although primary intestinal lymphangiectasia is usually adequately managed by nutritional therapy, complications such as anemia can occur and can prove to be a therapeutic challenge." ]

[ "Recently emerging diagnostic tools such as MammaPrint and oncotype-DX are beginning to have impact on clinical practice of breast cancer. They are based on gene expression profiling, i.e., gene expression analysis of a large number of genes. Their unique characteristic is the use of a score calculated from expression values of a number of genes, for which the Food and Drug Administration (FDA) created a new diagnostic category entitled \"in vitro diagnostic multivariate index assay (IVDMIA).\" In contrast to conventional biomarkers, IVDMIA requires an algorithm to calculate the diagnostic score. The linear classifier is the preferred algorithm. When the number of diagnostic genes is n, each tumor is represented by a point in an n-dimensional space made from gene expression values. Diagnostic algorithms (linear classifier) make an (n-1)-dimensional plane in the n-dimensional space to separate two patient groups. Calculation of the diagnostic score is achieved by dimension reduction. Currently, IVDMIA is restricted to gene expression profiling, and will also be applied to malignancies other than breast cancer.", "RAF kinase inhibitors have substantial therapeutic effects in patients with BRAF-mutant melanoma. However, only rarely do tumors regress completely, and the therapeutic effects are often temporary. Several mechanisms of resistance to RAF inhibitors have been proposed. The majority of these cause ERK signaling to become insensitive to treatment with RAF inhibitors by increasing the amount of RAF dimers in cells, whereas others bypass the dependence of the tumor on mutant RAF. One motivation for studying mechanisms of drug resistance is that such efforts may suggest new therapeutic targets or rational combination strategies that delay or prevent the emergence of drug-resistant clones. Here, we review the current model of RAF inhibitor resistance with a focus on the implications of this model on ongoing laboratory and clinical efforts to develop more effective therapeutic strategies for patients with BRAF-mutant tumors.", "BACKGROUND AND OBJECTIVE: Nasal continuous positive airway pressure (NCPAP) plus intubation, surfactant, and extubation (InSurE) with the option of back-up ventilation for those infants for whom noninvasive ventilatory support failed resulted in a significant increase in survival in extremely low birth weight (ELBW) infants. The authors sought to determine the outcome of ELBW infants treated with NCPAP and InSurE in a neonatal high care ward with limited back-up ventilation.METHODS: Three hundred eighteen inborn infants with birth weight 500-1000 g and gestational age ≥25 weeks who were admitted to the neonatal high care ward were included in this observational study. InSurE was administered to infants with respiratory distress syndrome on NCPAP who had severe in-drawing and recession, apneic spells, or an Fio(2) >0.4 within 1 hour of birth.RESULTS: Two hundred twelve (68.6%) infants could be treated with NCPAP only and 97 (31.4%) required InSurE. Seventeen infants were admitted to the NICU; 90%, 87%, and 74.8% of the infants survived until day 3, 7, and discharge, respectively. Only 2 infants developed a pneumothorax and 2 had chronic lung disease. Seventy-nine percent of the infants of ≥750 g or >26 weeks' gestation survived to discharge compared with 56% and 60% of the infants of <750 g or ≤26 weeks' gestation, respectively. Maternal antenatal steroid administration contributed significantly to the survival of the infants (P = 0.0017, odds ratio 2.7, 95% confidence interval 1.44-5.07).CONCLUSIONS: The use of NCPAP and InSurE in a neonatal high care ward with limited resources can improve the survival of ELBW infants. Maternal antenatal steroid administration contributed significantly to survival.", "Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with Suppression-Burst, is the most severe and the earliest developing age-related epileptic encephalopathy. Clinically, the syndrome is characterized by early onset tonic spasms associated with a severe and continuous pattern of burst activity. It is a debilitating and early progressive neurological disorder, resulting in intractable seizures and severe mental retardation. Specific mutations in at least four genes (whose protein products are essential in lower brain's neuronal and interneuronal functions, including mitochondrial respiratory chains have been identified in unrelated individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at 9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship between early myoclonic encephalopathy (EME-ErbB4 mutations) versus the EIEE spectrum of disorders.", "BACKGROUND: Monitoring of glycemic control with hemoglobin A1c (A1c) in hemodialysis patients may be compromised by anemia and erythropoietin therapy. Glycated albumin (GA) is an alternative measure of glycemic control but is not commonly used because of insufficient evidence of association to clinical outcomes. We tested whether GA measurements were associated with mortality in hemodialysis patients with diabetes mellitus.METHODS: The German Diabetes and Dialysis Study (4D) investigated effects of atorvastatin on survival in 1255 patients with diabetes mellitus receiving hemodialysis. We measured GA during months 0, 6, and 12. Cox proportional hazards analysis was used to measure associations between GA and A1c and all-cause mortality.RESULTS: Patients with high baseline GA (fourth quartile) had a 42% higher 4-year mortality compared to those in the first quartile (HR 1.42; 95% CI, 1.09-1.85, P = 0.009). Repeated measurements of GA during year one also demonstrated that individuals in the top quartile for GA (analyzed as a time-varying covariate) had a 39% higher 4-year mortality (HR 1.39; 95% CI, 1.05-1.85, P = 0.022). The associations between high A1c and mortality using similar analyses were less consistent; mortality in individuals with baseline A1c values in the 3rd quartile was increased compared to 1st quartile (HR 1.36; 95% CI, 1.04-1.77, P = 0.023), but risk was not significantly increased in the 2nd or 4th quartiles, and there was a less consistent association between time-varying A1c values and mortality.CONCLUSIONS: High GA measurements are consistently associated with increased mortality in patients with diabetes mellitus on hemodialysis.", "Conflict of interest statement: In relation to this presentation, we declare the following, real or perceived conflicts of interest: M. van den Bent has received grants from Abbvie, and honoraria from Cellgene, BMS, Boehringer, AGIOS and VaXIMM. A. Azaro has received consulting fees from Orion Pharmaceuticals and Amcure GmbH. F. De Vos has received financial support for conducting clinical trials from Novartis, BMS, AbbVie and Bioclin. J.M. Sepulveda has received consulting fees from Celgene, Pfizer and Abbvie; he has received research grants from Pfizer and Catalysis. W.K.A. Yung holds stocks in DNATrix; he has received honoraria from DNATrix and Boehringer Ingelheim; he holds patents, royalties and/or intellectual property in, and has participated in a consulting or advisory role for DNATrix; he has received travel and/or accommodation expenses from Boehringer Ingelheim. P. Wen has received grants/research support from Lilly USA, Agios, AstraZeneca, Beigene, Eli Lily, Immunocellular Therapeutics, Kazai, Kadmon, Karyopharm, Merck, Novartis, Oncoceutics, Vascular Biogenics and Vaccines; he has received speaker’s bureau fees from Merck; he has received consultant/advisory board fees from Genentech/Roche, Taiho Oncology, Novartis, Agios Pharmaceuticals Inc, Merck, Puma, Abbvie, AstraZeneca, Eli Lilly, GW Pharmaceuticals, Immunomic Therapeutics, Kadmon, Vascular Biogenics, Ziopharm, Monteris and Tocagen. A. Lassman reports grants and non-financial support from Novartis, during the conduct of the study; personal fees and non-financial support from Orbus, grants, personal fees and non-financial support from Karyopharm, personal fees and non-financial support from NW Biotherapeutics, grants and non-financial support from Oncoceutics, personal fees and non-financial support from Agios, personal fees and non-financial support from Celgene, personal fees and non-financial support from Novocure, non-financial support from Tocagen, non-financial support from BMS, grants, personal fees and non-financial support from Kadmon, grants and non-financial support from Genentech/Roche, grants and non-financial support from Amgen, grants and non-financial support from Millenium, non-financial support from Celldex, grants and non-financial support from Pfizer, non-financial support from Keryx/Aeterna Zentaris, grants and non-financial support from VBI Vaccines, grants and non-financial support from Beigene, personal fees from Bioclinica as an expert blinded independent reviewer of clinical and imaging data for a BMS-sponsored trial, personal fees from prIME Oncology, personal fees and non-financial support from Sapience, personal fees from WebMD, personal fees and non-financial support from Physicians' Education Resource, personal fees from Cortice, grants, personal fees and non-financial support from AbbVie, personal fees and non-financial support from Forma, personal fees and non-financial support from Bayer, grants and non-financial support from Global Coalition for Adaptive Research, personal fees and non-financial support from American Society of Clinical Oncology, grants and non-financial support from QED, grants, personal fees and non-financial support from NCI, non-financial support from New York University, grants and non-financial support from NRG Oncology/RTOG-Foundations, grants from UCLA, grants from Northwestern University, grants from James S. McDonnell Foundation, non-financial support from Yale University, non-financial support from Radiological Society of North America, non-financial support from FDA, personal fees from Italian Foundation for Cancer Research, personal fees and non-financial support from Abbott Molecular, and personal fees from Elsevier, outside the submitted work M. Joerger has received grants from BMS and AstraZeneca. G. Tabatabai has served on Advisory Boards for AbbVie and BMS, has received research/travel grants from Medac, Novocure and Roche Diagnostics, and has received speaker`s fees from Meda and Novocure. J. Rodon reports non-financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d'Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline; receiving consulting and travel fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma (including serving on the scientific advisory board from 2015-present), receiving research funding from Bayer and Novartis, and serving as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline, IPSEN and travel fees from ESMO, US Department of Defense, Louissiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC). R. Tiedt, T. Kirsilae and S. Vicente are employees of Novartis Pharma AG. S. Zhao is an employee of Novartis Institutes for Biomedical Research (China). A. Balbin is an employee of Novartis Institutes for Biomedical Research (US). H. Zhang is an employee of Novartis and holds shares with Novartis. W. Wick receives study support to the institution from Apogenix, Pfizer and Roche.", "Kawasaki's disease is a disease of unknown cause. The characteristic clinical features of Kawasaki's disease are fever> or =102 degrees F for> or =5 days accompanied by a bilateral bulbar conjunctivitis/conjunctival suffusion, erythematous rash, cervical adenopathy, pharyngeal erythema, and swelling of the dorsum of the hands/feet. Kawasaki's disease primarily affects children and is rare in adults. In children, Kawasaki's disease is more likely to be associated with aseptic meningitis, coronary artery aneurysms, and thrombocytosis. In adult Kawasaki's disease, unilateral cervical adenopathy, arthritis, conjunctival suffusion/conjunctivitis, and elevated serum transaminases (serum glutamic oxaloacetic transaminase [SGOT]/serum glutamate pyruvate transaminase [SGPT]) are more likely. Kawasaki's disease in adults may be mimicked by other acute infections with fever and rash, that is, group A streptococcal scarlet fever, toxic shock syndrome (TSS), and Rocky Mountain Spotted Fever (RMSF). Because there are no specific tests for Kawasaki's disease, diagnosis is based on clinical criteria and the syndromic approach. In addition to rash and fever, scarlet fever is characterized by circumoral pallor, oropharyngeal edema, Pastia's lines, and peripheral eosinophilia, but not conjunctival suffusion, splenomegaly, swelling of the dorsum of the hands/feet, thrombocytosis, or an elevated SGOT/SGPT. In TSS, in addition to rash and fever, there is conjunctival suffusion, oropharyngeal erythema, and edema of the dorsum of the hands/feet, an elevated SGOT/SGPT, and thrombocytopenia. Patients with TSS do not have cervical adenopathy or splenomegaly. RMSF presents with fever and a maculopapular rash that becomes petechial, first appearing on the wrists/ankles after 3 to 5 days. RMSF is accompanied by a prominent headache, periorbital edema, conjunctival suffusion, splenomegaly, thrombocytopenia, an elevated SGOT/SGPT, swelling of the dorsum of the hands/feet, but not oropharyngeal erythema. We present a case of adult Kawasaki's disease with myocarditis and splenomegaly. The patient's myocarditis rapidly resolved, and he did not develop coronary artery aneurysms. In addition to splenomegaly, this case of adult Kawasaki's disease is remarkable because the patient had highly elevated serum ferritin levels of 944-1303 ng/mL; (normal<189 ng/mL). To the best of our knowledge, this is the first report of adult Kawasaki's disease with highly elevated serum ferritin levels. This is also the first report of splenomegaly in adult Kawasaki's disease. We conclude that Kawasaki's disease should be considered in the differential diagnosis in adult patients with rash/fever for> or =5 days with conjunctival suffusion, cervical adenopathy, swelling of the dorsum of the hands/feet, thrombocytosis and otherwise unexplained highly elevated ferritin levels." ]

[ "The regulation of the aryl hydrocarbon receptor (AhR) protein levels has been an area of keen interest, given its important role in mediating the cellular adaptation and toxic response to several environmental pollutants. The carboxyl terminus of hsc70-interacting protein (CHIP) ubiquitin ligase was previously associated with the regulation of the aryl hydrocarbon receptor, although the mechanisms were not directly demonstrated. In this study, we established that CHIP could associate with the AhR at cellular levels of these two proteins, suggesting a potential role for CHIP in the regulation of the AhR complex. The analysis of the sucrose-gradient-fractionated in vitro translated AhR complexes revealed that CHIP can mediate hsp90 ubiquitination while cooperating with unidentified factors to promote the ubiquitination of mature unliganded AhR complexes. In addition, the immunophilin-like protein XAP2 was able to partially protect the AhR from CHIP-mediated ubiquitination in vitro. This protection required the direct interaction of the XAP2 with the AhR complex. Surprisingly, CHIP silencing in Hepa-1c1c7 cells by siRNA methods did not reveal the function of CHIP in the AhR complex, because it did not affect well-characterized activities of the AhR nor affect its steady-state protein levels. However, the presence of potential compensatory mechanisms may be confounding this particular observation. Our results suggest a model where the E3 ubiquitin ligase CHIP cooperates with other ubiquitination factors to remodel native AhR-hsp90 complexes and where co-chaperones such as the XAP2 may affect the ability of CHIP to target AhR complexes for ubiquitination.", "Abnormal development and fetal loss during postimplantation period are concerns for production of nuclear transferred animals. Aberrant DNA methylation is one of the reasons for poor survival of cloned animals. In mammalian genome DNA, CpG islands are preferentially located at the start of transcription of housekeeping genes and are associated with tissue-specific genes. The correct and consecutive mechanisms of DNA methylation in the CpG islands are necessary for selective gene expressions that determine the properties of individual cells, tissues, and organs. In this study, we investigated the methylation status of the CpG islands of the bovine Leptin and POU5F1 genes in fetal and placental tissues from fetuses produced by artificial insemination (AI) and nuclear transfer (NT) at days 48 and 59 of pregnancy. Altered DNA methylation was observed in the normal and cloned fetal, placental, and endometrial tissues using bisulfite sequencing and pyrosequencing. Different tissue-specific methylated regions in the bovine Leptin and POU5F1 genes show a variable methylation status in NT fetuses compared to AI control.", "MOTIVATION: Assembling peptides identified from tandem mass spectra into a list of proteins, referred to as protein inference, is an important issue in shotgun proteomics. The objective of protein inference is to find a subset of proteins that are truly present in the sample. Although many methods have been proposed for protein inference, several issues such as peptide degeneracy still remain unsolved.RESULTS: In this article, we present a linear programming model for protein inference. In this model, we use a transformation of the joint probability that each peptide/protein pair is present in the sample as the variable. Then, both the peptide probability and protein probability can be expressed as a formula in terms of the linear combination of these variables. Based on this simple fact, the protein inference problem is formulated as an optimization problem: minimize the number of proteins with non-zero probabilities under the constraint that the difference between the calculated peptide probability and the peptide probability generated from peptide identification algorithms should be less than some threshold. This model addresses the peptide degeneracy issue by forcing some joint probability variables involving degenerate peptides to be zero in a rigorous manner. The corresponding inference algorithm is named as ProteinLP. We test the performance of ProteinLP on six datasets. Experimental results show that our method is competitive with the state-of-the-art protein inference algorithms.AVAILABILITY: The source code of our algorithm is available at: https://sourceforge.net/projects/prolp/.CONTACT: zyhe@dlut.edu.cn.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Online.", "Hereditary hemochromatosis is an inherited disorder of iron metabolism in the Caucasian population with an autosomal recessive inheritance and a prevalence between 1 in 200 and 1 in 500. Until the discovery of HFE gene the diagnosis of hemochromatosis required documentation of iron overload or family linkage using HLA testing. The discovery of HFE gene has established the foundation for a better understanding of iron homeostasis and has changed hemochromatosis management: liver biopsy, gold standard diagnostic, was replaced by genetic test and it was suggested that population screening using genetic testing might be ideal for HFE related hemochromatosis. Considered for long time a unitary disease, a monogenic disorder characterized by excess tissue deposits of iron and subsequently organ damage, hemochromatosis is in fact a polygenic disease with many faces. The Online Mendelian Inheritance in Man database has lists four types of hereditary hemochromatosis, each of them caused by a different gene mutation (hepcidine, hemojuvelin, transferring receptor 2, ferroportin). The basic features shared by iron overload disorders associated with mutation in HFE, hepcidine, hemojuvelin, transferring receptor 2, ferroportin gene indicate that they are genetic variation of the same syndrome. Hereditary hemochromatosis must be distinguished from the other syndrome of iron overload and the classic term hereditary hemochromatosis should be reserved only for HFE related hemochromatosis.", "Murine acquired immunodeficiency syndrome (MAIDS) is characterized by lymphoproliferation, polyclonal B cell activation resulting in the production of autoantibodies, and a progressive immunodeficiency. These are all hallmarks of some autoimmune diseases. Yaa is a Y-chromosome-linked gene that accelerates autoimmune diseases in some autoimmune-prone strains of mice. To further elucidate a possible relationship with autoimmunity, the effect of the Yaa gene on MAIDS was investigated. Analysis of phenotypic and functional disease parameters revealed that Yaa does not accelerate MAIDS disease. This is probably due to the generalized activation of most or all lymphoid cells in MAIDS, which cannot be enhanced by the Yaa gene. This result is in accordance with the selective enhancing effect of the Yaa gene on the immune response against self and foreign antigens in a specific genetic background. It suggests that the autoimmune response associated with MAIDS is a secondary phenomenon. Interestingly, even in wild-type C57BL/6 mice, autoantibody production may contribute overproportionally to the hypergammaglobulinemia associated with MAIDS.", "BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. In this study, we evaluated the long-term efficacy, safety, and tolerability of monthly and quarterly fremanezumab.METHODS: Episodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg). Changes from baseline in monthly migraine days, monthly headache days of at least moderate severity, days of acute headache medication use, days with photophobia/phonophobia, days with nausea or vomiting, disability scores, and proportion of patients achieving a ≥50% or  ≥75% reduction in monthly migraine days were evaluated.RESULTS: Of the 807 patients who completed the 12-week double-blind treatment period and entered the open-label extension, 772 patients completed the study. In the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, patients had fewer average monthly migraine days (mean [standard deviation] change from baseline: - 4.7 [5.4]; - 5.1 [4.7]; - 5.5 [5.0]), monthly headache days of at least moderate severity (- 4.5 [5.0]; - 4.8 [4.5]; - 5.2 [4.9]), days per month of acute headache medication use (- 4.3 [5.2]; - 4.9 [4.6]; - 4.8 [4.9]), days with photophobia/phonophobia (- 3.1 [5.3]; - 3.4 [5.3]; - 4.0 [5.2]), and days with nausea or vomiting (- 2.3 [4.6]; - 3.1 [4.5]; - 3.0 [4.4]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days. Disability scores were substantially improved in all 3 treatment groups. There were low rates of adverse events leading to discontinuation (<1%).CONCLUSION: Fremanezumab demonstrated sustained efficacy up to 6 months and was well tolerated in patients with episodic migraine or chronic migraine and documented inadequate response to multiple migraine preventive medication classes.TRIAL REGISTRATION: ClinicalTrials.gov NCT03308968 (FOCUS).", "Author information:(1)Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. Electronic address: acarugo@mdanderson.org.(2)Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(3)Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(4)Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.(5)Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(6)Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(7)Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(8)Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan 20139, Italy.(9)Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy.(10)Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(11)Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(12)Department of Pathology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(13)Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.(14)Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. Electronic address: luisa.lanfrancone@ieo.eu.(15)C-4 Therapeutics, Cambridge, MA 02142, USA. Electronic address: theffernan@c4therapeutics.com.(16)Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: gdraetta@mdanderson.org." ]

[ "Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly. However, recent evidence has established another important role for titin: that of a regulatory node integrating, and perhaps coordinating, diverse signaling pathways, particularly in cardiomyocytes. We review key findings within this emerging field, including those related to phosphorylation of the titin springs, and also discuss how titin participates in hypertrophic gene regulation and protein quality control.", "Gluconeogenesis, the reverse process of glycolysis, is a favorable mechanism at conditions of glucose deprivation. Pck1 is a rate-limiting gluconeogenic enzyme, where its deficiency or mutation contributes to serious clinical situations as neonatal hypoglycemia and liver failure. A recent report confirms that Pck1 is a target for proteasomal degradation through its proline residue at the penultimate position, recognized by Gid4 E3 ligase, but with a lack of informative structural details. In this study, we delineate the localized sequence motif, degron, that specifically interact with Gid4 ligase and unravel the binding mode of Pck1 to the Gid4 ligase by using molecular docking and molecular dynamics. The peptide/protein docking HPEPDOCK web server along with molecular dynamic simulations are applied to demonstrate the binding mode and interactions of a Pck1 wild type (SPSK) and mutant (K4V) with the recently solved structure of Gid4 ligase. Results unveil a distinct binding mode of the mutated peptide compared with the wild type despite having comparable binding affinities to Gid4. Moreover, the four-residue peptide is found insufficient for Gid4 binding, while the seven-residue peptide suffices for binding to Gid4. The amino acids S134, K135, and N137 in the loop L1 (between β1 and β2) of the Gid4 are essential for the stabilization of the seven-residue peptide in the binding site of the ligase. The presence of Val4 instead of Lys4 smashes the H-bonds that are formed between Lys4 and Gid4 in the wild type peptide, making the peptide prone to bind with the other side of the binding pocket (L4 loop of Gid4). The dynamics of Gid4 L3 loop is affected dramatically once K4V mutant Pck1 peptide is introduced. This opens the door to explore the mutation effects on the binding mode and smooth the path to target protein degradation by design competitive and non-competitive inhibitors.", "Interstitial deletions of the long arm of chromosome 6 are rare. Clinically, these deletions are considered to be part of a unique microdeletion syndrome associated with intellectual disability and speech impairment, typical dysmorphic features, structural anomalies of the brain, microcephaly, and non-specific multiple organ anomalies. The critical region for the interstitial 6q microdeletion phenotype was mapped to 6q24-6q25, particularly the 6q25.3 region containing the genes ARID1B and ZDHHC14. It has been hypothesized that haploinsufficiency of these genes impairs normal development of the brain and is responsible for the phenotype. This case report describes a girl presenting with typical features of 6q microdeletion syndrome, including global developmental delay, speech impairment, distinct dysmorphic features, dysgenesis of the corpus callosum, common limb anomalies, and hearing loss. Chromosome analysis by array-CGH revealed a small interstitial 6q deletion spanning approximately 1.1 Mb of DNA and containing only one coding gene, ARID1B. We suggest that ARID1B is the key gene behind 6q microdeletion syndrome, and we discuss its possible role in the phenotypic manifestations.", "OBJECTIVE: To review the immunogenicity, efficacy, and safety of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in pediatric patients.DATA SOURCES: A MEDLINE search (2000-September 2011) was conducted using the key words Streptococcus pneumoniae and pneumococcal conjugate vaccine for clinical trials, limited to studies conducted in humans and published in English.STUDY SELECTION AND DATA EXTRACTION: Randomized, controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of PCV13. Literature on the epidemiology and pathology of pneumococcal infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed.DATA SYNTHESIS: PCV13 is approved for routine vaccination of all infants as a 4-dose series at age 2, 4, 6, and 12-15 months for children who previously received 1 or more doses of the 7-valent pneumococcal conjugate vaccine (PCV7), and for children with underlying medical conditions that increase their risk for pneumococcal disease or its complications. PCV13 has comparable immunogenicity to the serotypes common with PCV7 and also provides protection against 6 additional pneumococcal serotypes. PCV13 has also been shown to have a comparable adverse reaction profile to PCV7.CONCLUSIONS: Based on published immunogenicity and safety data, as well as the recent recommendations by the ACIP for routine use in infants and indications for high-risk pediatric patients, PCV13 is a revised formulation of pneumococcal vaccine that should be included on pharmacy formularies.", "In the giraffe (Giraffa camelopardalis), the masseter muscle was divided into several layers. The superficial and more medial (second) tendinous sheets of the masseter muscle fused with each other at the dorso-caudal part and a fleshy portion was located between these tendinous sheets. In the rostral part, the most superficial tendinous sheet turned around as a compact tendon and attached to the facial crest (Crista facialis). The turned tendinous sheet, however, never fused with the second tendinous sheet and this layer of the masseter muscle, that originated from the facial crest with the turned sheet, was inserted into the mandible with its fleshy portion. In the cattle, goat, sheep and Sika deer, the rostral layer of the masseter muscle arises from the facial crest with its fleshy portion and is inserted into the tubercle on the mandible through the strong tendinous sheet. In this study, the takin also showed the same structure of the masseter muscle. In the giraffe, however, the rostral layer inserted into the mandible through the strong tendinous sheet could not be distinguished, thus, there was no conspicuous tubercle on the mandible. Moreover in the masseteric region of the skull.,the giraffe was similar to the Sika deer in several ways. However, it is suggested that the giraffe exerts smaller forces on the cheek teeth than does the Sika deer because of its longer Margo interalveolaris.", "KCNQ2 and KCNQ3 K+ channel subunits underlie the muscarinic-regulated K+ current (I(KM)), a widespread regulator of neuronal excitability. Mutations in KCNQ2- or KCNQ3-encoding genes cause benign familiar neonatal convulsions (BFNCs), a rare autosomal-dominant idiopathic epilepsy of the newborn. In the present study, we have investigated, by means of electrophysiological, biochemical, and immunocytochemical techniques in transiently transfected cells, the consequences prompted by a BFNC-causing 1-bp deletion (2043deltaT) in the KCNQ2 gene; this frameshift mutation caused the substitution of the last 163 amino acids of the KCNQ2 C terminus and the extension of the subunit by additional 56 residues. The 2043deltaT mutation abolished voltage-gated K+ currents produced upon homomeric expression of KCNQ2 subunits, dramatically reduced the steady-state cellular levels of KCNQ2 subunits, and prevented their delivery to the plasma membrane. Metabolic labeling experiments revealed that mutant KCNQ2 subunits underwent faster degradation; 10-h treatment with the proteasomal inhibitor MG132 (20 microm) at least partially reversed such enhanced degradation. Co-expression with KCNQ3 subunits reduced the degradation rate of mutant KCNQ2 subunits and led to their expression on the plasma membrane. Finally, co-expression of KCNQ2 2043deltaT together with KCNQ3 subunits generated functional voltage-gated K+ currents having pharmacological and biophysical properties of heteromeric channels. Collectively, the present results suggest that mutation-induced reduced stability of KCNQ2 subunits may cause epilepsy in neonates.", "The molecular basis of sarcoma remains poorly understood. However, recent studies have begun to uncover some of the molecular pathways involved in sarcomagenesis. The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. There is growing evidence that overexpression of CXCR4 plays a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. Although further investigation is necessary to validate these pathways, there is potential for clinical application, particularly in the use of pharmacologic inhibitors of CXCR4 as means of preventing sarcoma metastasis.", "Author information:(1)School of Pharmacy, Tianjin Medical University, Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theragnostic), Tianjin, People's Republic of China.(2)School of Pharmacy, Tianjin Medical University, Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theragnostic), Tianjin, People's Republic of China; Department of Pharmacy, Tianjin Children's Hospital, People's Republic of China.(3)Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, People's Republic of China.(4)School of Pharmacy, Tianjin Medical University, Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theragnostic), Tianjin, People's Republic of China; Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China. Electronic address: duanhq@tmu.edu.cn.(5)School of Pharmacy, Tianjin Medical University, Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theragnostic), Tianjin, People's Republic of China. Electronic address: qinnan@tmu.edu.cn.", "Nucleotide excision repair (NER) is universally used to recognize and remove many types of DNA damage. In eubacteria, the NER system typically consists of UvrA, UvrB, UvrC, the UvrD helicase, DNA polymerase I, and ligase. In addition, when DNA damage blocks transcription, transcription-repair coupling factor (TRCF), the product of the mfd gene, recruits the Uvr complex to repair the damage. Previous work using selected mutants and assays have indicated that pathogenic Neisseria spp. carry a functional NER system. In order to comprehensively examine the role of NER in Neisseria gonorrhoeae DNA recombination and repair processes, the predicted NER genes (uvrA, uvrB, uvrC, uvrD, and mfd) were each disrupted by a transposon insertion, and the uvrB and uvrD mutants were complemented with a copy of each gene in an ectopic locus. Each uvr mutant strain was highly sensitive to UV irradiation and also showed sensitivity to hydrogen peroxide killing, confirming that all of the NER genes in N. gonorrhoeae are functional. The effect of RecA expression on UV survival was minor in uvr mutants but much larger in the mfd mutant. All of the NER mutants demonstrated wild-type levels of pilin antigenic variation and DNA transformation. However, the uvrD mutant exhibited higher frequencies of PilC-mediated pilus phase variation and spontaneous mutation, a finding consistent with a role for UvrD in mismatch repair. We conclude that NER functions are conserved in N. gonorrhoeae and are important for the DNA repair capabilities of this strict human pathogen.", "Author information:(1)Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. Electronic address: iguchi.takuma.kz@daiichisankyo.co.jp.(2)Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. Electronic address: goto.koichi.s7@daiichisankyo.co.jp.(3)Biomarker & Translational Research Department, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-0005, Japan. Electronic address: watanabe.kyoko.vw@daiichisankyo.co.jp.(4)Biomarker & Translational Research Department, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-0005, Japan. Electronic address: hashimoto.kazuyuki.v4@daiichisankyo.co.jp.(5)Oncology Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-0005, Japan. Electronic address: suzuki.takami.jt@daiichisankyo.co.jp.(6)Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. Electronic address: kishino.hiroyuki.jt@daiichisankyo.co.jp.(7)Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. Electronic address: fujimoto.kazunori.wr@daiichisankyo.co.jp.(8)Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. Electronic address: mori.kazuhiko.md@daiichisankyo.co.jp.", "The new information presented in Digestive Disease Week has allowed us to speculate on the future of inflammatory bowel disease. Manipulation of diet and the microbioma will probably play an increasingly important role in the treatment of this disease and, in the long term, in its prevention. Biological agents will probably be used earlier and more widely; new information on levels of biological agents, mucosal healing and new comparative studies will also allow these agents to be used in a more precise and personalized way. In addition to infliximab, adalimumab, natalizumab and certolizumab, other biological agents will be employed; among the first of these to be used will be ustekinumab, golimumab and vedolizumab. In the near future, biological agents will be used as frequently in ulcerative colitis as in Crohn's disease. New healthcare models will be developed that will progressively include greater participation among patients and nurses. The ability to predict new diagnostic and prognostic models will allow decisions to be more individualized.", "PURPOSE OF REVIEW: Vasculitides can affect small, medium and/or large vessels, leading to end-organ damage, decreased quality of life and death. Glucocorticoids remain the backbone of treatment for systemic vasculitis but are associated with numerous toxicities. In recent years, the efficacy of glucocorticoid-sparing biologic and novel small molecule therapies has been demonstrated.RECENT FINDINGS: In giant cell arteritis, tocilizumab was superior to glucocorticoid monotherapy in maintenance remission and cumulative glucocorticoid exposure and is now approved for the treatment of giant cell arteritis. In addition to the previously demonstrated efficacy of rituximab for remission induction in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, recent trials have also demonstrated its superiority for remission maintenance compared to alternative approaches. Mepolizumab is superior to standard of care alone with regard to remission rates and glucocorticoid-sparing effect in refractory eosinophilic granulomatosis with polyangiitis. Avacopan has shown significant promise in ANCA-associated vasculitis as part of a glucocorticoid-free induction regimen in a recently completed phase 3 trial. Use of biologics in rarer vasculitides remains guided by reports from small case series.SUMMARY: Biologics and other novel therapies have an increasingly important role in the management of systemic vasculitis. Additional studies are needed to define their optimal use and to guide their use in more rare forms of vasculitis.", "BACKGROUND: Phosphoenolpyruvate carboxykinase (PEPCK) is a metabolic enzyme in the gluconeogenesis pathway, where it catalyzes the reversible conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) and CO2. The substrates for Escherichia coli PEPCK are OAA and MgATP, with Mn2+ acting as a cofactor. Analysis of PEPCK structures have revealed amino acid residues involved in substrate/cofactor coordination during catalysis.METHODS: Key residues involved in coordinating the different substrates and cofactor bound to E. coli PEPCK were mutated. Purified mutant enzymes were used for kinetic assays. The structure of some mutant enzymes were determined using X-ray crystallography.RESULTS: Mutation of residues D269 and H232, which comprise part of the coordination sphere of Mn2+, reduced kcat by 14-fold, and significantly increased the Km values for Mn2+ and OAA. Mutation of K254 a key residue in the P-loop motif that interacts with MgATP, significantly elevated the Km value for MgATP and reduced kcat. R65 and R333 are key residues that interacts with OAA. The R65Q and R333Q mutations significantly increased the Km value for OAA and reduced kcat respectively.CONCLUSIONS: Our results show that mutation of residues involved in coordinating OAA, MgATP and Mn2+ significantly reduce PEPCK activity. K254 plays an important role in phosphoryl transfer, while R333 is involved in both OAA decarboxylation and phosphoryl transfer by E. coli PEPCK.GENERAL SIGNIFICANCE: In higher organisms including humans, PEPCK helps to regulate blood glucose levels, hence PEPCK is a potential drug target for patients with non-insulin dependent diabetes mellitus.", "Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown evidence of single-agent activity in glioblastoma (GBM), and in preclinical studies, we have demonstrated significant synergistic cytotoxicity between HDAC inhibitors and proteasome inhibitors in GBM cell lines. We therefore conducted a phase II trial to evaluate the efficacy of vorinostat in combination with the proteasome inhibitor bortezomib in patients with recurrent GBM. Vorinostat was administered at a dose of 400 mg daily for 14 days of a 21-day cycle, and bortezomib was administered at a dose of 1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of the cycle. A total of 37 patients were treated, and treatment was well tolerated: grade 3, 4 nonhematologic toxicity occurred in 30% of patients and consisted mainly of fatigue (14%) and neuropathy (5%); grade 3, 4 hematologic toxicity occurred in 37% of patients and consisted of thrombocytopenia (30%), lymphopenia (4%), and neutropenia (4%). The trial was closed at the predetermined interim analysis, with 0 of 34 patients being progression-free at 6 months. One patient achieved a partial response according to the Macdonald criteria. The median time to progression for all patients was 1.5 months (range, 0.5-5.6 months), and median overall survival (OS) was 3.2 months. Patients who had received prior bevacizumab therapy had a shorter time to progression and OS, compared with those who had not. On the basis of the results of this phase II study, further evaluation of the vorinostat-bortezomib combination in GBM patients in this dose and schedule is not recommended.", "Thyroid hormone has profound direct effects on cardiac function, but the hormonal interactions with the autonomic control of heart rate are unclear. Because thyroid hormone receptor (TR)-alpha1 has been implicated in the autonomic control of brown adipose energy metabolism, it might also play an important role in the central autonomic control of heart rate. Thus, we aimed to analyze the role of TRalpha1 signaling in the autonomic control of heart rate using an implantable radio telemetry system. We identified that mice expressing the mutant TRalpha1R384C (TRalpha1+m mice) displayed a mild bradycardia, which becomes more pronounced during night activity or on stress and is accompanied by a reduced expression of nucleotide-gated potassium channel 2 mRNA in the heart. Pharmacological blockage with scopolamine and the beta-adrenergic receptor antagonist timolol revealed that the autonomic control of cardiac activity was similar to that in wild-type mice at room temperature. However, at thermoneutrality, in which the regulation of heart rate switches from sympathetic to parasympathetic in wild-type mice, TRalpha1+m mice maintained sympathetic stimulation and failed to activate parasympathetic signaling. Our findings demonstrate a novel role for TRalpha1 in the adaptation of cardiac activity by the autonomic nervous system and suggest that human patients with a similar mutation in TRalpha1 might exhibit a deficit in cardiac adaptation to stress or physical activity and an increased sensitivity to beta-blockers.", "Rubinstein-Taybi Syndrome (RSTS, OMIM 180849) is a rare condition, which in 65% of cases is caused by haploinsufficiency of CREBBP (cAMP response element binding protein binding protein) localized to 16p13.3. A small subset of RSTS cases caused by 16p13.3 microdeletions involving neighboring genes have been recently suggested to be a true contiguous gene syndrome called severe RSTS or 16p13.3 deletion syndrome (OMIM 610543). In the present report, we describe a case of a 2-year-old female with RSTS who, besides most of the typical features of RSTS has corpus callosum dysgenesis and a Chiari type I malformation which required neurosurgical decompression. CGH microarray showed a approximately 520.7 kb microdeletion on 16p13.3 involving CREBBP, ADCY9, and SRL genes. We hypothesize that the manifestations in this patient might be influenced by the haploinsufficiency for ADCY9 and SRL.", "BACKGROUND: 3-hydroxy-3-methylglutaryl coenzyme A reductase reductase inhibitors (statins) are generally well tolerated, with statin-associated muscle symptoms (SAMS) the most common side effect (~10%) seen in statin users. However, studies and clinical observations indicate that many of the self-reported SAMS appear to be nonspecific (ie, potentially not attributable to statins).OBJECTIVE: Mental health and well-being influence self-perception of pain, so we sought to assess the effect of baseline well-being and depression on the development of muscle pain with 6 months of atorvastatin 80 mg/d (ATORVA) or placebo in healthy, statin-naive adults.METHODS: The Psychological General Well-being Index (n = 83) and Beck Depression Inventory (n = 55) questionnaires were administered at baseline in participants (aged 59.5 ± 1.2 years) from the effect of Statins on Skeletal Muscle Function and Performance (STOMP) trial (NCT00609063). Muscle pain (Short-Form McGill Pain Questionnaire [SF-MPQ]), pain that interferes with daily life (Brief Pain Inventory [BPI]), and pain severity (BPI) were then measured before, throughout, and after treatment.RESULTS: At baseline, there were no differences in well-being (Psychological General Well-being Index), depression (Beck Depression Inventory), or pain measures (SF-MPQ and BPI) (P values ≥ .05) between the placebo and ATORVA groups. Baseline well-being correlated negatively with baseline BPI pain severity (r = -0.290, P = .008). Baseline depression correlated with baseline pain (SF-MPQ; r = 0.314, P = .020). Baseline well-being and depression did not predict the change in pain severity or interference after 6 months among the total sample or between groups (P values ≥ .05).CONCLUSION: Baseline well-being and depression were not significant predictors of pain after 6 months of ATORVA (P values ≥ .05). Thus, they do not appear to increase the risk of SAMS in otherwise healthy adults.", "Nicotine-induced cell survival is associated with chemoresistance of human lung cancer cells, but our understanding of the intracellular mechanism(s) is fragmentary. Bax is a major proapoptotic member of the Bcl2 family and a molecule required for apoptotic cell death. Growth factor (i.e. granulocyte-macrophage colony-stimulating factor)-induced phosphorylation of Bax has been reported to negatively regulate its proapoptotic function. Because Bax is ubiquitously expressed in both small cell lung cancer and non-small cell lung cancer cells, nicotine may mimic growth factor(s) to regulate the activity of Bax. We found that nicotine potently induces Bax phosphorylation at Ser-184, which results in abrogation of the proapoptotic activity of Bax and increased cell survival. AKT, a known physiological Bax kinase, is activated by nicotine, co-localizes with Bax in the cytoplasm, and can directly phosphorylate Bax in vitro. Treatment of cells with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or specific depletion of AKT expression by RNA interference can block both nicotine-induced Bax phosphorylation and cell survival. Importantly, nicotine-induced Bax phosphorylation potently blocks stress-induced translocation of Bax from cytosol to mitochondria, impairs Bax insertion into mitochondrial membranes, and reduces the half-life of Bax protein (i.e. from 9-12 h to <6 h). Because knockdown of Bax expression by gene silencing results in prolonged cell survival following treatment with cisplatin in the absence or presence of nicotine, Bax may be an essential component in the nicotine survival signaling pathway. Thus, nicotine-induced survival and chemoresistance of human lung cancer cells may occur in a novel mechanism involving activation of PI3K/AKT that directly phosphorylates and inactivates the proapoptotic function of Bax.", "Stem cell-mediated root regeneration offers opportunities to regenerate a bio-root and its associated periodontal tissues to restore tooth loss. Periodontal ligament (PDL) and cementum complex and dentin pulp complex have been tissue engineered using human dental pulp stem cells and PDL stem cells, respectively. The aim of this study was to explore whether dentin formation could be induced using an inductive substrate and whether bioengineered dentin could induce cementum and PDL formation. First, dentin was bioengineered from tooth papillae of Sprague-Dawley (SD) rats with an inductive substrate, and its phenotype was characterized; then primarily cultured human PDL cells were seeded on the surface of dentin and transplanted under the skin of immunocompromised mice. Histological, immunohistochemical, and scanning electronic microscopy examinations results showed that bioengineered dentin could induce cementogenesis and PDL formation, and condense PDL arranged perpendicularly on the dentin surface via a layer of cementum-like tissue. The results indicated that tissue-engineered dentin could be induced using an inductive substrate and could be used as a further substrate for cementum and PDL tissue engineering.", "The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) generates soluble irisin. Initially described as being mainly produced in muscle during physical exercise, irisin mediates adipose tissue thermogenesis and also regulates carbohydrate and lipid metabolism. The aim of this study was to evaluate the hepatic expression of FNDC5 and its role in hepatocytes in Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of FNDC5 increased with hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese patients. The increased Fndc5 expression in fatty liver resulted from its upregulation in hepatocytes and non-parenchymal cells in mice. The local production of Fndc5 in hepatocytes was influenced by genotoxic stress and p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in primary mouse hepatocytes increased the expression of PEPCK, a key enzyme involved in gluconeogenesis associated with a decrease in the expression of master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations in FNDC5-silenced cells resulted to increased steatosis and insulin resistance in response to oleic acid and N-acetyl glucosamine, respectively. The downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in response to TNFα, which has been associated with decreased hepatoprotective autophagic flux. In conclusion, our human and experimental data strongly suggest that the hepatic expression of FNDC5 increased with hepatic steatosis and its upregulation in hepatocytes could dampen the development of NAFLD by negatively regulating steatogenesis and hepatocyte death." ]

[ "BACKGROUND: Slow progress in improving the outcome of ovarian cancer with chemotherapy over the last decade has stimulated research into molecularly targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors target DNA repair and are specifically active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated BRCA function have HR deficiency (HRD), which is also present in a significant proportion of non-BRCA-mutated ovarian cancer.DESIGN: In the last decade, olaparib, the first and most-investigated oral PARP inhibitor, has undergone phase I-III trials as a single agent, in comparison with and in addition to chemotherapy, and as a maintenance therapy following chemotherapy.RESULTS: The greatest benefit to-date has been in the maintenance setting, prolonging the progression-free survival of high-grade serous ovarian cancer with a BRCA1/2 mutation. In this group of patients, olaparib has received approval as maintenance following chemotherapy from the EMA, and accelerated approval as a single agent in women who have had three or more lines of therapy. Olaparib can be given for a prolonged period with few significant side-effects in most patients. Similar trials with other PARP inhibitors (rucaparib, niraparib and veliparib) are in progress and include non-BRCA-mutated ovarian cancer. Second-generation studies are exploring the combination of PARP inhibitors with anti-angiogenic drugs.CONCLUSIONS: PARP inhibitors represent a step change in the management of ovarian cancer. BRCA mutations are the first genotypic predictive markers in ovarian cancer and can be used to select patients who will most likely benefit from PARP inhibitors. BRCA testing is now becoming a routine part of the evaluation of women with ovarian cancer, and tests for HRD are being used to evaluate PARP inhibitors in an extended population of non-BRCA-mutated ovarian cancer.", "FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional \"antagonist\" and \"agonist\" mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.", "Background: The most widely used methods of describing traumatic brain injury (TBI) are the Glasgow Coma Scale (GCS) and the Abbreviated Injury Scale (AIS). Recent evidence suggests that presenting GCS in older patients may be higher than that in younger patients for an equivalent anatomical severity of TBI. This study aimed to assess these observations with a propensity-score matching approach using the data from Trauma Registry System in a Level I trauma center. Methods: We included all adult patients (aged ≥20 years old) with moderate to severe TBI from 1 January 2009 to 31 December 2016. Patients were categorized into elderly (aged ≥65 years) and young adults (aged 20-64 years). The severity of TBI was defined by an AIS score in the head (AIS 3‒4 and 5 indicate moderate and severe TBI, respectively). We examined the differences in the GCS scores by age at each head AIS score. Unpaired Student's t- and Mann-Whitney U-tests were used to analyze normally and non-normally distributed continuous data, respectively. Categorical data were compared using either the Pearson chi-square or two-sided Fisher's exact tests. Matched patient populations were allocated in a 1:1 ratio according to the propensity scores calculated using NCSS software with the following covariates: sex, pre-existing chronic obstructive pulmonary disease, systolic blood pressure, hemoglobin, sodium, glucose, and alcohol level. Logistic regression was used to evaluate the effects of age on the GCS score in each head AIS stratum. Results: The study population included 2081 adult patients with moderate to severe TBI. These patients were categorized into elderly (n = 847) and young adults (n = 1234): each was exclusively further divided into three groups of patients with head AIS of 3, 4, or 5. In the 162 well-balanced pairs of TBI patients with head AIS of 3, the elderly demonstrated a significantly higher GCS score than the young adults (14.1 ± 2.2 vs. 13.1 ± 3.3, respectively; p = 0.002). In the 362 well-balanced pairs of TBI patients with head AIS of 4, the elderly showed a significantly higher GCS score than the young adults (13.1 ± 3.3 vs. 12.2 ± 3.8, respectively; p = 0.002). In the 89 well-balance pairs of TBI patients with head AIS of 5, no significant differences were observed for the GCS scores. Conclusions: This study demonstrated that elderly patients with moderate TBI present higher GCS score than younger patients. This study underscores the importance of determining of TBI severity in this group of elderly patients based on the GCS score alone. A lower threshold of GCS cutoff should be adopted in the management of the elderly patients with TBI.", "Phlorotannin is the collective term for polyphenols derived from brown algae belonging to the genera Ascopyllum, Ecklonia, Eisenia, Fucus and Sargassum etc. Since the incidence of allergies is currently increasing in the world, there is a focus on phlorotannins having anti-allergic and anti-inflammatory effects. In this study, six purified phlorotannins (eckol; 6,6'-bieckol; 6,8'-bieckol; 8,8'-bieckol; phlorofucofuroeckol (PFF)-A and PFF-B) from Eisenia arborea, orally administered to mice, were examined for their suppression effects on ear swelling. In considering the suppression, we also examined whether the phlorotannins suppressed release of chemical mediators (histamine, leukotriene B₄ and prostaglandin E₂), and mRNA expression and/or the activity of cyclooxygenase-2 (COX-2), using RBL-2H3 cells, a cultured mast cell model. Results showed that the phlorotnannins exhibited suppression effects in all experiments, with 6,8'-bieckol, 8,8'-bieckol and PFF-A showing the strongest of these effects. In conclusion, orally administered phlorotannins suppress mouse ear swelling, and this mechanism apparently involves suppression of chemical mediator release and COX-2 mRNA expression or activity. This is the first report of the anti-allergic effects of the orally administered purified phlorotannins in vivo. Phlorotannins show potential for use in functional foods or drugs.", "The E1B 19K protein is a potent apoptosis inhibitor and the putative adenovirus Bcl-2 homolog. To investigate the mechanism of apoptosis regulation, 19K-interacting cellular proteins were identified using the yeast two-hybrid system, and Bax was one of seven 19-K interacting clones. Residues 50-78 of Bax containing a conserved region designated Bcl-2 homology region 3 (BH3) were sufficient for specific binding to both the E1B 19K and Bcl-2 proteins. The Bax-E1B 19K interaction was detectable in vitro and in lysates from mammalian cells, and Bax expression antagonized E1B 19K protein function. bax mRNA and protein levels were p53-inducible with kinetics identical to that of p21/Waf-1/Cip-1, and E1B 19K and Bcl-2 expression did not affect Bax or p21/Waf-1/Cip-1 accumulation. In cells where p53 was mutant, Bax expression induced apoptosis, suggesting that Bax was sufficient for apoptosis, and acted downstream of p53. p53 may simultaneously activate the transcription of genes required for both growth arrest (p21/Waf-1/Cip-1) and death (bax), and E1B 19K and Bcl-2 may act distally and function through interaction with and antagonism of Bax to prevent apoptosis. With the death pathway disabled, induction of growth arrest by p53 can then be manifested.", "Recent studies have demonstrated the power of deep re-sequencing of the whole genome or exome in understanding cancer genomes. However, targeted capture of selected genomic whole gene-body regions, rather than the whole exome, have several advantages: 1) the genes can be selected based on biology or a hypothesis; 2) mutations in promoter and intronic regions, which have important regulatory roles, can be investigated; and 3) less expensive than whole genome or whole exome sequencing. Therefore, we designed custom high-density oligonucleotide microarrays (NimbleGen Inc.) to capture approximately 1.7 Mb target regions comprising the genomic regions of 28 genes related to colorectal cancer including genes belonging to the WNT signaling pathway, as well as important transcription factors or colon-specific genes that are over expressed in colorectal cancer (CRC). The 1.7 Mb targeted regions were sequenced with a coverage ranged from 32× to 45× for the 28 genes. We identified a total of 2342 sequence variations in the CRC and corresponding adjacent normal tissues. Among them, 738 were novel sequence variations based on comparisons with the SNP database (dbSNP135). We validated 56 of 66 SNPs in a separate cohort of 30 CRC tissues using Sequenom MassARRAY iPLEX Platform, suggesting a validation rate of at least 85% (56/66). We found 15 missense mutations among the exonic variations, 21 synonymous SNPs that were predicted to change the exonic splicing motifs, 31 UTR SNPs that were predicted to occur at the transcription factor binding sites, 20 intronic SNPs located near the splicing sites, 43 SNPs in conserved transcription factor binding sites and 32 in CpG islands. Finally, we determined that rs3106189, localized to the 5' UTR of antigen presenting tapasin binding protein (TAPBP), and rs1052918, localized to the 3' UTR of transcription factor 3 (TCF3), were associated with overall survival of CRC patients.", "INTRODUCTION: Treprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. The availability of a formulation permitting convenient systemic delivery might have applicability to scleroderma vascular complications. We evaluated pharmacokinetics and perfusion in scleroderma patients with digital ischemia following escalating twice-daily doses of treprostinil diethanolamine SR.METHODS: Scleroderma patients with digital ulcers were enrolled in this dual-center, open-label, phase I pharmacokinetic study. Drug concentrations and perfusion, quantified by laser Doppler imaging, were measured over 12 hours at the 2 mg and 4 mg (or maximally tolerated) doses. Pharmacokinetic parameters were determined from individual plasma concentration versus time profiles using non-compartmental analysis methods. Digital perfusion and skin temperature were modeled as a function of log-transformed drug concentration and other covariates by performing repeated measures analyses using random effects models.RESULTS: Nineteen scleroderma patients (84% female, 53% limited scleroderma) received treprostinil diethanolamine SR with dose titration up to 4 mg twice daily as tolerated. Peak concentrations (mean maximum plasma concentration (Cmax) = 1,176 and 2,107 pg/mL) occurred approximately 3.6 hours after dose administration, and overall exposure (under the plasma concentration-time curve from time 0 to 12 hours post dose (AUC0-12) = 7,187 and 12,992 hr*pg/mL) was linear between the 2 mg and 4 mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4 mg dose (P = 0.015 and P = 0.013, respectively). The most frequent adverse events were similar to those seen with prostacyclin analogues.CONCLUSIONS: Oral treprostinil diethanolamine was effectively absorbed in patients with scleroderma. Drug administration was temporally associated with improved cutaneous perfusion and temperature. Treprostinil diethanolamine may provide a new therapeutic option for Raynaud's phenomenon and the peripheral vascular disease of scleroderma.TRIAL REGISTRATION: ClinicalTrials.gov NCT00848939." ]

[ "SUMMARY: Here we introduce Lipid Mini-On, an open-source tool that performs lipid enrichment analyses and visualizations of lipidomics data. Lipid Mini-On uses a text-mining process to bin individual lipid names into multiple lipid ontology groups based on the classification (e.g. LipidMaps) and other characteristics, such as chain length. Lipid Mini-On provides users with the capability to conduct enrichment analysis of the lipid ontology terms using a Shiny app with options of five statistical approaches. Lipid classes can be added to customize the user's database and remain updated as new lipid classes are discovered. Visualization of results is available for all classification options (e.g. lipid subclass and individual fatty acid chains). Results are also visualized through an editable network of relationships between the individual lipids and their associated lipid ontology terms. The utility of the tool is demonstrated using biological (e.g. human lung endothelial cells) and environmental (e.g. peat soil) samples.AVAILABILITY AND IMPLEMENTATION: Rodin (R package: https://github.com/PNNL-Comp-Mass-Spec/Rodin), Lipid Mini-On Shiny app (https://github.com/PNNL-Comp-Mass-Spec/LipidMiniOn) and Lipid Mini-On online tool (https://omicstools.pnnl.gov/shiny/lipid-mini-on/).SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "The fission yeast Schizosaccharomyces pombe normally has haploid cells of two mating types, which differ at the chromosomal locus mat1. After two consecutive asymmetric cell divisions, only one in four 'grand-daughter' cells undergoes a 'mating-type switch', in which genetic information is transferred to mat1 from the mat2-P or mat3-M donor loci. This switching pattern probably results from an imprinting event at mat1 that marks one sister chromatid in a strand-specific manner, and is related to a site-specific, double-stranded DNA break at mat1. Here we show that the genetic imprint is a strand-specific, alkali-labile DNA modification at mat1. The DNA break is an artefact, created from the imprint during DNA purification. We also propose and test the model that mat1 is preferentially replicated by a centromere-distal origin(s), so that the strand-specific imprint occurs only during lagging-strand synthesis. Altering the origin of replication, by inverting mat1 or introducing an origin of replication, affects the imprinting and switching efficiencies in predicted ways. Two-dimensional gel analysis confirmed that mat1 is preferentially replicated by a centromere-distal origin(s). Thus, the DNA replication machinery may confer different developmental potential to sister cells.", "A double-blind controlled trial of thyrotropin releasing hormone (TRH) 150 mg IM daily in 30 patients with amyotrophic lateral sclerosis is reported. The drug/placebo was administered for 2 months, followed by a 2-month \"wash-out\". Evaluation of strength, functional ability, and respiratory functions was performed. A temporary increase in the strength of some muscles was detected following the administration of TRH, but no change in functional performance was noted. Neither the patients nor the investigators believed the effects were of any marked clinical significance. The course of the illness was not altered.", "The rapid evolution of mass spectrometry (MS)-based lipidomics has enabled the simultaneous measurement of numerous lipid classes. With lipidomics datasets becoming increasingly available, lipidomic-focused software tools are required to facilitate data analysis as well as mining of public datasets, integrating lipidomics-unique molecular information such as lipid class, chain length, and unsaturation. To address this need, we developed lipidr, an open-source R/Bioconductor package for data mining and analysis of lipidomics datasets. lipidr implements a comprehensive lipidomic-focused analysis workflow for targeted and untargeted lipidomics. lipidr imports numerical matrices, Skyline exports, and Metabolomics Workbench files directly into R, automatically inferring lipid class and chain information from lipid names. Through integration with the Metabolomics Workbench API, users can search, download, and reanalyze public lipidomics datasets seamlessly. lipidr allows thorough data inspection, normalization, and uni- and multivariate analyses, displaying results as interactive visualizations. To enable interpretation of lipid class, chain length, and total unsaturation data, we also developed and implemented a novel lipid set enrichment analysis. A companion online guide with two live example datasets is presented at https://www.lipidr.org/. We expect that the ease of use and innovative features of lipidr will allow the lipidomics research community to gain novel detailed insights from lipidomics data.", "Mutations in the KCNJ11 gene are responsible for the majority of permanent neonatal diabetes mellitus (PNDM) cases. Some mutations in this gene, including p.Q52R, are associated with the developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. We describe a patient with PNDM who had no neurological finding although she was determined to have a novel mutation (p.Q52L) in the same residue of the KCNJ11 as in the previously reported cases with DEND syndrome. This case suggests that not all Q52 mutations in the KCNJ11 gene are necessarily related to DEND syndrome.", "Aim: To investigate whether plasma C-MYC level could be an indicator in clinical progression of breast cancer. Materials & methods: Plasma level of C-MYC expression was detected by quantitative real time PCR and the level of c-myc protein in breast cancer tissues was detected by immunohistochemistry. The expression level of C-MYC mRNA in supernatant of cancer cells culture was measured compared with the nonbreast cancer cells. Results: Plasma C-MYC level was significantly higher in patients with breast cancer than that in the controls, which associated with clinical stages, lymph node status, etc. Receiver operating characteristic curve analysis showed the sensitivity and specificity of plasma C-MYC level for diagnosis of breast cancer were 63.6 and 81.8%, respectively. The expression of c-myc protein in breast cancer tissues was associated with plasma C-MYC level, even C-MYC level in supernatant of cancer cells was elevated. Conclusion: Plasma C-MYC level might be a potential indicator in progression of breast cancer.", "Based on 152 mitochondrial genomes and 36 bacterial chromosomes that have been completely sequenced, as well as three long contigs for human chromosomes 6, 21, and 22, we examined skews of mononucleotide frequencies and the relative abundance of dinucleotides in one DNA strand. Each group of these genomes has its own characteristics. Regarding mitochondrial genomes, both CpG and GpT are underrepresented, while either GpG or CpC or both are overrepresented. The relative frequency of nucleotide T vs A and of nucleotide G vs C is strongly skewed, due presumably to strand asymmetry in replication errors and unidirectional DNA replication from single origins. Exceptions are found in the plant and yeast mitochondrial genomes, each of which may replicate from multiple origins. Regarding bacterial genomes, the \"universal\" rule of CpG deficiency is restricted to archaebacteria and some eubacteria. In other eubacteria, the most underrepresented dinucleotide is either TpA or GpT. In general, there are significant T vs A and G vs C skews in each half of the bacterial genome, although these are almost exactly canceled out over the whole genome. Regarding human chromosomes 6, 21, and 22, dinucleotide CpG tends to be avoided. The relative frequency of mononucleotides exhibits conspicuous local skews, suggesting that each of these chromosomal segments contains more than one DNA replication origin. It is concluded that, when there are several replicons in a genomic region, not only the number of DNA replication origins but also the directionality is important and that the observed patterns of nucleotide frequencies in the genome strongly support the hypothesis of strand asymmetry in replication errors.", "BACKGROUND: Resistance training in combination with practical blood flow restriction (pBFR) is thought to stimulate muscle hypertrophy by increasing muscle activation and muscle swelling. Most previous studies used the KAATSU device; however, little long-term research has been completed using pBFR.OBJECTIVE: To investigate the effects of pBFR on muscle hypertrophy.METHODS: Twenty college-aged male participants with a minimum of 1 year of resistance training experience were recruited for this study. Our study consisted of a randomized, crossover protocol consisting of individuals either using pBFR for the elbow flexors during the first 4 weeks (BFR-HI) or the second 4 weeks (HI-BFR) of an 8-week resistance training programme. Direct ultrasound-determined bicep muscle thickness was assessed collectively at baseline and at the end of weeks 4 and 8.RESULTS: There were no differences in muscle thickness between groups at baseline (P = 0·52). There were time (P<0·01, ES = 0·99) but no condition by time effects (P = 0·58, ES = 0·80) for muscle thickness in which the combined values of both groups increased on average from week 0 (3·66 ± 0·06) to week 4 (3·95 ± 0·05) to week 8 (4·11 ± 0·07). However, both the BFR-HI and HI-BFR increased significantly from baseline to week 4 (6·9% and 8·6%, P<0·01) and from weeks 4 to 8 (4·1%, 4·0%, P<0·01), respectively.CONCLUSION: The results of this study suggest that pBFR can stimulate muscle hypertrophy to the same degree to that of high-intensity resistance training.", "Congenital hypothyroidism is the most common neonatal metabolic disorder and results in severe neurodevelopmental impairment and infertility if untreated. Congenital hypothyroidism is usually sporadic but up to 2% of thyroid dysgenesis is familial, and congenital hypothyroidism caused by organification defects is often recessively inherited. The candidate genes associated with this genetically heterogeneous disorder form two main groups: those causing thyroid gland dysgenesis and those causing dyshormonogenesis. Genes associated with thyroid gland dysgenesis include the TSH receptor in non-syndromic congenital hypothyroidism, and Gsalpha and the thyroid transcription factors (TTF-1, TTF-2, and Pax-8), associated with different complex syndromes that include congenital hypothyroidism. Among those causing dyshormonogenesis, the thyroid peroxidase and thyroglobulin genes were initially described, and more recently PDS (Pendred syndrome), NIS (sodium iodide symporter), and THOX2 (thyroid oxidase 2) gene defects. There is also early evidence for a third group of congenital hypothyroid conditions associated with iodothyronine transporter defects associated with severe neurological sequelae. This review focuses on the genetic aspects of primary congenital hypothyroidism.", "Targeted therapies are widely used in cancer because of their effectiveness, even in tumours that are resistant to conventional chemotherapy such as kidney or hepatocellular carcinomas. There are different families classified according to their mode of action. The antiangiogenics block tumor angiogenesis by acting on VEGF or its receptor. The main molecules are bevacizumab, sunitinib, and sorafinib. HER inhibitors work by blocking these receptors, which control different signaling intracellular pathways, and include an inhibitor of HER2, trastuzumab, and various inhibitors of HER1, or EGFR, including cetuximab, erlotinib, and gefitinib. Inhibitors of KIT, a membrane receptor, are mainly represented by imatinib, an inhibitor of tyrosine kinase. Finally, mTOR inhibitors act on the signaling pathway PI3K/AKT/mTOR, and key molecules are temsirolimus, everolimus, and deforolimus.", "Author information:(1)UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. frederic.tran-mau-them@u-bourgogne.fr.(2)INSERM UMR1231 GAD, F-21000, Dijon, France. frederic.tran-mau-them@u-bourgogne.fr.(3)Universite Claude Bernard Lyon I, CHU de Lyon, Lyon, France.(4)Service de Radiologie, Hopital-Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France.(5)INSERM UMR1231 GAD, F-21000, Dijon, France.(6)Departement de Genetique, Hopital Pitie-Salpetriere, Paris, France.(7)Division of Genetics and Metabolic Phoenix Children's Hospital, Phoenix, Arizona, USA.(8)Inserm U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epinière, ICM, Paris, France.(9)Reference Center for Adult Neurometabolic Diseases, Pitie-Salpêtrière University Hospital, Paris, France.(10)Department of Genetics, University Medical Center, Utrecht, The Netherlands.(11)Centre de Reference maladies rares « Anomalies du Developpement et syndrome malformatifs » de l'Est, Centre de Genetique, Hopital d'Enfants, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France.(12)UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.(13)Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.(14)Department of Pediatrics, Division of Medical Genetics, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, Los Angeles, California, USA.(15)Division of Pediatric Neurology, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, California, USA.(16)GeneDx, Gaithersburg, Maryland, USA.(17)Genomed Ltd., Moscow, Russia.(18)Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moscow, Russia.(19)Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.(20)Departments of Human Genetics and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.(21)Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland.(22)Division of Pediatric Neurology, Children's Hospital, Lucerne, Switzerland.(23)Department of Neurosciences and Pediatrics UCSD/Rady Children's Hospital San Diego, Rady Children's Institute for Genomic Medicine, San Diego, California, USA.(24)UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. antonio.vitobello@u-bourgogne.fr.(25)INSERM UMR1231 GAD, F-21000, Dijon, France. antonio.vitobello@u-bourgogne.fr.", "BACKGROUND AND AIMS: Chocolate consumption may have a beneficial effect on cardiovascular health, but evidence from prospective cohort studies is still limited. We aimed to examine the prospective associations between chocolate consumption and risk of stroke among men and women in a large population-based cohort.METHODS: A total of 38,182 men and 46,415 women aged 44-76 years, and free of cardiovascular disease, diabetes, and cancer at baseline in 1995 and 1998, were followed up until the end of 2009 and 2010, respectively. We obtained data on chocolate consumption for each participant using a self-administrated food frequency questionnaire that included 138 food and beverage items. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of stroke in relation to chocolate consumption.RESULTS: During a median follow-up of 12.9 years, we identified 3558 incident strokes cases (2146 cerebral infarctions and 1396 hemorrhagic strokes). After adjustment for age, body mass index, life styles, dietary intakes, and other risk factors, chocolate consumption was associated with a significant lower risk of stroke in women (HR = 0.84; 95% CI, 0.71-0.99). However, the association in men was not significant (HR = 0.94; 95% CI, 0.80-1.10). In addition, the association did not vary by stroke subtypes in either men or women.CONCLUSIONS: Findings from this large Japanese cohort supported a significant inverse association between chocolate consumption and risk of developing stroke in women. However, residual confounding could not be excluded as an alternative explanation for our findings.", "Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial impairment are common, yet poorly characterized, findings in EDS patients. We investigated the frequency and types of psychiatric disorders and their relationship to systemic manifestations in a cohort of 106 classic and hypermobility type EDS patients. In this retrospective study, extensive medical chart review was performed for patients referred at two genetics clinics who were diagnosed with EDS. Statistical analysis was undertaken to determine the frequency of psychiatric disorders and association with systemic findings. Psychiatric disorders were found in 42.5% of the EDS cohort, with 22.7% of patients affected with 2 or more psychiatric diagnoses. Anxiety and depression were most commonly reported, with frequencies of 23.6 and 25.5%, respectively. A variety of other psychiatric diagnoses were also identified. Abdominal pain [odds ratio (OR) 7.38], neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR 2.85) and fatigue (OR 5.55) were significantly associated with the presence of a psychiatric disorder. The presence of any pain symptom was significantly associated with having a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR 5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were significantly associated with having an anxiety or mood disorder. Joint hypermobility and the classic dermatological features of EDS showed no significant association with having a psychiatric disorder. Our findings demonstrate a high frequency of psychiatric disorders and an association with pain symptoms in EDS.", "High resolution LC-MS untargeted lipidomics using data independent acquisition (DIA) has the potential to increase lipidome coverage, as it enables the continuous and unbiased acquisition of all eluting ions. However, the loss of the link between the precursor and the product ions combined with the high dimensionality of DIA data sets hinder accurate feature annotation. Here, we present LipidMS, an R package aimed to confidently identify lipid species in untargeted LC-DIA-MS. To this end, LipidMS combines a coelution score, which links precursor and fragment ions with fragmentation and intensity rules. Depending on the MS evidence reached by the identification function survey, LipidMS provides three levels of structural annotations: (i) \"subclass level\", e.g., PG(34:1); (ii) \"fatty acyl level\", e.g., PG(16:0_18:1); and (iii) \"fatty acyl position level\", e.g., PG(16:0/18:1). The comparison of LipidMS with freely available data dependent acquisition (DDA) and DIA identification tools showed that LipidMS provides significantly more accurate and structural informative lipid identifications. Finally, to exemplify the utility of LipidMS, we investigated the lipidomic serum profile of patients diagnosed with nonalcoholic steatohepatitis (NASH), which is the progressive form of nonalcoholic fatty liver disease, a disorder underlying a strong lipid dysregulation. As previously published, a significant decrease in lysophosphatidylcholines, phosphatidylcholines and cholesterol esters and an increase in phosphatidylethanolamines were observed in NASH patients. Remarkably, LipidMS allowed the identification of a new set of lipids that may be used for NASH diagnosis. Altogether, LipidMS has been validated as a tool to assist lipid identification in the LC-DIA-MS untargeted analysis of complex biological samples.", "Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. Here we report on 13 patients from seven unrelated families from the Arabian Peninsula. These patients have a constellation of features that fall within the WMS spectrum and follow an autosomal-recessive mode of inheritance. Individuals who came from two families and met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10. Linkage analysis and direct sequencing of candidate genes in another two families and a sporadic case with phenotypes best described as WMS-like led to the identification of three homozygous mutations in the closely related ADAMTS17 gene. Our clinical and genetic findings suggest that ADAMTS17 plays a role in crystalline lens zonules and connective tissue formation and that mutations in ADAMTS17 are sufficient to produce some of the main features typically described in WMS.", "INTRODUCTION: Mass spectrometry imaging (MSI) experiments result in complex multi-dimensional datasets, which require specialist data analysis tools.OBJECTIVES: We have developed massPix-an R package for analysing and interpreting data from MSI of lipids in tissue.METHODS: massPix produces single ion images, performs multivariate statistics and provides putative lipid annotations based on accurate mass matching against generated lipid libraries.RESULTS: Classification of tissue regions with high spectral similarly can be carried out by principal components analysis (PCA) or k-means clustering.CONCLUSION: massPix is an open-source tool for the analysis and statistical interpretation of MSI data, and is particularly useful for lipidomics applications." ]

[ "OBJECTIVE: To examine the incidence of preterm premature rupture of membranes (PPROM) in pregnancies affected by twin-twin transfusion syndrome (TTTS) treated with laser photocoagulation where an absorbable gelatin sponge was used as a chorioamnion sealant of the fetoscopic access port.METHOD: A retrospective review was undertaken of consecutive cases undergoing fetoscopic directed laser surgery for TTTS between October 2006 and November 2008 at Texas Children's Fetal Center, in which an absorbable gelatin sponge, used as a chorioamnion 'plug', was placed at the conclusion of the intervention as a possible prophylactic measure to prevent PPROM. We excluded cases that had a failure of plug placement and those in which it was not attempted. PPROM was defined as rupture of membranes before 34 weeks' gestation. A comparison was performed between the PPROM group and a no-PPROM group to determine risk factors and outcomes.RESULTS: Successful plug placement occurred in 79 of 84 cases (94%) in which it was attempted after laser surgery, with a rate of PPROM of 34% in these patients. PPROM occurred at an average gestational age of 26.5 +/- 3.6 weeks, with an average procedure-to-PPROM interval of 5.2 +/- 3.5 weeks. There were no statistically significant differences between the PPROM group and the no-PPROM group in maternal demographics or preoperative parameters including: amniotic fluid volumes in the recipient twin's gestational sac, volume of amnioreduction, and location of the placenta. The procedure-to-delivery interval for the total cohort (n = 79) was 9.2 +/- 4.7 weeks, without a significant difference between the two groups (P = 0.08). However, after exclusion of one PPROM outlier, the PPROM group had an average procedure-to-delivery time 2 weeks shorter than the group with no PPROM (P = 0.03). The live birth rates were similar in the PPROM and no-PPROM groups, at 77 and 73%, respectively. However, the average recipient's weight in the PPROM group was significantly lower than in the no-PPROM group (1321 +/- 493 vs. 1705 +/- 576 g; P = 0.02).CONCLUSION: The rate of PPROM and the mean gestational age at delivery in pregnancies in which an absorbable gelatin sponge was used as a sealant of the fetoscopic port following laser photocoagulation for TTTS were comparable to those that have been reported by other laser centers where membrane sealants were not used. A randomized controlled trial should be considered to evaluate the effect of chorioamnion plugging.", "BACKGROUND: A major technical limitation in preclinical cell replacement research is the ability to discriminate between donor and host tissue after transplantation. This problem has been lessened by the availability of transgenic animals that express \"reporter\" genes, such as green fluorescent protein (GFP).OBJECTIVE: We determined the usefulness of one such transgenic reporter rat to assess the survival of bone marrow-derived rat mesenchymal stem cells (MSCs) following direct transplantation into the intact adult brain. We also sought to determine if the expression of GFP in the brain affected the survival of the MSCs or the host's neuroimmune response to the cells.METHODS: Rats received intrastriatal injections of sterile transplantation medium, 100 000 normal MSCs, or 100 000 GFP-MSCs and were killed humanely 1, 4, 7, 28, and 42 days posttransplantation for astrocyte and microglial immunohistochemical staining.RESULTS: GFP-MSCs were evident at each examination, although their survival declined over time. Graft volume estimates comparing normal and GFP-MSCs revealed that GFP expression did not adversely affect the survival of the stem cells in the brain. Furthermore, immunostaining for astrocytes and microglia revealed that expression of the reporter protein did not affect the immunogenicity of the stem cells.CONCLUSIONS: These data indicate the usefulness of GFP for investigating the survival of MSCs following transplantation to the brain. However, the mechanisms responsible for the poor survival of the stem cells must be elucidated if these cells are to serve cell-based therapies for neurodegenerative disorders.", "OBJECTIVE: To estimate the budget impact of introducing avelumab as a second-line (2L) treatment option for patients with locally advanced or metastatic urothelial cancer (mUC) from the perspective of a US third-party payer (commercial and Medicare).METHODS: A budget impact model (BIM) with a three-year time horizon was developed for avelumab. Efficacy and safety data were sourced from published literature and US package inserts. The analysis was conducted in collaboration with a specialist oncologist who validated clinical assumptions. Costs were based on the number of eligible patients, time-to-treatment failure, overall survival, adverse events (AEs), and projected market shares of various treatments.RESULTS: In a hypothetical commercial health plan of 30,000,000 members, 884 patients were estimated to be eligible for 2L treatment over a three-year time period. Without avelumab, the total cost for treating patients with mUC was estimated to be US$70,268,035. The introduction of avelumab increased total costs by $73,438 (0.10% increase). In a hypothetical Medicare health plan of 30,000,000 beneficiaries, a total of 4,705 patients were estimated to be eligible for 2L treatment. Without avelumab, the total cost for treating patients with mUC was estimated to be $292,923,098 from a Medicare perspective; however, with avelumab, there was an increase of $719,324 (0.25% increase) in total costs. Results of the sensitivity analyses demonstrated a cost-neutral impact across all tested scenarios from both perspectives.CONCLUSION: The BIM estimated that avelumab would have a cost-neutral impact within a US commercial and a Medicare health plan. Overall, avelumab can be an affordable and valuable treatment option for patients with locally advanced or mUC in the 2L setting. These findings demonstrate a consistently favorable budget impact in both populations. Further studies should be conducted to more comprehensively assess the clinical and economic implications of adding avelumab to the treatment armamentarium of 2L mUC.", "Studying the sublethal effects of agrochemical pesticides on nontarget honeybees (Apis mellifera) is important for agricultural development. Carbendazim is a widely used broad-spectrum fungicide that inhibits mitotic microtubule formation and cell division. However, the impact of carbendazim on bee health and development has not been fully elucidated. Here, using proteomics approaches, we assessed in vitro the changes in the expression of functional proteins in the head of newly emerged adults following treatment with field concentration of carbendazim during the larval stage. Treatment with carbendazim severely altered 266 protein expression patterns in the heads of adults and 218 of them showed downregulation after carbendazim exposure. Notably, major royal jelly proteins, a crucial multifunctional protein family with irreplaceable function in sustaining the development of colonies, were significantly suppressed in carbendazim-treated bees. This result was verified in both head and hypopharyngeal gland of nurse bees. Moreover, visual and olfactory loss, immune functions, muscular activity, social behavior, neural and brain development, protein synthesis and modification, and metabolism-related proteins were likely inhibited by carbendazim treatment. Together, these results suggest that carbendazim is an environmental risk factor that likely weakens bee colonies, partially due to reduced expression of major royal jelly proteins, which may be potential causes of colony collapse disorder.", "Human RNA-binding protein HuR, a nucleocytoplasmic shuttling protein, is a ubiquitously expressed member of the family of Hu proteins, which consist of two N-terminal RNA recognition motifs (RRM1 and RRM2), a hinge region, and a C-terminal RRM (RRM3). Although in vitro experiments showed indiscriminate binding of Hu proteins synthesized in bacterial systems to many different AU-rich elements (AREs), in vivo studies have pointed to a cytoplasmic role for HuR protein in antagonizing the rapid decay of some specific ARE-containing mRNAs, depending on physiological situations. By ectopically overexpressing HuR and its mutant derivatives in NIH 3T3 cells to mimic HuR upregulation of specific ARE-containing mRNAs in other systems, we have examined the in vivo ARE-binding specificity of HuR and dissected its functionally critical domains. We show that in NIH 3T3 cells, HuR stabilizes reporter messages containing only the c-fos ARE and not other AREs. Two distinct binding sites were identified within the c-fos ARE, the 5' AUUUA-containing domain and the 3' U-stretch-containing domain. These actions of HuR are markedly different from those of another ARE-binding protein, hnRNP D (also termed AUF1), which in vivo recognizes AUUUA repeats found in cytokine AREs and can exert both stabilizing and destabilizing effects. Further experiments showed that any combination of two of the three RRM domains of HuR is sufficient for strong binding to the c-fos ARE in vitro and to exert an RNA stabilization effect in vivo comparable to that of intact HuR and that the hinge region containing nucleocytoplasmic shuttling signals is dispensable for the stabilization effect of HuR. Our data suggest that the ARE-binding specificity of HuR in vivo is modulated to interact only with and thus regulate specific AREs in a cell type- and physiological state-dependent manner.", "OBJECTIVES: Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored.METHODS: Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration.RESULTS: LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist.CONCLUSIONS: The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.", "We report on mutation analysis of five genes involved in the receptor tyrosine kinase (RET) or the endothelin-signalling pathways in 28 sporadic Japanese patients with Hirschsprung disease. Analysis of DNA obtained from peripheral blood cells revealed six mutations in the RET proto-oncogene, four of which were disease-causing mutations in exon 9 (D584G), the splice donor site of intron 10 (+2T to A), exon 11 (A654T), and exon 12 (T706A). A heterozygous A to G transition was found in 47 bases upstream from the 5' end of exon 2 in two HD patients but was also seen in one control subject (2/28; 1/24). A silent 2307T to G transversion was observed in exon 13. Two disease-causing mutations were detected in the endothelin receptor (EDNRB) gene, in the non-coding region of exon 1 (-26 G to A) and in exon 4 (A301T); the latter mutation was a novel one. One silent mutation was observed in exon 4 (codon 277). One heterozygous T to C mutation was found in the glial cell line-derived neurotrophic factor gene in 25 bases upstream of the coding region in exon 1. No nucleotide changes were detected in either the endothelin-3 or neurturin genes. Disease-causing mutation rates in the RET proto-oncogene and the EDNRB gene were estimated at 14.3% (4/28) and 10.7% (3/28), respectively. In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease. Further systematic studies of genetic variation in a large series of patients and controls are necessary for elucidating the pathogenesis of this disorder.CONCLUSION: This study provides further gene alterations as disease-causing mutations in Japanese cases of sporadic Hirschsprung disease. However, the low mutation rate of the susceptibility genes may indicate that Hirschsprung disease arises from a combination of genetic and environmental factors.", "Publisher: Los abejorros están constantemente expuestos a una amplia gama de agentes estresantes bióticos y abióticos de los que deben defenderse para sobrevivir. Los patógenos y los pesticidas son importantes factores estresantes que influyen en la salud de los abejorros, tanto cuando actúan solos como en combinación. Para tener un mejor conocimiento sobre la salud de los abejorros, debemos investigar cómo interactúan estos factores estresantes, pero los estudios experimentales hasta la fecha generalmente se centran en estudiar solo uno o dos factores. El objetivo de nuestro estudio es evaluar cómo los efectos combinados de cuatro importantes factores estresantes (el parásito intestinal Nosema ceranae, el insecticida neonicotinoide tiametoxam, el insecticida piretroide cipermetrina y el fungicida EBI tebuconazol) interactúan para afectar a los abejorros a nivel individual y de colonia. Establecimos siete grupos de tratamiento de colonias de abejorros que expusimos a diferentes combinaciones de estos factores estresantes durante dos semanas en condiciones de laboratorio, y posteriormente se colocaron en el campo durante siete semanas, para evaluar el efecto de los tratamientos sobre la prevalencia de N. ceranae en abejorros inoculados, los niveles de expresión de genes relacionados con la inmunidad y la desintoxicación, la recolección de alimentos, el aumento de peso, el número de obreras y machos, y la producción de cría de obreras, machos y reinas. La exposición a mezclas de pesticidas redujo la recolección de alimentos por parte de los abejorros. Todos los genes relacionados con la inmunidad se sobre-expresaron en los abejorros inoculados con N. ceranae cuando no habían estado expuestos a mezclas de pesticidas, y los abejorros expuestos al fungicida y al piretroide presentaron menos probabilidades de tener N. ceranae. La exposición combinada a la mezcla de tres pesticidas y N. ceranae redujo el crecimiento de la colonia de abejorros y todos los tratamientos tuvieron efectos perjudiciales en la producción de crías. Los grupos expuestos al insecticida neonicotinoide produjeron entre un 40 y un 76% menos de reinas que las colonias control. Nuestros hallazgos muestran que la exposición a combinaciones de factores estresantes con los que los abejorros entran frecuentemente en contacto tiene efectos perjudiciales sobre la salud y el rendimiento de la colonia y, por lo tanto, podría tener un impacto a nivel poblacional. Estos resultados también tienen importantes implicaciones para las prácticas y políticas actuales de evaluación de riesgos y uso de plaguicidas, ya que las combinaciones probadas aquí se aplican con frecuencia simultáneamente en el campo. Comprender las interacciones entre los diferentes factores de estrés es fundamental para mejorar nuestra capacidad de gestión de las poblaciones de abejas y así garantizar los servicios de polinización en el futuro." ]

[ "BACKGROUND: Mechanical ventilation can induce or aggravate lung injury, which is termed ventilator-induced lung injury (VILI). Piezo1 is a key element of the mechanotransduction process and can transduce mechanical signals into biological signals by mediating Ca2+ influx, which in turn regulates cytoskeletal remodeling and stress alterations. We hypothesized that it plays an important role in the occurrence of VILI, and investigated the underlying mechanisms.METHODS: High tidal volume mechanical ventilation and high magnitude cyclic stretch were performed on Sprague-Dawley rats, and A549 and human pulmonary microvascular endothelial cells, respectively, to establish VILI models. Immunohistochemical staining, flow cytometry, histological examination, enzyme-linked immunosorbent assay, western blotting, quantitative real-time polymerase chain reaction and survival curves were used to assess the effect of Piezo1 on induction of lung injury, as well as the signaling pathways involved.RESULTS: We observed that Piezo1 expression increased in the lungs after high tidal volume mechanical ventilation and in cyclic stretch-treated cells. Mechanistically, we observed the enhanced expression of RhoA/ROCK1 in both cyclic stretch and Yoda1-treated cells, while the deficiency or inhibition of Piezo1 dramatically antagonized RhoA/ROCK1 expression. Furthermore, blockade of RhoA/ROCK1 signaling using an inhibitor did not affect Piezo1 expression. GSMTx4 was used to inhibit Piezo1, which alleviated VILI-induced pathologic changes, water content and protein leakage in the lungs, and the induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats.CONCLUSIONS: These findings indicate that Piezo1 affects the development and progression of VILI through promotion of RhoA/ROCK1 signaling.", "PURPOSE OF REVIEW: The development of 'immune checkpoint inhibitors' or drugs targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has been a stunning success of cancer immunotherapy. This review provides a timely overview of the biology and function of the PD-1 pathway and discusses the rationale for therapeutic inhibition of this pathway in lymphoma.RECENT FINDINGS: Recent studies have evaluated the prevalence and prognostic implications of PD-1, PD-L1/2 expression in various lymphoma subtypes. We present an overview of the clinical trials evaluating pidilizumab, nivolumab, and pembrolizumab in patients with lymphoid malignancies, and highlight some of the more promising agents in this class, currently in development. Finally, we discuss biomarkers that may predict response to therapy in patients with lymphoma across these clinical trials.SUMMARY: A plethora of clinical trials are in progress testing immune checkpoint inhibitors in many subtypes of lymphoma, which will define their role both as a monotherapy and in combination with other biologic agents.", "Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial uncoupling protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as antiobesity medications, we developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis.", "BACKGROUND AND OBJECTIVES: Atemoya (Annona atemoya) is increasingly being consumed worldwide because of its pleasant taste. However, only limited information is available concerning possible atemoya-drug interactions. In the present study, the issue of whether atemoya shows food-drug interactions with substrate drugs of the major drug-metabolizing cytochrome P450s (i.e., CYP1A2, CYP2C9, and CYP3A) is addressed.METHODS: The ability of atemoya juice to inhibit the activities of phenacetin O-deethylase (CYP1A2), diclofenac 4'-hydroxylase (CYP2C9), and midazolam 1'-hydroxylase (CYP3A) was examined in vitro using human and rat liver microsomes. The in vivo pharmacokinetics of phenacetin and metabolites derived from it in rats when atemoya juice or fluvoxamine (a CYP1A2 inhibitor) was preadministered were also investigated.RESULTS: Atemoya juice significantly inhibited CYP1A2 activity in human liver microsomes, but not the activities of CYP2C9 and CYP3A. In spite of this inhibition, preadministration of atemoya had no effect on the pharmacokinetics of phenacetin, a CYP1A2 substrate, in rats. Meanwhile, preadministration of fluvoxamine significantly extended the time needed for the elimination of phenacetin, possibly due to the inhibition of CYP1A2. This suggests that the intake of an excess amount of atemoya juice is necessary to cause a change in the pharmacokinetics of phenacetin when the IC50 values for CYP1A2 inhibition by atemoya and fluvoxamine are taken into account.CONCLUSION: The results indicate that a daily intake of atemoya would not change the pharmacokinetics of CYP1A2 substrates such as phenacetin as well as CYP2C9- and CYP3A-substrate drugs.", "The authors report a female presenting with congenital heart defects, liver hemangiomas, and facial dysmorphisms admitted to hospital at 3 months of age because of feeding difficulties and poor growth. She had hypotonia and large tongue, \"coarse\" face, and umbilical hernia in presence of complex congenital cardiovascular malformations. In spite of normal neonatal screening we performed serum levels of thyroid hormones. Thyrotropin level was very high (>50 microU/ml; normal value 0.2-4 microU/ml), while serum free T(3) (FT3) and free T(4) (FT4) levels were normal (FT3 3.6 pg/ml, normal value 2.8-5.6 pg/ml; FT4 11.6 pg/ml, normal value 6.6-14 pg/ml); antithyroid autoantibodies were absent. Thyroid scintigraphy with sodium 99m Tc pertechnetate showed a small ectopic thyroid located in sublingual position, so treatment with L-thyroxine 37.5 microg/24 hr was started with rapid improvement of the clinical picture. At 17 months of age the patient developed the complete characteristic phenotype of Williams syndrome (WS); the clinical diagnosis was proven by fluorescent in situ hybridization (FISH) analysis which showed hemizygous deletion of the elastin gene on chromosome 7. Recently a case of thyroid hemiagenesis in a child with WS has been reported; our patient underscores the association of hypothyroidism and WS. Moreover, our case shows that clinical manifestations of hypothyroidism may be present and the treatment may be necessary as it is in isolated congenital hypothyroidism.", "BACKGROUND: Nephrotic syndrome is defined as urine total protein excretion greater than 3.5 g/d or total protein-creatinine ratio greater than 3.5 g/g, low serum albumin level, high serum cholesterol level, and peripheral edema. These threshold levels have not been rigorously evaluated in patients with diabetic kidney disease or by using urine albumin excretion, the preferred measure of proteinuria in patients with diabetes.STUDY DESIGN: Diagnostic test study.SETTING & PARTICIPANTS: Adults with type 2 diabetes, hypertension, and urine total protein level greater than 0.9 g/d enrolled in the Irbesartan in Diabetic Nephropathy Trial.INDEX TEST: Baseline measures of proteinuria (total protein and albumin excretion and protein-creatinine and albumin-creatinine ratios). Linear regression to relate measures.REFERENCE TEST: Other signs and symptoms of nephrotic syndrome at baseline (serum albumin < 3.5 g/dL, serum total cholesterol > 260 mg/dL or use of a statin, and edema or use of a loop diuretic); progression of chronic kidney disease during follow-up (doubling of baseline serum creatinine level or requirement for dialysis or kidney transplantation). Logistic regression to relate index and reference tests.RESULTS: In 1,608 participants, total urine protein level of 3.5 g/d was equivalent to urine albumin level of 2.2 g/d (95% confidence interval, 1.4 to 3.5). Of 1,467 participants, 641 (44%) had urine total protein level of 3.5 g/d or greater at baseline, 132 (9%) had other signs and symptoms of nephrotic syndrome at baseline, and 385 (26%) had progression of kidney disease during a mean follow-up of 2.6 years. Areas under the receiver operating curves for measures of proteinuria were 0.80 to 0.83 for other signs and symptoms of nephrotic syndrome and 0.72 to 0.74 for kidney disease progression. Threshold levels for nephrotic-range proteinuria and albuminuria were close to the points of maximal accuracy for both outcomes.LIMITATIONS: Study population limits generalizability; inability to adjust for several variables known to affect serum albumin levels; lack of spot urine samples.CONCLUSIONS: The historical definition of nephrotic-range proteinuria appears reasonable in patients with diabetic kidney disease. Equivalent thresholds for nephrotic-range albuminuria and albumin-creatinine ratio are 2.2 g/d and 2.2 g/g, respectively.", "The origin recognition complex (ORC) of Saccharomyces cerevisiae binds origin DNA and cooperates with Cdc6 and Cdt1 to load the replicative helicase MCM2-7 onto DNA. Helicase loading involves two MCM2-7 hexamers that assemble into a double hexamer around double-stranded DNA. This reaction requires ORC and Cdc6 ATPase activity, but it is unknown how these proteins control MCM2-7 double hexamer formation. We demonstrate that mutations in Cdc6 sensor-2 and Walker A motifs, which are predicted to affect ATP binding, influence the ORC-Cdc6 interaction and MCM2-7 recruitment. In contrast, a Cdc6 sensor-1 mutant affects MCM2-7 loading and Cdt1 release, similar as a Cdc6 Walker B ATPase mutant. Moreover, we show that Orc1 ATP hydrolysis is not involved in helicase loading or in releasing ORC from loaded MCM2-7. To determine whether Cdc6 regulates MCM2-7 double hexamer formation, we analysed complex assembly. We discovered that inhibition of Cdc6 ATPase restricts MCM2-7 association with origin DNA to a single hexamer, while active Cdc6 ATPase promotes recruitment of two MCM2-7 hexamer to origin DNA. Our findings illustrate how conserved Cdc6 AAA+ motifs modulate MCM2-7 recruitment, show that ATPase activity is required for MCM2-7 hexamer dimerization and demonstrate that MCM2-7 hexamers are recruited to origins in a consecutive process." ]

[ "PURPOSE: A common late effect of doxorubicin therapy for childhood cancer is reduced left-ventricular (LV) wall thickness resulting in elevated LV afterload and depressed LV function. Many children are given angiotensin-converting enzyme inhibitors, which have been studied primarily in adults. We document the long-term effects of angiotensin-converting enzyme inhibitors in doxorubicin-treated survivors of childhood cancer.PATIENTS AND METHODS: In this retrospective study, we reviewed records of 18 children who had regular echocardiographic examinations during enalapril therapy (mean age at cancer diagnosis, 8 years; mean time between completion of doxorubicin therapy and start of enalapril, 7 years; median follow-up since the start of enalapril, 10 years).RESULTS: Over the first 6 years of enalapril therapy, there was progressive improvement toward normal values in LV dimension, afterload, fractional shortening, and mass, but all these parameters deteriorated between 6 and 10 years. LV wall thickness deteriorated throughout the study period, as did LV contractility and systolic blood pressure. Diastolic blood pressure fell slightly. By 6 years on enalapril, all six patients who had had congestive heart failure at the start of enalapril therapy had either died or undergone cardiac transplantation, compared with three of the 12 asymptomatic patients.CONCLUSION: In doxorubicin-treated long-term survivors of childhood cancer, enalapril-induced improvement in LV structure and function is transient. The primary defect, which is LV wall thinning, continues to deteriorate, and thus the short-term improvement was mostly related to lowered diastolic blood pressure.", "Species-specific sets of chromosomes-karyotypes-are traditionally depicted as linear ideograms with individual chromosomes represented by vertical bars. However, linear visualization has its limitations when the shared collinearity and/or chromosomal rearrangements differentiating two or more karyotypes need to be demonstrated. In these instances, circular visualization might provide easier comprehension and interpretation of inter-species chromosomal collinearity. The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.", "The metabolic syndrome is a complex association of several risk factors including insulin resistance, dyslipidemia, and essential hypertension. Insulin resistance has been associated with sympathetic activation and endothelial dysfunction, which are the main mechanisms involved in the pathophysiology of hypertension and its related cardiovascular risk. According to the Sixth Report of the Joint National Committee, and guidelines of the World Health Organization/International Society of Hypertension, the presence of multiple risk markers suggests that both hypertension and risk factors should be aggressively managed in order to obtain a better outcome. Primary prevention of obesity at different levels--individual, familial, and social-- starting early in childhood has proven to be cost effective, and will be mandatory to reduce the world epidemic of obesity and its severe consequences.", "Acute ischemic stroke (AIS) is a significant cause of death and disability in the United States. It has been 10 years since tissue plasminogen activator became the first medication approved by the US Food and Drug Administration for treatment for AIS. However, this treatment simply reopens arteries. The identification of deleterious cellular reactions that occur secondary to cerebral ischemia has led investigators to search for neuroprotection strategies to complement reperfusion. More than 100 human trials, including a handful of phase III trials, had failed to produce an efficacious neuroprotective agent. In 2006, the first positive trial of neuroprotection was published: the SAINT I (Stroke-Acute Ischemic NXY Treatment) study. In February 2008, the SAINT II study was published, indicating that NXY-059 was not effective for AIS treatment.", "INTRODUCTION: Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents; ipilimumab, a humanized, IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and vemurafenib , a BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene.AREAS COVERED: The authors reviewed preclinical and clinical data examining the safety of vemurafenib in melanoma. MEDLINE and EMBASE were searched using the medical subject heading 'vemurafenib' and the following text terms: melanoma, BRAF inhibition, vemurafenib. This review provides the reader with an overview of current data examining the efficacy and safety of vemurafenib in metastatic melanoma.EXPERT OPINION: Vemurafenib is an oral agent licensed for patients with BRAF V600E mutation-positive inoperable and metastatic melanoma. The most common adverse effects observed in Phase III clinical trials were dermatological events, arthralgia and fatigue. Specific dermatological toxicities included development of cutaneous squamous cell cancers and keratoacanthomas. Prolongation of the QT interval was also reported. Regular dermatological assessments and electrocardiograms are recommended. Ongoing trials are examining vemurafenib in both the adjuvant setting and metastatic setting in combination with ipilimumab and MEK inhibitors (mitogen-activated protein kinase/extracellular signal-regulated kinase). Understanding and overcoming mechanisms of resistance to BRAF inhibitors is the focus of ongoing research.", "The clinical symptoms associated with chromosome 15q duplication syndrome manifest through a heterogeneous group of symptoms characterised by hypotonia, delay in motor skills and language development, cognitive and learning disabilities, autism spectrum disorder and refractory epilepsy. The late development of Lennox-Gastaut syndrome in patients with 15q11q13 duplication is a possibility that physicians should be aware of. We report the case of a 27-year-old man with a neurodevelopmental syndrome due to a 15q duplication, with intellectual disability, psychiatric disturbances, and an epileptic phenotype diagnosed as late-onset Lennox-Gastaut syndrome.", "BACKGROUND: Runt-related transcription factor 1 (RUNX1T1) isoforms are involved in adipogenesis. RUNX1T1 is mediated by the fat mass and obesity-associated (FTO). However, the extent to which RUNX1T1 single-nucleotide polymorphisms (SNPs) are associated with obesity risk or metabolic abnormalities in a community population basis is unknown.METHODS: Samples were obtained from the Australian Crossroads study bio-bank. SNPs located in the coding region and 3'untranslated regions of RUNX1T1 with minor allele frequency ≥0.05 were analysed using Taqman genotyping assays.RESULTS: Eight candidate SNPs were genotyped successfully in 1440 participants. Of these SNPs only rs34269950 located in the 'RRACH' motif, the most common N6-methyladenosine (m6A) methylation modification site (recognized by FTO), was significantly associated with obesity risk and metabolic abnormalities. Specifically, compared to AA genotype, rs34269950 del/del genotype was associated with a 1.47 [95% confidence interval (CI): 1.01-2.14, P = 0.042] fold higher rate of obesity risk. Additionally, the del/del genotype was associated with a 60% increased risk of metabolic syndrome (MetS) [odds ratio (OR) = 1.60, 95% CI: 1.10-2.32, P = 0.015], in comparison to the AA genotype. Finally, rs34269950 del/del increased the risk of a larger waist circumference (OR = 1.65, 95% CI: 1.15-2.36, P = 0.007), but not other components of MetS.CONCLUSION: Our study demonstrates that RUNX1T1 rs34269950, located in a potential FTO recognition motif, is significantly associated with waist circumference. This provides novel evidence to suggest SNPs located in RRACH motif may be involved in RNA m6A modification and mechanistic pathways that influence abdominal obesity." ]

[ "BACKGROUND: Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants.METHODS: In this phase 1, multicenter, double-blind, parallel-group trial, healthy adults (age 18-50 years) were randomized 1:1 to placebo or ubrogepant. Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary outcome measures were safety and tolerability.RESULTS: Of participants randomized (n = 518), 516 were included in the safety population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse events were reported in 45% of placebo and 44% of ubrogepant participants. The most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the upper limit of normal (five placebo, two ubrogepant) were reported and adjudicated by a panel of independent liver experts blinded to treatment. Four cases were judged unlikely related to treatment. Two cases (one placebo, one ubrogepant) were judged possibly related, and one (ubrogepant) probably related. Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two ubrogepant cases (possibly or probably related) were transient and resolved with continued dosing; both cases were asymptomatic, with no concurrent bilirubin elevation.CONCLUSION: Ubrogepant was well tolerated following intermittent, high-frequency dosing in healthy participants, with no clinically relevant signal of hepatotoxicity.TRIAL REGISTRATION: NA.", "N6-methyladenosine (m6A) modification plays a critical role in mammalian development. However, the role of m6A in the skeletal muscle development remains largely unknown. Here, we report a global m6A modification pattern of goat skeletal muscle at two key development stages and identified that the m6A modification regulated the expression of the growth arrest and DNA damage-inducible 45B (GADD45B) gene, which is involved in myogenic differentiation. We showed that GADD45B expression increased during myoblast differentiation, whereas the downregulation of GADD45B inhibits myogenic differentiation and mitochondrial biogenesis. Moreover, the expression of GADD45B regulates the expression of myogenic regulatory factors and peroxisome proliferator-activated receptor gamma coactivator 1 alpha by activating the p38 mitogen-activated protein kinase (MAPK) pathway. Conversely, the inactivation of p38 MAPK abolished the GADD45B-mediated myogenic differentiation. Furthermore, we found that the knockdown of fat mass and obesity-associated protein (FTO) increases GADD45B m6A modification and decreases the stability of GADD45B mRNA, which impairs myogenic differentiation. Our results indicate that the FTO-mediated m6A modification in GADD45B mRNA drives skeletal muscle differentiation by activating the p38 MAPK pathway, which provides a molecular mechanism for the regulation of myogenesis via RNA methylation.", "Targeted therapies are widely used in cancer because of their effectiveness, even in tumours that are resistant to conventional chemotherapy such as kidney or hepatocellular carcinomas. There are different families classified according to their mode of action. The antiangiogenics block tumor angiogenesis by acting on VEGF or its receptor. The main molecules are bevacizumab, sunitinib, and sorafinib. HER inhibitors work by blocking these receptors, which control different signaling intracellular pathways, and include an inhibitor of HER2, trastuzumab, and various inhibitors of HER1, or EGFR, including cetuximab, erlotinib, and gefitinib. Inhibitors of KIT, a membrane receptor, are mainly represented by imatinib, an inhibitor of tyrosine kinase. Finally, mTOR inhibitors act on the signaling pathway PI3K/AKT/mTOR, and key molecules are temsirolimus, everolimus, and deforolimus.", "Super-enhancers (SEs) are clusters of transcriptional enhancers which control the expression of cell identity and disease-associated genes. Current studies demonstrated the role of multiple factors in SE formation; however, a systematic analysis to assess the relative predictive importance of chromatin and sequence features of SEs and their constituents is lacking. In addition, a predictive model that integrates various types of data to predict SEs has not been established. Here, we integrated diverse types of genomic and epigenomic datasets to identify key signatures of SEs and investigated their predictive importance. Through integrative modeling, we found Cdk8, Cdk9, and Smad3 as new features of SEs, which can define known and new SEs in mouse embryonic stem cells and pro-B cells. We compared six state-of-the-art machine learning models to predict SEs and showed that non-parametric ensemble models performed better as compared to parametric. We validated these models using cross-validation and also independent datasets in four human cell-types. Taken together, our systematic analysis and ranking of features can be used as a platform to define and understand the biology of SEs in other cell-types.", "Neuroacanthocytosis syndromes are mainly comprised of two diseases: chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). There is a high incidence of psychiatric disorders such as mood disorder and schizophrenia among neuroacanthocytosis patients. We hypothesized that neuroacanthocytosis-related-genes might be associated with susceptibility to these psychiatric disorders. We performed a comprehensive mutation screen of VPS13A and XK, the gene responsible for ChAc and MLS, respectively, in 85 mood disorder subjects and XK in 86 schizophrenia subjects and compared the variants to 100 or more control alleles. We also performed copy number variation (CNV) analysis in 72 mood disorder subjects and 86 schizophrenia subjects. We identified three non-synonymous, two synonymous and six intron variants in mood disorder subjects and a novel GAT triplet repeat polymorphism in VPS13A. By CNV analysis, we identified a heterozygous exon 60-61 deletion in VPS13A in one mood disorder subject. We identified one non-synonymous and one intron variant in mood disorder and schizophrenia subjects, respectively, in XK. The presence of a pathogenic mutation or a potentially functional variant in mood disorder or schizophrenia subjects suggests that neuroacanthocytosis-related-genes might be involved in the pathogenesis of these psychiatric disorders.", "Oral amitriptyline has been used as an analgesic in a wide range of pain settings. Despite long-term availability of a parenteral form, the few reports about this formulation have been limited to pharmacokinetic studies in normal volunteers, trials in depressed patients, and analyses of electroencephalogram (EEG) activation. We retrospectively reviewed our experience using intravenous (IV) amitriptyline at Children's Hospital, Boston and at Children's Hospital at Stanford. Eight children (aged 5-16.6 years), who were unable to tolerate medications by the oral route, received IV amitriptyline for a variety of indications, including neuropathic pain, depression, sleep disturbance, and as an adjuvant agent for opioid analgesia. One patient experienced an extrapyramidal reaction temporally related to the administration of IV amitriptyline, which was successfully managed with diphenhydramine. Further prospective, controlled studies are needed to further assess the safety, efficacy and tolerability of this novel use of amitriptyline.", "Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system. Since TRH crosses the blood-brain barrier poorly, if at all, we postulated that the negative parenteral clinical trials could be a result of insufficient drug-receptor interaction. We thus carried out a blinded, placebo-controlled, crossover study of intrathecal TRH in 36 patients by delivery through an implanted, constant infusion pump achieving a steady-state CSF level comparable with that shown to be effective in tissue culture experiments. Utilizing a quantitative measurement technique to assess motor unit loss, we did not observe any alteration of the progressive course during 6 months on TRH and 6 months on saline placebo. However, the implanted pump delivery system proved to be safe, reliable, and well tolerated." ]

[ "BACKGROUND: Analyzing the amino acid sequence of an intrinsically disordered protein (IDP) in an evolutionary context can yield novel insights on the functional role of disordered regions and sequence element(s). However, in the case of many IDPs, the lack of evolutionary conservation of the primary sequence can hamper the study of functionality, because the conservation of their disorder profile and ensuing function(s) may not appear in a traditional analysis of the evolutionary history of the protein.RESULTS: Here we present DisCons (Disorder Conservation), a novel pipelined tool that combines the quantification of sequence- and disorder conservation to classify disordered residue positions. According to this scheme, the most interesting categories (for functional purposes) are constrained disordered residues and flexible disordered residues. The former residues show conservation of both the sequence and the property of disorder and are associated mainly with specific binding functionalities (e.g., short, linear motifs, SLiMs), whereas the latter class correspond to segments where disorder as a feature is important for function as opposed to the identity of the underlying sequence (e.g., entropic chains and linkers). DisCons therefore helps with elucidating the function(s) arising from the disordered state by analyzing individual proteins as well as large-scale proteomics datasets.CONCLUSIONS: DisCons is an openly accessible sequence analysis tool that identifies and highlights structurally disordered segments of proteins where the conformational flexibility is conserved across homologs, and therefore potentially functional. The tool is freely available both as a web application and as stand-alone source code hosted at http://pedb.vib.be/discons .", "Hypothalamic neurosecretory systems are fundamental regulatory circuits influenced by thyroid hormone. Monocarboxylate-transporter-8 (MCT8)-mediated uptake of thyroid hormone followed by type 3 deiodinase (D3)-catalyzed inactivation represent limiting regulatory factors of neuronal T3 availability. In the present study we addressed the localization and subcellular distribution of D3 and MCT8 in neurosecretory neurons and addressed D3 function in their axons. Intense D3-immunoreactivity was observed in axon varicosities in the external zone of the rat median eminence and the neurohaemal zone of the human infundibulum containing axon terminals of hypophysiotropic parvocellular neurons. Immuno-electronmicroscopy localized D3 to dense-core vesicles in hypophysiotropic axon varicosities. N-STORM-superresolution-microscopy detected the active center containing C-terminus of D3 at the outer surface of these organelles. Double-labeling immunofluorescent confocal microscopy revealed that D3 is present in the majority of GnRH, CRH and GHRH axons but only in a minority of TRH axons, while absent from somatostatin-containing neurons. Bimolecular-Fluorescence-Complementation identified D3 homodimers, a prerequisite for D3 activity, in processes of GT1-7 cells. Furthermore, T3-inducible D3 catalytic activity was detected in the rat median eminence. Triple-labeling immunofluorescence and immuno-electronmicroscopy revealed the presence of MCT8 on the surface of the vast majority of all types of hypophysiotropic terminals. The presence of MCT8 was also demonstrated on the axon terminals in the neurohaemal zone of the human infundibulum. The unexpected role of hypophysiotropic axons in fine-tuned regulation of T3 availability in these cells via MCT8-mediated transport and D3-catalyzed inactivation may represent a novel regulatory core mechanism for metabolism, growth, stress and reproduction in rodents and humans.", "After a young woman had scarlet fever associated with group C beta-hemolytic streptococcal pharyngitis, we reviewed all cases of pharyngitis treated at a student health clinic during that semester. From 541 cases of pharyngitis, 34 cultures yielded group C Streptococcus. The patients who harbored group C organisms were similar to the patients with group A streptococcal pharyngitis in the presence of fever, exudate, and cervical adenopathy. The severity of symptoms and the demonstration of scarlet fever developing from infection with this organism supports antibiotic treatment of patients with group C streptococcal pharyngitis.", "Nonpropulsive esophageal contractions radiologically described as tertiary contractions or \"corkscrew\" esophagus suggest the presence of an underlying motility disorder and may lead to impaired acid clearance. The goals of this study were to determine the prevalence and role of gastroesophageal reflux (GER) in patients with tertiary contractions. Thirty-five consecutive patients with spontaneous, repetitive, nonpropulsive esophageal contractions noted on esophagography were studied with endoscopy, infusion esophageal manometry, and 24-h ambulatory pH monitoring. All patients had esophageal symptoms, mainly dysphagia, heartburn, and chest pain, but only three were found to have esophagitis by endoscopy and biopsy. Nineteen patients had repetitive, nonlumen-obliterating, nonperistaltic (tertiary) contractions, six had corkscrew esophagus, and 10 had forceful, lumen-obliterating simultaneous contractions (rosary bead esophagus). Twenty patients (58%) had GER by pH criteria with mean values: % time pH less than 4, 40.9; %upright pH less than 4, 41; %supine pH less than 4, 44.3%; number of episodes with greater than 5 min of pH less than 4, 12. Esophageal motility revealed \"nutcracker\" esophagus in eight, low LESP in two, and nonspecific esophageal motility disorder in 10. Symptoms or severity of nonperistaltic contractions did not correlate with GER. Radiologically demonstrable free reflux or the presence of heartburn did not predict GER. We conclude that 1) GER occurs in up to 58% of patients with nonpropulsive (tertiary) esophageal contractions on esophagography, and may play a role in the induction of abnormal peristaltic activity of the esophageal body; 2) GER is usually not associated with endoscopic evidence of esophagitis or characteristic symptoms, and is recognized by 24-h pH monitoring. We speculate that detection and treatment of GER may improve the symptomatic management of patients with nonpropulsive esophageal contractions.", "Objective:To evaluate the value of improved Mallampati grading combined with NoSAS questionnaire in screening for obstructive sleep apnea （OSA）. Method:A total of 344 patients admitted to our hospital for sleep disorders were studied. All patients were measured for their height, weight, neck circumference and other parameters. NoSAS scores, improved Mallampati grading and polysomnography （PSG） were performed in these patients. According to AHI in PSG monitoring results, patients were divided into non-osa group （AHI<5） 93 cases and OSA group 251 cases. The OSA group were divided into mild （AHI 5-15）, moderate（AHI 16-30） and severe OSA group（AHI>30） according to the PSG result. The ROC curve was plotted to evaluate the screening value of NoSAS and improved Mallampati grading combined with NoSAS for OSA. Result:With the NoSAS score of 8 or 9 as cutoffs for analysis, the sensitivity for OSA was 0.733 and 0.701; the specificity for OSA was 0.538 and 0.624, respectively. The sensitivity and specificity of NoSAS combined with improved Mallampati grading for screening OSA were 0.813 and 0.710, respectively. Conclusion:As a new screening tool, NoSAS questionnaire is simple and convenient, and has certain screening value to OSA. The improved Mallampati grading combined with NoSAS questionnaire can obviously improve the screening sensitivity and specificity of Osa, and has higher application value.", "BACKGROUND: Mechanical ventilation can induce or aggravate lung injury, which is termed ventilator-induced lung injury (VILI). Piezo1 is a key element of the mechanotransduction process and can transduce mechanical signals into biological signals by mediating Ca2+ influx, which in turn regulates cytoskeletal remodeling and stress alterations. We hypothesized that it plays an important role in the occurrence of VILI, and investigated the underlying mechanisms.METHODS: High tidal volume mechanical ventilation and high magnitude cyclic stretch were performed on Sprague-Dawley rats, and A549 and human pulmonary microvascular endothelial cells, respectively, to establish VILI models. Immunohistochemical staining, flow cytometry, histological examination, enzyme-linked immunosorbent assay, western blotting, quantitative real-time polymerase chain reaction and survival curves were used to assess the effect of Piezo1 on induction of lung injury, as well as the signaling pathways involved.RESULTS: We observed that Piezo1 expression increased in the lungs after high tidal volume mechanical ventilation and in cyclic stretch-treated cells. Mechanistically, we observed the enhanced expression of RhoA/ROCK1 in both cyclic stretch and Yoda1-treated cells, while the deficiency or inhibition of Piezo1 dramatically antagonized RhoA/ROCK1 expression. Furthermore, blockade of RhoA/ROCK1 signaling using an inhibitor did not affect Piezo1 expression. GSMTx4 was used to inhibit Piezo1, which alleviated VILI-induced pathologic changes, water content and protein leakage in the lungs, and the induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats.CONCLUSIONS: These findings indicate that Piezo1 affects the development and progression of VILI through promotion of RhoA/ROCK1 signaling.", "Plasmodium, the causative agent of malaria, has to undergo sexual differentiation and development in anopheline mosquitoes for transmission to occur. To isolate genes specifically induced in both organisms during the early stages of Plasmodium differentiation in the mosquito, two cDNA libraries were constructed, one enriched for sequences expressed in differentiating Plasmodium berghei ookinetes and another enriched for sequences expressed in Anopheles stephensi guts containing invading ookinetes and early oocysts. Sequencing of 457 ookinete library clones and 652 early oocyst clones represented 175 and 346 unique expressed sequence tags, respectively. Nine of 13 Plasmodium and four of the five Anopheles novel expressed sequence tags analyzed on Northern blots were induced during ookinete differentiation and mosquito gut invasion. Ancaspase-7, an Anopheles effector caspase, is proteolytically activated during Plasmodium invasion of the midgut. WARP, a gene encoding a Plasmodium surface protein with a von Willebrand factor A-like adhesive domain, is expressed only in ookinetes and early oocysts. An anti-WARP polyclonal antibody strongly inhibits (70-92%) Plasmodium development in the mosquito, making it a candidate antigen for transmission blocking vaccines. The present results and those of an accompanying report (Srinivasan, P., Abraham, E. G., Ghosh, A. K., Valenzuela, J., Ribeiro, J. M. C., Dimopoulos G., Kafatos, F. C., Adams, J. H., and Jacobs-Lorena, M. (2004) J. Biol. Chem. 279, 5581-5587) provide the foundation for further analysis of Plasmodium differentiation in the mosquito and of mosquito responses to the parasite.", "BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. A Phase 3 withdrawal/re-treatment study (NCT01186744; OPT Retreatment) showed tofacitinib re-treatment was effective in patients with chronic plaque psoriasis.OBJECTIVES: To describe the effects of tofacitinib withdrawal/re-treatment on health-related quality of life (HRQoL) and disease symptoms measured by patient-reported outcomes (PROs).METHODS: The study was divided into initial treatment, treatment withdrawal, and re-treatment periods. Initial treatment: patients were randomized to receive tofacitinib 5 (n = 331) or 10 mg (n = 335) BID for 24 weeks. Treatment withdrawal: patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI) score from baseline and Physician's Global Assessment of 'clear'/'almost clear' at Week (W)24 received placebo (withdrawal) or the previous dose (continuous treatment). Re-treatment: at relapse (> 50% loss of W24 PASI response) or at W40, patients received their initial tofacitinib dose. PROs included: Dermatology Life Quality Index (DLQI), Itch Severity Item (ISI), Short Form-36 (SF-36) and Patient's Global Assessment (PtGA).RESULTS: After initial treatment with tofacitinib 5 and 10 mg BID, substantial and significant improvements were reported for mean DLQI (baseline: 12.6 and 12.6; W24: 5.1 and 2.6) and ISI (baseline: 6.7 and 6.9; W24: 2.9 and 1.6). Patients continuously treated with tofacitinib 5 and 10 mg BID maintained those improvements through Week 56 (DLQI: 3.0 and 2.1; ISI: 2.3 and 1.4). By W40, patients withdrawn from tofacitinib 5 and 10 mg BID showed worsening in DLQI (5.0 and 6.2) and ISI (3.7 and 4.0) scores; improvements were regained upon re-treatment (W56, DLQI: 3.4 and 2.4; ISI: 2.2 and 1.6). Similar results were reported for PtGA and SF-36.CONCLUSION: Continuous tofacitinib treatment provided sustained improvement in HRQoL and disease symptoms. Patients randomized to treatment withdrawal lost initial improvements. Upon re-treatment, improvements were recaptured to levels comparable to those seen with continuous treatment.", "BACKGROUND: To explore the role of the mechanosensitive ion channel Piezo1 in the proliferation and osteogenic differentiation of human dental follicle cells (hDFCs), and its mechanism, so as to provide the basis for the use of hDFCs to achieve bone regeneration.METHODS: hDFCs were obtained from fresh dental follicle tissues by enzymatic digestion, and cell phenotype and multipotential differentiation were identified. Identification of the expression of mechanosensitive ion channel Piezo1 was performed by immunofluorescence and immunohistochemistry. CCK-8 was used to determine the optimal concentration of the Piezo1 agonist, Yoda1. Then, according to the obtained results, Alizarin red staining, RT-PCR quantitative analysis and Western blot were used to further observe the osteogenic differentiation of hDFCs and its probable mechanism via Wnt/β-catenin signalling. The data were analysed by SPSS 22.0 software.RESULTS: The results of the concentration gradient experiments indicated that 0.5 µM Piezo1 agonist (Yoda1) enhanced the proliferation of hDFCs. Compared with the control group, a considerable number of calcium nodules showed that activating Piezo1 could promote the osteogenic differentiation of hDFCs. The relative mRNA and protein expression of Piezo1, ALP, RUNX2, OCN and BMP2 in the Piezo1 agonist group were higher than that of the control group. Furthermore, the expression of Wnt3a and β-catenin related to the classical osteogenic pathway were significantly up-regulated in the Piezo1 agonist group.CONCLUSION: Activating mechanosensitive ion channel Piezo1 with an appropriate concentration of Yoda1 has a positive effect on the proliferation and osteogenic differentiation of hDFCs. This mechanism of promoting osteogenic differentiation may be mediated by the Wnt/β-catenin pathway.", "1. ", "DISEASE OVERVIEW: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of one-two cases per 100,000 adults and accounts for ∼15% of newly diagnosed cases of leukemia in adults.DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein.FRONTLINE THERAPY: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for the first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined.SALVAGE THERAPY: For patients who fail standard-dose imatinib therapy, imatinib dose escalation is a second-line option. Alternative second-line options include 2nd generation TKIs. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. Patients who develop the T315I \"gatekeeper\" mutation display resistance to all currently available TKIs and are candidate for clinical trials. Allogeneic transplantation remains an important therapeutic option for CML-CP harboring the T315I mutation, patients who fail 2nd generation TKIs, and for all patients in advanced phase disease.", "BACKGROUND: Bundled care payments are increasingly being explored for neurosurgical interventions. In this setting, skilled nursing facility (SNF) is less desirable from a cost perspective than discharge to home, underscoring the need for better preoperative prediction of postoperative disposition.OBJECTIVE: To assess the capability of the Risk Assessment and Prediction Tool (RAPT) and other preoperative variables to determine expected disposition prior to surgery in a heterogeneous neurosurgical cohort, through observational study.METHODS: Patients aged 50 yr or more undergoing elective neurosurgery were enrolled from June 2016 to February 2017 (n = 623). Logistic regression was used to identify preoperative characteristics predictive of discharge disposition. Results from multivariate analysis were used to create novel grading scales for the prediction of discharge disposition that were subsequently compared to the RAPT Score using Receiver Operating Characteristic analysis.RESULTS: Higher RAPT Score significantly predicted home disposition (P < .001). Age 65 and greater, dichotomized RAPT walk score, and spinal surgery below L2 were independent predictors of SNF discharge in multivariate analysis. A grading scale utilizing these variables had superior discriminatory power between SNF and home/rehab discharge when compared with RAPT score alone (P = .004).CONCLUSION: Our analysis identified age, lower lumbar/lumbosacral surgery, and RAPT walk score as independent predictors of discharge to SNF, and demonstrated superior predictive power compared with the total RAPT Score when combined in a novel grading scale. These tools may identify patients who may benefit from expedited discharge to subacute care facilities and decrease inpatient hospital resource utilization following surgery.", "Accumulation of amyloid-β peptide (Aβ) in the brain is closely associated with cognitive decline in Alzheimer's disease (AD). Stereotaxic infusion of neprilysin-encoding viral vectors into the hippocampus has been shown to decrease Aβ in AD-model mice, but more efficient and global delivery is necessary to treat the broadly distributed burden in AD. Here we developed an adeno-associated virus (AAV) vector capable of providing neuronal gene expression throughout the brains after peripheral administration. A single intracardiac administration of the vector carrying neprilysin gene in AD-model mice elevated neprilysin activity broadly in the brain, and reduced Aβ oligomers, with concurrent alleviation of abnormal learning and memory function and improvement of amyloid burden. The exogenous neprilysin was localized mainly in endosomes, thereby effectively excluding Aβ oligomers from the brain. AAV vector-mediated gene transfer may provide a therapeutic strategy for neurodegenerative diseases, where global transduction of a therapeutic gene into the brain is necessary.", "OBJECTIVE: To examine the headache characteristics of women with migraine and endometriosis (EM), and differences in the prevalence of comorbid conditions between female migraineurs with EM, without EM and nonheadache controls.BACKGROUND: Migraine and EM are common conditions in women of reproductive age, and both are influenced by ovarian hormones. The comorbidity of migraine and EM is newly recognized, but reasons for the association are uncertain.METHODS: This is a cross-sectional study of female headache outpatients and healthy controls conducted at University of Toledo and Duke University in 2005 and 2006. After a headache specialist determined headache frequency and diagnosis (based on criteria of the second International Classification of Headache Disorders), patients completed a self-administered electronic survey with information on demographics, headache-related disability, menstrual disorders, premenstrual dysphoric disorder (PMDD), vascular event risk, and comorbid conditions, including irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), interstitial cystitis (IC), depression, and anxiety.RESULTS: Study enrolled 171 women with migraine and 104 controls. EM was reported more commonly in migraineurs than in controls (22% vs 9.6%, P < .01). Frequency of chronic headache was higher in migraineurs with EM compared to without EM (P= .002) and median headache-related disability scores were also higher in the EM group (P= .025). Symptoms of PMDD were more common in migraineurs, but frequency did not differ by EM status. Migraineurs with EM reported more menorrhagia, dysmenorrhea, and infertility compared to the migraine cohort without EM and to controls. Depression, anxiety, IBS, FM, CFS, and IC were more common in migraine with EM group than in controls. Anxiety (OR = 2.2, 95% CI 1.0-4.7), IC (OR = 10.6, 95% CI 1.9-56.5), and CFS (OR = 3.6, 95% CI 1.1-11.5) were more common in migraine with EM group, than in the cohort with migraine without EM.CONCLUSION: Prevalence of EM is higher in women with migraine than in nonheadache controls. Migraineurs with EM have more frequent and disabling headaches, and are more likely to have other comorbid conditions affecting mood and pain, compared to migraineurs without EM.", "Mechanosensitive channels are integral membrane proteins that sense mechanical stimuli. Like most plasma membrane ion channel proteins they must pass through biosynthetic quality control in the endoplasmic reticulum that results in them reaching their destination at the plasma membrane. Here we show that N-linked glycosylation of two highly conserved asparagine residues in the 'cap' region of mechanosensitive Piezo1 channels are necessary for the mature protein to reach the plasma membrane. Both mutation of these asparagines (N2294Q/N2331Q) and treatment with an enzyme that hydrolyses N-linked oligosaccharides (PNGaseF) eliminates the fully glycosylated mature Piezo1 protein. The N-glycans in the cap are a pre-requisite for N-glycosylation in the 'propeller' regions, which are present in loops that are essential for mechanotransduction. Importantly, trafficking-defective Piezo1 variants linked to generalized lymphatic dysplasia and bicuspid aortic valve display reduced fully N-glycosylated Piezo1 protein. Thus the N-linked glycosylation status in vitro correlates with efficient membrane trafficking and will aid in determining the functional impact of Piezo1 variants of unknown significance.", "A clinically relevant sleep-wake disturbance is found in up to half the patients with dementia, and the sundowning agitation is a common cause of institutionalisation of demented geriatric patients. The circadian rhythm of demented patients is levelled off with increased daytime sleep and disrupted night sleep. Particularly in vascular dementia, Korsakow syndrome, Parkinson's disease, and depression the alteration of sleep architecture may be pronounced, whereas in Alzheimer's disease prominent hypersomnolence or insomnia is typically only found in later stages of the diseases. Greatly increased daytime sleepiness or striking insomnia at the very beginning of suspected dementia should thus prompt the search for other, possibly treatable causes of dementia. Neuropathological and neurophysiological studies support the hypothesis of a deteriorated hypothalamic suprachiasmatic nucleus (harbouring the biological clock) as a cause for the deranged circadian sleep-wake system in dementia. Management of sundowning behaviour includes restriction of daytime sleep, exposure to bright lights, and social interaction schedules during the day. The benzodiazepines and analogues usually not being sufficiently effectual, low doses of mild neuroleptics are often needed. Whether recent reports on efficacy of melatonin in elderly insomniacs also apply to demented patients is yet uncertain. The careful search and treatment of possible extracerebral physiologic factors causing reversible hypersomnia or insomnia is an important requisite. Polysomnographic studies are needed to recognise treatable sleep disturbance which could deteriorate or mimic dementia and sundowning. Particularly, a sleep-apnea-hypopnea syndrome must be searched for at the beginning of a suspected dementia, when successful treatment is still possible. Sleep studies should also identify periodic leg movements of sleep with restless legs and/or increased daytime sleepiness, and hyperkinetic parasomnias such as REM sleep behaviour disorder which may complicate or imitate sundowning." ]

[ "BACKGROUND: Runt-related transcription factor 1 (RUNX1T1) isoforms are involved in adipogenesis. RUNX1T1 is mediated by the fat mass and obesity-associated (FTO). However, the extent to which RUNX1T1 single-nucleotide polymorphisms (SNPs) are associated with obesity risk or metabolic abnormalities in a community population basis is unknown.METHODS: Samples were obtained from the Australian Crossroads study bio-bank. SNPs located in the coding region and 3'untranslated regions of RUNX1T1 with minor allele frequency ≥0.05 were analysed using Taqman genotyping assays.RESULTS: Eight candidate SNPs were genotyped successfully in 1440 participants. Of these SNPs only rs34269950 located in the 'RRACH' motif, the most common N6-methyladenosine (m6A) methylation modification site (recognized by FTO), was significantly associated with obesity risk and metabolic abnormalities. Specifically, compared to AA genotype, rs34269950 del/del genotype was associated with a 1.47 [95% confidence interval (CI): 1.01-2.14, P = 0.042] fold higher rate of obesity risk. Additionally, the del/del genotype was associated with a 60% increased risk of metabolic syndrome (MetS) [odds ratio (OR) = 1.60, 95% CI: 1.10-2.32, P = 0.015], in comparison to the AA genotype. Finally, rs34269950 del/del increased the risk of a larger waist circumference (OR = 1.65, 95% CI: 1.15-2.36, P = 0.007), but not other components of MetS.CONCLUSION: Our study demonstrates that RUNX1T1 rs34269950, located in a potential FTO recognition motif, is significantly associated with waist circumference. This provides novel evidence to suggest SNPs located in RRACH motif may be involved in RNA m6A modification and mechanistic pathways that influence abdominal obesity.", "Cattle botulism is a fatal intoxication caused by botulinum neurotoxins (BoNTs) produced by Clostridium botulinum serotypes C and D resulting in economic losses. Vaccination is the most effective way to control botulism. However, the commercially available vaccines are difficult and hazardous to produce. Neutralizing antibodies against the C-terminal fragment of the BoNT heavy chain (HC) are known to protect against lethal doses of BoNTs. We report the vaccination of cattle with a previously tested recombinant chimera consisting of Escherichia coli heat-labile enterotoxin B subunit and the HC of BoNTs C and D. Vaccinated animals produced neutralizing antibodies against serotypes C and D averaging 5±0 and 6.14±1.06IU/mL, respectively. For BoNT D, the titers were greater than those measured for the commercial vaccine, which induced titers of 5±0 and 2.85±1.35 against the respective serotypes, suggesting that this chimera is effective against cattle botulism.", "Pathological conditions, including ischemia and heart failure, are associated with altered sodium channel function and increased late sodium current (I(Na,L)), leading to prolonged action potential duration, increased intracellular sodium and calcium concentrations, and arrhythmias. We used anemone toxin (ATX)-II to study the effects of increasing I(Na,L) on intracellular calcium cycling in rat isolated hearts. Cardiac contraction was abolished using paralytic agents. Ranolazine (RAN) was used to inhibit late I(Na). Hearts were loaded with fluo-4-acetoxymethyl ester, and myocyte intracellular calcium transients (CaTs) were measured using laser scanning confocal microscopy. ATX (1 nM) prolonged CaT duration at 50% recovery in hearts paced at a basal rate of 2 Hz and increased the sensitivity of the heart to the development of calcium alternans caused by fast pacing. ATX increased the time required for recovery of CaT amplitude following a previous beat, and ATX induced spontaneous calcium release waves during rapid pacing of the heart. ATX prolonged the duration of repolarization from the initiation of the activation to terminal repolarization in the pseudo-electrocardiogram. All actions of ATX were both reversed and prevented by subsequent or prior exposure, respectively, of hearts to RAN (10 microM). Most importantly, the increased vulnerability of the heart to the development of calcium alternans during rapid pacing was reversed or prevented by 10 microM RAN. These results suggest that enhancement of I(Na,L) alters calcium cycling. Reduction by RAN of I(Na,L)-induced dysregulation of calcium cycling could contribute to the antiarrhythmic actions of this agent in both reentrant and triggered arrhythmias.", "Gfi-1 and Gfi-1b are novel proto-oncogenes identified by retroviral insertional mutagenesis. By gene targeting, we establish that Gfi-1b is required for the development of two related blood lineages, erythroid and megakaryocytic, in mice. Gfi-1b(-/-) embryonic stem cells fail to contribute to red cells of adult chimeras. Gfi-1b(-/-) embryos exhibit delayed maturation of primitive erythrocytes and subsequently die with failure to produce definitive enucleated erythrocytes. The fetal liver of mutant mice contains erythroid and megakaryocytic precursors arrested in their development. Myelopoiesis is normal. Therefore, Gfi-1b is an essential transcriptional regulator of erythroid and megakaryocyte development.", "Circulating tumor cells (CTCs) served as an important biomarker for tumor recurrence and prediction of prognosis. However, selective capture and quantification of CTCs from whole blood was still full of challenge due to the extremely scare number of CTCs. Moreover, how to keep a high cell viability after capture remained to be solved. Here, we described a ratiometric fluorescent probe for the efficient capture and accurate determination of CTCs by conjugating graphitic carbon nitride quantum dots (g-CNQDs) with gold nanoclusters (AuNCs) and further linking with anti-EpCAM antibody to acquire the CTC-specific immune probe. In this probe, AuNCs protected by albumin V bovine played the role as the fluorophore reference and anti-EpCAM-attached g-CNQDs acted as both the response signal and specific recognition element for sensing CTCs. In the presence of CTCs, the quenched fluorescence of the immune probe at 500 nm was recovered due to the detachment of anti-EpCAM from the probe, whereas the intensity at 650 nm was essentially unchanged. This strategy realized the highly sensitive detection of CTCs in whole blood down to one CTC. Furthermore, it was demonstrated that the designed probe allowed capturing living CTCs with minimal cell damage. The subsequent reculture of captured cells for proliferation revealed that after a 7 day proliferation, almost 28 MCF-7 cells were obtained from one target cell. The immune probe was successfully applied into capture and detection of CTCs from clinical cancer patients. Our data suggested the good potential of fluorescent probe for the clinical diagnosis of cancers.", "Unmethylated CpG rich islands are a feature of vertebrate DNA: they are associated with housekeeping and many tissue specific genes. CpG islands on the active X chromosome of mammals are also unmethylated. However, islands on the inactive X chromosome are heavily methylated. We have identified a CpG island in the 5' region of the G6PD gene, and two islands forty Kb 3' from the G6PD gene, on the human X chromosome. Expression of the G6PD gene is associated with concordant demethylation of all three CpG islands. We have shown that one of the two islands is in the promoter region of a housekeeping gene, GdX. In this paper we show that the second CpG island is also associated with a gene, P3. The P3 gene has no homology to previously described genes. It is a single copy, 4 kb gene, conserved in evolution, and it has the features of a housekeeping two genes is within the CpG island and that sequences in the islands have promoter function.", "OBJECTIVE: To assess the predictive value of the metabolic syndrome in patients with type 1 diabetes.RESEARCH DESIGN AND METHODS: Patients were from the prospective Finnish Diabetic Nephropathy (FinnDiane) Study (n = 3,783): mean age 37 +/- 12 years and diabetes duration 23 +/- 12 years. Metabolic syndrome was defined according to World Health Organization (WHO), National Cholesterol Education Program (NCEP), and International Diabetes Federation (IDF) definitions. Follow-up time was median 5.5 years (interquartile range 3.7-6.7). Mortality data were complete, whereas morbidity data were available in 69% of the patients.RESULTS: The WHO definition was associated with a 2.1-fold increased risk of cardiovascular events and a 2.5-fold increased risk of cardiovascular- and diabetes-related mortality, after adjustment for traditional risk factors and diabetic nephropathy. The NCEP definition did not predict outcomes when adjusted for nephropathy but markedly added to the risk associated with elevated albuminuria alone (P < 0.001). The IDF definition did not predict outcomes.CONCLUSIONS: The metabolic syndrome is a risk factor, beyond albuminuria, for cardiovascular morbidity and diabetes-related mortality in type 1 diabetes." ]

[ "BACKGROUND: Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for whose treatment stiripentol (STP) has been recently licensed for add-on use.OBJECTIVES: To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) as therapy for patients with SMEI.SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (15 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4 of 12, The Cochrane Library, April 2013), MEDLINE (1946 to May 2013) and SCOPUS (1823 to May 2013). The online trials registries ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were systematically searched. The bibliographies of any identified study were searched for further references. We handsearched selected journals and conference proceedings. No language restrictions were imposed.SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single-blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment.DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. The following outcomes were assessed: at least 50% seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. Outcomes were assessed using a Mantel-Haenszel meta-analysis to calculate risk ratio (RR) with 95% confidence intervals (95% CIs).MAIN RESULTS: No RCTs assessing drugs other than STP were found. Two RCTs evaluating the use of STP (total of 64 children) were included. Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 vs 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 vs 1/31; RR 7.93, 95% CI 1.52 to 41.21). No significant difference in the proportion of dropouts was found in the STP group compared with the placebo group (2/33 vs 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects; higher proportions of participants were reported to experience side effects in the STP group compared with the placebo group (100% vs 25%; RR 3.73, 95% CI 1.81 to 7.67).AUTHORS' CONCLUSIONS: Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Further adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of SMEI.", "Author information:(1)Systems Biology Group, Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: martin.kuiper@ntnu.no.(2)Faculty of Information & Communication Technology, University of Malta, Msida, Malta.(3)Departamento de Informática y Sistemas, Universidad de Murcia, IMIB-Arrixaca, CP 30100, Murcia, Spain.(4)Swiss Institute of Bioinformatics, Quartier Sorge, Bâtiment Amphipôle, 1015 Lausanne, Switzerland.(5)Systems Biology and Bioinformatics Laboratory (SysBioLab), Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal.(6)SIB Swiss Institute of Bioinformatics, 1 Rue Michel-Servet, 1204 Geneva, Switzerland.(7)Institute of Protein Research, Russian Academy of Sciences, 142290, Institutskaya 4, Pushchino, Russia.(8)Department of Biology, University of Rome Tor Vergata, Rome, Italy.(9)Department of Molecular Biology, Faculty of Science, Radboud University, PO box 9101, Nijmegen 6500HG, the Netherlands.(10)Functional Gene Annotation, Pre-clinical and Fundamental Science, Institute of Cardiovascular Science, University College London, 5 University Street, London WC1E 6JF, UK.(11)Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, Gubkina 3, Moscow, Russia.(12)European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.(13)Department DIBEST, University of Calabria, Rende, Italy.(14)Fondazione Human Technopole, Department of Biology, Via Cristina Belgioioso, 171, 20157 Milan, Italy.(15)Department of Biomedical Informatics, University of Utah, 421 Wakara Way #140, Salt Lake City, UT 84108, United States.(16)Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Auenbruggerpl. 2, Graz, Austria.(17)Systems Biology Group, Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway.(18)European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.(19)Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.", "Histamine-N-methyltransferase (HMT) inactivates the neurotransmitter histamine. Central histaminergic deficits may contribute to the cognitive impairment of neurodegenerative disorders including Alzheimer's disease (AD) and Down syndrome (DS). However, there is no evidence for histaminergic deficits in Pick's disease (PiD). HMT levels were measured in the frontal cortex and cerebellum of brains of patients with AD, DS, and PiD, and normal aged subjects using proteomics techniques. In frontal cortex, HMT was significantly decreased in DS, but significantly increased in PiD compared with controls. HMT levels were comparable in cerebellum of all groups. Elevated HMT in PiD could lead to increased histamine degradation that in turn would be in agreement with impaired cognitive functions of PiD. Decreased HMT in DS would be compatible with findings of decreased histamine synthesis, thus reflecting a compensation mechanism to antagonize reduced synthesis by decreased degradation.", "Previous studies have shown that the DNA repair component Metnase (SETMAR) mediates resistance to DNA damaging cancer chemotherapy. Metnase has a nuclease domain that shares homology with the Transposase family. We therefore virtually screened the tertiary Metnase structure against the 550,000 compound ChemDiv library to identify small molecules that might dock in the active site of the transposase nuclease domain of Metnase. We identified eight compounds as possible Metnase inhibitors. Interestingly, among these candidate inhibitors were quinolone antibiotics and HIV integrase inhibitors, which share common structural features. Previous reports have described possible activity of quinolones as antineoplastic agents. Therefore, we chose the quinolone ciprofloxacin for further study, based on its wide clinical availability and low toxicity. We found that ciprofloxacin inhibits the ability of Metnase to cleave DNA and inhibits Metnase-dependent DNA repair. Ciprofloxacin on its own did not induce DNA damage, but it did reduce repair of chemotherapy-induced DNA damage. Ciprofloxacin increased the sensitivity of cancer cell lines and a xenograft tumor model to clinically relevant chemotherapy. These studies provide a mechanism for the previously postulated antineoplastic activity of quinolones, and suggest that ciprofloxacin might be a simple yet effective adjunct to cancer chemotherapy.", "Finerenone is a novel selective nonsteroidal mineralocorticoid receptor antagonist. Results in preclinical studies showed that lower doses of finerenone were needed to achieve similar cardiorenal protective effects compared to both spironolactone and eplerenone and phase II studies in finerenone in patients with heart failure, type-2 diabetes mellitus and/or chronic kidney disease are encouraging as the drug is effective and safe in patients on renin-angiotensin system inhibitors (significant reduction in albuminuria and a low rate of hyperkalemia), but the primary end points were \"soft\" end points (serum potassium, estimated glomerular filtration rate, albuminuria, N-terminal prohormone B-type natriuretic peptide levels). Thus, further, large-scale, long-term phase III trials are needed to confirm whether the greater affinity and selectivity is translated into improved clinical outcomes.", "Disease-modifying antirheumatic drugs (DMARDs) have become essential treatments in the management of patients with inflammatory rheumatic diseases. Their use has resulted in a marked improvement of disease control and a limitation of joint damage, although some patients still require subsequent corrective or joint replacement surgery. Due to their immunosuppressive effects, some DMARDs are associated with an increased risk of infection. The aim of this review is to discuss the available literature on the management of DMARDs during the perioperative period, particularly in the case of orthopaedic surgery. Conventional synthetic DMARDs such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine appear to be safe during the perioperative period. Conflicting results on biological DMARDs, mainly tumour necrosis factor antagonists, are reported in the literature, including both increased and unchanged risk of superimposed infections after surgery. Taking into account the available literature, we included some propositions for the management of patients who will undergo surgical interventions.", "Maintaining proper cell-cell adhesion in the intestine is essential for tissue homeostasis and barrier function. This adhesion is thought to be mediated by cell adhesion structures, including tight junctions, adherens junctions, and desmosomes, which concentrate in the apical junctional region. While clear roles for adherens and tight junctions have been established in simple epithelia, the function of desmosomes has not been addressed. In stratified epithelia, desmosomes impart mechanical strength to tissues by organizing and anchoring the keratin filament network. In this paper, we report that the desmosomal protein desmoplakin (DP) is not essential for cell adhesion in the intestinal epithelium. Surprisingly, when DP is lacking, keratin filament localization is also unperturbed, although keratin filaments no longer anchor at desmosomes. Unexpectedly, DP is important for proper microvillus structure. Our study highlights the tissue-specific functions of desmosomes and reveals that the canonical functions for these structures are not conserved in simple epithelium." ]

[ "INTRODUCTION: The heterogeneity of symptoms and complex etiology of depression pose a significant challenge to the personalization of treatment. Meanwhile, the current application of generic treatment approaches to patients with vastly differing biological and clinical profiles is far from optimal. Here, we conduct a meta-review to identify predictors of response to antidepressant therapy in order to select robust input features for machine learning models of treatment response. These machine learning models will allow us to learn associations between patient features and treatment response which have predictive value at the individual patient level; this learning can be optimized by selecting high-quality input features for the model. While current research is difficult to directly apply to the clinic, machine learning models built using knowledge gleaned from current research may become useful clinical tools.METHODS: The EMBASE and MEDLINE/PubMed online databases were searched from January 1996 to August 2017, using a combination of MeSH terms and keywords to identify relevant literature reviews. We identified a total of 1909 articles, wherein 199 articles met our inclusion criteria.RESULTS: An array of genetic, immune, endocrine, neuroimaging, sociodemographic, and symptom-based predictors of treatment response were extracted, varying widely in clinical utility.LIMITATIONS: Due to heterogeneous sample sizes, effect sizes, publication biases, and methodological disparities across reviews, we could not accurately assess the strength and directionality of every predictor.CONCLUSION: Notwithstanding our cautious interpretation of the results, we have identified a multitude of predictors that can be used to formulate a priori hypotheses regarding the input features for a computational model. We highlight the importance of large-scale research initiatives and clinically accessible biomarkers, as well as the need for replication studies of current findings. In addition, we provide recommendations for future improvement and standardization of research efforts in this field.", "Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with currently approved indications for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder and chronic headache. Paroxetine, a phenylpiperidine derivative, is the most potent inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT) of all the currently available antidepressants including the class of SSRIs. It is a very weak inhibitor of norepinephrine (NE) uptake but it is still more potent at this site than the other SSRIs. The selectivity of paroxetine, i.e., the ratio of inhibition of uptake of norepinephrine to serotonin (NE/5-HT) is amongst the highest of the SSRIs. Paroxetine has little affinity for catecholaminergic, dopaminergic or histaminergic systems and by comparison with tricyclic antidepressants (TCAs) has, therefore, a reduced propensity to cause central and autonomic side effects. Paroxetine exhibits some affinity for the muscarinic cholinergic receptor but much less than the TCAs. In addition, the adaptive changes of somatodendritic (5-HT(1A)) and terminal (5-HT(1B/1D)) autoreceptors observed with paroxetine are different to those observed with TCAs; it also inhibits nitric oxide synthase. It is both a substrate and an inhibitor of cytochrome isoenzyme P450 2D6. Paroxetine is well absorbed orally and undergoes extensive first pass metabolism that is partially saturable. Its metabolites are pharmacologically inactive in vivo. Steady state levels are achieved after 4-14 days and an elimination half-life of 21 h is consistent with once-daily dosing. There is wide inter-individual variation in the pharmacokinetics of paroxetine in adults as well as in the young and the elderly with higher plasma concentrations and slower elimination noted in the latter. Elimination is also reduced in severe renal and hepatic impairment. Serious adverse events are, however, extremely rare even in overdose. In summary, paroxetine is well tolerated and effective in the treatment of both depressive and anxiety disorders across the age range.", "Pancreatic cancer is the deadliest malignancy of the digestive system and is the seventh most common cause of cancer-related deaths worldwide. The incidence and mortality of pancreatic cancer continue to increase, and its 5-year survival rate remains the lowest among all cancers. N6-methyladenine (m6A) is the most abundant reversible RNA modification in various eukaryotic messenger and long noncoding RNAs and plays crucial roles in the occurrence and development of cancers. However, the role of m6A in pancreatic cancer remains unclear. The present study aimed to explore the role of m6A and its regulators in pancreatic cancer and assess its underlying molecular mechanism associated with pancreatic cancer cell proliferation, invasion, and metastasis. Reduced expression of the m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. Altogether, this study describes new, potential molecular therapeutic targets for pancreatic cancer that could pave the way to improve patient outcome.", "OBJECTIVE: This study aims to investigate the potentially protective effect of neuroglobin (Ngb) gene-modified bone marrow mesenchymal stem cells (BMSCs) on traumatic spinal cord injury (SCI) in rabbits.METHODS: A lentiviral vector containing an Ngb gene was constructed and used to deliver Ngb to BMSCs. Ngb gene-modified BMSCs were then injected at the SCI sites 24 hours after SCI. The motor functions of the rabbits were evaluated by the Basso-Beattie-Bresnahan rating scale. Fluorescence microscopy, quantitative real-time PCRs, Western blots, malondialdehyde (MDA) tests, and terminal deoxynucleotidyltransferase-mediated UTP end labeling assays were also performed.RESULTS: Ngb expression in the Ngb-BMSC group increased significantly. A more significant functional improvement was observed in the Ngb-BMSC group compared with those in the other groups. Traumatic SCI seemingly led to an increase in MDA level and number of apoptotic cells, which can be prevented by Ngb-BMSC treatment.CONCLUSION: This study demonstrates that Ngb gene-modified BMSCs can strengthen the therapeutic benefits of BMSCs in reducing secondary damage and improving the neurological outcome after traumatic SCI. Therefore, the combined strategy of BMSC transplantation and Ngb gene therapy can be used to treat traumatic SCI.", "BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. In this study, we evaluated the long-term efficacy, safety, and tolerability of monthly and quarterly fremanezumab.METHODS: Episodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg). Changes from baseline in monthly migraine days, monthly headache days of at least moderate severity, days of acute headache medication use, days with photophobia/phonophobia, days with nausea or vomiting, disability scores, and proportion of patients achieving a ≥50% or  ≥75% reduction in monthly migraine days were evaluated.RESULTS: Of the 807 patients who completed the 12-week double-blind treatment period and entered the open-label extension, 772 patients completed the study. In the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, patients had fewer average monthly migraine days (mean [standard deviation] change from baseline: - 4.7 [5.4]; - 5.1 [4.7]; - 5.5 [5.0]), monthly headache days of at least moderate severity (- 4.5 [5.0]; - 4.8 [4.5]; - 5.2 [4.9]), days per month of acute headache medication use (- 4.3 [5.2]; - 4.9 [4.6]; - 4.8 [4.9]), days with photophobia/phonophobia (- 3.1 [5.3]; - 3.4 [5.3]; - 4.0 [5.2]), and days with nausea or vomiting (- 2.3 [4.6]; - 3.1 [4.5]; - 3.0 [4.4]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days. Disability scores were substantially improved in all 3 treatment groups. There were low rates of adverse events leading to discontinuation (<1%).CONCLUSION: Fremanezumab demonstrated sustained efficacy up to 6 months and was well tolerated in patients with episodic migraine or chronic migraine and documented inadequate response to multiple migraine preventive medication classes.TRIAL REGISTRATION: ClinicalTrials.gov NCT03308968 (FOCUS).", "Developmental and Epileptic encephalopathies (DEE) describe heterogeneous epilepsy syndromes, characterized by early-onset, refractory seizures and developmental delay (DD). Several DEE associated genes have been reported. With increased access to whole exome sequencing (WES), new candidate genes are being identified although there are fewer large cohort papers describing the clinical phenotype in such patients. We describe 6 unreported individuals and provide updated information on an additional previously reported individual with heterozygous de novo missense variants in YWHAG. We describe a syndromal phenotype, report 5 novel, and a recurrent p.Arg132Cys YWHAG variant and compare developmental trajectory and treatment strategies in this cohort. We provide further evidence of causality in YWHAG variants. WES was performed in five patients via Deciphering Developmental Disorders Study and the remaining two were identified via Genematcher and AnnEX databases. De novo variants identified from exome data were validated using Sanger sequencing. Seven out of seven patients in the cohort have de novo, heterozygous missense variants in YWHAG including 2/7 patients with a recurrent c.394C > T, p.Arg132Cys variant; 1/7 has a second, pathogenic variant in STAG1. Characteristic features included: early-onset seizures, predominantly generalized tonic-clonic and absence type (7/7) with good response to standard anti-epileptic medications; moderate DD; Intellectual Disability (ID) (5/7) and Autism Spectrum Disorder (3/7). De novo YWHAG missense variants cause EE, characterized by early-onset epilepsy, ID and DD, supporting the hypothesis that YWHAG loss-of-function causes a neurological phenotype. Although the exact mechanism of disease resulting from alterations in YWHAG is not fully known, it is possible that haploinsufficiency of YWHAG in developing cerebral cortex may lead to abnormal neuronal migration resulting in DEE.", "Naltrexone/Bupropion ER (Contrave): Newly Approved Treatment Option for Chronic Weight Management in Obese Adults." ]

[ "Pif1 family helicases are conserved from bacteria to humans. Here, we report a novel DNA patrolling activity which may underlie Pif1's diverse functions: a Pif1 monomer preferentially anchors itself to a 3'-tailed DNA junction and periodically reel in the 3' tail with a step size of one nucleotide, extruding a loop. This periodic patrolling activity is used to unfold an intramolecular G-quadruplex (G4) structure on every encounter, and is sufficient to unwind RNA-DNA heteroduplex but not duplex DNA. Instead of leaving after G4 unwinding, allowing it to refold, or going beyond to unwind duplex DNA, Pif1 repeatedly unwinds G4 DNA, keeping it unfolded. Pif1-induced unfolding of G4 occurs in three discrete steps, one strand at a time, and is powerful enough to overcome G4-stabilizing drugs. The periodic patrolling activity may keep Pif1 at its site of in vivo action in displacing telomerase, resolving R-loops, and keeping G4 unfolded during replication, recombination and repair.DOI: http://dx.doi.org/10.7554/eLife.02190.001.", "Molluscum contagiosum is a virus that causes characteristic pearly lesions on the surface of the skin. Small clusters of mollusca are a nuisance rather than a serious health problem. However, the mollusca can be more widespread and disfiguring in people with impaired cell-mediated immunity. Molluscum contagiosum virus is common in children. In adults it can also be contracted during sexual activity and might indicate a need for diagnostic testing for other, more serious sexually transmitted infections in young, sexually active adults.", "HbVar (http://globin.bx.psu.edu/hbvar) is a locus-specific database (LSDB) developed in 2001 by a multi-center academic effort to provide timely information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Database records include extensive phenotypic descriptions, biochemical and hematological effects, associated pathology, and ethnic occurrence, accompanied by mutation frequencies and references. In addition to the regular updates to entries, we report significant advances and updates, which can be useful not only for HbVar users but also for other LSDB development and curation in general. The query page provides more functionality but in a simpler, more user-friendly format and known single nucleotide polymorphisms in the human alpha- and beta-globin loci are provided automatically. Population-specific beta-thalassemia mutation frequencies for 31 population groups have been added and/or modified and the previously reported delta- and alpha-thalassemia mutation frequency data from 10 population groups have also been incorporated. In addition, an independent flat-file database, named XPRbase (http://www.goldenhelix.org/xprbase), has been developed and linked to the main HbVar web page to provide a succinct listing of 51 experimental protocols available for globin gene mutation screening. These updates significantly augment the database profile and quality of information provided, which should increase the already high impact of the HbVar database, while its combination with the UCSC powerful genome browser and the ITHANET web portal paves the way for drawing connections of clinical importance, that is from genome to function to phenotype.", "A novel point mutation in the ND6 subunit of complex I at position 14,459 of the mitochondrial DNA (MTND6*LDY T14459A) was identified as a candidate mutation for the highly tissue-specific disease. Leber's hereditary optic neuropathy plus dystonia. Since the MTND6*LDYT14459A mutation was identified in a single family, other pedigrees with the mutation are needed to confirm its association with the disease. Clinical, biochemical, and genetic characterization is reported in two additional pedigrees. Leber's hereditary optic neuropathy developed in two family members in one pedigree. The daughter had clinically silent basal ganglia lesions. In a second pedigree, a single individual presented with childhood-onset generalized dystonia and bilateral basal ganglia lesions. Patient groups that included individuals with Leigh's disease, dystonia plus complex neurodegeneration, and Leber's hereditary optic neuropathy did not harbor the MTND6*LDYT14459A mutation, suggesting that this mutation displays a high degree of tissue specificity, thus producing a narrow phenotypic range. These results confirm the association of the MTND6*LDYT14459A mutation with Leber's hereditary optic neuropathy and/or dystonia. As the first genetic abnormality that has been identified to cause generalized dystonia, this mutation suggests that nuclear DNA or mitochondrial DNA mutations in oxidative phosphorylation genes are important considerations in the pathogenesis of dystonia.", "Author information:(1)Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.(2)School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.(3)Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, UK.(4)National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Centre, Tokyo, Japan.(5)Moorfields Eye Hospital, London, UK.(6)UCL Institute of Ophthalmology, London, UK.(7)Keio University School of Medicine, Tokyo, Japan.(8)Ghent University, Ghent, Belgium.(9)Division of Genetic Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, Switzerland.(10)The Jikei University School of Medicine, Tokyo, Japan.(11)Mie University Graduate School of Medicine, Mie, Japan.(12)Department of Genetics, Faculty of Science, Hazara University Mansehra, Dhodial, Pakistan.(13)Clinical Research Center, Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.(14)School of Biomedical Sciences, University of Leeds, Leeds, UK.(15)Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.(16)St Thomas's Hospital, London, UK.(17)Department of Ophthalmology, Great Ormond Street Hospital, London, UK.(18)Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.(19)Department of Ophthalmology, University Hospital Basel, Basel, Switzerland.(20)Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.(21)Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.(22)Leeds Teaching Hospitals NHS Trust, St James' University Hospital, Leeds, UK.(23)School of Physics and Astronomy, University of Leeds, Leeds, UK.", "Hemolyitic uremic syndrome (HUS), characterized by triad of acute kidney injury, thrombocytopenia, and hemolytic anemia, has considerable morbidity and mortality and is known to be associated with diarrheal illness. It usually occurs after a diarrheal illness due to Shiga-toxin-producing Escherichia coli. Streptococcus pneumoniae is a rare but well recognized trigger for non-diarrhea associated HUS in children, but has not been reported in adults. We report a case of an adult presenting with pneumococcal pneumonia complicated by HUS and required renal replacement therapy.", "Oncogenic BRAF and NRAS mutations are frequent in malignant melanoma. BRAF that is activated by the common V600E and other mutations, as well as by upstream NRAS mutations, has been shown to require the molecular chaperone heat shock protein 90 (HSP90) for stabilization and is depleted by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)]. Here, we explore the possible relationship between tumor BRAF and NRAS mutations and clinical response to 17-AAG in six patients with metastatic malignant melanoma who received pharmacologically active doses of 17-AAG as part of a phase I clinical trial. One patient with disease stabilization for 49 months had a (G13D)NRAS mutation and (WT)BRAF. A second patient who had stable disease for 15 months had a (V600E)BRAF mutation and (WT)NRAS. These preliminary results suggest that BRAF and NRAS mutation status should be determined in prospective phase II studies of HSP90 inhibitors in melanoma." ]

[ "The association between recent atrial fibrillation during the course of acute myocardial infarction and pericarditis or pericardial effusion occurring during the hospital phase of myocardial infarction was studied by means of serial echocardiographic examinations in 192 patients presenting with their first myocardial infarction. Clinical pericarditis was found in 8%, echocardiographic effusion in 43%, and atrial fibrillation in 5% of all patients. Atrial fibrillation was present in only 2% of patients without pericardial effusion compared to 15% of patients with more than minimal effusion (p = 0.0094). Thus, pericarditis might play a role in the development of recent atrial fibrillation during the course of myocardial infarction. Recent atrial fibrillation may be a sign of pericardial effusion which may be otherwise silent.", "INTRODUCTION: Atrial fibrillation is a supraventricular tachyarrhythmia characterised by the presence of fast and uncoordinated atrial activation leading to reduced atrial mechanical function. Risk factors for atrial fibrillation include increasing age, male sex, co-existing cardiac and thyroid disease, pyrexial illness, electrolyte imbalance, cancer, and co-existing infection.METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral medical treatments to control heart rate in people with chronic (defined as longer than 1 week for this review) non-valvular atrial fibrillation? What is the effect of different treatment strategies (rate versus rhythm) for people with persistent non-valvular atrial fibrillation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).RESULTS: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta-blockers (with or without digoxin), calcium channel blockers (with or without digoxin), calcium channel blockers (rate-limiting), digoxin, and rate versus rhythm control strategies.", "Multiple myeloma is the second most common hematologic malignancy in the US. Treatments utilizing alkylating agents, corticosteroids, proteasome inhibitors, and immunomodulatory drugs have resulted in significant survival benefits, however, despite the advances, relapse is inevitable. Decreased depth and duration of response obtained with each successive relapse of disease is typical of the disease course, thereby highlighting a continuing need for new treatment options. With the introduction of monoclonal antibodies for multiple myeloma, new options for treatment in the relapsed setting are on the horizon. Among the new immunologic agents is daratumumab (DARA), a humanized antibody to CD38 with potent multifaceted antitumor activity. Phase I and II clinical trials have demonstrated significant reduction in serum M-protein and bone marrow plasma cell percentage in refractory patients, with an acceptable toxicity profile. Moreover, ex vivo studies have shown that DARA may be particularly useful in combination with currently used anti-myeloma agents. With a recent breakthrough drug designation by the US Food and Drug Administration, DARA shows promise as mono- and combination therapy for the treatment of relapsed/refractory multiple myeloma.", "Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma.", "Mutations in genes encoding cilia proteins cause human ciliopathies, diverse disorders affecting many tissues. Individual genes can be linked to ciliopathies with dramatically different phenotypes, suggesting that genetic modifiers may participate in their pathogenesis. The ciliary transition zone contains two protein complexes affected in the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP). The BBSome is a third protein complex, affected in the ciliopathy Bardet-Biedl syndrome (BBS). We tested whether mutations in MKS, NPHP and BBS complex genes modify the phenotypic consequences of one another in both C. elegans and mice. To this end, we identified TCTN-1, the C. elegans ortholog of vertebrate MKS complex components called Tectonics, as an evolutionarily conserved transition zone protein. Neither disruption of TCTN-1 alone or together with MKS complex components abrogated ciliary structure in C. elegans. In contrast, disruption of TCTN-1 together with either of two NPHP complex components, NPHP-1 or NPHP-4, compromised ciliary structure. Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did. As in nematodes, disrupting two components of the mouse MKS complex did not cause additive phenotypes compared to single mutants. However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1. Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.", "PURPOSE: Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp.PATIENTS AND METHODS: Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment.RESULTS: Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNγ pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival.CONCLUSIONS: These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.", "PURPOSE OF REVIEW: Uveal melanoma is a distinct subtype of melanoma characterized by a unique biology and divergent response to immune therapies. In this review, we will discuss our current understanding of the pathophysiology of uveal melanoma, systemic treatment options for advanced disease, and potential future therapeutic directions.RECENT FINDINGS: Although treatment with single-agent checkpoint blockade has been generally disappointing, the results of combined checkpoint blockade are modestly more promising. Several alternative systemic therapeutic approaches have been or are currently being investigated, including two agents that have been taken into registration-intent clinical trials: tebentafusp, a T cell redirecting agent, and IDE196, an oral protein kinase C inhibitor. Treatment of advanced uveal melanoma remains challenging, however, encouraging results from novel agents offer hope for improvement in the near future.", "HINTERGRUND: Ziel dieser Arbeit war die Evaluierung der 70-Gen-Prognose-Signatur MammaprintTM bei Patientinnen ≥ 60 Jahre mit einem invasiven Mammakarzinom.PATIENTEN UND METHODEN: 60 Patientinnen wurden für diese prospektive Studie rekrutiert. Einschlusskriterien waren: pT1c-3, pN0–1a, Grading 2/3, Hormonrezeptor-Positivität und HER2-negativer Tumor. Das klinische Risikoprofil wurde mit dem Programm Adjuvant! Online (AOL) eingeschätzt.ERGEBNISSE: 38 Frauen (63%) wurden durch die 70-Gen-Signatur als Niedrigrisiko-Patienten eingestuft; demgegenüber stehen 22 (37%) in der Hochrisiko-Gruppe. Beim Vergleich zwischen den Niedrigund Hochrisiko-Gruppen wurde kein statistisch signifikanter Unterschied für die konventionellen Prognoseparameter gefunden, insbesondere nicht für Ki-67. In der AOL-Analyse wurden 33 Patientinnen (55%) als Hochrisiko-Patienten eingestuft, von denen 20 ein diskordantes 70-Gen-Signaturergebnis hatten. Eine Diskordanz zwischen der 70-Gen-Signatur und dem AOL-Ergebnis wurde bei 48% der Patientinnen ermittelt. Diese Rate liegt höher als in früheren Publikationen. Die Kombination von klinisch-pathologischer Risikoeinstufung und Gensignatur führte bei 11 Patientinnen (18%) zu einer Änderung der adjuvanten systemischen Therapieempfehlung.SCHLUSSFOLGERUNGEN: Die 70-Gen-Signatur könnte bei älteren Frauen mit einem mittleren Risiko ein Zusatzkriterium für bzw. gegen eine adjuvante Chemotherapieempfehlung sein. Die konventionellen klinischpathologischen Parameter korrelierten nicht mit der 70-Gen-Signatur für diese Patientinnen.", "Objective Investigate influence and change of self-directedness (SD) in Dialectical-Behavior Therapy (DBT) for 26 female outpatients with borderline personality disorder (BPS). Method Variance analyses are used to evaluate psychopathology and interpersonal problems in 2 subgroups (low vs. high SD) with questionnaires at 3 measuring times over the period of 1 year. Results Low SD was associated with higher psychopathology, more interpersonal problems and lower symptomreduction. Over time of intervention the SD of all patients improved significantly. Conclusion DBT strengthens the SD of patients with BPD. A screening of SD before intervention, and systematic support should be considered.", "The coincidence of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome and cortical blindness is an uncommon but very dramatic event. We describe a case of HELLP syndrome complicating with acute cortical blindness before delivery. A 27 year-old woman, gravida 1, para 0, with normal medical history, was referred to our emergency department at the 33th week of gestation due to headache, vomiting, and blurred vision. The ophthalmologic examination showed intact pupillary light reflexes and normal ophthalmoscopic findings, but no light perception in either eye. Brain computed tomography showed normal findings. HELLP syndrome and preeclampsia was diagnosed based on the findings of hypertension and proteinuria as well as laboratory data. Prompt delivery was performed in order to achieve good maternal and neonatal outcomes.", "Author information:(1)From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.).", "Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UMs are usually initiated by a mutation in GNAQ or GNA11, unlike cutaneous melanomas, which usually harbour a BRAF or NRAS mutation. The annual incidence in Europe and the USA is ~6 per million population per year. Risk factors include fair skin, light-coloured eyes, congenital ocular melanocytosis, ocular melanocytoma and the BAP1-tumour predisposition syndrome. Ocular treatment aims at preserving the eye and useful vision and, if possible, preventing metastases. Enucleation has largely been superseded by various forms of radiotherapy, phototherapy and local tumour resection, often administered in combination. Ocular outcomes are best with small tumours not extending close to the optic disc and/or fovea. Almost 50% of patients develop metastatic disease, which usually involves the liver, and is usually fatal within 1 year. Although UM metastases are less responsive than cutaneous melanoma to chemotherapy or immune checkpoint inhibitors, encouraging results have been reported with partial hepatectomy for solitary metastases, with percutaneous hepatic perfusion with melphalan or with tebentafusp. Better insight into tumour immunology and metabolism may lead to new treatments.", "Procalcitonin (PCT) is useful for differentiating between viral and bacterial infections and for reducing the unnecessary use of antibiotics. As the rise of antimicrobial resistance reaches \"alarming\" levels according to the World Health Organization, the importance of using biomarkers, such as PCT to limit unnecessary antibiotic exposure has further increased. Randomized trials in patients with respiratory tract infections have shown that PCT has prognostic implications and its use, embedded in stewardship protocols, leads to reductions in the use of antibiotics in different clinical settings without compromising clinical outcomes. However, available data are heterogeneous and recent trials found no significant benefit. Still, from these trials, we have learned several key considerations for the optimal use of PCT, which depend on the clinical setting, severity of presentation, and pretest probability for bacterial infection. For patients with respiratory infections and sepsis, PCT can be used to determine whether to initiate antimicrobial therapy in low-risk settings and, together with clinical data, whether to discontinue antimicrobial therapy in certain high-risk settings. There is also increasing evidence regarding PCT-guided therapy in patients with coronavirus disease 2019 (COVID-19). This review provides an up-to-date overview of the use of PCT in different clinical settings and diseases, including a discussion about its potential to improve the care of patients with COVID-19.", "OBJECTIVE: Fetal echogenic bowel has been observed in fetuses with meconium peritonitis, cystic fibrosis, aneuploidy, congenital viral infection and intrauterine growth restriction. The pathogenesis of echogenic bowel is unknown, but it may be attributed to bowel ischemia. Fetuses affected by homozygous alpha-thalassemia-1 are severely anemic and hypoxic. We investigated the incidence of echogenic bowel in these hypoxic fetuses in the first and second trimesters.DESIGN: Prospective observational study.SUBJECTS: Women referred for the prenatal diagnosis of homozygous alpha-thalassemia-1 before 24 weeks' gestation.METHODS: All subjects had one or more abdominal and/or vaginal ultrasound examination between 12 and 24 weeks' gestation. Echogenic bowel was diagnosed if the bowel appeared either isoechogenic or more echogenic than the bone.RESULTS: Between March 1997 and July 1998, 126 pregnancies were studied. Thirty-six fetuses were confirmed to be affected by homozygous alpha-thalassemia-1, and 11 of them (31%, 95% CI 16-48%) had echogenic bowel. These observations were made before the invasive test results were available. None of the fetuses unaffected by homozygous alpha-thalassemia-1 had echogenic bowel.CONCLUSION: There is a strong association between homozygous alpha-thalassemia-1 and echogenic bowel. The pathogenesis is unknown. Speculations include bowel hypoperistalsis or bowel wall edema due to severe anemia and hypoxia.", "Muller's ratchet, the inevitable accumulation of deleterious mutations in asexual populations, has been proposed as a major factor in genome degradation of obligate symbiont organisms. Essentially, if left unchecked the ratchet will with certainty cause extinction due to the ever increasing mutational load. This paper examines the evolutionary fate of insect symbionts, using mathematical modelling to simulate the accumulation of deleterious mutations. We investigate the effects of a hierarchical two level population structure. Since each host contains its own subpopulation of symbionts, there will be a large number of small symbiont populations linked indirectly via selection on the host level. We show that although the separate subpopulations will accumulate deleterious mutations quickly, the symbiont population as a whole will be protected from extinction by selection acting on the hosts. As a consequence, the extent of genome degradation observed in present day symbionts is more likely to represent loss of functions that were (near-) neutral to the host, rather than a snap shot of a decline towards complete genetic collapse.", "Invadopodia are matrix-degrading membrane protrusions in invasive carcinoma cells. The mechanisms regulating invadopodium assembly and maturation are not understood. We have dissected the stages of invadopodium assembly and maturation and show that invadopodia use cortactin phosphorylation as a master switch during these processes. In particular, cortactin phosphorylation was found to regulate cofilin and Arp2/3 complex-dependent actin polymerization. Cortactin directly binds cofilin and inhibits its severing activity. Cortactin phosphorylation is required to release this inhibition so cofilin can sever actin filaments to create barbed ends at invadopodia to support Arp2/3-dependent actin polymerization. After barbed end formation, cortactin is dephosphorylated, which blocks cofilin severing activity thereby stabilizing invadopodia. These findings identify novel mechanisms for actin polymerization in the invadopodia of metastatic carcinoma cells and define four distinct stages of invadopodium assembly and maturation consisting of invadopodium precursor formation, actin polymerization, stabilization, and matrix degradation.", "The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The kallikrein family is also emerging as a rich source of disease biomarkers with KLK3, commonly known as prostate-specific antigen, being the current serum biomarker for prostate cancer. The kallikrein locus is also notable because it is extraordinarily responsive to steroids and other hormones. Indeed, at least 14 functional hormone response elements have been identified in the kallikrein locus. A more comprehensive understanding of the transcriptional regulation of kallikreins may help the field make more informed hypotheses about the physiological functions of kallikreins and their effectiveness as biomarkers. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. We also focus on the transcriptional regulation of kallikreins by androgens, progestins, glucocorticoids, mineralocorticoids, estrogens, and other hormones in animal models and human prostate, breast, and reproductive tract tissues. The interaction of the androgen receptor with androgen response elements in the promoter and enhancer of KLK2 and KLK3 is also summarized in detail. There is evidence that all kallikreins are regulated by multiple nuclear receptors. Yet, apart from KLK2 and KLK3, it is not clear whether all kallikreins are direct transcriptional targets. Therefore, we argue that gaining more detailed information about the mechanisms that regulate kallikrein expression should be a priority of future studies and that the kallikrein locus will continue to be an important model in the era of genome-wide analyses.", "Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 leads to LQTS in patients with Timothy syndrome. To explore the effect of the Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes, we reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated these cells into cardiomyocytes. Electrophysiological recording and calcium (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) signalling properties of cardiomyocytes from Timothy syndrome patients. This study provides new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases.", "BACKGROUND: ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes.METHODS AND RESULTS: This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg. Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer. In terms of pharmacokinetics, the concentration-time profile of ARC1779 appeared monophasic. The observed concentration and area under the curve were dose proportional. The mean apparent elimination half-life was approximately 2 hours, and mean residence time was approximately 3 hours. The mean apparent volumes of distribution (at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from approximately 10% to approximately 21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC(90) value of 2.0 mug/mL (151 nmol/L) and of platelet function with an EC(90) value of 2.6 mug/mL (196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related.CONCLUSIONS: This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose- and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.", "We have investigated a family in which three siblings with the autosomal dominant disorder tuberous sclerosis had unaffected parents. The family were typed for polymorphic markers spanning the two genes known to cause tuberous sclerosis located at 9q34 (TSC1) and 16p13.3 (TSC2). TSC1 markers showed different maternal and paternal haplotypes in affected children, excluding a mutation in TSC1 as the cause of the disease. For the TSC2 markers all the affected children had the same maternal and paternal haplotypes, as did three of their unaffected siblings. Mutation screening by RT-PCR and direct sequencing of the TSC2 gene identified a 4 bp insertion TACT following nucleotide 2077 in exon 18 which was present in the three affected children but not in five unaffected siblings or the parents. This mutation would cause a frameshift and premature termination at codon 703. Absence of the mutation in lymphocyte DNA from the parents was consistent with germline mosaicism and this was confirmed by our finding of identical chromosome 16 haplotypes in affected and unaffected siblings, providing unequivocal evidence of two different cell lines in the gametes. Molecular analysis of the TSC2 alleles present in the affected subjects showed that the mutation had been inherited from the mother. This is the first case of germline mosaicism in tuberous sclerosis proven by molecular genetic analysis and also the first example of female germline mosaicism for a characterized autosomal dominant gene mutation apparently not associated with somatic mosaicism.", "The aim of this study was to establish a national database of mutations in the fibrillin-1 (FBN1) gene that cause Marfan syndrome (MFS) in the Taiwanese population. In this study, we screened 294 patients from 157 families for the presence of FBN1 mutations using polymerase chain reaction/ denaturing high performance liquid chromatography (PCR/DHPLC). We identified 56 mutations in 62 of the 157 (40%) families including 49 single-base substitutions (36 missense mutations, seven nonsense mutations, and six splicing sites), one small insertion, four small deletions, one small indel (insertion and deletion), and one exonic deletion (Exon 36). When family history was taken into consideration, the mutation detection rate rose to 91% (29 of 32). We further investigated the phenotypic data and found that one third (47 of 157) of the families fit the Ghent criteria for MFS. Based on that data, the mutation rate was 98% (46/47). That finding implies that family history and the Ghent criteria play a more important role than clinical manifestations in establishing a clinical diagnosis of Marfan syndrome. Among the 56 mutations found in this study, 40 (71%) have not been registered in the Human Gene Mutation Database (HGMD) or in the Universal Mutation Database (UMD). This is the first study of the mutation spectrum of MFS in a cohort of patients in Taiwan. The database is expected to considerably improve genetic counseling for and medical care of MFS families.", "A bispecific fusion protein designed to redirect T cells toward a melanoma-associated antigen helped prolong survival among patients with an aggressive form of eye cancer. If approved, tebentafusp could become the standard of care for metastatic uveal melanoma-but only for those patients with a particular HLA allele.", "During early mammalian embryogenesis, one of the two X chromosomes in somatic cells of the female becomes inactivated through a process that is thought to depend on a unique initiator region, the X-chromosome inactivation center (Xic). The recently characterized Xist sequence (X-inactive-specific transcript) is thought to be a possible candidate for Xic. In mice a further genetic element, the X chromosome-controlling element (Xce), is also known to influence the choice of which of the two X chromosomes is inactivated. We report that a region of the mouse X chromosome lying 15 kb distal to Xist contains several sites that show hypermethylation specifically associated with the active X chromosome. Analysis of this region in various Xce strains has revealed a correlation between the strength of the Xce allele carried and the methylation status of this region. We propose that such a region could be involved in the initial stages of the inactivation process and in particular in the choice of which of the two X chromosomes present in a female cell will be inactivated.", "The objective of this review is to update the recommendations of the 2010 Italian Consensus on the use of methotrexate (MTX) in rheumatoid arthritis (RA) and other rheumatic diseases. The literature published between 2008 and 2012 was systematically reviewed and updated recommendations on MTX use in rheumatic diseases, particularly RA, were formulated. These recommendations were approved by a panel of expert Italian Rheumatologists. A total of 10,238 references were identified, among which 70 studies were selected for critical evaluation. Sufficient evidence had accumulated to warrant changes to several of the recommendations in the new version. A new recommendation for patients with RA who are in MTX-induced clinical remission was also proposed and approved by the panel. Updated recommendations for the use of MTX in patients with RA or other rheumatologic disease are proposed." ]

[ "Generalized hypertrichosis is a common side-effect of oral minoxidil treatment for hypertension. However, hypertrichosis is uncommon after treatment with topical minoxidil for alopecia, and normally only occurs in areas close to the site of application. A 16-year-old girl is presented who developed generalized hypertrichosis 3 months after applying topical minoxidil for treatment of diffuse alopecia in doses greater than that prescribed. Four months after discontinuing treatment, the abnormal hair gradually diminished and disappeared.", "The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. Previously, we reported a strong familial component of ESCC among Turkmens, who constitute approximately one-half of the population of this region. We hypothesized that the genes which cause Fanconi anemia might be candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del), one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three patients had a strong family history of ESCC. In addition, four patients (out of 746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none of 1,373 matched controls (OR = 16.7, 95% CI = 6.2-44.2, P = 0.01). The p. Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95% CI = 1.97-6.91, P = 0.0002). In summary, both heterozygous and homozygous mutations in several Fanconi anemia-predisposing genes are associated with an increased risk of ESCC in Iran.", "BACKGROUND: The role of microRNAs (miRNAs) in multiple myeloma (MM) has yet to be fully elucidated. To identify miRNAs that are potentially deregulated in MM, we investigated those mapping within transcription units, based on evidence that intronic miRNAs are frequently coexpressed with their host genes. To this end, we monitored host transcript expression values in a panel of 20 human MM cell lines (HMCLs) and focused on transcripts whose expression varied significantly across the dataset.METHODS: miRNA expression was quantified by Quantitative Real-Time PCR. Gene expression and genome profiling data were generated on Affymetrix oligonucleotide microarrays. Significant Analysis of Microarrays algorithm was used to investigate differentially expressed transcripts. Conventional statistics were used to test correlations for significance. Public libraries were queried to predict putative miRNA targets.RESULTS: We identified transcripts specific to six miRNA host genes (CCPG1, GULP1, EVL, TACSTD1, MEST, and TNIK) whose average changes in expression varied at least 2-fold from the mean of the examined dataset. We evaluated the expression levels of the corresponding intronic miRNAs and identified a significant correlation between the expression levels of MEST, EVL, and GULP1 and those of the corresponding miRNAs miR-335, miR-342-3p, and miR-561, respectively. Genome-wide profiling of the 20 HMCLs indicated that the increased expression of the three host genes and their corresponding intronic miRNAs was not correlated with local copy number variations. Notably, miRNAs and their host genes were overexpressed in a fraction of primary tumors with respect to normal plasma cells; however, this finding was not correlated with known molecular myeloma groups. The predicted putative miRNA targets and the transcriptional profiles associated with the primary tumors suggest that MEST/miR-335 and EVL/miR-342-3p may play a role in plasma cell homing and/or interactions with the bone marrow microenvironment.CONCLUSION: Our data support the idea that intronic miRNAs and their host genes are regulated dependently, and may contribute to the understanding of their biological roles in cancer. To our knowledge, this is the first evidence of deregulated miRNA expression in MM, providing insights that may lead to the identification of new biomarkers and altered molecular pathways of the disease.", "Mutation in either the TSC1 or TSC2 tumor suppressor gene is responsible for the inherited genetic disease of tuberous sclerosis complex. TSC1 and TSC2 form a physical and functional complex to regulate cell growth. Recently, it has been demonstrated that TSC1.TSC2 functions to inhibit ribosomal S6 kinase and negatively regulate cell size. TSC2 is negatively regulated by Akt phosphorylation. Here, we report that TSC2, but not TSC1, associates with 14-3-3 in vivo. Phosphorylation of Ser(1210) in TSC2 is required for its association with 14-3-3. Our data indicate that 14-3-3 association may inhibit the function of TSC2 and represents a possible mechanism of TSC2 regulation.", "FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional \"antagonist\" and \"agonist\" mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.", "Twist1, a basic helix-loop-helix transcription factor, promotes breast tumor cell epithelial-mesenchymal transition (EMT), invasiveness, and metastasis. However, the mechanisms responsible for regulating Twist1 stability are unknown in these cells. We identified the serine 68 (Ser 68) as a major phosphorylation site of Twist1 by mass spectrometry and with specific antibodies. This Ser 68 is phosphorylated by p38, c-Jun N-terminal kinases (JNK), and extracellular signal-regulated kinases1/2 in vitro, and its phosphorylation levels positively correlate with Twist1 protein levels in human embryonic kidney 293 and breast cancer cells. Prevention of Ser 68 phosphorylation by an alanine (A) mutation (Ser 68A) dramatically accelerates Twist1 ubiquitination and degradation. Furthermore, activation of mitogen-activated protein kinases (MAPK) by an active Ras protein or TGF-β treatment significantly increases Ser 68 phosphorylation and Twist1 protein levels without altering Twist1 mRNA expression, whereas blocking of MAPK activities by either specific inhibitors or dominant negative inhibitory mutants effectively reduces the levels of both induced and uninduced Ser 68 phosphorylation and Twist protein. Accordingly, the mammary epithelial cells expressing Twist1 exhibit much higher degrees of EMT and invasiveness on stimulation with TGF-β or the active Ras and paclitaxel resistance compared with the same cells expressing the Ser 68A-Twist1 mutant. Importantly, the levels of Ser 68 phosphorylation in the invasive human breast ductal carcinomas positively correlate with the levels of Twist1 protein and JNK activity and are significantly higher in progesterone receptor-negative and HER2-positive breast cancers. These findings suggest that activation of MAPKs by tyrosine kinase receptors and Ras signaling pathways may substantially promote breast tumor cell EMT and metastasis via phoshorylation and stabilization of Twist1.", "Pyrimidine-purine DNAs with repeating sequences can be made to undergo a reversible transition to possibly a tetra-stranded complex. Physicochemical characterization of the new structures and model building are consistent with, in the case of d(TC)n-d(GA)n, a tetra-stranded complex forming by the addition of d(GA)n to the remaining space in the major groove of the triple-stranded complex d(TC)n-d(GA)n-d(CT)n. A possible role for tetra-stranded complexes in chromosome condensation is suggested by the natural occurrence of repeating sequence pyrimidine-purine DNAs and the properties of condensed chromosomes." ]

[ "PURPOSE: Fibromyalgia is a syndrome of unknown origin with a high prevalence. Multimodal approaches seem to be the treatment of choice in fibromyalgia. A multidisciplinary program was developed and implemented for patients with fibromyalgia in the primary care setting. The program included education (seven sessions) and physical therapy (25 sessions).METHOD: Patients were referred to the program by their general practitioner or by a medical specialist. A prospective non-controlled treatment study was performed, patients were evaluated before, after and three months after the program (single group time series design). The following measurements were performed: The Fibromyalgia Impact Questionnaire, RAND 36, the Pain Coping and Cognition List, the Tampa scale for kinesiophobia, two physical tests and a qualitative evaluation. Data of 65 patients with fibromyalgia were analysed, of whom 97% were female. The mean age was 44 and the mean duration of pain was nine years.RESULTS: Data of 65 patients with fibromyalgia were analysed, patients significantly improved on the domains feeling good, pain, fatigue, stiffness, quality of life, catastrophizing and on the physical tests.CONCLUSION: The multidisciplinary program fibromyalgia implemented in primary care seems feasible and the results are promising.", "Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.", "SUMMARY: We present SPar-K (Signal Partitioning with K-means), a method to search for archetypical chromatin architectures by partitioning a set of genomic regions characterized by chromatin signal profiles around ChIP-seq peaks and other kinds of functional sites. This method efficiently deals with problems of data heterogeneity, limited misalignment of anchor points and unknown orientation of asymmetric patterns.AVAILABILITY AND IMPLEMENTATION: SPar-K is a C++ program available on GitHub https://github.com/romaingroux/SPar-K and Docker Hub https://hub.docker.com/r/rgroux/spar-k.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "The development of proteasome inhibitors (PIs) and immunomodulatory drugs has significantly improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM); however, not all patients benefit from treatment with these agents and some patients can become drug refractory over time. Due to the largely incurable nature of multiple myeloma, the development of newer agents is ongoing and includes new oral PIs (ixazomib), immunotherapies (e.g., CD38- or SLAMF7-targeted antibodies), and small molecules. This review provides an overview of the advances in targeted therapy for patients with RRMM, including recently approved agents, with a focus on monotherapy and combined targeted therapies.", "The 2016 Conference on Retroviruses and Opportunistic Infections (CROI) highlighted hot spots in HIV infection. Men who have sex with men (MSM), transgender populations, people who inject drugs, fisherfolk, migrants, adolescents, and older adults are heavily impacted in a number of regions. Stigma contributes to risk behaviors and HIV acquisition across populations. HIV testing is a crucial first step in the HIV care continuum, and several large community-based surveys are underway in Africa to increase HIV testing, linkage to care, and uptake of antiretroviral treatment. Advances in preexposure prophylaxis (PrEP) featured prominently at CROI 2016. Two large efficacy trials of a vaginal ring containing the investigational drug dapivirine demonstrated efficacy and safety in preventing HIV infections in women in Africa. Data on the safety of long-acting injectable PrEP and several investigational PrEP drugs and formulations were also presented. Knowledge and use of PrEP among MSM in the United States appears to be increasing, and high uptake was seen among black MSM when provided as part of a culturally tailored support program. The use of broadly neutralizing antibodies for HIV prevention is a novel and promising approach to be evaluated in efficacy trials.", "Predicting the solvent accessible surface area (ASA) of transmembrane (TM) residues is of great importance for experimental researchers to elucidate diverse physiological processes. TM residues fall into two major structural classes (α-helix membrane protein and β-barrel membrane protein). The reported solvent ASA prediction models were developed for these two types of TM residues respectively. However, this prevents the general use of these methods because one cannot determine which model is suitable for a given TM residue without information of its type. To conquer this limitation, we developed a new computational model that can be used for predicting the ASA of both TM α-helix and β-barrel residues. The model was developed from 78 α-helix membrane protein chains and 24 β-barrel membrane protein. Its prediction ability was evaluated by cross validation method and its prediction result on an independent test set of 20 membrane protein chains. The results show that our model performs well for both types of TM residues and outperforms other prediction model which was developed for the specific type of TM residues. The prediction results also proved that the random forest model incorporating conservation score is an effective sequence-based computational approach for predicting the solvent ASA of TM residues.", "BACKGROUND: Recent studies show an increased adipose production of tumor necrosis factor-alpha (TNF-alpha) in human obesity. It was hypothesized from this finding and other data, that TNF-alpha may be a mediator of obesity-linked insulin resistance.OBJECTIVE: The aim of this study was to measure plasma concentrations of the two soluble TNF-alpha receptors, together with those of TNF-alpha in subjects with severe obesity with and without type 2 diabetes mellitus, in comparison to a lean control group, to examine whether plasma concentrations reflect an up-regulation of the TNF system in adipose tissue.PATIENTS AND METHODS: Plasma concentrations of the two soluble TNF-alpha receptors were measured in 49 obese subjects (mean body mass index (BMI): 44.9 kg/m2, 95% confidence intervals (CI) 42.3-47.5 kg/m2, including 19 type 2 diabetic individuals) and 28 lean controls, by using a highly sensitive enzyme-linked immunoassay (ELISA) technique. TNF-alpha concentrations were determined in 28 obese (10 with diabetes) and 23 lean subjects.RESULTS: The obese subjects showed significantly higher plasma concentrations of the soluble p60 and p80 TNF receptor, respectively, compared to the lean control group, independent of the presence of diabetes. Multiple regression analysis, with the p80 TNF receptor as dependent variable, revealed that BMI and log insulin significantly affected the plasma concentration of this soluble receptor subtype, explaining 46% of the variance, whereas for the p60 TNF receptor, only BMI turned out to influence plasma concentrations. TNF-alpha plasma concentrations were not different between the three groups (Kruskal-Wallis test: P=0.34), but due to the low power of the test, an effect of obesity on TNF-alpha is not excluded.CONCLUSION: These data indicate that plasma concentrations of both soluble TNF receptors are elevated in obesity and insulin resistance, possibly as a function of excess body fat. The reported adipose overexpression of TNF-alpha does not seem to be reflected by elevated plasma concentrations, suggesting a primarily local role of the cytokine." ]

[ "BACKGROUND: Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH.METHODS: In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis.RESULTS: A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo.CONCLUSIONS: In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.).", "Irinotecan is widely used in the treatment of colorectal, gastric, and lung cancers. However, adverse drug reactions such as severe diarrhea and neutropenia limit the dose of this drug. Irinotecan is metabolized by carboxylesterase to form an active metabolite, 7-ethyl-10-hydroxycamptothecin(SN-38), which in turn is subsequently conjugated by UGT-glucuronosyltransferase 1A1(UGT1A1)to yield an inactive form, SN-38 glucuronide(SN-38 G). The UGT1A1 gene polymorphisms contribute to the individual variation in adverse events among patients administered irinotecan. However, the distribution of polymorphisms shows large interethnic differences. The distribution of UGT1A1*28 greatly differs between Caucasians and Japanese; the frequency of UGT1A1*28 is high in Caucasians, whereas it is low in Asians including Japanese. Recently, it has been demonstrated that genetic variants of UGT1A1*6 in addition to UGT1A1*28 are associated with the occurrence of adverse events in irinotecan chemotherapy in Asians. This review summarizes recent studies to outline the role of UGT1A1*28 and UGT1A1*6 for irinotecan-induced adverse drug reaction in Japanese cancer patients.", "Proton beam therapy (PT) offers improved sparing of normal tissue, thus potentially reducing the risk for treatment related late sequelae and induction of secondary cancer. In addition, it can be an instrument for intensification of local therapy (\"dose escalation\") for disease currently not sufficiently controlled. Up to now, more than 70 000 patients have been treated with PT worldwide. In particular, tumors of the ocular fundus, the base of skull and prostate were targeted. In recent years an increasing number of children got treated, predominantly when suffering from sarcomas or brain tumors. In Europe, treatment was applied so far mainly in Switzerland (PSI) or France (Orsay). However, availability of particle therapy is about to increase considerably within the next years. The German Working Group of paediatric radiation oncology APRO=Arbeitsgemeinschaft für Pädiatrische Radioonkologie) is currently trying to embed PT in the multidisciplinary concepts of the GPOH, and PT experts are appointed for each relevant study. In addition, prospective documentation of the applied PT is to be performed according to the RISK protocol. Still, it is mandatory to reach out for the integration of PT into our cooperative network and the multidisciplinary trials. Best practice solutions have to be established in order to provide high quality and transparency of any applied particle therapy.", "Treatment options for advanced metastatic or progressive thyroid cancers are limited. Although targeted therapy specifically inhibiting intracellular kinase signaling pathways has markedly changed the therapeutic landscape, side-effects and resistance of single agent targeted therapy often leads to termination of the treatment. The objective of the present study was to identify the antitumor property of the non-selective β-adrenergic receptor antagonist propranolol for thyroid cancers. Human thyroid cancer cell lines 8505C, K1, BCPAP and BHP27 were used in the present study. Broad β-blocker propranolol and β2-specific antagonist ICI118551, but not β1-specific antagonist atenolol, inhibited the growth of 8505C and K1 cells. Propranolol treatment inhibited growth and induced apoptosis of 8505C cells in vitro and in vivo, which are closely associated with decreased expressions of cyclin D1 and anti-apoptotic Bcl-2. Expression of hexokinase 2 (HK2) and glucose transporter 1 (GLUT1) also decreased following propranolol intervention. 18F-FDG PET/CT imaging of the 8505C xenografts validated shrinkage of the tumors in the propranolol-treated group when compared to the phosphate‑buffered saline treated group. Finally, we found that propranolol can amplify the cytotoxicity of vemurafenib and sensitize thyroid cancer cells to cytotoxic effect of vemurafenib. Our present results suggest that propranolol has potential activity against thyroid cancers and investigation of the combination with targeted molecular therapy for progressive thyroid cancers could be beneficial.", "The protein alpha-synuclein (AS) is the primary fibrillar component of Lewy bodies, the pathological hallmark of Parkinson's disease. Wild-type human AS and the three mutant forms linked to Parkinson's disease (A53T, A30P, and E46K) all form fibrils through a nucleation-dependent pathway; however, the biophysical details of these fibrillation events are not yet well understood. Atomic-level structural insight is required in order to elucidate the potential role of AS fibrils in Parkinson's disease. Here we show that low temperature acquisition of magic-angle spinning NMR spectra of wild type AS fibrils-greatly enhances spectral sensitivity, enabling the detection of a substantially larger number of spin systems. At 0 +/- 3 degrees C sample temperature, cross polarization (CP) experiments yield weak signals. Lower temperature spectra (-40 +/- 3 degrees C) demonstrated several times greater signal intensity, an effect further amplified in 3D 15N-13C-13C experiments, which are required to perform backbone assignments on this sample. Thus 3D experiments enabled assignments of most amino acids in the rigid part of the fibril (approximately residues 64 to 94), as well as tentative site-specific assignments for T22, V26, A27, Y39, G41, S42, H50, V52, A53, T54, V55, V63, A107, I112, and S129. Most of these signals were not observed in 2D or 3D spectra at 0 +/- 3 degrees C. Spectra acquired at low temperatures therefore permitted more complete chemical shift assignments. Observation of the majority of residues in AS fibrils represents an important step towards solving the 3D structure.", "Author information:(1)Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.(2)Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 3Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.(3)Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.(4)Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.(5)Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.(6)Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.(7)Department of Ophthalmology, Xingtai Eye Hospital, Xingtai, Hebei, China.(8)Department of Ophthalmology, The Third Affiliated Hospital, Xinxiang Medical College, Xinxiang, Henan, China.(9)School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.(10)Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology, Beijing, China.(11)Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.(12)Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China 8Division of Human Genetics, Cincinnati Chi.", "SUMMARY: JUCHMME is an open-source software package designed to fit arbitrary custom Hidden Markov Models (HMMs) with a discrete alphabet of symbols. We incorporate a large collection of standard algorithms for HMMs as well as a number of extensions and evaluate the software on various biological problems. Importantly, the JUCHMME toolkit includes several additional features that allow for easy building and evaluation of custom HMMs, which could be a useful resource for the research community.AVAILABILITY AND IMPLEMENTATION: http://www.compgen.org/tools/juchmme, https://github.com/pbagos/juchmme.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online." ]

[ "Abnormal angiogenesis is critically involved in tumor progression and metastasis including endometrial cancer and is regulated by microRNAs such as microRNA-101 (miR-101). We hypothesize that miR-101 expression is disrupted in endometrial cancer and modulation of miR-101 levels is sufficient to regulate tumor growth through angiogenesis. We examined the expression levels of miR-101 and factors involved in angiogenesis in the patients with endometrial cancer. We also overexpressed or inhibited miR-101 in RL-95-2 cells and examined their effects on cell toxicity and tumor growth. Finally, we determined if miR-101 regulated tumorigenesis through cyclooxygenase-2 (COX-2). We found that miR-101 levels were significantly reduced. Factors involved in angiogenesis included vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and aromatase (P450arom), which were increased in endometrial carcinoma. Modulation of miR-101 level was sufficient to affect tumor growth. Finally, we found that the effects of miR-101 inhibition on tumor growth were suppressed by COX-2 inhibition. Our results suggest that modulating miR-101 and COX-2 levels or their activity may be a potential therapeutic strategy for endometrial cancer.", "DNA tumor viruses ensure genome amplification by hijacking the cellular replication machinery and forcing infected cells to enter the S phase. The retinoblastoma (Rb) protein controls the G1/S checkpoint, and is targeted by several viral oncoproteins, among these the E7 protein from human papillomaviruses (HPVs). A quantitative investigation of the interaction mechanism between the HPV16 E7 protein and the RbAB domain in solution revealed that 90% of the binding energy is determined by the LxCxE motif, with an additional binding determinant (1.0 kcal.mol(-1)) located in the C-terminal domain of E7, establishing a dual-contact mode. The stoichiometry and subnanomolar affinity of E7 indicated that it can bind RbAB as a monomer. The low-risk HPV11 E7 protein bound 2.0 kcal.mol(-1) more weakly than the high-risk HPV16 and HPV18 type counterparts, but the modularity and binding mode were conserved. Phosphorylation at a conserved casein kinase II site in the natively unfolded N-terminal domain of E7 affected the local conformation by increasing the polyproline II content and stabilizing an extended conformation, which allowed for a tighter interaction with the Rb protein. Thus, the E7-RbAB interaction involves multiple motifs within the N-terminal domain of E7 and at least two conserved interaction surfaces in RbAB. We discussed a mechanistic model of the interaction of the Rb protein with a viral target in solution, integrated with structural data and the analysis of other cellular and viral proteins, which provided information about the balance of interactions involving the Rb protein and how these determine the progression into either the normal cell cycle or transformation.", "Several cytokines signalling via Janus Kinase (JAK) proteins have been implicated in the pathogenesis of immune-mediated inflammatory diseases, including psoriasis and rheumatoid arthritis (RA). Tofacitinib, a small JAK inhibitor, is approved for the treatment of RA and has demonstrated good efficacy in psoriasis phase III clinical trials. In this work, we analysed the in vitro effects of tofacitinib on the functions of human dendritic cells (DCs) and macrophages. When assessing the effects of tofacitinib on monocyte-derived DCs, we observed reduced differentiation of monocytes into immature DCs, as evidenced by a decreased transcription of CD209 and CD80. Phenotype assessment in the presence of tofacitinib suggested a switch towards a M1-like macrophage phenotype, as evidenced by the expression of M1 markers such as iNOS, as well as cytokines typically expressed by M1 cells, including IL-12 and IL-23. Of note, Arginase1 and CD200R, typically expressed by M2 cells, were absent on tofacitinib-treated DCs. Furthermore, tofacitinib affected the response of differentiated DCs to maturation stimuli such as LPS and IFNγ, resulting in a partial up-regulation of IL-23 and down-regulation of IL-12, as assessed by qPCR. When investigating macrophage development, we found that tofacitinib inhibited the ability of monocytes to differentiate and polarize into regulatory M2 macrophages, while rather enhancing the ability to develop into inflammatory M1-like macrophages, as evidenced by decreased expression of the M2 marker CD200R and enhanced production of IL-12 and IL-23. In conclusion, tofacitinib impacts the differentiation of human DCs and macrophages, it particularly favours generation of M1-like pro-inflammatory macrophages.", "Psoriasis is a chronic inflammatory skin condition, characterized by T-helper (Th) 1 and Th17 cell activation. Ustekinumab is a fully human immunoglobulin G1κ monoclonal antibody that targets the common p40 subunit that is shared by both interleukin (IL)-12 and IL-23, consequently inhibiting T-cell differentiation along both Th1 and Th17 pathways. This is a report of two patients who developed psoriatic arthritis during ustekinumab treatment for psoriasis. Neither patient had a personal or family history of arthritis.", "Hydroxylation of lysyl residues is crucial for the unique glycosylation pattern found in collagens and for the mechanical strength of fully assembled extracellular collagen fibers. Hydroxylation is catalyzed in the lumen of the endoplasmic reticulum (ER) by a specific enzyme, lysyl hydroxylase (LH). The absence of the known ER-specific retrieval motifs in its primary structure and its association with the ER membranes in vivo have suggested that the enzyme is localized in the ER via a novel retention/retrieval mechanism. We have identified here a 40-amino acid C-terminal peptide segment of LH that is able to convert cathepsin D, normally a soluble lysosomal protease, into a membrane-associated protein. The same segment also markedly slows down the transport of the reporter protein from the ER into post-ER compartments, as assessed by our pulse-chase experiments. The retardation efficiency mediated by this C-terminal peptide segment is comparable with that of the intact LH but lower than that of the KDEL receptor-based retrieval mechanism. Within this 40-amino acid segment, the first 25 amino acids appear to be the most crucial ones in terms of membrane association and ER localization, because the last 15 C-terminal amino acids did not possess substantial retardation activity alone. Our findings thus define a short peptide segment very close to the extreme C terminus of LH as the only necessary determinant both for its membrane association and localization in the ER.", "Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the alimentary tract rarely observed in children. The treatment of choice for GIST is surgical resection. Although the prognosis of GISTs with low malignant potential is excellent, high-malignant-potential GISTs have a high rate of recurrence. Prognostic factors such as tumor size, mitotic rate and presence of metastases may provide an indication for adjuvant imatinib mesylate (IM) treatment. Here we present a young patient with a large GIST with high-risk features who is in complete remission after surgical excision and adjuvant IM treatment. This patient is the only colon-located CD117-positive case where IM was administered. The exact indications as well as the optimal dose and duration of IM need to be clarified with the contribution of new cases and the growing experience of this rare disease.", "Thirty experimental and fifteen control Wistar rats were studied to determine whether hypoglycin A influences insulin levels in the body to contribute to the state of hypoglycemia usually observed in Jamaican vomiting sickness, a condition arising after ingestion of unripe ackees. This fruit also grows in other Caribbean islands, as well as North and Central America. Hypoglycin A is one of the toxic compounds found in unripe ackees and is capable of inducing hypoglycemia. A fall in blood glucose occurred after administration of hypoglycin A. The lowest level of 42.60 +/- 4.84 mg/dl was attained 3 hr after administration of the drug. This alteration of blood glucose from the fasting level of 80.31 +/- 5.20 mg/dl was significant (P less than 0.01). The blood glucose level in the control rats showed no significant change from the fasting level. The insulin level in portal and peripheral blood showed no significant change. Results showed that, although hypoglycin A induced severe hypoglycemia after intravenous application, there was no significant change in insulin levels. This observation suggests that hypoglycin A has a mechanism of action other than an alteration in insulin levels to induce hypoglycemia." ]

[ "Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, paired-like homeodomain transcription factor 1 (PITX1) was found specifically up-regulated in patients with FSHD. In addition, we showed that the double homeobox 4 gene (DUX4) that maps within the D4Z4 repeat unit was up-regulated in patient myoblasts at both mRNA and protein level. We further showed that the DUX4 protein could activate transient expression of a luciferase reporter gene fused to the Pitx1 promoter as well as the endogenous Pitx1 gene in transfected C2C12 cells. In EMSAs, DUX4 specifically interacted with a 30-bp sequence 5'-CGGATGCTGTCTTCTAATTAGTTTGGACCC-3' in the Pitx1 promoter. Mutations of the TAAT core affected Pitx1-LUC activation in C2C12 cells and DUX4 binding in vitro. Our results suggest that up-regulation of both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease.", "The underrepresentation of non-Europeans in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world's population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide.", "Twenty-four hours after a tetracycline injection, the unimpeded, and more rapidly erupting, mouse mandibular incisor contained 20% to 44% more tetracycline than the contralateral, uncut incisor. It was concluded that the increased tetracycline incorporation reflected a higher rate of mineralization associated with faster tooth formation in the unimpeded tooth. By measuring the amount of tetracycline which became incorporated at different times after an incisor was shortened, it was possible to investigate an early stage of the response of the incisor to cutting. A significant increase in the capacity of the tooth to incorporate tetracycline was detectable 4 h after shortening the tooth, and this was maximal after another 4 h.", "BACKGROUND: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality.METHODS: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria.RESULTS: At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis.CONCLUSIONS: Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).", "Nanog is a newly identified homeodomain gene that functions to sustain the pluripotency of embryonic stem cells. However, the molecular mechanism through which nanog regulates stem cell pluripotency remains unknown. Mouse nanog encodes a polypeptide of 305 residues with a divergent homeodomain similar to those in the NK-2 family. The rest of nanog contains no apparent homology to any known proteins characterized so far. It is hypothesized that nanog encodes a transcription factor that regulates stem cell pluripotency by switching on or off target genes. To test this hypothesis, we constructed fusion proteins between nanog and DNA binding domains of the yeast transcription factor Gal4 and tested the transactivation potentials of these constructs. Our data demonstrate that both regions N- and C- terminal to the homeodomain have transcription activities. Despite the fact that it contains no apparent transactivation motifs, the C-terminal domain is about 7 times as active as the N-terminal one. This unique arrangement of dual transactivators may confer nanog the flexibility and specificity to regulate downstream genes critical for both pluripotency and differentiation of stem cells.", "The sudden cardiac death (SCD) of an athlete is always a dramatic event, and one wonders if it could have been prevented by pre-participation cardiovascular screening. For years now, a pro/con debate has been taking place on the pre-participation screening of athletes: the method, who is responsible, cost-effectiveness, obligatory or voluntary screening. In this pro-article, which agrees with the \"sudden cardiac death can be prevented by routinely pre-participation cardiovascular screening\"-standpoint, the unique Italian experience is the best argument for the support of screening. This study clearly demonstrated a reduction in SCD in those athletes who were screened in accordance with Italian law.", "BRCA1 is a tumor suppressor gene that is mutated in families with breast and ovarian cancer. Several BRCA1 splice variants are found in different tissues, but their subcellular localization and functions are poorly understood at the moment. We previously described BRCA1 splice variant BRCA1a to induce apoptosis and function as a tumor suppressor of triple negative breast, ovarian and prostate cancers. In this study we have analyzed the function of BRCA1 isoforms (BRCA1a and BRCA1b) and compared them to the wild-type BRCA1 protein using several criteria like studying expression in normal and tumor cells by RNase protection assays, subcellular localization/fractionation by immunofluorescence microscopy and Western blot analysis, transcription regulation of biological relevant proteins and growth suppression in breast cancer cells. We are demonstrating for the first time that ectopically expressed GFP-tagged BRCA1, BRCA1a, and BRCA1b proteins are localized to the mitochondria, repress ELK-1 transcriptional activity and possess antiproliferative activity on breast cancer cells. These results suggest that the exon 9, 10, and 11 sequences (aa 263-1365) which contain two nuclear localization signals, p53, Rb, c-Myc, gamma-tubulin, Stat, Rad51, Rad50 binding domains, angiopoietin-1 repression domain are not absolutely required for mitochondrial localization and growth suppressor function of these proteins. Since mitochondrial dysfunction is a hallmark of cancer, we can speculate that the mitochondrial localization of BRCA1 proteins may be functionally significant in regulating both the mitochondrial DNA damage as well as apoptotic activity of BRCA1 proteins and mislocalization causes cancer. J. Cell. Physiol. 219: 634-641, 2009. (c) 2009 Wiley-Liss, Inc." ]

[ "Food allergies are a growing public health concern with an estimated 8% of US children affected. Peanut allergies are also on the rise and often do not spontaneously resolve, leaving individuals at-risk for potentially life-threatening anaphylaxis throughout their lifetime. Currently, two forms of peanut immunotherapy, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT), are in Phase III clinical trials and have shown promise to induce desensitization in many subjects. However, there are several limitations with OIT and EPIT, such as allergic side effects, daily dosing requirements, and the infrequent outcome of long-term tolerance. Next-generation therapies for peanut allergy should aim to overcome these limitations, which may be achievable with adjuvanted immunotherapy. An adjuvant can be defined as anything that enhances, accelerates, or modifies an immune response to a particular antigen. Adjuvants may allow for lower doses of antigen to be given leading to decreased side effects; may only need to be administered every few weeks or months rather than daily exposures; and may induce a long-lasting protective effect. In this review article, we highlight examples of adjuvants and formulations that have shown pre-clinical efficacy in treating peanut allergy.", "Myasthenia gravis is an important indication for the long-term prescription of corticosteroids. We present a patient with myasthenia gravis who had worsening of symptoms associated with the use of alendronate. A 24-year-old patient with myasthenia gravis had been administered oral systemic corticosteroid (deflazacort 40 mg/day) for 3 years in order to control his myasthenic symptoms. One year earlier, his lumbar spine bone mineral density was decreased. He was started on oral calcium/vitamin D3 and alendronate (70-mg tablets once a week) for osteoporosis. He reported an exacerbation of muscle weakness and extreme fatigue on days when he took alendronate. He could not work on these days and has to be on leave. Alendronate was stopped, and he was started on intravenous ibandronate injections given every 3 months. He did not experience muscle weakness and fatigue with ibandronate therapy. Alendronate should be used with caution in patients with myasthenia gravis who have corticosteroid-induced osteoporosis.", "Author information:(1)Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Institute of Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany.(2)Molecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK; Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.(3)Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK; Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Toma Ciorbă 1, 2052 Chisinau, Republic of Moldova.(4)Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London WC1E 6BT, UK.(5)Neurology Dept., Ghaem Hospital, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.(6)Department of Molecular Genetics, Next Generation Genetic Polyclinic, Mashhad 009851, Iran.(7)Molecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK; Department of Molecular Genetics, Next Generation Genetic Polyclinic, Mashhad 009851, Iran.(8)Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.(9)Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Institute of Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany. Electronic address: mert.karakaya@uk-koeln.de.", "Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (CLR + RAMP1) offer considerable improvements over existing drugs in migraine prophylaxis and are the first designed to act on the trigeminal pain system. Erenumab is approved by the FDA and EMA and has reached the market since May 2018. Two antibodies, fremanezumab and galcanezumab, directed towards the CGRP ligand, were approved by the FDA in September 2018. To view this Bench to Bedside, open or download the PDF.", "Laparoscopic excision is considered as the 'gold standard' treatment of ovarian endometrioma. However, a frustrating aspect is that disease can recur. While laparoscopic excision is known to improve fertility, recurrence can cause significant ovarian damage and adverse affects on fertility. It is therefore crucial to prevent recurrence in order to conserve 'improved' fertility. Recurrence rates for endometrioma are reported from 11 to 32% within 1-5 years after excision. The recurrence rate is higher in patients with advanced endometriosis at surgery and in younger patients. Previous medical treatment for endometriosis prior laparoscopy is a risk factor for recurrence. Pregnancy soon after surgery has a protective effect for recurrence. The accumulating evidence suggests that the administration of oral contraceptives (OC), levonorgestrel-releasing intrauterine system (LNG-IUS) and a combination of gonadotropin releasing hormone (GnRH) analogue and OC may also have therapeutic benefits. Collectively, we propose that women should be well informed about the risks of endometrioma recurrence. We recommend that women who wish pregnancy should try conception as soon as possible. Further, we strongly advise hormonal therapy for patients, who do not want to conceive immediately, and until pregnancy is desired.", "RhoGDIα is a key regulator of Rho proteins, coordinating their GTP/GDP and membrane/cytosol cycle. Recently, it was demonstrated by quantitative mass spectrometry that RhoGDIα is heavily targeted by post-translational lysine acetylation. For one site in its N-terminal domain, namely K52, we reported earlier that acetylation completely switches off RhoGDIα function. Herein we show that K52-acetylated RhoGDIα is specifically deacetylated by the sirtuin deacetylase Sirt2. We show that acetylation at K52 decelerates cervical cancer cell proliferation, suggesting RhoGDIα acetylation to be a promising therapeutic target. We demonstrate that treatment of cervical cancer cells with a RhoGDIα-derived K52-trifluoroacetylated, substrate-derived peptidic sirtuin inhibitor severely impairs cell proliferation. Finally, we conclude that the potency of substrate-derived sirtuin inhibitors depends on structural features, the substrate-derived amino acid sequence as a determinant for selectivity, as well as the presence of an acetyl-lysine analogue to increase its potency. These data reveal a prospective therapeutic potential for novel substrate-derived sirtuin inhibitors.", "The heritability of schizophrenia has been reported to be as high as ~80%, but the contribution of genetic variants identified to this heritability remains to be estimated. Long non-coding RNAs (LncRNAs) are involved in multiple processes critical to normal cellular function and dysfunction of lncRNA MIAT may contribute to the pathophysiology of schizophrenia. However, the genetic evidence of lncRNAs involved in schizophrenia has not been documented. Here, we conducted a two-stage association analysis on 8 tag SNPs that cover the whole MIAT locus in two independent Han Chinese schizophrenia case-control cohorts (discovery sample from Shanxi Province: 1093 patients with paranoid schizophrenia and 1180 control subjects; replication cohort from Jilin Province: 1255 cases and 1209 healthy controls). In discovery stage, significant genetic association with paranoid schizophrenia was observed for rs1894720 (χ(2)=74.20, P=7.1E-18), of which minor allele (T) had an OR of 1.70 (95% CI=1.50-1.91). This association was confirmed in the replication cohort (χ(2)=22.66, P=1.9E-06, OR=1.32, 95%CI 1.18-1.49). Besides, a weak genotypic association was detected for rs4274 (χ(2)=4.96, df=2, P=0.03); the AA carriers showed increased disease risk (OR=1.30, 95%CI=1.03-1.64). No significant association was found between any haplotype and paranoid schizophrenia. The present studies showed that lncRNA MIAT was a novel susceptibility gene for paranoid schizophrenia in the Chinese Han population. Considering that most lncRNAs locate in non-coding regions, our result may explain why most susceptibility loci for schizophrenia identified by genome wide association studies were out of coding regions." ]

[ "Author information:(1)Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: fryae@cardiff.ac.uk.(2)Department of Biological Sciences, Hunter College of City University, 695 Park Avenue, New York, NY 10065, USA; Program in Biology, Graduate Center of City University, 365 Fifth Avenue, New York, NY 10016, USA.(3)Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK.(4)Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK; Neurology department, Morriston Hospital, Swansea Bay University Hospital Health Board, Swansea SA6 6NL, UK.(5)Paediatric Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.(6)Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.(7)Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK.(8)Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust and Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.(9)Department of Paediatric Neurology, Royal Manchester Children's Hospital, Oxford Road, Manchester M13 9WL, UK.(10)Department of Neurology, Salford Royal Hospital NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK.(11)Department of Radiology, Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool L12 2AP, UK.(12)West Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK.(13)Department of Paediatrics, McMaster University, 1200 Main St. W., Hamilton, ON L8N 3Z5, Canada.(14)Department of Pediatrics, Peking University First Hospital, Xicheng District, Beijing 100034, China.(15)Cipher Gene Ltd, Beijing, China.(16)Genomics England, London EC1M 6BQ, UK.(17)Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK; Faculty of Medicine and Health, Camperdown, University of Sydney, NSW 2006, Australia.(18)Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK; Kids Neuroscience Centre, Kids Research, Children Hospital at Westmead, Sydney, NSW 2145, Australia; Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, NSW 2050, Australia.", "The smallpox vaccine based on the vaccinia virus was successfully used to eradicate smallpox, but although very effective, it was a very reactogenic vaccine and responsible for the deaths of one to two people per million vaccinated. Modified Vaccinia virus Ankara (MVA) is an attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. MVA can encode one or more foreign antigens and thus can function as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant properties, and induces humoral and cellular immune responses. Many clinical trials of these new vaccines have been conducted, and the safety of MVA is now well documented. Immunogenicity is influenced by the dose and vaccination regimen, and information on the efficacy of MVA-vectored vaccines is now beginning to accumulate. In this chapter, we provide protocols for generation, isolation, amplification, and purification of recombinant MVA for preclinical and clinical evaluation.", "BACKGROUND: Sports-related head trauma is common but still there is no established laboratory test used in the diagnostics of minimal or mild traumatic brain injuries. Further the effects of recurrent head trauma on brain injury markers are unknown. The purpose of this study was to investigate the relationship between Olympic (amateur) boxing and cerebrospinal fluid (CSF) brain injury biomarkers.METHODS: The study was designed as a prospective cohort study. Thirty Olympic boxers with a minimum of 45 bouts and 25 non-boxing matched controls were included in the study. CSF samples were collected by lumbar puncture 1-6 days after a bout and after a rest period for at least 14 days. The controls were tested once. Biomarkers for acute and chronic brain injury were analysed.RESULTS: NFL (mean ± SD, 532±553 vs 135±51 ng/L p = 0.001), GFAP (496±238 vs 247±147 ng/L p<0.001), T-tau (58±26 vs 49±21 ng/L p<0.025) and S-100B (0.76±0.29 vs 0.60±0.23 ng/L p = 0.03) concentrations were significantly increased after boxing compared to controls. NFL (402±434 ng/L p = 0.004) and GFAP (369±113 ng/L p = 0.001) concentrations remained elevated after the rest period.CONCLUSION: Increased CSF levels of T-tau, NFL, GFAP, and S-100B in >80% of the boxers demonstrate that both the acute and the cumulative effect of head trauma in Olympic boxing may induce CSF biomarker changes that suggest minor central nervous injuries. The lack of normalization of NFL and GFAP after the rest period in a subgroup of boxers may indicate ongoing degeneration. The recurrent head trauma in boxing may be associated with increased risk of chronic traumatic brain injury.", "Repressed PHO5 gene chromatin, isolated from yeast in the native state, was remodeled by yeast extract in a gene activator-dependent, ATP-dependent manner. The product of the reaction bore the hallmark of the process in vivo, the selective removal of promoter nucleosomes, without effect on open reading frame nucleosomes. Fractionation of the extract identified a single protein, chromodomain helicase DNA binding protein 1 (Chd1), capable of the remodeling activity. Deletion of the CHD1 gene in an isw1Δ pho80Δ strain abolished PHO5 gene expression, demonstrating the relevance of the remodeling reaction in vitro to the process in vivo.", "Ospemifene (Osphena™) is an oral selective estrogen receptor modulator (SERM), with tissue-specific estrogenic agonist/antagonist effects. QuatRx Pharmaceuticals conducted the global development of the agent before licensing it to Shionogi for regulatory filing and commercialization worldwide. Ospemifene is the first non-estrogen treatment approved for moderate to severe dyspareunia in women with menopause-related vulvar and vaginal atrophy. The drug is approved in the USA, and application for EU regulatory approval is underway. This article summarizes the milestones in the development of ospemifene leading to this first approval for moderate to severe dyspareunia, a symptom of postmenopausal vulvar and vaginal atrophy.", "Lung cancer has increased in incidence throughout the twentieth century and is now the most common cancer in the Western World. It has a poor prognosis, only 10-15% of patients survive 5 years or longer. Outcome is dependent on clinical stage and cancer cell type. Lung cancer is broadly subclassified on the basis of histological features into squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell carcinoma. The histopathological type of lung cancer correlates with tumour behaviour and prognosis. Staging based on prognosis is essential in clinical trials comparing different management strategies, and enables universal communication regarding the efficacy of different treatments in specific patient groups. The anatomic extent of disease determined either preoperatively using imaging supplemented by invasive procedures such as mediastinoscopy, and anterior mediastinotomy or following resection are described according to the T-primary tumour, N-regional lymph nodes, M-distant metastasis classification. The International System for Staging Lung Cancer attempts to group together patients with similar prognosis and treatment options. Various combinations of T, N, and M define different clinical or surgical-pathological stages (IA-IV) characterised by different survival characteristics. Refinements in staging based on imaging findings have enabled clinical staging to more accurately reflect the surgical-pathological stage and therefore more accurately predict prognosis. Recent advances including the use of positron emission tomography in combination with conventional staging promises to increase the accuracy of staging and therefore to reduce the number of invasive staging procedures and inappropriate thoracotomies.", "The \"Mozart effect\" refers to claims that people perform better on tests of spatial abilities after listening to music composed by Mozart. We examined whether the Mozart effect is a consequence of between-condition differences in arousal and mood. Participants completed a test of spatial abilities after listening to music or sitting in silence. The music was a Mozart sonata (a pleasant and energetic piece) for some participants and an Albinoni adagio (a slow, sad piece) for others. We also measured enjoyment, arousal, and mood. Performance on tbe spatial task was better following the music than the silence condition but only for participants who heard Mozart. The two music selections also induced differential responding on the enjoyment, arousal and mood measures. Moreover, when such differences were held constant by statistical means, the Mozart effect disappeared. These findings provide compelling evidence that the Mozart effect is an artifact of arousal and mood." ]

[ "OBJECTIVE: To identify disease-related genes and immune-regulatory pathways in the pathogenesis of systemic lupus erythematosus (SLE) by using gene expression profiling and protein-protein interaction analysis.METHODS: Peripheral white blood cell gene expression profiles of 10 SLE patients were determined by oligonucleotide microarray analysis. Clustering of the gene expression profile was compared with the clinical immune phenotype. SLE-induced genes that were over- or under-expressed were determined and independently validated using a real-time polymerase chain reaction (PCR) method. To study their potential function and the possible pathways involved, a candidate gene was cloned and a GST (glutathione S-transferase) fusion protein was expressed in Escherichia coli. The fusion protein was further purified using the glutathione Sepharose 4B system, and was treated as bait to capture prey from SLE peripheral white blood cell lysate. MALDI-TOF (matrix-assisted laser desorption/ionization-time-of-flight) mass spectrometry was then performed to determine the prey protein.RESULTS: Similarity was found between the gene expression profile and the immune phenotype clusters of the SLE patients. More than 20 disease-associated genes were identified, some of which have not been related to SLE previously. Of these genes, a cluster of interferon-induced genes were highly correlated. IFIT1 (interferon-induced with tetratricopeptide repeats 1) was one of these genes, and overexpression of its mRNA was confirmed independently by real-time PCR in a larger population (40 SLE patients and 29 normal controls). An IFIT1 protein- protein interaction study showed that IFIT1 may interact with Rho/Rac guanine nucleotide exchange factor.CONCLUSION: The gene expression profile seems to be the molecular basis of the diverse immune phenotype of SLE. On the basis of the SLE-related genes found in this study, we suggest that the interferon-related immune pathway is important in the pathogenesis of SLE. IFIT1 is the first gene described as a candidate gene for SLE, and may function by activating Rho proteins through interaction with Rho/Rac guanine nucleotide exchange factor. IFIT1 and the interferon-related pathway may provide potential targets for novel interventions in the treatment of SLE.", "Lactose intolerance (LI) is characterized by the presence of primarily gastrointestinal clinical signs resulting from colonic fermentation of lactose, the absorption of which is impaired due to a deficiency in the lactase enzyme. These clinical signs can be modified by several factors, including lactose dose, residual lactase expression, concurrent ingestion of other dietary components, gut-transit time, and enteric microbiome composition. In many of individuals with lactose malabsorption, clinical signs may be absent after consumption of normal amounts of milk or, in particular, dairy products (yogurt and cheese), which contain lactose partially digested by live bacteria. The intestinal microbiota can be modulated by biotic supplementation, which may alleviate the signs and symptoms of LI. This systematic review summarizes the available evidence on the influence of prebiotics and probiotics on lactase deficiency and LI. The literature search was conducted using the MEDLINE (via PUBMED) and SCOPUS databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and included randomized controlled trials. For each study selected, the risk of bias was assessed following the Cochrane Collaboration methodology. Our findings showed varying degrees of efficacy but an overall positive relationship between probiotics and LI in relation to specific strains and concentrations. Limitations regarding the wide heterogeneity between the studies included in this review should be taken into account. Only one study examined the benefits of prebiotic supplementation and LI. So further clinical trials are needed in order to gather more evidence.", "Lactose intolerance is a common condition caused by lactase deficiency and may result in symptoms of lactose malabsorption (bloating, flatulence, abdominal discomfort, and change in bowel habits). As current data is limited, the aim of our study was to assess the efficacy of probiotics with a β-galactosidase activity on symptoms of lactose malabsorption and on the lactose hydrogen breath test (LHBT). The study group comprised eight symptomatic female patients with a positive LHBT. Patients were treated for 6 months with a probiotic formula with β-galactosidase activity (Bio-25, Ambrosia-SupHerb, Israel). All patients completed a demographic questionnaire as well as a diary for the assessment of symptom severity and frequency at entry, every 8 weeks, and at the end of the treatment period. Measurements of hydrogen (H2) levels (parts per million, ppm) at each of these time points were also performed. End points were a decrease of 50% in symptom severity or frequency, and the normalization (decrease below cutoff point of 20 ppm) of the breath test. Mean age and mean body mass index (BMI) were 36.4 ± 18.6 years and 23.2 kg/m2, respectively. Compared to baseline scores, the frequency of most symptoms, and the severity of bloating and flatulence, improved after treatment. Normalization of LHBT was obtained in only two patients (25%). In this pilot study, Bio-25, a unique formulation of probiotics with β-galactosidase activity, demonstrated symptom resolution in most patients with lactose malabsorption. A larger randomized trial is warranted to confirm these preliminary findings.", "Ca(V) channels are multi-subunit protein complexes that enable inward cellular Ca(2+) currents in response to membrane depolarization. We recently described structure-function studies of the intracellular α1 subunit domain I-II linker, directly downstream of domain IS6. The results show the extent of the linker's helical structure to be subfamily dependent, as dictated by highly conserved primary sequence differences. Moreover, the difference in structure confers different biophysical properties, particularly the extent and kinetics of voltage and calcium-dependent inactivation. Timothy syndrome is a human genetic disorder due to mutations in the Ca(V)1.2 gene. Here, we explored whether perturbation of the I-II linker helical structure might provide a mechanistic explanation for a Timothy syndrome mutant's (human Ca(V)1.2 G406R equivalent) biophysical effects on inactivation and activation. The results are equivocal, suggesting that a full mechanistic explanation for this Timothy syndrome mutation requires further investigation.", "Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours and breast cancer cell lines. Tumours that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell-line extracts. Knockdown experiments show that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression causes cell cycle deviations, cell death, DNA fragmentation, γ-H2AX accumulation and C-to-T mutations. Our data suggest a model in which APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumours evolve rapidly and manifest heterogeneity.", "Parkinson's disease is typically treated with oral dopamine replacement therapies. However, long-term use is complicated by motor fluctuations from intermittent stimulation of dopamine receptors and off-target effects. ProSavin, a lentiviral vector based gene therapy that delivers local and continuous dopamine, was previously shown to be well tolerated in a Phase I/II first-in-human study, with significant improvements in motor behavior from baseline at 1 year. Here, patients with Parkinson's disease from the open-label trial were followed up in the long term to assess the safety and efficacy of ProSavin after bilateral injection into the putamen. Fifteen patients who were previously treated with ProSavin have been followed for up to 5 years, with some having been seen for 8 years. Eight patients received deep brain stimulation at different time points, and their subsequent assessments continued to assess safety. Ninety-six drug-related adverse events were reported (87 mild, 6 moderate, 3 severe) of which more than half occurred in the first year. The most common drug-related events were dyskinesias (33 events, 11 patients) and on-off phenomena (22 events, 11 patients). A significant improvement in the defined \"off\" Unified Parkinson's Disease Rating Scale part III motor scores, compared to baseline, was seen at 2 years (mean score 29 · 2 vs. 38 · 4, n = 14, p < 0.05) and at 4 years in 8/15 patients. ProSavin continued to be safe and well tolerated in patients with Parkinson's disease. Moderate improvements in motor behavior over baseline continued to be reported in the majority of patients who could still be evaluated up to 5 years of follow-up.", "The turning point in antimicrobial therapy of Mycobacterium avium infections came with the development of two new macrolides, clarithromycin and azithromycin. Controlled clinical trials, the first ever conducted with any agent among patients with M. avium infection, indicated the high efficiency of clarithromycin, in either acquired immune deficiency syndrome (AIDS) patients having a disseminated infection or non-AIDS patients with localized pulmonary disease. Monotherapy with clarithromycin resulted in elimination of bacteremia in almost all patients with disseminated infection, which is inevitably followed by a relapse of bacteremia in patients who survived long enough to reach this event. The strains susceptible to clarithromycin isolated before therapy contained 10(-8) or 10(-9) resistant mutants, and the relapses of bacteremia were caused by multiplication of these pre-existing mutants. Clarithromycin-resistance was associated with a mutation in the 23S rRNA gene. Cross-resistance between clarithromycin and azithromycin was confirmed with laboratory mutants and clinical isolates. At least two methods for determining the susceptibility of the M. avium isolates to clarithromycin are available: one is minimum inhibitory concentration (MIC) determination on Mueller-Hinton agar (pH 7.4) supplemented with 10% Oleic acid-albumin-dextrose catalase, the other is MIC determination in 7H12 broth, also at pH 7.4. The breakpoints for 'susceptible' for these methods are < or = 8.0 micrograms/ml and < or = 2.0 micrograms/ml, respectively. The breakpoints for 'resistant' are > 128 micrograms/ml for the agar method and > 32.0 micrograms/ml for the broth method. The predictability value of MIC determination was confirmed by comparing the test results with the patients' clinical and bacteriological response to therapy. The remaining major problem in the therapy of the M. avium infections is a selection of companion drugs to be used in combination with clarithromycin (or azithromycin) to prevent the emergence of the macrolide-resistance. A number of clinical trials are now in progress to find a solution to this problem.", "mTORC1 (mammalian target of rampamycin complex 1) is a highly conserved protein complex regulating cell growth and metabolism via its kinase mTOR (mammalian target of rapamycin). The activity of mTOR is under the control of various GTPases, of which Rheb and the Rags play a central role. The presence of amino acids is a strict requirement for mTORC1 activity. The heterodimeric Rag GTPases localize mTORC1 to lysosomes by their amino-acid-dependent interaction with the lysosomal Ragulator complex. Rheb is also thought to reside on lysosomes to activate mTORC1. Rheb is responsive to growth factors, but, in conjunction with PLD1 (phospholipase D1), is also an integral part of the machinery that stimulates mTORC1 in response to amino acids. In the present article, we provide a brief overview of novel mechanisms by which amino acids affect the function of Rags. On the basis of existing literature, we postulate that Rheb is activated at the Golgi from where it will travel to lysosomes. Maturation of endosomes into lysosomes may be required to assure a continuous supply of GTP-bound Rheb for mTORC1 activation, which may help to drive the maturation process.", "Lynch syndrome, or hereditary nonpolyposis colon cancer (HNPCC), is an autosomal-dominant disease accounting for approximately 1-5% of all colorectal cancer cases. Due to the lack of pathognomonic morphological or biomolecular markers, HNPCC has traditionally posed unique problems to clinicians and geneticists alike, both in terms of diagnosis and clinical management. Recently, novel insight into the pathogenesis of this syndrome has been provided by the identification of its molecular basis. In HNPCC families, germline mutations in any of four genes encoding proteins of a specialized DNA repair system, the mismatch repair, predispose to cancer development. Mutations in mismatch repair genes lead to an overall increase of the mutation rate and are associated with a phenotype of length instability of microsatellite loci. The present report summarizes the clinicopathological aspects of HNPCC and reviews the most recent molecular and biochemical findings.", "PTH-related peptide (PTHrP) mediates the syndrome of humoral hypercalcemia of malignancy, a frequent complication of squamous cell carcinomas of the lung. This study was undertaken to determine whether 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and two nonhypercalcemic analogs, EB1089 and 22-oxa-1,25-(OH)2D3 (22-oxacalcitriol), suppress serum- and epidermal growth factor (EGF)-induced PTHrP gene expression in a human lung squamous cancer cell line, NCI H520. PTHrP expression was up-regulated by serum and EGF in a concentration- and time-dependent manner. Nuclear run-on analysis showed that this induction was mediated via a transcriptional mechanism, and that sequences within promoter 1 were responsible. All three vitamin D3 compounds decreased both basal and serum- and EGF-induced steady state PTHrP messenger RNA and secreted peptide levels. These effects were again mediated via a transcriptional mechanism through sequences within promoter 1. All three vitamin D3 compounds also decreased the proliferation of NCI H520 cells in a concentration- and time-dependent manner. 1,25-(OH)2D3 is hypercalcemic in vivo. However, the noncalcemic analogs EB1089 and 22-oxa-1,25-(OH)2D3 have therapeutic potential, as they suppress not only the basal but also the growth factor-stimulated levels of PTHrP in a cancer cell line associated with hypercalcemia.", "Lactose is a reducing sugar consisting of galactose and glucose, linked by a β (1→4) glycosidic bond, considered as an antioxidant due to its α-hydroxycarbonyl group. Lactose is widely ingested through the milk and other unfermented dairy products and is considered to be one of the primary foods. On the other hand, lactose is also considered as one of the most widely used excipients for the development of pharmaceutical formulations. In this sense, lactose has been related to numerous drug-excipient or drug-food pharmacokinetic interactions. Intolerance, maldigestion and malabsorption of carbohydrates are common disorders in clinical practice, with lactose-intolerance being the most frequently diagnosed, afflicting 10% of the world's population. Four clinical subtypes of lactose intolerance may be distinguished, namely lactase deficiency in premature infants, congenital lactase deficiency, adult-type hypolactasia and secondary lactase intolerance. An overview of the main uses of lactose in human nutrition and in the pharmaceutical industry and the problems derived from this circumstance are described in this review.", "A thermodynamic analysis of a cold-adapted protein, type III anti-freeze protein (AFP), was carried out. The results indicate that the folding equilibrium of type III AFP is a reversible, unimolecular, two-state process with no populated intermediates. Compared to most mesophilic proteins whose folding is two-state, the psychrophilic type III AFP has a much lower thermodynamic stability at 25 degrees C, approximately 3 kcal/mol, and presents a remarkably downshifted stability-temperature curve, reaching a maximum of 5 kcal/mol around 0 degrees C. Type III AFPs contain few and non-optimally distributed surface charges relative to their mesophilic homologs, the C-terminal domains of sialic acid synthases. We used thermodynamic double mutant cycles to evaluate the energetic role of every surface salt bridge in type III AFP. Two isolated salt bridges provided no contribution to stability, while the Asp36-Arg39 salt bridge, involved in a salt bridge network with the C-terminal carboxylate, had a substantial contribution (approximately 1 kcal/mol). However, this contribution was more than counteracted by the destabilizing effect of the Asp36 carboxylate itself, whose removal led to a net 30% increase in stability at 25 degrees C. This study suggests that type III AFPs may have evolved for a minimally acceptable stability at the restricted, low temperature range (around 0 degrees C) at which AFPs must function. In addition, it indicates that salt bridge networks are used in nature also for the stability of psychrophilic proteins, and has led to a type III AFP variant of increased stability that could be used for biotechnological purposes.", "OBJECTIVE: To provide recovery rates after stroke for specific functions using the Orpington Prognostic Scale (OPS).DESIGN: Prospective cohort.SETTING: Hospital and community.PARTICIPANTS: 413 stroke survivors entered the study 3 to 14 days after suffering a stroke.MEASUREMENTS: A cohort of hospitalized stroke survivors were recruited 3 to 14 days after stroke and assessed at 1, 3, and 6 months poststroke for neurological, functional, and health status. Baseline OPS score was used to predict five functional outcomes at 3 and 6 months using development and validation datasets and receiver operating characteristic (ROC) curves.RESULTS: In 413 stroke survivors, functional recovery rates at 3 and 6 months were similar. Baseline OPS predicted significant differences in recovery rates for all five outcomes (P < .0001 for all five outcomes at 3 and 6 months). Personal care dependence was present at 3 months in only 3% of persons with baseline OPS scores of 3.2 or less compared with over 50% with OPS of 4.8 or higher. Independent personal care, meal preparation, and self-administration of medication were achieved by 80% who had baseline OPS scores of 2.4 or lower compared with less than 20% when OPS scores were 4.4 or higher. Independent community mobility was achieved in 50% of those who had OPS scores of 2.4 or lower but only 3% of those with OPS scores of 4.4 or higher. The area under ROC curves assessing OPS scores against each of the five outcomes ranged from 0.805 to 0.863 at 3 months and 0.74 to 0.806 at 6 months.CONCLUSION: OPS scores can predict widely differing rates of functional recovery in five important functional abilities. These estimates can be useful to survivors, families, providers, and healthcare systems who need to plan for the future.", "Dairy products have been a key component of dietary guidance in the United States for more than 100 years. In light of major advances in the understanding of dietary intake and metabolism, the aim of this review was to examine whether dairy should remain a single commodity in federal guidance. Considerations include recognizing that a substantial proportion of the world's adult population (65%-70%) exhibits lactase nonpersistence, a reduced ability to metabolize lactose to glucose and galactose. Shifts in the US population, including a greater proportion of African Americans and Asians, are of key importance because several studies have shown a markedly higher prevalence of lactase nonpersistence and, consequently, a lower dairy intake among these groups. While cow's milk alternatives are available, families who use them will pay up to an additional $1400 per year compared with those who are able to consume dairy products. Dietary guidance also contains downstream effects for government assistance, such as the US Department of Agriculture's National School Lunch Program and School Breakfast Program. For reasons like these, Canada has recently removed dairy as a separate food group in national dietary guidance. The results of the present review suggest that consideration of this modification when developing population-level guidelines in the United States is warranted.", "Precise regulation of kinetochore-microtubule attachments is essential for successful chromosome segregation. Central to this regulation is Aurora B kinase, which phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the N-terminal \"tail\" domain of Hec1, which is a component of the NDC80 complex, a force-transducing link between kinetochores and microtubules. Although Aurora B is regarded as the \"master regulator\" of kinetochore-microtubule attachment, other mitotic kinases likely contribute to Hec1 phosphorylation. In this study, we demonstrate that Aurora A kinase regulates kinetochore-microtubule dynamics of metaphase chromosomes, and we identify Hec1 S69, a previously uncharacterized phosphorylation target site in the Hec1 tail, as a critical Aurora A substrate for this regulation. Additionally, we demonstrate that Aurora A kinase associates with inner centromere protein (INCENP) during mitosis and that INCENP is competent to drive accumulation of the kinase to the centromere region of mitotic chromosomes. These findings reveal that both Aurora A and B contribute to kinetochore-microtubule attachment dynamics, and they uncover an unexpected role for Aurora A in late mitosis.", "Neisseria meningitidis still leads to deaths and severe disability in children, adolescents and adults. Six different capsular groups of N. meningitidis cause invasive meningococcal disease in the form of meningitis and septicaemia in humans. Although conjugate meningococcal vaccines have been developed to provide protection against four of the capsular groups causing most diseases in humans, vaccines against capsular group B, which causes 85% of cases in Australia and the United Kingdom, have only recently been developed. A capsular group B meningococcal vaccine - 4CMenB (Bexsero) - has recently been licensed in the European Union, Canada and Australia. In Australia, a submission for inclusion of 4CMenB in the funded national immunization programme has recently been rejected. The vaccine will now be introduced into the national immunization programme in the United Kingdom following negotiation of a cost-effective price. With the current low incidence of invasive meningococcal disease in many regions, cost-effectiveness of a new capsular group B meningococcal vaccine is borderline in both the United Kingdom and Australia. Cost-effectiveness of an infant programme is determined largely by the direct protection of those vaccinated and is driven by the higher rate of disease in this age group. However, for an adolescent programme to be cost-effective, it must provide both long-term protection against both disease and carriage. The potential of vaccination to reduce the rate of severe invasive disease is a real possibility. A dual approach using both an infant and adolescent immunization programme to provide direct protection to those age groups at highest risk of meningococcal disease and to optimize the potential herd immunity effects is likely to be the most effective means of reducing invasive meningococcal disease. This commentary aims to describe the known disease burden and consequences of meningococcal disease, and the development and potential effectiveness of new capsular group B meningococcal vaccines.", "Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.", "INTRODUCTION: Adult lactose intolerance (ALI) significantly alters calcium intake and absorption, and thus may promote osteoporosis. ALI is a recessive condition with a geographical north-south gradient characterised by decreased levels of intestinal lactase. PCR-based genotyping of lactase (LCT) gene polymorphisms is a safe and easy way to diagnose ALI and may complement diagnostic procedures to identify individuals at risk for reduced calcium intake and subsequently osteoporosis due to lactose malabsorption. Therefore, we investigated the frequency of ALI and its influence on calcium intake, markers of bone metabolism and bone mineral density (BMD) in a cohort of Turkish immigrants living in Germany.MATERIALS AND METHODS: We investigated single nucleotide polymorphisms of the LCT gene, calcium intake, markers of bone metabolism and BMD in 183 Turkish immigrants.RESULTS: ALI was diagnosed in 154 out of 183 (81%) probands. ALI was significantly associated with self-reported lactose intolerance (p < 0.001) and dislike for dairy products (p < 0.01). Osteopenia was diagnosed in 59 out of 183 (32%) and osteoporosis in 15 out of 183 (8%) probands. Probands with reduced BMD had ALI in 86%. All probands had a decreased calcium intake [mg/week]. There was no significant association between ALI, calcium intake, markers of bone metabolism or BMD.CONCLUSION: Turkish immigrants mostly have ALI and overall show a reduced calcium intake per week. However, ALI did not significantly influence calcium intake, markers of bone metabolism or BMD in this cohort. Therefore, ALI in Turkish immigrants does not seem to be a risk factor for osteoporosis.", "Hunter disease or mucopolysaccharidosis type II is an X-linked disease caused by the deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). The IDS gene (24 kb) contains nine exons and has been completely sequenced. A pseudogene (IDS-2 locus) distal to the functional IDS gene has recently been identified. This work reports the characterization of IDS gene alterations in two severely affected patients. Patient 1 has a partial deletion that removes exons I to VI and extends about 200 kb upstream of the IDS gene. Patient 2 has an internal deletion of exons IV, V, VI, and VII, which results from an IDS gene-pseudogene exchange between highly homologous regions. In the rearranged gene, the junction intron contains pseudogene intron 3- and intron 7-related sequences. An interchromosomal recombination is probably the cause of this rearranged X chromosome.", "The quality control system in the endoplasmic reticulum of eukaryotic cells ensures that newly synthesized proteins that fail to fold into the correct conformation or unassembled orphan subunits of oligomeric proteins are rapidly eliminated by proteolytic degradation. This entails the export of proteins from the endoplasmic reticulum to the cytosol followed by their destruction by the cytosolic ubiquitin/proteasome pathway. While this mechanism effectively prevents the cellular accumulation of non-functional or unwanted endogenous proteins, it renders the cell vulnerable to certain viruses and toxins that are able to subvert this degradative mechanism for their own advantage." ]

[ "PURPOSE: We aimed to determine the clinical role of the p53 family members p53 and p73 in the responsiveness to platinum-based chemotherapy and survival in ovarian cancer, considering their cross-talk and the p53 polymorphism at codon 72.EXPERIMENTAL DESIGN: A detailed analysis of p53 and p73 in a series of 122 ovarian cancers was done. We used a functional yeast-based assay to determine the p53 mutational status. Red yeast colonies, indicating mutant p53, were subsequently sequenced to determine the specific p53 alteration. p53 mutations were divided into two groups according to their previous characterization in the literature: those that efficiently inhibit transcriptionally active TAp73 function and those that do not. A p53 polymorphism at codon 72 was determined in corresponding normal tissue or blood of ovarian cancer patients. Isoform-specific p73 expression analysis using real-time reverse transcription-PCR has previously been done in the majority of ovarian cancers included in this study. In a retrospective chart review, responsiveness to chemotherapy was assessed, and survival data with long follow-up times were collected.RESULTS: Eighty of 122 (65.6%) of ovarian cancers harbored p53 mutations. p53 mutational status was an important determinant of responsiveness to platinum-based chemotherapy in all patients with a residual tumor of <2 cm in diameter after initial surgery (wild-type versus mutant, P = 0.029). In addition, p53 mutational status was a strong prognosticator for recurrence-free and overall survival (P < 0.0001 and P = 0.003, respectively) in univariate analyses. High expression levels of dominant-negative p73 isoforms (DeltaNp73 and DeltaN'p73) significantly correlated with chemotherapeutic failure (P = 0.048) and with worse recurrence-free and overall survival in patients with p53 mutant cancers (P = 0.048 and P = 0.005, respectively). Eight p53 mutations, present in 19 cases, were found that efficiently inhibit TAp73 (i.e., 175H, 220C, 245S, 245D, 248W, 248Q, 266E, and 273H). Patients with p53 mutations that efficiently inhibit TAp73 function had a significantly shorter overall survival than patients with p53 mutations of unknown effect on TAp73 (P = 0.044). The p53 polymorphism at codon 72 had no influence on responsiveness to chemotherapy or survival.CONCLUSION: We provide the first clinical evidence that dominant-negative p73 isoforms contribute to drug resistance in vivo, underscoring the importance of a p53-p73 cross-talk. NH2-terminally truncated p73 isoforms were of significant clinical effect by providing an additional unfavorable factor for response to platinum-based chemotherapy and survival in p53 mutant ovarian cancers.", "HERV-H family is the most abundant HERV families in the human genome with more than 1000 copies including full-length, truncated form, and solitary LTRs. We investigated envelope (env) gene fragments of HERV-H family in various human tissues and cancer cells. The env fragments were detected in mRNA of several human tissues (placenta, skeletal muscle, spleen, and thymus) and cancer cells (RT4, BT-474, HCT-116, TE-1, UO-31, Jurkat, HepG2, A549, MCF7, OVCAR-3, MIA-PaCa-2, PC3, LOX-IMVI, AZ521, 2F7, U-937, and C-33A) by RT-PCR approach. The RT-PCR products were cloned and sequenced. New 12 clones from human tissues and 48 clones from cancer cells of env gene sequences belonging to the HERV-H family showed 84.3-98.1% sequence similarity to that of HERV-H (AF108843). Deduced amino acid sequences of 60 clones from human tissues and cancer cell lines showed multiple frameshifts and termination codons caused by deletion/insertion or point mutation with the exception of eight clones as following: HHE9-1, HHE9-5 (skeletal muscle), HHE10-5 (spleen), CHE10-9 (MCF7), CHE12-4, CHE12-5 (MIA-PaCa-2), and CHE18-1, CHE18-3 (C-33A) to that of HERV-H (AF108843). A phylogenetic tree of the HERV-H family was constructed to understand their relationship, indicating that they were divided into three groups, one major (group I) and two minor (group II and III), through sequence divergence. The HERV-H families in group I has been proliferated on human genome during hominoid evolution. These active HERV-H elements are worthy of further investigations as potential pathogenic effects to various human diseases including cancers.", "BACKGROUND: Neutrophil elastase (NE) is implicated in chronic obstructive pulmonary disease (COPD). AZD9668 is a reversible and selective inhibitor of NE, well tolerated at doses of 60 mg bid during Phase I/IIa development.METHODS: This 12-week, randomised, double-blind, placebo-controlled, Phase IIb, trial (NCT01023516), investigated the efficacy and safety of AZD9668 (60 mg bid) versus placebo in patients with symptomatic COPD and a history of exacerbation receiving maintenance budesonide/formoterol. Primary outcome variable: forced expiratory volume in one second (FEV1). Secondary endpoints included: post-bronchodilator FEV1, pre- and post-bronchodilator forced vital capacity, FEV6, forced expiratory flow between 25% and 75% of vital capacity and inspiratory capacity; peak expiratory flow and FEV1 measured at home; EXAcerbations of Chronic pulmonary disease Tool and Breathlessness, Cough and Sputum Scores; St George's respiratory questionnaire for COPD (SGRQ-C) scores; exacerbations; and safety assessments.RESULTS: Six hundred and fifteen patients were randomised: placebo (302), AZD9668 60 mg bid (313). AZD9668 showed no effect on lung function: change in mean pre-bronchodilator FEV1 versus placebo was 0.01L (95% confidence interval: -0.03, 0.05; p=0.533). AZD9668 did not significantly improve respiratory signs and symptoms, SGRQ-C score or time to first exacerbation. Adverse events were similar for AZD9668 and placebo.CONCLUSIONS: Three months' treatment with AZD9668 did not improve lung function, respiratory signs and symptoms or SGRQ-C score when added to budesonide/formoterol maintenance therapy in patients with COPD. In the absence of definitive biomarkers of short-term disease progression, further research is needed to determine the optimal duration of studies to evaluate NE inhibitors as disease-modifying agents.", "The gene that encodes the ATM protein kinase is mutated in ataxia-telangiectasia (A-T). One of the prominent features of A-T is progressive neurodegeneration. We have previously reported that primary astrocytes isolated from Atm(-/-) mice grow slowly and die earlier than control cells in culture. However, the mechanisms for this remain unclear. We show here that intrinsic elevated intracellular levels of reactive oxygen species (ROS) are associated with the senescence-like growth defect of Atm(-/-) astrocytes. This condition is accompanied by constitutively higher levels of ERK1/2 phosphorylation and p16(Ink4a) in Atm(-/-) astrocytes. We also observe that ROS-induced up-regulation of p16(Ink4a) occurs correlatively with ERK1/2-dependent down-regulation and subsequent dissociation from chromatin of Bmi-1. Furthermore, both mitogen-activated protein kinase (MAPK)/ERK inhibitor PD98059 and antioxidant N-acetyl-l-cysteine restored normal proliferation of Atm(-/-) astrocytes. These results suggest that ATM is required for normal astrocyte growth through its ability to stabilize intracellular redox status and that the inability to control ROS is the molecular basis of limited cell growth of Atm(-/-) astrocytes. This defect may be mediated by a mechanism involving ERK1/2 activation and Bmi-1 derepression of p16(Ink4a). These data identify new potential targets for therapeutic intervention in A-T neurodegeneration.", "Mitochondrial membranes were isolated from the myocardium of young (4-month-old) and aged (33-month-old) male Long-Evans rats and compared in terms of cholesterol content and phospholipid and fatty acid composition. In aged rats, as compared to young, the major observations include: markedly higher cholesterol content; increased percentage of sphingomyelin and diphosphatidylglycerol (cardiolipin); in fatty acids, variable changes, with a predominant increase in the 16:0 in most phospholipids except cardiolipin, and sporadic increase in the longer chain (20:0, 24:0) fatty acids in cardiolipin; decreased unsaturation index for most phospholipids but increased for cardiolipin. These results are tentatively interpreted as indicative of an aging-related decrease in fluidity and energy transduction of mitochondrial membrane in the heart of aged rats and may be responsible, in part, for the decrements in cardiac function with aging.", "The metabolic syndrome is a clustering of risk factors which predispose an individual to cardiovascular morbidity and mortality. There is general consensus regarding the main components of the syndrome (glucose intolerance, obesity, raised blood pressure and dyslipidaemia [elevated triglycerides, low levels of high-density lipoprotein cholesterol]) but different definitions require different cut points and have different mandatory inclusion criteria. Although insulin resistance is considered a major pathological influence, only the World Health Organization (WHO) and European Group for the study of Insulin Resistance (EGIR) definitions include it amongst the diagnostic criteria and only the International Diabetes Federation (IDF) definition has waist circumference as a mandatory component. The prevalence of metabolic syndrome within individual cohorts varies with the definition used. Within each definition, the prevalence of metabolic syndrome increases with age and varies with gender and ethnicity. There is a lack of diagnostic concordance between different definitions. Only about 30% of people could be given the diagnosis of metabolic syndrome using most definitions, and about 3540% of people diagnosed with metabolic syndrome are only classified as such using one definition. There is currently debate regarding the validity of the term metabolic syndrome, but the presence of one cardiovascular risk factor should raise suspicion that additional risk factors may also be present and encourage investigation. Individual risk factors should be treated.", "Anti-TNF treatments have given patients with rheumatoid arthritis considerable hope and relief. However, 20-30% of patients do not respond sufficiently to a given anti-TNF drug. In this situation, current strategies include switching to an alternative agent, increasing the dose of the current agent or to return to conventional DMARDs. The arrival of new biologics, which target different molecules than TNF, opens the perspective to other pathways of immunomodulation in RA. These drugs include rituximab (anti-CD20), abatacept (CTLA4Ig) and tocilizumab (anti- IL6R). Comparative studies are urgently needed to assess the efficacy of the different treatment options in order to provide the best therapeutic strategy for our patients." ]

[ "\"Aortitis\" is a pathologic term that refers to an abnormal inflammation of the aortic wall. A wide spectrum of infectious, inflammatory, and idiopathic conditions may result in the development of aortitis. Infectious aortitis may be secondary to bacterial, tubercular, syphilitic, and viral pathogens. Although Takayasu arteritis and giant cell arteritis are the most common rheumatologic causes of aortitis, the other systemic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Behçet disease, and Cogan syndrome, may also be associated with aortitis. In addition, aortitis may also occur without any systemic diseases or infectious causes (idiopathic). Clinical features of aortitis are nonspecific and may include fever, abdominal or chest pain, and vascular insufficiency. Patients may have elevated serum levels of acute phase reactants. A high index of clinical suspicion is always needed for the diagnosis of aortitis in a timely manner. Cross-sectional imaging techniques, such as computed tomographic angiography, magnetic resonance imaging, magnetic resonance angiography, and positron emission tomography, are extremely helpful in diagnosis, assessing disease activity, treatment planning, and post-treatment follow-up. Many of the patients with aortitis may require a multimodality imaging approach for appropriate diagnosis. Knowledge of the clinical features and cross-sectional imaging findings of different types of aortitis permit optimal patient management.", "Lambert-Eaton syndrome (LES) is an immune-mediated disorder of the presynaptic neuromuscular junction due to the blocking effect of the voltage-gated calcium channel (VGCC) antibodies. Small-cell lung cancer (SCLC) is the most common cause of LES. We report an unusual case of LES associated with large-cell neuroendocrine carcinoma (LCNEC) of the lung. In this case, clinical symptoms of LES predated the diagnosis of LCNEC by 6 years. After tumor resection, the patient experienced clinical and electrophysiological improvement. In addition, he had a decrease in VGCC antibody titer from 130 to 80 pmol/L. The onset of LES can be prolonged, and tumor surveillance should continue in these cases.", "Author information:(1)Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.(2)Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.(3)Department of Haematology, NHS Blood and Transplant Centre, University of Cambridge, Cambridge CB2 0XY, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.(4)Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK; European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.(5)Microscopy Area, Core Facilities, Istituto Superiore di Sanità, Rome 00161, Italy.(6)Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.(7)Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.(8)Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.(9)Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.(10)Genomics England, London, UK.(11)Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome 00168, Italy.(12)Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome 00168, Italy; Università Cattolica del Sacro Cuore, Rome 00168, Italy.(13)Unit of Mechanisms, Biomarkers and Models, Department of Environment and Health, Istituto Superiore di Sanità, Rome 00161, Italy.(14)Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.(15)Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.(16)Department of Clinical Genetics, Liverpool Women's Hospital, Liverpool L8 7SS, UK.(17)Department of Medical Genetics, Guys' and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.(18)Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.(19)Phoenix Children's Hospital, Phoenix, AZ 76109, USA.(20)Cook Children's Medical Centre, Fort Worth, TX 76104, USA.(21)Colchester Hospital, East Suffolk and North Essex NHS Foundation Trust, Essex CO4 5JL, UK.(22)Ophthalmology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.(23)Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova 16163, Italy; Area of Neuroscience, SISSA, Trieste 34136, Italy.(24)Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy. Electronic address: marco.tartaglia@opbg.net.(25)Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: ealr4@cam.ac.uk.", "About 5000 (25%) of the ~20400 human protein-coding genes currently lack any experimental evidence at the protein level. For many others, there is only little information relative to their abundance, distribution, subcellular localization, interactions, or cellular functions. The aim of the HUPO Human Proteome Project (HPP, www.thehpp.org ) is to collect this information for every human protein. HPP is based on three major pillars: mass spectrometry (MS), antibody/affinity capture reagents (Ab), and bioinformatics-driven knowledge base (KB). To meet this objective, the Chromosome-Centric Human Proteome Project (C-HPP) proposes to build this catalog chromosome-by-chromosome ( www.c-hpp.org ) by focusing primarily on proteins that currently lack MS evidence or Ab detection. These are termed \"missing proteins\" by the HPP consortium. The lack of observation of a protein can be due to various factors including incorrect and incomplete gene annotation, low or restricted expression, or instability. neXtProt ( www.nextprot.org ) is a new web-based knowledge platform specific for human proteins that aims to complement UniProtKB/Swiss-Prot ( www.uniprot.org ) with detailed information obtained from carefully selected high-throughput experiments on genomic variation, post-translational modifications, as well as protein expression in tissues and cells. This article describes how neXtProt contributes to prioritize C-HPP efforts and integrates C-HPP results with other research efforts to create a complete human proteome catalog.", "Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.", "SUMMARY: Transcription factors regulate gene expression by binding to specific short DNA sequences of 5-20 bp to regulate the rate of transcription of genetic information from DNA to messenger RNA. We present PWMScan, a fast web-based tool to scan server-resident genomes for matches to a user-supplied PWM or transcription factor binding site model from a public database.AVAILABILITY AND IMPLEMENTATION: The web server and source code are available at http://ccg.vital-it.ch/pwmscan and https://sourceforge.net/projects/pwmscan, respectively.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "BACKGROUND: Malaria affects 200-300 million individuals per year worldwide. Plasmodium falciparum is the causative agent of the most severe and mortal type of malaria. The need for new antimalarials comes from the widespread resistance to those in current use. New antimalarial targets are required to increase chemical diversity and effectiveness of the drugs. The research for such new targets and drug chemotypes is aided by structure-based drug design. We present a model of the TBP-TFIIB complex from P. falciparum (pfTBP-pfTFIIB) and a detailed study of the interactions at the TBP-TFIIB interface.METHODS: The model was built using standard methodology, optimized energetically and evaluated structurally. We carried out an analysis of the interface considering its evolution, available experimental data on TBP and TFIIB mutants, and the main conserved and non-conserved interactions. To support the perspective of using this complex as a new target for rational antimalarial design, we present the comparison of the pfTBP-pfTFIIB interface with its human homolog.RESULTS: Despite the high residue conservation at the interface, we identified a potential region, composed of species-specific residues that can be used for rational antimalarial design.CONCLUSIONS: Currently there are no antimalarial drugs targeted to stop the nuclear transcription process, a vital event for all replication stages of P. falciparum. Due to its absolute requirement in transcription initiation, we consider the pfTBP-pfTFIIB interface as a new potential target for novel antimalarial chemotypes." ]

[ "This study was undertaken to analyze DNA methylation profiling at the monoamine oxidase A (MAOA) locus, in order to determine whether abnormal DNA methylation is involved in the development of schizophrenia. We recruited a total of 371 patients with paranoid schizophrenia (199 males and 172 females) and 288 unrelated control subjects (123 males and 165 females) for analysis of DNA methylation. Diagnosis was made based on the Structured Clinical Interview for DSM-VI. Genomic DNA extracted from peripheral blood was chemically modified using bisulfite, and DNA methylation profiles of the MAOA promoter were determined by BSP-sequencing. DNA methylation ratios of individual CpG residues and overall methylation ratios were measured on each subject. The results showed that there was no significant difference in overall DNA methylation ratios between patients and controls either in the female group (P = 0.42) or in the male group (P = 0.24). Of 15 CpG residues that showed significant differences in DNA methylation status between the patient group and the control group in females, eight of which had an increased level and seven, a decreased level, with a combined P value of 1 (df = 160). In male subjects, however, six individual CpG residues showed an increased methylation level with a combined P value of 5.80E-35 (df = 158). In conclusion, abnormalities of DNA methylation at the MAOA promoter may be associated with schizophrenia in males.", "Raised plasma concentrations of atrial natriuretic peptide (ANP) have been reported in patients with Type 1 (insulin dependent) diabetes mellitus (DM) who have poor glycaemic control and are associated with the presence of microalbuminuria. To test the hypothesis that elevations in plasma ANP concentration increase urinary albumin excretion in Type 1 DM, we have studied the effects of intravenous infusions of ANP in eight such subjects with established microalbuminuria. Blood glucose was maintained between 4 and 7 mmol l-1 in all subjects for the duration of studies; after euglycaemia had been established, a standard oral water load (20 ml kg-1 plus replacement of urinary losses) was given. Once steady state diuresis was attained, subjects received intravenous infusion of either placebo (0.9% saline), low dose (2.5 pmol kg-1 min-1) or high dose (5.0 pmol kg-1 kg min-1) ANP solution in a randomized, double-blind protocol. Infusion of ANP caused a dose-dependent increase in urinary albumin excretion rate (placebo, 11.3 (SD 8.9) to 8.7 (SD 6.8) micrograms min-1; low dose ANP, 12.4 (SD 9.9) to 26.5 (SD 27.5) micrograms min-1, p < 0.01; high dose ANP 10.3 (SD 7.3) to 36.6 (SD 28.5) micrograms min-1, p < 0.001, ANOVA). Only high dose ANP caused an increase in urine flow. Blood glucose remained unchanged in all studies. We conclude that intravenous infusions of ANP cause a dose-dependent increase in urinary albumin excretion rate in Type 1 DM subjects with microalbuminuria. These data support the hypothesis that ANP has albuminuric actions which may contribute to microalbuminuria in Type 1 DM.", "OBJECTIVE: Epigenetic changes in gene expression, including DNA methylation and histone modifications, might contribute to autoimmunity. DNA methylation is mediated by a family of DNA methyltransferases. Polymorphisms of the DNA methyltransferase 3B (DNMT3B) gene may influence DNMT3B activity on DNA methylation, thereby modulating the susceptibility to some diseases. The purpose of this study was to investigate the association between the single nucleotide polymorphism (SNP) in promoter of the DNMT3B gene and the risk for development of idiopathic thrombocytopenic purpura (ITP).METHODS: In this hospital-based case-control study, the DNMT3B SNP was genotyped in 201 patients with ITP and 136 healthy controls by polymerase chain reaction-restriction fragment length polymorphism.RESULTS: The C/C genotype was not detected in both the patients with ITP and the controls. In the controls, the frequencies of T/T and C/T genotypes and T and C alleles were 97.8%, 2.2%, 98.9%, and 1.1%, respectively. There was no significant difference in genotype and allele distribution between the patients with ITP and the controls (P = 0.745 and 0.747, respectively). No significant difference was observed in genotype and allele distribution between the two groups when stratified by the age. The similar results were shown among the four groups of patients with ITP: acute childhood, chronic childhood, acute adult, and chronic adult.CONCLUSION: This polymorphism was distributed similarly between the patients with ITP and the controls. It demonstrated that it may not be used as a stratification marker to predict the susceptibility to ITP, at least in the population of North China.", "Alu elements are the most abundant repetitive elements in the human genome; they have amplified by retrotransposition to reach the present number of more than one million copies. Alu elements can be transcribed in two different ways, by two independent polymerases. 'Free Alu RNAs' are transcribed by Pol III from their own promoter, while 'embedded Alu RNAs' are transcribed by Pol II as part of protein- and non-protein-coding RNAs. Recent studies have demonstrated that both free and embedded Alu RNAs play a major role in post transcriptional regulation of gene expression, for example by affecting protein translation, alternative splicing and mRNA stability. These discoveries illustrate how a part of the 'junk DNA' content of the human genome has been recruited to important functions in regulation of gene expression.", "Lipid-linked oligosaccharides (LLOs) play an important role in the N-glycosylation pathway as the donor substrate of oligosaccharyltransferases (OSTs), which are responsible for the en bloc transfer of glycan chains onto a nascent polypeptide. The lipid component of LLO in both eukarya and archaea consists of a dolichol, and an undecaprenol in prokarya, whereas the number of isoprene units may change between species. Given the potential relevance of LLOs and their related enzymes to diverse biotechnological applications, obtaining reliable LLO models from distinct domains of life could support further studies on complex formation and their processing by OSTs, as well as protein engineering on such systems. In this work, molecular modeling techniques, such as quantum mechanics calculations, molecular dynamics simulations, and metadynamics were employed to study eukaryotic (Glc3-Man9-GlcNAc2-PP-Dolichol), bacterial (Glc1-GalNAc5-Bac1-PP-Undecaprenol), and archaeal (Glc1-Man1-Gal1-Man1-Glc1-Gal1-Glc1-P-Dolichol) LLOs in membrane bilayers. Microsecond molecular dynamics simulations and metadynamics calculations of LLOs revealed that glycan chains are more prone to interact with the membrane lipid head groups, while the PP linkages are positioned at the lipid phosphate head groups level. The dynamics of isoprenoid chains embedded within the bilayer are described, and membrane dynamics and related properties are also investigated. Overall, there are similarities regarding the structure and dynamics of the eukaryotic, the bacterial, and the archaeal LLOs in bilayers, which can support the comprehension of their association with OSTs. These data may support future studies on the transferring mechanism of the oligosaccharide chain to an acceptor protein.", "Oligosaccharyltransferases (OSTs) mediate the en bloc transfer of N-glycan intermediates onto the asparagine residue in glycosylation sequons (N-X-S/T, X≠P). These enzymes are typically heteromeric complexes composed of several membrane-associated subunits, in which STT3 is highly conserved as a catalytic core. Metazoan organisms encode two STT3 genes (STT3A and STT3B) in their genome, resulting in the formation of at least two distinct OST isoforms consisting of shared subunits and complex specific subunits. The STT3A isoform of OST primarily glycosylates substrate polypeptides cotranslationally, whereas the STT3B isoform is involved in cotranslational and post-translocational glycosylation of sequons that are skipped by the STT3A isoform. Here, we describe mutant constructs of monomeric enhanced green fluorescent protein (mEGFP), which are susceptible to STT3B-dependent N-glycosylation. The endoplasmic reticulum-localized mEGFP (ER-mEGFP) mutants contained an N-glycosylation sequon at their C-terminus and exhibited increased fluorescence in response to N-glycosylation. Isoform-specific glycosylation of the constructs was confirmed by using STT3A- or STT3B-knockout cell lines. Among the mutant constructs that we tested, the ER-mEGFP mutant containing the N185 -C186 -T187 sequon was the best substrate for the STT3B isoform in terms of glycosylation efficiency and fluorescence change. Our results suggest that the mutant ER-mEGFP is useful for monitoring STT3B-dependent post-translocational N-glycosylation in cells of interest, such as those from putative patients with a congenital disorder of glycosylation.", "OBJECTIVE: To determine the flare rate and the change in Safety of Estrogens in Lupus Erythematosus: National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA SLEDAI) score with disease flare in pediatric systemic lupus erythematosus (pSLE).METHODS: A retrospective chart review of 62 patients with pSLE (ages 5-20 yrs). A flare was defined as the start of, or increase in, the dose of corticosteroids and/or the addition of an immunosuppressive medication. All pre-flare, flare, and post-flare visits were recorded with a SELENA SLEDAI score calculated for each visit. The flare rate was calculated by dividing the total number of flares in the cohort by the total followup years.RESULTS: Sixty-two patients were eligible. Forty-seven patients had 112 flares. The average number of flares/patient was 1.8 +/- 2.0 and the mean inter-flare time was 15.4 +/- 17.9 months. The flare rate in pSLE was 0.46 flares/patient-year of followup. The median time to first flare from the date of diagnosis was 14.3 months. Patients with cytopenia, pleuritis, or pericarditis, or a positive antibody to Smith nuclear antigen at the time of diagnosis had a significantly higher flare rate than those who did not. The average SELENA SLEDAI score at presentation was 12.5 +/- 5.4, at the pre-flare visit 6.3 +/- 3.5, and during a flare 7.9 +/- 5.1.CONCLUSION: This is the first large study to report a flare rate (0.46 flares/patient-year of followup) in pSLE. The flare rate was similar to what has been reported in pSLE previously but significantly lower than that reported in adults with lupus. The average change in the SELENA SLEDAI score with disease flare is 2 points.", "Glycosylation is increasingly recognised as a common protein modification within bacterial proteomes. While great strides have been made in identifying species that contain glycosylation systems, our understanding of the proteins and sites targeted by these systems is far more limited. Within this work we explore the conservation of glycoproteins and glycosylation sites across the pan-Burkholderia glycoproteome. Using a multi-protease glycoproteomic approach, we generate high-confidence glycoproteomes in two widely utilized B. cenocepacia strains, K56-2 and H111. This resource reveals glycosylation occurs exclusively at Serine residues and that glycoproteins/glycosylation sites are highly conserved across B. cenocepacia isolates. This preference for glycosylation at Serine residues is observed across at least 9 Burkholderia glycoproteomes, supporting that Serine is the dominant residue targeted by PglL-mediated glycosylation across the Burkholderia genus. Combined, this work demonstrates that PglL enzymes of the Burkholderia genus are Serine-preferring oligosaccharyltransferases that target conserved and shared protein substrates.", "Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a well-characterized X-linked inherited disorder in humans but has not been reported in horses. We describe a persistent hemolytic anemia and hyperbilirubinemia due to a severe G6PD deficiency in an American Saddlebred colt. Other abnormalities in the colt's erythrocytes as compared with those of healthy horses (n = 22-35) included increased activities of hexokinase and pyruvate kinase, decreased concentrations of reduced glutathione and reduced nicotinamide adenine dinucleotide phosphate (NADP), and increased concentration of oxidized NADP. Morphologic abnormalities included eccentrocytosis, pyknocytosis, anisocytosis, macrocytosis, and increased number of Howell-Jolly bodies. Scanning and transmission electron microscopic examinations revealed that eccentrocytes had contracted to spherical regions and thin collapsed regions. Eccentrocytes were more electron dense than were normal erythrocytes when examined by transmission electron microscopy. When exposed to acetylphenylhydrazine, erythrocytes from the G6PD-deficient colt produced more and smaller Heinz bodies than did erythrocytes from normal horses. Abnormalities in the colt's dam included presence of eccentrocytes and pyknocytes; her average erythrocyte G6PD activity was slightly below the range of reference values.", "Multivalent polyions can undergo complex coacervation, producing membraneless compartments that accumulate ribozymes and enhance catalysis, and offering a mechanism for functional prebiotic compartmentalization in the origins of life. Here, we evaluate the impact of lower, more prebiotically-relevant, polyion multivalency on the functional performance of coacervates as compartments. Positively and negatively charged homopeptides with 1-100 residues and adenosine mono-, di-, and triphosphate nucleotides are used as model polyions. Polycation/polyanion pairs are tested for coacervation, and resulting membraneless compartments are analyzed for salt resistance, ability to provide a distinct internal microenvironment (apparent local pH, RNA partitioning), and effect on RNA structure formation. We find that coacervates formed by phase separation of the shorter polyions more effectively generated distinct pH microenvironments, accumulated RNA, and preserved duplexes than those formed by longer polyions. Hence, coacervates formed by reduced multivalency polyions are not only viable as functional compartments for prebiotic chemistries, they can outperform higher molecular weight analogues.", "Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer.", "Much has been learned about thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT) and much remains a diagnostic and management challenge. While the pentad of thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal and neurologic abnormalities characterize the clinical presentation of TTP, few patients present with all signs and symptoms. Worse yet, the pentad and its components are seen in other so-called thrombotic microangiopathies that demand different treatment approaches. HIT is another systemic disorder presenting with thrombocytopenia and/or thrombosis with potential devastating consequences whose diagnosis is difficult and management is still evolving. Highlights of the conditions and clinical and laboratory hints that allow physicians to diagnose TTP and HIT efficiently and offer patients the best available therapeutic interventions are presented.", "BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a rare disorder of unknown cause. The classical triad of MRS is orofacial edema, recurrent facial paralysis, and a fissured tongue.PATIENT: We present a 9-year-old girl with a recurrent peripheral facial paralysis. She experienced the first episode of a peripheral facial paralysis on the same side without orofacial swelling and lingua plicata 1 year ago. She was diagnosed with Hashimoto thyroiditis 9 months earlier, as confirmed by an endocrinologic investigation.RESULTS: While the patient was hospitalized with recurrent facial paralysis, we found that serum levels of free thyroxine (1.3 ng/dL) and thyrotropin (0.4 uIU/mL) were within normal range, but the level of antithyroperoxidase antibodies (772.0 IU/mL) was very increased. She had been taking an oral prednisolone orally for 2 weeks. At the 1-month follow-up, the patient's symptoms had completely disappeared.DISCUSSION: The possible correlation between MRS and autoimmune disorders has been documented in only one report, which described an adult with autoimmune thyroiditis (Hashimoto thyroiditis) and MRS. We suggest that the co-occurrence of MRS and Hashimoto thyroiditis is not coincidental but linked to autoimmunity.", "PURPOSE: To evaluate the risk factors associated with lung cancer (LC) and other second neoplasms (SN) in Hodgkin lymphoma (HL) survivors.METHODS: We retrospectively analyzed the clinical characteristics and outcomes of 604 patients treated in our institution between 1968 and 2012.RESULTS: 90 out of 604 patients developed SN: 27 LC and 63 other SN. The median time elapsed until LC and other SN was 16.5 and 11.8 years, respectively (p = 0.003). In the LC group, 85.5 % of patients were male and 84.6 % smokers (HR 7, 95 % CI 2.4-20.7, p < 0.001). Radiotherapy (RT) doses applied were higher in the SN group with an increased risk of LC (HR: 4.0 95 % CI 1.1-11.6, p = 0.010) and other SN (HR: 3.3 95 % CI 1.6-6.7 p = 0.001) with doses higher than 42 Gy. No association was found between alkylating agents and development of SN. In LC, the most frequent histology was adenocarcinoma with an elapsed time after HL of 13.2 years in early stages and 21.3 in advanced (p = 0.02). Median OS after a diagnosis of LC was 12.6 months ranging from 5.9 (in cases presenting due to symptoms) to 49.1 (incidentally diagnosed cases) (p = 0.005).CONCLUSIONS: RT treatment, especially with doses higher than 42 Gy, and smoking increase the risk of SN after HL. In this series, LC patients with early stages had a shorter elapsed time from HL diagnosis and longer OS, therefore the role of LC screening in HL survivors should be prospectively evaluated and smoking cessation counseling ought to be a key aspect during follow-up.", "The crowned dens syndrome (CDS) is a clinicoradiological entity defined as acute neck pain due to deposition of crystals surrounding the odontoid process. Crystal deposition may occur without symptoms or exhibit myelopathy by compressing the spinal cord. Neck pain on lateral rotation has been described in the previous papers for CDS. We tested the validity of \"painful neck on rotation\" as a potential diagnostic tool to differentiate CDS from meningeal irritation. Patients 1 and 2 were relatively young females and showed acute cervico-occipital pain, with marked limitation on neck rotation. Patient 2 was suspected to have neck strain, since there was no fever and no elevated CRP. In contrast, patient 3 was an older female and showed headache and limitation of neck rotation. Cerebrospinal fluid was normal in spite of inflammatory reaction on laboratory markers. All three patients showed absence of or only a mild limitation on neck flexion. A computed tomography scan focused on the craniocervical junction revealed mottled calcification around the odontoid process. Painful neck on rotation may have diagnostic implications for CDS in patients with cervico-occipital pain.", "4'-Thio-2'-deoxycytidine was synthesized as a 5'- protected phosphoramidite compatible with solid phase DNA synthesis. When incorporated as the target cytosine (C*) in the GC*GC recognition sequence for the DNA methyltransferase M. HhaI, methyl transfer was strongly inhibited. In contrast, these same oligonucleotides were normal substrates for the cognate restriction endonuclease R. HhaI and its isoschizomer R. Hin P1I. M. HhaI was able to bind both 4'-thio-modified DNA and unmodified DNA to equivalent extents under equilibrium conditions. However, the presence of 4'-thio-2'-deoxycytidine decreased the half-life of the complex by >10-fold. The crystal structure of a ternary complex of M. HhaI, AdoMet and DNA containing 4'-thio-2'-deoxycytidine was solved at 2.05 A resolution with a crystallographic R-factor of 0.186 and R-free of 0.231. The structure is not grossly different from previously solved ternary complexes containing M. HhaI, DNA and AdoHcy. The difference electron density suggests partial methylation at C5 of the flipped target 4'-thio-2'-deoxycytidine. The inhibitory effect of the 4'sulfur atom on enzymatic activity may be traced to perturbation of a step in the methylation reaction after DNA binding but prior to methyl transfer. This inhibitory effect can be partially overcome after a considerably long time in the crystal environment where the packing prevents complex dissociation and the target is accurately positioned within the active site.", "Protein glycosylation, or the attachment of sugar moieties (glycans) to proteins, is important for protein stability, activity, and immunogenicity. However, understanding the roles and regulations of site-specific glycosylation events remains a significant challenge due to several technological limitations. These limitations include a lack of available tools for biochemical characterization of enzymes involved in glycosylation. A particular challenge is the synthesis of oligosaccharyltransferases (OSTs), which catalyze the attachment of glycans to specific amino acid residues in target proteins. The difficulty arises from the fact that canonical OSTs are large (>70 kDa) and possess multiple transmembrane helices, making them difficult to overexpress in living cells. Here, we address this challenge by establishing a bacterial cell-free protein synthesis platform that enables rapid production of a variety of OSTs in their active conformations. Specifically, by using lipid nanodiscs as cellular membrane mimics, we obtained yields of up to 420 μg/ml for the single-subunit OST enzyme, \"Protein glycosylation B\" (PglB) from Campylobacter jejuni, as well as for three additional PglB homologs from Campylobacter coli, Campylobacter lari, and Desulfovibrio gigas. Importantly, all of these enzymes catalyzed N-glycosylation reactions in vitro with no purification or processing needed. Furthermore, we demonstrate the ability of cell-free synthesized OSTs to glycosylate multiple target proteins with varying N-glycosylation acceptor sequons. We anticipate that this broadly applicable production method will advance glycoengineering efforts by enabling preparative expression of membrane-embedded OSTs from all kingdoms of life.", "Bioconjugate vaccines, consisting of polysaccharides attached to carrier proteins, are enzymatically generated using prokaryotic glycosylation systems in a process termed bioconjugation. Key to bioconjugation are a group of enzymes known as oligosaccharyltransferases (OTases) that transfer polysaccharides to engineered carrier proteins containing conserved amino acid sequences known as sequons. The most recently discovered OTase, PglS, has been shown to have the broadest substrate scope, transferring many different types of bacterial glycans including those with glucose at the reducing end. However, PglS is currently the least understood in terms of the sequon it recognizes. PglS is a pilin-specific O-linking OTase that naturally glycosylates a single protein, ComP. In addition to ComP, we previously demonstrated that an engineered carrier protein containing a large fragment of ComP is also glycosylated by PglS. Here we sought to identify the minimal ComP sequon sufficient for PglS glycosylation. We tested >100 different ComP fragments individually fused to Pseudomonas aeruginosa exotoxin A (EPA), leading to the identification of an 11-amino acid sequence sufficient for robust glycosylation by PglS. We also demonstrate that the placement of the ComP sequon on the carrier protein is critical for stability and subsequent glycosylation. Moreover, we identify novel sites on the surface of EPA that are amenable to ComP sequon insertion and find that Cross-Reactive Material 197 fused to a ComP fragment is also glycosylated. These results represent a significant expansion of the glycoengineering toolbox as well as our understanding of bacterial O-linking sequons.", "Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naïve-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naïve-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.", "Propionic acidemia (PA, MIM 232000 and 232050) is caused by a deficiency of mitochondrial biotin-dependent propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a heteropolymeric enzyme composed of alpha and beta subunits, which are encoded by the PCCA and PCCB genes, respectively. The PCCA protein (alpha subunit) is responsible for the formation of carboxybiotin upon hydrolysis of ATP and contains a C-terminal biotin-binding domain and a biotin carboxylase domain, defined by homology with other biotin-dependent carboxylases, some of them characterized structurally. More than 24 mutations have been found in the PCCA gene in patients with PA, among them 14 missense mutations and one in-frame deletion, for which the precise molecular effect is unknown. In this study, we have established the pathogenicity of 11 PCCA mutations (10 missense and an in-frame deletion) by expression studies in deficient fibroblasts and in a cell-free in vitro system, and analyzed the effect of each mutation on PCC activity, protein stability and domain structure. The results show that most mutant proteins show an increased turnover and are functionally deficient, suggesting that the structural alterations they cause are incompatible with normal assembly to produce a stable, functional PCC oligomer. These results are discussed in the context of the genotype-phenotype correlations in PCCA-deficient PA patients." ]

[ "Insomnia persistently affects the quality and quantity of sleep. Currently approved treatments for insomnia primarily target γ-aminobutyric acid-A (GABA-A) receptor signalling and include benzodiazepines and GABA-A receptor modulators. These drugs are used to address this sleep disorder, but have the potential for side effects such as tolerance and dependence, making them less attractive as maintenance therapy. Forward and reverse genetic approaches in animals have implicated orexin signalling (also referred to as hypocretin signalling) in the control of vigilance and sleep/wake states. Screening for orexin receptor antagonists using in vitro and in vivo methods in animals has identified compounds that block one or other of the orexin receptors (single or dual orexin receptor antagonists [SORAs and DORAs], respectively) in animals and humans. SORAs have primarily been used as probes to further elucidate the roles of the individual orexin receptors, while a number of DORAs have progressed to clinical development as pharmaceutical candidates for insomnia. The DORA almorexant demonstrated significant improvements in a number of clinically relevant sleep parameters in animal models and in patients with insomnia but its development was halted. SB-649868 and suvorexant have demonstrated efficacy and tolerability in Phase II and III trials respectively. Furthermore, suvorexant is currently under review by the Food and Drug Administration for the treatment of insomnia. Based on the publication of recent non-clinical and clinical data, orexin receptor antagonists potentially represent a targeted, effective and well-tolerated new class of medications for insomnia.", "The present review surveys the available data on the involvement of adenine deamination in RNA molecules in the formation of structurally and functionally diverse RNA and protein subforms in eukaryotic cells. Deamination of adenine by adenosine deaminases that act on RNA (ADARs) leads to the conversion of adenine into inosine (A-I editing) recognized by the splicing and translation systems as guanine. This may modify splicing sites in pre-mRNA and codons in translated regions ofmRNA and also affect the RNA secondary structure. Apart from mRNA, editing also involves microRNAs whose regulatory functions in multicellular animals are associated with the inhibition of transcription of target genes or with the degradation of certain RNA transcripts. ADARs can inhibit the production of mature microRNAs or modify microRNAs so that their specificity to target genes is altered. Adenosine deaminases editing adenines in transport RNAs (ADATs) convert adenine into inosine in tRNAs of all eukaryotes; as a result, the diversity of tRNA forms in the cell increases.", "Clustering is the process of grouping different data objects based on similar properties. Clustering has applications in various case studies from several fields such as graph theory, image analysis, pattern recognition, statistics and others. Nowadays, there are numerous algorithms and tools able to generate clustering results. However, different algorithms or parameterizations may produce quite dissimilar cluster sets. In this way, the user is often forced to manually filter and compare these results in order to decide which of them generate the ideal clusters. To automate this process, in this study, we present VICTOR, the first fully interactive and dependency-free visual analytics web application which allows the visual comparison of the results of various clustering algorithms. VICTOR can handle multiple cluster set results simultaneously and compare them using ten different metrics. Clustering results can be filtered and compared to each other with the use of data tables or interactive heatmaps, bar plots, correlation networks, sankey and circos plots. We demonstrate VICTOR's functionality using three examples. In the first case, we compare five different network clustering algorithms on a Yeast protein-protein interaction dataset whereas in the second example, we test four different parameters of the MCL clustering algorithm on the same dataset. Finally, as a third example, we compare four different meta-analyses with hierarchically clustered differentially expressed genes found to be involved in myocardial infarction. VICTOR is available at http://victor.pavlopouloslab.info or http://bib.fleming.gr:3838/VICTOR.", "The replication of many viral and subviral pathogens as well as the amplification of certain cellular genes proceeds via a rolling circle mechanism. For potato spindle tuber (PSTVd) and related viroids, the possible role of a circular (-)strand RNA as a template for synthesis of (+)strand progeny is unclear. Infected plants appear to contain only multimeric linear (-)strand RNAs, and attempts to initiate infection with multimeric (-)PSTVd RNAs generally have failed. To examine critically the infectivity of monomeric (-)strand viroid RNAs, we have developed a ribozyme-based expression system for the production of precisely full length (-)strand RNAs whose termini are capable of undergoing facile circularization in vitro. Mechanical inoculation of tomato seedlings with electrophoretically purified (-)PSTVd RNA led to a small fraction of plants becoming infected whereas parallel assays with an analogous tomato planta macho viroid (-)RNA resulted in a much larger fraction of infected plants. Ribozyme-mediated production of (-)PSTVd RNA in transgenic plants led to the appearance of monomeric circular (-)PSTVd RNA and large amounts of (+)PSTVd progeny. No monomeric circular (-)PSTVd RNA could be detected in naturally infected plants by using either ribonuclease protection or electrophoresis under partially denaturing conditions. Although not a component of the normal replicative pathway, precisely full length (-)PSTVd RNA appears to contain all of the structural and regulatory elements necessary for initiation of viroid replication.", "BACKGROUND: Facing a growing workload and dwindling resources, the US National Library of Medicine (NLM) created the Indexing Initiative project in 1996. This cross-library team's mission is to explore indexing methodologies for ensuring quality and currency of NLM document collections. The NLM Medical Text Indexer (MTI) is the main product of this project and has been providing automated indexing recommendations since 2002. After all of this time, the questions arise whether MTI is still useful and relevant.METHODS: To answer the question about MTI usefulness, we track a wide variety of statistics related to how frequently MEDLINE indexers refer to MTI recommendations, how well MTI performs against human indexing, and how often MTI is used. To answer the question of MTI relevancy compared to other available tools, we have participated in the 2013 and 2014 BioASQ Challenges. The BioASQ Challenges have provided us with an unbiased comparison between the MTI system and other systems performing the same task.RESULTS: Indexers have continually increased their use of MTI recommendations over the years from 15.75% of the articles they index in 2002 to 62.44% in 2014 showing that the indexers find MTI to be increasingly useful. The MTI performance statistics show significant improvement in Precision (+0.2992) and F1 (+0.1997) with modest gains in Recall (+0.0454) over the years. MTI consistency is comparable to the available indexer consistency studies. MTI performed well in both of the BioASQ Challenges ranking within the top tier teams.CONCLUSIONS: Based on our findings, yes, MTI is still relevant and useful, and needs to be improved and expanded. The BioASQ Challenge results have shown that we need to incorporate more machine learning into MTI while still retaining the indexing rules that have earned MTI the indexers' trust over the years. We also need to expand MTI through the use of full text, when and where it is available, to provide coverage of indexing terms that are typically only found in the full text. The role of MTI at NLM is also expanding into new areas, further reinforcing the idea that MTI is increasingly useful and relevant.", "BACKGROUND: Disease Activity Score in 28 Joints (DAS28) is a scoring system to evaluate disease activity and treatment response in rheumatoid arthritis (RA). A DAS28 score of greater than 3.2 is a well-described limit for treatment intensification; however, the reliability of DAS28 might be overestimated.OBJECTIVE: The aim of this study was to evaluate the reliability of DAS28 in RA, especially focusing on a subgroup of patients with a DAS28 score of greater than 3.2.METHODS: Data from RA patients registered in the local part of Danish DANBIO Registry were collected in May 2015. Patients were categorized into 2 groups: First, those with DAS28 >3.2 with at least one swollen joint (SJ) or elevated C-reactive protein (CRP) (\"objective group\"), and second, patients with a DAS28 >3.2 who had no SJ, and CRP values were within the reference range (\"subjective group\"). Disease Activity Score in 28 Joints, Clinical Disease Activity Index, and Health Assessment Questionnaire scores were calculated for each group. We defined new score, DAS28 subjective, to focus on subjective parameters.RESULTS: Two hundred thirty patients were included; 198 (86.1%) and 32 (13.9%) patients were in the objective and subjective groups, respectively. Patients in the subjective group had lower mean values of DAS28 (P < 0.001) and Evaluator Global Assessment (P < 0.001) with less common immunoglobulin M rheumatoid factor (P < 0.001) and anti-cyclic citrullinated peptide positivity (P = 0.02) and contrarily higher mean values of tender joints (P = 0.04) and DAS28 based on subjective parameters (P = 0.003) compared with the objective group.CONCLUSIONS: Rheumatoid arthritis scoring systems should be used cautiously in patients who are considered for treatment intensification. Patients with central sensitization and psychological problems and those with false-positive diagnosis of RA are at high risk of overtreatment.", "Certain tumor cell responses to the growth factor-inducible early response gene product CCN1/Cyr61 overlap with those induced by the hepatocyte growth factor (HGF)/c-Met signaling pathway. In this study, we investigate if Cyr61 is a downstream effector of HGF/c-Met pathway activation in human glioma cells. A semiquantitative immunohistochemical analysis of 112 human glioma and normal brain specimens showed that levels of tumor-associated Cyr61 protein correlate with tumor grade (P < 0.001) and with c-Met protein expression (r(2) = 0.4791, P < 0.0001). Purified HGF rapidly upregulated Cyr61 mRNA (peak at 30 minutes) and protein expression (peak at 2 hours) in HGF(-)/c-Met(+) human glioma cell lines via a transcription- and translation-dependent mechanism. Conversely, HGF/c-Met pathway inhibitors reduced Cyr61 expression in HGF(+)/c-Met(+) human glioma cell lines in vitro and in HGF(+)/c-Met(+) glioma xenografts. Targeting Cyr61 expression with small interfering RNA (siRNA) inhibited HGF-induced cell migration (P < 0.01) and cell growth (P < 0.001) in vitro. The effect of Cyr61 on HGF-induced Akt pathway activation was also examined. Cyr61 siRNA had no effect on the early phase of HGF-induced Akt phosphorylation (Ser(473)) 30 minutes after stimulation with HGF. Cyr61 siRNA inhibited a second phase of Akt phosphorylation measured 12 hours after cell stimulation with HGF and also inhibited HGF-induced phosphorylation of the Akt target glycogen synthase kinase 3alpha. We treated preestablished subcutaneous glioma xenografts with Cyr61 siRNA or control siRNA by direct intratumoral delivery. Cyr61 siRNA inhibited Cyr61 expression and glioma xenograft growth by up to 40% in a dose-dependent manner (P < 0.05). These results identify a Cyr61-dependent pathway by which c-Met activation mediates cell growth, cell migration, and long-lasting signaling events in glioma cell lines and possibly astroglial malignancies." ]

[ "BACKGROUND: Premorbid body mass index, physical activity, diabetes and cardiovascular disease have been associated with an altered risk of developing amyotrophic lateral sclerosis (ALS). There is evidence of shared genetic risk between ALS and lipid metabolism. A very large prospective longitudinal population cohort permits the study of a range of metabolic parameters and the risk of subsequent diagnosis of ALS.METHODS: The risk of subsequent ALS diagnosis in those enrolled prospectively to the UK Biobank (n=502 409) was examined in relation to baseline levels of blood high and low density lipoprotein (HDL, LDL), total cholesterol, total cholesterol:HDL ratio, apolipoproteins A1 and B (apoA1, apoB), triglycerides, glycated haemoglobin A1c (HbA1c) and creatinine, plus self-reported exercise and body mass index.RESULTS: Controlling for age and sex, higher HDL (HR 0.84, 95% CI 0.73 to 0.96, p=0.010) and apoA1 (HR 0.83, 95% CI 0.72 to 0.94, p=0.005) were associated with a reduced risk of ALS. Higher total cholesterol:HDL was associated with an increased risk of ALS (HR 1.17, 95% CI 1.05 to 1.31, p=0.006). In models incorporating multiple metabolic markers, higher LDL or apoB was associated with an increased risk of ALS, in addition to a lower risk with higher HDL or apoA. Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of ALS.CONCLUSIONS: The association of HDL, apoA1 and LDL levels with risk of ALS contributes to an increasing body of evidence that the premorbid metabolic landscape may play a role in pathogenesis. Understanding the molecular basis for these changes will inform presymptomatic biomarker development and therapeutic targeting.", "Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.", "1. ", "BACKGROUND: Although Zika virus (ZIKV) infection is typically self-limiting, other associated complications such as congenital birth defects and the Guillain-Barré syndrome are well described. There are no approved vaccines against ZIKV infection.METHODS: In this phase 1, open-label clinical trial, we evaluated the safety and immunogenicity of a synthetic, consensus DNA vaccine (GLS-5700) encoding the ZIKV premembrane and envelope proteins in two groups of 20 participants each. The participants received either 1 mg or 2 mg of vaccine intradermally, with each injection followed by electroporation (the use of a pulsed electric field to introduce the DNA sequence into cells) at baseline, 4 weeks, and 12 weeks.RESULTS: The median age of the participants was 38 years, and 60% were women; 78% were White and 22% Black; in addition, 30% were Hispanic. At the interim analysis at 14 weeks (i.e., after the third dose of vaccine), no serious adverse events were reported. Local reactions at the vaccination site (e.g., injection-site pain, redness, swelling, and itching) occurred in approximately 50% of the participants. After the third dose of vaccine, binding antibodies (as measured on enzyme-linked immunosorbent assay) were detected in all the participants, with geometric mean titers of 1642 and 2871 in recipients of 1 mg and 2 mg of vaccine, respectively. Neutralizing antibodies developed in 62% of the samples on Vero-cell assay. On neuronal-cell assay, there was 90% inhibition of ZIKV infection in 70% of the serum samples and 50% inhibition in 95% of the samples. The intraperitoneal injection of postvaccination serum protected 103 of 112 IFNAR knockout mice (bred with deletion of genes encoding interferon-α and interferon-β receptors) (92%) that were challenged with a lethal dose of ZIKV-PR209 strain; none of the mice receiving baseline serum survived the challenge. Survival was independent of the neutralization titer.CONCLUSIONS: In this phase 1, open-label clinical trial, a DNA vaccine elicited anti-ZIKV immune responses. Further studies are needed to better evaluate the safety and efficacy of the vaccine. (Funded by GeneOne Life Science and others; ZIKA-001 ClinicalTrials.gov number, NCT02809443.).", "Eph/ephrin signaling has been implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data published recently, we hypothesized a key role for the Eph/ephrin signaling system in medulloblastoma invasion. In primary medulloblastoma samples, a significantly higher expression of EphB2 and the ligand ephrin-B1 was observed compared with normal cerebellum. Furthermore, medulloblastoma cell lines showed high expression of EphA2, EphB2, and EphB4. Stimulation of medulloblastoma cells with ephrin-B1 resulted in a marked decrease in in vitro cell adhesion and an increase in the invasion capacity of cells expressing high levels of EphB2. The cell lines that showed an ephrin-B1-induced phenotype possessed increased levels of phosphorylated EphB2 and, to a lesser extent, EphB4 after stimulation. Knockdown of EphB2 expression by short hairpin RNA completely abolished ephrin ligand-induced effects on adhesion and migration. Analysis of signal transduction identified p38, Erk, and mTOR as downstream signaling mediators potentially inducing the ephrin-B1 phenotype. In conclusion, the observed deregulation of Eph/ephrin expression in medulloblastoma enhances the invasive phenotype, suggesting a potential role in local tumor cell invasion and the formation of metastases.", "Biogenesis of mitochondria involves the expression of genes located on nuclear chromosomes as well as on mitochondrial DNA. We studied the coordination of the two genomes by measuring transcript levels for nuclear (IV, Va, and VIc) and mitochondrial (II and III) subunits of cytochrome-c oxidase after altering the mitochondrial content of rat muscle and liver by altering the thyroid state of the animals. Tissue levels of these mRNAs were generally decreased in hypothyroid animals and were up-regulated again after thyroid hormone (T3) treatment. However, significant increases in the levels of all nuclear transcripts were observed in the liver 24 h after T3 treatment, but were delayed or remained unaltered (VIc) in muscle. In contrast, levels of mitochondrial transcripts were elevated early in muscle and late in liver. The abundance of the corresponding polypeptides, which were analyzed by immunoblotting, changed in direction and magnitude according to the changes in their mRNAs, indicating pretranslational control. We conclude that the two genomes are regulated by T3 not through a common coordinating mechanism, but via two separate pathways, which respond to T3 with tissue-specific kinetics. S1-nuclease protection analysis showed that probably only one transcript for subunit VIc is present in both tissues, thus excluding the possibility that the tissue-specific response is due to the expression of two isogenes. The abundance of mitochondrial DNA was unaltered despite the observed changes in mitochondrial transcripts, indicating that mitochondrial gene expression is regulated by transcriptional mechanisms and not by gene dosage as has been postulated by others.", "Author information:(1)Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.(2)Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA.(3)Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.(4)Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.", "BACKGROUND: Zika virus (ZIKV) infection has been associated with prolonged viral excretion in human semen and causes testicular atrophy and infertility in 10-week-old immunodeficient mice.METHODS: Male IFNAR-/- mice, knockout for type I interferon receptor, were immunized with GLS-5700, a deoxyribonucleic acid-based vaccine, before a subcutaneous ZIKV challenge with 6 × 105 plaque-forming units at 13 weeks of age. On day 28 postinfection, testes and epididymides were collected in some mice for histological and functional analyses, whereas others were mated with naive female wild-type C57BL/6J.RESULTS: Although all mice challenged with ZIKV developed viremia, most of them were asymptomatic, showed no weight loss, and survived infection. On day 28 postinfection, none of the unvaccinated, infected mice (9 of 9) exhibited abnormal spermatozoa counts or motility. However, 33% (3 of 9) and 36% (4 of 11) of mated males from this group were infertile, from 2 independent studies. Contrarily, males from the noninfected and the vaccinated, infected groups were all fertile. On days 75 and 207 postinfection, partial recovery of fertility was observed in 66% (2 of 3) of the previously infertile males.CONCLUSIONS: This study reports the effects of ZIKV infection on male fertility in a sublethal, immunodeficient mouse model and the efficacy of GLS-5700 vaccination in preventing male infertility.", "Tivozanib is a potent and highly specific orally available, tyrosine kinase inhibitor that targets vascular endothelial growth factor (VEGF) receptor-1, VEGF receptor-2, and VEGF receptor-3 at very low concentrations with a long half-life (4 days). After its promising activity in xenograft and preclinical models, tivozanib was evaluated in early phase clinical trials in various solid tumors. The phase III trial (TIVO-1) compared tivozanib with sorafenib in metastatic clear cell renal cell carcinoma (RCC). Because of detrimental overall survival (OS), Oncology Drug Advisory Committee (ODAC) voted against its approval in RCC. Tivozanib is also being evaluated in various other solid tumors like breast, gastrointestinal cancers, hepatocellular cancer, sarcomas, and gynecological cancer. In BATON-CRC trial, low-serum neuropilin-1 (NRP-1) levels were associated with better progression-free survival (PFS) in patients treated with tivozanib. The NRP-1 will be evaluated as a biomarker for tivozanib response in future clinical trials. Ongoing clinical trial will further characterize activity of tivozanib in hepatocellular carcinoma, sarcomas, and gynecologic cancers.", "Methylating and ethylating agents are used in the chemical industry and produced during tobacco smoking. They generate DNA base damage whose role in cancer induction has been documented. Alkylated bases are repaired by the base excision repair pathway. We have established the repair efficiency of methylated and ethylated bases by various Escherichia coli repair proteins, namely 3-methyladenine-DNA-glycosylase I (TagA protein), which excises 3-methyladenine and 3-methylguanine, 3-methyladenine-DNA-glycosylase II (AlkA protein), which has a broad substrate specificity including 3- and 7-alkylated purines and the formamidopyrimidine(Fapy)-DNA-glycosylase (Fpg protein) repairing imidazole ring-opened 7-methylguanine. The comparison of the Km values of these various enzymes showed that methylated bases were excised more efficiently than ethylated bases. Several 3-alkyladenine derivatives have been synthesized and examined for their ability to inhibit the activity of the various repair proteins. We have shown that 3-ethyl-, 3-propyl-, 3-butyl- and 3-benzyladenine were much more efficient inhibitors of TagA protein than 3-methyladenine. The inhibitory effect was increased with the increase of the size of alkyl-group and IC50 for 3-benzyladenine was 0.4 +/- 0.1 microM as compared to 1.5 +/- 0.3 mM for 3-methyladenine. These compounds inhibited neither the AlkA protein nor human 3-methyladenine-DNA-glycosylase (ANPG protein). Moreover, 3-hydroxyethyladenine did not affect the activity of any of these enzymes. Taken together, these results suggest that hydrophobic interactions are involved in the mechanism of inhibition and/or recognition and excision of alkylated purines by TagA protein.", "The amino acid selenocysteine is encoded by UGA, usually a stop codon, thus requiring a specialized machinery to enable its incorporation into selenoproteins. The machinery comprises the tRNA(Sec), a 3'-UTR mRNA stem-loop termed SElenoCysteine Insertion Sequence (SECIS), which is mandatory for recoding UGA as a Sec codon, the SECIS Binding Protein 2 (SBP2), and other proteins. Little is known about the molecular mechanism and, in particular, when, where, and how the SECIS and SBP2 contact the ribosome. Previous work by others used the isolated SECIS RNA to address this question. Here, we developed a novel approach using instead engineered minimal selenoprotein mRNAs containing SECIS elements derivatized with photoreactive groups. By cross-linking experiments in rabbit reticulocyte lysate, new information could be gained about the SBP2 and SECIS contacts with components of the translation machinery at various translation steps. In particular, we found that SBP2 was bound only to the SECIS in 48S pre-initiation and 80S pretranslocation complexes. In the complex where the Sec-tRNA(Sec) was accommodated to the A site but transpeptidation was blocked, SBP2 bound the ribosome and possibly the SECIS element as well, and the SECIS had flexible contacts with the 60S ribosomal subunit involving several ribosomal proteins. Altogether, our findings led to broadening our understanding about the unique mechanism of selenocysteine incorporation in mammals.", "Translational control of many mRNAs in developing metazoan embryos is achieved by alterations in their poly(A) tail length. A family of cytoplasmic poly(A)-binding proteins (PABPs) bind the poly(A) tail and can regulate mRNA translation and stability. However, despite the extensive biochemical characterization of one family member (PABP1), surprisingly little is known about their in vivo roles or functional relatedness. Because no information is available in vertebrates, we address their biological roles, establishing that each of the cytoplasmic PABPs conserved in Xenopus laevis [PABP1, embryonic PABP (ePABP), and PABP4] is essential for normal development. Morpholino-mediated knockdown of PABP1 or ePABP causes both anterior and posterior phenotypes and embryonic lethality. In contrast, depletion of PABP4 results mainly in anterior defects and lethality at later stages. Unexpectedly, cross-rescue experiments reveal that neither ePABP nor PABP4 can fully rescue PABP1 depletion, establishing that PABPs have distinct functions. Comparative analysis of the uncharacterized PABP4 with PABP1 and ePABP shows that it shares a mechanistically conserved core role in promoting global translation. Consistent with this analysis, each morphant displays protein synthesis defects, suggesting that their roles in mRNA-specific translational regulation and/or mRNA decay, rather than global translation, underlie the functional differences between PABPs. Domain-swap experiments reveal that the basis of the functional specificity is complex, involving multiple domains of PABPs, and is conferred, at least in part, by protein-protein interactions." ]

[ "OBJECTIVES: PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations.METHODS: PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener's) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls.RESULTS: The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, χ(2 )= 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, χ(2 )= 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, χ(2 )= 7.258, OR = 1.98), lung involvement (P = 0.0060, χ(2 )= 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, χ(2 )= 16.567, OR = 3.73).CONCLUSION: The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.", "BACKGROUND: Runt-related transcription factor 1 (RUNX1T1) isoforms are involved in adipogenesis. RUNX1T1 is mediated by the fat mass and obesity-associated (FTO). However, the extent to which RUNX1T1 single-nucleotide polymorphisms (SNPs) are associated with obesity risk or metabolic abnormalities in a community population basis is unknown.METHODS: Samples were obtained from the Australian Crossroads study bio-bank. SNPs located in the coding region and 3'untranslated regions of RUNX1T1 with minor allele frequency ≥0.05 were analysed using Taqman genotyping assays.RESULTS: Eight candidate SNPs were genotyped successfully in 1440 participants. Of these SNPs only rs34269950 located in the 'RRACH' motif, the most common N6-methyladenosine (m6A) methylation modification site (recognized by FTO), was significantly associated with obesity risk and metabolic abnormalities. Specifically, compared to AA genotype, rs34269950 del/del genotype was associated with a 1.47 [95% confidence interval (CI): 1.01-2.14, P = 0.042] fold higher rate of obesity risk. Additionally, the del/del genotype was associated with a 60% increased risk of metabolic syndrome (MetS) [odds ratio (OR) = 1.60, 95% CI: 1.10-2.32, P = 0.015], in comparison to the AA genotype. Finally, rs34269950 del/del increased the risk of a larger waist circumference (OR = 1.65, 95% CI: 1.15-2.36, P = 0.007), but not other components of MetS.CONCLUSION: Our study demonstrates that RUNX1T1 rs34269950, located in a potential FTO recognition motif, is significantly associated with waist circumference. This provides novel evidence to suggest SNPs located in RRACH motif may be involved in RNA m6A modification and mechanistic pathways that influence abdominal obesity.", "Ameloblastoma is a benign odontogenic tumor generally present in the jaw bone. The tumor originates from the residual epithelium of the tooth germ, epithelium of odontogenic cysts stratified squamous epithelium and epithelium of the enamel organ. It represents approximately 1% of oral tumors. About 80% of ameloblastomas occur in the mandible mainly the third molar region and the remaining 20% in the upper jaw. Ameloblastoma clinically appears as an aggressive odontogenic tumor, often asymptomatic and slow-growing, with no evidence of swelling. This article deals with a complete review on ameloblastoma.", "BACKGROUND: Measles virus (MV) is a member of the Paramyxoviridae family and an important human pathogen causing strong immunosuppression in affected individuals and a considerable number of deaths worldwide. Currently, measles is a re-emerging disease in developed countries. MV is usually quantified in infectious units as determined by limiting dilution and counting of plaque forming unit either directly (PFU method) or indirectly from random distribution in microwells (TCID50 method). Both methods are time-consuming (up to several days), cumbersome and, in the case of the PFU assay, possibly operator dependent.METHODS/FINDINGS: A rapid, optimized, accurate, and reliable technique for titration of measles virus was developed based on the detection of virus infected cells by flow cytometry, single round of infection and titer calculation according to the Poisson's law. The kinetics follow up of the number of infected cells after infection with serial dilutions of a virus allowed estimation of the duration of the replication cycle, and consequently, the optimal infection time. The assay was set up to quantify measles virus, vesicular stomatitis virus (VSV), and human immunodeficiency virus type 1 (HIV-1) using antibody labeling of viral glycoprotein, virus encoded fluorescent reporter protein and an inducible fluorescent-reporter cell line, respectively.CONCLUSION: Overall, performing the assay takes only 24-30 hours for MV strains, 12 hours for VSV, and 52 hours for HIV-1. The step-by-step procedure we have set up can be, in principle, applicable to accurately quantify any virus including lentiviral vectors, provided that a virus encoded gene product can be detected by flow cytometry.", "Collaborators: Powers WJ, Grubb RL Jr, Videen TO, Derdeyn CP, Papps CH, McElvany K, Counts L, Kelly C, Barnard T, Ferrari J, Davis T, Hall T, Clarke WR Jr, Adams HP Jr, Costigan M, Singletary K, Fang Y, Marmet J, Ecklund D, Wichman M, Hansen M, Peters R, Anderson D, Woolson RF, Diltz C, Lang J, Beane L, Sieren J, Zhang Y, Videen TO, Hood JT Jr, Adams HP Jr, Weir BK, Brott T, Gorelick P, Ferguson G, Marler J, Ravina B, Galpern W, Moy C, Janis S, Haley EC, Grady S, Palesch Y, Eidelberg D, Derdeyn CP, Shinawi L, Hantler N, Tyler A, Catanzaro M, Fritsch S, Dacey R, Chicoine M, Zipfel G, Davis P, Olalde H, Rogers M, Jacobs P, Hitchon P, Leira E, Howard M, Hoballah J, Ireland J, Marshall R, Slane K, Connolly ES, Festa J, Solomon R, Dhamoon M, Wiley J, Linares G, Marchidann A, Szeder V, Noskin O, Antoniello D, Liberato B, Frontera J, Prabhakaran S, Chong J, Wright C, Zuccarello M, Koenig C, Sprafka L, Flaherty M, Kissela B, Kleindorfer D, Kempinsky-Cliver S, Broderick J, Roggee C, Kanter D, Woo D, Schneider A, Ewing I, Charbel F, Watson K, Mlinarevich N, Ruland S, Sepideh AH, Grysiewicz R, Jones J, Wilson J, Glazier S, Miller C, Jenkins W, Mintz A, Craig J, Tegeler C, O'Brien K, Ching M, Ionita C, Lee-Kwen P, Chan R, Munschauer F 3rd, Parkes K, Coad ML, Wrest K, Olson K, Harrington S, Hopkins LN, Grand W, Ferguson R, Heckler E, Pereira L, Sawyer R, Budny J, Levy E, Nemeth L, Ali J, Rasmussen P, Andrews-Hinders D, Katzan I, Uchino K, Mayberg M, Gupta R, Bartholomew J, Urbain JL, Wheeler T, Strozniak L, Krisht A, Partington S, Fewell D, Schmidley J, Steinberg G, Coburn M, Luu D, Wijman C, Darsaut T, Sinclair J, Guzman R, Ciaravino A, Varga M, Biederman K, Horner T, Payner T, Redelman K, Fleck J, Scott J, Barrow D, Holland E, Nahab F, Rahimazadeh K, Waddy S, Burke S, Chimowitz M, Frankel M, Samuels O, Sailor S, Braimah J, Stark C, Lane B, Lessard N, Howlett-Smith H, Ezzedine M, Stern B, Shipp B, Hanson K, Turan T, Osman N, Ivan C, Bruno A, Biller J, Lincoln FN, Guingrich S, Micheels A, Pritz M, Fleck J, Williams L, Jones W, Sears A, Faber K, Lopez A, Chadwick L, Matthews V, Girdler M, Lawton M, Hannegan L, Smith W, Dempsey R, Winne P, Washburn M, Li A, Sattin J, Jensen M, Chacon M, Dulli D, Newman G, Geraghty M, Page N, Kish J, Chan R, Hesser K, Lownie S, Hachinski V, Frank C, Fleming L, Baptista K, Matijevic S, Jovin T, Yonas H, Uchino K, Billigen J, Kirby L, Hammer M, Jumaa M, Lin R, Malik A, Ranawat N, Reddy V, Wechsler L, Zaidi S, Ranawat N, Rothfus MA, Adelson D, Gupta R, Tayal A, Gebel J, Nemoto E, Pindzola R, Mallory Y, Thompson BG, Auer D, Persad C, Powells D, Zahuranec D, Brown D, Hickenbottom S, Rosenwasser R, Simons E, Jensen M, Bell R, Kumar M, Moussouttas M, Pineda C, August D, Veznedaroglu E, Brock D, McGinnis G, Scollon R, Hilbert K, Johnson M, Unwin H, Graybeal D, Kopitnik T, Davis L, Blair A, Samson D, Lee J, Kassab M, Martin N, Saver J, Guzy J, Haines J, Varma J, Smith H, Fiaz R, Ali L, Carmichael ST, Liebeskind D, Ovbiagele B, Vespa P, Duke K, Starkman S, Froehler M, Tenser M, Villablanca P, Miller C, Shah S, Czernin J, Suzuki S, Dobkin B, Towfighi A, Kidwell C, Fredieu A, Tremwel M, Manglona D, Zabramski J, Snyder J, Frey J, Spetzler R, Flaster M, Mahmood MA, Akins P, Byer J, Schaefer J, Wentworth D, Croopnick S, Newman L, Cabe K, Hanson S, Castle A, Nussbaum E, Kuno L, Mattson J, Yonas H, Brown A, Malkoff M, Graham G, Stack E, Kirby L, Diaz F, Fessler R, Gordon V, Jacobs B, Ogilvy C, Buckley D, Mansala J, Bruce A, Buonanno F, Greer D, Whalen M, Meyer F, Fode-Thomas N, Thalacker S, Piepgras D, Fulgham J, Atkinson J, Biller J, Chadwick L, Anderson D, Schneck M, Dafer R, Vidal SM, Duckworth E, Selman W, Zalaski G, Cwiklinski V, Sila C, Tarr R, Bambakadis N, Suarez J, Graffagnino C, Stoner J, Moore S, Friedman A, Chilikuri V, Kesler J, Watridge C, Pannell M, Miller G, Jaciewicz M, Wright L, Newell D, Kraybill BM, Likosky W, French B, Bush J, Brown A, Block J, Blanchard B, Becker K, Sekhar L, Newell D, Tanzi P, Nuxoll D, Bybee H, Cramer S, Volpi J, Bautista M, Zhang J, Chiu D, Ling J, Bledsoe D, Tenorio J, Abdulrauf S, Kane M, Richard C, Swoboda M, Cruz-Flores S, Ibata B, Fessler R, Telck K, Gordon V, Pieper D, Silverman B, Diaz F, Whapham J, Hanson S, Castle A, Nussbaum E, Sherman D, Leonard A, Moreno L, Tonarelli S, Hart R, Carolin M, Roman G, Caron JL, Benevente O, Vollmer D, Sher A, Jett S, Neely G, Wallis RA, Panizzon K, Licht E, Cheng E, Gardner R, McAdoo J, Haupt D, Riggs-Ruupp K, Kassab M, Wehner S, Majid A, Slivka A, Agriesti J, Dobbs M, Fowler A, Pettigrew LC, Vaishnar A, Ryan S, Williams S, Nichols F, Close B, Bruno A, Switzer J, Hess D, Hall C, Rogalsky-Nacca J, Wilson S, Aucutt-Walter N, Huang D, Poole R, Ostrander M, Logan W, Schroer S, Friday G, Brown J, Derdeyn CP, Lich L, Schwarz S, Gaehle G, Mantil J, Strohmeyer P, Gagermeier E, Mattmuller S, Narayanan T, Shi B, Satter M, Simmons G, Christian B, Carone M, Perkins T, Brackney M, Mountz J, Price J, Sashin D, Meltzer C, Mathis C, Abella E, Cariddi D, Finley B, Valk P, Cronin J, Tesar R, Hichwa R, Sunderland J, Watkins L, Ponto L, Van Heertum R, Simpson N, Saxena C, Lockwood A, Haka M, Chugani H, Ferguson L, Musik O, Manger T, Reiman E, Intorcia D, Reeder S, Bandy D, Giurlani T, Prouty A, Burns C, Stone C, Christian B, Converse A, Roberts A, Oakes T, Dabbs K, Mullan B, Jacobson M, Kemp B, Brinkman T, Garg P, Morton K, Stroud P, Link K, Brown-Proctor C, Fahey F, Wollenweber S, Smith H, Fox P, Hardies J, Morena L, Narayana S, Jerabek P, Mazziotta J, Woods R, Fernandez O, Jaffer N, Brady T, Fischman A, Callahan R, Correi J, Goodman M, Crowe R, Votaw J, Bremner JD, Nye J, Eary J, Krohn K, Kauno K, Lewellen B, Kimura L, Shoner S, Lewellen T, Coleman RE, Petry N.", "BACKGROUND: There is no consensus on vancomycin dosing in newborns and young infants.OBJECTIVE: The first objective was to assess the efficiency of a simplified dosing regimen with a cohort study. The secondary objective was to examine pharmacokinetic data to determine how this simplified dosing could be improved.METHODS: All neonates admitted to our intensive care unit and treated with vancomycin were included in the pharmacokinetic study (PK group, 83 treatments, 156 measurements). The vancomycin dosing regimen consisted of a loading dose of 7 mg/kg, followed by a constant continuous dose of 30 mg/kg/day. The target serum vancomycin concentration ranged from 10 mg/l to 30 mg/l. Data from patients whose medications followed the scheduled dosing without modifications or prescription errors (actual dosing group: 62 treatments, 108 measurements) were analysed separately. A population pharmacokinetic analysis was performed (PK group) to simulate several vancomycin dosings.RESULTS: Prescription errors were found in 10 of 83 treatments (12%). In the actual dosing group, 89.2% of vancomycin measurements were within the target range. Serum creatinine remained stable throughout treatment. Vancomycin concentrations varied widely. The modified regimen for a target vancomycin concentration of 25 mg/l consisted of a bolus of 20 mg/kg followed by continuous infusion of 30 mg/kg.CONCLUSION: Our pharmacokinetic data and bedside results suggest that a simplified schedule of vancomycin can achieve the targeted drug concentrations in most patients while avoiding secondary renal toxicity. The proposed new dosing scheme should be validated in a drug survey, but due to pharmacokinetic variability, still requires therapeutic drug monitoring.", "PURPOSE OF REVIEW: Peripheral nerve pain is common among patients with typical management including the use of pain medications, neuropathic agents, steroid injections, and nerve blocks. Additionally, the use of pulsed radiofrequency (PRF) and radiofrequency ablation (RFA) can be used in the management of chronic peripheral nerve pain. Previous studies investigating the effectiveness of RFA and PRF, typically case reports, have demonstrated that peripheral nerve RFA and PRF have the potential to provide relief of chronic pain for long duration. Our study aimed at testing efficacy of RFA/PRF for treating peripheral neuralgia. This was a retrospective review. We identified 16 patients who received 17 RFAs/PRFs. Outcomes of interest collected included pain scores before and after procedures, percent improvement in pain after each procedure, and duration of improvement until the time of data collection. In addition, demographic data including age, sex, and nerves involved were collected.RECENT FINDINGS: Eleven patients (12 RFAs/PRFs) (80%) reported improvement after their procedure. Pain scores improved significantly from 6.3 ± 2.3 before each procedure to 3.6 ± 2.7 after each procedure (p = 0.003). Eleven patients (12 RFAs/PRFs) reported an average improvement of 60.8% ± 35% after their procedure with an average duration of improvement of 128.8 ± 106.8 days. RFA and PRF can be used to treat chronic peripheral pain after conservative methods fail to do so. Large clinical trials are needed to confirm our finding." ]

[ "Lactate contains a chiral carbon and thus has two optical isomers-d-lactate and l-lactate. l-Lactate is the predominant form that is produced by the body and can be delivered to the organs. On the other hand, gut microbiota produce both isomers, which can then flow into the body. Although both d-lactate and l-lactate can contribute to energy metabolism, their potential roles in adipocyte differentiation remain to be elucidated. Here, we investigated the effects of l-lactate and d-lactate on the differentiation of 3T3-L1 preadipocytes. Both lactate enantiomers were demonstrated to enhance triglyceride accumulation by stimulating the early phase of adipocyte differentiation. Notably, d-lactate was more potent than l-lactate in inducing triglyceride accumulation. The degree of triglyceride accumulation induced by l-lactate was similar to that induced by pyruvate. d-Lactate was more potent than l-lactate in increasing the activity of glycerol-3-phosphate dehydrogenase. Both lactate enantiomers did not affect cell viability. Moreover, both enantiomers upregulated the expression of peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein (C/EBP) α, sterol regulatory element-binding protein-1c, and fatty acid synthase, with d-lactate exerting stronger effects than l-lactate. By contrast, lactate did not influence the expression of C/EBPβ and C/EBPδ. d-Lactate significantly increased and l-lactate tended to increase p38 MAPK phosphorylation, and the p38 MAPK inhibitor SB203580 inhibited the stimulation of adipocyte differentiation by d-lactate and l-lactate. These findings showed that both lactate enantiomers stimulate preadipocyte differentiation, with d-lactate showing more potent effects than l-lactate. In addition, our study demonstrated that d-lactate and l-lactate exert different effects on physiological events.", "Pseudomelanosis duodeni is a rare entity characterized by dark pigmentation of duodenal mucosa of uncertain etiology and clinical significance. We report a case with endoscopic and pathologic correlation. Some aspects about etiology, clinical and histopathologic characteristics are discussed.", "Nuclear T3 receptor (NTR) have been characterized in separated cultures of neurons and astrocytes. Scatchard analysis indicated the presence of a single class of high-affinity sites in both cell lines. The apparent equilibrium association constant ranged from 1.80 +/- 0.41 X 10(10) M-1 to 3.27 +/- 0.74 +/- 10(10) M-1 in neurons and from 1.01 +/- 0.09 to 1.80 +/- 0.73 X 10(10) M-1 in astrocytes depending on the time in culture. In neurons, the maximal binding capacity (MBC) increased from 0.049 +/- 0.008 ng T3/mg DNA to 0.328 +/- 0.052 ng T3/mg DNA between 3 and 12 days of culture. In astrocytes, the changes in MBC were less pronounced ranging from a minimum of 0.095 +/- 0.024 ng T3/mg DNA at the 7th day of culture to a maximum of 0.198 +/- 0.048 ng T3/mg DNA at the 21st day. The relative binding affinity of the receptor for thyroid hormone analogs was in the order TRIAC greater than L-T3 greater than D-T3 greater than L-T4 in both cell lines. These results show that nuclear T3 receptors similar to those found in vivo are present in primary cultures of both astrocytes and neurons.", "We have isolated mutants defective in DNA topoisomerases and an endonuclease from the fission yeast Schizosaccharomyces pombe by screening individual extracts of mutagenized cells. Two type I topoisomerase mutants (top1) and three endonuclease mutants (end1) were all viable. The double mutant top1 end1 was also viable and, in its extract, Mg2+- and ATP- dependent type II activity could be detected. Three temperature-sensitive (ts-) mutants having heat-sensitive (hs-) type II enzymes were isolated, and the ts- marker cosegregated with the hs- type II activity. All the ts- mutations fell in one gene (top2) tightly linked to leul in chromosome II. The nuclear division of single top2 mutants was blocked at the restrictive temperature, but the formation of a septum was not inhibited so that the nucleus was cut across with the cell plate. In contrast, the double top1 top2 mutants were rapidly arrested at various stages of the cell cycle, showing a strikingly altered nuclear chromatin region. The type II topoisomerase may have an essential role in the compaction and/or segregation of chromosomes during the nuclear division but also complement the defect of the type I enzyme whose major function is the maintenance of chromatin organization throughout the cell cycle.", "Selenoprotein synthesis is conserved from bacteria to man. It involves the differential decoding of the UGA stop codon as selenocysteine. The proteomes of both prokaryotes and eukaryotes, with the exception of yeast, contain only few selenoproteins. This low number is explained by a counterselection of readily oxidized selenocysteine after the introduction of oxygen into the atmosphere and the need to conserve selenoenzymes that control redox homeostasis of cells. Lack of selenoprotein synthesis in vertebrates impairs the oxidative stress defence and causes lethality. Here we show that Drosophila mutants that lack the translation elongation factor SelB/eEFsec fail to decode the UGA codon as selenocysteine, but they are viable and fertile. Oxidative stress responses and the lifespan of these flies are not affected. Protecting cells from oxidative stress can therefore not account for the selection pressure that conserves selenoprotein biosynthesis during the course of evolution.", "Author information:(1)Department of Physiology, School of Medicine, Taipei Medical University, 110301 Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, 115201 Taipei, Taiwan.(2)Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.(3)Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Department of Otolaryngology - Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany.(4)NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.(5)Genetics and Molecular Cell Sciences Research Centre, St George's University of London, Cranmer Terrace, SW17 0RE London, UK.(6)Centogene AG, 18055 Rostock, Germany.(7)Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.(8)Department of Paediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, 1105 AZ Amsterdam, the Netherlands.(9)Department of Cell and Molecular Biology & Microbiology, University of Isfahan, 8174673441 Isfahan, Iran.(10)Confocal Microscopy Core Facility, Research Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.(11)Department of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia; Qatar Biomedical Research Institute, Hamad Bin Khalifa University, 34110 Doha, Qatar.(12)Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, 352540 Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, 352540 Haifa, Israel.(13)Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, 352540 Haifa, Israel.(14)Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel.(15)Department of Pediatric Endocrinology, Gaziantep Cengiz Gökcek Maternity & Children's Hospital, 27010 Gaziantep, Turkey.(16)Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.(17)Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Institute of Bioinformatics, Julius Maximilians University, 97070 Würzburg, Germany.(18)Unidade de Endocrinologia Genética, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246903 Sao Paulo, Brazil.(19)Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 05403000 Sao Paulo, Brazil.(20)Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel.(21)Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, SE1 9RT London, UK; Birmingham Women's and Children's NHS Foundation Trust, University of Birmingham, B4 6NH Birmingham, UK.(22)Department of Paediatrics, Sheikh Khalifa Medical City, 51900 Abu Dhabi, United Arab Emirates.(23)Johns Hopkins Aramco Healthcare, 34465 Dhahran, Saudi Arabia.(24)Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, SE1 9RT London, UK.(25)Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel.(26)Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.(27)Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.(28)Department of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia.(29)Institute of Biomedical Sciences, Academia Sinica, 115201 Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 110301 Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, 112304, Taipei, Taiwan. Electronic address: rbyang@ibms.sinica.edu.tw.(30)Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.", "We describe a child with ATR-16 [alpha-thalassemia (thal)/mental retardation], who was referred for genetic evaluation because of minor anomalies and developmental delay. Cytogenetic analysis demonstrated a de novo complex rearrangement of chromosome 16. Fluorescence in situ hybridization (FISH) analysis, using chromosome 16 subtelomeric probes, showed that this patient had a deletion of the distal short arm of chromosome 16 that contains the alpha-globin genes and a duplication of 16q. Analysis of the alpha-globin locus by Southern blot showed a half normal dose of the alpha-globin gene. Microsatellite marker studies revealed that the duplicated 16q region was maternal in origin. Hematological studies revealed anemia, hypochromia and occasional cells with Hb H inclusion bodies. A hematological screening for alpha-thal should be considered in patients with mild developmental delay and a suggestive phenotype of ATR-16 with microcytic hypochromic anemia and normal iron status. The stellate pattern of the iris, a new finding in our patient, may contribute to a better clinical delineation of both syndromes, ATR-16 and/or duplication of 16qter." ]

[ "BACKGROUND: The membranous structure of vestibular schwannoma is an important factor in its surgical treatment. Herein, we report intraoperative and microscopic findings relating to an outermost dura-like membrane in cases of vestibular schwannoma and the importance of these findings.METHODS: Intraoperative findings of 16 cases of vestibular schwannoma treated with an initial surgery were studied with an aim to determine if the cases had a dura-like membrane. Then we studied microscopic findings of the dura-like membrane using hematoxylin and eosin, Masson trichrome, and immunohistochemical staining in 2 cases.RESULTS: The dura-like membrane was observed in 8 out of 16 cases. The average tumor size of the cases that had a dura-like membrane was 30 ± 8.1 mm, and Koos grading 4 was in 7 out of 8 cases, and one was grade 3. In cases without a dura-like membrane, these values were significantly smaller, with an average tumor size of 12.8 ± 5.2 mm, and Koos grading 4 was only in 1 of 8 cases, grade 3 was in 2 cases, and other 5 cases were grade 2. The outermost dura-like membrane enveloped the vestibular schwannoma around the internal acoustic meatus and was continuous with the dura mater. Reactive angiogenesis was observed in the dura mater. Microscopic findings proved its continuity with the dura mater. In one case, the facial nerve was damaged before it was identified during subcapsular dissection. In that case, the dura-like membrane negatively affected our ability to identify the facial nerve.CONCLUSIONS: A dura-like membrane sometimes envelops vestibular schwannoma around the internal acoustic meatus. Recognition of this membranous structure is important for the surgical preservation of facial and acoustic nerves.", "Author information:(1)Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: etsiolaki@biol.uoa.gr.(2)Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: gnasi@biol.uoa.gr.(3)Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: fbaltoumas@biol.uoa.gr.(4)Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: nlouros@biol.uoa.gr.(5)Department of Pharmacy, University of Patras, Patras 26504, Greece. Electronic address: magafa@upatras.gr.(6)Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: shamodr@biol.uoa.gr.(7)Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: veconom@biol.uoa.gr.", "km23-1 was originally identified as a TGFß receptor-interacting protein that plays an important role in TGFß signaling. Moreover, km23-1 is actually part of an ancient superfamily of NTPase-regulatory proteins, widely represented in archaea and bacteria. To further elucidate the function of km23-1, we identified novel protein interacting partners for km23-1 by using tandem affinity purification (TAP) and tandem mass spectrometry (MS). Here we show that km23-1 interacted with a class of proteins involved in actin-based cell motility and modulation of the actin cytoskeleton. We further showed that km23-1 modulates the formation of a highly organized stress fiber network. More significantly, we demonstrated that knockdown (KD) of km23-1 decreased RhoA activation in Mv1Lu epithelial cells. Finally, our results demonstrated for the first time that depletion of km23-1 inhibited cell migration of human colon carcinoma cells (HCCCs) in wound-healing assays. Overall, our findings demonstrate that km23-1 regulates RhoA and motility-associated actin modulating proteins, suggesting that km23-1 may represent a novel target for anti-metastatic therapy.", "Carpal tunnel syndrome (CTS) after distal radius fractures can present in 3 forms: acute, transient, and delayed. Acute CTS requires an emergent carpal tunnel release. Many patients with transient CTS after distal radius fracture do not require surgical release of the carpal tunnel once the fracture is repaired. Prophylactic carpal tunnel release in the absence of signs and symptoms of CTS after a distal radius fracture is not indicated. For patients with delayed CTS after a distal radius fracture, all possible causes of nerve compression should be considered and addressed in standard fashion.", "SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1), also known as HARP, is an ATP-dependent annealing helicase that stabilizes replication forks during DNA damage. Mutations in this gene are the cause of Schimke immune-osseous dysplasia (SIOD), an autosomal recessive disorder characterized by T-cell immunodeficiency and growth dysfunctions. In this review, we summarize the main roles of SMARCAL1 in DNA repair, telomere maintenance and replication fork stability in response to DNA replication stress.", "OBJECTIVE: To track and analyze two false positive cases from non-invasive prenatal testing for potential fetal aneuploidy.METHODS: The two cases, respectively reported to have XO (+++) and T18 (1/20) XO(+), were analyzed with conventional karyotyping, fluorescence in situ hybridization (FISH) and massively parallel genomic sequencing (MPS).RESULTS: The first fetus, who was suspected for XO(+++), was verified to have super female syndrome (47,XXX/46,XX) due to confined placental mosaicism by karyotyping of amniotic fluid cells, FISH analysis of placenta and massively parallel sequencing (MPS) of fetal tissue. The second fetus, suspected to have trisomy 18 (1/20) XO(+), was verified to have Turner syndrome by karyotyping, FISH and MPS analyses of umbilical cord blood cells. And the karyotype was 45,X[48]/46, X, der(X) del(X) (p11.21) del(X) (q13.3)[62].CONCLUSION: Non-invasive prenatal testing carries a risk for false positive diagnosis of fetal sex chromosome and trisomy 18. Combined cytogenetic and molecular techniques are required to ensure an accurate diagnosis.", "Injury is sustained by isolated hearts on repletion with calcium after a short period of perfusion with calcium-free medium at 37 degrees. A possible mechanism for the 'calcium paradox' is that exposure to a calcium-fre medium removes extracellular calcium rendering the sarcolemma more permeable to calcium. On calcium repletion, cell injury is triggered by calcium influx. Since lanthanum is known to displace calcium from extracellular pools in heart, it was used in an attempt to modulate the injury of the calcium paradox. The presence of 10 microM lanthanum in the calcium-free perfusion fluid was found to inhibit totally protein release normally produced by subsequent calcium exposure. When lanthanum was added after the calcium-free period and before calcium repletion, protein release was only partly prevented. This shows that a change in membrane properties occurred during the calcium-free perfusion period which could be prevented, but not reversed, by the addition of lanthanum." ]

[ "There is an expanding list of examples by which one mRNA can posttranscriptionally influence the expression of others. This can involve RNA sponges that sequester regulatory RNAs of mRNAs in the same regulon, but the underlying molecular mechanism of such mRNA cross talk remains little understood. Here, we report sponge-mediated mRNA cross talk in the posttranscriptional network of GcvB, a conserved Hfq-dependent small RNA with one of the largest regulons known in bacteria. We show that mRNA decay from the gltIJKL locus encoding an amino acid ABC transporter generates a stable fragment (SroC) that base-pairs with GcvB. This interaction triggers the degradation of GcvB by RNase E, alleviating the GcvB-mediated mRNA repression of other amino acid-related transport and metabolic genes. Intriguingly, since the gltIJKL mRNA itself is a target of GcvB, the SroC sponge seems to enable both an internal feed-forward loop to activate its parental mRNA in cis and activation of many trans-encoded mRNAs in the same pathway. Disabling this mRNA cross talk affects bacterial growth when peptides are the sole carbon and nitrogen sources.", "AIMS AND OBJECTIVES: To estimate the diagnostic value and determine the feasibility of the NEECHAM Confusion Scale on critically ill older patients.BACKGROUND: Delirium is a common syndrome in hospitalised older patients, especially in surgical intensive care units, and the consequences of under-detection can be very serious for older people. Therefore, assessment of the cognitive status of older patients using a valid instrument is important in intensive care units.DESIGN: A descriptive prospective design was used.METHODS: Consecutive nonintubated patients aged 65 and older, admitted to a surgical intensive care unit of an Italian hospital during a seven months period, were assessed for delirium using the NEECHAM scale and the Confusion Assessment Method for intensive care unit, once per shift, for 48 hours after admission. Cohen's kappa coefficient, ROC curve, sensitivity and specificity were estimated. An open ended questionnaire was used to assess user-friendliness of the scale.RESULTS: A sample of 41 older patients with a mean age of 78·3 years was studied. The kappa coefficient was 0·95. The sensitivity was 99·19%, specificity 95% at cut-off of 25, and the area under the curve was 0·99 (CI 0·99-1·00). Nurses evaluated positively the scale as they were able to collect data during care process in maximum 10 minutes, but experienced problems in rating the appearance behaviour and physiological control items of the scale.CONCLUSIONS: Findings from this study confirm the good diagnostic value and ease of application of the NEECHAM scale with nonventilated intensive care patients.RELEVANCE TO CLINICAL PRACTICE: The NEECHAM scale can be used to detect delirium during the routine nursing assessment of nonintubated older patients as it requires minimal demand and stress on the patient as well as on the bedside nurse.", "Imagine a parent innocently swinging around a toddler ... a yank on an outstretched arm to keep a preschooler from falling ... a caregiver attempting to move a reluctant child by dragging the child by the hand ... a helping hand to lift a young child up over the curb or a high step. None of these activities is ever intended to hurt a child, yet the result of these specific activities send many children with anxious parents and caregivers to emergency departments and unscheduled pediatrician appointments each year. Nursemaid's elbow, also known as a pulled elbow or a subluxated radial head, may result from the specific activities described above and is the most common dislocation injury handled by pediatricians. Most commonly occurring in the 1-year to 4-year old age group, nursemaid's elbow is easily treated and generally has no long-term sequelae.", "DNA methylation patterns are established and maintained by three DNA methyltransferases (DNMT): DNMT1, DNMT3A, and DNMT3B. Although essential for development, methylation patterns are frequently disrupted in cancer and contribute directly to carcinogenesis. Recent studies linking polycomb group repression complexes (PRC1 and PRC2) to the DNMTs have begun to shed light on how methylation is targeted. We identified previously a panel of genes regulated by DNMT3B. Here, we compare these with known polycomb group targets to show that approximately 47% of DNMT3B regulated genes are also bound by PRC1 or PRC2. We chose 44 genes coregulated by DNMT3B and PRC1/PRC2 to test whether these criteria would accurately identify novel targets of epigenetic silencing in colon cancer. Using reverse transcription-PCR, bisulfite genomic sequencing, and pyrosequencing, we show that the majority of these genes are frequently silenced in colorectal cancer cell lines and primary tumors. Some of these, including HAND1, HMX2, and SIX3, repressed cell growth. Finally, we analyzed the histone code, DNMT1, DNMT3B, and PRC2 binding by chromatin immunoprecipitation at epigenetically silenced genes to reveal a novel link between DNMT3B and the mark mediated by PRC1. Taken together, these studies suggest that patterns of epigenetic modifiers and the histone code influence the propensity of a gene to become hypermethylated in cancer and that DNMT3B plays an important role in regulating PRC1 function.", "BACKGROUND: Preclinical data suggest that dual blockade of the insulin-like growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC selected for high IGF-1 serum levels.PATIENTS AND METHODS: CARRIE was an international, randomized, double-blind, placebo-controlled phase II study for patients with previously untreated metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 : 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or placebo combined with gemcitabine/nab-paclitaxel at approved dose schedule. The co-primary endpoints were progression-free survival (PFS) in patients with high IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin (HRG)+ tumors. Key secondary endpoints were overall survival (OS), objective response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate.RESULTS: A total of 317 patients were screened, with 88 patients randomized in part 2 (experimental arm n = 43; control n = 45). In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental versus control arms, respectively [hazard ratio (HR) = 1.88, P = 0.027]. In the high IGF-1/HRG+ subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39, P = 0.42). Median OS and ORR for the overall population were similar between two arms. No significant difference in serious or grade ≥3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) versus control arm (24.4%).CONCLUSIONS: Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls.CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02399137; EUDRA CT: 2014-004572-34.", "Zika virus belongs to Aedes mosquito-borne flavivirus. In response to the current cluster of congenital malformations (microcephaly) and other neurological complications (Guillain-Barré Syndrome) that could be linked to Zika virus infection, WHO declares that Zika virus is of global public health importance. Data sources were from peer review articles and WHO documents. The sources of Zika virus infection would include patients, people with asymptomatic infections and primates. The infectious period of Zika virus remains unclear. However, according to the period that RNA of Zika virus can be positively detected in blood, saliva, urine or semen, we can presume that the communicable period may last for 2 months or even longer. Zika virus is primarily transmitted to humans by infected Aedes spp. mosquitoes. Presumptive vertical, blood or sexual routes of transmission have been reported. More evidence indicated the existence of a cause-effect relationship between Zika virus infection and congenital microcephaly/Guillain-Barre syndrome. Strategies include successful control the amount of mosquitoes and minimize the contacts between mosquitoes and human beings could effectively prevent the Zika virus transmission. Other preventive measures as cutting off vertical, blood or sexual routes of transmission should also be adopted. The epidemiology of Zika virus remains uncertain which calls for further research.", "Cardioembolism accounts for approximately 20% of ischaemic strokes, and is associated with high mortality and propensity to recurrences. Approximately, 30% of ischaemic strokes remain cryptogenic despite improved imaging modalities and technological improvements to identify their cause. Of the long list of various cardiac conditions associated with an increased risk of cardioembolic strokes, non-valvular atrial fibrillation is the most common cause. Unsurprisingly, the stroke risk associated with these conditions is highly variable and non-homogenous, with many risk factors additive to the overall risk profile. Treatment with vitamin K-antagonists substantially reduces the long-term complications associated with cardioembolism in some high-risk patients, for example, in atrial fibrillation. Careful selection of antithrombotic drug regime needs to be carried out in patients individually to minimise the risk of bleeding encountered with such therapy. Apart from atrial fibrillation, there is relatively limited evidence for the role of antithrombotic therapy for other cardiac conditions associated with cardioembolism and how long one should treat." ]

[ "Certain lysine residues on histone tails could be methylated by protein lysine methyltransferases (PKMTs) using S-adenosyl-L-methionine (AdoMet) as the methyl donor. Since the methylation states of the target lysines play a fundamental role in the regulation of chromatin structure and gene expression, it is important to study the property of PKMTs that allows a specific number of methyl groups (one, two or three) to be added (termed as product specificity). It has been shown that the product specificity of PKMTs may be controlled in part by the existence of specific residues at the active site. One of the best examples is a Phe/Tyr switch found in many PKMTs. Here quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed on wild type G9a-like protein (GLP) and its F1209Y and Y1124F mutants for understanding the energetic origin of the product specificity and the reasons for the change of product specificity as a result of single-residue mutations at the Phe/Tyr switch as well as other positions. The free energy barriers of the methyl transfer processes calculated from our simulations are consistent with experimental data, supporting the suggestion that the relative free energy barriers may determine, at least in part, the product specificity of PKMTs. The changes of the free energy barriers as a result of the mutations are also discussed based on the structural information obtained from the simulations. The results suggest that the space and active-site interactions around the ε-amino group of the target lysine available for methyl addition appear to among the key structural factors in controlling the product specificity and activity of PKMTs.", "Ectopia lentis (EL) is a condition that can either herald underlying systemic conditions, or be isolated. The recent expansion in the genetics of these conditions has furthered the understanding of the underlying molecular aetiology. It is becoming apparent that novel genes, and in particular the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, are important in ocular development. The common link in these genes seems to be EL. The clinical management of EL is challenging. In particular, the options for addressing surgically induced aphakia in the context of an ectopic capsule are varied. Little evidence exists to direct management of these issues. This review summarises the molecular pathogenesis of EL and conditions associated with it, using the genetic aetiology as a framework. Furthermore, it summarises some of the issues involved in its clinical management.", "A complete ophthalmic examination is not routinely performed on infants with Miller-Dieker syndrome (MDS, chromosome 17p13.3 microdeletion). The authors present the cases of four cousins with MDS who also carried a 16p13.3 microduplication (not associated with Rubinstein-Taybi syndrome). Retinopathy of prematurity-like proliferative peripheral retinopathy (PPR) was detected in two male first cousins, but was not detected in the female half-cousins. PPR in the first infant resolved by 4 months, but the second infant's PPR progressed, requiring photocoagulation followed by lens-sparing vitrectomy. While ocular abnormalities are more prevalent and severe in other lissencephalopathies, the PPR in these MDS infants underscores the sight-saving potential of performing an ophthalmologic exam with early molecular testing for all lissencephaly infants.", "The Hippo pathway is an important organ size control signaling network and the major regulatory mechanism of cell-contact inhibition. Yes associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are its targets and terminal effectors: inhibition of the pathway promotes YAP/TAZ translocation to the nucleus, where they interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes, promoting cell proliferation. Defects in the pathway can result in overgrowth phenotypes due to deregulation of stem-cell proliferation and apoptosis; members of the pathway are directly involved in cancer development. The pharmacological regulation of the pathway might be useful in cancer prevention, treatment, and regenerative medicine applications; currently, a few compounds can selectively modulate the pathway. In this review, we present an overview of the Hippo pathway, the sequence and structural analysis of YAP/TAZ, the known pharmacological modulators of the pathway, especially those targeting YAP/TAZ-TEAD interaction.", "The HDM2-p53 loop is crucial for monitoring p53 level and human pathologies. Therefore, identification of novel molecules involved in this regulatory loop is necessary for understanding the dynamic regulation of p53 and treatment of human diseases. Here, we characterized that the ribosomal protein L6 binds to and suppresses the E3 ubiquitin ligase activity of HDM2, and subsequently attenuates HDM2-mediated p53 polyubiquitination and degradation. The enhanced p53 activity further slows down cell cycle progression and leads to cell growth inhibition. Conversely, the level of p53 is dramatically decreased upon the depletion of RPL6, indicating that RPL6 is essential for p53 stabilization. We also found that RPL6 translocalizes from the nucleolus to nucleoplasm under ribosomal stress, which facilitates its binding with HDM2. The interaction of RPL6 and HDM2 drives HDM2-mediated RPL6 polyubiquitination and proteasomal degradation. Longer treatment of actinomycin D increases RPL6 ubiquitination and destabilizes RPL6, and thereby putatively attenuates p53 response until the level of L6 subsides. Therefore, RPL6 and HDM2 form an autoregulatory feedback loop to monitor the level of p53 in response to ribosomal stress. Together, our study identifies the crucial function of RPL6 in regulating HDM2-p53 pathway, which highlights the importance of RPL6 in human genetic diseases and cancers.", "Recent genome-wide studies have revealed a remarkable correspondence between nucleosome positions and exon-intron boundaries, and several studies have implicated specific histone modifications in regulating alternative splicing. In addition, recent progress in cracking the 'splicing code' shows that sequence motifs carried on the nascent RNA molecule itself are sufficient to accurately predict tissue-specific alternative splicing patterns. Together, these studies shed light on the complex interplay between RNA sequence, DNA sequence, and chromatin properties in regulating splicing.", "The chromones are a class of chemical compounds characterised by the presence of the structure 5:6 benz-1:4-pyrone in their chemical make-up. The first chromone in clinical use, khellin, was extracted from the seeds of the plant Ammi visnaga, and had been used for centuries as a diuretic and as a smooth muscle relaxant. Its use in bronchial asthma was reported in 1947. In the 1950s, Benger's Laboratories embarked on a research programme to synthesise and develop modifications of khellin for the treatment of asthma. New compounds were screened using animal models to test the ability of the compound to prevent the anaphylactic release of histamine and SRS-A (leukotrienes) from sensitised guinea pig lung, and a human model to check the ability to reduce the bronchoconstriction induced by inhaled antigen bronchial challenge. For initial screening the human work was undertaken by Dr. R.E.C. Altounyan, who suffered from allergic bronchial asthma and was employed by Benger's Laboratories. After 8 years and more than 600 challenges using over 200 compounds, in 1965 Altounyan arrived at disodium cromoglycate (DSCG), the chromone that met the criteria of providing more than 6 h of protection. DSCG is still used today as a mast cell stabiliser." ]

[ "The rapidly increasing number of people with obesity and type 2 diabetes is one of the most serious problems of the contemporary world. Until recently, it was thought that the main cause of this phenomenon is the change of lifestyle and dietary habits. According to recent reports, the gut microbiota may also play an important role in the \"epidemic\" of obesity and diabetes. Changes in its composition have been observed in people suffering from these diseases. In addition, the fact that the intestinal microbiota may affect body weight, insulin sensitivity or sugar and lipid metabolism has led to the hypothesis that these changes may contribute to the pathogenesis of obesity and diabetes. Scientists, using antibacterial drugs, pro- and prebiotics, are trying to modify the intestinal flora and thus affect its interaction with the host. The results are very promising, lead to further analysis and indicate gut microbiota as a potential therapeutic target for obesity and diabetes treatment.", "Pannexins (Panx) are proteins homologous to the invertebrate gap junction proteins called innexins (Inx) and are traditionally described as transmembrane channels connecting the intracellular and extracellular compartments. Three distinct Panx paralogs (Panx1, Panx2 and Panx3) have been identified in vertebrates but previous reports on Panx expression and functionality focused primarily on Panx1 and Panx3 proteins. Several gene expression studies reported that Panx2 transcript is largely restricted to the central nervous system (CNS) hence suggesting that Panx2 might serve an important role in the CNS. However, the lack of suitable antibodies prevented the creation of a comprehensive map of Panx2 protein expression and Panx2 protein localization profile is currently mostly inferred from the distribution of its transcript. In this study, we characterized novel commercial monoclonal antibodies and surveyed Panx2 expression and distribution at the mRNA and protein level by real-time qPCR, Western blotting and immunofluorescence. Panx2 protein levels were readily detected in every tissue examined, even when transcriptional analysis predicted very low Panx2 protein expression. Furthermore, our results indicate that Panx2 transcriptional activity is a poor predictor of Panx2 protein abundance and does not correlate with Panx2 protein levels. Despite showing disproportionately high transcript levels, the CNS expressed less Panx2 protein than any other tissues analyzed. Additionally, we showed that Panx2 protein does not localize at the plasma membrane like other gap junction proteins but remains confined within cytoplasmic compartments. Overall, our results demonstrate that the endogenous expression of Panx2 protein is not restricted to the CNS and is more ubiquitous than initially predicted.", "BACKGROUND: The rotator cuff tendon is known to exert a shear force between the superficial and deep layers. Owing to this characteristic, separate repair of delaminated rotator cuff tears has been introduced for the restoration of the physiological biomechanics of the rotator cuff. However, whether conventional en masse repair or separate repair is superior is controversial in terms of outcomes.PURPOSE: To compare clinical outcomes between conventional en masse repair and separate double-layer double-row repair for the treatment of delaminated rotator cuff tears.STUDY DESIGN: Randomized controlled study; Level of evidence, 2.METHODS: Between August 2007 and March 2014, a total of 82 patients who underwent arthroscopic rotator cuff repair of a delaminated tear were enrolled and randomized into 2 groups. In group 1 (n = 48), arthroscopic conventional en masse repair was performed. In group 2 (n = 34), separate double-layer double-row repair was performed. The American Shoulder and Elbow Surgeons score, Constant score, Simple Shoulder Test score, and visual analog scale (VAS) score for pain and range of motion (ROM) were assessed before surgery; at 3, 6, and 12 months after surgery; and at the last follow-up visit. Magnetic resonance imaging (MRI) was performed at 12 months postoperatively to examine the retear rate and pattern.RESULTS: There was no significant difference between groups in the preoperative demographic data, including patient age, sex, symptom duration, tear size, and functional scores (P > .05). The mean follow-up period was 25.9 ± 1.2 months. Significant improvements in functional and pain scores were observed in both groups at the last follow-up visit. However, no significant differences in functional scores and ROM were found between the 2 groups at each time point, except that group 2 had significantly lower VAS pain scores (P < .05) at 3, 6, and 12 months postoperatively. Eight (17%) of 48 patients in group 1 and 6 (18%) of 34 patients in group 2 showed retears on MRI at 12-month follow-up (P > .05).CONCLUSION: Both conventional en masse repair and separate double-layer double-row repair were effective in improving clinical outcomes in the treatment of delaminated rotator cuff tears. Lower pain scores were seen in patients who underwent separate double-layer double-row repair.", "Familial cylindromatosis is an autosomal dominant predisposition to tumours of skin appendages called cylindromas. Familial cylindromatosis is caused by mutations in a gene encoding the CYLD protein of previously unknown function. Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis. CYLD inhibits activation of NF-kappaB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappaB. The inhibition of NF-kappaB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR-associated factor 2 (TRAF2) and, to a lesser extent, TRAF6. These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappaB that is required for appropriate cellular homeostasis of skin appendages.", "Stroke is a major cause of mortality and morbidity, and thrombolysis has served as a catalyst for major changes in the management of acute ischaemic stroke. Intravenous alteplase (recombinant tissue plasminogen activator) is the only approved thrombolytic agent at present indicated for acute ischaemic stoke. While the licensed time window extends to 3h from symptom onset, recent data suggest that the trial window can be extended up to 4.5 h with overall benefit. Nonetheless, 'time is brain' and every effort must be made to reduce the time delay to thrombolysis. Intracranial haemorrhage is the major complication associated with thrombolysis, and key factors increasing risk of haemorrhage include increasing age, high blood pressure, diabetes and stroke severity. Currently, there is no direct evidence to support thrombolysis in patients >80 years of age, with a few case series indicating no overt harm. Identification of viable penumbra based on computed tomography/magnetic resonance imaging may allow future extension of the time window. Adjuvant transcranial Doppler ultrasound has the potential to improve reperfusion rates. While intra-arterial thrombolysis has been in vogue for a few decades, there is no clear advantage over intravenous thrombolysis. The evidence base for thrombolysis in specific situations (e.g. dissection, pregnancy) is inadequate, and individualized decisions are needed, with a clear indication to the patient/carer about the lack of direct evidence, and the risk-benefit balance. Patient-friendly information leaflets may facilitate the process of consent for thrombolysis. This article summarizes the recent advances in thrombolysis for acute ischaemic stroke. Key questions faced by clinicians during the decision-making process are answered based on the evidence available.", "Eptinezumab-jjmr (referred to as eptinezumab hereafter; Vyepti™) is a humanised monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) and blocks its binding to the receptor. CGRP is believed to play a major role in the pathophysiology of migraine. Eptinezumab, delivered by intravenous (IV) administration, is being developed by Lundbeck Seattle BioPharmaceuticals for the prevention of migraine. In February 2020, eptinezumab was approved in the USA for the preventive treatment of migraine in adults. This article summarizes the milestones in the development of eptinezumab leading to this first approval.", "Germline mutations in the RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, NF1 or VHL genes are identified in about 30% of patients with pheochromocytoma or paraganglioma and somatic mutations in RET, VHL or MAX genes are reported in 17% of sporadic tumors. In the present study, using mutation screening of the NF1 gene, mapping of chromosome aberrations by single nucleotide polymorphism (SNP) array, microarray-based expression profiling and immunohistochemistry (IHC), we addressed the implication of NF1 somatic alterations in pheochromocytomas and paragangliomas. We studied 53 sporadic tumors, selected because of their classification with RET/NF1/TMEM127-related tumors by genome wide expression studies, as well as a second set of 11 independent tumors selected on their low individual levels of NF1 expression evaluated by microarray. Direct sequencing of the NF1 gene in tumor DNA identified the presence of an inactivating NF1 somatic mutation in 41% (25/61) of analyzed sporadic tumors, associated with loss of the wild-type allele in 84% (21/25) of cases. Gene expression signature of NF1-related tumors highlighted the downregulation of NF1 and the major overexpression of SOX9. Among the second set of 11 tumors, two sporadic tumors carried somatic mutations in NF1 as well as in another susceptibility gene. These new findings suggest that NF1 loss of function is a frequent event in the tumorigenesis of sporadic pheochromocytoma and strengthen the new concept of molecular-based targeted therapy for pheochromocytoma or paraganglioma." ]

[ "High-throughput assays of three-dimensional interactions of chromosomes have shed considerable light on the structure of animal chromatin. Despite this progress, the precise physical nature of observed structures and the forces that govern their establishment remain poorly understood. Here we present high resolution Hi-C data from early Drosophila embryos. We demonstrate that boundaries between topological domains of various sizes map to DNA elements that resemble classical insulator elements: short genomic regions sensitive to DNase digestion that are strongly bound by known insulator proteins and are frequently located between divergent promoters. Further, we show a striking correspondence between these elements and the locations of mapped polytene interband regions. We believe it is likely this relationship between insulators, topological boundaries, and polytene interbands extends across the genome, and we therefore propose a model in which decompaction of boundary-insulator-interband regions drives the organization of interphase chromosomes by creating stable physical separation between adjacent domains.", "Progress on several unresolved issues in cancer epigenetics will benefit from rapid and standardized methods for profiling DNA methylation genome-wide. In the area of epigenetic therapy, the demethylating drug decitabine (5-aza-2'-deoxycytidine) is increasingly used to treat acute myelogenous leukemia and myelodysplastic syndrome, but the mechanisms of its anticancer activity have remained unclear. Given the clinical efficacy of decitabine and the uncertainties about its mode of action, it will be useful to optimize methods for following DNA methylation as a biochemical response in individual patients. Here, we describe a single nucleotide polymorphism (SNP) chip-based method (MSNP) for profiling DNA methylation. Using this procedure, the extent of demethylation in bone marrow aspirates from patients with leukemia receiving decitabine can be assessed genome-wide using commercially available (Affymetrix) SNP chips. We validated the accuracy of MSNP by comparing the results with combined bisulfite restriction analysis and by sequencing cloned PCR products from bisulfite-converted DNA. We further validated MSNP in a Wilms' tumor/normal kidney comparison, comparing the results with methylation-sensitive Southern blotting. MSNP simultaneously detects aberrations in DNA copy number and loss of heterozygosity, making it a generally useful approach for combined genetic and epigenetic profiling in tissue samples from cancer patients.", "This work aimed at investigating the effect of resveratrol on (1) DNA integrity and (2) fertilizing capacity of sperm by quantifying the presence of key paternal transcripts considered as markers for male fertility (protamine 1 [PRM1] and protamine 2 [PRM2]) and pregnancy success (adducin 1 alpha [ADD1]) in cryopreserved human spermatozoa through modulation of AMP-activated protein kinase (AMPK). The study populations was drawn from 22 normozoospermic healthy volunteers which were incubated with or without AMPK activator (resveratrol [RSV], 15 µM) or inhibitor (Compound C [CC], 30 µM) for 1 h and were then cryopreserved. Untreated frozen-thawed spermatozoa served as controls. The RSV-induced AMPK activation decreased the level of DNA fragmentation in comparison with the control (21.18 ± 0.92 vs. 22.50 ± 0.40; p < 0.01). The relative mRNA expression levels of protamines (1 and 2) and ADD1 in RSV pretreated frozen-thawed human spermatozoa were also improved significantly compared to the control (p < 0.05). Conversely, the inhibitory effect of CC on AMPK activity deteriorated the deleterious effects of cryopreservation on these parameters (p < 0.01). In conclusion, these results demonstrated the cryoprotective effect of the RSV-induced increase in AMPK activity on DNA integrity and key paternal transcripts of cryopreserved human spermatozoa. These findings are of great importance for improving the available cryopreservation protocols in terms of the number of lesions that produced over key genes and the dramatic effects on sperm DNA fragmentation.", "The current interest in malaria elimination has led to a renewed interest in drugs that can be used for mass administration to minimize malaria transmission. Primaquine (PQ) is the only generally available drug with a strong activity against mature Plasmodium falciparum gametocytes, the parasite stage responsible for transmission. Despite concerns about PQ-induced hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, a single dose of PQ may be safe and efficacious in clearing gametocytes that persist after conventional treatment. As part of a mass drug intervention, we determined the hemolytic effect of sulfadoxine-pyrimethamine (SP) plus artesunate (AS) plus a single dose of primaquine (PQ; 0.75 mg/kg of body weight) in children aged 1 to 12 years. Children were randomized to receive SP+AS+PQ or placebo; those with a hemoglobin (Hb) level below 8 g/dl were excluded from receiving PQ and received SP+AS. The Hb concentration was significantly reduced 7 days after SP+AS+PQ treatment but not after placebo or SP+AS treatment. This reduction in Hb was most pronounced in G6PD-deficient (G6PD A-) individuals (-2.5 g/dl; 95% confidence interval [95% CI], -1.2 to -3.8 g/dl) but was also observed in heterozygotes (G6PD A) (-1.6 g/dl; 95% CI, -0.9 to -2.2 g/dl) and individuals with the wild-type genotype (G6PD B) (-0.5 g/dl; 95% CI, -0.4 to -0.6 g/dl). Moderate anemia (Hb level of <8 g/dl) was observed in 40% (6/15 individuals) of the G6PD A-, 11.1% (3/27 individuals) of the G6PD A, and 4.5% (18/399 individuals) of the G6PD B individuals; one case of severe anemia (Hb level of <5 g/dl) was observed. PQ may cause moderate anemia when coadministered with artemisinins, and excluding individuals based on G6PD status alone may not be sufficient to prevent PQ-induced hemolysis.", "Familial spontaneous pneumothorax (FSP) accounts for 10% of primary spontaneous pneumothoraces. Appropriate investigation of FSP enables early diagnosis of serious monogenic diseases and the practice of precision medicine. Here, we show that a pneumothorax genetics multidisciplinary team (MDT) can efficiently diagnose a range of syndromic causes of FSP. A sizeable group (73.6%) of clinically unclassifiable FSPs remains. Using whole genome sequencing we demonstrate that most of these cases are not known monogenic disorders. Therefore, clinico-radiological assessment by an MDT has high sensitivity for currently known clinically important monogenic causes of FSP, which has relevance for the design of efficient pneumothorax services.", "Waardenburg syndrome (WS) type I is a non-progressive auditory-pigmentary disorder comprising congenital sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum (lateral displacement of the inner canthi). Affected individuals may have higher risk of: neural tube defects, cleft lip and palate, limb abnormalities, and Hirschsprung disease. The diagnosis is clinical and should be considered if the individual has two major or one major plus two minor criteria. PAX3 is the only known gene associated to the syndrome. Nevertheless, its use is mostly for genetic counseling. Regarding different diagnosis, we may list: other causes of non-progressive auditory-pigmentary disorder comprising congenital sensorineural hearing loss, other types of Waardenburg syndrome, piebaldism, albinism, vitiligo and Teitz syndrome. This paper presents a case of an eleven year old boy with deafness and ophthalmologic alterations, based on his files and exams. It reinforced the importance of the ophthalmologist contributing for the diagnosis of this rare systemic disease, as it includes some ophthalmologic alterations. We remind that the early diagnosis allows adequate stimulation for the hearing loss, as well as preventive measures in case of pregnant women affected by genetic counseling.", "An essential requisite for transmission of Plasmodium, the causative agent of malaria, is the successful completion of a complex developmental cycle in its mosquito vector. Of hundreds of ookinetes that form in the mosquito midgut, only few transform into oocysts, a loss attributed to the action of the mosquito immune system. However, once oocysts form, they appear to be resistant to mosquito defences. During oocyst development, a thick capsule forms around the parasite and appears to function as a protective cover. Little information is available about the composition of this capsule. Here we report on the identification and partial characterization of the first Plasmodium oocyst capsule protein (PbCap380). Genetic analysis indicates that the gene is essential and that PbCap380(-) mutant parasites form oocysts in normal numbers but are gradually eliminated. As a result, mosquitoes infected with PbCap380(-) parasites do not transmit malaria. Targeting of the oocyst capsule may provide a new strategy for malaria control." ]

[ "A new rapid method for the determination of honey diastase activity using direct potentiometric principles has been proposed. A platinum redox sensor has been used to quantify the amount of free triiodide released from a starch triiodide complex after starch hydrolysis by honey diastase. The method was tested on honey samples with varying diastase activities. The first 5 min of data for each sample were used for linear regression analysis in order to calculate diastase activity. The new method was compared with classical Schade and commercial Phadebas procedures. The results showed good correlations with both methods and offered a simple method for unit conversion to DN units for diastase activity, making the method suitable for routine analysis.", "Sedative-analgesic treatment of patients on long-term artificial ventilation aims at protection from stress related to their disease or therapy. By stabilising both the patient's vital functions and psychological state this treatment may contribute to therapeutic success. The choice of drugs depends primarily on the nature and course of the underlying disease. Midazolam and propofol are available as hypnotics for short-term sedation during the post-operative period. The purpose of this study was to evaluate the effects of both agents on cardiovascular function, cortisol production, lipometabolism, and the recovery period following 24-h sedation. METHODS. Twenty female patients (mean body weight: 72 kg, mean age: 60 years) were randomly assigned to receive either midazolam or propofol over 24 h following major abdominal surgery. Balanced anaesthesia (halothane/O2/N2O/fentanyl) was administered for the surgical procedure. Assisted ventilation was used in all patients during the post-operative sedation period. Sedation depth was maintained at III-IV on the Ramsey scale. On arrival in the intensive care unit (ICU), an initial i.v. bolus of midazolam 0.1 mg/kg or propofol 1 mg/kg was followed by a continuous infusion (midazolam: 0.1 mg/kg.h; propofol: 2 mg/kg.h). Supplementary boluses of one-half the initial dose were given if required. Post-operative analgesia was achieved with 3 mg intravenous piritramide at 2-h intervals. A 7F Swan-Ganz catheter was inserted in the pulmonary artery and haemodynamic and biochemical parameters were monitored at 4-h intervals over 24 h starting 2 h after arrival in the ICU. Catecholamines were measured by high-pressure lipid chromatography (HPLC), cortisol by radioimmunoassay, midazolam by HPLC and ultraviolet detection, and propofol by HPLC and fluorescence detection. Data were calculated as means. The statistical analysis was performed according to the Mann-Whitney test, and significance was accepted for P less than 0.05. RESULTS. On administration of the propofol bolus at the onset of sedation, a decrease in blood pressure was particularly observed in patients with masked hypovolaemia, however, this decrease was easily controlled by volume administration. Independent of the type of sedation, the haemodynamic parameters remained unchanged throughout the observation period. At all times of measurement the mean heart rate was lower in the propofol group (90/min) when compared with the midazolam group (100/min), however, this difference did not reach significance. There were also no significant differences in cardiac index at all times of measurement, although it increased in both groups within the first 12 h by 0.6 l/min.min2. In both groups this increase was associated with a reduction in peripheral resistance and an increase in rectal temperature. To achieve the desired sedation depth, midazolam was administered at a mean dosage of 0.11 mg/kg.h and propofol at 1.9 mg/kg.h. Catecholamine levels decreased in both groups within the first 8 h: after 8 h of sedation the plasma levels of noradrenaline and adrenaline were 525 and 65 pg/ml, respectively, in the midazolam group and 327 and 51 pg/ml in the propofol group. (ABSTRACT TRUNCATED AT 400 WORDS)", "Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.", "L1 (LINE-1), a long interspersed repetitive DNA family of mammalian genomes, is thought to be a sequence family derived from a retrotransposon-like element(s), but its actively transposable unit(s) has not been identified yet. We developed a novel method for selective isolation of the human L1 sequences which transposed in a relatively recent past and may have still retained a feature of the 'active L1' unit. From the inspection of the nucleotide sequences, we conjectured that the 'active L1' or 'nearly active L1' units should have a high content of the CpG dinucleotide sequence, a mutation hot spot sequence, and contain several sites for rare cutters such as BssH II and Nar I at their 5' terminal regions. Using these rare cutter sites as selection markers, the L1 sequences were isolated, which had the high content of CpG at the 5' terminal regions and over 90% homology to L1 transcripts found in a human teratocarcinoma cell line. These L1s were shown to be 'relatively new L1' units which had integrated into chromosomes within these several million years during evolution. From the sequence data of these L1s and L1 cDNA, a consensus sequence of the 5' terminal region of high CpG L1s were constructed. A region of the consensus sequence showed about 69% homology to the 5' terminal region of Drosophila jockey element.", "OBJECTIVE: To assess the long-term safety and tolerability and to monitor benefits of extended use of bimagrumab in individuals with sporadic inclusion body myositis (sIBM) who completed a single-dose core study.METHODS: In this multicenter, open-label extension study, 10 adults received bimagrumab 10 mg/kg IV every 4 weeks up to 2 years (104 weeks). Safety (primary endpoint) was assessed by recording adverse events (AEs). Clinical benefits were assessed by changes from baseline in thigh muscle volume (TMV), lean body mass (LBM), 6-minute walk distance (6MWD), handgrip, and quadriceps strength.RESULTS: Participants had a mean age of 70.1 (SD 10.4) years. All participants (n = 10) discontinued the treatment due to early termination of the study (n = 7) or AEs (n = 3; myocardial infarction, esophageal carcinoma, and dementia, none of which were treatment related). The most common AEs were muscle spasms and falls (both 9 of 10, 90%), followed by diarrhea (6 of 10, 60%) and acne and skin eruption (both 5 of 10, 50%). At weeks 8 and 16, mean TMV increased from baseline by 4.1% (SD 4.3%) and 4.5% (SD 6.3%). Mean LBM increased from baseline and was sustained at 6.9% (SD 3.9%) at week 76. Means of 6MWD showed a progressive decline from baseline to week 76, during which there was a modest numerical increase in handgrip strength and no significant changes in quadriceps strength.CONCLUSIONS: Long-term treatment up to 2 years with bimagrumab had a good safety profile and was well tolerated in individuals with sIBM. An increase in muscle mass was noted on a group level; however, there was no evidence of clinical improvement.CLINICALTRIALSGOV IDENTIFIER: NCT02250443.CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term bimagrumab treatment was safe and well tolerated and did not lead to functional improvement.", "BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal, rare hereditary disease with an estimated prevalence of 1:10 000. The genetic variants that cause CPVT are usually highly penetrant. To date, about 189 variants in 5 genes (RYR2, CASQ2, CALM1, TRND, and KCNJ2) have been associated with CPVT pathogenesis.METHODS AND RESULTS: The Exome Sequencing Project database (ESP; n=6503) was systematically searched for previously published missense and nonsense CPVT-associated variants reported in several comprehensive reviews and in 2 databases: The Human Gene Mutation Database and The Inherited Arrhythmias Database. We used 4 different prediction tools to assess all missense variants previously associated with CPVT and compared the prediction of protein damage between CPVT-associated variants identified in the ESP and those variants not identified in the ESP. We identified 11% of the variants previously associated with CPVT in the ESP population. In the literature, 57% of these variants were reported as novel disease-causing variants absent in the healthy control subjects. These putative CPVT variants were identified in 41 out of 6131 subjects in the ESP population, corresponding to a prevalence of CPVT of up to 1:150. Using an agreement of ≥3, in silico prediction tools showed a significantly higher frequency of damaging variants among the CPVT-associated variants not identified in the ESP database (83%) compared with those variants identified in the ESP (50%; P=0.021).CONCLUSIONS: We identified a substantial overrepresentation of CPVT-associated variants in a large exome database, suggesting that these variants are not necessarily the monogenic cause of CPVT.", "BACKGROUND: Facing a growing workload and dwindling resources, the US National Library of Medicine (NLM) created the Indexing Initiative project in 1996. This cross-library team's mission is to explore indexing methodologies for ensuring quality and currency of NLM document collections. The NLM Medical Text Indexer (MTI) is the main product of this project and has been providing automated indexing recommendations since 2002. After all of this time, the questions arise whether MTI is still useful and relevant.METHODS: To answer the question about MTI usefulness, we track a wide variety of statistics related to how frequently MEDLINE indexers refer to MTI recommendations, how well MTI performs against human indexing, and how often MTI is used. To answer the question of MTI relevancy compared to other available tools, we have participated in the 2013 and 2014 BioASQ Challenges. The BioASQ Challenges have provided us with an unbiased comparison between the MTI system and other systems performing the same task.RESULTS: Indexers have continually increased their use of MTI recommendations over the years from 15.75% of the articles they index in 2002 to 62.44% in 2014 showing that the indexers find MTI to be increasingly useful. The MTI performance statistics show significant improvement in Precision (+0.2992) and F1 (+0.1997) with modest gains in Recall (+0.0454) over the years. MTI consistency is comparable to the available indexer consistency studies. MTI performed well in both of the BioASQ Challenges ranking within the top tier teams.CONCLUSIONS: Based on our findings, yes, MTI is still relevant and useful, and needs to be improved and expanded. The BioASQ Challenge results have shown that we need to incorporate more machine learning into MTI while still retaining the indexing rules that have earned MTI the indexers' trust over the years. We also need to expand MTI through the use of full text, when and where it is available, to provide coverage of indexing terms that are typically only found in the full text. The role of MTI at NLM is also expanding into new areas, further reinforcing the idea that MTI is increasingly useful and relevant." ]

[ "FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCF(FBW7) degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer.", "Author information:(1)Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.(2)Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.(3)Science for Life Laboratory, Solna, Sweden.(4)Department of Applied Statistics, Operations Research and Quality, Universitat Politècnica de València, Valencia, Spain.(5)MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.(6)Department of Developmental and Cell Biology and Center for Complex Biological Systems, University of California, Irvine, CA, USA.(7)Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.(8)Protein Analysis Unit, Biomedical Center, Ludwig Maximilian University of Munich, Munich, Germany.(9)Division of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.(10)Biomax Informatics AG, Planegg, Germany.(11)Centre for Human Metabolomics, Faculty of Natural Sciences, North-West University (Potchefstroom Campus), Potchefstroom, South Africa.(12)Microbiology and Cell Science Department, Institute for Food and Agricultural Research, Genetics Institute, University of Florida, Gainesville, Florida, USA.(13)Computer Science Department, University of Crete, Heraklion, Greece.(14)Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia, United States.(15)Gnosis Data Analysis PC, Heraklion, Greece.(16)QIAGEN Aarhus A/S, Silkeborgvej 2, 8000, Aarhus, Denmark.(17)Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.(18)MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK. matthias.merkenschlager@lms.mrc.ac.uk.(19)Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. jesper.tegner@kaust.edu.sa.(20)Science for Life Laboratory, Solna, Sweden. jesper.tegner@kaust.edu.sa.(21)Biological and Environmental Sciences and Engineering Division, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia. jesper.tegner@kaust.edu.sa.(22)Microbiology and Cell Science Department, Institute for Food and Agricultural Research, Genetics Institute, University of Florida, Gainesville, Florida, USA. aconesa@ufl.edu.", "PURPOSE OF REVIEW: To provide an update on the development of small molecular compounds as novel therapeutics for the treatment of rheumatoid arthritis. The development of such orally available agents has long been hoped for in rheumatology; in the past year, it has become clear that the expectations are becoming fulfilled.RECENT FINDINGS: Over the past year, a large number of clinical trials have been published or presented reporting positive therapeutic results with tyrosine kinase inhibitors, a large class of orally available drugs that are also being developed in other medical fields. This class of drugs includes the Janus kinase (JAK) inhibitors, and data on tofacitinib published during the past year have attested to the biologic-like efficacy of this drug and supported its subsequent U.S. Food and Drugs Administration (FDA) approval. Positive clinical trial results have also been reported for several other JAK inhibitors including baricitinib. Several other JAK inhibitors and other small molecular entities are also being developed in studies ranging from preclinical models to large clinical trials.SUMMARY: Tyrosine kinase inhibition has emerged as a major new direction in rheumatoid arthritis therapy.", "The domestic apple (Malus domestica; also known as Malus pumila Mill.) has become a model fruit crop in which to study commercial traits such as disease and pest resistance, grafting, and flavor and health compound biosynthesis. To speed the discovery of genes involved in these traits, develop markers to map genes, and breed new cultivars, we have produced a substantial expressed sequence tag collection from various tissues of apple, focusing on fruit tissues of the cultivar Royal Gala. Over 150,000 expressed sequence tags have been collected from 43 different cDNA libraries representing 34 different tissues and treatments. Clustering of these sequences results in a set of 42,938 nonredundant sequences comprising 17,460 tentative contigs and 25,478 singletons, together representing what we predict are approximately one-half the expressed genes from apple. Many potential molecular markers are abundant in the apple transcripts. Dinucleotide repeats are found in 4,018 nonredundant sequences, mainly in the 5'-untranslated region of the gene, with a bias toward one repeat type (containing AG, 88%) and against another (repeats containing CG, 0.1%). Trinucleotide repeats are most common in the predicted coding regions and do not show a similar degree of sequence bias in their representation. Bi-allelic single-nucleotide polymorphisms are highly abundant with one found, on average, every 706 bp of transcribed DNA. Predictions of the numbers of representatives from protein families indicate the presence of many genes involved in disease resistance and the biosynthesis of flavor and health-associated compounds. Comparisons of some of these gene families with Arabidopsis (Arabidopsis thaliana) suggest instances where there have been duplications in the lineages leading to apple of biosynthetic and regulatory genes that are expressed in fruit. This resource paves the way for a concerted functional genomics effort in this important temperate fruit crop.", "Recent advances in endocrinology open a door for clinical application of selective estrogen receptor modulator (SERM) and selective progesterone receptor modulator (SPRM) in the treatment of uterine leiomyoma. With regard to SERM, treatment with raloxifene is shown to reduce leiomyoma size in postmenopausal women. Although raloxifene causes shrinkage of leiomyomas in combination with gonadotropin-releasing hormone agonist in premenopausal women, the effects of monotherapy with raloxifene on leiomyoma growth in premenopausal women remain controversial. By contrast, tamoxifen may not be suitable for long-term treatment of leiomyomas due to an agonistic action on the endometrium. Treatment with progesterone antagonist (RU486) or SPRM (J867) has been demonstrated to inhibit leiomyoma growth and improve clinical symptoms in premenopausal women. No serious adverse effects associated with SERM or SPRM have been reported. In light of therapeutic efficacy and few adverse effects, SERM and SPRM may hold promise as novel treatment modalities for leiomyoma. Further studies are warranted to determine the optimal strategy for the treatment of leiomyoma with SERM and SPRM.", "The cytoplasmic events that control mammalian gene expression, primarily mRNA stability and translation, potently influence the cellular response to internal and external signals. The ubiquitous RNA-binding protein (RBP) HuR is one of the best-studied regulators of cytoplasmic mRNA fate. Through its post-transcriptional influence on specific target mRNAs, HuR can alter the cellular response to proliferative, stress, apoptotic, differentiation, senescence, inflammatory and immune stimuli. In light of its central role in important cellular functions, HuR's role in diseases in which these responses are aberrant is increasingly appreciated. Here, we review the mechanisms that control HuR function, its influence on target mRNAs, and how impairment in HuR-governed gene expression programs impact upon different disease processes. We focus on HuR's well-recognized implication in cancer and chronic inflammation, and discuss emerging studies linking HuR to cardiovascular, neurological, and muscular pathologies. We also discuss the progress, potential, and challenges of targeting HuR therapeutically.", "BACKGROUND: Kawasaki-like syndrome occurring in children during the COVID-19 pandemic has been labelled multisystem inflammatory syndrome in children (MIS-C) by the CDC and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS) by the ECDC.CASE REPORT: We report the case of an 18-year-old male patient presenting with a 72-hour history of abdominal pain, fever, erythematous skin rash, vomiting and diarrhoea. Examination showed he also had shock and he was first thought to have oedematous cholecystitis. SARS-CoV-2 infection was also diagnosed. He was admitted to the ICU, and echocardiography showed cardiac dysfunction, with a low ejection fraction and low cardiac index. High-sensitivity troponin serum levels were elevated. The patient received inotropic and vasopressor support. As he fulfilled several criteria for MIS-C/PIMS-TS, he was administered acetylsalicylic acid, corticosteroids and immunoglobulin, with a good clinical response.CONCLUSION: This case emphasizes how this severe presentation of COVID-19 can easily be misdiagnosed if the clinician is less aware of this syndrome in younger patients.LEARNING POINTS: SARS-CoV-2 infection is a diagnostic challenge in some patients with atypical clinical presentations, who may have MIS-C/PIMS-TS.Physicians should be aware of this condition when evaluating teenagers and young adults with COVID-19." ]

[ "BACKGROUND: Prior study demonstrated that baseline 22-item Sino-Nasal Outcome Test (SNOT-22) aggregate scores accurately predict selection of surgical intervention in patients with chronic rhinosinusitis (CRS). Factor analysis of the SNOT-22 survey has identified five distinct domains that are differentially impacted by endoscopic sinus surgery (ESS). This study sought to quantify SNOT-22 domains in patient cohorts electing both surgical or medical management and postinterventional change in these domains.METHODS: CRS patients were prospectively enrolled into a multi-institutional, observational cohort study. Subjects elected continued medical management or ESS. SNOT-22 domain scores at baseline were compared between treatment cohorts. Postintervention domain score changes were evaluated in subjects with at least six-month follow-up.RESULTS: A total of 363 subjects were enrolled with 72 (19.8%) electing continued medical management, whereas 291 (80.2%) elected ESS. Baseline SNOT-22 domain scores were comparable between treatment cohorts in sinus-specific domains (rhinologic, extranasal rhinologic, and ear/facial symptoms; p > 0.050); however, the surgical cohort reported significantly higher psychological (mean ± standard deviation [SD]: 16.0 ± 8.4 vs 12.0 ± 7.1; p < 0.001) and sleep dysfunction (13.7 ± 6.8 vs 10.5 ± 6.2; p < 0.001) than the medical cohort. Effect sizes for ESS varied across domains with rhinologic and extranasal rhinologic symptoms experiencing the greatest gains (1.067 and 0.997, respectively), whereas psychological and sleep dysfunction experiencing the smallest improvements (0.805 and 0.818, respectively). Patients experienced greater mean improvements after ESS in all domains compared to medical management (p < 0.001).CONCLUSION: Subjects electing ESS report higher sleep and psychological dysfunction compared to medical management but have comparable sinus-specific symptoms. Subjects undergoing ESS experience greater gains compared to medical management across all domains; however, these gains are smallest in the psychological and sleep domains.", "Honey bees are large-scale monitoring tools due to their extensive environmental exploration. In their activities and from the hive ecosystem complex, they get in close contact with many organisms whose traces can be transferred into the honey, which can represent an interesting reservoir of environmental DNA (eDNA) signatures and information useful to analyse the honey bee hologenome complexity. In this study, we tested a deep shotgun sequencing approach of honey DNA coupled with a specifically adapted bioinformatic pipeline. This methodology was applied to a few honey samples pointing out DNA sequences from 191 organisms spanning different kingdoms or phyla (viruses, bacteria, plants, fungi, protozoans, arthropods, mammals). Bacteria included the largest number of species. These multi-kingdom signatures listed common hive and honey bee gut microorganisms, honey bee pathogens, parasites and pests, which resembled a complex interplay that might provide a general picture of the honey bee pathosphere. Based on the Apis mellifera filamentous virus genome diversity (the most abundant detected DNA source) we obtained information that could define the origin of the honey at the apiary level. Mining Apis mellifera sequences made it possible to identify the honey bee subspecies both at the mitochondrial and nuclear genome levels.", "Matrix gla protein (MGP) is a potent inhibitor of extracellular matrix (ECM) mineralization. MGP-deficiency in humans leads to Keutel syndrome, a rare genetic disease hallmarked by abnormal soft tissue calcification. MGP-deficient (Mgp(-/-)) mice show progressive deposition of hydroxyapatite minerals in the arterial walls and die within 2 months of age. The mechanism of antimineralization function of MGP is not fully understood. We examined the progression of vascular calcification and expression of several chondrogenic/osteogenic markers in the thoracic aortas of Mgp(-/-) mice at various ages. Although cells with chondrocyte-like morphology have been reported in the calcified aorta, our gene expression data indicate that chondrogenic/osteogenic markers are not upregulated in the arteries prior to the initiation of calcification. Interestingly, arterial calcification in Mgp(-/-) mice appears first in the elastic laminae. Considering the known mineral scaffolding function of elastin (ELN), a major elastic lamina protein, we hypothesize that elastin content in the laminae is a critical determinant for arterial calcification in Mgp(-/-) mice. To investigate this, we performed micro-computed tomography (µCT) and histological analyses of the aortas of Mgp(-/-);Eln(+/-) mice and show that elastin haploinsufficiency significantly reduces arterial calcification in this strain. Our data suggest that MGP deficiency leads to alterations of vascular ECM that may in turn initiate arterial calcification.", "Cell competition involves a conserved fitness-sensing process during which fitter cells eliminate neighbouring less-fit but viable cells1. Cell competition has been proposed as a surveillance mechanism to ensure normal development and tissue homeostasis, and has also been suggested to act as a barrier to interspecies chimerism2. However, cell competition has not been studied in an interspecies context during early development owing to the lack of an in vitro model. Here we developed an interspecies pluripotent stem cell (PSC) co-culture strategy and uncovered a previously unknown mode of cell competition between species. Interspecies competition between PSCs occurred in primed but not naive pluripotent cells, and between evolutionarily distant species. By comparative transcriptome analysis, we found that genes related to the NF-κB signalling pathway, among others, were upregulated in less-fit 'loser' human cells. Genetic inactivation of a core component (P65, also known as RELA) and an upstream regulator (MYD88) of the NF-κB complex in human cells could overcome the competition between human and mouse PSCs, thereby improving the survival and chimerism of human cells in early mouse embryos. These insights into cell competition pave the way for the study of evolutionarily conserved mechanisms that underlie competitive cell interactions during early mammalian development. Suppression of interspecies PSC competition may facilitate the generation of human tissues in animals.", "5-Methylcytosine (5 mC) in genomic DNA has important epigenetic functions in embryonic development and tumor biology. 5-Hydroxymethylcytosine (5 hmC) is generated from 5 mC by the action of the TET (Ten-Eleven-Translocation) enzymes and may be an intermediate to further oxidation and finally demethylation of 5 mC. We have used immunohistochemistry (IHC) and isotope-based liquid chromatography mass spectrometry (LC-MS) to investigate the presence and distribution of 5 hmC in human brain and brain tumors. In the normal adult brain, IHC identified 61.5% 5 hmC positive cells in the cortex and 32.4% 5 hmC in white matter (WM) areas. In tumors, positive staining of cells ranged from 1.1% in glioblastomas (GBMs) (WHO Grade IV) to 8.9% in Grade I gliomas (pilocytic astrocytomas). In the normal adult human brain, LC-MS also showed highest values in cortical areas (1.17% 5 hmC/dG [deoxyguanosine]), in the cerebral WM we measured around 0.70% 5 hmC/dG. levels were related to tumor differentiation, ranging from lowest values of 0.078% 5 hmC/dG in GBMs (WHO Grade IV) to 0.24% 5 hmC/dG in WHO Grade II diffuse astrocytomas. 5 hmC measurements were unrelated to 5 mC values. We find that the number of 5 hmC positive cells and the amount of 5 hmC/dG in the genome that has been proposed to be related to pluripotency and lineage commitment in embryonic stem cells is also associated with brain tumor differentiation and anaplasia.", "BACKGROUND: The performance of CURB65 in predicting mortality in community-acquired pneumonia (CAP) has been tested in two large observational studies. However, it has not been tested against generic sepsis and early warning scores, which are increasingly being advocated for identification of high-risk patients in acute medical wards.METHOD: A retrospective analysis was performed of data prospectively collected for a CAP quality improvement study. The ability to stratify mortality and performance characteristics (sensitivity, specificity, positive predictive value, negative predictive value and area under the receiver operating curve) were calculated for stratifications of CURB65, CRB65, the systemic inflammatory response syndrome (SIRS) criteria and the standardised early warning score (SEWS).RESULTS: 419 patients were included in the main analysis with a median age of 74 years (men = 47%). CURB65 and CRB65 stratified mortality in a more clinically useful way and had more favourable operating characteristics than SIRS or SEWS; for example, mortality in low-risk patients was 2% when defined by CURB65, but 9% when defined by SEWS and 11-17% when defined by variations of the SIRS criteria. The sensitivity, specificity, positive predictive value and negative predictive value of CURB65 was 71%, 69%, 35% and 91%, respectively, compared with 62%, 73%, 35% and 89% for the best performing version of SIRS and 52%, 67%, 27% and 86% for SEWS. CURB65 had the greatest area under the receiver operating curve (0.78 v 0.73 for CRB65, 0.68 for SIRS and 0.64 for SEWS).CONCLUSIONS: CURB65 should not be supplanted by SIRS or SEWS for initial prognostic assessment in CAP. Further research to identify better generic prognostic tools is required.", "BACKGROUND: Keutel syndrome is a rare autosomal-recessive condition characterized by abnormal cartilage calcification. Neuroimaging findings associated with this condition have been randomly described in the literature.OBJECTIVE: To systematically evaluate the neuroimaging findings in a series of children with Keutel syndrome to broaden our base of knowledge.MATERIALS AND METHODS: Four children with confirmed Keutel syndrome were reviewed for the brain, head and neck imaging findings.RESULTS: Three of the four children, all siblings, showed evidence of moyamoya syndrome. All four siblings had pinna cartilage calcification.CONCLUSION: We propose that Keutel syndrome be considered and included among the secondary causes of moyamoya syndrome. In children with petrified auricle and neurological symptoms, Keutel syndrome should be considered and brain MRI with MRA is required.", "In cell lines established from Marek's disease tumors, several viral transcripts are expressed and among them the products of pp38/pp24 mRNA and 1.8 kb-mRNA have been suggested to be involved in viral oncogenicity. The long inverted repeats of Marek's Disease virus serotype 1 (MDV1) genome contain closely located transcriptional promoters for phosphorylated protein pp38/pp24 and 1.8 kb-mRNA. These promoters initiate transcription in opposite directions and are separated only by a short enhancer region, which is likely to regulate both promoters simultaneously. We have analyzed the transcription activity of these promoters in MDV1 (Md5 strain) infected CEF by transient expression of CAT reporter genes and found that the promoters were in fact active in infected cells and the promoter for 1.8 kb-mRNA was more active than the pp38/pp24 promoter. Deletion analysis of the short enhancer region revealed that the 30 bp region overlapping the enhancer elements for 1.8 kb-mRNA was important for promoter activity for pp38/pp24. The gel shift analysis revealed that nuclear factor(s) actually bound to the overlapping 30 bp region. In addition, the activity of these promoters in infected cells varied with MDV strains. These results suggest that pp38/pp24 and 1.8 kb-mRNA promoters share a common regulatory sequence but a viral or a cellular factor(s) induced by viral infection regulates the promoter by distinct mechanisms.", "BACKGROUND: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC).METHODS: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111.FINDINGS: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group.INTERPRETATION: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin.FUNDING: Eli Lilly and Company.", "OBJECTIVE: Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine.BACKGROUND: The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs).METHODS: This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks.RESULTS: The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal.CONCLUSION: Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.", "Tracheobronchial cartilage calcification is a rare finding in the pediatric population. Keutel syndrome (OMIM 245150) is a very rare syndrome characterized with diffuse calcification of cartilage, brachytelephalangia, pulmonary stenosis, midline defects, stippled epiphysis in infancy, and hearing loss accompanied by recurrent respiratory infections and asthma-like attacks. Here, we present a 14-year-old patient who was followed up with the diagnosis of asthma, but did not respond to appropriate asthma treatment. She was subsequently diagnosed as having Keutel syndrome with cartilage calcification on the tracheobranchial tree and auricula, atypical facial features, recurrent otitis media, hearing loss, and recurrent asthma-like symptoms.", "An 83-year-old Japanese man had a 29-year history of well-controlled diabetes mellitus. His HbA1c level was approximately 6.0%, with no microalbuminuria and a serum creatinine level seven days before admission of 0.8 mg/dl (eGFR: 69.67 ml/min/1.73 m(2)). Five days before admission, he visited an ophthalmologist with inflammation of the right palpebra and conjunctiva and began taking valacyclovir at a dose of 3,000 mg for the treatment of herpes zoster. Two days before admission, he was prescribed loxoprofen at a dose of 180 mg for a headache. One day prior to admission, he developed dysarthria, wandering and loss of appetite. He was subsequently admitted to our hospital with progressive deterioration of consciousness (Japan Coma Scale: II-20). On admission, he exhibited renal dysfunction, with a serum creatinine level of 5.11 mg/dl (eGFR: 9.16 ml/min/1.73 m(2)). Based on his diverse symptoms and current treatment with valacyclovir, the patient was diagnosed with acyclovir-induced neurotoxicity and his symptoms rapidly improved after hemodialysis. The serum acyclovir level on admission was found to be 9.25 μg/ml. Although acyclovir-induced neurotoxicity is commonly seen in elderly patients with renal dysfunction, there are also reports of this condition in patients with a normal renal function. Valacyclovir is frequently prescribed to the elderly to treat diseases such as herpes zoster. As valacyclovir induces renal dysfunction, which raises the serum acyclovir level to the toxic range, special attention must be paid when administering this drug in elderly subjects." ]

[ "In January 2016, the World Health Organization warned that Zika virus is \"spreading explosively\" in the Americas and that up to 4 million infections could be present worldwide within a year. Soon thereafter, some politicians and authors publicly advocated for quarantine of travelers returning from regions where mosquitoes carrying Zika virus are prevalent. The public health tool of quarantine can be used to prevent the spread of infection by restricting the movement of persons who have been exposed to a deadly disease that can be transmitted from person to person before symptom onset. With 80% of Zika virus infections being asymptomatic, no rapid test being available to detect the virus, and primary transmission being via the bites of certain mosquitoes, application of quarantine in this setting is not scientifically sound or practically feasible. Rather, public health interventions should focus on preventing bites from infected mosquitoes, counseling pregnant women on the risks of fetal microcephaly and other birth defects, and identifying patients with signs and symptoms of Guillain-Barré syndrome. As was seen in the Ebola virus disease outbreak of 2014, non-evidence-based factors can influence policy decisions. Public health experts must ensure that policy makers are informed that quarantine is not a scientifically sound approach for the control of Zika virus. (Disaster Med Public Health Preparedness. 2016;0:1-3).", "BACKGROUND: We sought to assess the occurrence of events after blinded study drug discontinuation and transition to open-label vitamin K antagonist (VKA) in ARISTOTLE.METHODS: At the end of ARISTOTLE, blinded study drug was stopped, and open-label VKA was recommended. For patients completing the trial on blinded study drug, a 2-day bridging period with apixaban or apixaban placebo was recommended (while beginning open-label VKA). Outcomes were assessed during the 30 days after stopping blinded study drug.RESULTS: Of the 6,809 patients in the apixaban group and 6,588 in the warfarin group who completed the trial on study drug, there were 21 strokes or systemic emboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban group (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and 10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), with most of the imbalance between groups being after the first week. Similar results were seen in the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic emboli (5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen when starting apixaban. No similar increase in events with apixaban versus warfarin was seen during temporary or permanent study drug discontinuation during the trial.CONCLUSIONS: The excess in thrombotic and bleeding events in the apixaban group after study drug discontinuation appears to be related to an increased risk associated with the initiation of a VKA rather than a direct effect of apixaban. Whether ≥2 days of apixaban bridging improves outcomes during VKA transition is unknown and deserves further evaluation.", "BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).", "OBJECTIVE: Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine.BACKGROUND: The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs).METHODS: This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks.RESULTS: The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal.CONCLUSION: Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.", "Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations, which were used to inform the phase III dose-selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one phase II trial. A population pharmacokinetic model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from phase II to phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the phase III clinical trials.", "The Notch signaling pathway is involved in a wide variety of highly conserved developmental processes in mammals. Importantly, mutations of the Notch protein and components of its signaling pathway have been implicated in an array of human diseases (T-cell leukemia and other cancers, Multiple Sclerosis, CADASIL, Alagille Syndrome, Spondylocostal Dysostosis). In mammals, Notch becomes activated upon binding of its extracellular domain to ligands (Delta and Jagged/Serrate) that are present on the surface of apposed cells. The extracellular domain of Notch contains up to 36 tandem Epidermal Growth Factor-like (EGF) repeats. Many of these EGF repeats are modified at evolutionarily-conserved consensus sites by an unusual form of O-glycosylation called O-fucose. Work from several groups indicates that O-fucosylation plays an important role in ligand mediated Notch signaling. Recent evidence also suggests that the enzyme responsible for addition of O-fucose to Notch, protein O-fucosyltransferase-1 (POFUT1), may serve a quality control function in the endoplasmic reticulum. Additionally, some of the O-fucose moieties are further elongated by the action of members of the Fringe family of beta-1,3-N-acetylglucosaminyltransferases. The alteration in O-fucose saccharide structure caused by Fringe modulates the response of Notch to its ligands. Thus, glycosylation serves an important role in regulating Notch activity. This review focuses on the role of glycosylation in the normal functioning of the Notch pathway. As well, potential roles for glycosylation in Notch-related human diseases, and possible roles for therapeutic targeting of POFUT1 and Fringe in Notch-related human diseases, are discussed.", "AIMS/INTRODUCTION: Obesity is characterized by disturbed adipocytokine expression and insulin resistance in adipocytes. Growth arrest-specific 6 (GAS6) is a gene encoding the Gas6 protein, which is expressed in fibroblasts, and its related signaling might be associated with adipose tissue inflammation, glucose intolerance and insulin resistance. The aim of this study was to investigate the associations among Gas6, adipocytokines and insulin resistance in adipocytes.MATERIALS AND METHODS: Mature Simpson Golabi Behmel Syndrome adipocytes were treated with high levels of insulin to mimic insulin resistance, and were examined for the expressions of Gas6, cytokines and adipocytokines from preadipocytes in differentiation. In an animal study, high-fat diet-induced obese mice were used to verify the Gas6 expression in vitro.RESULTS: During the differentiation of adipocytes, the expression of Gas6 gradually decreased, and was obviously downregulated with adipocyte inflammation and insulin resistance. Gas6 levels were found to be in proportion to the expression of adiponectin, which has been regarded as closely relevant to improved insulin sensitivity after metformin treatment. Similar results were also confirmed in the animal study.CONCLUSIONS: Our results suggest that Gas6 might modulate the expression of adiponectin, and might therefore be associated with insulin resistance in adipose tissues." ]

[ "The E3 ubiquitin ligase CHIP (C-terminus of Hsc70-interacting protein) is believed to be a central player in the cellular triage decision, as it links the molecular chaperones Hsp70/Hsc70 and Hsp90 to the ubiquitin proteasomal degradation pathway. To better understand the decision process, we determined the affinity of CHIP for Hsp70 and Hsp90 using isothermal titration calorimetry. We analyzed the influence of CHIP on the ATPase cycles of both chaperones in the presence of co-chaperones and a substrate, and determined the ubiquitination efficacy of CHIP in the presence of the chaperones. We found that CHIP has a sixfold higher affinity for Hsp90 compared with Hsc70. CHIP had no influence on ADP dissociation or ATP association, but reduced the Hsp70 cochaperone Hdj1-stimulated single-turnover ATPase rates of Hsc70 and Hsp70. CHIP did not influence the ATPase cycle of Hsp90 in the absence of co-chaperones or in the presence of the Hsp90 cochaperones Aha1 or p23. Polyubiquitination of heat-denatured luciferase and the native substrate p53 was much more efficient in the presence of Hsc70 and Hdj1 than in the presence of Hsp90, indicating that CHIP preferentially ubiquitinates Hsp70-bound substrates.", "The Kaufman-McKusick syndrome (MK 23670) is a rare autosomal recessive disorder characterized by the triad of hydrometrocolpos, postaxial polydactyly, and congenital heart disease. Multiple other anomalies have been ascribed to this syndrome. Hydrometrocolpos, especially if unrecognized, may be a serious, life-threatening condition in the newborn girl. Forty-four cases have been so far reported in the literature. A great phenotypic variability occurs in this syndrome, therefore making it very difficult to identify the disorder at its presentation and classify it correctly. We shall hereafter review current data regarding the prominent clinical features, the diagnosis and treatment of this syndrome. Problems in genetic counseling will be discussed.", "Myelin allows for the rapid and precise timing of action potential propagation along neuronal circuits and is essential for healthy auditory system function. In this article, we discuss what is currently known about myelin in the auditory system with a focus on the timing of myelination during auditory system development, the role of myelin in supporting peripheral and central auditory circuit function, and how various myelin pathologies compromise auditory information processing. Additionally, in keeping with the increasing recognition that myelin is dynamic and is influenced by experience throughout life, we review the growing evidence that auditory sensory deprivation alters myelin along specific segments of the brain's auditory circuit. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 80-92, 2018.", "BACKGROUND: The goal of text mining is to make the information conveyed in scientific publications accessible to structured search and automatic analysis. Two important subtasks of text mining are entity mention normalization - to identify biomedical objects in text - and extraction of qualified relationships between those objects. We describe a method for identifying genes and relationships between proteins.RESULTS: We present solutions to gene mention normalization and extraction of protein-protein interactions. For the first task, we identify genes by using background knowledge on each gene, namely annotations related to function, location, disease, and so on. Our approach currently achieves an f-measure of 86.4% on the BioCreative II gene normalization data. For the extraction of protein-protein interactions, we pursue an approach that builds on classical sequence analysis: motifs derived from multiple sequence alignments. The method achieves an f-measure of 24.4% (micro-average) in the BioCreative II interaction pair subtask.CONCLUSION: For gene mention normalization, our approach outperforms strategies that utilize only the matching of genes names against dictionaries, without invoking further knowledge on each gene. Motifs derived from alignments of sentences are successful at identifying protein interactions in text; the approach we present in this report is fully automated and performs similarly to systems that require human intervention at one or more stages.AVAILABILITY: Our methods for gene, protein, and species identification, and extraction of protein-protein are available as part of the BioCreative Meta Services (BCMS), see http://bcms.bioinfo.cnio.es/.", "Author information:(1)From Genomics England (D.S., K.R.S., A.M., E.A.T., E.M.M., A.T., G.C., K.I., L.M., M. Wielscher, A.N., M. Bale, E.B., C.B., H.B., M. Bleda, A. Devereau, D.H., E. Haraldsdottir, Z.H., D.K., C. Patch, D.P., A.M., R. Sultana, M.R., A.L.T.T., C. Tregidgo, C. Turnbull, M. Welland, S. Wood, C.S., E.W., S.L., R.E.F., L.C.D., O.N., I.U.S.L., C.F.W., J.C., R.H.S., T.F., A.R., M.C.), the William Harvey Research Institute, Queen Mary University of London (D.S., K.R.S., V.C., A.T., L.M., M.R.B., D.K., S. Wood, P.C., J.O.J., T.F., M.C.), University College London (UCL) Institute of Ophthalmology (V.C., G.A., M.M., A.T.M., S. Malka, N.P., P.Y.-W.-M., A.R.W.), UCL Genetics Institute (V.C., N.W.W.), GOSgene (H.J.W.), Genetics and Genomic Medicine Programme (L.V., M.R., M.D., L.C., P. Beales, M.B.-G.), National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) (M.R., S. Grunewald, S.C.-L., F.M., C. Pilkington, L.R.W., L.C., P. Beales, M.B.-G.), Infection, Immunity, and Inflammation Research and Teaching Department (P.A., L.R.W.), Stem Cells and Regenerative Medicine (N.T.), and Mitochondrial Research Group (S. Rahman), UCL Great Ormond Street Institute of Child Health, UCL Ear Institute (L.V.), the Department of Renal Medicine (D. Bockenhauer), and Institute of Cardiovascular Science (P.E.), UCL, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust (V.C., G.A., M.M., A.T.M., S. Malka, N.P., A.R.W.), the National Hospital for Neurology and Neurosurgery (J.V., E.O., J.Y., K. Newland, H.R.M., J.P., N.W.W., H.H.), the Metabolic Unit (L.A., S. Grunewald, S. Rahman), London Centre for Paediatric Endocrinology and Diabetes (M.D.), and the Department of Gastroenterology (N.T.), Great Ormond Street Hospital for Children NHS Foundation Trust (L.V., D. Bockenhauer, A. Broomfield, M.A.C., T. Lam, E.F., V.G., S.C.-L., F.M., C. Pilkington, R. Quinlivan, C.W., L.R.W., A. Worth, L.C., P. Beales, M.B.-G., R.H.S.), the Clinical Genetics Department (M.R., T.B., C. Compton, C.D., E. Haque, L.I., D.J., S. Mohammed, L.R., S. Rose, D.R., G.S., A.C.S., F.F., M.I.) and St. John's Institute of Dermatology (H.F., R. Sarkany), Guy's and St. Thomas' NHS Foundation Trust, the Division of Genetics and Epidemiology, Institute of Cancer Research (C. Turnbull), Florence Nightingale Faculty of Nursing, Midwifery, and Palliative Care (T.B.), Division of Genetics and Molecular Medicine (M.A.S.), and Division of Medical and Molecular Genetics (M.I.), King's College London, NIHR BRC at Moorfields Eye Hospital (P.Y.-W.-M.), NHS England and NHS Improvement, Skipton House (V.D., A. Douglas, S. Hill), and Imperial College Healthcare NHS Trust, Hammersmith Hospital (K. Naresh), London, Open Targets and European Molecular Biology Laboratory-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton (E.M.M.), the Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine, and Health, University of Manchester (J.M.E., S.B., J.C.-S., S.D., G.H., H.B.T., R.T.O., G. Black, W.N.), and the Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust (J.M.E., Z.H., S.B., J.C.-S., S.D., G.H., G. Black, W.N.), Manchester, the Department of Genetic and Genomic Medicine, Institute of Medical Genetics, Cardiff University, Cardiff (H.J.W.), the Department of Clinical Neurosciences (T.R., W.W., R.H., P.F.C.), the Medical Research Council (MRC) Mitochondrial Biology Unit (T.R., W.W., P.Y.-W.-M., P.F.C.), the Department of Paediatrics (T.R.), the Department of Haematology (K.S., C. Penkett, S. Gräf, R.M., W.H.O., A.R.), the School of Clinical Medicine (K.R., E.L., R.A.F., K.P., F.L.R.), the Department of Medicine (S. Gräf), and Cambridge Centre for Brain Repair, Department of Clinical Neurosciences (P.Y.-W.-M.), University of Cambridge, NIHR BioResource, Cambridge University Hospitals (K.S., S.A., R.J., C. Penkett, E.D., S. Gräf, R.M., M.K., J.R.B., P.F.C., W.H.O., F.L.R.), and Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust (G.F., P.T., O.S.-B., S. Halsall, K.P., A. Wagner, S.G.M., N.B., M.K.), Cambridge Biomedical Campus, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge BRC (M.G.), Congenica (A.H., H.S.), Illumina Cambridge (A. Wolejko, B.H., G. Burns, S. Hunter, R.J.G., S.J.H., D. Bentley), NHS Blood and Transplant (W.H.O.), and Wellcome Sanger Institute (W.H.O.), Cambridge, the Health Economics Research Centre (J. Buchanan, S. Wordsworth) and the Wellcome Centre for Human Genetics (C. Camps, J.C.T.), University of Oxford, NIHR Oxford BRC (J. Buchanan, S. Wordsworth, J.D., C. Crichton, J.W., K.W., C. Camps, S.P., N.B.A.R., A.S., J.T., J.C.T.), the Oxford Centre for Genomic Medicine (A. de Burca, A.H.N.), and the Departments of Haematology (N.B.A.R.) and Neurology (A.S.), Oxford University Hospitals NHS Foundation Trust, Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital (C. Campbell, K.G., T. Lester, J.T.), the MRC Weatherall Institute of Molecular Medicine (N.K., N.B.A.R., A.O.M.W.) and the Oxford Epilepsy Research Group (A.S.), Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford, and the Department of Clinical Immunology (S.P.), John Radcliffe Hospital, Oxford, Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust (E.B.), and the University of Exeter Medical School (E.B., C.F.W.), Royal Devon and Exeter Hospital (S.E.), Exeter, Newcastle Eye Centre, Royal Victoria Infirmary (A.C.B.), the Institute of Genetic Medicine, Newcastle University, International Centre for Life (V.S., P. Brennan), Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University (G.S.G., R.H., A.M.S., D.M.T., R. Quinton, R.M., R.W.T., J.A.S.), Highly Specialised Mitochondrial Service (G.S.G., A.M.S., D.M.T., R.M., R.W.T.) and Northern Genetics Service (J. Burn), Newcastle upon Tyne Hospitals NHS Foundation Trust (J.A.S.), and NIHR Newcastle BRC (G.S.G., D.M.T., J.A.S.), Newcastle upon Tyne, the Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, University of Birmingham (C. Palles), and Birmingham Women's Hospital (D.M.), Birmingham, the Genomic Informatics Group (E.G.S.), University Hospital Southampton (I.K.T.), and the University of Southampton (I.K.T.), Southampton, Liverpool Women's NHS Foundation Trust, Liverpool (A. Douglas), the School of Cellular and Molecular Medicine, University of Bristol, Bristol (A.D.M.), and Yorkshire and Humber, Sheffield Children's Hospital, Sheffield (G.W.) - all in the United Kingdom; Fabric Genomics, Oakland (M. Babcock, M.G.R.), and the Ophthalmology Department, University of California, San Francisco School of Medicine, San Francisco (A.T.M.) - both in California; the Jackson Laboratory for Genomic Medicine, Farmington, CT (P.N.R.); and the Center for Genome Research and Biocomputing, Environmental and Molecular Toxicology, Oregon State University, Corvallis (M.H.).", "AMP-activated protein kinase (AMPK) is an energy-sensing enzyme whose activity is inhibited in settings of insulin resistance. Exposure to a high glucose concentration has recently been shown to increase phosphorylation of AMPK at Ser(485/491) of its α1/α2 subunit; however, the mechanism by which it does so is not known. Diacylglycerol (DAG), which is also increased in muscle exposed to high glucose, activates a number of signaling molecules including protein kinase (PK)C and PKD1. We sought to determine whether PKC or PKD1 is involved in inhibition of AMPK by causing Ser(485/491) phosphorylation in skeletal muscle cells. C2C12 myotubes were treated with the PKC/D1 activator phorbol 12-myristate 13-acetate (PMA), which acts as a DAG mimetic. This caused dose- and time-dependent increases in AMPK Ser(485/491) phosphorylation, which was associated with a ∼60% decrease in AMPKα2 activity. Expression of a phosphodefective AMPKα2 mutant (S491A) prevented the PMA-induced reduction in AMPK activity. Serine phosphorylation and inhibition of AMPK activity were partially prevented by the broad PKC inhibitor Gö6983 and fully prevented by the specific PKD1 inhibitor CRT0066101. Genetic knockdown of PKD1 also prevented Ser(485/491) phosphorylation of AMPK. Inhibition of previously identified kinases that phosphorylate AMPK at this site (Akt, S6K, and ERK) did not prevent these events. PMA treatment also caused impairments in insulin-signaling through Akt, which were prevented by PKD1 inhibition. Finally, recombinant PKD1 phosphorylated AMPKα2 at Ser(491) in cell-free conditions. These results identify PKD1 as a novel upstream kinase of AMPKα2 Ser(491) that plays a negative role in insulin signaling in muscle cells.", "A 32-year-old woman is described as having the following characteristics of Emery-Dreifuss muscular dystrophy: humeroperoneal muscular atrophy and weakness, neck and elbow contractures with sinus bradycardia, first-degree atrioventricular block, and dilated cardiomyopathy. The biopsy specimen of skeletal muscle showed dystrophic character; a cardiac endomyocardial biopsy specimen showed adipose tissue infiltration and deposition of antihuman IgG. Emery-Dreifuss muscular dystrophy is an X-linked recessive myopathy. The patient had no familial background of the disease. This patient might have a sporadic inheritance pattern with severe cardiac involvement." ]

[ "Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.", "Anaplastic lymphoma kinase (ALK) rearrangement is detected in 3-7% of patients with non-small-cell lung cancer. Crizotinib is an ALK inhibitor, which was approved in 2011 for the treatment of ALK-positive lung cancer. Despite the initial enthusiasm, most of the patients develop resistance within the first year of treatment. The main mechanisms are secondary mutations and bypass track activation. Moreover, crizotinib has low penetration into the central nervous system. The need to overcome these limitations has led to the development of second-generation inhibitors that have better effectiveness against crizotinib-resistant mutations and brain metastases. Ceritinib and alectinib are the only approved drugs of this group. Many ongoing trials try to define the most appropriate agent for the treatment of ALK-positive lung cancer depending on the responsible mechanism. This review focuses on the current data regarding the potential mechanisms of resistance to ALK inhibitors and the strategies to overcome it.", "BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria.METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS.RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 μg per milliliter at the time of controlled human malaria infection.CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).", "Ewing's sarcomas are characterized by recurrent chromosomal translocations expressing EWS-ETS fusion proteins, the most common of which is EWS-FLI.(1-5) EWS-FLI is an oncogenic transcription factor that regulates genes involved in tumorigenesis.(6,7) Because the Ewing's sarcoma cell of origin remains unknown, a variety of model systems have been developed to study EWS-FLI fusions,(8-14) and multiple microarray experiments describing potential EWS-FLI target genes have been reported.(8,10,11,13,15-21) Each model has potential benefits and drawbacks, but a large-scale comparison of these has not been reported. Herein we report a meta-analysis of the genes that are dysregulated by EWS-FLI in Ewing's sarcoma model systems. In general, EWS-FLI gain- and loss-of-function models in human cell types were well correlated to patient-derived tumor samples, while murine models were not. Using frequency analysis of dysregulated genes across multiple model systems, we identified a conserved \"core\" EWS-FLI transcriptional signature. This signature contained many of the genes known to be involved in the tumorigenic phenotype of Ewing's sarcoma, and also contained genes that have not been previously reported. Comparisons between the core EWS-FLI signature and published mesenchymal stem cell data support the recent assertion that mesenchymal stem cells are likely the Ewing's sarcoma precursor cell.(15) These results demonstrate the utility of using comparative analysis to validate model systems and emphasize the unique potential of this approach to identify both oncogenic and background cell signatures.", "CIS43 is a potent neutralizing human mAb that targets a highly conserved \"junctional\" epitope in the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP). Enhancing the durability of CIS43 in vivo will be important for clinical translation. Here, 2 approaches were used to improve the durability of CIS43 in vivo while maintaining potent neutralization. First, the Fc domain was modified with the LS mutations (CIS43LS) to increase CIS43 binding affinity for the neonatal Fc receptor (FcRn). CIS43LS and CIS43 showed comparable in vivo protective efficacy. CIS43LS had 9- to 13-fold increased binding affinity for human (6.2 nM versus 54.2 nM) and rhesus (25.1 nM versus 325.8 nM) FcRn at endosomal pH 6.0 compared with CIS43. Importantly, the half-life of CIS43LS in rhesus macaques increased from 22 days to 39 days compared with CIS43. The second approach for sustaining antibody levels of CIS43 in vivo is through adeno-associated virus (AAV) expression. Mice administered once with AAV-expressing CIS43 had sustained antibody levels of approximately 300 μg/mL and mediated protection against sequential malaria challenges up to 36 weeks. Based on these data, CIS43LS has advanced to phase I clinical trials, and AAV delivery provides a potential next-generation approach for malaria prevention.", "OBJECTIVES: We describe the first cohort-based analysis of the impact of genetic disorders in craniosynostosis. We aimed to refine the understanding of prognoses and pathogenesis and to provide rational criteria for clinical genetic testing.METHODS: We undertook targeted molecular genetic and cytogenetic testing for 326 children who required surgery because of craniosynostosis, were born in 1993-2002, presented to a single craniofacial unit, and were monitored until the end of 2007.RESULTS: Eighty-four children (and 64 relatives) had pathologic genetic alterations (86% single-gene mutations and 14% chromosomal abnormalities). The FGFR3 P250R mutation was the single largest contributor (24%) to the genetic group. Genetic diagnoses accounted for 21% of all craniosynostosis cases and were associated with increased rates of many complications. Children with an initial clinical diagnosis of nonsyndromic craniosynostosis were more likely to have a causative mutation if the synostoses were unicoronal or bicoronal (10 of 48 cases) than if they were sagittal or metopic (0 of 55 cases; P = .0003). Repeat craniofacial surgery was required for 58% of children with single-gene mutations but only 17% of those with chromosomal abnormalities (P = .01).CONCLUSIONS: Clinical genetic assessment is critical for the treatment of children with craniosynostosis. Genetic testing of nonsyndromic cases (at least for FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses. Single-gene disorders that disrupt physiologic signaling in the cranial sutures often require reoperation, whereas chromosomal abnormalities follow a more-indolent course, which suggests a different, secondary origin of the associated craniosynostosis.", "Malaria affects more than 3 billion people in 95 countries, with an estimated mortality rate of 400,000 per year. The female Anopheles spp mosquito most commonly transmits malaria, and the main burden of disease is due to Plasmodium falciparum. The most abundant antigen on the sporozoite surface is the Plasmodium falciparum circumsporozoite protein (PfCSP). PfCSP is required for parasite development and attachment to host hepatocytes. The first potential protein vaccine, RTS,S/ASO1, consists of a recombinant fusion antigen based on PfCSP. Initial findings from a phase 3 trial of RTS,S/ASO1 were promising but resulted in recommendations for further evaluation in large-scale trials. R21, a circumsporozoite protein-based vaccine, combined with an adjuvant, Matrix-M (MM), was recently evaluated in a phase 2 investigational study in children between 5-17 months of age in Burkina Faso. The R21/MM candidate vaccine resulted in high titers of malaria-specific antibodies. On August 26, 2021, the findings from a phase 1 trial on a new monoclonal antibody to PfCSP, CIS43LS, showed that a single dose of the CIS43LS monoclonal antibody resulted in protection against malaria. These new findings have implications for the seasonal control of malaria in endemic regions and a possible future role in public health strategies to eliminate malaria. This Editorial aims to provide the background to developing and evaluating the new malaria vaccines that target PfCSP, including the first monoclonal antibody vaccine to malaria.", "OBJECTIVE: To describe the clinical evidence supporting the safety, efficacy, and clinical utility of oral dimethyl fumarate for the treatment of multiple sclerosis (MS).DATA SOURCES: A comprehensive PubMed search was conducted in July 2013 using the search terms dimethyl fumarate and Tecfidera. Reference lists of abstracted publications were reviewed to identify relevant works that were not retrieved via the electronic search. Additional information was obtained from the FDA Web site, manufacturer prescribing information, and Clinicaltrials.gov.STUDY SELECTION AND DATA ABSTRACTION: Clinical trials and review articles that included the use of dimethyl fumarate in the treatment of MS and were available in English were abstracted for review.DATA SYNTHESIS: The safety and efficacy of dimethyl fumarate for the treatment of relapsing remitting MS was confirmed in 2 phase III trials, DEFINE and CONFIRM. Relative to placebo, twice-daily dimethyl fumarate was found to reduce the proportion of patients with relapses at 2 years by 34% to 49% and the annualized relapse rate by 44% to 53%. Although the incidence of serious adverse effects did not differ from that of placebo, intolerable flushing and gastrointestinal adverse effects prompted discontinuation in 3% and 4% of patients, respectively.CONCLUSIONS: In March 2013, dimethyl fumarate was approved as a third oral option for patients with relapsing forms of MS. Although no head-to-head trials have been conducted, a comparison of data from phase III trials suggests that the efficacy of dimethyl fumarate is comparable to that of existing oral agents and may offer a preferable safety profile.", "\"Product sampling\" is an effective marketing strategy which lowers consumer buying resistance by providing a free sample of the product for the consumer to test. We used this strategy to demonstrate the palatability of the prudent diet (30-35% of calories from total fats, less than 10% from saturated fats, less than 3 g sodium, and increased fiber) to physicians attending a 5-day family practice continuing medical education conference. The effect of the intervention was evaluated with pre- and postintervention questionnaires and a 20% random sample of participants was surveyed 1 year later. The proportion of physicians who reported that they considered the diet to be \"very palatable\" rose from 26% before the demonstration to 64% after the demonstration. Only 5% of the physicians did not report a favorable response to the demonstration. Sixty-two percent of the physicians reported that the diet was better than expected, and 82% reported that the demonstration encouraged them to recommend the diet to their patients. One year after the intervention 60% considered the diet \"very palatable\" and 55% reported that the demonstration stimulated them to increase their dietary intervention activities. These data suggest that serving the prudent diet at continuing medical education programs helps to remove prejudices about the diet and encourages physicians to recommend the diet to their patients.", "Eighty measurements of plasma creatinine concentration, height:creatinine ratio, and plasma beta 2 microglobulin concentration were made on 72 children (age 4 months-18.5 years) with known renal disease. Results were compared with simultaneous measurements of glomerular filtration rate using plasma clearance of 51Cr edetic acid to assess the performance of each test as an initial screening procedure of renal insufficiency. Height:creatinine index less than 2.1 was found to have a higher sensitivity and predictive value of a normal result than the other tests and is therefore the preferred test for a screening procedure.", "BACKGROUND: The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. In preclinical studies, high tumour FGFR mRNA expression predicted response to rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary clinical activity of rogaratinib.METHODS: We did a phase 1 dose-escalation and dose-expansion study of rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years or older, and were ineligible for standard therapy, with an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of at least 3 months, and at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose escalation, rogaratinib was administered orally twice daily at 50-800 mg in continuous 21-day cycles using a model-based dose-response analysis (continuous reassessment method). In the dose-expansion phase, all patients provided an archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a new biopsy at screening for the analysis of FGFR1-3 mRNA expression. In the dose-expansion phase, rogaratinib was given at the recommended dose for expansion to patients in four cohorts: urothelial carcinoma, head and neck squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other solid tumour types. Primary endpoints were safety and tolerability, determination of maximum tolerated dose including dose-limiting toxicities and determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. Safety analyses were reported in all patients who received at least one dose of rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due to an adverse event or dose-limiting toxicity were included in the evaluation of recommended phase 2 dose. Efficacy analyses were reported for all patients who received at least one dose of study drug and who had available post-baseline efficacy data. This ongoing study is registered with ClinicalTrials.gov, number NCT01976741, and is fully recruited.FINDINGS: Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected patients in the dose-escalation phase and 103 patients with FGFR mRNA-overexpressing tumours [52 patients with urothelial carcinoma, eight patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour types] in the dose-expansion phase). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; 800 mg twice daily was established as the recommended phase 2 dose and was selected for the dose-expansion phase. The most common adverse events of any grade were hyperphosphataemia (in 77 [61%] of 126 patients), diarrhoea (in 65 [52%]), and decreased appetite (in 48 [38%]); and the most common grade 3-4 adverse events were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 10 [8%]). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], retinopathy [urothelial carcinoma], and vomiting [urothelial carcinoma] in one patient each); no treatment-related deaths occurred. Median follow-up after cessation of treatment was 32 days (IQR 25-36 days). In the expansion cohorts, 15 (15%; 95% CI 8·6-23·5) out of 100 evaluable patients achieved an objective response, with responses recorded in all four expansion cohorts (12 in the urothelial carcinoma cohort and one in each of the other three cohorts), and in ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic aberration.INTERPRETATION: Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment.FUNDING: Bayer AG.", "PURPOSE: Circulating and cellular proangiogenic and antiangiogenic proteins such as vascular endothelial growth factor (VEGF) and endostatin contribute to the local angiogenic balance. We explored the effects of tamoxifen and aromatase inhibitors on concentrations of VEGF and endostatin in plasma, serum, and platelet releasate (induced by platelet activation).EXPERIMENTAL DESIGN: VEGF and endostatin concentrations were measured with a quantitative immunoassay before and after 1 to 5 weeks of treatment in 30 women with breast cancer treated with either tamoxifen (n = 14) or aromatase inhibitors (n = 16). Platelet activation was induced by a thrombin receptor agonist.RESULTS: Tamoxifen therapy resulted in an increase in platelet releasate concentrations of VEGF (P = 0.01) but no change in plasma VEGF. In contrast, aromatase inhibitor therapy did not affect serum, plasma, or platelet releasate VEGF. In univariate analysis, aspirin use attenuated the tamoxifen-associated increase in VEGF in the platelet releasate and decreased serum levels of VEGF (P = 0.03). Aromatase inhibitor therapy resulted in a decrease in serum endostatin concentrations (P = 0.04), whereas plasma concentrations of endostatin tended to be higher during treatment with aromatase inhibitors (P = 0.06). Tamoxifen therapy resulted in no change in serum or plasma endostatin concentrations. Platelet releasate concentrations of endostatin did not change with either treatment. Interindividual variability was noted among both aromatase inhibitor--and tamoxifen-treated patients.CONCLUSIONS: Tamoxifen and aromatase inhibitor therapy affect VEGF and endostatin levels and likely contribute to the angiogenic balance in breast cancer patients. Aspirin decreased the proangiogenic effects of tamoxifen, suggesting that antiplatelet and/or antiangiogenic therapy might improve the effectiveness of tamoxifen in women with breast cancer." ]

[ "Groucho related gene 5 (GRG5) is a multifunctional protein that has been implicated in late embryonic and postnatal mouse development. Here, we describe a previously unknown role of GRG5 in early developmental stages by analyzing its function in stem cell fate decisions. By both loss and gain of function approaches we demonstrate that ablation of GRG5 deregulates the Embryonic Stem Cell (ESC) pluripotent state whereas its overexpression leads to enhanced self-renewal and acquisition of cancer cell-like properties. The malignant characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its pro-oncogenic potential. Furthermore, transcriptomic analysis and cell differentiation approaches underline GRG5 as a multifaceted signaling regulator that represses mesendodermal-related genes. When ESCs exit pluripotency, GRG5 promotes neuroectodermal specification via Wnt and BMP signaling suppression. Moreover, GRG5 promotes the neuronal reprogramming of fibroblasts and maintains the self-renewal of Neural Stem Cells (NSCs) by sustaining the activity of Notch/Hes and Stat3 signaling pathways. In summary, our results demonstrate that GRG5 has pleiotropic roles in stem cell biology functioning as a stemness factor and a neural fate specifier.", "HYPOTHESIS: We hypothesized that late pulmonary dead space fraction (Fd(late)) would be a useful tool to screen for pulmonary embolism (PE) in a group of surgical patients, including patients who required mechanical ventilation and patients with adult respiratory distress syndrome.DESIGN: We prospectively calculated Fd(late) in patients with suspected PE who underwent pulmonary angiography.SETTING: University-based, level I trauma center.MAIN OUTCOME MEASURE: Ability of Fd(late) to identify patients with PE.RESULTS: Twelve patients had 14 angiograms for suspected PE. The Fd(late) was 0.12 or above in all 5 patients who had PE; 4 required mechanical ventilation. The Fd(late) values were below 0.12 in 8 of 9 patients without PE. Four patients had adult respiratory distress syndrome. The Fd(late) had 100% sensitivity and 89% specificity for the detection of PE.CONCLUSIONS: The Fd(late) is a valuable tool for bedside screening of PE in surgical patients. We were able to accurately detect all PEs.", "Author information:(1)HM Sanchinarro University Hospital-CIBERONC, Madrid, Spain.(2)HM Sanchinarro University Hospital, Madrid, Spain.(3)La Paz University Hospital, Madrid, Spain.(4)Ramon y Cajal University Hospital, IRYCIS and CIBERESP, Madrid, Spain.(5)Germans Trias i Pujol University Hospital, Badalona, Spain.(6)Catalan Institute of Oncology-Germans Trias i Pujol University Hospital, Universitat Autònoma Barcelona (UAB), Badalona-Applied Research Group of Oncology (B-ARGO), Badalona, Spain.(7)General University Hospital-ISABIAL, Alicante, Spain.(8)Institute of Health Research-Jimenez Diaz Foundation-CIBERONC, Madrid, Spain.(9)Institute of Health Research-Jimenez Diaz Foundation, Madrid, Spain.(10)Vall d'Hebron University Hospital, Barcelona, Spain.(11)Quironsalud Hospital, Barcelona, Spain.(12)La Fe University Hospital, Valencia, Spain.(13)Clinico San Carlos University Hospital, Madrid, Spain.(14)Puerta del Mar University Hospital, Cadiz, Spain.(15)Clinico de Santiago University Hospital, Santiago De Compostela, Spain.(16)Insular Materno-Infantil University Hospital Complex, Las Palmas de Gran Canaria, Spain.(17)Clinic Hospital, Barcelona, Spain.(18)Alvaro Cunqueiro Hospital, Vigo, Spain.(19)University of Navarra Clinic, Pamplona, Spain.(20)Marques de Valdecilla University Hospital, Santander, Spain.(21)Hospital del Mar, Barcelona, Spain.(22)Clinico University Hospital, Valencia, Spain.(23)Cruces University Hospital, Baracaldo, Spain.(24)Miguel Servet University Hospital, Zaragoza, Spain.(25)University Hospital of Gran Canaria Doctor Negrin, Las Palmas de Gran Canaria, Spain.(26)12 de Octubre University Hospital, Madrid, Spain.(27)Ramon y Cajal University Hospital, Madrid, Spain.(28)12 de Octubre University Hospital-CIBERONC, Madrid, Spain.(29)Ramon y Cajal University Hospital-CIBERONC, Madrid, Spain.(30)HM Sanchinarro University Hospital-CIBERONC, Madrid, Spain. Electronic address: flopezrios@hmhospitales.com.", "OBJECT: The h index is a recently developed bibliometric that assesses an investigator's scientific impact with a single number. It has rapidly gained popularity in the physical and, more recently, medical sciences.METHODS: The h index for all 1120 academic neurosurgeons working at all Electronic Residency Application Service-listed training programs was determined by reference to Google Scholar. A random subset of 100 individuals was investigated in PubMed to determine the total number of publications produced.RESULTS: The median h index was 9 (range 0-68), with the 75th, 90th, and 95th percentiles being 17, 26, and 36, respectively. The h indices increased significantly with increasing academic rank, with the median for instructors, assistant professors, associate professors, and professors being 2, 5, 10, and 19, respectively (p < 0.0001, Kruskal-Wallis; all groups significantly different from each other except the difference between instructor and assistant professor [Conover]). Departmental chairs had a median h index of 22 (range 3-55) and program directors a median of 17 (range 0-62). Plot of the log of the rank versus h index demonstrated a remarkable linear pattern (R(2) = 0.995, p < 0.0001), suggesting that this is a power-law relationship.CONCLUSIONS: A survey of the h index for all of academic neurosurgery is presented. Results can be used for benchmark purposes. The distribution of the h index within an academic population is described for the first time and appears related to the ubiquitous power-law distribution.", "Percutaneous coronary intervention is first-line therapy for acute coronary syndromes (ACS) but can promote cardiomyocyte death and cardiac dysfunction via reperfusion injury, a phenomenon driven in large part by oxidative stress. Therapies to limit this progression have proven elusive, with no major classes of new agents since the development of anti-platelets/anti-thrombotics. We report that cardiac troponin I-interacting kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes ischemia/reperfusion injury, oxidative stress, and myocyte death. TNNI3K-mediated injury occurs through increased mitochondrial superoxide production and impaired mitochondrial function and is largely dependent on p38 mitogen-activated protein kinase (MAPK) activation. We developed a series of small-molecule TNNI3K inhibitors that reduce mitochondrial-derived superoxide generation, p38 activation, and infarct size when delivered at reperfusion to mimic clinical intervention. TNNI3K inhibition also preserves cardiac function and limits chronic adverse remodeling. Our findings demonstrate that TNNI3K modulates reperfusion injury in the ischemic heart and is a tractable therapeutic target for ACS. Pharmacologic TNNI3K inhibition would be cardiac-selective, preventing potential adverse effects of systemic kinase inhibition.", "Abstract BACKGROUND:Morton's neuroma is a frequently painful condition of the forefoot, causing sufferers to seek medical care to alleviate symptoms. A plethora of therapeutic options are available, some of which include injection therapies. Researchers have investigated injection therapy for Morton's neuroma, and latterly the evidence base has been augmented with methodologies which utilise diagnostic ultrasound (US) as a vehicle to deliver the injectate under image guidance for additional accuracy. There appears to date to be no consensus that US-guided injections provide better therapeutic outcomes than non US-guided (blind) injections for treatment of Morton's neuroma. METHODS:A systematic review was chosen, as this methodology can undertake such a process. The review process identified 13 key papers using pre-determined inclusion and exclusion criteria, which then underwent methodological quality assessment using a pre-tested Quality Index. A narrative synthesis of the review findings was presented in light of the heterogeneity of the data from the extraction process. RESULTS:This systematic review provides an argument that ultrasound-guidance can produce better short- and long-term pain relief for corticosteroid injections, can reduce the need for additional procedures in a series of sclerosing alcohol injections, can reduce the surgical referral rate, and adds efficacy to a single injection.CONCLUSIONS: Ultrasound guidance should be considered for injection therapy in the management of Morton's neuroma.", "Autophagy is an evolutionarily conserved cellular process in which intracellular components are eliminated via lysosomal degradation to supply nutrients for organelle biogenesis and metabolic homeostasis. Flavivirus infections underlie multiple human diseases and thus exert an immense burden on public health worldwide. Mounting evidence indicates that host autophagy is subverted to modulate the life cycles of flaviviruses, such as hepatitis C virus, dengue virus, Japanese encephalitis virus, West Nile virus and Zika virus. The diverse interplay between autophagy and flavivirus infection not only regulates viral growth in host cells but also counteracts host stress responses induced by viral infection. In this review, we summarize the current knowledge on the role of autophagy in the flavivirus life cycle. We also discuss the impacts of virus-induced autophagy on the pathogeneses of flavivirus-associated diseases and the potential use of autophagy as a therapeutic target for curing flavivirus infections and related human diseases." ]

[ "BACKGROUND: It is estimated that 1-13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a \"gold standard\" diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability.METHODS: UK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC.RESULTS: 16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort.CONCLUSIONS: Genetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.", "The microorganisms inhabiting the human gut are abundant (10(14) cells) and diverse (approximately 500 species per individual). It is now acknowledged that the microbiota has coevolved with its host to achieve a symbiotic relationship, leading to physiological homeostasis. The gut microbiota ensures vital functions, such as food digestibility, maturation of the host immune system, and protection against pathogens. Over the last few decades, the gut microbiota has also been associated with numerous diseases, such as inflammatory bowel disease, irritable bowel syndrome, obesity, and metabolic diseases. In most of these pathologies, a microbial dysbiosis has been found, indicating shifts in the taxonomic composition of the gut microbiota and changes in its functionality. Our understanding of the influence of the gut microbiota on human health is still growing. Working with microorganisms residing in the gut is challenging since most of them are anaerobic and a vast majority (approximately 75%) are uncultivable to date. Recently, a wide range of new approaches (meta-omics) has been developed to bypass the uncultivability and reveal the intricate mechanisms that sustain gut microbial homeostasis. After a brief description of these approaches (metagenomics, metatranscriptomics, metaproteomics, and metabolomics), this review will discuss the importance of considering the gut microbiome as a structured ecosystem and the use of meta-omics to decipher dysfunctions of the gut microbiome in diseases.", "Gamma-secretase is a multisubunit complex with intramembrane proteolytic activity. In humans it was identified in genetic screens of patients suffering from familial forms of Alzheimer's disease, and since then it was shown to mediate cleavage of more than 80 substrates, including amyloid precursor protein or Notch receptor. Moreover, in animals, γ-secretase was shown to be involved in regulation of a wide range of cellular events, including cell signalling, regulation of endocytosis of membrane proteins, their trafficking, and degradation. Here we show that genes coding for γ-secretase homologues are present in plant genomes. Also, amino acid motifs crucial for γ-secretase activity are conserved in plants. Moreover, all γ-secretase subunits: PS1/PS2, APH-1, PEN-2, and NCT colocalize and interact with each other in Arabidopsis thaliana protoplasts. The intracellular localization of γ-secretase subunits in Arabidopsis protoplasts revealed a distribution in endomembrane system compartments that is consistent with data from animal studies. Together, our data may be considered as a starting point for analysis of γ-secretase in plants.", "BACKGROUND: Blepharospasm is a form of focal dystonia that manifests as repetitive involuntary closure of the eyes. The pathogenesis of blepharospasm and the neuroanatomic substrates involved are not fully understood. Dysfunction of the basal ganglia traditionally is presumed to be the main cause of most forms of dystonia, but a growing body of evidence suggests that a network of additional cortical and subcortical structures may be involved.METHODS: The medical records of 1114 patients with blepharospasm seen over past 10 years at Emory University were reviewed to identify potentially contributing brain lesions. A systematic review of the published literature was also conducted to identify potentially contributing brain lesions.RESULTS: Among patients with blepharospasm at Emory University, 18 had focal lesions on imaging studies available for review. The literature review revealed 25 articles describing 30 additional cases of blepharospasm associated with focal lesions. Among all 48 cases, lesions were found in multiple regions including the thalamus (n=12), lower brainstem (n=11), basal ganglia (n=9), cerebellum (n=9), midbrain (n=7), and cortex (n=1).CONCLUSIONS: These data in combination with functional imaging studies of primary blepharospasm support a model in which a network of different regions plays a role in the pathogenesis of blepharospasm.", "More than a decade has passed since the initial identification of ribosomal protein gene mutations in patients with Diamond-Blackfan anemia (DBA), a hematologic disorder that became the founding member of a class of diseases known as ribosomopathies. In these diseases, genetic abnormalities that result in defective ribosome biogenesis cause strikingly tissue-specific phenotypes in patients, specifically bone marrow failure, craniofacial abnormalities and skeletal defects. Several animal models and numerous in vitro studies have demonstrated that the p53 pathway is central to the ribosomopathy phenotype. Additionally, there is mounting evidence of a link between the dysregulation of components of the translational machinery and the pathology of various malignancies. The importance of the role of ribosomal dysfunction in the pathogenesis of hematologic disorders is becoming clearer, and elucidation of the underlying mechanisms could have broad implications for both basic cellular biology and clinical intervention strategies.", "Alport syndrome (ATS) is a hereditary nephropathy often associated with sensorineural hypoacusis and ocular abnormalities. Mutations in the COL4A5 gene cause X-linked ATS. Mutations in COL4A4 and COL4A3 genes have been reported in both autosomal recessive and autosomal dominant ATS. The conventional mutation screening, performed by DHPLC and/or Sanger sequencing, is time-consuming and has relatively high costs because of the absence of hot spots and to the high number of exons per gene: 51 (COL4A5), 48 (COL4A4) and 52 (COL4A3). Several months are usually necessary to complete the diagnosis, especially in cases with less informative pedigrees. To overcome these limitations, we designed a next-generation sequencing (NGS) protocol enabling simultaneous detection of all possible variants in the three genes. We used a method coupling selective amplification to the 454 Roche DNA sequencing platform (Genome Sequencer junior). The application of this technology allowed us to identify the second mutation in two ATS patients (p.Ser1147Phe in COL4A3 and p.Arg1682Trp in COL4A4) and to reconsider the diagnosis of ATS in a third patient. This study, therefore, illustrates the successful application of NGS to mutation screening of Mendelian disorders with locus heterogeneity.", "RATIONALE: Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (I(Na)), reducing the net cytosolic Ca(2+) efflux.OBJECTIVE: Oxidative stress in the DOCA-salt model may increase late I(Na), resulting in diastolic dysfunction amenable to treatment with ranolazine.METHODS AND RESULTS: Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E':sham, 31.9 ± 2.8, sham+ranolazine, 30.2 ± 1.9, DOCA-salt, 41.8 ± 2.6, and DOCA-salt+ranolazine, 31.9 ± 2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16 ± 0.01 versus sham+ranolazine, 0.18 ± 0.01 versus DOCA-salt, 0.23 ± 0.2 versus DOCA-salt+ranolazine, 0.17 ± 0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt, 0.18 ± 0.02, DOCA-salt+ranolazine, 0.13 ± 0.01, sham, 0.11 ± 0.01, sham+ranolazine, 0.09 ± 0.02 seconds; P=0.0004). Neither late I(Na) nor the Ca(2+) transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca(2+) with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca(2+) response and cross-bridge kinetics.CONCLUSIONS: Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus." ]

[ "MOTIVATION: While drug combination therapies are a well-established concept in cancer treatment, identifying novel synergistic combinations is challenging due to the size of combinatorial space. However, computational approaches have emerged as a time- and cost-efficient way to prioritize combinations to test, based on recently available large-scale combination screening data. Recently, Deep Learning has had an impact in many research areas by achieving new state-of-the-art model performance. However, Deep Learning has not yet been applied to drug synergy prediction, which is the approach we present here, termed DeepSynergy. DeepSynergy uses chemical and genomic information as input information, a normalization strategy to account for input data heterogeneity, and conical layers to model drug synergies.RESULTS: DeepSynergy was compared to other machine learning methods such as Gradient Boosting Machines, Random Forests, Support Vector Machines and Elastic Nets on the largest publicly available synergy dataset with respect to mean squared error. DeepSynergy significantly outperformed the other methods with an improvement of 7.2% over the second best method at the prediction of novel drug combinations within the space of explored drugs and cell lines. At this task, the mean Pearson correlation coefficient between the measured and the predicted values of DeepSynergy was 0.73. Applying DeepSynergy for classification of these novel drug combinations resulted in a high predictive performance of an AUC of 0.90. Furthermore, we found that all compared methods exhibit low predictive performance when extrapolating to unexplored drugs or cell lines, which we suggest is due to limitations in the size and diversity of the dataset. We envision that DeepSynergy could be a valuable tool for selecting novel synergistic drug combinations.AVAILABILITY AND IMPLEMENTATION: DeepSynergy is available via www.bioinf.jku.at/software/DeepSynergy.CONTACT: klambauer@bioinf.jku.at.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "The main aim of this investigation was to evaluate the changes in total antioxidant capacity (TAC) and aerobic and anaerobic performance induced by supplementation of coffeeberry (CB) formulation for 4 weeks in college athletes. Twenty college athletes (14 males and 6 females) were allocated to two randomly assigned trials. Subjects in the CB group orally ingested capsules that contained CB formulation at a dose of 800 mg per day in two equal doses for 28 days, while subjects in the placebo (P) group ingested an equal number of identical-looking caps that contained cellulose. There were no changes in glucose, cholesterol, and lipoproteins within or between trials (p > 0.05). Total antioxidant capacity (TAC) was significantly higher in the CB versus P trial at the post- supplementation trial (1.66 +/- 0.16 vs. 1.51 +/- 0.05 mmol/L; p < 0.05). There were no statistically significant changes in average anaerobic power, index of anaerobic fatigue, maximal heart rate, blood lactate, and maximal oxygen uptake within or between trials (p > 0.05). Heart rate recovery (HRR) index increased significantly in CB group as compared with baseline level (38 +/- 4 vs. 32 +/- 5 beats/min; p < 0.05). Blood lactate after 10 min of recovery (Lact(rec)) significantly decreased in the CB group after supplementation protocol as compared with initial results (7.6 +/- 4.2 vs. 5.5 +/- 2.6 mmol/L; p < 0.05). No subject reported any side effects from CB or P. The results of the present study indicate that supplementation with a CB formulation slightly increased antioxidant capacity, but there were minimal effects on recovery parameters after exercise in college athletes.", "In vertebrate mitosis, cohesion between sister chromatids is lost in two stages. In prophase and prometaphase, cohesin release from chromosome arms occurs under the control of Polo-like kinase 1 and Aurora B, while Shugoshin is thought to prevent removal of centromeric cohesin until anaphase. The regulatory enzymes that act to sustain centromeric cohesion are incompletely described, however. Haspin/Gsg2 is a histone H3 threonine-3 kinase required for normal mitosis. We report here that both H3 threonine-3 phosphorylation and cohesin are located at inner centromeres. Haspin depletion disrupts cohesin binding and sister chromatid association in mitosis, preventing normal chromosome alignment and activating the spindle assembly checkpoint, leading to arrest in a prometaphase-like state. Overexpression of Haspin hinders cohesin release and stabilizes arm cohesion. We conclude that Haspin is required to maintain centromeric cohesion during mitosis. We also suggest that Aurora B regulates cohesin removal through its effect on the localization of Shugoshin.", "The use of medicinal plants concomitantly with conventional drugs can result in herb-drug interactions that cause fluctuations in drug bioavailability and consequent therapeutic failure and/or toxic effects. The CYP superfamily of enzymes plays an important role in herb-drug interactions. Among CYP enzymes, CYP3A4 and CYP2D6 are the most relevant since they metabolize about 50% and 30% of the drugs on the market, respectively. Thus, the main goal of this study was to evaluate the occurrence of in vitro interactions between medicinal plant extracts and drug substrates of CYP3A4 and CYP2D6 enzymes. Standardized extracts from nine medicinal plants (Bauhinia forficata, Cecropia glaziovii, Cimicifuga racemosa, Cynara scolymus, Echinacea sp., Ginkgo biloba, Glycine max, Ilex paraguariensis, and Matricaria recutita) were evaluated for their potential interactions mediated by CYP3A4 and CYP2D6 enzymes. Among the extracts tested, C. glaziovii (red embaúba) showed the most relevant inhibitory effects of CYP3A4 and CYP2D6 activity, while I. paraguariensis (yerba mate) inhibited CYP3A4 activity. Both extracts were chemically analyzed by UPLC-MS/MS, and these inhibitory effects could lead to clinically potential and relevant interactions with the drug substrates of these isoenzymes.", "Recent discoveries of reversible N(6)-methyladenosine (m(6)A) methylation on messenger RNA (mRNA) and mapping of m(6)A methylomes in mammals and yeast have revealed potential regulatory functions of this RNA modification. In plants, defects in m(6)A methyltransferase cause an embryo-lethal phenotype, suggesting a critical role of m(6)A in plant development. Here, we profile m(6)A transcriptome-wide in two accessions of Arabidopsis thaliana and reveal that m(6)A is a highly conserved modification of mRNA in plants. Distinct from mammals, m(6)A in A. thaliana is enriched not only around the stop codon and within 3'-untranslated regions, but also around the start codon. Gene ontology analysis indicates that the unique distribution pattern of m(6)A in A. thaliana is associated with plant-specific pathways involving the chloroplast. We also discover a positive correlation between m(6)A deposition and mRNA abundance, suggesting a regulatory role of m(6)A in plant gene expression.", "Eukaryotic histones serve as prototypical examples of posttranslational complexity with diverse modifications (PTMs) on many different residues that comprise a \"Histone Code\". To help crack this code more efficiently, we demonstrate a new strategy for protein characterization wherein complete PTM descriptions are obtained by database retrieval instead of manual interpretation of information-rich data from high-resolution tandem mass spectrometry (MS/MS). A database of nearly 50 000 modified histone H4 sequences was created and queried with 91 fragment ions from electron capture dissociation of a histone form +112 Da (versus unmodified mass) selectively accumulated in a quadrupole Fourier transform hybrid mass spectrometer. The correct form atop the retrieval list indicated dimethylation at Lys20, acetylation at the N terminus, and acetylation at Lys16 (resolved from trimethylation, Deltam = 0.036 Da). A statistical evaluation reveals the critical role of mass accuracy and that PTM \"isomers\" are retrieved as next-best matches. The applicability of shotgun annotation to forms of H4 with up to six PTMs is demonstrated, with extensibility to other histones (e.g., H2A, H2B, H3) and other protein classes projected.", "Determining the optimal dose of warfarin for frail elderly patients is a challenging task because of the low dose requirements in such patients, the wide interindividual variability of response, and the associated risk of bleeding. The objective of this study was to address the influence of 13 common variations in eight genes on the maintenance dose of warfarin in a cohort of frail elderly inpatients. For our study, we enrolled 300 Caucasian subjects who were hospital inpatients, with a mean age of 86.7 +/- 6 years. In addition to age, genetic variants of VKORC1, CYP2C9, CYP4F2, and EPHX1 were found to be significant predictor variables for the maintenance dose of warfarin, explaining 26.6% of dose variability. Among 132 patients in whom warfarin therapy was initiated with the same low-dose regimen, we studied the relative influences of genetic and nongenetic factors. The time to first international normalized ratio (INR) > or =2 was influenced by VKORC1 and CYP2C9 genotypes (P = 0.0003 and P = 0.0016, respectively); individuals with multiple variant alleles were at highest risk for overanticoagulation (INR >4) (odds ratio, 12.8; 95% confidence interval, 2.73-60.0). In this special population of frail elderly patients with multiple comorbidities and polypharmacy, we demonstrated the main impact of genetic factors on warfarin response." ]

[ "Recent data support the view that transcription factors - in particular, homeoproteins - can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities. This intercellular transfer, based on atypical internalization and secretion, has important biotechnological consequences. But the real excitement stems from the physiological and developmental implications of this mode of signal transduction.", "Glutamatergic excitotoxicity is crucial in the pathogenesis of numerous brain disorders. Luteolin, a flavonoid compound, inhibits glutamate release, however, its ability to affect glutamate-induced brain injury is unknown. Therefore, this study evaluated the protective effect of luteolin against brain damage induced by kainic acid (KA), a glutamate analog. Rats were treated with luteolin (10 or 50mg/kg, intraperitoneally) 30min before an intraperitoneal injection of KA (15mg/kg). Luteolin treatment reduced the KA-induced seizure score and elevations of glutamate levels in the hippocampus. A histopathological analysis showed that luteolin attenuated KA-induced neuronal death and microglial activation in the hippocampus. An immunoblotting analysis showed that luteolin restored the KA-induced reduction in Akt phosphorylation in the hippocampus. Furthermore, a Morris water maze test revealed that luteolin effectively prevented KA-induced learning and memory impairments. The results suggest that luteolin protected rat brains from KA-induced excitotoxic damage by reducing glutamate levels, mitigating inflammation, and enhancing Akt activation in the hippocampus. Therefore, luteolin may be beneficial for preventing or treating brain disorders associated with excitotoxic neuronal damage.", "The use of medicinal plants concomitantly with conventional drugs can result in herb-drug interactions that cause fluctuations in drug bioavailability and consequent therapeutic failure and/or toxic effects. The CYP superfamily of enzymes plays an important role in herb-drug interactions. Among CYP enzymes, CYP3A4 and CYP2D6 are the most relevant since they metabolize about 50% and 30% of the drugs on the market, respectively. Thus, the main goal of this study was to evaluate the occurrence of in vitro interactions between medicinal plant extracts and drug substrates of CYP3A4 and CYP2D6 enzymes. Standardized extracts from nine medicinal plants (Bauhinia forficata, Cecropia glaziovii, Cimicifuga racemosa, Cynara scolymus, Echinacea sp., Ginkgo biloba, Glycine max, Ilex paraguariensis, and Matricaria recutita) were evaluated for their potential interactions mediated by CYP3A4 and CYP2D6 enzymes. Among the extracts tested, C. glaziovii (red embaúba) showed the most relevant inhibitory effects of CYP3A4 and CYP2D6 activity, while I. paraguariensis (yerba mate) inhibited CYP3A4 activity. Both extracts were chemically analyzed by UPLC-MS/MS, and these inhibitory effects could lead to clinically potential and relevant interactions with the drug substrates of these isoenzymes.", "To maintain genomic integrity, DNA repair enzymes continually remove damaged bases and lesions resulting from endogenous and exogenous processes. These repair enzymes must distinguish damaged bases from normal bases to prevent the inadvertent removal of normal bases, which would promote genomic instability. The mechanisms by which this high level of specificity is accomplished are as yet unresolved. One member of the uracil-DNA glycosylase family of repair enzymes, Escherichia coli mismatch-specific uracil-DNA glycosylase (Mug), is reported to distinguish U:G mispairs from U:A base pairs based upon specific contacts with the mispaired guanine after flipping the target uracil out of the duplex. However, recent studies suggest other mechanisms for base selection, including local duplex stability. In this study, we used the modified base N6-methyladenine to probe the effect of local helix perturbation on Mug recognition of uracil. N6-Methyladenine is found in E. coli as part of both the mismatch repair and restriction-modification systems. In its cis isomer, N6-methyladenine destabilizes hydrogen bonding by interfering with pseudo-Watson-Crick base pairing. It is observed that the selection of uracil by Mug is sequence dependent and that uracil residues in sequences of reduced thermostability are preferentially removed. The replacement of adenine by N6-methyladenine increases the frequency of removal of the uracil residue paired opposite the modified adenine. These results are in accord with suggestions that local helix stability is an important determinant of base recognition by some DNA repair enzymes and provide a potential strategy for identifying the sequence location of modified bases in DNA.", "TGFβ is the quintessential cytokine of T cell homeostasis. TGFβ signaling is required for the efficient differentiation and maintenance of CD4(+)FOXP3(+) T cells that inhibit immune responses. Conversely, in conjunction with the inflammatory cytokine IL-6, TGFβ promotes Th17 cell differentiation. The mechanism by which TGFβ signals synergize with IL-6 to generate inflammatory versus immunosuppressive T cell subsets is unclear. TGFβ signaling activates receptor SMADs, SMAD2 and SMAD3, which associate with a variety of nuclear factors to regulate gene transcription. Defining relative contributions of distinct SMAD molecules for CD4 T cell differentiation is critical for mapping the versatile intracellular TGFβ-signaling pathways that tailor TGFβ activities to the state of host interaction with pathogens. We show here that SMAD2 is essential for Th17 cell differentiation and that it acts in part by modulating the expression of IL-6R on T cells. Although mice lacking SMAD2 specifically in T cells do not develop spontaneous lymphoproliferative autoimmunity, Smad2-deficient T cells are impaired in their response to TGFβ in vitro and in vivo, and they are more pathogenic than controls when transferred into lymphopenic mice. These results demonstrate that SMAD2 is uniquely essential for TGFβ signaling in CD4(+) T effector cell differentiation.", "We have previously demonstrated proteasomal degradation of DNMT1 in mammalian cells following treatment with several DNA hypomethylating agents. Here, we demonstrate dose-dependent degradation of Dnmt1 in mouse embryonic stem (ES) cells expressing catalytic site mutant (cys-ser), confirming that the covalent bond formation between Dnmt1 and decitabine-incorporated DNA is not essential for this process. DNMT1o, the oocyte-specific isoform that lacks the N-terminal 118-amino acid domain, did not undergo decitabine-mediated degradation, which further proves the requirement of multiple domains including nuclear localization signal, KEN box, and BAH domains for this process. Analysis of glycerol density gradient fractions of micrococcal nuclease-digested nuclei showed that both nucleosomal and nucleoplasmic DNMT1 are degraded upon decitabine treatment. Among different inhibitors tested, the inhibitors of the proteasomal pathway and several protein kinases impeded decitabine-induced DNMT1 degradation. The maximal effect caused by inhibiting protein kinase C (PKC) persuaded us to investigate further its role in decitabine-mediated DNMT1 degradation. Blockage of the degradation process after treatment with rottlerin, an inhibitor of PKCδ, or after siRNA-mediated depletion of PKCδ, indicated that this protein kinase is involved in decitabine-mediated depletion of DNMT1. PKCδ interacted with and phosphorylated DNMT1 in vitro. Moreover, rottlerin inhibited both basal and decitabine-induced phosphorylation of DNMT1. These studies provide substantial evidence that decitabine-induced degradation of the maintenance methyltransferase DNMT1 does not require covalent bond formation with the substrate and also elucidate its underlying molecular mechanism.", "The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and highly conserved from Drosophila to human. It has important roles in transcriptional insulation and the formation of a high-dimensional chromatin structure. CTCF has a paralog called \"Brother of Regulator of Imprinted Sites\" (BORIS) or \"CTCF-like\" (CTCFL). It binds DNA at sites similar to those of CTCF. However, the expression profiles of the two proteins are quite different. We investigated the evolutionary trajectories of the two proteins after the duplication event using a phylogenomic and interactomic approach. We find that CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all interactors already existed before the emergence of CTCF and CTCFL. The unique secondary loss of CTCF from several nematodes is paralleled by a loss of two of its interactors, the polycomb repressive complex subunit SuZ12 and the multifunctional transcription factor TYY1. In contrast to earlier studies reporting the absence of BORIS from birds, we present evidence for a multigene synteny block containing CTCFL that is conserved in mammals, reptiles, and several species of birds, indicating that not the entire lineage of birds experienced a loss of CTCFL. Within this synteny block, BORIS and its genomic neighbors seem to be partitioned into two nested chromatin loops. The high expression of SPO11, RAE1, RBM38, and PMEPA1 in male tissues suggests a possible link between CTCFL, meiotic recombination, and fertility-associated phenotypes. Using the 65,700 exomes and the 1000 genomes data, we observed a higher number of intergenic, non-synonymous, and loss-of-function mutations in CTCFL than in CTCF, suggesting a reduced strength of purifying selection, perhaps due to less functional constraint." ]

[ "Most disease-modifying therapeutic approaches in Alzheimer's disease (AD) aim to reduce the accumulation of neurotoxic amyloid-beta (Abeta) peptides as a hallmark of AD pathogenesis. Here we report the in vitro basis for a potential autologous stem cell-based strategy for widespread delivery of enzymatic activities against Abeta formation in the brain. We detected the functional induction of two genes upon neuroectodermal conversion of human adult mesenchymal stem cells (MSCs), namely F-spondin and neprilysin (CD10), with a 4,992 + or - 697-fold and 692 + or - 226-fold increase of mRNA levels in converted cells compared to MSCs, respectively (n = 3; P < 0.01). These genes are known to be involved in the formation and degradation of Abeta peptides, respectively. Consistently, coincubation of the neuroectodermally converted MSCs with HEK-293 cells stably expressing amyloid precursor protein (APP) lead to a significant cell dose-dependent decrease of Abeta peptides. These in vitro results indicate that MSCs might be useful vehicles for delivering anti-Abeta activity depicting a causal stem cell-based therapeutic approach to treat AD.", "BACKGROUND: The \"long/short\"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors.OBJECTIVE: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression.DESIGN: Double-blind, randomized 8-week study.SETTING: Eighteen academic and private outpatient clinics.PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression.INTERVENTIONS: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122).MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes.RESULTS: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses.CONCLUSIONS: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.", "Muenke syndrome, defined by heterozygosity for a Pro250Arg substitution in fibroblast growth factor receptor 3 (FGFR3), is the most common genetic cause of craniosynostosis in humans. We have used gene targeting to introduce the Muenke syndrome mutation (equivalent to P244R) into the murine Fgfr3 gene. A rounded skull and shortened snout (often skewed) with dental malocclusion was observed in a minority of heterozygotes and many homozygotes. Development of this incompletely penetrant skull phenotype was dependent on genetic background and sex, with males more often affected. However, these cranial abnormalities were rarely attributable to craniosynostosis, which was only present in 2/364 mutants; more commonly, we found fusion of the premaxillary and/or zygomatic sutures. We also found decreased cortical thickness and bone mineral densities in long bones. We conclude that although both cranial and long bone development is variably affected by the murine Fgfr3(P244R) mutation, coronal craniosynostosis is not reliably reproduced.", "The mammalian target of rapamycin (mTOR), a member of the phosphoinositide 3-kinase related kinase (PIKK) family, plays a central role in the regulation of cell growth. The cellular function of mTOR has been proposed based solely on loss-of-function analyses using the specific inhibitor rapamycin or RNAi-mediated knockdown. There have been recent reports of mTOR mutants with enhanced activity that were isolated by genetic screening in yeast. These isolated mTOR mutants exhibited enhanced kinase activity in vitro, and when expressed in cells, prevented the dephosphorylation of known mTOR substrates. The application of these mutants in gain-of-function analyses has enabled a re-evaluation of the function of mTOR. Although these studies confirmed many of the proposed mTOR functions some unexpected observations urged a reconsideration of the regulatory mechanisms and the physiological function of the mTOR pathway. Hyperactive mTOR mutants are thus valuable tools for analysis of the activation mechanism as well as the in vivo function of mTOR.", "Author information:(1)Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem 2650, Belgium.(2)Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem 2650, Belgium; Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.(3)Laboratory of Physiopharmacology, University of Antwerp, Antwerp 2610, Belgium.(4)Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem 2650, Belgium; StatUa Center for Statistics, University of Antwerp, Antwerp 2000, Belgium.(5)Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem 2650, Belgium; Laboratory of Molecular, Cellular and Network Excitability, Department of Biomedical Sciences, University of Antwerp, Antwerp 2610, Belgium.(6)Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp 2610, Belgium.(7)Prince Sultan Cardiac Centre, Qassim 31982, Saudi Arabia.(8)NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.(9)Bristol Genetics Laboratory, South West Genomic Laboratory Hub, Southmead Hospital, Bristol BS10 5NB, UK.(10)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77021, USA.(11)Department of Pediatric Cardiology, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels 1200, Belgium.(12)Birmingham Women's and Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham B4 6NH, UK.(13)Birmingham Women & Children's Hospital, Birmingham B4 6NH, UK.(14)Musgrove Park Hospital, Somerset NHS Foundation Trust, Taunton TA1 5DA, UK.(15)Department of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, UK.(16)Pediatric Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 009851, Iran.(17)Department of Pediatric Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad 009851, Iran.(18)Department of Molecular Genetics, Next Generation Genetic Polyclinic, Mashhad University of Medical Sciences, Mashhad 009851, Iran.(19)Department of Pediatric Neurology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad 009851, Iran.(20)Cardiovascular Genetic Program, Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11564, Saudi Arabia.(21)West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, B15 2TG, UK.(22)Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels 1200, Belgium.(23)Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies (Charleroi) 6041, Belgium.(24)The Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.(25)Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.(26)GeneDx, Gaithersburg, MD 20877, USA.(27)Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.(28)Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem 2650, Belgium; Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands. Electronic address: bart.loeys@uantwerpen.be.(29)Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem 2650, Belgium. Electronic address: aline.verstraeten@uantwerpen.be.", "Nuclear factor kappaB (NFkappaB) regulates the expression of various genes essential for cell survival. Here we demonstrate that suppression of NFkappaB nuclear import with SN50 peptide carrying the nuclear localization sequence (NLS) of the NFkappaB p50 subunit induces apoptosis in human peripheral blood T lymphocytes (T-PBL), which can be blocked with the pan-caspase inhibitor Z-VAD.fmk. However, even when caspase function is blocked, the addition of SN50 induces irreversible cell loss due to the reduction in the mitochondrial transmembrane potential (DeltaPsim) followed by disruption of the cell membrane, hallmarks of necrosis. These observations demonstrate that although inhibition of NFkappaB nuclear translocation by SN50 peptide can induce caspase-dependent apoptosis in T-PBL, cell death may still proceed in the absence of functional caspase activity. The availability of downstream caspases appears to determine the mode of cell death in NFkappaB defective cells.", "Gaucher disease (GD) is the most common of the lysosomal storage disorders and is caused by defects in the GBA gene encoding glucocerebrosidase (GlcCerase). The accumulation of its substrate, glucocylceramide (GlcCer) is considered the main cause of GD. We found here that the expression of human mutated GlcCerase gene (hGBA) that is associated with neuronopathy in GD patients causes neurodevelopmental defects in Drosophila eyes. The data indicate that endoplasmic reticulum (ER) stress was elevated in Drosophila eye carrying mutated hGBAs by using of the ER stress markers dXBP1 and dBiP. We also found that Ambroxol, a potential pharmacological chaperone for mutated hGBAs, can alleviate the neuronopathic phenotype through reducing ER stress. We demonstrate a novel mechanism of neurodevelopmental defects mediated by ER stress through expression of mutants of human GBA gene in the eye of Drosophila." ]

[ "Vortioxetine is a novel antidepressant with effects on multiple 5-HT receptors and on the serotonin transporter. This paper reviews preclinical and clinical evidence regarding its mechanism of action, its tolerability, and its efficacy in treating major depression. Clinical studies indicate that vortioxetine is effective in the treatment of major depression, though there is no suggestion of superiority over active comparators. There may be a clinically meaningful advantage in terms of tolerability.", "Saethre-Chotzen syndrome is a common craniosynostosis syndrome characterized by craniofacial and limb anomalies. Intragenic mutations of the TWIST gene within 7p21 have been identified as a cause of this disorder. There is phenotypic overlap with other craniosynostosis syndromes, and intragenic mutations in FGFR2 (fibroblast growth factor receptor 2) and FGFR3 (fibroblast growth factor receptor 3) have been demonstrated in the other conditions. Furthermore, complete gene deletions of TWIST have also been found in a significant proportion of patients with Saethre-Chotzen syndrome. We investigated 11 patients clinically identified as having the Saethre-Chotzen phenotype and 4 patients with craniosynostosis but without a clear diagnosis. Of the patients with the Saethre-Chotzen phenotype, four were found to carry the FGFR3 P250R mutation, three were found to be heterozygous for three different novel mutations in the coding region of TWIST, and two were found to have a deletion of one copy of the entire TWIST gene. Developmental delay was a distinguishing feature of the patients with deletions, compared to patients with intragenic mutations of TWIST, in agreement with the results of Johnson et al. [1998: Am J Hum Genet 63:1282-1293]. No mutations were found for the four patients with craniosynostosis without a clear diagnosis. Therefore, 9 of our 11 patients (82%) with the Saethre-Chotzen phenotype had detectable genetic changes in FGFR3 or TWIST. We propose that initial screening for the FGFR3 P250R mutation, followed by sequencing of TWIST and then fluorescence in situ hybridization (FISH) for deletion detection of TWIST, is sufficient to detect mutations in > 80% of patients with the Saethre-Chotzen phenotype.", "Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed.", "Shone's syndrome is a rare congenital heart disease that includes 4 cardiovascular anomalies: supravalvular mitral ring, parachute mitral valve, subaortic stenosis, and coarctation of the aorta. Early diagnosis and treatment result in better outcomes. Echocardiography plays an important role in the diagnosis and is the optimal examination for detecting this disease. Pressure gradients are often unreliable and inaccurate; thus, careful anatomical observation of the left ventricular inflow and outflow tracts, particularly the mitral valve, is vital for accurate diagnosis and planning appropriate management. Herein, we describe 9 cases of Shone's syndrome, diagnosed with echocardiography and treated surgically.", "We have previously shown that acute thyroid hormone treatment could limit reperfusion injury and increase post-ischemic recovery of function. In the present study, we further explore potential initiating mechanisms of this response. Thus, isolated rat hearts were subjected to 30 min zero-flow global ischemia (I) followed by 60-min reperfusion (R). Reperfusion injury was assessed by post-ischemic recovery of left ventricular developed pressure (LVDP%) and LDH release. T3 at a dose of 60 nM which had no effect on contractile function of non-ischemic myocardium, significantly increased LVDP% [48% (2.9) vs. 30.2% (3.3) for untreated group, P < 0.05] and reduced LDH release [8.3 (0.3) vs. 10 (0.42) for untreated group, P < 0.05] when administered at R. T4 (60 and 400 nM) had no effect on contractile function either in non-ischemic or ischemic myocardium. Administration of debutyl-dronedarone (DBD), a TRα1 antagonist abolished the T3-limiting effect on reperfusion injury: Thus, co-administration of T3 and DBD resulted in significantly lower LVDP%, [23% (4.7) vs. 48% (2.9) for T3 group, P < 0.05] and higher LDH release [9.9 (0.3) vs. 8.3 (0.3), for T3 group, P < 0.05]. In conclusion, acute T3 and not T4 treatment will be able to protect against reperfusion injury. T3 can exert this beneficial effect on ischemic myocardium at a dose that has no effects on non-ischemic myocardium. Acute T3-limiting effect on reperfusion injury is mediated, at least in part, via TRα1 receptor.", "Bleomycin is an antineoplastic agent that causes a dose-related lung fibrosis that limits its therapeutic effectiveness. It has been proposed that the cellular toxicity and antitumor effects of bleomycin occur by formation of O2-Fe(II)-bleomycin complexes that degrade DNA and release O2- and OH radicals that attack other cellular components. Twice daily injections of the iron chelator deferoxamine were utilized in an attempt to ameliorate bleomycin-induced lung fibrosis. They failed to diminish bleomycin-induced lung inflammation and fibrosis in rats.", "Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 microm3 at 16 days after treatment and reached 5100 microm3 at 4 months. In this interval, nearly 20% of myocytes reached the adult phenotype, varying in size from 10,000 to 20,000 microm3. Moreover, there were 43+/-13 arterioles and 155+/-48 capillaries/mm2 myocardium at 16 days, and 31+/-6 arterioles and 390+/-56 capillaries at 4 months. Myocardial regeneration induced increased survival and rescued animals with infarcts that were up to 86% of the ventricle, which are commonly fatal. In conclusion, the heart has an endogenous reserve of CSCs-ECCs that can be activated to reconstitute dead myocardium and recover cardiac function.", "Pulmonary hypertension (PH) is a progressive disease that is accompanied by a poor prognosis. Pulmonary vasoconstriction is facilitated through multiple pathways and results in increased pulmonary vascular pressure leading to cell proliferation, vascular remodeling, right ventricular hypertrophy/failure, and ultimately death. Until recently, just six medications were approved -all for one subclass of PH. On October 8, 2013, riociguat (Adempas®) became the first medication approved for multiple etiologies of PH. Preclinical studies have demonstrated safety and efficacy with significant clinical trials supporting its advancement into phase IV trials. Although long-term safety and efficacy and place in therapy remain to be established, riociguat presents as an exciting new option for the treatment of PH and potentially has additional indications in the near future.", "The derangement of neuro-endocrine control of circulation influences both disease evolution and response to treatment in patients with heart failure, but little data are available about the complex relationships between the degree of neuro-hormonal activation and clinical severity. We studied the relationships between cardiac natriuretic hormones (CNHs) and several neuro-hormones and immunological markers in a prospective cohort of 105 consecutive patients with cardiomyopathy (77 men and 28 women, mean age 66.7+/-12.4 years, range 33-89 years). We assayed the circulating levels of CNHs (atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)), plasma renin activity (PRA), aldosterone, cortisol, adrenaline, noradrenaline, thyroid hormones and thyroid stimulating hormone (TSH), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The concentrations of all CNHs and neurohormones were higher in patients with heart failure compared to normal subjects, except for free triiodothyronine (FT3), which was below normal values. ANP was positively related to NYHA class, IL-6, adrenaline, noradrenaline and cortisol, while negatively with ejection fraction and FT3. BNP was positively related to age, NYHA class, IL-6, TNF-alpha, adrenaline, noradrenaline and cortisol, while negatively with ejection fraction and FT3. A stepwise multiple linear regression indicated that plasma ANP depended only on ejection fraction, adrenaline and noradrenaline values, while for plasma BNP variation NYHA class contributed too. Our data confirm a progressive activation of hormonal and immunological systems in patients with heart failure. Furthermore, CNH circulating levels in heart failure are affected not only by cardiac function and disease severity, but also by activation of neuro-hormonal and stress-related cytokine systems, as well as by the thyroid hormones, even on usual medical treatment.", "OBJECTIVE: Shone's syndrome is a complex consisting of mitral valve stenosis in addition to left ventricle outflow obstruction. There are a few studies evaluating the long-term outcomes in this population. We sought to determine the long-term outcomes in our paediatric population with Shone's syndrome and the factors associated with left heart growth.METHODS: All patients diagnosed with Shone's syndrome with biventricular circulation treated between 1978 and 2010 were reviewed. Baseline echocardiograms and data from catheterisations were also reviewed. Number of interventions (surgical+transcatheter), incidence of mitral valve replacement, and incidence of heart transplantation were tracked. Survival of the population and left heart structural growth were also reviewed.RESULTS: A total of 121 patients with Shone's syndrome presented at a median age of 28 days (0-17.3 years) and were followed-up for 7.2 years (0.01-35.5 years). These patients underwent 258 interventions during the study period, and the presence of coarctation was associated with repeat left heart interventions. The 10-year, transplant-free survival was 86%. Presence of pulmonary hypertension was associated with mortality. Left heart structural growth was seen for mitral and aortic valve annuli and left ventricular end-diastolic dimension over time.CONCLUSIONS: Shone's syndrome patients undergo a number of left heart interventions. Coarctation of the aorta is associated with an increased likelihood for repeat interventions. Survival appears to be more favourable than expected. Significant left heart growth will occur in the population. Pulmonary hypertension is associated with an increased risk of mortality.", "BACKGROUND: Shone's complex is a rare lesion affecting the mitral valve (MV) and left ventricular outflow tract (LVOT). The objective of this study is to report the outcomes after Shone's complex repair, the growth of mitral and aortic valve and LVOT, and long-term survival.METHODS: This retrospective study included all patients diagnosed with Shone's complex, who underwent biventricular repair. Data including patients' characteristics, type of the MV lesion and the associated lesions were collected. Patients were followed up regularly with echocardiography, and the changes in mitral and aortic valve z-score and LVOT z-score were recorded.RESULTS: Thirty-seven patients were included in the study, the median age was 3.4 months, and 11 patients (30.6%) had pulmonary hypertension. The main procedure performed during the first surgical intervention was coarctation repair in 26 patients (70%). Twelve patients had MV repair, and five had MV replacement. Operative mortality occurred in 1 patient (2.7%), median follow up was 52 (25-75th percentile: 22-84) months. Survival at 1, 5, and 10 years was 94.4%, 90%, and 76.9%, respectively. Reoperation was required in 13 patients, mainly for LVOT repair (n = 8). Reoperation was significantly associated with associated aortic valve lesion (p = .044). The growth of the MV z-score was 0.35 per year; p < .001, aortic valve z-score 0.086 per year; p = 0.422, and the LVOT z-score was 0.53 per year; p = .01.CONCLUSION: Biventricular repair of Shone's complex has good outcomes. Reoperation is frequently encountered, especially with low aortic valve z-score. The MV and LVOT have significant growth following Shone's complex repair.", "DNA double strand breaks (DSBs) are highly toxic to the cells and accumulation of DSBs results in several detrimental effects in various cellular processes which can lead to neurological, immunological and developmental disorders. Failure of the repair of DSBs spurs mutagenesis and is a driver of tumorigenesis, thus underscoring the importance of the accurate repair of DSBs. Two major canonical DSB repair pathways are the non-homologous end joining (NHEJ) and homologous recombination (HR) pathways. 53BP1 and BRCA1 are the key mediator proteins which coordinate with other components of the DNA repair machinery in the NHEJ and HR pathways respectively, and their exclusive recruitment to DNA breaks/ends potentially decides the choice of repair by either NHEJ or HR. Recently, Rap1 interacting factor 1 has been identified as an important component of the DNA repair pathway which acts downstream of the ATM/53BP1 to inhibit the 5'-3' end resection of broken DNA ends, in-turn facilitating NHEJ repair and inhibiting homology directed repair. Rif1 is conserved from yeast to humans but its function has evolved from telomere length regulation in yeast to the maintenance of genome integrity in mammalian cells. Recently its role in the maintenance of genomic integrity has been expanded to include the regulation of chromatin structure, replication timing and intra-S phase checkpoint. We present a summary of these important findings highlighting the various aspects of Rif1 functions and discuss the key implications for genomic integrity.", "OBJECTIVES: The underlying mechanisms of protective immunity of placental trophoblast cells against bacterial infection remain largely unknown. NOD1 are intracellular pattern recognition receptors that are activated by bacterial peptides and mediate innate immunity. This study aimed to investigate the expression and function of NOD1 in first trimester trophoblast cells, and evaluate the potential role of trophoblast cells in infection-associated inflammation.STUDY DESIGN: Human extravillous trophoblast cell line HTR8 cells were stimulated with various concentrations of iE-DAP for various periods of time. NOD1 expression was detected by immunofluorescence, and the changes in NOD1 and RICK mRNA and protein in H8 cells were determined by real-time polymerase chain reaction and Western blot analysis. The concentrations of interleukin (IL)-8 and IL-6 secreted by H8 cells were examined by enzyme-linked immunosorbent assay. NF-κB transcription activity and P65 expression were detected by electrophoretic mobility shift assay and Western blot analysis.RESULTS: H8 cells expressed NOD1, and the effects of iE-DAP on NOD1 were dose- and time-dependent. The concentration of IL-8 increased gradually with increasing concentration of iE-DAP, and the levels of IL-8 and IL-6 were associated with the duration of exposure to iE-DAP. The dose of iE-DAP was significantly associated with expression of RICK and P65, and stimulation of H8 cells by iE-DAP altered NF-κB transcription activity.CONCLUSIONS: NOD1 may have a role in mediating infection-associated inflammation. Once iE-DAP is recognized by NOD1, the inflammatory response may be induced via NOD1-RICK-NF-κB-mediated pathways.", "Nonsense-mediated decay (NMD), also called mRNA surveillance, is an evolutionarily conserved pathway that degrades mRNAs that prematurely terminate translation. To date, the pathway in mammalian cells has been shown to depend on the presence of a cis-acting destabilizing element that usually consists of an exon-exon junction generated by the process of pre-mRNA splicing. Whether or not mRNAs that derive from naturally intronless genes, that is, mRNAs not formed by the process of splicing, are also subject to NMD has yet to be investigated. The possibility of NMD is certainly reasonable considering that mRNAs of Saccharomyces cerevisiae are subject to NMD even though most derive from naturally intronless genes. In fact, mRNAs of S. cerevisiae generally harbor a loosely defined splicing-independent destabilizing element that has been proposed to function in NMD analogously to the spliced exon-exon junction of mammalian mRNAs. Here, we demonstrate that nonsense codons introduced into naturally intronless genes encoding mouse heat shock protein 70 or human histone H4 fail to elicit NMD. Failure is most likely because each mRNA lacks a cis-acting destabilizing element, because insertion of a spliceable intron a sufficient distance downstream of a nonsense codon within either gene is sufficient to elicit NMD.", "Subclinical hypothyroidism (SH), defined by elevated serum levels of thyroid stimulating hormone (TSH) with normal levels of free thyroid hormones, is common in adults, especially in women over 60 years of age. Among individuals with this condition, up to two-thirds have serum TSH levels between 5-10 mU/L and thyroid autoantibodies; almost half of them may progress to overt thyroid failure, the annual percent risk increasing with serum TSH level. There is evidence that elevated TSH levels in patients with SH do not reflect pituitary compensation to maintain euthyroidism, but a mild tissue hypothyroidism sensu strictu. When lasting more than 6-12 months, SH may be associated with an atherogenic lipid profile, a hypercoagulable state, a subtle cardiac defect with mainly diastolic dysfunction, impaired vascular function, and reduced submaximal exercise capacity. The deviation from normality usually increases with serum TSH level ('dosage effect' phenomenon). Restoration of euthyroidism by levothyroxine (LT4) treatment may correct the lipid profile and cardiac abnormalities, especially in patients with an initially higher deviation from normality and higher serum TSH levels. Importantly, a strong association between SH and atherosclerotic cardiovascular disease, independent of the traditional risk factors, has been recently reported in a large cross-sectional survey (the Rotterdam Study). However, whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy. Therefore, until randomized, controlled, prospective, and adequately powered trials provide unequivocal answers to these critical questions, it is advisable to prescribe LT4 therapy on a case-by-case basis, taking into account the risk of progressive thyroid failure and the risk of cardiovascular events.", "Shone's complex is a rare congenital cardiac malformation characterized by serial obstructive lesions of the left heart at multiple levels. Presently described is an unusual case of an adult male patient who presented with palpitations and worsening dyspnea. An echocardiographic evaluation revealed Shone's complex associated with left ventricular non-compaction cardiomyopathy (NCC). To our knowledge, an association between NCC and Shone's complex has not been previously described." ]

[ "The vertebrate circadian clock was thought to be highly localized to specific anatomical structures: the mammalian suprachiasmatic nucleus (SCN), and the retina and pineal gland in lower vertebrates. However, recent findings in the zebrafish, rat and in cultured cells have suggested that the vertebrate circadian timing system may in fact be highly distributed, with most if not all cells containing a clock. Our understanding of the clock mechanism has progressed extensively through the use of mutant screening and forward genetic approaches. The first vertebrate clock gene was identified only a few years ago in the mouse by such an approach. More recently, using a syntenic comparative genetic approach, the molecular basis of the the tau mutation in the hamster was determined. The tau gene in the hamster appears to encode casein kinase 1 epsilon, a protein previously shown to be important for PER protein turnover in the Drosophila circadian system. A number of additional clock genes have now been described. These proteins appear to play central roles in the transcription-translation negative feedback loop responsible for clock function. Post-translational modification, protein dimerization and nuclear transport all appear to be essential features of how clocks are thought to tick.", "Chimeric antigen receptor (CAR) T-cell therapy has quickly emerged as a highly promising treatment for patients with relapsed and refractory multiple myeloma. There are numerous candidates under development, each with their unique characteristics and points of differentiation. The most recent US Food and Drug Administration approval of the first B-cell maturation antigen-targeted CAR-T cell therapy on March 26, 2021, has paved a path forward for the eventual evaluation of more of these investigational agents undergoing clinical trials. Herein, we highlight, from a clinical development perspective, the CAR-T cell therapies farthest along in development with updated data from the American Society of Hematology 2020 annual meeting. We also discuss potential paths of overcoming resistance to these therapies and the future direction for CAR-T cell therapeutics in multiple myeloma.", "MOTIVATION: Genomic context analysis, also known as phylogenetic profiling, is widely used to infer functional interactions between proteins but rarely applied to non-coding cis-regulatory DNA elements. We were wondering whether this approach could provide insights about utlraconserved non-coding elements (UCNEs). These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. Their molecular functions and the reasons for their high degree of conservation remain enigmatic.RESULTS: In a special setting of genomic context analysis, we analyzed the fate of GRBs after a whole-genome duplication event in five fish genomes. We found that in most cases all UCNEs were retained together as a single block, whereas the corresponding target genes were often retained in two copies, one completely devoid of UCNEs. This 'winner-takes-all' pattern suggests that UCNEs of a GRB function in a highly cooperative manner. We propose that the multitude of interactions between UCNEs is the reason for their extreme sequence conservation.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online and at http://ccg.vital-it.ch/ucne/", "OBJECTIVES: In a post-hoc analysis, we aimed to validate the Lupus Low Disease Activity State (LLDAS) definition as an endpoint in an systemic lupus erythematosus (SLE) Phase IIb randomised controlled trial (RCT) (MUSE [NCT01438489]) and then utilize LLDAS to discriminate between anifrolumab and placebo.METHODS: Patients received intravenous placebo (n=102) or anifrolumab (300 mg, n=99; 1,000 mg, n=104) Q4W plus standard of care for 48 weeks. LLDAS attainment (SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician's Global Assessment ≤1, prednisolone ≤7.5 mg/d and standard immunosuppressant dosage tolerance) was assessed. Associations with endpoints and LLDAS attainment differences between treatments were explored.RESULTS: LLDAS attainment at Week 52 was associated with SLE Responder Index 4 (SRI[4]) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) (74/85[87%] and 62/84[74%] were also SRI[4] and BICLA responders, respectively; both nominal p<0.001). Only 74/159 (47%) of SRI(4) and 62/121 (51%) of BICLA responders reached LLDAS.Anifrolumab-treated patients achieved earlier LLDAS, and more spent at least half their observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34 to 6.92, nominal p=0.008; 1,000 mg: 2.17, 95% CI 0.93 to 5.03, nominal p=0.072) vs placebo-treated patients. At Week 52, 17/102 (17%), 39/99 (39%) and 29/104 (28%) of patients on placebo, anifrolumab 300 and 1,000 mg, respectively, attained LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73 to 6.76, p<0.001; 1,000 mg: 2.03, 95% CI 1.01 to 4.07, nominal p=0.046).CONCLUSIONS: LLDAS attainment represents a clinically meaningful SLE outcome measure, and anifrolumab is associated with more patients who met LLDAS criteria versus placebo. These data support LLDAS as an SLE RCT endpoint.TRIAL REGISTRATION NUMBER: NCT1438489; Post-results.", "Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naïve-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naïve-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.", "The intermediate syndrome (IMS) following organophosphorus (OP) insecticide poisoning was first described in the mid-1980s. The syndrome described comprised characteristic symptoms and signs occurring after apparent recovery from the acute cholinergic syndrome. As the syndrome occurred after the acute cholinergic syndrome but before organophosphate-induced delayed polyneuropathy, the syndrome was called 'intermediate syndrome'. The IMS occurs in approximately 20% of patients following oral exposure to OP pesticides, with no clear association between the particular OP pesticide involved and the development of the syndrome. It usually becomes established 2-4 days after exposure when the symptoms and signs of the acute cholinergic syndrome (e.g. muscle fasciculations, muscarinic signs) are no longer obvious. The characteristic features of the IMS are weakness of the muscles of respiration (diaphragm, intercostal muscles and accessory muscles including neck muscles) and of proximal limb muscles. Accompanying features often include weakness of muscles innervated by some cranial nerves. It is now emerging that the degree and extent of muscle weakness may vary following the onset of the IMS. Thus, some patients may only have weakness of neck muscles whilst others may have weakness of neck muscles and proximal limb muscles. These patients may not require ventilatory care but close observation and monitoring of respiratory function is mandatory. Management is essentially that of rapidly developing respiratory distress and respiratory failure. Delays in instituting ventilatory care will result in death. Initiation of ventilatory care and maintenance of ventilatory care often requires minimal doses of non-depolarising muscle relaxants. The use of depolarising muscle relaxants such as suxamethonium is contraindicated in OP poisoning. The duration of ventilatory care required by patients may differ considerably and it is usual for patients to need ventilatory support for 7-15 days and even up to 21 days. Weaning from ventilatory care is best carried out in stages, with provision of continuous positive airway pressure prior to complete weaning. Continuous and close monitoring of respiratory function (arterial oxygen saturation, partial pressure of oxygen in arterial blood, partial pressure of carbon dioxide in arterial blood) and acid-base status are an absolute necessity. Prophylactic antibiotics are usually not required unless there has been evidence of aspiration of material into the lungs. Close monitoring of fluid and electrolyte balance is mandatory in view of the profuse offensive diarrhoea that most patients develop. Maintenance of nutrition, physiotherapy, prevention of bed sores and other routine measures to minimise discomfort during ventilatory care are necessary. Recovery from the intermediate syndrome is normally complete and without any sequelae. The usefulness of oximes during the IMS remains uncertain. In animal experiments, very early administration of oximes has prevented the occurrence of myopathy. There are reports from developed countries where administration of oximes at recommended doses and within 2 hours of ingestion of OP insecticide did not prevent the onset of the IMS. Controlled randomised clinical studies are necessary to evaluate the efficacy of oximes in combating the IMS. Electrophysiological studies following OP poisoning have revealed three characteristic phenomena: (i) repetitive firing following a single stimulus; (ii) gradual reduction in twitch height or compound muscle action potential followed by an increase with repetitive stimulation (the 'decrement-increment response'); and (iii) continued reduction in twitch height or compound muscle action potential with repetitive simulation ('decrementing response'). Of these, the decrementing response is the most frequent finding during the IMS, whilst repetitive firing is observed during the acute cholinergic syndrome. The distribution of the weakness in human cases of the IMS, in general, parallels the distribution of the myopathy observed in a number of studies in experimental animals. This has led to speculation that myopathy is involved in the causation of the IMS. However, while myopathy and the IMS have a common origin in acetylcholine accumulation, they are not causally related to one another.", "BACKGROUND: Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival.OBJECTIVE: We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis.METHODS: Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8.RESULTS: Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline.CONCLUSION: Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.", "The NF-κB transcription factor family plays a central role in innate immunity and inflammation processes and is frequently dysregulated in cancer. We developed an NF-κB functional assay in yeast to investigate the following issues: transactivation specificity of NF-κB proteins acting as homodimers or heterodimers; correlation between transactivation capacity and in vitro DNA binding measurements; impact of co-expressed interacting proteins or of small molecule inhibitors on NF-κB-dependent transactivation. Full-length p65 and p50 cDNAs were cloned into centromeric expression vectors under inducible GAL1 promoter in order to vary their expression levels. Since p50 lacks a transactivation domain (TAD), a chimeric construct containing the TAD derived from p65 was also generated (p50TAD) to address its binding and transactivation potential. The p50TAD and p65 had distinct transactivation specificities towards seventeen different κB response elements (κB-REs) where single nucleotide changes could greatly impact transactivation. For four κB-REs, results in yeast were predictive of transactivation potential measured in the human MCF7 cell lines treated with the NF-κB activator TNFα. Transactivation results in yeast correlated only partially with in vitro measured DNA binding affinities, suggesting that features other than strength of interaction with naked DNA affect transactivation, although factors such as chromatin context are kept constant in our isogenic yeast assay. The small molecules BAY11-7082 and ethyl-pyruvate as well as expressed IkBα protein acted as NF-κB inhibitors in yeast, more strongly towards p65. Thus, the yeast-based system can recapitulate NF-κB features found in human cells, thereby providing opportunities to address various NF-κB functions, interactions and chemical modulators." ]

[ "The aim of the present study was to develop an experimental paradigm for the study of serotonergic neurotransmission in humans using positron emission tomography and the 5-HT2A selective radioligand [18F]altanserin. [18F]altanserin studies were conducted in seven subjects using the bolus/infusion approach designed for attaining steady state in blood and brain 2 hours after the initial [18F]altanserin administration. Three hours after commencement of radiotracer administration, 0.25 mg/kg of the selective serotonin reuptake inhibitor, citalopram (Lundbeck, Valby, Denmark), was administered to all subjects as a constant infusion for 20 minutes. To reduce 5-HT1A-mediated autoinhibition of cortical 5-HT release, four of the seven subjects were pretreated with the partial 5-HT1A agonist pindolol for 3 days at an increasing oral dose (25 mg on the day of scanning). In each subject, the baseline condition (120 to 180 minutes) was compared with the stimulated condition (195 to 300 minutes). Despite a pronounced increase in plasma prolactin and two subjects reporting hot flushes compatible with an 5-HT-induced adverse effect, cortical [18F]altanserin binding was insensitive to the citalopram challenge, even after pindolol pretreatment. The biochemical and cellular events possibly affecting the unsuccessful translation of the citalopram/pindolol challenge into a change in 5-HT2A receptor binding of [18F]altanserin are discussed.", "Enhancers are critical genomic elements that define cellular and functional identity through the spatial and temporal regulation of gene expression. Recent studies suggest that key genes regulating cell type-specific functions reside in enhancer-dense genomic regions (i.e., super enhancers, stretch enhancers). Here we report that enhancer RNAs (eRNAs) identified by global nuclear run-on sequencing are extensively transcribed within super enhancers and are dynamically regulated in response to cellular signaling. Using Toll-like receptor 4 (TLR4) signaling in macrophages as a model system, we find that transcription of super enhancer-associated eRNAs is dynamically induced at most of the key genes driving innate immunity and inflammation. Unexpectedly, genes repressed by TLR4 signaling are also associated with super enhancer domains and accompanied by massive repression of eRNA transcription. Furthermore, we find each super enhancer acts as a single regulatory unit within which eRNA and genic transcripts are coordinately regulated. The key regulatory activity of these domains is further supported by the finding that super enhancer-associated transcription factor binding is twice as likely to be conserved between human and mouse than typical enhancer sites. Our study suggests that transcriptional activities at super enhancers are critical components to understand the dynamic gene regulatory network.", "CONTEXT: Effects of thyroid hormone therapy on postoperative morbidity and mortality in adults remain controversial.OBJECTIVE: The aim was to conduct a systematic review evaluating effects and risks of postoperative T(3) therapy in adults.DATA SOURCES: Electronic databases and reference lists through March 2010 were searched.STUDY SELECTION: Studies with comparable control groups comparing T(3) to placebo therapy in randomized controlled trials were selected.DATA EXTRACTION: Two reviewers independently screened and reviewed titles, abstracts, and articles. Data were abstracted from 14 randomized controlled trials (13 cardiac surgery and one renal transplantation). In seven studies, iv T(3) was given in high doses (0.175-0.333 μg/kg · h) for 6 to 9 h, in four studies iv T(3) was given in low doses (0.0275-0.0333 μg/kg · h for 14 to 24 h), and in three studies T(3) was given orally in variable doses and durations.DATA SYNTHESIS: Both high- and low-dose iv T(3) therapy increased cardiac index after coronary artery bypass surgery. Mortality was not significantly altered by high-dose iv T(3) therapy and could not be assessed for low-dose iv or oral T(3). Effects on systemic vascular resistance, heart rate, pulmonary capillary wedge pressure, new onset atrial fibrillation, inotrope use, serum TSH and T(4) were inconclusive.LIMITATIONS: Numbers of usable unique studies and group sizes were small. Duration of T(3) therapy was short, and dosages and routes of administration varied.CONCLUSIONS: Short duration postoperative iv T(3) therapy increases cardiac index and does not alter mortality. Effects on other parameters are inconclusive.", "PURPOSE OF REVIEW: In recent years, the N6-methyladenosine (m6A) modification of RNA has been shown to play an important role in the development of acute myeloid leukemia (AML) and the maintenance of leukemic stem cells (LSCs). In this review we summarise the recent findings in the field of epitranscriptomics related to m6A and its relevance in AML.RECENT FINDINGS: Recent studies have focused on the role of m6A regulators in the development of AML and their potential as translational targets. The writer Methyltransferase Like 3 and its binding partner Methyltransferase Like 14, as well as the reader YTH domain-containing family protein 2, were shown to be vital for LSC survival, and their loss has detrimental effects on AML cells. Similar observations were made with the demethylases fat mass and obesity-associated protein and AlkB homologue 5 RNA demethylase. Of importance, loss of any of these genes has little to no effect on normal hemopoietic stem cells, suggesting therapeutic potential.SUMMARY: The field of epitranscriptomics is still in its infancy and the importance of m6A and other RNA-modifications in AML will only come into sharper focus. The development of therapeutics targeting RNA-modifying enzymes may open up new avenues for treatment of such malignancies.", "NSD3/WHSC1L1 histone methyltransferase gene aberrations are observed in leukemia and in breast and lung carcinomas, suggesting that NSD3 is implicated in carcinogenesis. In this study we examined in human breast cancer cells the NSD3L isoform which contains the catalytic histone methyltransferase SET-domain. siRNA directed depletion of NSD3L followed by genome-wide microarray analysis identified NSD3L regulated genes which could be functionally linked to cellular signaling pathways such as cell growth, cell cycle, cell motility, transcription, and apoptosis. Notably up-regulated genes are the cell cycle regulators E2F2 and Arl2. In accordance with a function of NSD3L in cell cycle regulation NSD3L depletion resulted in an increase in the number of cells in the S and G2/M cell cycle phases. Moreover, NSD3L depletion increased the invasiveness of MDA-MB-231 breast cancer cells indicating that NSD3L normally restrain cellular metastatic potential. Together the presented data indicates that NSD3L is a candidate tumor suppressor.", "Renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are one of the most prescribed antihypertensive medications. Previous studies showed RAAS inhibitors increase the expression of ACE2, a cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which provokes a concern that the use of ACEI and ARB in hypertensive individuals might lead to increased mortality and severity of coronavirus disease 2019 (COVID-19). To further investigate the effects of ACEI/ARB on COVID-19 patients, we systematically reviewed relevant studies that met predetermined inclusion criteria in search of PubMed, Embase, Cochrane Library databases, medRxiv, and bioRxiv. The search strategy included clinical data published through October 12, 2020. Twenty-six studies involving 8104 hypertensive patients in ACEI/ARB-treated group and 8203 hypertensive patients in non-ACEI/ARB-treated group were analyzed. Random-effects meta-analysis showed ACEI/ARB treatment was significantly associated with a lower risk of mortality in hypertensive COVID-19 patients (odds ratio [OR] = 0.624, 95% confidence interval [CI] = 0.457-0.852, p = .003, I2  = 74.3%). Meta-regression analysis showed that age, gender, study site, Newcastle-Ottawa Scale scores, comorbidities of diabetes, coronary artery disease, chronic kidney disease, or cancer has no significant modulating effect of ACEI/ARB treatment on the mortality of hypertensive COVID-19 patients (all p > .1). In addition, the ACEI/ARB treatment was associated with a lower risk of ventilatory support (OR = 0.682, 95% CI = 0.475-1.978, p = .037, I2  = 0.0%). In conclusion, these results suggest that ACEI/ARB medications should not be discontinued for hypertensive patients in the context of COVID-19 pandemic.", "Potential female donors frequently ask whether unilateral nephrectomy will impair future childbearing capabilities. To address this question, we surveyed 220 women who underwent donor nephrectomy between 1985 and 1992. Of the 144 women who responded, 33 became pregnant after donation for a total of 45 pregnancies. Seventy-five percent of the pregnancies were carried to term without difficulty. Complications incurred during gestation included miscarriage (13.3%), preeclampsia (4.4%), gestational hypertension (4.4%), proteinuria (4.4%), and tubal pregnancy (2.2%). Four of the 45 pregnancies (excluding miscarriages) required preterm hospitalization, resulting in an overall morbidity of 8.8%. There were no pregnancy-related deaths, and no fetal abnormalities were reported. Problems with persistent hypertension, proteinuria, or changes in renal function were not noted. None of the above complications exceeded what has been noted for the general population. Infertility was a problem in 8.3% (3/36) of our respondents, compared with a worldwide incidence of 16.7%. Based on these results, we conclude that donor nephrectomy is not detrimental to the prenatal course or outcome of future pregnancies." ]

[ "Exencephaly is a rare precursor of anencephaly in which a large amount of brain tissue is present despite the absence of the calvaria. It was discovered together with hydramnios in a near-term fetus. Sonographic, angiographic, and pathologic findings are discussed.", "The aim of this study was to compare the economic revenue related to the use of low- or high-efficacy anthelmintic drugs within suppressive or strategic schemes of treatment in growing heifers. Heifers raised in a semi-intensive grazing system in southern Brazil were used. Levamisole and ivermectin were selected as the high- and the low-efficacy drugs, respectively, based on a previous efficacy test. Subsequently, these drugs were used within strategic (Strat; four times per year) or suppressive (Supp; once a month) treatment regimens in the heifers, and their liveweight and eggs per gram of feces counts were monthly evaluated during a 13-month period. The total costs of the treatments and their cost-benefit ratio in regard to liveweight gain were calculated. Final mean liveweight gains (kg) observed were 126.7 (Strat-Low), 133.6 (Supp-Low), 141.3 (Strat-High), 142.9 (Supp-High), and 125.8 (Control). Treatments with a high-efficacy drug resulted in monetary gains of US$ 19.56 (Strat-High) and US$ 14.98 (Supp-High), but Supp-Low and Strat-Low treatments caused economic losses. Total cost of the efficacy test (US$ 374.79) could be paid by the additional liveweight gain of 20 heifers from the Strat-High group. These results showed that it would be preferable not to treat the heifers against GIN if compared with treating them with a low-efficacy drug. In addition, we showed that the use of four treatments per year with a high-efficacy drug-selected by efficacy test-resulted in a profitable management to control GIN in growing heifers raised in a semi-intensive gazing system in southern Brazil.", "A large body of evidence supports an important role for calcitonin gene-related peptide (CGRP) in migraine pathophysiology. This evidence gave rise to a global effort to develop a new generation of therapeutics that inhibit the interaction of CGRP with its receptor in migraineurs. Recently, a new class of such drugs, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs), were found to be effective in reducing the frequency of migraine. The purpose of this study was to better understand how the CGRP-mAb fremanezumab (TEV-48125) modulates meningeal sensory pathways. To answer this question, we used single-unit recording to determine the effects of fremanezumab (30 mg/kg, IV) and its isotype control Ab on spontaneous and evoked activity in naive and cortical spreading depression (CSD)-sensitized trigeminovascular neurons in the spinal trigeminal nucleus of anesthetized male and female rats. The study demonstrates that, in both sexes, fremanezumab inhibited naive high-threshold (HT) neurons, but not wide-dynamic range trigeminovascular neurons, and that the inhibitory effects on the neurons were limited to their activation from the intracranial dura but not facial skin or cornea. In addition, when given sufficient time, fremanezumab prevents the activation and sensitization of HT neurons by CSD. Mechanistically, these findings suggest that HT neurons play a critical role in the initiation of the perception of headache and the development of cutaneous allodynia and central sensitization. Clinically, the findings may help to explain the therapeutic benefit of CGRP-mAb in reducing headaches of intracranial origin such as migraine with aura and why this therapeutic approach may not be effective for every migraine patient.SIGNIFICANCE STATEMENT Calcitonin gene-related peptide (CGRP) monoclonal antibodies (CGRP-mAbs) are capable of preventing migraine. However, their mechanism of action is unknown. In the current study, we show that, if given enough time, a CGRP-mAb can prevent the activation and sensitization of high-threshold (central) trigeminovascular neurons by cortical spreading depression, but not their activation from the skin or cornea, suggesting a potential explanation for selectivity to migraine headache, but not other pains, and a predominantly peripheral site of action.", "In developing countries, low-cost control and treatment programs that offer combined approaches against diseases and their vectors are certainly needed. Ivermectin (IVM) has been well known for its role in the treatment of parasitic diseases, due to its effect on glutamate-gated chloride channels. These same channels are also present in the mosquito vector, and thus, research has focused on the insecticidal effects of this drug. Possible alternative mechanisms of IVM on the physiology of mosquitoes, however, have not been sufficiently elaborated. We assessed the protease activity, lipid peroxidation, and local expression of STAT, p53, caspase-3, and Bax markers to study the effect of this antibiotic on digestion and immunity in Culex pipiens. Sugar- and blood-feeding assays were employed to investigate the potential influence of blood feeding on the dynamics of these parameters. IVM was found to have an effect on protease activity, lipid peroxidation as well as the expression of different markers investigated in this work. The focus on the detailed effect of this drug certainly opens the gate to broadening the spectrum of IVM and expanding its health and economic benefit, especially that it is relatively more affordable than other antibiotics on the market.", "Voltage-gated potassium channels (Kv) and thromboxane A(2) (TXA(2)) have been involved in several forms of human and experimental pulmonary hypertension. We have reported that the TXA(2) analog U46619, via activation of TP receptors and PKCzeta, inhibited Kv currents in rat pulmonary artery smooth muscle cells (PASMC), increased cytosolic calcium, and induced a contractile response in isolated rat and piglet pulmonary arteries (PA). Herein, we have analyzed the role of reactive oxygen species (ROS) in this signaling pathway. In rat PA, U46619 increased dichlorofluorescein fluorescence, an indicator of intracellular hydrogen peroxide, and this effect was prevented by the NADPH oxidase inhibitor apocynin and by polyethyleneglycol-catalase (PEG-catalase, a membrane-permeable form of catalase). U46619 inhibited Kv currents in native PASMC and these effects were strongly inhibited by apocynin. The contractile responses to U46619 in isolated PA were inhibited by PEG-catalase and the NADPH oxidase inhibitors diphenylene iodonium (DPI) and apocynin. A membrane permeable of hydrogen peroxide, t-butyl hydroperoxide, also inhibited Kv currents and induced a contractile response. Activation of NADPH oxidase and the subsequent production of hydrogen peroxide are involved in the Kv channel inhibition and the contractile response induced by TP receptor activation in rat PA.", "Phosphorylation of proteins on tyrosine residues is regulated by the activities of protein tyrosine kinases and protein tyrosine phosphatases. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) essentially and transiently expressed during development of the central and peripheral nervous systems. ALK has been identified as a major neuroblastoma predisposition gene and activating mutations have been identified in a subset of sporadic neuroblastoma tumors. We previously established that the mutated receptors were essentially retained in the endoplasmic reticulum/Golgi compartments due to their constitutive activity. Intriguingly we demonstrated a stronger phosphorylation for the minor pool of receptor addressed to the plasma membrane. We decided to investigate the potential involvement of tyrosine phosphatase in dephosphorylation of this intracellular pool. In this study we first showed that general inhibition of tyrosine phosphatases resulted in a dramatic increase of the tyrosine phosphorylation of the wild type but also of the mutated receptors. This increase not only required the intrinsic kinase activity of the ALK receptor but also involved the Src tyrosine kinase family. Second we provided strong evidences that the endoplasmic reticulum associated phosphatase PTP1B is key player in the control of ALK phosphorylation. Our data shed a new light on the biological significance of the basal phosphorylation levels of both wild type and mutated ALK receptors and could be essential to further understand their roles in malignancies.", "AIMS: Glucocorticoids, such as dexamethasone, enhance hepatic energy metabolism and gluconeogenesis partly through changes in mitochondrial function. Mitochondrial function is influenced by the balance between mitochondrial fusion and fission events. However, whether glucocorticoids modulate mitochondrial function through the regulation of mitochondrial dynamics is currently unknown.RESULTS: Here, we report that the effects of dexamethasone on mitochondrial function and gluconeogenesis in hepatoma cells are dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Dexamethasone increased routine oxygen consumption, maximal respiratory capacity, superoxide anion, proton leak, and gluconeogenesis in hepatoma cells. Under these conditions, dexamethasone altered mitochondrial morphology, which was paralleled by a large increase in Drp1 expression, and reduced mitofusin 1 (Mfn1) and Mfn2. In vivo dexamethasone treatment also enhanced Drp1 expression in mouse liver. On the basis of these observations, we analyzed the dependence on the Drp1 function of dexamethasone effects on mitochondrial respiration and gluconeogenesis. We show that the increase in mitochondrial respiration and gluconeogenesis induced by dexamethasone are hampered by the inhibition of Drp1 function.INNOVATION: Our findings provide the first evidence that the effects of glucocorticoids on hepatic metabolism require the mitochondrial fission protein Drp1.CONCLUSION: In summary, we demonstrate that the mitochondrial effects of dexamethasone both on mitochondrial respiration and on the gluconeogenic pathway depend on Drp1.", "Identification of gene mutations in Mendelian disorders is often determined by linkage analysis and positional cloning, an approach that is difficult for fibrodysplasia ossificans progressiva (FOP) due to a low reproductive fitness that results in a small number of multigenerational families showing inheritance of the disease. Altered signaling pathways can be investigated as a complementary method to identify the consequences of the mutated gene responsible for FOP and to identify potential therapeutic targets. Candidate signaling pathways for FOP are those that malfunctioning could account for the malformation of the great toes during embryonic development and could explain the postnatal progressive heterotopic endochondral ossification. Signaling pathways that fit these criteria are the BMP signaling pathway and its interacting pathways. A large body of data suggest that the BMP-4 signaling pathway is dysregulated in FOP.", "We investigated DNA sequence diversity for loci on chromosomes 1 and 2 in six natural populations of Arabidopsis lyrata and tested for the role of natural selection in structuring genomewide patterns of variability, specifically examining the effects of recombination rate on levels of silent polymorphism. In contrast with theoretical predictions from models of genetic hitchhiking, maximum-likelihood-based analyses of diversity and divergence do not suggest reduction of diversity in the region of suppressed recombination near the centromere of chromosome 1, except in a single population from Russia, in which the pericentromeric region may have undergone a local selective sweep or demographic process that reduced variability. We discuss various possibilities that might explain why nucleotide diversity in most A. lyrata populations is not related to recombination rate, including genic recombination hotspots, and low gene density in the low recombination rate region.", "Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production.", "The family of interleukin 17 receptors (IL17Rs), subtypes IL17RA-IL17RE, is targeted by the group of pro-inflammatory IL17 cytokines (IL17A-F) and moreover the newly developed anti-IL17A antibody secukinumab (AIN457) has shown promise in Phase II trials in multiple sclerosis. Here, we show that human astrocytes, isolated from a fetal cerebral cortex, express IL17RA and IL17RC and in vitro treatment with IL17A increases protein levels of IL6 in human astrocytes, which is enhanced in the presence of TNFα, as determined by homogeneous time resolved fluorescence. Studies on acutely isolated mouse astrocytes are comparable to human astrocytes although the protein levels of IL6 are lower in mouse astrocytes, which also show a lower response to IL17F and IL1β in promoting IL6 levels. In human astrocytes, IL17A and TNFα also induce mRNA expression of IL6, IL8 and the Th17 cytokines CXCL1, CXCL2, and CCL20, with little effect on Th1 cytokines CXCL9, CXCL10, and CXCL11. The effects of IL17A are associated with nuclear translocation of the NF-κB transcription factor, as determined by immunocytochemistry, where treatment of human astrocytes with the inhibitors of the NF-κB pathway and with secukinumab inhibits the IL17A and IL17A/TNFα-induced increase in nuclear translocation of NF-κB and levels of IL6. Taken together the data shows that IL17A signaling plays a key role in regulating the levels of cytokines, such as IL6, in human astrocytes via a mechanism that involves NF-κB signaling and that selective inhibition of IL17A signaling attenuates levels of pro-inflammatory molecules in astrocytes.", "Publisher: OBJECTIF: L'ivermectine est sûr et largement utilisé pour traiter les helminthiases. Il tue également les arthropodes se nourrissant sur les sujets traités, y compris les vecteurs du paludisme. Ainsi, l'administration en masse d'ivermectine en tant qu'outil supplémentaire de lutte contre le paludisme est actuellement évaluée par l'OMS. Comme les données in vitro, les expériences sur animaux et les observations épidémiologiques suggèrent que l'ivermectine a un effet direct sur les stades hépatiques du parasite du paludisme, cette étude a été conçue pour évaluer l'effet prophylactique de l'ivermectine sur l'infection paludéenne humaine par Plasmodium falciparum contrôlée. MÉTHODES: Quatre volontaires ont été randomisés pour un placebo et 8 volontaires ont été randomisés pour recevoir de l'ivermectine à 0,4 mg/kg en une fois par voie orale, 2 heures avant d'être expérimentalement infectés par voie intraveineuse avec 3.200 sporozoïtes de P. falciparum. Le critère d'évaluation principal était le temps à la parasitémie détectée par un frottis sanguin épais positif. Une RT-qPCR a été réalisée en parallèle. RÉSULTATS: Tous les volontaires sauf un sont devenus positifs pour les frottis sanguins épais entre le jour 11 et le jour 12 après l'infection et il n'y avait aucun effet significatif de l'ivermectine sur la parasitémie.CONCLUSION: L'ivermectine - à la dose utilisée - n'a aucune activité cliniquement pertinente contre les stades pré-érythrocytaires de P. falciparum." ]

[ "Williams syndrome (WS) is a well-known microdeletion syndrome characterized by specific facial features, retardation in growth and development, typical personality and cardiac defects. Poor growth potential is further affected by central precocious puberty (CPP) which is frequent in these patients. A WS patient with CPP is presented, whose pubertal development and bone age progression were arrested by administration of GnRH analogues. The case is reported to discuss the role of GnRH analogues for management of CPP in patients with WS.", "Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing impairment, presence of goiter, and a partial defect in iodide organification, which may be associated with insufficient thyroid hormone synthesis. Goiter development and development of hypothyroidism are variable and depend on nutritional iodide intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4 gene, which encodes pendrin, a transporter of chloride, bicarbonate and iodide. This review discusses the controversies surrounding the potential role of pendrin in mediating apical iodide efflux into the lumen of thyroid follicles, and discusses its functional role in the kidney and the inner ear.", "BACKGROUND: The incidence of inflammatory bowel disease (IBD) in childhood and adolescence is 5-11 cases per 100 000 persons per year, corresponding to a new diagnosis of IBD in 800-1470 patients in Germany each year.METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, including guidelines from Germany and abroad.RESULTS: Children and adolescents with IBD often have extensive involvement and an aggressive course of disease. Nonetheless, infliximab and adalimumab are the only biological agents that have been approved for this group of patients. In Crohn's disease, exclusive enteral nutrition is the treatment of first choice for inducing a remission. Patients with (peri-)anal fistulae are treated primarily with infliximab. Corticosteroids and aminosalicylates should be used with caution. In contrast, children and adolescents with ulcerative colitis are treated with either aminosalicylates or prednisolone to induce a remission. As a rule, maintenance pharmacotherapy with thiopurines in Crohn's disease and severe ulcerative colitis, or with aminosalicylates in mild to moderate ulcerative colitis, is indicated for several years, at least until the end of puberty. Patients with refractory disease courses are treated with methylprednisolone, anti-TNF-α-antibodies, and/or calcineurin inhibitors. The spectrum of surgical interventions is the same as for adults. Specific aspects of the treatment of children and adolescents with IBD include adverse drug effects, the areas of nutrition, growth, and development, and the structured transition to adult medicine.CONCLUSION: Children and adolescents with IBD or suspected IBD should be cared for by pediatric gastroenterologists in a center where such care is provided. Individualized treatment with multidisciplinary, family-oriented longterm care is particularly important. Drug trials in children and adolescents are needed so that the off-label use of drugs to patients in this age group can be reduced.", "OBJECTIVE: To determine the effect of avanafil, a novel phosphodiesterase-5 inhibitor, on the treatment of erectile dysfunction associated with type 2 diabetes mellitus (T2DM).METHODS: In 2-day-old rats, T2DM was induced by single intraperitoneal injection of 90 mg/kg of streptozotocin (STZ; i.p.). Erectile responses were evaluated after 10 weeks on intracavernosal injection of avanafil (1 μM) to anesthetized rats and data expressed as intracavernosal pressure (ICP)/mean arterial pressure and total ICP. The relaxant and contractile responses of corpus cavernosum (CC) strips were obtained in vitro studies.RESULTS: ICP/mean arterial pressure and total ICP responses were significantly reduced in T2DM rats compared with controls. Avanafil partially restored diminished ICP responses in diabetic rats. In CC strips from the diabetic group, electrical field stimulation (1-20 Hz)-induced relaxation responses were markedly enhanced by 45%, whereas acetylcholine (ACh; 10(-8)-10(-3))-induced relaxation responses were diminished by 73%. In addition, phenylephrine (PE; 10(-8)-10(-3)) and electrical field stimulation (1-40 Hz)-induced contractile responses were significantly reduced in the diabetic group compared with controls. CC relaxant responses to sodium nitroprusside (SNP, 10(-8)-10(-3)) and avanafil (10(-8)-10(-3)) were unaltered in both groups.CONCLUSION: The cavernous injection of avanafil in T2DM rats resulted in partial improvement in erectile responses. These findings suggest that intracavernosal administration of avanafil might be beneficial for the treatment of erectile dysfunction in patients with T2DM.", "The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that Prdm16, a brown adipose determination factor, is selectively expressed in subcutaneous white adipocytes relative to other white fat depots in mice. Transgenic expression of Prdm16 in fat tissue robustly induced the development of brown-like adipocytes in subcutaneous, but not epididymal, adipose depots. Prdm16 transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. shRNA-mediated depletion of Prdm16 in isolated subcutaneous adipocytes caused a sharp decrease in the expression of thermogenic genes and a reduction in uncoupled cellular respiration. Finally, Prdm16 haploinsufficiency reduced the brown fat phenotype in white adipose tissue stimulated by β-adrenergic agonists. These results demonstrate that Prdm16 is a cell-autonomous determinant of a brown fat-like gene program and thermogenesis in subcutaneous adipose tissues.", "INTRODUCTION: Atherosclerotic Coronary Artery Disease (ASCAD) is the leading cause of mortality worldwide. Novel therapeutic approaches aiming to improve the atheroprotective functions of High Density Lipoprotein (HDL) include the use of reconstituted HDL forms containing human apolipoprotein A-I (rHDL-apoA-I). Given the strong atheroprotective properties of apolipoprotein E3 (apoE3), rHDL-apoE3 may represent an attractive yet largely unexplored therapeutic agent.OBJECTIVE: To evaluate the atheroprotective potential of rHDL-apoE3 starting with the unbiased assessment of global transcriptome effects and focusing on endothelial cell (EC) migration as a critical process in re-endothelialization and atherosclerosis prevention. The cellular, molecular and functional effects of rHDL-apoE3 on EC migration-associated pathways were assessed, as well as the potential translatability of these findings in vivo.METHODS: Human Aortic ECs (HAEC) were treated with rHDL-apoE3 and total RNA was analyzed by whole genome microarrays. Expression and phosphorylation changes of key EC migration-associated molecules were validated by qRT-PCR and Western blot analysis in primary HAEC, Human Coronary Artery ECs (HCAEC) and the human EA.hy926 EC line. The capacity of rHDL-apoE3 to stimulate EC migration was assessed by wound healing and transwell migration assays. The contribution of MEK1/2, PI3K and the transcription factor ID1 in rHDL-apoE3-induced EC migration and activation of EC migration-related effectors was assessed using specific inhibitors (PD98059: MEK1/2, LY294002: PI3K) and siRNA-mediated gene silencing, respectively. The capacity of rHDL-apoE3 to improve vascular permeability and hypercholesterolemia in vivo was tested in a mouse model of hypercholesterolemia (apoE KO mice) using Evans Blue assays and lipid/lipoprotein analysis in the serum, respectively.RESULTS: rHDL-apoE3 induced significant expression changes in 198 genes of HAEC mainly involved in re-endothelialization and atherosclerosis-associated functions. The most pronounced effect was observed for EC migration, with 42/198 genes being involved in the following EC migration-related pathways: 1) MEK/ERK, 2) PI3K/AKT/eNOS-MMP2/9, 3) RHO-GTPases, 4) integrin. rHDL-apoE3 induced changes in 24 representative transcripts of these pathways in HAEC, increasing the expression of their key proteins PIK3CG, EFNB2, ID1 and FLT1 in HCAEC and EA.hy926 cells. In addition, rHDL-apoE3 stimulated migration of HCAEC and EA.hy926 cells, and the migration was markedly attenuated in the presence of PD98059 or LY294002. rHDL-apoE3 also increased the phosphorylation of ERK1/2, AKT, eNOS and p38 MAPK in these cells, while PD98059 and LY294002 inhibited rHDL-apoE3-induced phosphorylation of ERK1/2, AKT and p38 MAPK, respectively. LY had no effect on rHDL-apoE3-mediated eNOS phosphorylation. ID1 siRNA markedly decreased EA.hy926 cell migration by inhibiting rHDL-apoE3-triggered ERK1/2 and AKT phosphorylation. Finally, administration of a single dose of rHDL-apoE3 in apoE KO mice markedly improved vascular permeability as demonstrated by the reduced concentration of Evans Blue dye in tissues such as the stomach, the tongue and the urinary bladder and ameliorated hypercholesterolemia.CONCLUSIONS: rHDL-apoE3 significantly enhanced EC migration in vitro, predominantly via overexpression of ID1 and subsequent activation of MEK1/2 and PI3K, and their downstream targets ERK1/2, AKT and p38 MAPK, respectively, and improved vascular permeability in vivo. These novel insights into the rHDL-apoE3 functions suggest a potential clinical use to promote re-endothelialization and retard development of atherosclerosis.", "Procalcitonin (PCT) is useful for differentiating between viral and bacterial infections and for reducing the unnecessary use of antibiotics. As the rise of antimicrobial resistance reaches \"alarming\" levels according to the World Health Organization, the importance of using biomarkers, such as PCT to limit unnecessary antibiotic exposure has further increased. Randomized trials in patients with respiratory tract infections have shown that PCT has prognostic implications and its use, embedded in stewardship protocols, leads to reductions in the use of antibiotics in different clinical settings without compromising clinical outcomes. However, available data are heterogeneous and recent trials found no significant benefit. Still, from these trials, we have learned several key considerations for the optimal use of PCT, which depend on the clinical setting, severity of presentation, and pretest probability for bacterial infection. For patients with respiratory infections and sepsis, PCT can be used to determine whether to initiate antimicrobial therapy in low-risk settings and, together with clinical data, whether to discontinue antimicrobial therapy in certain high-risk settings. There is also increasing evidence regarding PCT-guided therapy in patients with coronavirus disease 2019 (COVID-19). This review provides an up-to-date overview of the use of PCT in different clinical settings and diseases, including a discussion about its potential to improve the care of patients with COVID-19." ]

[ "Pheochromocytomas synthesize and release catecholamines, which subsequently are related to various clinical manifestations of the disease. However, pheochromocytomas are not innervated and the catecholamine release and synthesis are not initiated by neural impulses. It is still unknown how catecholamine synthesis is regulated in pheochromocytomas. As a first step toward understanding the molecular mechanisms by which catecholamine synthesis is controlled in the tumor, we measured the levels of mRNA coding for the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH) and catecholamines in 6 pheochromocytomas and 2 normal adrenal glands. The TH mRNA level was overexpressed and the catecholamine contents were high in 4 out of 6 pheochromocytomas. There was a close correlation between the TH mRNA level and the catecholamines content in the tumors. We also examined the gene expression of the messengers of other catecholamine synthesizing enzymes, dopamine beta-hydroxylase (DBH) and aromatic 1-amino acid decarboxylase (AADC) in pheochromocytomas. The expression of these genes was in parallel with that of TH mRNA in the tumors. These findings indicate that catecholamine overproduction in pheochromocytomas is mediated by the overexpression of genes coding for catecholamines synthesizing enzymes, TH, DBH, and AADC.", "X-linked myotubular myopathy (XLMTM) is a congenital muscular disease characterized by severe hypotonia and generalized muscle weakness, leading in most cases to early postnatal death. The gene responsible for the disease, MTM1, encodes a dual specificity phosphatase, named myotubularin, which is highly conserved throughout evolution. To date, 139 MTM1 mutations in independent patients have been reported, corresponding to 93 different mutations. In this report we describe the identification of 21 mutations (14 novel) in XLMTM patients. Seventeen mutations are associated with a severe phenotype in males, with death occurring mainly before the first year of life. However, four mutations-three missense (R241C, I225T, and novel mutation P179S) and one single-amino acid deletion (G294del)-were found in patients with a much milder phenotype. These patients, while having a severe hypotonia at birth, are still alive at the age of 4, 7, 13, and 15 years, respectively, and display mild to moderate muscle weakness.", "Cyclooxgenase-2 (COX-2) knock-out mouse experiments showed that COX-2 was necessary for in vivo allergic inflammation, such as passive cutaneous anaphylaxis, passive systemic anaphylaxis, and triphasic cutaneous allergic reaction. TargetScan analysis predicted COX-2 as a target of miR-26a and miR-26b. miR-26a/-26b decreased luciferase activity associated with COX-2-3'-UTR. miR-26a/-26b exerted negative effects on the features of in vitro and in vivo allergic inflammation by targeting COX-2. ChIP assays showed the binding of HDAC3 and SNAIL, but not COX-2, to the promoter sequences of miR-26a and miR-26b. Cytokine array analysis showed that the induction of chemokines, such as MIP-2, in the mouse passive systemic anaphylaxis model occurred in a COX-2-dependent manner. ChIP assays showed the binding of HDAC3 and COX-2 to the promoter sequences of MIP-2. In vitro and in vivo allergic inflammation was accompanied by the increased expression of MIP-2. miR-26a/-26b negatively regulated the expression of MIP-2. Allergic inflammation enhanced the tumorigenic and metastatic potential of cancer cells and induced positive feedback involving cancer cells and stromal cells, such as mast cells, macrophages, and endothelial cells. miR-26a mimic and miR-26b mimic negatively regulated the positive feedback between cancer cells and stromal cells and the positive feedback among stromal cells. miR-26a/-26b negatively regulated the enhanced tumorigenic potential by allergic inflammation. COX-2 was necessary for the enhanced metastatic potential of cancer cells by allergic inflammation. Taken together, our results indicate that the miR26a/-26b-COX-2-MIP-2 loop regulates allergic inflammation and the feedback relationship between allergic inflammation and the enhanced tumorigenic and metastatic potential.", "The aim of this study, using a Fleming single-stage design, was to explore the efficacy and safety of Taxotere 100 x mg x m(-2) docetaxel and FEC 75 cyclophosphamide 500 mg x m(-2), fluorouracil 500 x mg x m(-2) and epirubicin 75 mg x m(-2), in alternating and sequential schedules for the first-line treatment of metastatic breast cancer. One hundred and thirty-six women were randomly allocated, to one of three treatment regimens: DTX 100 plus FEC 75, alternated for eight courses (ALT); four courses of DTX 100 followed by four courses of FEC 75 (SEQ T); or four courses of FEC 75 followed by four courses of DTX 100 (SEQ F). One hundred and thirty-one women were evaluable for tumour response. Although the treatment outcome was equivalent in the two sequential arms and the alternating regimen (P=0.110, not significant), the response rate was less encouraging in the SEQ F arm (52.3%) than in the other two arms (71.1% for ALT and 70.5% for SEQ T), in which docetaxel was administered first. Time to progression was similar in the ALT, SEQ T and SEQ F arms (9.5, 9.3 and 10.4 months respectively). Grade 3-4 neutropenia was observed in nearly all patients; febrile neutropenia occurred in 9% (ALT), 16% (SEQ T) and 2% (SEQ F) of patients. Few patients (< or =9%) developed grade 3-4 non-haematological toxicities. Relative dose intensity was 97-99% for all regimens. All treatment regimens were active and well tolerated.", "BACKGROUND AND OBJECTIVES: Kell antigens are encoded by the KEL gene on the long arm of chromosome 7. Kx antigen is encoded by the XK gene on the short arm of the X chromosome. Kell and Kx proteins in the red cell membrane are covalently linked by a disulphide bond. The McLeod phenotype is characterized by weakened expression of antigens in the Kell blood group system, absence of Km and Kx antigens, and acanthocytosis. It has an X-linked mode of inheritance with transmission through carrier females. Some males with the McLeod syndrome also have chronic granulomatous disease (CGD). It is generally believed that patients with non-CGD McLeod may develop anti-Km but not anti-Kx, but that those with CGD McLeod can develop both anti-Km and anti-Kx.MATERIALS AND METHODS: We present serological data, DNA genotyping and gene sequencing, monocyte monolayer assay and neutrophil oxidative burst test from a patient with the McLeod phenotype without clinical evidence of CGD.RESULTS: We report here the second example of a patient with non-CGD McLeod who developed anti-Kx in addition to anti-Km. Sequencing of our patient's XK gene confirmed the presence of a mutation resulting in a premature stop codon and lack of Kx protein in the red cell membrane, which is consistent with the diagnosis of McLeod syndrome. Neutrophil oxidative burst test was normal, indicating that our patient did not have CGD. The challenge of providing 10 compatible blood units for multiple surgeries was met.CONCLUSION: The second case of a rare entity, a patient with non-CGD McLeod who developed anti-Kx and anti-Km, was managed successfully with a combination of autologous donations and procurement of compatible units from national and international sources.", "Author information:(1)Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics.(2)Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology.(3)Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics.(4)Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.(5)Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.(6)Sahlgrenska Translational Melanoma Group (SATMEG), Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg.(7)Department of Pharmacy and.(8)Science for Life Laboratory Drug Discovery and Development Platform, ADME of Therapeutics facility, Department of Phamracy, Uppsala University, Uppsala, Sweden.(9)Swedish Toxicology Sciences Research Center, Södertälje, Sweden.(10)National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm.(11)SP Process Development, Södertälje, Sweden.(12)Uppsala Drug Optimisation and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Uppsala University, Uppsala, Sweden.(13)Institute of biomedical sciences, Academia Sinica, Taipei-115, Taiwan.(14)Biomedical Research Foundation of the Academy of Athens, Athens, Greece.(15)Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.(16)Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics thomas.helleday@scilifelab.se.", "People with rare hypertrichosis syndromes became crowd-drawing money-making phenomena in many 19th century sideshow acts. These individuals have been referred to as dog-men, hair-men, and werewolves. In 1993, Baumister et al. described congenital hypertrichosis lanuginose or Ambras syndrome: a distinct form of congenital hypertrichosis characterized by excessive hair growth over the body and face associated with facial and occasional dental anomalies. Much is not known about this syndrome since fewer than 50 cases have been documented worldwide. In this case report, a nine year old girl presented with excessive hair growth throughout her body that was denser along her midline. Furthermore, her face displayed the typical dysmorphic features characteristic of Ambras syndrome: a round tip nose, thickened nasal cartilage, antiverted nares, prominent philtrum with deep groove, and a trapezoid mouth. Oral examination revealed normal oral mucosa with completely missing and unerupted decidious and permanent teeth. Panoramic radiographs confirmed unerupted deciduous teeth. Previous case reports have mentioned the presence of occasional dental anomalies such as retarded first and second dentition and absence of some teeth. However, this is the first reported case of Ambras syndrome presenting with complete anodontia. Prior cytogenetic studies performed on persons with Ambras syndrome have implicated a balanced pericentric inversion of chromosome 8. However, it is likely that dental anomalies are likely a result of a different genetic rearrangement. Further studies are needed to explore the cause of this rare phenotype of Ambras syndrome with complete unerupted dentition." ]

[ "We report a successful case of extracorporeal membrane oxygenation (ECMO) support for a 7-year-old girl with acute fulminant myocarditis, and describe the pitfalls and management of ECMO. The problem with ECMO is that it may not reduce the afterload of the left ventricle (LV), and may be associated with increased LV wall stress and deteriorating pulmonary congestion. It is important for ECMO management to find the best balance between flow support and LV afterload.", "A novel telomerase inhibitor, telomestatin, isolated from Streptomyces anulatus is the most potent telomerase inhibitor so far. Telomestatin specifically inhibited telomerase without affecting reverse transcriptases and polymerases. In addition, telomestatin induced telomere shortening, but its ratio was extremely faster than that observed in physiological telomere shortening. These results suggested the existence of other mechanisms to inhibit telomerase. Telomeres consist of guanine rich sequences which compose a characteristic three-dimensional structure designated as G-quadruplex. Stabilization of G-quadruplex structure inhibited the catalysis of not only telomerase but also other DNA interacting molecules. Telomestatin potently stabilized G-quadruplex structure in a specific manner. G-quadruplex structure is also involved in a lot of oncogene promoters. Thus, telomestatin provide the novel therapeutic molecular target for cancer chemotherapy.", "BACKGROUND: Filgrastim is an effective granulocyte colony-stimulating factor (G-CSF) used to reduce periods of neutropenia and the risk of infection after chemotherapy courses. Pegfilgrastim is a pegylated filgrastim with a longer plasma half-life that is administered once per cycle.OBJECTIVE: The aim of this study was to compare the efficacy of pegfilgrastim and filgrastim administered after chemotherapy in children with Ewing sarcoma.METHODS: We performed a retrospective chart review of pediatric patients with Ewing sarcoma. Every patient received both types of G-CSF in different treatment courses of chemotherapy, which consisted of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE); vincristine, actinomycin D, and ifosfamide (VAI); or vincristine, actinomycin D, and cyclophosphamide (VAC). A single injection of pegfilgrastim 100 microg/kg SC or a daily injection of filgrastim 5 to 10 microg/kg SC was administered 48 to 72 hours after the completion of chemotherapy. The following data were collected from the medical charts: proportion of chemotherapy courses with grade 4 neutropenia, duration of grade 4 neutropenia, proportion with severe neutropenia, duration of severe neutropenia, proportion with febrile neutropenia, duration of antibiotic treatment, duration of hospitalization, and percentage of patients receiving transfusion. Grade 4 neutropenia was defined as an absolute neutrophil count of <500 x 10(9)/L; severe neutropenia was defined as a count of <200 x 10(9)/L. Adverse events were collected from the medical charts.RESULTS: Twenty children were included (13 girls and 7 boys). The patients' median age was 12.8 years (range, 9-17 years) and median weight was 45.2 kg (range, 28-90 kg). A total of 178 chemotherapy courses (108 VIDE; 70 VAI or VAC) were administered and evaluated, including 134 courses with pegfilgrastim and 44 courses with filgrastim. Considering all types of chemotherapy combined, those courses in which pegfilgrastim was used were associated with a significantly lower incidence of severe neutropenia (0.21 vs 0.85; P = 0.03), a shorter duration of severe neutropenia (0.49 vs 2.36 days; P = 0.01), and a shorter duration of antibiotic treatment (1.07 vs 4.22 days; P = 0.03) compared with courses treated with filgrastim. No statistically significant differences were observed for the proportion and duration of grade 4 neutropenia, proportion of febrile neutropenia, duration of hospitalization, or red blood cell and platelet transfusions. Adverse effects were few and comparable between pegfilgrastim and filgrastim.CONCLUSIONS: In this retrospective chart review of children with Ewing sarcoma, using pegfilgrastim after chemotherapy courses was associated with significantly reduced frequency and shorter duration of severe neutropenia compared with those courses followed by filgrastim. Randomized controlled trials are needed to confirm these preliminary observations.", "OBJECTIVE: Developmental epileptic encephalopathies (DEEs) are genetically heterogeneous severe childhood-onset epilepsies with developmental delay or cognitive deficits. In this study, we explored the pathogenic mechanisms of DEE-associated de novo mutations in the CACNA1A gene.METHODS: We studied the functional impact of four de novo DEE-associated CACNA1A mutations, including the previously described p.A713T variant and three novel variants (p.V1396M, p.G230V, and p.I1357S). Mutant cDNAs were expressed in HEK293 cells, and whole-cell voltage-clamp recordings were conducted to test the impacts on CaV 2.1 channel function. Channel localization and structure were assessed with immunofluorescence microscopy and three-dimensional (3D) modeling.RESULTS: We find that the G230V and I1357S mutations result in loss-of-function effects with reduced whole-cell current densities and decreased channel expression at the cell membrane. By contrast, the A713T and V1396M variants resulted in gain-of-function effects with increased whole-cell currents and facilitated current activation (hyperpolarized shift). The A713T variant also resulted in slower current decay. 3D modeling predicts conformational changes favoring channel opening for A713T and V1396M.SIGNIFICANCE: Our findings suggest that both gain-of-function and loss-of-function CACNA1A mutations are associated with similarly severe DEEs and that functional validation is required to clarify the underlying molecular mechanisms and to guide therapies.", "BACKGROUND AND OBJECTIVES: Atemoya (Annona atemoya) is increasingly being consumed worldwide because of its pleasant taste. However, only limited information is available concerning possible atemoya-drug interactions. In the present study, the issue of whether atemoya shows food-drug interactions with substrate drugs of the major drug-metabolizing cytochrome P450s (i.e., CYP1A2, CYP2C9, and CYP3A) is addressed.METHODS: The ability of atemoya juice to inhibit the activities of phenacetin O-deethylase (CYP1A2), diclofenac 4'-hydroxylase (CYP2C9), and midazolam 1'-hydroxylase (CYP3A) was examined in vitro using human and rat liver microsomes. The in vivo pharmacokinetics of phenacetin and metabolites derived from it in rats when atemoya juice or fluvoxamine (a CYP1A2 inhibitor) was preadministered were also investigated.RESULTS: Atemoya juice significantly inhibited CYP1A2 activity in human liver microsomes, but not the activities of CYP2C9 and CYP3A. In spite of this inhibition, preadministration of atemoya had no effect on the pharmacokinetics of phenacetin, a CYP1A2 substrate, in rats. Meanwhile, preadministration of fluvoxamine significantly extended the time needed for the elimination of phenacetin, possibly due to the inhibition of CYP1A2. This suggests that the intake of an excess amount of atemoya juice is necessary to cause a change in the pharmacokinetics of phenacetin when the IC50 values for CYP1A2 inhibition by atemoya and fluvoxamine are taken into account.CONCLUSION: The results indicate that a daily intake of atemoya would not change the pharmacokinetics of CYP1A2 substrates such as phenacetin as well as CYP2C9- and CYP3A-substrate drugs.", "Charophytes is a green algal group closely related to land plants. We investigated the effects of antibiotics that interfere with peptidoglycan biosynthesis on chloroplast division in the desmid Closterium peracerosum-strigosum-littorale complex. To detect cells just after division, we used colchicine, which inhibits Closterium cell elongation after division. Although normal Closterium cells had two chloroplasts before and after cell division, cells treated with ampicillin, D-cycloserine, or fosfomycin had only one chloroplast after cell division, suggesting that the cells divided without chloroplast division. The antibiotics bacitracin and vancomycin showed no obvious effect. Electron microscopic observation showed that irregular-shaped chloroplasts existed in ampicillin-treated Closterium cells. Because antibiotic treatments resulted in the appearance of long cells with irregular chloroplasts and cell death, we counted cell types in the culture. The results suggested that cells with one chloroplast appeared first and then a huge chloroplast was generated that inhibited cell division, causing elongation followed by cell death.", "Diphtheria toxin and exotoxin A are well-characterized members of the ADP-ribosyltransferase toxin family that function as virulence factors in the pathogenic bacteria Corynebacterium diphtheriae and Pseudomonas aeruginosa. Recent high-resolution structural data of the Michaelis (enzyme-substrate) complex of the P. aeruginosa toxin with an NAD(+) analog and eukaryotic elongation factor 2 (eEF2) have provided insights into the mechanism of inactivation of protein synthesis caused by these protein factors. In addition, rigorous steady-state and stopped-flow kinetic analyses of the toxin-catalyzed reaction, in combination with inhibitor studies, have resulted in a quantum leap in our understanding of the mechanistic details of this deadly enzyme mechanism. It is now apparent that these toxins use stealth and molecular mimicry in unleashing their toxic strategy in the infected host eukaryotic cell." ]

[ "INTRODUCTION: Koebner phenomenon in psoriasis presents development of psoriatic lesions, after injury of uninvolved skin, which are identical in morphology with the previous trauma. The aim of this study was to establish the correlation of Koebner phenomenon with sex and age distribution, clinical variants of psoriasis vulgaris, age of onset and incidence in psoriasis among relatives of affected patients.MATERIAL AND METHODS: Sixty patients, with severe clinical picture, participated in this study: 38 patients in acute flare of a chronic form; 10 with acute exanthematic form; 8 with a chronic stable form; 3 with psoriatic changes on palms and soles and one patient with psoriatic erythroderma. According to the presence of Koebner phenomenon they were divided in two groups, one with positive and the other with negative Koebner phenomenon which presented the control group at the same time.RESULTS AND DISCUSSION: The Koebner reaction is often thought to be more frequent in actively spreading, severe psoriasis. Although this may be true, it has to be established by prospective studies. According to our investigation, Koebner phenomenon did not depend on clinical picture of psoriasis vulgaris. This reaction also appears to be a marker for a subgroup of patients with a tendency to early onset, but that was not confirmed by our study. In available literature we did not find any data about relations of Koebner phenomenon to sex and age or familiar incidence of psoriasis vulgaris. Our results demonstrated no connection of Koebner phenomenon with sex and age structure. At the same time its presence did not depend on familiar incidence of psoriasis vulgaris.CONCLUSIONS: There is no relationship between Koebner phenomenon and sex and age distribution. It does not depend on clinical picture and also does not predict the age of onset and familiar incidence of psoriasis vulgaris.", "Author information:(1)Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. cousin.margot@mayo.edu.(2)Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA. cousin.margot@mayo.edu.(3)Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.(4)Department of Pediatrics, Duke University Medical Center, Duke University, Durham, NC, USA.(5)GeneDx, Gaithersburg, MD, USA.(6)Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA.(7)Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.(8)Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.(9)Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.(10)Human Pluripotent Stem Cell Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.(11)Department of Pathology, Yale University, New Haven, CT, USA.(12)Department of Neurology, Columbia University, New York, NY, USA.(13)Institute for Genomic Medicine, Columbia University, New York, NY, USA.(14)Laboratory of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.(15)Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.(16)Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.(17)McMaster University, Hamilton, Ontario, Canada.(18)Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.(19)Spectrum Health Medical Genetics, Grand Rapids, MI, USA.(20)Division of Neurology, Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.(21)The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.(22)Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA.(23)Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.(24)Genetics, Driscoll Children's Hospital, Corpus Christi, TX, USA.(25)Service de Génétique Médicale, CHU Nantes, Nantes, France.(26)Université de Nantes, CNRS, INSERM, L'Institut du Thorax, Nantes, France.(27)William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK.(28)Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, UK.(29)Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.(30)Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.(31)Neuropediatrics, Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.(32)Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.(33)Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.(34)Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.(35)Nicklaus Children's Hospital, Miami, FL, USA.(36)Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.(37)Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.(38)Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.(39)Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.(40)Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.(41)Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.(42)Divisions of Clinical/Metabolic Genetics and Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.(43)Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.(44)Institute of Human Genetics, Technical University of Munich, Munich, Germany.(45)Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.(46)Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.(47)Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.(48)Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.(49)Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.(50)Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.(51)Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, USA.(52)Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.(53)Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. damaris_lorenzo@med.unc.edu.(54)Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. damaris_lorenzo@med.unc.edu.(55)Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. damaris_lorenzo@med.unc.edu.(#)Contributed equally", "Recent advances in pathophysiological and genetic mechanisms of some neuromuscular diseases and a rapid progress in new pharmacological technologies led to an accelerated development of innovative treatments, generating an unexpected therapeutic revolution. In part 1, we report already commercially available drugs, just approved drugs and new therapeutic promises in the treatment of peripheral neuropathies. Hereditary transthyretin amyloidosis (hATTR) is a devastating disease due to amyloid accumulation in peripheral nerves, heart and autonomic system. The first specific drug approved for hATTR was tafamidis, a TTR tetramer stabilizer. In 2018, the positive results of two phase 3 trials have been reported leading to start of regulatory approval route for inotersen, an antisense oligonucleotide and patisiran, the first-ever RNA interference (RNAi) therapeutic. System biology targeting approach has indicated baclofen, naltrexone and sorbitol in combination (PXT3003) as candidate drugs for Charcot-Marie-Tooth disease type 1A. This hypothesis was confirmed in experimental models and in phase 2 and 3 clinical trials. Givosiran, another RNAi therapeutic, targeting 5-aminolevulinic acid synthase, has been positively tested in acute intermittent porphyria in phase 1/2 and ongoing phase 3 trials. Although allogenic hematopoietic stem cell transplantation resulted recently a long-term therapy in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a new strategy is liver transplantation which is able to revert the severe biochemical and clinical imbalance of the disease. Recently, a gene therapy has been tested in a MNGIE murine model, indicating that it may become a new therapeutic option.", "Huntington's disease (HD) is an incurable, fatal neurodegenerative disorder that is caused by a polyglutamine expansion in the huntingtin (Htt) protein. Neuronal death in the striatum-the most obvious manifestation of the disease-is likely to result from widespread dysregulation of gene expression in various brain regions. To date, several potential mechanisms for this have been discovered, including one involving REST (RE1-Silencing Transcription Factor), a master regulator of neuronal genes. Recently, independent studies have demonstrated that post-transcriptional gene regulation by microRNAs is also disrupted in HD. Expression of key neuronal microRNAs-including mir-9/9*, mir-124 and mir-132-is repressed in the brains of human HD patients and mouse models. These changes occur downstream of REST, and are likely to result in major disruption of mRNA regulation and neuronal function. In this study we will discuss these findings and their implications for our understanding of HD. Using updated bioinformatic analysis, we predict 21 new candidate microRNAs in HD. We propose future strategies for unifying large-scale transcriptional and microRNA datasets with the aim of explaining HD aetiology. By way of example, we show how available genomic datasets can be integrated to provide independent, analytical validation for dysregulation of REST and microRNA mir-124 in HD. As a consequence, gene ontology analysis indicates that HD is characterised by a broad-based depression of neural genes in the caudate and motor cortex. Thus, we propose that a combination of REST, microRNAs and possibly other non-coding RNAs profoundly affect the neuronal transcriptome in HD.", "Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.", "Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited, genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals. Most mutations affect either the triple-helical domain of the protein or the expression of one COL5A1 allele. We identified a novel splice-acceptor mutation (IVS4-2A-->G) in the N-propeptide-encoding region of COL5A1, in one patient with EDS type I. The outcome of this mutation was complex: In the major product, both exons 5 and 6 were skipped; other products included a small amount in which only exon 5 was skipped and an even smaller amount in which cryptic acceptor sites within exon 5 were used. All products were in frame. Pro-alpha1(V) chains with abnormal N-propeptides were secreted and were incorporated into extracellular matrix, and the mutation resulted in dramatic alterations in collagen fibril structure. The two-exon skip occurred in transcripts in which intron 5 was removed rapidly relative to introns 4 and 6, leaving a large (270 nt) composite exon that can be skipped in its entirety. The transcripts in which only exon 5 was skipped were derived from those in which intron 6 was removed prior to intron 5. The use of cryptic acceptor sites in exon 5 occurred in transcripts in which intron 4 was removed subsequent to introns 5 and 6. These findings suggest that the order of intron removal plays an important role in the outcome of splice-site mutations and provide a model that explains why multiple products derive from a mutation at a single splice site.", "RNA-binding proteins CUG-binding protein 1 (CUGBP1) and HuR are highly expressed in epithelial tissues and modulate the stability and translation of target mRNAs. Here we present evidence that CUGBP1 and HuR jointly regulate the translation of occludin and play a crucial role in the maintenance of tight junction (TJ) integrity in the intestinal epithelial cell monolayer. CUGBP1 and HuR competed for association with the same occludin 3'-untranslated region element and regulated occludin translation competitively and in opposite directions. CUGBP1 overexpression decreased HuR binding to occludin mRNA, repressed occludin translation, and compromised the TJ barrier function, whereas HuR overexpression inhibited CUGBP1 association with occludin mRNA and promoted occludin translation, thereby enhancing the barrier integrity. Repression of occludin translation by CUGBP1 was due to the colocalization of CUGBP1 and tagged occludin RNA in processing bodies (P-bodies), and this colocalization was prevented by HuR overexpression. These findings indicate that CUGBP1 represses occludin translation by increasing occludin mRNA recruitment to P-bodies, whereas HuR promotes occludin translation by blocking occludin mRNA translocation to P-bodies via the displacement of CUGBP1." ]

[ "Selenoprotein P (SeP) is an extracellular glycoprotein with 8-10 selenocysteines per molecule, containing approximately 50% of total selenium in human serum. An antioxidant function of SeP has been postulated. In the present study, we show that SeP protects low-density lipoproteins (LDL) against oxidation in a cell-free in-vitro system. LDL were isolated from human blood plasma and oxidized with CuCl2, 2,2'-azobis(2-amidinopropane) (AAPH) or peroxynitrite in the presence or absence of SeP, using the formation of conjugated dienes as parameter for lipid peroxidation. SeP delayed the CuCl2- and AAPH-induced LDL oxidation significantly and more efficiently than bovine serum albumin used as control. In contrast, SeP was not capable of inhibiting peroxynitrite-induced LDL oxidation. The protection of LDL against CuCl2- and AAPH-induced oxidation provides evidence for the antioxidant capacity of SeP. Because SeP associates with endothelial membranes, it may act in vivo as a protective factor inhibiting the oxidation of LDL by reactive oxygen species.", "A relationship between sport or fitness activities and urinary incontinence (UI) previously has been described in women. We report our preliminary experience with the use of a complete pelvic floor rehabilitation program in three female athletes affected by UI. The athletes were submitted to a combined pelvic floor rehabilitation program, including biofeedback, functional electrical stimulation, pelvic floor muscle exercises, and vaginal cones. After the scheduled rehabilitation scheme, none of the patients reported incontinence, nor referred to urine leakage during sport or during daily life. We therefore conclude that UI that affects female agonistic athletes may be effectively treated with this combined approach.", "Unipept is an open source web application that is designed for metaproteomics analysis with a focus on interactive datavisualization. It is underpinned by a fast index built from UniProtKB and the NCBI taxonomy that enables quick retrieval of all UniProt entries in which a given tryptic peptide occurs. Unipept version 2.4 introduced web services that provide programmatic access to the metaproteomics analysis features. This enables integration of Unipept functionality in custom applications and data processing pipelines.AVAILABILITY AND IMPLEMENTATION: The web services are freely available at http://api.unipept.ugent.be and are open sourced under the MIT license.CONTACT: Unipept@ugent.beSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "BACKGROUND: The reported prevalence of Alport syndrome varies from one in 5000 to one in 53,000 individuals. This study estimated the frequencies of predicted pathogenic COL4A3-COL4A5 variants in sequencing databases of populations without known kidney disease.METHODS: Predicted pathogenic variants were identified using filtering steps based on the ACMG/AMP criteria, which considered collagen IV α3-α5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic COL4A3-COL4A5 variants were then determined per mean number of sequenced alleles. Population frequencies for compound heterozygous and digenic combinations were calculated from the results for heterozygous variants.RESULTS: COL4A3-COL4A5 variants resulting in position 1 Gly substitutions were confirmed to be associated with hematuria (for each, P<0.001). Predicted pathogenic COL4A5 variants were found in at least one in 2320 individuals. p.(Gly624Asp) represented nearly half (16 of 33, 48%) of the variants in Europeans. Most COL4A5 variants (54 of 59, 92%) had a biochemical feature that potentially mitigated the clinical effect. The predicted pathogenic heterozygous COL4A3 and COL4A4 variants affected one in 106 of the population, consistent with the finding of thin basement membrane nephropathy in normal donor kidney biopsy specimens. Predicted pathogenic compound heterozygous variants occurred in one in 88,866 individuals, and digenic variants in at least one in 44,793.CONCLUSIONS: The population frequencies for Alport syndrome are suggested by the frequencies of predicted pathogenic COL4A3-COL4A5 variants, but must be adjusted for the disease penetrance of individual variants and for the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.", "The DNA damage response encompasses a complex series of signaling pathways that function to regulate and facilitate the repair of damaged DNA. Recent studies have shown that the repair of transcriptionally inactive chromatin, named heterochromatin, is dependent upon the phosphorylation of the co-repressor, Krüppel-associated box (KRAB) domain-associated protein (KAP-1), by the ataxia telangiectasia-mutated (ATM) kinase. Co-repressors, such as KAP-1, function to regulate the rigid structure of heterochromatin by recruiting histone-modifying enzymes, such HDAC1/2, SETDB1, and nucleosome-remodeling complexes such as CHD3. Here, we have characterized a phosphorylation site in the HP1-binding domain of KAP-1, Ser-473, which is phosphorylated by the cell cycle checkpoint kinase Chk2. Expression of a nonphosphorylatable S473A mutant conferred cellular sensitivity to DNA-damaging agents and led to defective repair of DNA double-strand breaks in heterochromatin. In addition, cells expressing S473A also displayed defective mobilization of the HP1-β chromodomain protein. The DNA repair defect observed in cells expressing S473A was alleviated by depletion of HP1-β, suggesting that phosphorylation of KAP-1 on Ser-473 promotes the mobilization of HP1-β from heterochromatin and subsequent DNA repair. These results suggest a novel mechanism of KAP-1-mediated chromatin restructuring via Chk2-regulated HP1-β exchange from heterochromatin, promoting DNA repair.", "Lon1 is an ATP-dependent protease and chaperone located in the mitochondrial matrix in plants. Knockout in Arabidopsis (Arabidopsis thaliana) leads to a significant growth rate deficit in both roots and shoots and lowered activity of specific mitochondrial enzymes associated with respiratory metabolism. Analysis of the mitochondrial proteomes of two lon1 mutant alleles (lon1-1 and lon1-2) with different severities of phenotypes shows a common accumulation of several stress marker chaperones and lowered abundance of Complexes I, IV, and V of OXPHOS. Certain enzymes of the tricarboxylic acid (TCA) cycle are modified or accumulated, and TCA cycle bypasses were repressed rather than induced. While whole tissue respiratory rates were unaltered in roots and shoots, TCA cycle intermediate organic acids were depleted in leaf extracts in the day in lon1-1 and in both lon mutants at night. No significant evidence of broad steady-state oxidative damage to isolated mitochondrial samples could be found, but peptides from several specific proteins were more oxidized and selected functions were more debilitated in lon1-1. Collectively, the evidence suggests that loss of Lon1 significantly modifies respiratory function and plant performance by small but broad alterations in the mitochondrial proteome gained by subtly changing steady-state protein assembly, stability, and damage of a range of components that debilitate an anaplerotic role for mitochondria in cellular carbon metabolism.", "A retrospective study was conducted on patients with burning mouth syndrome (BMS) to assess demographics, onset characteristics, temporal behavior (frequency), duration, and progression of oral burning symptoms. Additionally, treatments provided by health practitioners prior to a definitive diagnosis of BMS were analyzed with an overview of current management strategies. The records of 49 adult patients diagnosed with BMS were reviewed. Descriptive statistics and a Pearson correlation with a statistical significance at p < 0.05 were utilized to analyze the data. The majority of patients were mid-life white women who reported a sudden onset of constant oral burning symptoms that increased in intensity. On average, patients reported oral burning symptoms for 41 months (standard deviation = 73.5, range = 2-360 months, median = 20 months), and 38 of the patients received/trialed 71 various interventions (mean = 1.9) prior to receiving a definitive diagnosis for their oral burning symptoms. This study sample shared many characteristics with those reported previously in the literature. The authors found that patients frequently reported delays in receiving a definitive diagnosis with an array of various trialed interventions. For this reason, the authors provide this overview of current management strategies in order to assist dental practitioners in providing appropriate interventions for patients with BMS.", "Massively parallel sequencing identifies pathogenic variants in the genes affected in Alport syndrome (COL4A3-COL4A5) in as many as 30% of individuals with focal and segmental glomerulosclerosis (FSGS), 10% of those with kidney failure of unknown cause, and 20% with familial immunoglobulin A (IgA) glomerulonephritis. FSGS associated with COL4A3-COL4A5 variants is usually present by the onset of kidney failure and may develop because the abnormal glomerular membranes result in podocyte loss and secondary hyperfiltration. The association of COL4A3-COL4A5 variants with kidney failure or IgA glomerulonephritis may be coincidental. However, pathogenic variants in these conditions occur more often than they should by chance, which suggests that the variants are disease-causing. COL4A3-COL4A5 variants are also found in cystic kidney diseases after autosomal dominant polycystic kidney disease has been excluded. COL4A3-COL4A5 variants should be suspected in individuals with FSGS, kidney failure of unknown cause, or familial IgA glomerulonephritis, especially where there is persistent hematuria and a family history of hematuria or kidney failure." ]

[ "Bergapten is a natural furocoumarin, also known as 5-methoxypsoralen, and its medicinal value has been paid more and more attention. By sorting out the pharmacological literature of bergapten, we found that bergapten has a wide range of pharmacological effects, including neuroprotection, organ protection, anticancer, antiinflammatory, antimicrobial, and antidiabetes effects. However，bergapten has complex impacts on the hepatic metabolic enzyme. Moreover, pharmacokinetic studies showed that bergapten has higher absolute bioavailability and can cross the blood-brain barrier and has a great potential for treating brain disease, but the mechanism needs further clarification to make greater use of its ability to treat brain diseases. Furthermore, the phototoxicity of bergapten combined with ultraviolet light has always been mentioned. In view of its wide range of pharmacological activities, bergapten is expected to be a potential drug candidate for the treatment of diabetes and diabetes-induced osteoporosis, epilepsy, Alzheimer's disease, depression, and cancer. However, further studies are needed to elucidate its molecular mechanisms and targets. The phototoxicity of bergapten as a side effect should be further avoided. On the other hand, the photoactivation of bergapten in the anticancer aspect can be better utilized.", "Medical ethics generally applies to individual interactions between physicians and patients. Conversely, public health ethics typically applies to interactions between an agency or institution and a community or population. Four main principles underlie medical ethics: autonomy, nonmaleficence, beneficence, and justice. By contrast, public health ethical principles address issues such as interdependence, community trust, fundamentality, and justice. In large part because of the significant community-level effects of public health issues, medical ethics are suboptimal for assessing community-level public health interventions or plans-especially in the area of emergency preparedness. To be effective, as well as ethical, public health preparedness efforts must address all of the core principles of public health ethics.", "Appendix-containing inguinal hernias are known as Amyand hernias. Traditionally, these hernias have been diagnosed at surgery but are increasingly diagnosed on abdominal computed tomography scans. The classification of Amyand hernias determines their subsequent surgical management; as such, it is important for the radiologist to be familiar with the appearances of the subtypes of Amyand hernias.", "Eukaryotic cells have evolved a variety of parallel and redundant DNA damage response pathways that function in a coordinated fashion to prevent the fixation of DNA damage as mutations. Despite the wealth of knowledge on DNA damage signaling on downstream cellular events, the mechanisms of DNA damage recognition, DNA repair as well as DNA damage signaling in the context of chromatin is poorly understood. Chromodomain helicase DNA-binding proteins (CHD) belong to a group of highly conserved chromatin remodeling proteins that are implicated in regulation of transcription. In an effort to understand the physiological role of one of the CHD members in a mammalian model system, we developed a mutant mouse model for the Chd2 gene. The Chd2 mutant mice are highly susceptible to spontaneous lymphoid tumor formation. In this study, we present evidence that the Chd2 mutant cells are defective in their ability to repair DNA damage induced by ionizing and ultraviolet radiation. Consistent with the role of Chd2 in regulating DNA damage responses, the Chd2 mutant cells are also sensitive to DNA damaging agents in clonogenic assays. In summary, our data suggest that the Chd2 protein is involved in regulating the DNA damage responses at the chromatin level.", "The relation between urinary albumin excretion rate (UAE), transcapillary escape rate of albumin (TERalb), haemostatic factors, ambulatory blood pressure, and metabolic variables was investigated in 45 Type II (non-insulin-dependent) diabetic patients without overt nephropathy or uncontrolled blood pressure. We enrolled 44 patients in a placebo controlled study to test the effects of 3 week long treatment with low-molecular weight heparin (tinzaparin) on the same variables. BMI, 24 h systolic and diastolic blood pressure, plasma concentrations of triglycerides, fasting glucose, factor VIII, von Willebrand factor (vWf), fibrinogen, alpha-2 macroglobulin, and fibronectin were notably higher in patients with increased albuminuria compared with normoalbuminuric patients, whereas the TERalb was similar in the two groups. TERalb correlated with fasting plasma glucose. UAE correlated more closely than TERalb with 24 h ambulatory blood pressure, vWf, and factor VIII. Urinary albumin excretion rate was unchanged during tinzaparin [28.9+/-5.6 vs 28.1+/-6.0 microg/min (geometric mean (antilog SD)] vs placebo (18.0+/-5.4 vs 17.6+/-5.3 microg/min), and no change was found in TERalb [6.3+/-1.6 vs 6.0+/-1.5%/h (means +/- SD), and 6.3+/-1.5 vs 5.6+/-1.8%/h; tinzaparin versus placebo, respectively]. Only minor changes were observed in blood pressure, lipids, glycaemic control and haemostatic factors. This study shows no correlation between albuminuria and transcapillary escape rate in Type II diabetic patients without overt nephropathy or uncontrolled-blood pressure. UAE is related to markers of atherosclerosis, endothelial injury and dysfunction, and haemostatic factors. Moreover, UAE correlates much more than TERalb with 24 h ambulatory blood pressure, von Willebrand factor, and factor VIII. Finally, short-term treatment with tinzaparin does not change the transvascular or glomerular leakage of albumin. These results indicate that TERalb is not a sensitive marker of microvascular dysfunction in such patients and that factors other than abnormal glycosaminoglycan metabolism may contribute to the vascular damage of these patients.", "Author information:(1)Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.(2)McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada H3A 0G1.(3)Research Center for Genetic Medicine, Children's National Health System, Washington, District Of Columbia 20010, USA.(4)Institute for Biomedical Sciences, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.(5)Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, Québec, Canada H4A 3J1.(6)Division of Pathology, Children's National Health System, Washington, District Of Columbia 20010, USA.(7)Center for Cancer and Blood Disorders, Children's National Health System, Washington, District Of Columbia 20010, USA.(8)The Department of Neurological Surgery, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.(9)Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusett 02115, USA.(10)Department of Pathology, CHU Ste-Justine, Université de Montréal, Montreal, Québec, Canada H3T 1C5.(11)UQ Child Health Research Centre, The University of Queensland, Brisbane, Queensland 4101, Australia.(12)University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland 4102, Australia.(13)Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland 4101, Australia.(14)National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892, USA.(15)Department of Pathology, Montreal Neurological Hospital, McGill University, Montreal, Québec, Canada H3A 2B4.(16)Brain Tumour Institute, Center for Neuroscience and Behavioral Medicine, Children's National Health System, Washington, District Of Columbia, 20010, USA.(17)Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.", "Background. Thalamotomy is effective in alleviating tremor in Parkinson's disease (PD). Methods. Seven PD patients, mean age 59.4 ± 9.8 years (range, 46-74) with a mean disease duration of 5.4 ± 2.8 years (range, 2-10) suffering from severe refractory tremor, underwent ventral intermediate nucleus thalamotomy using MRI guided focused ultrasound (MRgFUS), an innovative technology that enables noninvasive surgery. Results. Tremor stopped in the contralateral upper extremity in all patients immediately following treatment. Total UPDRS decreased from 37.4 ± 12.2 to 18.8 ± 11.1 (p = 0.007) and PDQ-39 decreased from 42.3 ± 16.4 to 21.6 ± 10.8 (p = 0.008) following MRgFUS. These effects were sustained (mean follow-up 7.3 months). Adverse events during MRgFUS included headache (n = 3), dizziness (n = 2), vertigo (n = 4), and lip paresthesia (n = 1) and following MRgFUS were hypogeusia (n = 1), unsteady feeling when walking (n = 1, resolved), and disturbance when walking tandem (n = 1, resolved). Conclusions. Thalamotomy using MRgFUS is safe and effective in PD patients. Large randomized studies are needed to assess prolonged efficacy and safety." ]

[ "The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.", "SET domain genes have been identified in numbers of bacterial genomes based on similarity to SET domains of eukaryotic histone methyltransferases. Herein, a Chlamydophila pneumoniae SET domain gene was clarified to be coincidently expressed with hctA and hctB genes encoding chlamydial histone H1-like proteins, Hc1 and Hc2, respectively. The SET domain protein (cpnSET) is localized in chlamydial cells and interacts with Hc1 and Hc2 through the C-terminal SET domain. As expected from conservation of catalytic sites in cpnSET, it functions as a protein methyltransferase to murine histone H3 and Hc1. However, little is known about protein methylation in the molecular pathogenesis of chlamydial infection. cpnSET may play an important role in chlamydial cell maturation due to modification of chlamydial histone H1-like proteins.", "Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is crucial for both mitochondrial function and cellular processes outside of the mitochondria. The importance of CL in cardiovascular health is underscored by the life-threatening genetic disorder Barth syndrome (BTHS), which manifests clinically as cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation. BTHS is caused by mutations in the gene encoding tafazzin, the transacylase that carries out the second CL remodeling step. In addition to BTHS, CL is linked to other cardiovascular diseases (CVDs), including cardiomyopathy, atherosclerosis, myocardial ischemia-reperfusion injury, heart failure, and Tangier disease. The link between CL and CVD may possibly be explained by the physiological roles of CL in pathways that are cardioprotective, including mitochondrial bioenergetics, autophagy/mitophagy, and mitogen activated protein kinase (MAPK) pathways. In this review, we focus on the role of CL in the pathogenesis of CVD as well as the molecular mechanisms that may link CL functions to cardiovascular health.", "Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.", "The eukaryotic replisome is rapidly disassembled during DNA replication termination. In metazoa, the cullin-RING ubiquitin ligase CUL-2LRR-1 drives ubiquitylation of the CMG helicase, leading to replisome disassembly by the p97/CDC-48 \"unfoldase\". Here, we combine in vitro reconstitution with in vivo studies in Caenorhabditis elegans embryos, to show that the replisome-associated TIMELESS-TIPIN complex is required for CUL-2LRR-1 recruitment and efficient CMG helicase ubiquitylation. Aided by TIMELESS-TIPIN, CUL-2LRR-1 directs a suite of ubiquitylation enzymes to ubiquitylate the MCM-7 subunit of CMG. Subsequently, the UBXN-3 adaptor protein directly stimulates the disassembly of ubiquitylated CMG by CDC-48_UFD-1_NPL-4. We show that UBXN-3 is important in vivo for replisome disassembly in the absence of TIMELESS-TIPIN. Correspondingly, co-depletion of UBXN-3 and TIMELESS causes profound synthetic lethality. Since the human orthologue of UBXN-3, FAF1, is a candidate tumour suppressor, these findings suggest that manipulation of CMG disassembly might be applicable to future strategies for treating human cancer.", "Parent-of-origin-specific expression at imprinted genes is regulated by allele-specific DNA methylation at imprinting control regions (ICRs). This mechanism of gene regulation, where one element controls allelic expression of multiple genes, is not fully understood. Furthermore, the mechanism of gene dysregulation through ICR epimutations, such as loss or gain of DNA methylation, remains a mystery. We have used genetic mouse models to dissect ICR-mediated genetic and epigenetic regulation of imprinted gene expression. The H19/insulin-like growth factor 2 (Igf2) ICR has a multifunctional role including insulation, activation and repression. Microdeletions at the human H19/IGF2 ICR (IC1) are proposed to be responsible for IC1 epimutations associated with imprinting disorders such as Beckwith-Wiedemann syndrome (BWS). Here, we have generated and characterized a mouse model that mimics BWS microdeletions to define the role of the deleted sequence in establishing and maintaining epigenetic marks and imprinted expression at the H19/IGF2 locus. These mice carry a 1.3 kb deletion at the H19/Igf2 ICR [Δ2,3] removing two of four CCCTC-binding factor (CTCF) sites and the intervening sequence, ∼75% of the ICR. Surprisingly, the Δ2,3 deletion does not perturb DNA methylation at the ICR; however, it does disrupt imprinted expression. While repressive functions of the ICR are compromised by the deletion regardless of tissue type, insulator function is only disrupted in tissues of mesodermal origin where a significant amount of CTCF is poly(ADP-ribosyl)ated. These findings suggest that insulator activity of the H19/Igf2 ICR varies by cell type and may depend on cell-specific enhancers as well as posttranslational modifications of the insulator protein CTCF.", "Author information:(1)1] CGAT Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK [2].(2)1] Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, BA2 7AY Bath, UK [2].(3)Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, BA2 7AY Bath, UK.(4)Respiratory Research Group, University Hospital of South Manchester, University of Manchester, Southmoor Road, Manchester M23 9LY, UK.(5)Airways Disease, National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.(6)Department of Functional and Comparative Genomics, Centre for Genomic Research, University of Liverpool, Liverpool L69 3BX, UK.(7)CGAT Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK.(8)1] Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, BA2 7AY Bath, UK [2] Respiratory Research Group, University Hospital of South Manchester, University of Manchester, Southmoor Road, Manchester M23 9LY, UK [3] Airways Disease, National Heart and Lung Institute, Imperial College, London SW3 6LY, UK." ]

[ "Human toxocariasis which is caused mainly by the larvae of Toxocara canis and Toxocara cati, is a worldwide zoonotic disease that can be a potentially serious human infection. The enzyme-linked immunosorbent assay (ELISA) using T. canis excretory-secretory (TES) antigens harvested from T. canis larvae is currently the serological test for confirming toxocariasis. An alternative to producing large amounts of Toxocara TES and improved diagnosis for toxocariasis is through the development of highly specific recombinant antigens such as the T. canis second stage larva excretory-secretory 30 kDa protein (recTES-30). The aim of this study was to evaluate the sensitivity and specificity of a rapid diagnostic kit (RDT, named as iToxocara kit) in comparison to recTES-30 ELISA in Serendah Orang Asli village in Selangor, Malaysia. A total of 133 subjects were included in the study. The overall prevalence rates by ELISA and RDT were 29.3% and 33.1%, respectively, with more positive cases detected in males than females. However, no association was found between toxocariasis and gender or age. The percentage sensitivity, specificity, positive predictive value and negative predictive value of RDT were 85.7%, 90.1%, 80% and 93.2%, respectively. The prevalence for toxocariasis in this population using both ELISA and RDT was 27.1% (36/133) and the K-concordance test suggested good agreement of the two tests with a Cohen's kappa of 0.722, P<0.01. In addition, the followed-up Spearman rank correlation showed a moderately high correlation at R=0.704 and P<0.01. In conclusion, the RDT kit was faster and easier to use than an ELISA and is useful for the laboratory diagnosis of hospitalized cases of toxocariasis.", "Nucleosomes, the basic organizational units of chromatin, package and regulate eukaryotic genomes. ATP-dependent nucleosome-remodeling factors endow chromatin with structural flexibility by promoting assembly or disruption of nucleosomes and the exchange of histone variants. Furthermore, most remodeling factors induce nucleosome movements through sliding of histone octamers on DNA. We summarize recent progress toward unraveling the basic nucleosome sliding mechanism and the interplay of the remodelers' DNA translocases with accessory domains. Such domains optimize and regulate the basic sliding reaction and exploit sliding to achieve diverse structural effects, such as nucleosome positioning or eviction, or the regular spacing of nucleosomes in chromatin.", "Transcriptional silencing is known to occur at centromeres, telomeres and the mating type region in the nucleus of fission yeast, Schizosaccharomyces pombe. Mating-type silencing factors have previously been shown also to affect transcriptional repression within centromeres and to some extent at telomeres. Mutations in the clr4+, rik1+ and swi6+ genes dramatically reduce silencing at certain centromeric regions and cause elevated chromosome loss rates. Recently, Swi6p was found to co-localise with the three silent chromosomal regions. Here the involvement of clr4+, rik1+ and swi6+ in centromere function is investigated in further detail. Fluorescence in situ hybridisation (FISH) was used to show that, as in swi6 mutant cells, centromeres lag on late anaphase spindles in clr4 and rik1 mutant cells. This phenotype is consistent with a role for these three gene products in fission yeast centromere function. The Swi6 protein was found to be delocalised from all three silent chromosomal regions, and dispersed within the nucleus, in both clr4 and rik1 mutant cells. The phenotypic similarity observed in all three mutants is consistent with the products of both the clr4+ and rik1+ genes being required to recruit Swi6p to the centromere and other silent regions. Mutations in clr4, rik1 and swi6 also result in elevated sensitivity to reagents which destabilise microtubules and show a synergistic interaction with a mutation in the beta-tubulin gene (nda3). These observations suggest that clr4+ and rik1+ must play a role in the assembly of Swi6p into a transcriptionally silent, inaccessible chromatin structure at fission yeast centromeres which is required to facilitate interactions with spindle microtubules and to ensure normal chromosome segregation.", "WHAT IS KNOWN: Treprostinil diolamine (oral treprostinil) is a prostacyclin analogue currently being evaluated for the treatment of pulmonary arterial hypertension as a sustained-release (SR) oral tablet. Previous data have demonstrated that the oral bioavailability of treprostinil was improved when taken with a meal containing at least 500 calories.OBJECTIVE: As twice-daily intake of a high-fat, high-calorie meal may be undesirable or not feasible for some patients, this open-label, randomized, crossover study evaluated the effect of different meal compositions [a 500-calorie well-balanced meal (WB500), a 250-calorie well-balanced meal (WB250), a 250-calorie high-fat meal (HF250) and a 250-calorie well-balanced liquid meal (Ensure®)] on the relative bioavailability of oral treprostinil.METHODS: Thirty-two healthy volunteers were administered a single 1-mg SR tablet of oral treprostinil immediately following each study meal. Each dose of oral treprostinil was separated by a 7-day washout period. Serial plasma samples were obtained over a 36-h postdose. Safety was assessed in all patients who received study drug.RESULTS AND DISCUSSION: Treprostinil plasma exposure (Cmax and AUC0-inf) decreased only slightly, 5-15% with decreasing caloric and increasing fat content. Headache was the most commonly reported prostacyclin-related adverse event (three reports).WHAT IS NEW AND CONCLUSION: Overall, there were no clinically significant differences in the relative bioavailability of oral treprostinil when administered immediately after meals containing 250-500 calories and 30-50% fat. These data support the administration of oral treprostinil with a meal containing as few as 250 calories and 30-50% fat, which is significant for ensuring patient convenience and compliance, particularly as consistency with regard to meals may impact oral treprostinil pharmacokinetics.", "PD98059 is a reversible MEK inhibitor that we are investigating as a potential treatment for neurochemical changes in the brain that drive neurohumoral excitation in heart failure. In a rat model that closely resembles human heart failure, we found that central administration of PD98059 inhibits phosphorylation of ERK1/2 in the paraventricular nucleus of the hypothalamus, ultimately reducing sympathetic excitation which is a major contributor to clinical deterioration. Studies revealed that the pharmacokinetics and biodistribution of PD98059 match a two-compartment model, with drug found in brain as well as other body tissues, but with a short elimination half-life in plasma (approximately 73 min) that would severely limit its potential clinical usefulness in heart failure. To increase its availability to tissues, we prepared a sustained release PD98059-loaded PLGA microparticle formulation, using an emulsion solvent evaporation technique. The average particle size, yield percent, and encapsulation percent were found to be 16.73 μm, 76.6%, and 43%, respectively. In vitro drug release occurred over 4 weeks, with no noticeable burst release. Following subcutaneous injection of the microparticles in rats, steady plasma levels of PD98059 were detected by HPLC for up to 2 weeks. Furthermore, plasma and brain levels of PD98059 in rats with heart failure were detectable by LC/MS, despite expected erratic absorption. These findings suggest that PD98059-loaded microparticles hold promise as a novel therapeutic intervention countering sympathetic excitation in heart failure, and perhaps in other disease processes, including cancers, in which activated MAPK signaling is a significant contributing factor. Graphical abstract.", "Achondroplasia is a common form of human dwarfism with characteristically rhizomelic shortening of extremities and relative macrocephaly. It is transmitted as an autosomally dominant inheritance, and about 80% of affected individuals result from sporadic mutations without positive family histories. Achondroplasia comes from the genetic point mutations in the fibroblastic growth factor receptor 3 gene (FGFR3), which enables abnormal cartilage growth-plate differentiation and insufficient bony development. The most common genetic mutations in this receptor are G to A at position 1138 (G1138A), which result in the substitution of glycine to arginine at codon 380. Based on genetic information, molecular genetic testing can provide an exact diagnosis comparing to radiological and prenatal ultrasound evaluations. Here we introduce denaturing high-performance liquid chromatography (DHPLC) for the detection of 17 cases of achondroplasia and 120 unaffected cases. After coupling heteroduplex and fluorescence-enhanced primer-extension analysis, all affected patients with G1138A were identified successfully. In conclusion, we demonstrated that DHPLC is an efficient, accurate, and sensitive technique to detect the single gene mutation of achondroplasia in clinical applications.", "Hepcidin is a small liver-derived peptide central in the regulation of systemic iron homeostasis. Although the gene regulation has been extensively studied at transcriptional level, the corresponding effects on the production of bioactive peptide are largely unknown. We therefore applied a proteomics-based approach by combining immunocapture with time-of-flight mass spectrometry to characterize hepcidin-25 produced by hepatocyte-derived cell lines. Similar to its transcriptional regulation, mature hepcidin-25 was strongly secreted upon stimulation with BMPs and IL-6. The immunocaptured peptide down-modulated iron-exporter ferroportin on the monocyte/macrophage surface. Further mass spectrometry-based analyses indicated that hepcidin-25 in its bioactive conformation was very stable in serum and urine and not converted into its smaller isoforms. Hepcidin-25 was processed in the Golgi apparatus from its precursor, while the unprocessed prohepcidin was secreted only when furin-like protease activity was intracellularly inhibited. Furthermore, the amounts of hepatocytic secretion of hepcidin-25 are highly correlated with the gene transcript levels. An unexpected observation was the synergistic effect of BMPs and IL-6 on hepcidin-25 secretion, which points towards cross-talk between iron and inflammatory stimuli. The study underscores hepcidin-25 quantification as a valuable tool to unravel regulatory pathways in iron metabolism." ]

[ "Congenital myopathies are clinical and genetic heterogeneous disorders characterized by skeletal muscle weakness ranging in severity. Three major forms have been identified: actin myopathy, intranuclear rod myopathy, and nemaline myopathy. Nemaline myopathy is the most common of these myopathies and is further subdivided into seven groups according to severity, progressiveness, and age of onset. At present, five genes have been linked to congenital myopathies. These include alpha-actin (ACTA1), alpha- and beta-tropomyosin (TPM3 and TPM2), troponin T (TNNT1), and nebulin (NEB). Their protein products are all components of the thin filament of the sarcomere. The mutations identified within these genes have varying impacts on protein structure and give rise to different forms of congenital myopathies. Greater understanding of muscle formation and cause of disease can be established through the study of the effect of mutations on the functional proteins. However, a major limitation in the understanding of congenital myopathies is the lack of correlation between the degree of sarcomeric disruption and disease severity. Consequently, great difficulty may be encountered when diagnosing patients and predicting the progression of the disorders. There are no existing cures for congenital myopathies, although improvements can be made to both the standard of living and the life expectancy of the patient through various therapies.", "INTRODUCTION: A number of withdrawn drugs are known to undergo bioactivation by a range of drug metabolizing enzymes to chemically reactive metabolites that bind covalently to protein and DNA resulting in organ toxicity and carcinogenesis, respectively. An important goal in drug discovery is to identify structural sites of bioactivation within discovery molecules for providing strategic modifications that eliminate or minimize reactive metabolite formation, while maintaining target potency, selectivity and desired pharmacokinetic properties leading to the development of efficacious and nontoxic drugs.AREAS COVERED: This review covers experimental techniques currently used to detect reactive drug metabolites and provides recent examples where information from mechanistic in vitro studies was successfully used to redesign candidate drugs leading to blocked or minimized bioactivation. Reviewed techniques include in vitro radiolabeled drug covalent binding to protein and reactive metabolite trapping with reagents such as glutathione, cyanide, semicarbazide and DNA bases. Case studies regarding reactive metabolite detection using a combination of varied techniques, including liquid chromatography-tandem mass spectrometry and NMR analyses and subsequent structural modification are discussed.EXPERT OPINION: Information derived from state-of-art mechanistic drug metabolism studies can be used successfully to direct medicinal chemistry towards the synthesis of candidate drugs devoid of bioactivation liabilities, while maintaining desired pharmacology and pharmacokinetic properties.", "OBJECTIVES: The present study was aimed to determine whether trefoil factor family (TFF) peptides which were generally considered to be resistant to proteolysis could be digested by gingipains, a major proteinases produced by Porphyromonas gingivalis.MATERIALS AND METHODS: Recombinant human TFF1, TFF2, and TFF3 peptides were used as substrates. Gingipains including arginine gingipain (RgpB) and lysine gingipain (Kgp) were used as enzymes. Trypsin was used as a control protease. Matrix-assisted laser desorption/ionization with time-of-flight / time-of-flight (MALDI-TOF/TOF) and liquid chromatography mass spectrometry (LC-MS) were used for analyzing peptide mass signals and amino acid sequences of digested TFF peptides.RESULTS: MALDI-TOF/TOF analyses demonstrated that Kgp, RgpB, and trypsin were able to cleave TFF1 and TFF2 peptides, resulting in different patterns of digested fragments. However, impurity in recombinant TFF3 peptide substrates affected the interpretations of enzymatic reaction by MALDI-TOF/TOF. LC-MS analyses demonstrated that identified fragments of TFF1, TFF2, and TFF3 from digestion by gingipains were similar to those by trypsin.CONCLUSIONS: Using MALDI-TOF/TOF and LC-MS, the present study provides new information that gingipains containing trypsin-like activities are able to digest TFF peptides.CLINICAL RELEVANCE: The proteolytic effects of gingipains on TFF peptides may be responsible for reduction of salivary TFF peptides in chronic periodontitis patients. Further investigations to determine the pathological effects of gingipains on TFF peptides in saliva and periodontal tissues of patients with chronic periodontitis would be of interest.", "Interstitial deletions of the middle portion of the long arm of chromosome 5 are relatively rare. So far, only 36 cases have been reported. Because of the repetitive banding pattern of this region, the extent and localization of the deleted segment has not been well characterized in the majority of reported cases. This has complicated attempts to establish a definite karyotype-phenotype correlation. We report a further case with a de novo interstitial deletion of the region 5q?15 to 5q?22 identified by standard karyotype analysis. The proband presented with failure to thrive, developmental delay, distinct craniofacial dysmorphic features, and associated structural anomalies (amongst them cleft palate, iris colobomata, and horseshoe kidney, which have previously been reported in 5q deletion cases). In addition, this child had an Arnold-Chiari type I malformation that required surgical decompression. FISH studies using BAC clones spanning the 5q15 to 5q22 region revealed that these were all present in both homologues. Use of more distal clones allowed delineation of the deleted region to 5q22.3q23.3 and to narrow down the breakpoints to approximately 200 kb. The 14 Mb deleted region contains about 60 genes but, with the possible exception of FBN2 and DMXL1, there are no obvious candidate genes for the specific components of the phenotype. This case illustrates the discrepancy between cytogenetic and molecular techniques in trying to delineate 5q interstitial deletions. Molecular studies need to be performed on these patients, to establish genotype-phenotype correlation and to understand the role and influence of genes in this region.", "P53 tumor suppressor gene mutations occur in the majority of human cancers and contribute to tumor development, progression and therapy resistance. Direct functional restoration of p53 as a transcription factor has been difficult to achieve in the clinic. We performed a functional screen using a bioluminescence-based transcriptional read-out to identify small molecules that restore the p53 pathway in mutant p53-bearing cancer cells. We identified CB002, as a candidate that restores p53 function in mutant p53-expressing colorectal cancer cells and without toxicity to normal human fibroblasts. Cells exposed to CB002 show increased expression of endogenous p53 target genes NOXA, DR5, and p21 and cell death which occurs by 16 hours, as measured by cleaved caspases or PARP. Stable knockdown of NOXA completely abrogates PARP cleavage and reduces sub-G1 content, implicating NOXA as the key mediator of cell death induction by CB002. Moreover, CB002 decreases the stability of mutant p53 in RXF393 cancer cells and an exogenously expressed R175H p53 mutant in HCT116 p53-null cells. R175H p53 expression was rescued by addition of proteasome inhibitor MG132 to CB002, suggesting a role for ubiquitin-mediated degradation of the mutant protein. In summary, CB002, a p53 pathway-restoring compound that targets mutant p53 for degradation and induces tumor cell death through NOXA, may be further developed as a cancer therapeutic.", "Author information:(1)Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany.(2)Division of Medical Genetics, Department of Pediatrics, Dalhousie University, Halifax, NS B3K 6R8, Canada.(3)Maritime Medical Genetics Service IWK Health Centre, Halifax, NS B3R 6R8 Canada.(4)Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr. Str. 1, 6020 Innsbruck, Austria; Institute of Human Genetics, Technical University of Munich, Trogerstr. 32, 81675 Munich, Germany.(5)Department of Pediatrics, Landeskrankenhaus Bregenz, Carl-Pedenz-Str. 2, 6900 Bregenz, Austria.(6)Department of Pathology and Histology, Al-Quds University, Eastern Jerusalem 19356, Palestine.(7)Palestine Medical Complex, Ramallah, Palestine.(8)Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.(9)Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.(10)Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.(11)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.(12)Department of Medical Genetics, Cukurova University Faculty of Medicine, 01330 Adana, Turkey.(13)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.(14)Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.(15)Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.(16)Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.(17)Abortion Research Centre, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.(18)Department of Neurology and Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.(19)GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.(20)Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.(21)Faculty of Medicine, Al-Quds University, Eastern Jerusalem 19356, Palestine.(22)Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.(23)Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.(24)National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.(25)Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.(26)Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester M13 9WL, UK.(27)Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester M13 9WL, UK.(28)Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.(29)Genomics England, London EC1M 6BQ, UK.(30)Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.(31)Department of Neuroradiology, University Hospital of Tuebingen, 72076 Tübingen, Germany.(32)Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany; NGS Competence Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.(33)Proteome Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.(34)Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.(35)Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK. Electronic address: rmaroofian@gmail.com.(36)Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany. Electronic address: ludger.schoels@uni-tuebingen.de.", "Intravenous durvalumab (Imfinzi™; AstraZeneca) is a fully human monoclonal antibody that blocks programmed cell death ligand-1 binding to its receptors (PD-1 and CD80), resulting in enhanced T-cell responses against cancer cells. The US FDA has granted durvalumab accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Durvalumab ± tremelimumab is under phase III clinical trials in urothelial carcinoma, non-small cell lung cancer, small cell lung cancer and head and neck squamous cell carcinoma. The drug is also being evaluated in phase I or II clinical trials in a wide range of solid tumours and haematological malignancies. This article summarizes the milestones in the development of durvalumab leading to this first approval for urothelial carcinoma." ]

[ "The cyclophilins are widely expressed enzymes that catalyze the interconversion of the cis and trans peptide bonds of prolines. The immunosuppressive natural products cyclosporine A and sanglifehrin A inhibit the enzymatic activity of the cyclophilins. Chemical modification of both the cyclosporine and sanglifehrin scaffolds has produced many analogues that inhibit cyclophilins in vitro but have reduced immunosuppressive properties. Three nonimmunosuppressive cyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated clinical efficacy for the treatment of hepatitis C infection. Additional candidates are in various stages of preclinical development for the treatment of hepatitis C or myocardial reperfusion injury. Recent publications suggest that cyclophilin inhibitors may have utility for the treatment of diverse viral infections, inflammatory indications, and cancer. In this review, we document the structure-activity relationships of the nonimmunosuppressive cyclosporins and sanglifehrins in clinical and preclinical development. Aspects of the pharmacokinetic behavior and chemical biology of these drug candidates are also described.", "Electron transfer dissociation (ETD) is an analytically useful tool for primary structure interrogation of intact proteins, but its utility is limited by higher-order reactions with the products. To inhibit these higher-order reactions, first-generation fragment ions are kinetically excited by applying an experimentally tailored parallel ion parking waveform during ETD (ETD-PIP). In combination with subsequent ion/ion proton transfer reactions, precursor-to-product conversion was maximized as evidenced by the consumption of more than 90% of the 21 kDa Protein G precursor to form ETD product ions. The employment of ETD-PIP increased sequence coverage to 90% from 80% with standard ETD. Additionally, the inhibition of sequential electron transfers was reflected in the high number of complementary ion pairs from ETD-PIP (90%) compared to standard ETD (39%).", "ARID2 loss-of-function is associated with a rare genetic disorder characterized in 14 reported patients to date. ARID2 encodes a member of the SWItch/sucrose non-fermentable chromatin remodeling complex. Other genes encoding subunits of this complex, such as ARID1A, ARID1B, and SMARCA2, are mutated in association with Coffin-Siris syndrome (CSS) and Nicolaides Baraitser syndrome (NCBRS) phenotypes. Previously reported ARID2 mutations manifested clinically with a CSS-like phenotype including intellectual disability, coarsened facial features, fifth toenail hypoplasia, and other recognizable dysmorphisms. However, heterogeneity exists between previously reported patients with some patients showing more overlapping features with NCBRS. Herein, we present a patient with a novel disease-causing ARID2 loss-of-function mutation. His clinical features included intellectual disability, coarse and dysmorphic facial features, toenail hypoplasia, ADHD, short stature, and delayed development consistent with prior reports. Our patient also presented with previously unreported clinical findings including ophthalmologic involvement, persistent fetal fingertip and toetip pads, and diffuse hyperpigmentary and hypopigmentary changes sparing his face, palms, and soles. The anomalous skin findings are particularly of interest given prior literature outlining the role of ARID2 in melanocyte homeostasis and melanoma. This clinical report and review of the literature is further affirming of the characteristic symptoms and expands the phenotype of this newly described and rare syndrome.", "OBJECTIVE: To review the immunogenicity, efficacy, and safety of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in pediatric patients.DATA SOURCES: A MEDLINE search (2000-September 2011) was conducted using the key words Streptococcus pneumoniae and pneumococcal conjugate vaccine for clinical trials, limited to studies conducted in humans and published in English.STUDY SELECTION AND DATA EXTRACTION: Randomized, controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of PCV13. Literature on the epidemiology and pathology of pneumococcal infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed.DATA SYNTHESIS: PCV13 is approved for routine vaccination of all infants as a 4-dose series at age 2, 4, 6, and 12-15 months for children who previously received 1 or more doses of the 7-valent pneumococcal conjugate vaccine (PCV7), and for children with underlying medical conditions that increase their risk for pneumococcal disease or its complications. PCV13 has comparable immunogenicity to the serotypes common with PCV7 and also provides protection against 6 additional pneumococcal serotypes. PCV13 has also been shown to have a comparable adverse reaction profile to PCV7.CONCLUSIONS: Based on published immunogenicity and safety data, as well as the recent recommendations by the ACIP for routine use in infants and indications for high-risk pediatric patients, PCV13 is a revised formulation of pneumococcal vaccine that should be included on pharmacy formularies.", "Copper is an essential nutrient that serves as a co-factor for enzymes involved in critical cellular processes including energy generation, peptide hormone maturation, oxidative stress protection, and iron homeostasis. Although genes have been identified from yeast and mammals encoding a homologous subunit of a plasma membrane high affinity copper transporter, the presence of additional subunits that function as part of a copper transport complex has not been reported. We observed that ctr4(+), a previously identified copper transport protein from the fission yeast Schizosaccharomyces pombe, fails to complement bakers' yeast cells defective in high affinity copper transport and fails to be targeted to the plasma membrane. However, selection for S. pombe genes, which, when co-expressed with Ctr4, confer high affinity copper transport to S. cerevisiae cells resulted in the identification of ctr5(+). Both Ctr4 and Ctr5 are integral membrane proteins, are co-regulated by copper levels and the copper-sensing transcription factor Cuf1, physically associate in vivo, are interdependent for secretion to the plasma membrane, and are each essential for high affinity copper transport. These studies in S. pombe identify Ctr4 and Ctr5 as components of a novel eukaryotic heteromeric plasma membrane complex that is essential for high affinity copper transport.", "OBJECTIVES: Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms.STUDY DESIGN: Thirty-six children (age: 5.7 +/- 2 years, mean +/- SD) with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension.RESULTS: Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic duodenitis in 24. The number of Paneth's cells in the duodenal crypts was significantly elevated in autistic children compared with non-autistic control subjects. Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function. Seventy-five percent of the autistic children (27/36) had an increased pancreatico-biliary fluid output after intravenous secretin administration. Nineteen of the 21 patients with diarrhea had significantly higher fluid output than those without diarrhea.CONCLUSIONS: Unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of the non-verbal autistic patients. The observed increase in pancreatico-biliary secretion after secretin infusion suggests an upregulation of secretin receptors in the pancreas and liver. Further studies are required to determine the possible association between the brain and gastrointestinal dysfunctions in children with autistic disorder.", "Among the various hypolipidemic drugs, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (also known as \"statins\") belong to a heterogeneous class of compounds, sharing an identical hypocholesterolemic effect that develops through direct inhibition of a rate-limiting step in endogenous cholesterol synthesis. Their mechanism of action entails competitive inhibition of HMG-CoA reductase. Several lines of evidence suggest that the pleiotropic effects of statins may also play a role in prevention of venous thrombosis, wherein hypercholesterolemic patients are characterized by enhanced thrombin generation, increased susceptibility to endothelial dysfunction and platelet hyperreactivity, so that limiting or counteracting the burden of one or more of these mechanisms would provide an effective means of prophylaxis. Plausible biological links can also be found between statin therapy and reduction of thrombotic risk, mainly targeting immune system, blood coagulation, endothelium, lipid metabolism, and inflammation. The earlier JUPITER (Justification for the Use of Statins in Primary Prevention) trial provided appealing evidence that the risk of venous thrombosis may be lowered by statins. The results of the following studies and those of recent meta-analyses have, however, questioned this assumption. Currently, it seems thereby cautious to conclude that the use of statins as part of the approach used for preventing venous thromboembolism appears unwarranted. This is due to the existence of controversial clinical evidence, to the large number of patients who would need to be treated to prevent one case of venous thrombosis, as well as to the tangible risk of side effects. More randomized and the larger studies are needed before definitive conclusions can be drawn.", "Electron-based fragmentation methods have revolutionized biomolecular mass spectrometry, in particular native and top-down protein analysis. Here, we report the use of a new electromagnetostatic cell to perform electron capture dissociation (ECD) within a quadrupole/ion mobility/time-of-flight mass spectrometer. This cell was installed between the ion mobility and time-of-flight regions of the instrument, and fragmentation was fast enough to be compatible with mobility separation. The instrument was already fitted with electron transfer dissociation (ETD) between the quadrupole and mobility regions prior to modification. We show excellent fragmentation efficiency for denatured peptides and proteins without the need to trap ions in the gas phase. Additionally, we demonstrate native top-down backbone fragmentation of noncovalent protein complexes, leading to comparable sequence coverage to what was achieved using the instrument's existing ETD capabilities. Limited collisional ion activation of the hemoglobin tetramer before ECD was reflected in the observed fragmentation pattern, and complementary ion mobility measurements prior to ECD provided orthogonal evidence of monomer unfolding within this complex. The approach demonstrated here provides a powerful platform for both top-down proteomics and mass spectrometry-based structural biology studies.", "Foamy viruses are a family of complex retroviruses that establish common, productive infections in a wide range of nonhuman primates. In contrast, humans appear nonpermissive for foamy virus replication, although zoonotic infections do occur. Here we have analyzed the ability of primate and mouse APOBEC3G proteins to inhibit the infectivity of primate foamy virus (PFV) virions produced in their presence. We demonstrate that several APOBEC3 proteins can potently inhibit the infectivity of a PFV-based viral vector. This inhibition correlated with the packaging of inhibitory APOBEC3 proteins into PFV virions, due to a specific PFV Gag/APOBEC3 interaction, and resulted in the G to A hypermutation of PFV reverse transcripts. While inhibition of PFV virion infectivity by primate APOBEC3 proteins was largely relieved by coexpression of the PFV Bet protein, a cytoplasmic auxiliary protein of previously uncertain function, Bet failed to relieve inhibition caused by murine APOBEC3. PFV Bet bound to human, but not mouse, APOBEC3 proteins in coexpressing cells, and this binding correlated with the specific inhibition of their incorporation into PFV virions. Of note, both PFV Bet and a second Bet protein, derived from an African green monkey foamy virus, rescued the infectivity of Vif-deficient human immunodeficiency virus type 1 (HIV-1) virions produced in the presence of African green monkey APOBEC3G and blocked the incorporation of this host factor into HIV-1 virion particles. However, neither foamy virus Bet protein reduced APOBEC3 protein expression levels in virion producer cells. While these data identify the foamy virus Bet protein as a functional ortholog of the HIV-1 Vif auxiliary protein, they also indicate that Vif and Bet block APOBEC3 protein function by distinct mechanisms.", "OBJECTIVES: We sought to establish the prognostic value of a comprehensive cardiovascular magnetic resonance (CMR) examination in risk stratification of hypertrophic cardiomyopathy (HCM) patients.BACKGROUND: With annual mortality rates ranging between 1% and 5%, depending on patient selection, a small but significant number of HCM patients are at risk for an adverse event. Therefore, the identification of and prophylactic therapy (i.e., defibrillator placement) in patients with HCM who are at risk of dying are imperative.METHODS: Two-hundred forty-three consecutive patients with HCM were prospectively enrolled. All patients underwent initial CMR, and 220 were available for clinical follow-up. The mean follow-up time was 1,090 days after CMR. End points were all-cause and cardiac mortality.RESULTS: During follow-up 20 of the 220 patients died, and 2 patients survived sudden cardiac death due to adequate implantable cardioverter-defibrillator discharge. Most events (n = 16) occurred for cardiac reasons; the remaining 6 events were related to cancer and accidents. Our data indicate that the presence of scar visualized by CMR yields an odds ratio of 5.47 for all-cause mortality and of 8.01 for cardiac mortality. This might be superior to classic clinical risk factors, because in our dataset the presence of 2 risk factors yields an odds ratio of 3.86 for all-cause and of 2.20 for cardiac mortality, respectively. Multivariable analysis also revealed the presence of late gadolinium enhancement as a good independent predictor of death in HCM patients.CONCLUSIONS: Among our population of largely low or asymptomatic HCM patients, the presence of scar indicated by CMR is a good independent predictor of all-cause and cardiac mortality.", "Knowledge of the detailed structure of a protein is crucial to our understanding of the biological functions of that protein. The gap between the number of solved protein structures and the number of protein sequences continues to widen rapidly in the post-genomics era due to long and expensive processes for solving structures experimentally. Computational prediction of structures from amino acid sequence has come to play a key role in narrowing the gap and has been successful in providing useful information for the biological research community. We have developed a prediction pipeline, PROSPECT-PSPP, an integration of multiple computational tools, for fully automated protein structure prediction. The pipeline consists of tools for (i) preprocessing of protein sequences, which includes signal peptide prediction, protein type prediction (membrane or soluble) and protein domain partition, (ii) secondary structure prediction, (iii) fold recognition and (iv) atomic structural model generation. The centerpiece of the pipeline is our threading-based program PROSPECT. The pipeline is implemented using SOAP (Simple Object Access Protocol), which makes it easier to share our tools and resources. The pipeline has an easy-to-use user interface and is implemented on a 64-node dual processor Linux cluster. It can be used for genome-scale protein structure prediction. The pipeline is accessible at http://csbl.bmb.uga.edu/protein_pipeline.", "Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations1-6. cis-regulatory elements (CREs) represent a highly enriched subset of the non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas7,8. We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification1. This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology.", "O-glycosylation is a highly diverse and complex form of protein post-translational modification. Mucin-type O-glycosylation is initiated by the transfer of N-acetyl-galactosamine (GalNAc) to the hydroxyl group of serine, threonine and tyrosine residues through catalysis by a family of glycosyltransferases, the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (E.C. 2.4.1.41) that are conserved across metazoans. In the last decade, structural characterization of glycosylation has substantially advanced due to the development of analytical methods and advances in mass spectrometry. However, O-glycosite mapping remains challenging since mucin-type O-glycans are densely packed, often protecting proteins from cleavage by proteases. Adding to the complexity is the fact that a given glycosite can be modified by different glycans, resulting in an array of glycoforms rising from one glycosite. In this study, we investigated conditions of solid phase extraction (SPE) enrichment, protease digestion, and Electron-transfer/Higher Energy Collision Dissociation (EThcD) fragmentation to optimize identification of O-glycosites in densely glycosylated proteins. Our results revealed that anion-exchange stationary phase is sufficient for glycopeptide enrichment; however, the use of a hydrophobic-containing sorbent was detrimental to the binding of polar-hydrophilic glycopeptides. Different proteases can be employed for enhancing coverage of O-glycosites, while derivatization of negatively charged amino acids or sialic acids would enhance the identification of a short O-glycopeptides. Using a longer than normal electron transfer dissociation (ETD) reaction time, we obtained enhanced coverage of peptide bonds that facilitated the localization of O-glycosites. O-glycosite mapping strategy via proteases, cut-off filtration and solid-phase chemoenzymatic processing. Glycopeptides are enriched by SPE column, followed by release of N-glycans, collection of higher MW O-glycopeptides via MW cut-off filter, O-glycopeptide release via O-protease, and finally detected by LC-MS/MS using EThcD.", "MicroRNAs (miRNAs) represent a class of non-coding RNA molecules playing pivotal roles in cellular and developmental processes. miRNAs modulate the expression of multiple target genes at the post-transcriptional level and are predicted to affect up to one-third of all human protein-encoding genes. Recently, miRNA involvement in the adaptive and innate immune systems has been recognized. Rheumatoid arthritis serves an example of a chronic inflammatory disorder in which miRNAs modulate the inflammatory process in the joints, with the potential to serve as biomarkers for both the inflammatory process and the potential for therapeutic response. This review discusses the investigations that led to miRNA discovery, miRNA biogenesis and mode of action, and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We conclude with a discussion of the implications of miRNA biology in rheumatoid arthritis and other autoimmune disorders.", "Bloodstream infections with Staphylococcus aureus are clinically significant and are often treated with empirical methicillin resistance (MRSA, methicillin-resistant S. aureus) coverage. However, vancomycin has associated harms. We hypothesized that MRSA screening correlated with resistance in S. aureus bacteremia and could help determine the requirement for empirical vancomycin therapy. We reviewed consecutive S. aureus bacteremias over a 5-year period at two tertiary care hospitals. MRSA colonization was evaluated in three ways: as tested within 30 days of bacteremia (30-day criterion), as tested within 30 days but accounting for any prior positive results (ever-positive criterion), or as tested in known-positive patients, with patients with unknown MRSA status being labeled negative (known-positive criterion). There were 409 S. aureus bacteremias: 302 (73.8%) methicillin-susceptible S. aureus (MSSA) and 107 (26.2%) MRSA bacteremias. In the 167 patients with MSSA bacteremias, 7.2% had a positive MRSA test within 30 days. Of 107 patients with MRSA bacteremia, 68 were tested within 30 days (54 positive; 79.8%), and another 21 (19.6%) were previously positive. The 30-day criterion provided negative predictive values (NPV) exceeding 90% and 95% if the prevalence of MRSA in S. aureus bacteremia was less than 33.4% and 19.2%, respectively. The same NPVs were predicted at MRSA proportions below 39.7% and 23.8%, respectively, for the ever-positive criterion and 34.4% and 19.9%, respectively, for the known-positive criterion. In MRSA-colonized patients, positive predictive values exceeded 50% at low prevalence. MRSA screening could help avoid empirical vancomycin therapy and its complications in stable patients and settings with low-to-moderate proportions of MRSA bacteremia.", "Middle-down proteomics has emerged as the method of choice to study combinatorial histone post translational modifications (PTMs). In the common bottom-up workflow, histones are digested into relatively short peptides (4-20 aa), separated using reversed-phase chromatography and analyzed using typical proteomics methods in mass spectrometry. In middle-down, histones are cleaved into longer polypeptides (50-60 aa) mostly corresponding to their N-terminal tails, resolved using weak cation exchange-hydrophilic interaction liquid chromatography (WCX-HILIC) and analyzed with less conventional mass spectrometry, i.e. using Electron Transfer Dissociation (ETD) for analyte fragmentation. Middle-down is not nearly as utilized as bottom-up for PTM analysis, partially due to its limited reproducibility and robustness. This has also limited the establishment of rigorous benchmarks to discriminate good vs poor quality experiments. Here, we describe critical aspects of the middle-down workflow to assist the user in evaluating the presence of biased and misleading results. Specifically, we tested the use of porous graphitic carbon (PGC) during the desalting step, demonstrating that desalting using only C18 material leads to sample loss. We also tested different salts in the WCX-HILIC buffers for their effect on retention, selectivity, and reproducibility of analysis of variants of histone tail fragments, in particular replacing ammonium ion with ethylenediammonium ion in buffer A. These substitutions had marked effects on selectivity and retention. Our results provide a streamlined way to evaluate middle-down performance to identify and quantify combinatorial histone PTMs." ]

[ "Bergapten is a natural furocoumarin, also known as 5-methoxypsoralen, and its medicinal value has been paid more and more attention. By sorting out the pharmacological literature of bergapten, we found that bergapten has a wide range of pharmacological effects, including neuroprotection, organ protection, anticancer, antiinflammatory, antimicrobial, and antidiabetes effects. However，bergapten has complex impacts on the hepatic metabolic enzyme. Moreover, pharmacokinetic studies showed that bergapten has higher absolute bioavailability and can cross the blood-brain barrier and has a great potential for treating brain disease, but the mechanism needs further clarification to make greater use of its ability to treat brain diseases. Furthermore, the phototoxicity of bergapten combined with ultraviolet light has always been mentioned. In view of its wide range of pharmacological activities, bergapten is expected to be a potential drug candidate for the treatment of diabetes and diabetes-induced osteoporosis, epilepsy, Alzheimer's disease, depression, and cancer. However, further studies are needed to elucidate its molecular mechanisms and targets. The phototoxicity of bergapten as a side effect should be further avoided. On the other hand, the photoactivation of bergapten in the anticancer aspect can be better utilized.", "Toxoplasma gondii was discovered by scientists working in North Africa and Brazil around 100 years ago. The parasite has since been found to be capable of infecting all warm-blooded animals including humans making it one of the most successful parasitic organisms worldwide. The pathogenic potential of T. gondii was recognized in the 1920s and 1930s, in congenitally infected children presenting with the classic triad of symptoms, namely hydrocephalus, retinochoroiditis and encephalitis. In addition, around the same time T. gondii parasites were found to be associated with severe intraocular inflammation. In the 1980s, T. gondii emerged as a major cause of death in patients with acquired immunodeficiency syndrome, illustrating the importance of the immune system in controlling T. gondii infection. T. gondii was reported as a major cause of abortion in sheep in New Zealand in the 1950s, which raised questions about potential new transmission routes for the parasite. The discovery of the cat as the definitive host in the 1960s was a very important finding as it helped to complete our understanding of the parasite's life cycle, and the oocyst stage of T. gondii shed in the faeces of infected cats was found to be an important source of infection for many intermediate hosts and helped to explain infection in herbivorous animals and people with a vegetarian diet. In addition, this stage of the parasite was very robust and could survive in the environment, depending on the climatic conditions, for up to 12-18 months. Knowledge of the parasite's life cycle, transmission routes, risk groups and host immune responses has helped in the development of strategies to control the disease, reduce transmission of the parasite and limit environmental contamination.", "Sox genes share a highly conserved DNA-binding motif, the HMG (high mobility group)-box domain, and have diverse roles in vertebrate embryonic development. A novel SRY-related cDNA (temporarily called Sox33) isolated from the Chinese alligator (Alligator sinensis) is 1,819 bp in length, with an open reading frame from 220 to 1113 bp, encoding a protein of 298 amino acids. Two putative polyadenylation signal sequences (AATAAA) are present upstream of the poly(A) tail in the 3' UTR (at 1255-1260 and 1774-1779). The putative protein contains an HMG-box domain most closely related to hSox12, mSox4, rtSox11, and mSox11 homologs, indicating that alligator Sox33 belongs to group C in the Sox gene family. Alligator adult and developing tissues were tested for Sox33 mRNA by independent Northern blots using a 336-bp probe (at 907-1243) between the HMG-box and the poly(A) site I and a 277-bp probe (at 1477-1754) between the two polyadenylation sites. Two transcripts (1.3 kb and 1.8 kb) in developing brain and one (1.8 kb) in adult brain were identified by the 336-bp probe; only one transcript (1.8 kb) in developing and adult brains was detected by the 277-bp probe. The results suggest that alligator Sox33 may use a different polyadenylation mechanism in the developing brain and play a role in the development and maintenance of the nervous system.", "AIMS: Mutations in the cardiac ryanodine receptor Ca(2+) release channel, RyR2, underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited life-threatening arrhythmia. CPVT is triggered by spontaneous RyR2-mediated sarcoplasmic reticulum (SR) Ca(2+) release in response to SR Ca(2+) overload during beta-adrenergic stimulation. However, whether elevated SR Ca(2+) content--in the absence of protein kinase A activation--affects RyR2 function and arrhythmogenesis in CPVT remains elusive.METHODS AND RESULTS: Isolated murine ventricular myocytes harbouring a human RyR2 mutation (RyR2(R4496C+/-)) associated with CPVT were investigated in the absence and presence of 1 micromol/L JTV-519 (RyR2 stabilizer) followed by 100 micromol/L ouabain intervention to increase cytosolic [Na(+)] and SR Ca(2+) load. Changes in membrane potential and intracellular [Ca(2+)] were monitored with whole-cell patch-clamping and confocal Ca(2+) imaging, respectively. At baseline, action potentials (APs), Ca(2+) transients, fractional SR Ca(2+) release, and SR Ca(2+) load were comparable in wild-type (WT) and RyR2(R4496C+/-) myocytes. Ouabain evoked significant increases in diastolic [Ca(2+)], peak systolic [Ca(2+)], fractional SR Ca(2+) release, and SR Ca(2+) content that were quantitatively similar in WT and RyR2(R4496C+/-) myocytes. Ouabain also induced arrhythmogenic events, i.e. spontaneous Ca(2+) waves, delayed afterdepolarizations and spontaneous APs, in both groups. However, the ouabain-induced increase in the frequency of arrhythmogenic events was dramatically larger in RyR2(R4496C+/-) when compared with WT myocytes. JTV-519 greatly reduced the frequency of ouabain-induced arrhythmogenic events.CONCLUSION: The elevation of SR Ca(2+) load--in the absence of beta-adrenergic stimulation--is sufficient to increase the propensity for triggered arrhythmias in RyR2(R4496C+/-) cardiomyocytes. Stabilization of RyR2 by JTV-519 effectively reduces these triggered arrhythmias.", "Adipose triglyceride lipase (ATGL) is the key triacylglycerol hydrolase in adipocytes. The precise mechanisms by which ATGL action is regulated by lipid droplet (LD) coat proteins and responds to hormonal stimulation are incompletely defined. By combining usage of loss- and gain-of-function approaches, we sought to determine the respective roles of perilipin 1 and fat-specific protein 27 (FSP27) in the control of ATGL-mediated lipolysis in adipocytes. Knockdown of endogenous perilipin 1 expression resulted in elevated basal lipolysis that was less responsive to β-adrenergic agonist isoproterenol. In comparison, depletion of FSP27 protein increased both basal and stimulated lipolysis with no significant impact on the overall response of cells to isoproterenol. In vitro assays showed that perilipin but not FSP27 was able to inhibit the triacylglycerol hydrolase activity of ATGL. Perilipin 1 also attenuated dose-dependent activation of ATGL by its Coactivator Comparative Gene identification-58. Accordingly, depletion of perilipin 1 and CGI-58 in adipocytes inversely affected basal lipolysis specifically mediated by overexpressed ATGL. Moreover, although depletion of perilipin 1 abolished the LD translocation of ATGL stimulated by isoproterenol, absence of FSP27 resulted in multilocularization of LDs along with increased LD presence of ATGL under both basal and stimulated conditions. Interestingly, knockdown of ATGL expression increased LD size and decreased LD number in FSP27-depeleted cells. Together, our results demonstrate that although FSP27 acts to constitutively limit the LD presence of ATGL, perilipin 1 plays an essential role in mediating the response of ATGL action to β-adrenergic hormones.", "Cardiolipin is a major membrane phospholipid in the mitochondria and is essential for cellular energy metabolism mediated through mitochondrial oxidative phosphorylation. Recent studies indicate that it plays a diverse role in cellular metabolism. Eukaryotic cardiolipin is synthesized de novo from phosphatidic acid via the cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol pathway and is deacylated to monolysocardiolipin in order for it to be remodelled into the form that is observed in mitochondrial membranes. This resynthesis of deacylated cardiolipin from monolysocardiolipin occurs via the Barth Syndrome gene product tafazzin and acyllysocardiolipin acyltransferase-1, monolysocardiolipin acyltransferase-1 and the alpha subunit of trifunctional protein. Heart failure is a disease condition in which the amount and type of cardiolipin is altered. Several animal models have been generated to study the role of altered cardiolipin in heart failure. In many of these models loss of the tetralinoleoyl-cardiolipin species is observed during the development of the heart failure. In the doxycycline inducible short hairpin RNA tafazzin knock down mouse, loss of tetralinoleoyl-cardiolipin is associated with a mitochondrial bioenergetic disruption. Reduction in mitochondrial supercomplex formation and NADH dehydrogenase activity within these supercomplexes is observed. Modulation of CL fatty acyl composition may serve as a therapeutic strategy for the treatment of several pathologies including cardiac dysfunction.We propose that increasing cardiolipin may improve mitochondrial function and potentially serve as a therapy for diseases which exhibit mitochondrial dysfunction involving reduced cardiolipin.", "INTRODUCTION: Currarino syndrome (Currarino triad) was described in 1981 as a triad syndrome with a common embryogenesis in infants and with three characteristics: anorectal stenosis, a defect in the sacral bone, and a presacral mass. We describe here an unusual case of Currarino syndrome in an adult presenting with a presacral abscess but no meningitis.CASE PRESENTATION: A 32-year-old Japanese man presented with fever, arthralgia and buttock pain. A digital rectal examination showed mild rectal stenosis with local warmth and tenderness in the posterior wall of his rectum. Computed tomography showed a scimitar-shaped deformity of his sacrum and an 8cm presacral mass, which continued to a pedicle of his deformed sacrum. This was diagnosed as Currarino syndrome with a presacral abscess. The abscess was drained by a perianal approach with our patient treated with antibiotics. His symptoms soon disappeared. After three months, an excision was performed through a posterior sagittal approach. His postoperative course was uneventful and he was discharged 10 days after surgery. A histopathological examination revealed an infected epidermoid cyst. He has been free from recurrence as of four years and six months after surgery.CONCLUSIONS: We report a case of Currarino syndrome in an adult who presented with a presacral abscess but no meningitis. Abscess drainage followed by radical surgery resulted in a successful outcome." ]

[ "Epidermal growth factor receptor (EGFR) is a known target in cancer therapy and targeting the receptor has proven to be extremely successful in treating cancers that are dependent on EGFR signaling. To that effect, targeted therapies to EGFR such as Cetuximab, Panitumumab-monoclonal antibodies and Gefitinib, Erlotinib-tyrosine kinase inhibitors have had success in therapeutic scenarios. However, the development of resistance to these drugs makes it necessary to combine anti- EGFR therapies with other inhibitors, so that resistance can be overcome by the targeting of alternate signaling pathways. On the other hand, components of the inflammatory pathway, within and around a tumor, provide a conducive environment for tumor growth by supplying numerous cytokines and chemokines that foster carcinogenesis. Interleukin 6 (IL-6) is one such cytokine that is found to be associated with inflammation-driven cancers and which also plays a crucial role in acquired resistance to anti-EGFR drugs. The EGFR and IL-6 signaling pathways crosstalk in multiple ways, through various mediators and downstream signaling pathways driving resistance and hence co-targeting them has potential for future cancer treatments. Here we provide an overview on the crosstalk between the EGFR and IL-6 pathways, and discuss how co-targeting these two pathways could be a promising combination therapy of the future.", "Mitochondria in cells comprise a tubulovesicular network shaped continuously by complementary fission and fusion events. The mammalian Drp1 protein plays a key role in fission, while Mfn1, Mfn2, and OPA1 are required for fusion. Shifts in the balance between these opposing processes can occur rapidly, indicating that modifications to these proteins may regulate mitochondrial membrane dynamics. We highlight posttranslational modifications of the mitochondrial fission protein Drp1, for which these regulatory mechanisms are best characterized. This dynamin-related GTPase undergoes a number of steps to mediate mitochondrial fission, including translocation from cytoplasm to the mitochondrial outer membrane, higher-order assembly into spirals, GTP hydrolysis associated with a conformational change and membrane deformation, and ultimately disassembly. Many of these steps may be influenced by covalent modification of Drp1. We discuss the dynamic nature of Drp1 modifications and how they contribute not only to the normal regulation of mitochondrial division, but also to neuropathologic processes.", "BACKGROUND: High myopia with alopecia areata in the occipital region has been observed in patients with Knobloch syndrome caused by COL18A1 mutations. This study investigated other possible genetic causes of high myopia in patients with alopecia areata in the cranial midline.METHODS: Six patients with early onset high myopia and alopecia areata in the cranial midline were recruited. Targeted high-throughput sequencing was performed on the proband's DNA to detect potential pathogenic variants. Cosegregation analysis was performed for available family members. Minigene assay and RNA Sequencing were used to validate the abnormality of possible splicing change and gross deletion. Ophthalmological and neuroimaging examinations were performed.RESULTS: Eight novel and one known loss-of-function mutants were detected in all six patients, including a gross deletion detected by RNA sequencing. Four COL18A1 mutants in three patients with scalp leisure in the occipital region; and five LAMA1 mutations in three patients with scalp leisure in the parietal region. Further assessments indicated that patients with COL18A1 mutations had Knobloch syndrome, and the patients with LAMA1 mutations had Poretti-Boltshauser syndrome.CONCLUSION: Our study found that early onset high myopia with midline alopecia areata could be caused not only by mutations of the COL18A1 gene but also by mutations in the LAMA1 gene. To our knowledge, we are the first to observe scalp defects in patients with LAMA1 mutations. High myopia with alopecia areata in the cranial midline could be treated as an early diagnostic clue for ophthalmologists to consider the two kinds of rare diseases.", "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", "Paediatric neurology syndromes are a broad and complex group of conditions with a large spectrum of clinical phenotypes. Joubert syndrome is a genetically heterogeneous neurological ciliopathy syndrome with molar tooth sign as the neuroimaging hallmark. We reviewed the clinical, radiological and genetic data for several families with a clinical diagnosis of Joubert syndrome but negative genetic analysis. We detected biallelic pathogenic variants in LAMA1, including novel alleles, in each of the four cases we report, thereby establishing a firm diagnosis of Poretti-Boltshauser syndrome. Analysis of brain MRI revealed cerebellar dysplasia and cerebellar cysts, associated with Poretti-Boltshauser syndrome and the absence of typical molar tooth signs. Using large UK patient cohorts, the relative prevalence of Joubert syndrome as a cause of intellectual disability was 0.2% and of Poretti-Boltshauser syndrome was 0.02%. We conclude that children with congenital brain disorders that mimic Joubert syndrome may have a delayed diagnosis due to poor recognition of key features on brain imaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We advocate the inclusion of LAMA1 genetic analysis on all intellectual disability and Joubert syndrome gene panels and promote a wider awareness of the clinical and radiological features of these syndromes.", "Oral health-related quality of life (OHRQoL) is an important aspect of health outcomes and its assessment should be made using validated instruments. The psychosocial impact of dental aesthetics questionnaire (PIDAQ) is an OHRQoL instrument that assesses the psychosocial impact of dental aesthetics was developed and validated for use on young adults. The aim of the present study was to assess the reliability, validity, and applicability of the PIDAQ for young adults in Brazil. After translation and cross-cultural adaptation, the questionnaire was completed by 245 individuals (124 males and 121 females) aged 18-30 years from the city of Belo Horizonte, Brazil. In order to test discriminant validity, the subjects were examined for the presence or absence of malocclusion based on the dental aesthetic index criteria. Dental examinations were carried out by a previously calibrated examiner [weighted kappa = 0.64-1.00, intraclass correlation coefficient (ICC) = 0.78-1.00]. Internal consistency measured by Cronbach's alpha of the subscales was between 0.75 and 0.91 and test-retest reliability was assessed using the ICC, which ranged from 0.89 to 0.99 for dental self-confidence and social impact, thereby revealing satisfactory reliability. Discriminant validity revealed that subjects without malocclusion had different PIDAQ scores when compared with those with malocclusion. The results suggest that the Brazilian version of the PIDAQ has satisfactory psychometric properties and is thus applicable to young adults in Brazil. Further research is needed to assess these properties in population studies.", "Parkinson's disease (PD) is the second most common neurodegenerative disease. A key pathological feature of PD is Lewy bodies, of which the major protein component is α-synuclein (α-syn). Human genetic studies have shown that mutations (A53T, A30P, E46K) and multiplication of the α-syn gene are linked to familial PD. Mice overexpressing the human A53T mutant α-syn gene develop severe movement disorders. However, the molecular mechanisms of α-syn toxicity are not well understood. Recently, mitochondrial dysfunction has been linked with multiple neurodegenerative diseases including Parkinson's disease. Here we investigated whether mitochondrial motility, dynamics and respiratory function are affected in primary neurons from a mouse model expressing the human A53T mutation. We found that mitochondrial motility was selectively inhibited in A53T neurons while transport of other organelles was not affected. In addition, A53T expressing neurons showed impairment in mitochondrial membrane potential and mitochondrial respiratory function. Furthermore, we found that rapamycin, an autophagy inducer, rescued the decreased mitochondrial mobility. Taken together, these data demonstrate that A53T α-syn impairs mitochondrial function and dynamics and the deficit of mitochondrial transport is reversible, providing further understanding of the disease pathogenesis and a potential therapeutic strategy for PD.", "Epidemiological data suggests suicide is uncommon in childhood but becomes an extremely serious issue among adolescents.Several risk factors have been identified and include the presence of psychiatric illness, a previous suicide attempt, family factors, substance abuse, sexual and physical abuse, disorders in gender identity or bullying. Pediatricians have a primary role in searching for these risk factors, recognizing them and acting synergistically with other specialists to prevent and treat suicidal behavior.Pediatricians should also be able to identify the \"warning signs\" for suicide since their presence implies a need for immediate action, as attempted suicide may occur in a few hours or days.The use of antidepressant drugs and its association with suicidal risk in pediatric age is another topic of ongoing debate. Food and Drug Administration has recently introduced the so-called \"black box\" on antidepressants' packages with the aim of gaining attention to the possible risk of suicide among adolescents who are treated with antidepressants, with a warning that the risk of suicide is higher when starting a therapy or while adjusting its dosage." ]

[ "Feline infectious peritonitis (FIP) is one of the most important infectious diseases in cats and is caused by feline coronavirus (FCoV). Tissue culture-adapted type I FCoV shows reduced FIP induction in experimental infections, which complicates the understanding of FIP pathogenesis caused by type I FCoV. We previously found that the type I FCoV strain C3663 efficiently induces FIP in specific-pathogen-free cats through the naturally infectious route. In this study, we employed a bacterial artificial chromosome-based reverse genetics system to gain more insights into FIP caused by the C3633 strain. We successfully generated recombinant virus (rC3663) from Fcwf-4 cells transfected with infectious cDNA that showed growth kinetics similar to those shown by the parental virus. Next, we constructed a reporter C3663 virus carrying the nanoluciferase (Nluc) gene to measure viral replication with high sensitivity. The inhibitory effects of different compounds against rC3663-Nluc could be measured within 24 h postinfection. Furthermore, we found that A72 cells derived from canine fibroblasts permitted FCoV replication without apparent cytopathic effects. Thus, our reporter virus is useful for uncovering the infectivity of type I FCoV in different cell lines, including canine-derived cells. Surprisingly, we uncovered aberrant viral RNA transcription of rC3663 in A72 cells. Overall, we succeeded in obtaining infectious cDNA clones derived from type I FCoV that retained its virulence. Our recombinant FCoVs are powerful tools for increasing our understanding of the viral life cycle and pathogenesis of FIP-inducing type I FCoV.IMPORTANCE Feline coronavirus (FCoV) is one of the most significant coronaviruses, because this virus induces feline infectious peritonitis (FIP), which is a lethal disease in cats. Tissue culture-adapted type I FCoV often loses pathogenicity, which complicates research on type I FCoV-induced feline infectious peritonitis (FIP). Since we previously found that type I FCoV strain C3663 efficiently induces FIP in specific-pathogen-free cats, we established a reverse genetics system for the C3663 strain to obtain recombinant viruses in the present study. By using a reporter C3663 virus, we were able to examine the inhibitory effect of 68 compounds on C3663 replication in Fcwf-4 cells and infectivity in a canine-derived cell line. Interestingly, one canine cell line, A72, permitted FCoV replication but with low efficiency and aberrant viral gene expression.", "Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM- and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.", "BACKGROUND: Systemic lupus erythematosus (SLE) is a complex multi-system disease, characterized by both autoimmune and autoinflammatory clinical and laboratory features. The role of type I interferon (IFN) in SLE has been demonstrated from the 2000s, by gene expression analyses showing significant over-expression of genes related to type I IFN signalling pathway (IFN signature). However, several studies questioned the role of measuring the intensity of IFN signature (IFN score) to chase SLE activity. We would assess if the IFN signature can help the clinical and therapeutic stratification of patients with pediatric SLE.METHODS: We measured the IFN score in peripheral whole blood from a series of subjects with childhood-onset SLE and correlated the results with clinical and laboratory parameters.RESULTS: Thirty-one subjects were included in the study, among which the 87% displayed a positive IFN score. The only significant relation was found for high IFN score in subjects with normocomplementemia. No correlation was observed between IFN score and SLEDAI-2K, BILAG-2004 and SLICC. Patients with high IFN score and normal complement levels also presented lower anti-dsDNA antibodies.CONCLUSIONS: The integration between IFN signature analysis and complement levels may easily distinguish two groups of subjects, in which the autoimmune or autoinflammatory component of the disease seems to be prevalent.", "BACKGROUND: Urinary tract infections (UTIs) are common among women and frequently recur. Depletion of vaginal lactobacilli is associated with UTI risk, which suggests that repletion may be beneficial. We conducted a double-blind placebo-controlled trial of a Lactobacillus crispatus intravaginal suppository probiotic (Lactin-V; Osel) for prevention of recurrent UTI in premenopausal women.METHODS: One hundred young women with a history of recurrent UTI received antimicrobials for acute UTI and then were randomized to receive either Lactin-V or placebo daily for 5 d, then once weekly for 10 weeks. Participants were followed up at 1 week and 10 weeks after intervention and for UTIs; urine samples for culture and vaginal swabs for real-time quantitative 16S ribosomal RNA gene polymerase chain reaction for L. crispatus were collected.RESULTS: Recurrent UTI occurred in 7/48 15% of women receiving Lactin-V compared with 13/48 27% of women receiving placebo (relative risk [RR], .5; 95% confidence interval, .2-1.2). High-level vaginal colonization with L. crispatus (≥10(6) 16S RNA gene copies per swab) throughout follow-up was associated with a significant reduction in recurrent UTI only for Lactin-V (RR for Lactin-V, .07; RR for placebo, 1.1; P < .01).CONCLUSIONS: Lactin-V after treatment for cystitis is associated with a reduction in recurrent UTI. Larger efficacy trials of this novel preventive method for recurrent UTI are warranted. CLINICAL TRIALS REGISTRATION. NCT00305227.", "The TAM subfamily of Receptor Tyrosine Kinases (RTKs) contains three human proteins of therapeutical interest, Axl, Mer, and Tyro3. Our goal was to design a type II inhibitor specific for this family, i.e. able to interact with the allosteric pocket and with the hinge region of the kinase. We report the synthesis of several series of purine analogues of BMS-777607. The structural diversity of the designed inhibitors was expected to modify the interactions formed in the binding site and consequently to modulate their selectivity profiles. The most potent inhibitor 6g exhibits Kds of 39, 42, 65 and 200 nM against Axl, Mer, Met and Tyro3 respectively. Analysis of the affinity of 6g for active and inactive forms of Abl1, an RTK protein that does not belong to the TAM subfamily, together with the binding modes of 6g predicted by docking studies, indicates that 6g displays some selectivity for the TAM family and may act as a type II inhibitor.", "OBJECTIVE: This study is the first in a series investigating the relationship between autonomic nervous system dysfunction and chronic cerebrospinal venous insufficiency in multiple sclerosis patients. We screened patients for the combined presence of the narrowing of the internal jugular veins and symptoms of autonomic nervous system dysfunction (fatigue, cognitive dysfunction, sleeping disorders, headache, thermal intolerance, bowel/bladder dysfunction) and determined systolic and diastolic blood pressure responses to balloon angioplasty.METHODS: The criteria for eligibility for balloon angioplasty intervention included ≥ 50% narrowing in one or both internal jugular veins, as determined by the magnetic resonance venography, and ≥ 3 clinical symptoms of autonomic nervous system dysfunction. Blood pressure was measured at baseline and post-balloon angioplasty.RESULTS: Among patients who were screened, 91% were identified as having internal jugular veins narrowing (with obstructing lesions) combined with the presence of three or more symptoms of autonomic nervous system dysfunction. Balloon angioplasty reduced the average systolic and diastolic blood pressure. However, blood pressure categorization showed a biphasic response to balloon angioplasty. The procedure increased blood pressure in multiple sclerosis patients who presented with baseline blood pressure within lower limits of normal ranges (systolic ≤ 105 mmHg, diastolic ≤ 70 mmHg) but decreased blood pressure in patients with baseline blood pressure above normal ranges (systolic ≥ 130 mmHg, diastolic ≥ 80 mmHg). In addition, gender differences in baseline blood pressure subcategories were observed.DISCUSSION: The coexistence of internal jugular veins narrowing and symptoms of autonomic nervous system dysfunction suggests that the two phenomena may be related. Balloon angioplasty corrects blood pressure deviation in multiple sclerosis patients undergoing internal jugular vein dilation. Further studies should investigate the association between blood pressure deviation and internal jugular veins narrowing, and whether blood pressure normalization affects Patient's clinical outcomes.", "Gene expression profiling using transcriptional drug perturbations are useful for many biomedical discovery studies including drug repurposing and elucidation of drug mechanisms (MoA) and many other pharmacogenomic applications. However, limited data availability across cell types has severely hindered our capacity to progress in these areas. To fill this gap, recently, the LINCS program generated almost 1.3 million profiles for over 40,000 drug and genetic perturbations for over 70 different human cell types, including meta information about the experimental conditions and cell lines. Unfortunately, Big Data like the ones generated from the ongoing LINCS program do not enable easy insights from the data but possess considerable challenges toward their analysis. In this paper, we address some of these challenges. Specifically, first, we study the gene expression signature profiles from all cell lines and their perturbagents in order to obtain insights in the distributional characteristics of available conditions. Second, we investigate the differential expression of genes for all cell lines obtaining an understanding of condition dependent differential expression manifesting the biological complexity of perturbagents. As a result, our analysis helps the experimental design of follow-up studies, e.g., by selecting appropriate cell lines.", "BACKGROUND: Bacterial vaginosis affects 15 to 50% of women of reproductive age, and recurrence is common after treatment with an antibiotic agent. The high incidence of recurrence suggests the need for new treatments to prevent recurrent bacterial vaginosis.METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial to evaluate the ability of Lactobacillus crispatus CTV-05 (Lactin-V) to prevent the recurrence of bacterial vaginosis. Women 18 to 45 years of age who had received a diagnosis of bacterial vaginosis and who had completed a course of vaginal metronidazole gel as part of the eligibility requirements were randomly assigned, in a 2:1 ratio, to receive vaginally administered Lactin-V or placebo for 11 weeks; follow-up occurred through week 24. The primary outcome was the percentage of women who had a recurrence of bacterial vaginosis by week 12.RESULTS: A total of 228 women underwent randomization: 152 to the Lactin-V group and 76 to the placebo group; of these participants, 88% in the Lactin-V group and 84% in the placebo group could be evaluated for the primary outcome. In the intention-to-treat population, recurrence of bacterial vaginosis by week 12 occurred in 46 participants (30%) in the Lactin-V group and in 34 participants (45%) in the placebo group (risk ratio after multiple imputation for missing responses, 0.66; 95% confidence interval [CI], 0.44 to 0.87; P = 0.01). The risk ratio for recurrence by week 24 (also calculated with multiple imputation for missing responses) was 0.73 (95% CI, 0.54 to 0.92). At the 12-week visit, L. crispatus CTV-05 was detected in 79% of participants in the Lactin-V group. The percentage of participants who had at least one adverse event related to Lactin-V or placebo by week 24 did not differ significantly between the groups. The percentage of participants with local or systemic adverse events was similar in the two groups.CONCLUSIONS: The use of Lactin-V after treatment with vaginal metronidazole resulted in a significantly lower incidence of recurrence of bacterial vaginosis than placebo at 12 weeks. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02766023.).", "IMPORTANCE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recently approved for lowering low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) and have potential for broad ASCVD prevention. Their long-term cost-effectiveness and effect on total health care spending are uncertain.OBJECTIVE: To estimate the cost-effectiveness of PCSK9 inhibitors and their potential effect on US health care spending.DESIGN, SETTING, AND PARTICIPANTS: The Cardiovascular Disease Policy Model, a simulation model of US adults aged 35 to 94 years, was used to evaluate cost-effectiveness of PCSK9 inhibitors or ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14,350 (based on mean wholesale acquisition costs of evolocumab and alirocumab); adopted a health-system perspective, lifetime horizon; and included probabilistic sensitivity analyses to explore uncertainty.EXPOSURES: Statin therapy compared with addition of ezetimibe or PCSK9 inhibitors.MAIN OUTCOMES AND MEASURES: Lifetime major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke), incremental cost per quality-adjusted life-year (QALY), and total effect on US health care spending over 5 years.RESULTS: Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 MACE at a cost of $503,000 per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $493,000-$1,737,000). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY (80% UI, $277,000-$1,539,000). Reducing annual drug costs to $4536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY. At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38% increase over 2015 prescription drug expenditures). In contrast, initiating statins in these high-risk populations in all statin-tolerant individuals who are not currently using statins was estimated to save $12 billion.CONCLUSIONS AND RELEVANCE: Assuming 2015 prices, PCSK9 inhibitor use in patients with heterozygous FH or ASCVD did not meet generally acceptable incremental cost-effectiveness thresholds and was estimated to increase US health care costs substantially. Reducing annual drug prices from more than $14,000 to $4536 would be necessary to meet a $100,000 per QALY threshold.", "BACKGROUND: Bacterial vaginosis is a very common vaginal infection. The lack of endogenous lactobacilli and overgrowth of pathogens facilitate numerous gynecological complications.METHODS: A phase I dose-ranging safety trial tested the safety, tolerability, and acceptability of Lactobacillus crispatus CTV-05 (LACTIN-V) administered by vaginal applicator. Twelve healthy volunteers were enrolled in 3 blocks of 4 (5 x 10, 1 x 10, and 2 x 10 cfu/dose). Each block was randomized in a 3:1 ratio of active product to placebo. Participants used study product for 5 consecutive days, returned for follow-up on days 7 and 14, and had phone interviews on days 2 and 35.RESULTS: All 12 participants took 5 doses and completed study follow-up.Overall, 45 adverse events (AEs) occurred, of which 31 (69%) were genitourinary (GU) AEs. GU AEs appeared evenly distributed between the 3 treatment blocks and between LACTIN-V and placebo arms. The most common GU AEs were vaginal discharge in 5 subjects (42%), abdominal pain in 4 subjects (33%), metrorrhagia in 4 subjects (33%), vulvovaginitis in 4 subjects (33%), vaginal candidiasis in 3 subjects (25%), and vaginal odor in 3 subjects (25%). Forty-one (91%) AEs were mild (grade 1) in severity. All 4 moderate AEs (grade 2) were unrelated to product use. No grade 3 or 4 AEs or serious adverse events (SAE) occurred. Laboratory parameters and colposcopy findings were within normal limits or clinically insignificant. The product was well-tolerated and accepted.CONCLUSION: All 3 dose levels of LACTIN-V appeared to be safe and acceptable in healthy volunteers.", "Periampullary adenocarcinomas are rare neoplasm that originates from the pancreatic head, the ampulla of vater, the distal bile duct or the duodenum. Surgical resection followed by adjuvant therapy is considered as the standard of care treatment for these carcinomas. Despite several advances in diagnostics and therapeutics, only 5% of these patients have an overall survival of five years or more. Currently, there is a dearth of viable therapeutic targets for this disease. The role of HER2 in cancer biology has been studied extensively in several tumour subtypes, and HER2 based targeted therapies have shown to have therapeutic benefits on different cancers. In this case report, we present a case of HER2 positive distal common bile duct carcinoma - a subtype of periampullary carcinoma with multiple relapses where multi-analyte testing with Encyclopedic Tumor Analysis (ETA) (Exacta®) identified amplification and over expression of HER2 gene which was used as a potential target to treat the patient with trastuzumab. Synchronous in vitro chemosensitivity profiling on Circulating Tumor Asscociated Cells (C-TACs) isolated from blood aided us to design the personalized chemotherapeutic regimen with cyclophosphamide and methotrexate. The combination of trastuzumab with cyclophosphamide and methotrexate yielded excellent treatment response with the patient remaining in complete response till the last follow-up. Our study suggests HER2 directed therapy as a potent pathway for treatment in the subset of HER-2 amplified distal common bile duct carcinomas.", "Author information:(1)Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region, Russian Federation; Biology Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia; Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation. Electronic address: vuversky@health.usf.edu.(2)Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation; St. Petersburg State Polytechnical University, St. Petersburg, Russian Federation.(3)AnalizaDx Inc., 3615 Superior Ave., Suite 4407B, Cleveland, OH 44114, USA.", "PURPOSE: To report on isolated central retinal artery occlusion (CRAO) as an initial presentation in two patients with undiagnosed paroxysmal nocturnal hemoglobinuria (PNH).METHODS: CRAO related to the aggravation of PNH was observed in 2 of 98 consecutive PNH patients for 10 years. Ocular and systemic manifestations were evaluated before and after systemic steroid, eculizumab and anticoagulant administration with adjuvant ocular treatments.RESULTS: Two young patients presented with complaints of acute painless monocular vision loss. In both cases, fundus examination revealed retinal edema and a cherry-red spot in the macula, consistent with CRAO. On systemic evaluation, severe anemia and thrombocytopenia were observed, and simultaneously thrombogenic processes were suggested by increased D-dimers, fibrinogen degradation products and/or portal vein thrombosis. PNH testing of red blood cells revealed a CD55 and CD59 deficiency consistent with PNH in both cases. The systemic complications typically associated with thrombosis were not observed for the following several months with early conservative treatments including eculizumab.CONCLUSIONS: Acute blindness from CRAO can be a unique manifestation of undiagnosed PNH and its subsequent aggravation. Systemic evaluations including PNH testing, especially in young CRAO patients, are strongly recommended for early detection of the further systemic thrombogenic processes.", "BACKGROUND: Bacterial vaginosis (BV) is a common vaginal infection caused by a lack of endogenous lactobacilli and overgrowth of pathogens that frequently recurs following antibiotic treatment.METHODS: A phase 2a study assessed colonization efficiency, safety, tolerability, and acceptability of Lactobacillus crispatus CTV-05 (LACTIN-V) administered by a vaginal applicator. Twenty-four women with BV were randomized in a 3:1 ratio of active product to placebo. Participants used LACTIN-V at 2 × 10 colony-forming units (cfu)/dose or placebo for 5 initial consecutive days, followed by a weekly application over 2 weeks. They returned for follow-up on Days 10 and 28.RESULTS: Sixty-one percent of the 18 women randomized to the LACTIN-V group were colonized with L. crispatus CTV-05 at Day 10 or Day 28. Among LACTIN-V users with complete adherence to the study regimen, 78% were colonized at Day 10 or Day 28. Of the 120 adverse events (AEs) that occurred, 108 (90%) and 12 (10%) were of mild and moderate severity, respectively. AEs were evenly distributed between the LACTIN-V and placebo group. Of the total AEs, 93 (78%) were genitourinary in origin. The most common genitourinary AEs included vaginal discharge (46%), abdominal pain (46%), dysuria (21%), pollakiuria (21%), vaginal odor (21%), and genital pruritus (17%). No grade 3 or 4 AEs or serious AEs occurred and no deep epithelial disruption was seen during colposcopic evaluation. The product was well tolerated and accepted.CONCLUSIONS: LACTIN-V colonized well, and was safe and acceptable in women treated for BV.", "OBJECTIVE: Chronically elevated free fatty acids contribute to insulin resistance and pancreatic β-cell failure. Among numerous potential factors, the involvement of endoplasmic reticulum (ER) stress has been postulated to play a mechanistic role. Here we examined the efficacy of the chemical chaperone, sodium phenylbutyrate (PBA), a drug with known capacity to reduce ER stress in animal models and in vitro, on lipid-induced insulin resistance and β-cell dysfunction in humans.RESEARCH DESIGN AND METHODS: Eight overweight or obese nondiabetic men underwent four studies each, in random order, 4 to 6 weeks apart. Two studies were preceded by 2 weeks of oral PBA (7.5 g/day), followed by a 48-h i.v. infusion of intralipid/heparin or saline, and two studies were preceded by placebo treatment, followed by similar infusions. Insulin secretion rates (ISRs) and sensitivity (S(I)) were assessed after the 48-h infusions by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively.RESULTS: Lipid infusion reduced S(I), which was significantly ameliorated by pretreatment with PBA. Absolute ISR was not affected by any treatment; however, PBA partially ameliorated the lipid-induced reduction in the disposition index (DI = ISR × S(I)), indicating that PBA prevented lipid-induced β-cell dysfunction.CONCLUSIONS: These results suggest that PBA may provide benefits in humans by ameliorating the insulin resistance and β-cell dysfunction induced by prolonged elevation of free fatty acids.", "Long QT and Brugada syndromes are two hereditary cardiac diseases. Brugada syndrome has so far been associated with only one gene, SCN5A, which encodes the cardiac sodium channel. However, in long QT syndrome (LQTS) at least six genes, including the SCN5A, are implicated. The substitution (D1790G) causes LQTS and the insertion (D1795) induces both LQTS and Brugada syndromes in carrier patients. hH1/insD1795 and hH1/D1790G mutant channels were expressed in the tsA201 human cell line and characterized using the patch clamp technique in whole-cell configuration. Our data revealed a persistent inward sodium current of about 6% at -30 mV for both D1790G and insD1795, and a reduction of 62% of channel expression for the insD1795. Moreover, a shift of steady-state inactivation curve in both mutants was also observed. Our findings uphold the idea that LQT3 is related to a persistent sodium current whereas reduction in the expression level of cardiac sodium channels is one of the biophysical characteristics of Brugada syndrome." ]

[ "Cancer is the third cause of death worldwide, with complex etiology, and is defined as an uncontrolled growth of cells. A high proportion of cancer incidence and deaths are due to different environmental and genetic factors such as high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, alcohol consumption, exposure to radiation, chronic infections, and heredity also. In addition, oxidative stress plays a crucial role in the pathophysiology of different types of cancer. Hence, screening and testing of more effective compounds with minimum side effects for the prevention and treatment of cancers started a few decades ago. Regarding this, much attention has been paid to natural antioxidants as a novel prevention and treatment strategy for cancer. Flavonoids are one of the most important ingredients in vegetables and fruits, especially in the genus Citrus. Hesperidin is a flavonone glycoside, belonging to the flavonoid family, which is widely found in Citrus species and acts as a potent antioxidant and anticancer agent. In the present review, we attempt to provide an overview and summarize the scientific literature about the cancer chemoprotective effects of hesperidin with an emphasis on its relation to the protection roles against oxidative stress.", "Protein lysine methylation occurs extensively in the Crenarchaeota, a major kingdom in the Archaea. However, the enzymes responsible for this type of posttranslational modification have not been found. Here we report the identification and characterization of the first crenarchaeal protein lysine methyltransferase, designated aKMT, from the hyperthermophilic crenarchaeon Sulfolobus islandicus. The enzyme was capable of transferring methyl groups to selected lysine residues in a substrate protein using S-adenosyl-l-methionine (SAM) as the methyl donor. aKMT, a non-SET domain protein, is highly conserved among crenarchaea, and distantly related homologs also exist in Bacteria and Eukarya. aKMT was active over a wide range of temperatures, from ~25 to 90 °C, with an optimal temperature at ~60 to 70 °C. Amino acid residues Y9 and T12 at the N terminus appear to be the key residues in the putative active site of aKMT, as indicated by sequence conservation and site-directed mutagenesis. Although aKMT was identified based on its methylating activity on Cren7, the crenarchaeal chromatin protein, it exhibited broad substrate specificity and was capable of methylating a number of recombinant Sulfolobus proteins overproduced in Escherichia coli. The finding of aKMT will help elucidate mechanisms underlining extensive protein lysine methylation and the functional significance of posttranslational protein methylation in crenarchaea.", "A patient with a mood disorder and a Parkinsonian syndrome with frontal cognitive impairment thought to resemble progressive supranuclear palsy defied precise diagnosis until the development of respiratory compromise, prompting consideration of the diagnosis of Perry syndrome. A mutation in the dynactin 1 gene confirmed the diagnosis. Few examples of this disorder, characterised by depression, Parkinsonism, and respiratory insufficiency, have been reported but it may be more commonly recognised with the availability of genetic testing. Perry syndrome needs to be considered in the differential diagnosis of Parkinsonism, particularly in autosomal dominant pedigrees. Diagnosis early in the disease course may facilitate monitoring and prompt intervention to avoid potentially fatal respiratory failure.", "Previous work with the yeast Saccharomyces cerevisiae has demonstrated a role for a phosphatidylinositol-specific PI 3-kinase, the product of the VPS34 gene, in the targeting of newly synthesized proteins to the vacuole, an organelle functionally equivalent to mammalian lysosomes (Schu, P. V., K. Takegawa, M. J. Fry, J. H. Stack, M. D. Waterfield, and S. D. Emr. 1993. Science [Wash. DC]. 260:88-91). The activity of Vps34p kinase is significantly reduced by the PI 3-kinase inhibitors wortmannin, a fungal metabolite, and LY294002, a quercetin analog (Stack, J. H., and S. D. Emr. 1994. J. Biol. Chem. 269:31552-31562). We show here that at concentrations which inhibit VPS34-encoded PI 3-kinase activity, wortmannin also inhibits the processing and delivery of newly synthesized cathepsin D to lysosomes in mammalian cells with half-maximal inhibition of delivery occurring at 100 nM wortmannin. As a result of wortmannin action, newly synthesized, unprocessed cathepsin D is secreted into the media. Moreover, after accumulation in the trans-Golgi network (TGN) at 20 degrees C, cathepsin D was rapidly missorted to the secretory pathway after addition of wortmannin and shifting to 37 degrees C. At concentrations that inhibited lysosomal enzyme delivery, both wortmannin and LY294002 caused a highly specific dilation of mannose 6-phosphate receptor (M6PR)-enriched vesicles of the prelysosome compartment (PLC), which swelled to approximately 1 micron within 15 min after treatment. With increasing time, the inhibitors caused a significant yet reversible change in M6PR distribution. By 3 h of treatment, the swollen PLC vacuoles were essentially depleted of receptors and, in addition, there was a fourfold loss of receptors from the cell surface. However, M6PRs were still abundant in the TGN. These results are most consistent with the interpretation that PI 3-kinase regulates the trafficking of lysosomal enzymes by interfering with a M6PR-dependent sorting event in the TGN. Moreover, they provide evidence that trafficking of soluble hydrolases to mammalian lysosomes and yeast vacuoles rely on similar regulatory mechanisms.", "Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naïve-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naïve-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.", "BACKGROUND: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined.METHODS AND RESULTS: Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively.CONCLUSION: Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date.CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT01439880.", "Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.", "The occupancy of nucleosomes along chromosome is a key factor for gene regulation. However, except promoter regions, genome-wide properties and functions of nucleosome organization remain unclear in mammalian genomes. Using the computational model of Increment of Diversity with Quadratic Discriminant (IDQD) trained from the microarray data, the nucleosome occupancy score (NOScore) was defined and applied to splice junction regions of constitutive, cassette exon, alternative 3' and 5' splicing events in the human genome. We found an interesting relation between NOScore and RNA splicing: exon regions have higher NOScores compared with their flanking intron sequences in both constitutive and alternative splicing events, indicating the stronger nucleosome occupation potential of exon regions. In addition, NOScore valleys present at approximately 25 bp upstream of the acceptor site in all splicing events. By defining folding diversity-to-energy ratio to describe RNA structural flexibility, we demonstrated that primary RNA transcripts from nucleosome occupancy regions are relatively rigid and those from nucleosome depleted regions are relatively flexible. The negative correlation between nucleosome occupation/depletion of DNA sequence and structural flexibility/rigidity of its primary transcript around splice junctions may provide clues to the deeper understanding of the unexpected role for nucleosome organization in the regulation of RNA splicing." ]

[ "Epigenetic silencing of miRNA is a primary mechanism of aberrant miRNA expression in cancer, and hypermethylation of miRNA promoters has been reported to contribute to prostate cancer initiation and progression. Recent data have shown that the miR-193b promoter is hypermethylated in prostate cancer compared with normal tissue, but studies assessing its functional significance have not been performed. We aimed to elucidate the function of miR-193b and identify its critical targets in prostate cancer. We observed an inverse correlation between miR-193b level and methylation of its promoter in The Cancer Genome Atlas (TCGA) cohort. Overexpression of miR-193b in prostate cancer cell lines inhibited invasion and induced apoptosis. We found that a majority of the top 150 genes downregulated when miR-193b was overexpressed in liposarcoma are overexpressed in metastatic prostate cancer and that 41 miR-193b target genes overlapped with the 86 genes in the aggressive prostate cancer subtype 1 (PCS1) signature. Overexpression of miR-193b led to the inhibition of the majority of the 41 genes in prostate cancer cell lines. High expression of the 41 genes was correlated with recurrence of prostate cancer. Knockdown of miR-193b targets FOXM1 and RRM2 in prostate cancer cells phenocopied overexpression of miR-193b. Dual treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors decreased miR-193b promoter methylation and restored inhibition of FOXM1 and RRM2. Our data suggest that silencing of miR-193b through promoter methylation may release the inhibition of PCS1 genes, contributing to prostate cancer progression and suggesting a possible therapeutic strategy for aggressive prostate cancer.", "Diastolic dysfunction of the heart is correlated with cardiac mortality. Serum cystatin C (CysC) is an endogenous marker of kidney function. It is not clear whether serum CysC is associated with diastolic dysfunction in patients with varying cardiac conditions with concomitant diastolic abnormalities and preserved ejection fraction (EF). The authors measured serum CysC levels in patients with cardiac diseases and examined the relationships between serum CysC levels and diastolic function. Serum CysC was measured and echocardiography was performed in 124 consecutive patients with cardiac diseases. Transmitral flow (TMF) patterns surrogating diastolic function were categorized into two groups: a normal group and an abnormal group. Serum CysC and BNP showed a significant positive correlation. There were no significant differences in serum CysC among those cardiac diseases. Seventy-eight patients with cardiac disease and preserved EF (left ventricular EF ≥50%) and without renal dysfunction (estimated glomerular filtration rate ≥60 mL/minute/1.73 m(2) ) were examined. Multivariate linear regression analysis demonstrated that left atrium diameter and abnormal TMF patterns were independent determinants of serum CysC. Furthermore, patients with elevated serum CysC levels had poor prognosis. Serum CysC is associated with diastolic dysfunction in patients with various cardiac diseases and preserved EF. Serum CysC might be a biomarker of cardiac diastolic dysfunction in patients with preserved EF.", "BACKGROUND: Various bleeding risk scores have been proposed to assess the risk of bleeding in patients with atrial fibrillation taking oral anticoagulants. Limited data are available with these scores, in users of non-vitamin K antagonist oral anticoagulants.METHODS: Using the Danish registries, we evaluated and compared the risk classification properties of the Hypertension, Age, Stroke, Bleeding tendency/predisposition, Labile international normalized ratios, Elderly age/frailty, Drugs such as concomitant aspirin/nonsteroidal anti-inflammatory drugs or alcohol excess (HAS-BLED), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), and Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) scores for predicting major bleeding in 57,930 atrial fibrillation patients (44.6% female; mean age 73.5 years, standard deviation 11.4 years; mean CHA2DS2-VASc score 3.2, standard deviation 1.8).RESULTS: At 1-year follow-up, C-statistics for ATRIA, HAS-BLED, and ORBIT were approximately 0.59, with only minor differences between scores. Both ATRIA and ORBIT categorized more patients as \"low risk\" (both >83%, when compared with HAS-BLED, only 53%), and qualitatively, the receiver operating characteristic curves revealed higher sensitivity (62.8%) for HAS-BLED compared with ATRIA (29.7%) and ORBIT (37.1%). The clinical usefulness of scores was evaluated using decision curve analyses at a 1-year perspective. If the intervention threshold is low (<1.7%), the benefit is toward monitoring all patients. If preference is for a major bleeding risk threshold between 1.7% and 2.0%, most benefit was obtained by using HAS-BLED. The ORBIT and ATRIA scores provided better benefit for thresholds between 2.0% and 6.0%.CONCLUSION: This analysis of contemporary bleeding risk score stratification in a \"real-world\" non-vitamin K antagonist oral anticoagulant users population with atrial fibrillation showed modest predictive values using C-statistics. The scores represent different risk thresholds, with HAS-BLED classifying least patients at low risk and achieving the highest benefit if applying a major bleeding intervention threshold of approximately 2%, whereas benefit from using either ATRIA score or ORBIT score was only evident using higher intervention thresholds.", "The Ebola virus disease (EVD), formerly known as a hemorrhagic fever and discovered in 1976, is dangerous, highly infectious disease with very high mortality. There are no licensed therapeutics against EVD, although a range of medicines and therapies are currently being evaluated. During the 2014 Ebola outbreak, an experimental drug named ZMapp was administered on an emergency basis to seven patients of which five were recovered. Currently, since February 2015, ZMapp is tested in clinical trials. ZMapp is a mixture (named a cocktail) of three chimaeric monoclonal antibodies (mAbs) of IgG class, which bind to three different epitopes on Ebola surface glycoprotein (GP). ZMapp was created by systematic selection of antibodies from two other three-component cocktails--MB-003 and ZMab the components of which were produced by rapid transient expression method in tobacco species of Australian origin--Nicotiana benthamiana. The ZMapp antibodies of pharmaceutical grade are manufactured in green-house grown N.benthamiana according to the cGMP (current Good Manufacturing Practice), using RAMP platform (Rapid Antibody Manufacturing Platform) and MagnICON system, which utilizes transient expression by magnifection method using viral vectors delivered to plant tissue by a bacterium--Agrobacterium tumefaciens. The applied glycosylation mutant of N.benthamiana (delta XTFT) synthesizes human-like, biantennary N-glycans, with terminal N-acetylglucoseamine and without typical of plants, immunogenic sugar epitopes-beta1,2-linked xylose and alpha1,3-linked fucose. Due to an absence of fucose on N-glycans attached to the Fc domains, the plant-produced anti-Ebola mAbs elicited significantly stronger antibody-dependent cellular cytotoxicity (ADCC) than the analogous anti-Ebola mAbs with fucosylated (alpha1,6-linked fucose) N-glycans produced in a mammalian CHO cell line--the basic expression system for the industrial production of recombinant therapeutical glycoproteins. As far as a vaccine against Ebola virus disease is considered, so-called Ebola Immunogenic Complex (EIC) consisting of assembled molecules of a humanized IgG mAb--6D8 specific for Ebola GPI with GP1 fused to the C-terminus of the heavy chains, was obtained by transient expression in N. benthamiana.", "Children with classic galactosemia are at risk for motor speech disorders resulting from disruptions in motor planning and programming (childhood apraxia of speech or CAS) or motor execution (dysarthria). In the present study of 33 children with classic galactosemia, 21% were diagnosed with CAS, 3% with ataxic dysarthria, and 3% with mixed CAS-dysarthria. Voice disorders due to laryngeal insufficiency were common in children with dysarthria and co-occurred with CAS. Most (58%) of the children with classic galactosemia had decreased respiratory-phonatory support for speech, and 33% had disturbed vocal quality that was indicative of cerebellar dysfunction. Three children, two diagnosed with CAS and one not diagnosed with a motor speech disorder, had vocal tremors. Treatment of voice dysfunction in neurogenic speech disorders is discussed.", "miRNAs have proven to be key regulators of gene expression and are differentially expressed in various diseases, including cancer. Our aim was to identify epigenetically dysregulated genes in prostate cancer. We performed miRNA expression profiling after relieving epigenetic modifications in 6 prostate cancer cell lines and nonmalignant prostate epithelial cells. Thirty-eight miRNAs showed increased expression in any prostate cancer cell line after 5-aza-2'-deoxycytidine (5azadC) and trichostatin A (TSA) treatments. Six of these also had decreased expression in clinical prostate cancer samples compared to benign prostatic hyperplasia. Among these, miR-193b was methylated in 22Rv1 cell line at a CpG island approximately 1 kb upstream of the miRNA locus. Expressing miR-193b in 22Rv1 cells using pre-miR-193b oligonucleotides caused a significant growth reduction (p < 0.001) resulting from a decrease of cells in S-phase of the cell cycle (p < 0.01). In addition, the anchorage independent growth was partially inhibited in transiently miR-193b-expressing 22Rv1 cells (p < 0.01). Altogether, our data suggest that miR-193b is an epigenetically silenced putative tumor suppressor in prostate cancer.", "BACKGROUND: The kidney plays an important role in glucose metabolism, and has been considered a target for therapeutic intervention. The sodium-glucose cotransporter type 2 (SGLT2) mediates most of the glucose reabsorption from the proximal renal tubule. Inhibition of SGLT2 leads to glucosuria and provides a unique mechanism to lower elevated blood glucose levels in diabetes. The purpose of this review is to explore the physiology of SGLT2 and discuss several SGLT2 inhibitors which have clinical data in patients with type 2 diabetes.METHODS: We performed a PubMed search using the terms \"SGLT2\" and \"SGLT2 inhibitor\" through April 10, 2012. Published articles, press releases, and abstracts presented at national and international meetings were considered.RESULTS: SGLT2 inhibitors correct a novel pathophysiological defect, have an insulin-independent action, are efficacious with glycosylated hemoglobin reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence of hypoglycemia, complement the action of other antidiabetic agents, and can be used at any stage of diabetes. They are generally well tolerated. However, due to side effects, such as repeated urinary tract and genital infections, increased hematocrit, and decreased blood pressure, appropriate patient selection for drug initiation and close monitoring after initiation will be important. Results of ongoing clinical studies of the effect of SGLT2 inhibitors on diabetic complications and cardiovascular safety are crucial to determine the risk-benefit ratio. A recent decision by the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products, including insulin, and as a monotherapy for metformin-intolerant patients. Clinical research also remains to be carried out on the long-term effects of glucosuria and other potential effects of SGLT2 inhibitors, especially in view of the observed increase in the incidence of bladder and breast cancer. SGLT2 inhibitors represent a promising approach for the treatment of diabetes, and could potentially be an addition to existing therapies.", "OBJECTIVE: To determine whether intensive combinations of conventional synthetic disease-modifying antirheumatic drugs (csDMARDS) achieve similar clinical benefits more cheaply than high-cost biologics such as tumor necrosis factor inhibitors (TNFi) in patients with active rheumatoid arthritis (RA) whose illness has failed to respond to methotrexate and another DMARD.METHODS: We used within-trial cost-effectiveness and cost-utility analyses from health and social care and 2 societal perspectives. Participants were recruited into an open-label, 12-month, pragmatic, randomized, multicenter, 2-arm, noninferiority trial in 24 rheumatology clinics in England and Wales. Costs were linked with the Health Assessment Questionnaire (HAQ; primary outcome) and quality-adjusted life years derived from 2 measures (Short-Form 36 health survey and EuroQol 5-domain 3-level instrument).RESULTS: In total, 205 participants were recruited, 104 in the csDMARD arm and 101 in the TNFi arm. Participants in the csDMARD arm with poor response at 6 months were offered TNFi; 46 participants (44%) switched. Relevant cost and outcome data were available for 93% of participants at 6-month follow-up and for 91-92% of participants at 12-month follow-up. The csDMARD arm had significantly lower total costs from all perspectives (6-month health and social care adjusted mean difference -£3,615 [95% confidence interval (95% CI) -4,104, -3,182]; 12-month health and social care adjusted mean difference -£1,930 [95% CI -2,599, -1,301]). The HAQ score showed benefit to the csDMARD arm at 12 months (-0.16 [95% CI -0.32, -0.01]); other outcomes/follow-ups showed no differences.CONCLUSION: Starting treatment with csDMARDs, rather than TNFi, achieves similar outcomes at significantly lower costs. Patients with active RA and who meet the National Institute for Health and Care Excellence criteria for expensive biologics can be treated with combinations of intensive csDMARDs in a cost-effective manner." ]

[ "OBJECTIVE: To explore what considerations patients have when deciding about disease-modifying antirheumatic drugs (DMARDs) and what information patients need to participate in the decision-making process.METHODS: In-depth face-to-face interviews were conducted with 32 patients with inflammatory arthritis who recently consulted their rheumatologist and discussed initiating DMARDs.RESULTS: Beliefs in the necessity of DMARDs, either for relief of symptoms or prevention of future joint damage, were reasons to initiate DMARDs. Furthermore, trust in the rheumatologist and the health care system was important in this respect. Patients expressed many concerns about initiating DMARDS. These related to the perceived aggressive and harmful nature of DMARDs, potential (or unknown) side effects, influence on fertility and pregnancy, combination with other medicines, time to benefit, and manner of administration. Participants also worried about the future regarding long-term medication use and drug dependency, and if a medicine proved to be ineffective, about the risks of future treatments and running out of options. To decrease uncertainty, participants wanted to be informed about multiple treatment options, both current and future. They not only wanted clinical information but also information on how the medications could affect their daily lives.CONCLUSION: Health education should inform patients about multiple treatment options, for the present as well as for the future. It should enable patients to compare treatments with regard to both clinical aspects as well as possible consequences for their daily lives.", "BACKGROUND: Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus.OBJECTIVE: The goal of this study was to investigate potential drug-drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers.METHODS: The potential drug-drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5.RESULTS: Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0-∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87-107.20; Cmax: GMR, 92.39%; 90% CI, 85.38-99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05-100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65-111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51-116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73-119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00-101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67-104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0-∞ (GMR, 106.11%; 90% CI, 96.71-116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33-130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies.CONCLUSIONS: No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril).", "Puffer fish, Takifugu niphobles, collected from the Hong Kong coastal waters were screened for tetrodotoxin-producing bacteria. A Gram-negative, non-acid-fast, non-sporing and rod shaped bacterial strain (designated as gutB01) was isolated from the intestine of the puffer fish and was shown to produce tetrodotoxin (TTX). Based on the Microbial Identification (MIDI) and 16S-23S rDNA internal transcribed spacer (ITS) phylogenetic analysis, the strain was identified as Raoultella terrigena. The TTX production ability of the strain was confirmed by mouse bioassay, ELISA and mass spectrometry (MALDI-TOF). Our results reiterate that the TTX found in puffer fish was likely produced by the associated bacteria and TTX are widely produced amongst a diversity of bacterial species.", "OBJECTIVES: To assess the feasibility of using ultrasound (US) image features related to the median nerve echogenicity and shape for carpal tunnel syndrome (CTS) diagnosis.METHODS: In 31 participants (21 healthy participants and 10 patients with CTS), US images were collected with a 30-MHz transducer from median nerves at the wrist crease in 2 configurations: a neutral position and with wrist extension. Various morphologic features, including the cross-sectional area (CSA), were calculated to assess the nerve shape. Carpal tunnel syndrome commonly results in loss of visualization of the nerve fascicular pattern on US images. To assess this phenomenon, we developed a nerve-tissue contrast index (NTI) method. The NTI is a ratio of average brightness levels of surrounding tissue and the median nerve, both calculated on the basis of a US image. The area under the curve (AUC) from a receiver operating characteristic curve analysis and t test were used to assess the usefulness of the features for differentiation of patients with CTS from control participants.RESULTS: We obtained significant differences in the CSA and NTI parameters between the patients with CTS and control participants (P < .01), with the corresponding highest AUC values equal to 0.885 and 0.938, respectively. For the remaining investigated morphologic features, the AUC values were less than 0.685, and the differences in means between the patients and control participants were not statistically significant (P > .10). The wrist configuration had no impact on differences in average parameter values (P > .09).CONCLUSIONS: Patients with CTS can be differentiated from healthy individuals on the basis of the median nerve CSA and echogenicity. Carpal tunnel syndrome is not manifested in a change of the median nerve shape that could be related to circularity or contour variability.", "OBJECTIVES: Patients and rheumatologists have a number of options to consider for the treatment of rheumatoid arthritis (RA), including biologic response modifier (BRM) therapy and diseasemodifying antirheumatic drugs (DMARDs). The objective of this study was to identify the considerations that are most important to patients and rheumatologists when deciding to initiate BRM therapy for RA.METHODS: An online survey was conducted by Harris Interactive (Rochester, NY) and completed in January 2007. Patients receiving BRMs were asked to rank their considerations in initiating BRM therapy, patients receiving DMARDs were asked to rank their considerations in switching to or initiating BRM therapy, and rheumatologists were asked to rank their considerations in prescribing BRM therapy. Participants arranged the following 9 factors from most to least important: efficacy, safety/side effects, years on market, physician's experience with product, physician's personal preference, method of administration, dosing frequency, cost (out of pocket), and patient support programs.RESULTS: A total of 400 rheumatologists and 729 patients were surveyed (BRMs, n = 504; DMARDs, n = 225). The following factors were ranked consistently high across groups: safety (ranked first, first, and second for BRM patients, DMARD patients, and rheumatologists, respectively), efficacy (second, fourth, and first, respectively), and physician's experience with the drug (third for all 3 groups). Years on market (ranked seventh, sixth, and seventh, respectively) and availability of patient support groups ranked consistently low.CONCLUSIONS: When considering BRM therapy for RA, the 3 most important factors for patients and physicians are safety, efficacy, and the physician's experience with the product.", "BACKGROUND: Tetraiodothyroacetic acid (tetrac) is a deaminated analogue of L-thyroxine that blocks the actions of L-thyroxine and 3,5,3'-triiodo-L-thyronine at the cell surface receptor for thyroid hormone on integrin alpha v beta 3. Tetrac blocks the proliferative effects of thyroid hormone on tumor cells and the proangiogenesis actions of the hormone. In the absence of thyroid hormone, tetrac also blocks angiogenesis induced by various growth factors. Covalently linked to poly(lactide-co-glycolide), tetrac nanoparticles (tetrac NP) do not gain access to the cell interior and act exclusively at the integrin receptor. Here, the activity of tetrac and tetrac NP against follicular thyroid carcinoma (FTC)-236 cells was studied in two models: (1) tumor cell implants in the chick chorioallantoic membrane (CAM) system and (2) xenografts in the nude mouse.METHODS: FTC-236 cells (10(6)) were implanted in the CAM (n = 8 each for control, and for tetrac and tetrac NP, both at 1 microg/CAM) and the actions of tetrac and tetrac NP were determined after 8 days on tumor-related angiogenesis and tumor growth. Xenografts of 10(7) FTC-236 cells were implanted in nude mice (n = 8 per group). Tetrac or tetrac NP was administered intraperitoneal (1 mg/kg and 1 mg tetrac equivalent/kg, respectively) every other day for 32 days beginning on day 10, when tumor volume was 200-250 mm(3). Animals were monitored after discontinuation of treatment up to day 40.RESULTS: In the CAM paradigm, tetrac and tetrac NP arrested tumor-related angiogenesis and tumor growth. In the xenograft model, tetrac and tetrac NP promptly and progressively reduced tumor volume (p < 0.01) over 32 days. There was some regrowth of tumor after interruption of tetrac treatment, but at day 40, tumor volume and tumor weight at sacrifice were 45-55% below those of controls (p < 0.01). Animal weight gain was comparable in the control and treatment groups of animals.CONCLUSIONS: Tetrac and tetrac NP effectively arrest FTC-236 cell tumor growth in the CAM and xenograft models, suggesting its potential utility against FTC.", "Impaired healing of the skin is a notable cause of patient morbidity and mortality. In diabetic individuals, dysregulated inflammation contributes to delayed wound healing. Specific immunomodulatory agents may have a role in the treatment of diabetic wounds. One of these molecules is interleukin-1 receptor antagonist (Anakinra; Amgen Corp.). Although interleukin-1 receptor antagonist (Anakinra; Amgen Corp.) is approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis and neonatal-onset multisystem inflammatory disease, little is known about the local use this drug in cutaneous wound healing. Therefore, the aim of this study is to determine the effect of locally administered interleukin-1 receptor antagonist on delayed wound healing, specifically, in a diabetic mouse model. Two 6-mm full-thickness wounds were created on the dorsa of diabetic (db/db) mice and stented. One-hour postwounding, wound margins were subcutaneously injected with either (1) low-dose interleukin-1 receptor antagonist in a gelatin-transglutaminase gel vehicle or (2) the gel vehicle only. Wounds were imaged on days 0, 7, 14, and 21 postwounding, and wound area was determined. Wound biopsies were collected on day 21 and immunohistochemically stained for neutrophil and macrophage infiltration. Wounds treated with interleukin-1 receptor antagonist had significantly smaller wound area than nontreated wounds on day 7 and day 14 postwounding. Treated wounds also showed significantly less neutrophil and macrophage infiltration. These findings support the hypothesis that interleukin-1 receptor antagonist may have an important role in cutaneous wound healing, possibly by promoting successful resolution of acute inflammation and hence accelerating wound closure. Thereby, administration of IL-1Ra may be useful in the treatment of nonhealing wounds." ]

[ "Atopic Dermatitis (AD) is a chronic inflammatory disease persisting predominantly in the pediatric population. Treatment is generally supervised by various medical specialists, including primary care practitioners, allergists, and dermatologists. This divergence in disease management allows various therapeutic approaches to be administered to patients by supervised physicians. This article covers etiology of the disease and summarizes dermatologic treatment standards of selected countries binding prior to the registration of dupilumab by both the European Medicines Agency (EMA) and Federal Drug Administration (FDA) in 2017. Before recent development in targeted therapies (small molecules and biologic agents), standards in AD treatment remained unchanged for years with extensive similarities across a sample group of countries in particular geographic and economic regions. The spectrum of available and popular therapeutic options can be categorized into three dominating groups: non-pharmacologic, pharmacologic, and systemic interventions. Their prescription, in principle, was historically driven by disease severity and previous treatment history. However, advances in targeted therapies may change AD management guidelines and medical care standards.", "Optogenetic technology, also known as optogenetics, is a novel multidisciplinary field in biotechnology that integrates genetic engineering, electrophysiology, and optical and electronic engineering. This recently developed technology has evolved rapidly and generated considerable excitement in neuroscience research. This technology successfully solves the severe problem of achieving both high temporal and spatial precision within intact neural tissues of animals that electrical stimulation and pharmacological methods cannot achieve. It allows neurons to express light-sensitive genes that enable the identification, dissection, and manipulation of specific neural populations and their connections in the tissues and organs of awake animals with unprecedented spatial and temporal precision. Light-sensitive genes chiefly including the genetically targeted light-gated channels channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR) cause intracellular ion flow during optical illumination. Subsequently, the neurons undergo a series of changes resulting from membrane depolarization or hyperpolarization. To date, there are many published research articles and reviews that describe this new technology; however, few of the reports concern its application to neuropsychiatric diseases. In this review, we summarize the most recent optogenetic research in these diseases, including Parkinson's disease (PD), epilepsy, schizophrenia, anxiety, fear, reward behaviors, and sleep disorders. We propose that novel optogenetics technology creates excellent opportunities for innovative treatment strategies of neuropsychiatric diseases.", "The surface-exposed NadA adhesin produced by a subset of capsular serogroup B strains of Neisseria meningitidis is currently being considered as a vaccine candidate to prevent invasive disease caused by a hypervirulent lineage of meningococci. Levels of NadA are known to be controlled by both transcriptional regulatory factors and a component of human saliva, 4-hydroxyphenylacetic acid. Herein, we confirmed the capacity of a DNA-binding protein termed FarR to negatively control nadA expression. We also found that a known transcriptional regulator of farR in N. gonorrhoeae termed MtrR can have a negative regulatory impact on farR and nadA expression, especially when over-expressed. MtrR-mediated repression of nadA was found to be direct, and its binding to a target DNA sequence containing the nadA promoter influenced formation and/or stability of FarR::nadA complexes. The complexity of the multi-layered regulation of nadA uncovered during this investigation suggests that N. meningitidis modulates NadA adhesin protein levels for the purpose of interacting with host cells yet avoiding antibody directed against surface exposed epitopes.", "Tepotinib is an oral MET inhibitor approved for metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. Examining treatment-naive or tepotinib-resistant cells with MET amplification or METex14 skipping mutations identifies other receptor tyrosine kinases (RTKs) that co-exist in cells prior to tepotinib exposure and become more prominent upon tepotinib resistance. In a small cohort of patients with lung cancer with MET genetic alterations treated with tepotinib, gene copy number gains of other RTKs were found at baseline and affected treatment outcome. An Src homology 2 domain-containing phosphatase 2 (SHP2) inhibitor delayed the emergence of tepotinib resistance and synergized with tepotinib in treatment-naive and tepotinib-resistant cells as well as in xenograft models. Alternative signaling pathways potentially diminish the effect of tepotinib monotherapy, and the combination of tepotinib with an SHP2 inhibitor enables the control of tumor growth in cells with MET genetic alterations.", "A patient with the Lambert-Eaton syndrome (LES) and small cell lung cancer developed respiratory failure several hours after verapamil was given. Improvement in respiratory function did not occur when guanidine was given, but was delayed until verapamil was discontinued 3 days later. Although other factors may have contributed to the clinical deterioration of our patient, the temporal relationship to verapamil and the theoretical danger of calcium channel blockade lead us to believe that the drug should be used cautiously in LES.", "Phospholemman (FXYD1) is a single-transmembrane protein regulator of Na,K-ATPase, expressed strongly in heart, skeletal muscle, and brain and phosphorylated by protein kinases A and C at Ser-68 and Ser-63, respectively. Binding of FXYD1 reduces Na,K-ATPase activity, and phosphorylation at Ser-68 or Ser-63 relieves the inhibition. Despite the accumulated information on physiological effects, whole cell studies provide only limited information on molecular mechanisms. As a complementary approach, we utilized purified human Na,K-ATPase (α1β1 and α2β1) reconstituted with FXYD1 or mutants S63E, S68E, and S63E,S68E that mimic phosphorylation at Ser-63 and Ser-68. Compared with control α1β1, FXYD1 reduces Vmax and turnover rate and raises K0.5Na. The phosphomimetic mutants reverse these effects and reduce K0.5Na below control K0.5Na. Effects on α2β1 are similar but smaller. Experiments in proteoliposomes reconstituted with α1β1 show analogous effects of FXYD1 on K0.5Na, which are abolished by phosphomimetic mutants and also by increasing mole fractions of DOPS in the proteoliposomes. Stopped-flow experiments using the dye RH421 show that FXYD1 slows the conformational transition E2(2K)ATP → E1(3Na)ATP but does not affect 3NaE1P → E2P3Na. This regulatory effect is explained simply by molecular modeling, which indicates that a cytoplasmic helix (residues 60-70) docks between the αN and αP domains in the E2 conformation, but docking is weaker in E1 (also for phosphomimetic mutants). Taken together with previous work showing that FXYD1 also raises binding affinity for the Na(+)-selective site III, these results provide a rather comprehensive picture of the regulatory mechanism of FXYD1 that complements the physiological studies.", "In cell-free extracts of Xenopus eggs that support the assembly of replication-competent nuclei, we found that lamin B(3) specifically associates with four polypeptides (termed SLAPs, soluble lamin associated proteins). Here, one SLAP is identified as the nuclear pore complex protein Nup153, one member of the F/GXFG motif-containing nucleoporins. In vitro translated Nup153 and lamin B(3) co-immunoprecipitate, and lamin B(3) interacts specifically with the C-terminal domain of Nup153. During nuclear envelope assembly, other F/GXFG-containing nucleoporins are incorporated into the nuclear envelope preceding lamina assembly. Incorporation of Nup153 occurs at the same time as lamina assembly. When lamina assembly is prevented using the dominant-negative mutant XlaminB delta 2+, Nup153 does not appear at the nuclear envelope, while other F/GXFG-containing nucleoporins and Nup93 are recruited normally. When the lamina of pre-assembled nuclei is disrupted using the same dominant-negative mutant, the distribution of other nucleoporins is unaffected. However, Nup153 recruitment at the nuclear envelope is lost. Our results indicate that both the recruitment and maintenance of Nup153 at the pore are dependent upon the integrity of the lamina." ]

[ "Paget's disease of the breast is a disorder of the nipple-areola complex that, while rare, is often associated with an underlying carcinoma. It is characterized by eczematoid changes of the nipple. Two theories have been proposed to explain the pathogenesis of Paget's disease. The Epidermotropic, which is the most accepted theory, suggests that Paget's cells originate from ductal cancer cells that had migrated from the underlying breast parenchyma. It is supported by the predominance of breast cancer markers found in Paget's disease. This article provides an overview of Paget's disease of the breast with special attention to immunohistochemistry and raises the question of new therapeutic approaches.", "BACKGROUND: An increasing number of neurological surgeons have sought fellowship training in recent years, and previous analyses have suggested these practitioners are more likely to pursue an academic career. Scholarly productivity is a key component in academic advancement.OBJECTIVE: We used the h-index to evaluate whether fellowship training impacts research productivity and whether any differences exist in scholarly output among practitioners in the various neurosurgical subspecialties.METHODS: Online listings from academic neurological surgery departments were used to organize faculty by academic rank and fellowship training. Using the Scopus database, we calculated the h-index for 869 full-time clinical faculty.RESULTS: Mean h-index did not differ between fellowship- and nonfellowship-trained practitioners (h = 12.6 vs. 13.0, P = 0.96). When organized by academic rank, the difference between h-indices of those who completed fellowships was substantially greater at all ranks, with statistical significance at the associate professor rank (P = 0.003). Upon further examination by individual subspecialties, significant differences in relative research impact were noted (P < 0.0001). The stereotactic and functional fellowship was found to have the greatest mean h-index score, whereas the trauma/critical care fellowship had the lowest.CONCLUSION: No significant difference existed between the mean h-index scores of neurological surgeons who completed fellowships and those who did not. However, when stratified by academic rank, a trend was observed showing greater mean h-index scores for those who completed fellowships. This trend persists across nearly all subspecialties. Overall, being a senior faculty member corresponds with a greater h-index score, regardless of whether a fellowship was completed.", "O6-Alkylguanine DNA-alkyltransferase (ATase) repairs toxic, mutagenic and carcinogenic O6-alkylguanine (O6-alkG) lesions in DNA by a highly conserved reaction involving the stoichiometric transfer of the alkyl group to the active centre cysteine residue of the ATase protein. In the Escherichia coli Ada ATase, which is effectively refactory to inhibition by O6-benzylguanine (O6-BzG), the residue corresponding to glycine-160 (G160) for the mammalian proteins of this class is replaced by a tryptophan (W). Therefore, to investigate the potential role of the G160 of the human ATase (hAT) protein in determining sensitivity to O6-BzG, site-directed mutagenesis was used to produce a mutant protein (hATG160W) substituted at position 160 with a W residue. The hATG160W mutant was found to be stably expressed and was 3- and 5-fold more sensitive than hAT to inactivation by O6-BzG, in the absence and presence of additional calf-thymus DNA respectively. A similar, DNA dependent increased sensitivity of the hATG160W mutant relative to wild-type was also found for O6-methylguanine mediated inactivation. The potential role of the W160 residue in stabilising the binding of the O6-alkG to the protein is discussed in terms of a homology model of the structure of hAT. The region occupied by G/W-160 forms the site of a putative hinge that could be important in the conformational change that is likely to occur on DNA binding. Three sequence motifs have been identified in this region which may influence O6-BzG access to the active site; YSGG or YSGGG in mammals (YAGG in E. coli Ogt, YAGS in Dat from Bacillus subtilis), YRWG in E. coli Ada and Salmonella typhimurium (but YKWS in Saccharomyces cerevisiae) or YRGGF in AdaB from B. Subtilis. Finally,conformational and stereoelectronic analysis of the putative transition states for the alkyl transfer from a series of inactivators of hAT, including O6-BzG was undertaken to rationalise the unexpected weak inhibition shown by the alpha-pi-unsaturated electrophiles.", "In multiple sclerosis (MS), inflammation in the central nervous system (CNS) leads to damage of axons and myelin. Early during the clinical course, patients can compensate this damage, but little is known about the changes that underlie this improvement of neurological function. To study axonal changes that may contribute to recovery, we made use of an animal model of MS, which allows us to target inflammatory lesions to the corticospinal tract (CST), a major descending motor pathway. We demonstrate that axons remodel at multiple levels in response to a single neuroinflammatory lesion as follows: (a) surrounding the lesion, local interneurons show regenerative sprouting; (b) above the lesion, descending CST axons extend new collaterals that establish a \"detour\" circuit to the lumbar target area, whereas below the lesion, spared CST axons increase their terminal branching; and (c) in the motor cortex, the distribution of projection neurons is remodeled, and new neurons are recruited to the cortical motor pool. Behavioral tests directly show the importance of these changes for recovery. This paper provides evidence for a highly plastic response of the motor system to a single neuroinflammatory lesion. This framework will help to understand the endogenous repair capacity of the CNS and to develop therapeutic strategies to support it.", "INTRODUCTION: Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice.METHODS: B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated.RESULTS: In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis.CONCLUSIONS: These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.", "Interactive data visualization is imperative in the biological sciences. The development of independent layers of interactivity has been in pursuit in the visualization community. We developed bigPint, a data visualization package available on Bioconductor under the GPL-3 license (https://bioconductor.org/packages/release/bioc/html/bigPint.html). Our software introduces new visualization technology that enables independent layers of interactivity using Plotly in R, which aids in the exploration of large biological datasets. The bigPint package presents modernized versions of scatterplot matrices, volcano plots, and litre plots through the implementation of layered interactivity. These graphics have detected normalization issues, differential expression designation problems, and common analysis errors in public RNA-sequencing datasets. Researchers can apply bigPint graphics to their data by following recommended pipelines written in reproducible code in the user manual. In this paper, we explain how we achieved the independent layers of interactivity that are behind bigPint graphics. Pseudocode and source code are provided. Computational scientists can leverage our open-source code to expand upon our layered interactive technology and/or apply it in new ways toward other computational biology tasks.", "The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a population-based case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically- and geographically-selected populations." ]

[ "The fates of RNA species in a cell are controlled by ribonucleases, which degrade them by exploiting the universal structural 2'-OH group. This phenomenon plays a key role in numerous transformative technologies, for example, RNA interference and CRISPR/Cas13-based RNA editing systems. These approaches, however, are genetic or oligomer-based and so have inherent limitations. This has led to interest in the development of small molecules capable of degrading nucleic acids in a targeted manner. Here we describe click-degraders, small molecules that can be covalently attached to RNA species through click-chemistry and can degrade them, that are akin to ribonucleases. By using these molecules, we have developed the meCLICK-Seq (methylation CLICK-degradation Sequencing) a method to identify RNA modification substrates with high resolution at intronic and intergenic regions. The method hijacks RNA methyltransferase activity to introduce an alkyne, instead of a methyl, moiety on RNA. Subsequent copper(I)-catalyzed azide-alkyne cycloaddition reaction with the click-degrader leads to RNA cleavage and degradation exploiting a mechanism used by endogenous ribonucleases. Focusing on N6-methyladenosine (m6A), meCLICK-Seq identifies methylated transcripts, determines RNA methylase specificity, and reliably maps modification sites in intronic and intergenic regions. Importantly, we show that METTL16 deposits m6A to intronic polyadenylation (IPA) sites, which suggests a potential role for METTL16 in IPA and, in turn, splicing. Unlike other methods, the readout of meCLICK-Seq is depletion, not enrichment, of modified RNA species, which allows a comprehensive and dynamic study of RNA modifications throughout the transcriptome, including regions of low abundance. The click-degraders are highly modular and so may be exploited to study any RNA modification and design new technologies that rely on RNA degradation.", "Accumulating evidence from mice expressing ALS-causing mutations in superoxide dismutase (SOD1) has implicated pathological immune responses in motor neuron degeneration. This includes microglial activation, lymphocyte infiltration, and the induction of C1q, the initiating component of the classic complement system that is the protein-based arm of the innate immune response, in motor neurons of multiple ALS mouse models expressing dismutase active or inactive SOD1 mutants. Robust induction early in disease course is now identified for multiple complement components (including C1q, C4, and C3) in spinal cords of SOD1 mutant-expressing mice, consistent with initial intraneuronal C1q induction, followed by global activation of the complement pathway. We now test if this activation is a mechanistic contributor to disease. Deletion of the C1q gene in mice expressing an ALS-causing mutant in SOD1 to eliminate C1q induction, and complement cascade activation that follows from it, is demonstrated to produce changes in microglial morphology accompanied by enhanced loss, not retention, of synaptic densities during disease. C1q-dependent synaptic loss is shown to be especially prominent for cholinergic C-bouton nerve terminal input onto motor neurons in affected C1q-deleted SOD1 mutant mice. Nevertheless, overall onset and progression of disease are unaffected in C1q- and C3-deleted ALS mice, thus establishing that C1q induction and classic or alternative complement pathway activation do not contribute significantly to SOD1 mutant-mediated ALS pathogenesis in mice.", "We investigated the requirements for selenocysteine insertion at single or multiple UGA codons in eukaryotic selenoproteins. Two functional SECIS elements were identified in the 3' untranslated region of the rat selenoprotein P mRNA, with predicted stem-loops and critical nucleotides similar to those in the SECIS elements in the type I iodothyronine 5' deiodinase (5'DI) and glutathione peroxidase selenoprotein mRNAs. Site-directed mutational analyses of three SECIS elements confirmed that conserved nucleotides in the loop and in unpaired regions of the stem are critical for activity. This indicates that multiple contact sites are required for SECIS function. Stop codon function at any of five out-of-context UGA codons in the 5'DI mRNA was suppressed by SECIS elements from the 5'DI or selenoprotein P genes linked downstream. Thus, the presence of SECIS elements in eukaryotic selenoprotein mRNAs permits complete flexibility in UGA codon position.", "Polycystic kidney disease (PKD) includes a group of disorders that are characterized by the presence of cysts in the kidney and other organs, including the pancreas. Here we show that in orpk mice, a model system for PKD that harbors a mutation in the gene that encodes the polaris protein, pancreatic defects start to occur at the end of gestation, with an initial expansion of the developing pancreatic ducts. Ductal dilation continues rapidly after birth and results in the formation of large, interconnected cysts. Expansion of pancreatic ducts is accompanied by apoptosis of neighboring acinar cells, whereas endocrine cell differentiation and islet formation appears to be unaffected. Polaris has been shown to co-localize with primary cilia, and these structures have been implicated in the formation of renal cysts. In the orpk pancreas, cilia numbers are reduced and cilia length is decreased. Expression of polycystin-2, a protein involved in PKD, is mislocalized in orpk mice. Furthermore, the cellular localization of beta-catenin, a protein involved in cell adhesion and Wnt signaling, is altered. Thus, polaris and primary cilia function are required for the maturation and maintenance of proper tissue organization in the pancreas.", "OBJECTIVE: Listening to Mozart K.448 has been demonstrated to improve spatial task scores, leading to what is known as the Mozart effect. Our previous work revealed the positive effects of Mozart K.448 in reducing epileptiform discharges in children with epilepsy. However, the mechanism remains unclear. parasympathetic activation has been shown to help seizure control in many studies. In this study, we investigated the effect of Mozart music on epileptiform discharges and autonomic activity.METHODS: Sixty-four epileptic children with epileptiform discharges were included. They all received electroencephalogram and electrocardiogram examinations simultaneously before, during, and after listening to Mozart K.448 or K.545. The total number of epileptiform discharges during each session (before, during, and after music) were divided by the duration (in minutes) of the session and then compared. Heart rate variability including time and frequency domain analysis was used to represent the autonomic function.RESULTS: The results showed that epileptiform discharges were significantly reduced during and right after listening to Mozart music (33.3 ± 31.1% reduction, p<0.001, during Mozart K.448 and 38.6 ± 43.3% reduction, p<0.001, during Mozart K.545) (28.1 ± 43.2% reduction, p<0.001, after Mozart K.448 and 46.0 ± 40.5% reduction, p<0.001, after Mozart K.545). No significant difference was noticed between the two pieces of music. The reduction was greatest in patients with generalized seizures and discharges. Significant increases in high-frequency (HF), the square root of the mean squared differences of successive RR intervals (RMSSD), the standard deviation of differences between adjacent RR intervals (SDSD), and a decrease in mean beats per minute (bpm) were found during listening to Mozart music. Most of the patients with reduced epileptiform discharges also showed a decreased LF/HF ratio, low-frequency normalized units (LF nu), mean bpm, and an increased high-frequency normalized units (HF nu).CONCLUSIONS: Listening to Mozart music decreased epileptiform discharges in children with epilepsy. The majority of these patients showed an increase in parasympathetic tone during music exposure.SIGNIFICANCE: Our results suggested that Mozart music stimuli induced parasympathetic activation which may be involved in the effect of music in reducing epileptiform discharges and the recurrence rate of seizures.", "We report a female teenager who presented with a gastrointestinal stromal tumor of the stomach and a paraganglioneuroma. She later developed a pulmonary chondroma, fulfilling the requirements of Carney's triad. This patient demonstrates the course of the disease, which included severe emotional symptoms. She died, at 30 years of age, 16 years after the onset of disease, riddled with metastases. Many patients with Carney's triad survive for many years, but we can not predict the prognosis in any patient. During her lifetime, the patient had considerable emotional suffering, perhaps because of her disease.", "Budding yeast RNA polymerase III (Pol III) contains a small, essential subunit, named C11, that is conserved in humans and shows a strong homology to TFIIS. A mutant Pol III, heterocomplemented with Schizosaccharomyces pombe C11, was affected in transcription termination in vivo. A purified form of the enzyme (Pol III Delta), deprived of C11 subunit, initiated properly but ignored pause sites and was defective in termination. Remarkably, Pol III Delta lacked the intrinsic RNA cleavage activity of complete Pol III. In vitro reconstitution experiments demonstrated that Pol III RNA cleavage activity is mediated by C11. Mutagenesis in C11 of two conserved residues, which are critical for the TFIIS-dependent cleavage activity of Pol II, is lethal. Immunoelectron microscopy data suggested that C11 is localized on the mobile thumb-like stalk of the polymerase. We propose that C11 allows the enzyme to switch between an RNA elongation and RNA cleavage mode and that the essential role of the Pol III RNA cleavage activity is to remove the kinetic barriers to the termination process. The integration of TFIIS function into a specific Pol III subunit may stem from the opposite requirements of Pol III and Pol II in terms of transcript length and termination efficiency." ]

[ "OBJECTIVE: To critically review the effectiveness of the novel oral anticoagulants (rivaroxaban, dabigatran, ximelagatran, and apixaban) in the treatment of acute venous thromboembolism.DESIGN: Systematic review and random effects meta-analysis. Data were extracted independently by two investigators. An adjusted indirect comparison was performed to compare between novel oral anticoagulants.DATA SOURCES: Medline, Embase, and Cochrane Library (from inception to April 2012). Hand searching of relevant scientific works and contact with experts.STUDY SELECTION: Randomised controlled trials of novel oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism. Selected outcomes were recurrent events, major bleeding, and all cause mortality.RESULTS: Nine studies met our inclusion criteria, involving 16,701 patients evaluated for efficacy and 16,611 for safety. Data were stratified according to different novel oral anticoagulants. For recurrent acute venous thromboembolism, there were no significant differences in events rates between any of the anticoagulants and conventional treatment (rivaroxaban (four studies): relative risk 0.85, 95% confidence interval 0.55 to 1.31; dabigatran (two studies): 1.09, 0.76 to 1.57; ximelagatran (two studies): 1.06, 0.62 to 1.80; and apixaban (one study): 0.98, 0.20 to 4.79). Rivaroxaban reduced the risk of major bleeding compared with conventional treatment (0.57, 0.39 to 0.84), whereas other novel oral anticoagulants did not (0.76 (0.49 to 1.18) for dabigatran; 0.54 (0.28 to 1.03) for ximelagatran; 2.95 (0.12 to 71.82) for apixaban). For all cause mortality there were no significant differences between the novel oral anticoagulants and conventional treatment (0.96 (0.72 to 1.27) for rivaroxaban; 1.00 (0.67 to 1.50) for dabigatran; 0.67 (0.42 to 1.08) for ximelagatran; 6.89 (0.36 to 132.06) for apixaban). The adjusted indirect comparison between rivaroxaban and dabigatran did not show superiority of either drug over the others for major bleeding (0.75, 0.41 to 1.34) or the other endpoints.CONCLUSIONS: Compared with vitamin K antagonists, the novel oral anticoagulants had a similar risk of recurrence of acute venous thromboembolism and all cause mortality, though rivaroxaban was associated with a reduced risk of bleeding.", "To classify the cerebral cavernous malformations and to investigate the natural history of cavernous malformations according to the classification, 41 patients with 61 cavernous malformations (40 cavernous malformations from 22 patients treated with gamma knife surgery) were regularly followed up using magnetic resonance (MR) imaging for a mean period of 25.5 months in treated cavernous malformations and 20.7 months in untreated cavernous malformations, respectively. Cavernous malformations were classified into four types: type I, extralesional gross hemorrhage beyond cavernous malformation; type II, mixture of subacute and chronic hemorrhage; type III, area of hemosiderin with small central core; and type IV, area of hemosiderin deposition without central core. Follow-up MR images were analyzed to evaluate changes in size, signal intensity, rebleeding, and perilesional adverse reaction of irradiation. A total of 61 cavernous malformations including 17 in type I, 23 in type II, 10 in type III, and 11 in type IV showed usual degradation of blood product in 22 cavernous malformations, no change in shape and signal intensity in 31 cavernous malformations, and eight cavernous malformations with rebleedings in the serial MR images. In these eight cavernous malformations with rebleedings, six occurred in type II and two in type III, but none in type I or IV. Rebleedings were more frequent in type II than in other types (p = 0.044). Adverse reaction of irradiation was observed in five of 22 patients treated with gamma knife surgery. Although most cerebral cavernous malformations showed evolution of hemorrhage or no change in size or shape on follow-up MR images, cerebral cavernous malformations represented as mixture of subacute and chronic hemorrhage with hemosiderin rim (type II) have a higher frequency to rebleed than other types of cerebral cavernous malformations. Cerebral cavernous malformations represented as hemosiderin deposition without central core (type IV) have a lower tendency to rebleed than other types and do not need any treatment. Most of the adverse reaction of irradiation after gamma knife surgery around cavernous malformations are transient findings and are considered to be perilesional edema.", "Genome integrity in eukaryotes depends on licensing mechanisms that prevent loading of the minichromosome maintenance complex (MCM2-7) onto replicated DNA during S phase. Although the principle of licensing appears to be conserved across all eukaryotes, the mechanisms that control it vary, and it is not clear how licensing is regulated in plants. In this work, we demonstrate that subunits of the MCM2-7 complex are coordinately expressed during Arabidopsis (Arabidopsis thaliana) development and are abundant in proliferating and endocycling tissues, indicative of a role in DNA replication. We show that endogenous MCM5 and MCM7 proteins are localized in the nucleus during G1, S, and G2 phases of the cell cycle and are released into the cytoplasmic compartment during mitosis. We also show that MCM5 and MCM7 are topologically constrained on DNA and that the MCM complex is stable under high-salt conditions. Our results are consistent with a conserved replicative helicase function for the MCM complex in plants but not with the idea that plants resemble budding yeast by actively exporting the MCM complex from the nucleus to prevent unauthorized origin licensing and rereplication during S phase. Instead, our data show that, like other higher eukaryotes, the MCM complex in plants remains in the nucleus throughout most of the cell cycle and is only dispersed in mitotic cells.", "Most individuals with osteogenesis imperfecta (OI) are heterozygous for dominant mutations in one of the genes that encode the chains of type I collagen. Each of the more than 30 mutations characterized to date has been unique to the affected member(s) of the family. We have determined that two individuals with a progressive deforming variety of OI, OI type III, have the same new dominant mutation [alpha 1(I)gly154 to arg] and that two unrelated infants with perinatal lethal OI, OI type II, share a second new dominant mutation [alpha 1(I)gly1003 to ser]. These mutations occurred at CpG dinucleotides, in a manner consistent with deamination of a methylated cytosine residue, and raise the possibility that CpG dinucleotides are common sites of recurrent mutations in collagen genes. Further, these findings confirm that the OI type-III phenotype, previously thought to be inherited in an autosomal recessive manner, can result from new dominant mutations in the COL1A1 gene of type-I collagen.", "BACKGROUND: Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer's disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.METHODS: In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13-22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.RESULTS: We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.", "Approximately 1 million tons of Agave tequilana plants are processed annually by the Mexican Tequila industry generating vast amounts of agricultural waste. The aim of this study was to investigate the potential use of Agave tequilana waste as substrate for the production of commercially important enzymes. Two strains of Aspergillus niger (CH-A-2010 and CH-A-2016), isolated from agave fields, were found to grow and propagate in submerged cultures using Agave tequilana waste as substrate. Isolates showed simultaneous extracellular inulinase, xylanase, pectinase, and cellulase activities. Aspergillus CH-A-2010 showed the highest production of inulinase activity (1.48 U/ml), whereas Aspergillus niger CH-A-2016 produced the highest xylanase (1.52 U/ml) and endo-pectinase (2.7U/ml) activities. In both cases production of enzyme activities was significantly higher on Agave tequilana waste than that observed on lemon peel and specific polymeric carbohydrates. Enzymatic hydrolysis of raw A. tequilana stems and leaves, by enzymes secreted by the isolates yielded maximum concentrations of reducing sugars of 28.2 g/l, and 9.9 g/l respectively. In conclusion, Agave tequilana waste can be utilized as substrate for the production of important biotechnological enzymes.", "Author information:(1)Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.(2)Department of Pediatrics, Yokohama City University, School of Medicine, Yokohama, Kanagawa, Japan.(3)Division of Clinical Research Planning, Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan.(4)Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, UK.(5)Department of Haematology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.(6)Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, OH, US.(7)Division of Pediatric Hematology/Oncology, Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, US.(8)Assistance Publique Hôpitaux de Paris, Hôpital Necker Enfants Malades, Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de référence M3C, Paris, France.(9)University Paris Descartes, Paris, France.(10)Université Paris Descartes, Inserm Unité Mixte de Recherche (UMR)-S, Paris, France.(11)University Paris Descartes, INSERM UMR 1147, Paris, France.(12)Influenza and Emerging Respiratory Pathogens, BC Centre for Disease Control, Vancouver, BC, Canada.(13)Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.(14)Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.(15)Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.(16)Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.(17)Department of Cardiology, Kanagawa Children's Medical Center, Yokohama, Japan.(18)Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.(19)Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.(20)Division of Pediatric Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.(21)Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada. shinya.ito@sickkids.ca." ]

[ "BACKGROUND: We describe the clinical characteristics and epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in children with cystic fibrosis (CF) from the U.S. CF center with the highest MRSA prevalence.METHODS: Medical records of children with CF were retrospectively reviewed from 1997-2009. MRSA clinical isolates from 2007-2009 were analyzed by polymerase chain reaction and pulsed field gel electrophoresis.RESULTS: The prevalence of MRSA was 1% in 1997 and 49% in 2009. Fifty-five children (26%) had persistent MRSA infection. Sixty-eight percent of MRSA isolates were hospital-associated (HA) MRSA, of which 52% were pulsed-field type USA 100. Ninety-three percent of HA MRSA isolates were clindamycin resistant. Twelve children acquired MRSA before 1 year of age, 83% of whom were hospitalized prior to acquisition of MRSA. Ten of 11 sibling pairs carried indistinguishable MRSA strains. Children with persistent MRSA were hospitalized more often (P = .01), required inhaled medications more frequently (P = .01), and had higher rates of Pseudomonas aeruginosa coinfection (P < .001).CONCLUSION: MRSA prevalence in children with CF is increasing, and most children are infected with HA MRSA. Exposure to health care facilities and gastrointestinal surgeries may facilitate early acquisition of MRSA. Siblings carry indistinguishable MRSA strains, indicating household transmission of MRSA. Children with persistent MRSA had worse pulmonary morbidity. Coinfection with MRSA and P aeruginosa is likely associated with further increased pulmonary morbidity.", "Five per cent of patients with primary Sjogren's syndrome (pSS) develop malignant non-Hodgkin's lymphoma (NHL), usually of the mucosa-associated lymphoid tissue (MALT) and most frequently located in the major salivary glands. Rituximab (RTX), a chimeric monoclonal antibody against the CD20 molecule expressed on the surface of mature B cells that has been approved for the treatment of NHL, has been used to treat pSS-associated lymphoma. We have described two cases: one with MALT lymphoma in the parotid glands and the other with a rare thymus lymphoma accompanied by the rare complication of a bullous pneumopathy. Both were treated with RTX at haematological doses, which was unsuccessful in the patient with a salivary lymphoma; in the case of the patient with a thymus lymphoma, the mediastinum mass disappeared and did not relapse. Both patients experienced an improvement in the subjective symptoms of dryness, and their Schirmer's test and scialoscintigraphy results stabilised. The pulmonary bullae remained unchanged.", "OBJECTIVE: Marfan's syndrome is a heritable connective tissue disorder that has been associated with intracranial aneurysms. However, the prevalence of intracranial aneurysms in Marfan's syndrome is unknown and pathological studies of affected vessels have not been reported. We therefore examined the neuropathological findings in a group of patients with Marfan's syndrome.METHODS: We identified all patients with Marfan's syndrome in whom postmortem examination had been performed at the Mayo Clinic between 1969 and 1993.RESULTS: Autopsy included examination of the brain in seven patients with Marfan's syndrome (five men and two women with a mean age of 28 yr). Each of two patients had one or more intracranial aneurysms. The first patient, a 32-year-old man who died as a result of aortic dissection, was observed to have an incidental saccular supraclinoid carotid artery aneurysm (7 mm). Microscopic examination of the remainder of the cerebral arteries revealed duplication and fragmentation of the internal elastic lamina. The second patient, a 20-year-old man who died as a result of a subarachnoid hemorrhage, had ruptured saccular supraclinoid carotid artery (3 mm) and anterior cerebral artery (20 mm) aneurysms as well as unruptured fusiform middle cerebral artery (18 mm) and posterior cerebral artery (13 mm) aneurysms. Microscopic examination of the cerebral arteries revealed widespread changes consisting of intimal proliferation, medial degeneration, and fragmentation of the internal elastic lamina.CONCLUSION: These findings confirm an association between Marfan's syndrome and intracranial aneurysms. Microscopic involvement of cerebral arteries in Marfan's syndrome may be variable, even among those with intracranial aneurysms.", "Primary cilia are nonmotile organelles implicated in signaling and sensory functions. Understanding how primary cilia assemble could shed light on the many human diseases caused by mutations in ciliary proteins. The centrosomal protein CP110 is known to suppress ciliogenesis through an unknown mechanism. Here, we report that CP110 interacts with CEP290--a protein whose deficiency is implicated in human ciliary disease--in a discrete complex separable from other CP110 complexes involved in regulating the centrosome cycle. Ablation of CEP290 prevents ciliogenesis without affecting centrosome function or cell-cycle progression. Interaction with CEP290 is absolutely required for the ability of CP110 to suppress primary cilia formation. Furthermore, CEP290 and CP110 interact with Rab8a, a small GTPase required for cilia assembly. Depletion of CEP290 interferes with localization of Rab8a to centrosomes and cilia. Our results suggest that CEP290 cooperates with Rab8a to promote ciliogenesis and that this function is antagonized by CP110.", "Genome integrity in eukaryotes depends on licensing mechanisms that prevent loading of the minichromosome maintenance complex (MCM2-7) onto replicated DNA during S phase. Although the principle of licensing appears to be conserved across all eukaryotes, the mechanisms that control it vary, and it is not clear how licensing is regulated in plants. In this work, we demonstrate that subunits of the MCM2-7 complex are coordinately expressed during Arabidopsis (Arabidopsis thaliana) development and are abundant in proliferating and endocycling tissues, indicative of a role in DNA replication. We show that endogenous MCM5 and MCM7 proteins are localized in the nucleus during G1, S, and G2 phases of the cell cycle and are released into the cytoplasmic compartment during mitosis. We also show that MCM5 and MCM7 are topologically constrained on DNA and that the MCM complex is stable under high-salt conditions. Our results are consistent with a conserved replicative helicase function for the MCM complex in plants but not with the idea that plants resemble budding yeast by actively exporting the MCM complex from the nucleus to prevent unauthorized origin licensing and rereplication during S phase. Instead, our data show that, like other higher eukaryotes, the MCM complex in plants remains in the nucleus throughout most of the cell cycle and is only dispersed in mitotic cells.", "Author information:(1)Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.(2)Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Departamento de Ciências Biológicas, Insituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.(3)Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma 88806-000, Santa Catarina, Brazil.(4)Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, Minas Gerais, Brazil.(5)Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.(6)Fundação Hospitalar do Estado de Minas Gerais, Hospital Eduardo de Menezes, Belo Horizonte 30622-020, Minas Gerais, Brazil.(7)Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, Minas Gerais, Brazil.(8)Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.(9)Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, Minas Gerais, Brazil. Electronic address: eduardoferrazcoelho@yahoo.com.br.", "Author information:(1)Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region, Russian Federation; Biology Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia; Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation. Electronic address: vuversky@health.usf.edu.(2)Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation; St. Petersburg State Polytechnical University, St. Petersburg, Russian Federation.(3)AnalizaDx Inc., 3615 Superior Ave., Suite 4407B, Cleveland, OH 44114, USA.", "Normal B lymphocytes receive signals from B-cell antigen receptor (BCR) that are triggered by binding of the BCR to an external antigen. Tonic signaling through the BCR provides growth and signals to chronic lymphocytic leukemia (CLL) cells, and plays an important role in the pathogenesis and progression of the disease. Antigen engagement of BCR is followed by intracellular recruitment and activation of BCR-associated kinases including spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk) and phosphatidylinositol 3-kinases (PI3K). Inhibition of signaling pathways downstream of the BCR induces disruption of chemokine-mediated CLL cell migration and cell killing. BCR signal transduction inhibitors represent a promising new strategy for targeted CLL treatment. A number of therapeutic agents have recently been developed with significant activity in CLL. The compounds that are currently investigated in patients with CLL include ibrutinib -inhibitor of Btk, fostamatinib-inhibitor of Syk and idelalisib (GS-1101) -a specific isoform of the PI3K (PI3K) inhibitor. The clinical activity of ibrutinib, GS-1101 and fostamatinib in patients with CLL is associated with marked lymphocytosis due to release of tumor cells from the lymph nodes into the peripheral blood. Further studies are ongoing with single agents and their combinations with other targeted and conventional therapies. This article will review the preclinical rationale of BCR signaling inhibitors in the treatment of CLL, and the clinical evidence supporting the use of these agents in CLL patients.", "This study aimed to evaluate the quality of the royal jelly produced by Apis mellifera bees in the presence of different iron concentrations (ferrous sulfate heptahydrate-0, 25, 50, and 100 mg L-1). Two-dimensional electrophoresis was used for the fractionation of royal jelly proteins, and iron level was quantified using flame atomic absorption spectrometry technique. The proteins were identified using electrospray ionisation mass spectrometry. Analysis of variance followed by the Tukey test (P < 0.05) was utilised. Dietary supplementation with mineral Fe affected the protein content and number of proteins in the experimental period. Further, the diet containing the highest iron concentration showed a greater number of spots containing iron, as well as in the abdomen of the bees. The most protein containing Fe were classified as major royal jelly proteins. These results showed that Fe influenced the quality of royal jelly and can improve its nutritional value.", "Honey bees provision glandular secretions in the form of royal jelly as larval nourishment to developing queens. Exposure to chemicals and nutritional conditions can influence queen development and thus impact colony fitness. Previous research reports that royal jelly remains pesticide-free during colony-level exposure and that chemical residues are buffered by the nurse bees. However, the impacts of pesticides can also manifest in quality and quantity of royal jelly produced by nurse bees. Here, we tested how colony exposure to a multi-pesticide pollen treatment influences the amount of royal jelly provisioned per queen and the additional impacts on royal jelly nutritional quality. We observed differences in the metabolome, proteome, and phytosterol compositions of royal jelly synthesized by nurse bees from multi-pesticide exposed colonies, including significant reductions of key nutrients such as 24-methylenecholesterol, major royal jelly proteins, and 10-hydroxy-2-decenoic acid. Additionally, quantity of royal jelly provisioned per queen was lower in colonies exposed to pesticides, but this effect was colony-dependent. Pesticide treatment had a greater impact on royal jelly nutritional composition than the weight of royal jelly provisioned per queen cell. These novel findings highlight the indirect effects of pesticide exposure on queen developmental nutrition and allude to social consequences of nurse bee glandular degeneration.", "Intrinsic radioresistance, tumor hypoxia and ability of cancer cells to undergo rapid repopulation during radiotherapy are associated with failure of radiotherapy. Tumors with low alpha/beta-ratio values or hypoxic tumors unable to undergo re-oxygenation, are unlikely to be eradicated with standard radiotherapy. Although the therapeutic efficacy of accelerated regimens based on low-dose per fraction may be high since they minimize the adverse role of rapid tumor repopulation, the cellular compartment with low alpha/beta-ratio values (i.e. hypoxic cells) remains a limiting factor. Accelerated hypofractionation, which may be more effective in such tumors, cannot be safely applied unless normal tissues are protected. In the present study we assessed the feasibility of hypofractionated and accelerated radiotherapy supported by cytoprotection (HypoARC) with high dose daily amifostine. Fifteen breast cancer patients with locally advanced disease entered radiation-dose escalation protocoL Twelve consecutive fractions of 3.5-4Gy (5 fractions/week) were given to the breast/chest wall, supraclavicular and axillary area, within 17 days. A high dose of amifostine, at 1,000 mg flat dose, was given 20 minutes before each radiotherapy fraction. Amifostine administration was well- tolerated with minor side-effects (vomiting in 6 out of 15 and hypotention in 2 out of 15 patients). Radiation induced acute skin toxicity was negligible (grade 3 in 1 out of 15 patients). Ten out of 15 patients survived more than 12 months and 7 out of 15 more than 18 months following HypoARC. None of these patients showed any signs of late sequellae, such as lung and myoskeletal fibrosis, or brachial plexopathy. Complete and partial responses were obtained in 11 out of 15 (73%) and in 4 out of 15 (27%) patients, respectively. High dose daily amifostine during hypofractionated radiotherapy is feasible. HypoARC regimen is well-tolerated, effective and has minimal acute and late toxicity to normal breast, chest and axillary tissues.", "Understanding the effect of pesticides on the survival of honeybee colonies is important because these pollinators are reportedly declining globally. In the present study, we examined the changes in the head proteome of nurse honeybees exposed to individual and combined pesticides (the fungicide pyraclostrobin and the insecticide fipronil) at field-relevant doses (850 and 2.5 ppb, respectively). The head proteomes of bees exposed to pesticides were compared with those of bees that were not exposed, and proteins with differences in expression were identified by mass spectrometry. The exposure of nurse bees to pesticides reduced the expression of four of the major royal jelly proteins (MRJP1, MRJP2, MRJP4, and MRJP5) and also several proteins associated with carbohydrate metabolism and energy synthesis, the antioxidant system, detoxification, biosynthesis, amino acid metabolism, transcription and translation, protein folding and binding, olfaction, and learning and memory. Overall, when pyraclostrobin and fipronil were combined, the changes in protein expression were exacerbated. Our results demonstrate that vital proteins and metabolic processes are impaired in nurse honeybees exposed to pesticides in doses close to those experienced by these insects in the field, increasing their susceptibility to stressors and affecting the nutrition and maintenance of both managed and natural colonies.", "Guillain-Barré syndrome (GBS) is an autoimmune disease that leads to an axonal demyelination and/or degeneration of peripheral nerves through molecular mimicry. The usual pattern is an ascending areflexic motor paralysis with a distinct cerebral-spinal fluid (CSF) showing elevated protein level without accompanying pleocytosis. Diagnosis is essentially clinical, but the CSF studies and electrodiagnostic features may help confirming the diagnosis. Prognosis is usually good, with complete recovery in 80-85% of the cases. However, 10% will remain with permanent neurological damage and about 5% will die. Immunomodulation is the goal treatment, but supportive care is of the utmost importance in the treatment and prevention of complications. The purpose of this work was to review all GBS diagnosed between 1st January 1997 and 31st December 2001, in patients 18 or older admitted to Hospital Pedro Hispano (Portugal). During the 5-year study period, 62446 patients were admitted to hospital, of which 15 with GBS. Thirteen had a good evolution: 10 with total recovery over a period of a maximum of six months; one remain with serious neurological damage at 2 years of evolution and the remaining one died with a pure motor form of GBS (both had a previous gastrointestinal infection). The results of this review are in accordance with what is described in the literature, regarding incidence, epidemiological data and clinical behaviour.", "Royal jelly (RJ) is a yellowish-white and acidic secretion of hypopharyngeal and mandibular glands of nurse bees used to feed young worker larvae during the first three days and the entire life of queen bees. RJ is one of the most appreciated and valued natural product which has been mainly used in traditional medicines, health foods, and cosmetics for a long time in different parts of the world. It is also the most studied bee product, aimed at unravelling its bioactivities, such as antimicrobial, antioxidant, anti-aging, immunomodulatory, and general tonic action against laboratory animals, microbial organisms, farm animals, and clinical trials. It is commonly used to supplement various diseases, including cancer, diabetes, cardiovascular, and Alzheimer's disease. Here, we highlight the recent research advances on the main bioactive compounds of RJ, such as proteins, peptides, fatty acids, and phenolics, for a comprehensive understanding of the biochemistry, biological, and pharmaceutical responses to human health promotion and life benefits. This is potentially important to gain novel insight into the biological and pharmaceutical properties of RJ.", "BACKGROUND: A novel meningococcal multicomponent vaccine, 4CMenB (Bexsero®), has been approved in Europe, Canada, Australia and US. The potential impact of 4CMenB on strain coverage is being estimated by using Meningococcal Antigen Typing System (MATS), an ELISA assay which measures vaccine antigen expression and diversity in each strain. Here we show the genetic characterization and the 4CMenB potential coverage of Spanish invasive strains (collected during one epidemiological year) compared to other European countries and discuss the potential reasons for the lower estimate of coverage in Spain.MATERIAL AND METHODS: A panel of 300 strains, a representative sample of all serogroup B Neisseria meningitidis notified cases in Spain from 2009 to 2010, was characterized by multilocus sequence typing (MLST) and FetA variable region determination. 4CMenB vaccine antigens, PorA, factor H binding protein (fHbp), Neisseria Heparin Binding Antigen (NHBA) and Neisserial adhesin A (NadA) were molecularly typed by sequencing. PorA coverage was assigned to strain with VR2 = 4. The levels of expression and cross-reactivity of fHbp, NHBA and NadA were analyzed using MATS ELISA.FINDINGS: Global estimated strain coverage by MATS was 68.67% (95% CI: 47.77-84.59%), with 51.33%, 15.33% and 2% of strains covered by one, two and three vaccine antigens, respectively. The predicted strain coverage by individual antigens was: 42% NHBA, 36.33% fHbp, 8.33% PorA and 1.33% NadA. Coverage within the most prevalent clonal complexes (cc) was 70.37% for cc 269, 30.19% for cc 213 and 95.83% for cc 32.CONCLUSIONS: Clonal complexes (cc) distribution accounts for variations in strain coverage, so that country-by-country investigations of strain coverage and cc prevalence are important. Because the cc distribution could also vary over time, which in turn could lead to changes in strain coverage, continuous detailed surveillance and monitoring of vaccine antigens expression is needed in those countries where the multicomponent vaccine is introduced. This is really important in countries like Spain where most of the strains are predicted to be covered by only one vaccine antigen and the chance for escape mutants to emerge with vaccine use is higher. Based on the observed data, cc213 should receive special attention as it is associated with low predicted strain coverage, and has recently emerged in Spain.", "Author information:(1)MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China. Electronic address: chenjiaming000@126.com.(2)MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China. Electronic address: caocao2008@zju.edu.cn.(3)MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China. Electronic address: cyc000@yeah.net.(4)MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China. Electronic address: tukh@zju.edu.cn.(5)MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China. Electronic address: hjwang@zju.edu.cn.(6)MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China. Electronic address: lqwang@zju.edu.cn." ]

[ "OBJECTIVE: To assess ictal adiponectin (ADP) levels before and after acute abortive treatment in women episodic migraineurs.METHODS: Peripheral blood specimens were collected from women episodic migraineurs before and after acute abortive treatment with sumatriptan/naproxen sodium vs placebo. Univariate and multivariate models were utilized to examine the relationship between serum total ADP (T-ADP), ADP oligomers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]-ADP), and ADP ratio levels and pain severity. Paired t-tests and random intercept longitudinal models were utilized to assess the mean changes in T-ADP, ADP oligomers, and ratios over time in treatment responders and nonresponders.RESULTS: Twenty participants (11 responders, 9 nonresponders) have been studied to date. In all participants, increases in the HMW : LMW ADP ratio were associated with an increase in pain severity. For every 1 point increase in the HMW : LMW ratio, pain severity increased by 0.22 (Confidence Interval [CI]: 0.07, 0.37; P = .004). In contrast, for every 0.25 μg/mL increase in LMW-ADP, pain severity decreased by 0.20 (CI: -0.41, -0.002; P = .047). In treatment responders, T-ADP levels were reduced at 30 minutes (12.52 ± 3.4; P = .03), 60 minutes (12.32 ± 3.2; P = .017), and 120 minutes (12.65 ± 3.2; P = .016) after treatment as compared with onset (13.48 ± 3.8). Additionally, in responders, the HMW : LMW ratio level was greater at pain onset (3.70 ± 1.9 μg/mL) as compared with nonresponders (2.29 ± 0.71 μg/mL), P = .050. Responders also showed a decrease in the HMW : LMW ratio at 60 minutes (2.37 ± 1.1; P = .002) and 120 minutes (2.76 ± 1.4; P = .02) after treatment as compared with onset (3.70 ± 1.9). These changes in responders remained significant after adjusting for covariates, including measured body mass index (m-BMI). Although nonresponders showed no significant changes in unadjusted T-ADP or ADP oligomer or ratio levels, the HMW : LMW ratio was increased in nonresponders after adjustments (P = .025).CONCLUSION: In this pilot study of women episodic migraineurs, the HMW : LMW ADP ratio level was associated with migraine severity and predictive of acute treatment response. ADP and the HMW : LMW ratio of ADP represent potential novel biomarkers and drug targets for episodic migraine.", "Milvexian (BMS-986177/JNJ-70033093) is a small molecule, active-site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two-part, double-blind, placebo-controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200- and 500-mg panels investigated the pharmacokinetic impact of a high-fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once- or twice-daily) or placebo for 14 days. All milvexian dosing regimens were safe and well-tolerated, with only mild treatment-emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half-life (T1/2 ) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose-proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose-dependent fashion. In MAD panels, steady-state milvexian plasma concentration was reached within 3 and 6 dosing days with once- and twice-daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.", "Capmatinib (Tabrecta™) is an oral, small molecule mesenchymal-epithelial transition (MET) inhibitor being developed by Novartis Oncology, under a license from Incyte Corporation, for the treatment of lung cancer. Capmatinib targets and selectively binds to MET, including the mutant variant produced by exon 14 skipping, and inhibits cancer cell growth driven by the mutant MET variant. In May 2020, oral capmatinib received its first global approval in the USA for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumours have a mutation that leads to MET exon 14 skipping, as detected by an FDA-approved test. Clinical development for the treatment of glioblastoma, liver cancer, malignant melanoma, breast cancer, colorectal cancer, head and neck cancer and solid tumours is ongoing in several countries. This article summarizes the milestones in the development of capmatinib leading to its first approval.", "BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail.METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability.RESULTS: In the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death.CONCLUSIONS: These results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.", "A century of traditional vaccinology lost the fight against meningococcus serogroup B (MenB). However, thanks to an innovative genome-based approach, the first broadly effective MenB vaccine, Bexsero® (GSK Vaccines), was developed and has been licensed for use in various age groups by the European Commission and other regulatory authorities. Genes encoding for the main meningococcus B antigens were identified and screened in order to achieve a broadly protective vaccine, taking into account the fact that meningococcus B has many different subtypes whose membrane proteins may be different. Since the antigens selected for Bexsero® are also harbored by meningococci belonging to other serogroups there may be the potential for Bexsero® to offer a certain level of protection against non-B serogroups. Therefore preliminary studies were carried out to investigate the potential of the vaccine to also provide a degree of cross protection against non-B serogroups. Here we review the potential for Bexsero® to offer a certain level of protection against the diversity of meningococcus type B subtypes and its potential ability to offer some cross protection from non-B serogroups. Lastly, we describe the future perspectives in pentavalent meningococcal vaccine (ABCWY) development which hopefully will result in a vaccine able to help prevent Invasive Meningococcal Diseases (IMD) from the majority of currently circulating meningococcal strains.", "DNA methylation plays a critical role in the regulation of gene expression. Most studies of DNA methylation have been performed in herbaceous plants, and little is known about the methylation patterns in tree genomes. In the present study, we generated a map of methylated cytosines at single base pair resolution for Betula platyphylla (white birch) by bisulfite sequencing combined with transcriptomics to analyze DNA methylation and its effects on gene expression. We obtained a detailed view of the function of DNA methylation sequence composition and distribution in the genome of B. platyphylla. There are 34,460 genes in the whole genome of birch, and 31,297 genes are methylated. Conservatively, we estimated that 14.29% of genomic cytosines are methylcytosines in birch. Among the methylation sites, the CHH context accounts for 48.86%, and is the largest proportion. Combined transcriptome and methylation analysis showed that the genes with moderate methylation levels had higher expression levels than genes with high and low methylation. In addition, methylated genes are highly enriched for the GO subcategories of binding activities, catalytic activities, cellular processes, response to stimulus and cell death, suggesting that methylation mediates these pathways in birch trees.", "Choroid plexus neoplasms are rare epithelial tumors of the central nervous system. A carcinoma of the choroid plexus occurred in a child from a family with the breast cancer-sarcoma syndrome (Li-Fraumeni or SBLA syndrome), an inherited condition characterized by the development of diverse neoplasms (sarcoma, breast cancer, brain tumors, leukemia, adrenal cortical carcinoma, and others). Choroid plexus carcinomas were identified in two kindreds previously reported with the syndrome. The literature contains reports of choroid plexus neoplasms occurring in families and in individuals with multiple primary tumors. Choroid plexus neoplasm may be a manifestation of the inherited proclivity to tumor development in the breast cancer-sarcoma syndrome." ]

[ "The tools and techniques used in single-cell analysis of DNA damage in yeast Saccharomyces cerevisiae are limited. In this study, we modified the single cell gel electrophoresis assay, namely, the single chromosome comet assay based on DNA break analysis, at the chromosomal level. We studied the largest yeast chromosome XII, which contains the rDNA locus, and we investigated its instability using cell cycle checkpoint-, DNA damage- and antioxidative defence-deficient, and lifespan-deregulated yeast mutant strains. Moreover, we compared chromosome XII instability with the variability of nucleolar rDNA fluorescence signals. Three single-gene-deletion strains, cells lacking single-stranded DNA endonuclease, Rad1p; NAD(+)-dependent histone deacetylase, Sir2p; and gamma glutamylcysteine synthetase, Gsh1p, were more prone to chromosome XII instability compared to corresponding wildtype strains, indicating that DNA damage repair machinery, chromatin silencing and redox homeostasis may contribute to genome stability. Elevation in the number of DNA breaks was correlated with a high variability in the levels of nucleolar rDNA in the Δrad1 background, while unaffected chromosome XII and low variability in nucleolar rDNA fluorescence signals were observed in the Δtor1 longevity mutant. Taken together, the single chromosome comet assay may be successfully used to study DNA damage at the chromosomal level, which might be overlooked using whole population analysis on DNA breaks with PFGE separation.", "Pseudomelanosis duodeni is a rare entity characterized by dark pigmentation of duodenal mucosa of uncertain etiology and clinical significance. We report a case with endoscopic and pathologic correlation. Some aspects about etiology, clinical and histopathologic characteristics are discussed.", "OBJECT: This study aimed at investigating the clinical significance and biological function of ubiquitination factor E4B (UBE4B) in human renal cell carcinoma (RCC).METHODS: 19 paired clear cell renal cell carcinoma (ccRCC) tumor samples and the matched neighboring non-tumor samples were used to detect the expression of UBE4B in RCC tumor by Western blotting and RT-qPCR. UBE4B expression was also detected in 151 ccRCC paraffin-embedded tumor samples by using immunohistochemistry. Overall survival (OS) in different UBE4B expression groups were compared with Log rank test. The prognostic value of UBE4B expression in OS was evaluated with the univariate and multivariate Cox regression models. UBE4B was knocked down by small interfering RNA (siRNA) technology, and the effect of UBE4B on cell proliferation, colony formation, metastasis, apoptosis and cell cycle of RCC cells were examined in vitro.RESULTS: Both protein and mRNA levels of UBE4B were up-regulated in ccRCC tumor tissues in contrast to the corresponding adjacent nontumor ones. UBE4B expression was positively associated with tumor-node-metastasis (TNM) stage and distant metastasis in ccRCC patients. Survival analyses indicated that low expression of UBE4B was associated with increased OS in ccRCC patients. Functional analyses demonstrated that siRNA silencing of UBE4B expression in SKRC39 and ACHN cells further reduced the growth, motility and invasiveness of RCC cells. Moreover, siRNA silencing of UBE4B in the RCC cell lines did not induce apoptosis, and an increase in the cell population was observed during the G0/G1 phase of the cell cycle.CONCLUSION: UBE4B might act as an oncogene in regulating RCC development. Therefore it could be served as an effective indicator to predict OS and a potential biomarker for targeted therapy of RCC patients.", "Bi-valvular pneumococcal endocarditis in Austrian syndrome, which includes a triad of pneumococcal endocarditis, pneumonia, and meningitis, is a rare but life-threatening disease. We present a case of a woman found to have Austrian syndrome who presented to the emergency department (ED) with dehydration and radiographical signs of lobar pneumonia and quickly deteriorated to fulminant cardiogenic shock in less than four hours. An early echocardiogram in the ED confirmed a diagnosis of bi-valvular endocarditis with severe aortic and mitral valve insufficiency and large vegetations on the valve leaflets requiring emergent surgical intervention with double valve replacement. Assumed meningitis as a part of the triad of Austrian syndrome was confirmed by imaging the day after hospital admission. Early diagnosis of endocarditis by obtaining the echocardiogram in the ED along with emergent surgical intervention allowed for a favorable outcome for the patient.", "Staphylococcal bi-component pore-forming toxins, also known as leukocidins, target and lyse human phagocytes in a receptor-dependent manner. S-components of the leukocidins Panton-Valentine leukocidin (PVL), γ-haemolysin AB (HlgAB) and CB (HlgCB), and leukocidin ED (LukED) specifically employ receptors that belong to the class of G-protein coupled receptors (GPCRs). Although these receptors share a common structural architecture, little is known about the conserved characteristics of the interaction between leukocidins and GPCRs. In this study, we investigated host cellular pathways contributing to susceptibility towards S. aureus leukocidin cytotoxicity. We performed a genome-wide CRISPR/Cas9 library screen for toxin-resistance in U937 cells sensitized to leukocidins by ectopic expression of different GPCRs. Our screen identifies post-translational modification (PTM) pathways involved in the sulfation and sialylation of the leukocidin-receptors. Subsequent validation experiments show differences in the impact of PTM moieties on leukocidin toxicity, highlighting an additional layer of refinement and divergence in the staphylococcal host-pathogen interface. Leukocidin receptors may serve as targets for anti-staphylococcal interventions and understanding toxin-receptor interactions will facilitate the development of innovative therapeutics. Variations in the genes encoding PTM pathways could provide insight into observed differences in susceptibility of humans to infections with S. aureus.", "OBJECTIVE: Ghrelin is a hormone secreted mainly in the stomach which stimulates appetite and food intake. Endocrine factors are among the causes of anorexia in elderly people. The main objective of the present study was to examine the effect of age on ghrelin levels in non-institutionalized elderly people.DESIGN AND SETTING: Observational, cross-sectional, population-based study.PARTICIPANTS: A random sample of men aged 70 yr or older was taken from the municipal census.MEASUREMENTS: All participants underwent a physical examination which measured weight and height, grip strength, functional capacity (according to the Barthel Index) and nutritional status (according to the short form of the Mini Nutritional Assessment). Blood was taken for basic biochemical analysis, determination of somatotropic, corticotropic, and gonadotropic hormones, and for measurement of ghrelin and cholecystokinin.RESULTS: 152 men with a mean (SD) age of 76.7 (5.4) yr were recruited. Mean ghrelin levels were 1143 (401) pg/ml. A weak negative correlation was found between ghrelin levels and age (r=-0.16, p=0.057). Multiple linear regression analysis showed a significant and independent effect of age (beta=-12.1, p=0.049), body mass index (BMI) (beta=-22.0, p=0.021), and creatinine levels (beta=407.7, p=0.002) on ghrelin. No correlations with age and BMI were found for cholecystokinin.CONCLUSIONS: There is a slight decrease in ghrelin levels with age in older men aged 70 yr or more, although the clinical relevance of this finding remains unclear.", "The post-transcriptional fate of messenger RNAs (mRNAs) is largely dictated by their 3' untranslated regions (3' UTRs), which are defined by cleavage and polyadenylation (CPA) of pre-mRNAs. We used poly(A)-position profiling by sequencing (3P-seq) to map poly(A) sites at eight developmental stages and tissues in the zebrafish. Analysis of over 60 million 3P-seq reads substantially increased and improved existing 3' UTR annotations, resulting in confidently identified 3' UTRs for >79% of the annotated protein-coding genes in zebrafish. mRNAs from most zebrafish genes undergo alternative CPA, with those from more than a thousand genes using different dominant 3' UTRs at different stages. These included one of the poly(A) polymerase genes, for which alternative CPA reinforces its repression in the ovary. 3' UTRs tend to be shortest in the ovaries and longest in the brain. Isoforms with some of the shortest 3' UTRs are highly expressed in the ovary, yet absent in the maternally contributed RNAs of the embryo, perhaps because their 3' UTRs are too short to accommodate a uridine-rich motif required for stability of the maternal mRNA. At 2 h post-fertilization, thousands of unique poly(A) sites appear at locations lacking a typical polyadenylation signal, which suggests a wave of widespread cytoplasmic polyadenylation of mRNA degradation intermediates. Our insights into the identities, formation, and evolution of zebrafish 3' UTRs provide a resource for studying gene regulation during vertebrate development." ]

[ "BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and make up 1-2% of all gastrointestinal malignancies. Traditionally, the treatment of choice for primary disease is surgical resection; however, no single surgeon or institution gets extensive exposure to these patients so appropriate decision-making is difficult, particularly since the introduction of the tyrosine kinase inhibitor imatinib, which has become an important additional management tool.METHOD: All patients were diagnosed and treated for GISTs in Christchurch Hospital (Christchurch, New Zealand) between 1 January 2000 and 31 December 2010. We maintain a prospective database of all patients with GISTs. Data on clinical and histopathological variables, management and survival outcomes were recorded. These were then reviewed.RESULTS: There were 93 patients in this study. Fifty were women. Median age was 69 (interquartile range (IQR) 59-76) years. Fifty-one tumours were located in the stomach, 27 in the small bowel, six in the colon, three in the oesophagus, one in the rectum and five were extra-gastrointestinal. In total, 22 patients received imatinib therapy; four patients with metastatic disease had imatinib as sole therapy. The median follow-up was 58 (IQR 30-90) months. The 5-year overall survival and disease-free survival (DFS) for the entire study population was 69% and 64%, respectively. The 5-year DFS was higher for all patients who have localized disease when compared with those who have metastatic disease (76% versus 28%, P-value 0.001).CONCLUSION: Surgery aiming at an R0 resection remains the mainstay of treatment. We propose the most effective way to grow the knowledge base in New Zealand is the establishment of a national register, thereby allowing better clinical decision-making by interpretation of a larger data set.", "PURPOSE: To study the efficacy and tolerability of valproic acid (VPA) and radiation, followed by VPA and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG).METHODS: Children 3 to 21 years of age received radiation therapy and VPA at 15 mg/kg/day and dose adjusted to maintain a trough range of 85 to 115 μg/mL. VPA was continued post-radiation, and bevacizumab was started at 10 mg/kg intravenously biweekly, four weeks after completing radiation therapy.RESULTS: From September 2009 through August 2015, 20 DIPG and 18 HGG patients were enrolled (NCT00879437). During radiation and VPA, grade 3 or higher toxicities requiring discontinuation or modification of VPA dosing included grade 3 thrombocytopenia (1), grade 3 weight gain (1), and grade 3 pancreatitis (1). During VPA and bevacizumab, the most common grade 3 or higher toxicities were grade 3 neutropenia (3), grade 3 thrombocytopenia (3), grade 3 fatigue (3), and grade 3 hypertension (4). Two patients discontinued protocol therapy prior to disease progression (one grade 4 thrombosis and one grade 1 intratumoral hemorrhage). Median event-free survival (EFS) and overall survival (OS) for DIPG were 7.8 (95% CI 5.6-8.2) and 10.3 (7.4-13.4) months, and estimated one-year EFS was 12% (2%-31%). Median EFS and OS for HGG were 9.1 (6.4-11) and 12.1 (10-22.1) months, and estimated one-year EFS was 24% (7%-45%). Four patients with glioblastoma and mismatch-repair deficiency syndrome had EFS of 28.5, 16.7, 10.4, and 9 months.CONCLUSION: Addition of VPA and bevacizumab to radiation was well tolerated but did not appear to improve EFS or OS in children with DIPG or HGG.", "BACKGROUND: Sulfonylureas (SUs) are commonly used in the treatment of type 2 diabetes (T2DM), usually as second-line treatment after the failure of metformin. However, SUs are associated with poor durability, hypoglycemia and weight gain. Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor in development for the treatment of T2DM. In Phase II/III trials, empagliflozin reduced hyperglycemia, body weight and blood pressure, with a low incidence of hypoglycemia. The aim of this Phase III study is to compare the effects of empagliflozin and the SU glimepiride as second-line therapy in patients with T2DM inadequately controlled with metformin immediate release (IR) and diet/exercise.METHOD: After a 2-week placebo run-in, patients were randomized to receive empagliflozin 25 mg once daily (qd) or glimepiride 1-4 mg qd double-blind for 2 years, in addition to metformin IR. Patients who participate in the initial 2-year randomization period will be eligible for a 2-year double-blind extension. The primary endpoint is change from baseline in HbA1c. Secondary endpoints are change from baseline in body weight, the incidence of confirmed hypoglycemia and changes in systolic and diastolic blood pressure. Exploratory endpoints include markers of insulin secretion, body composition and responder analyses. Safety endpoints include the incidence of adverse events (AEs) (including macro- and microvascular adverse events) and changes from baseline in clinical laboratory parameters.RESULTS: Between August 2010 and June 2011, 1549 patients were randomized and 1545 patients were treated. At baseline, mean (SD) age was 55.9 (10.4) years, HbA1c was 7.92 (0.84)%, body mass index was 30.11 (5.59) kg/m², systolic blood pressure was 133.5 (15.9) mmHg and diastolic blood pressure was 79.5 (9.4) mmHg.DISCUSSION: This is the largest study to compare the efficacy and safety of an SGLT2 inhibitor with an SU in patients with T2DM inadequately controlled on metformin to date. In addition to determining the effects of these treatments on glycemic control over the long term, this study will investigate effects on beta-cell function, cardiovascular risk factors and markers of renal function/damage. The results will help to inform the choice of second-line treatment in patients with T2DM who have failed on metformin.TRIAL REGISTRATION: Clinicaltrials.gov NCT01167881.", "INTRODUCTION: The measles virus is a major human pathogen responsible for approximately 150,000 deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible, in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence, combined with public anxiety over the vaccination's safety, has led to increased vaccine refusal, especially in Europe. This has led to the resurgence of measles in some areas.AREAS COVERED: This article discusses whether synergizing effective measles therapeutics with the measles vaccination could contribute to finally eradicating measles. The authors identify key elements in a desirable drug profile and review current disease management strategies and the state of experimental inhibitor candidates. The authors also evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics in the management of persistent central nervous system (CNS) viral infection. Finally, the authors contemplate the possible impact of therapeutics in controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles.EXPERT OPINION: Efficacious therapeutics used for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps; this is due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent population, dictates the drug profile. It also has to be safe and efficacious, orally available, shelf-stable at ambient temperature and amenable to cost-effective manufacturing.", "The sorting nexins Atg20/Snx42 and Snx41 regulate membrane traffic and endosomal protein sorting and are essential for Cvt and/or pexophagy in yeast. Previously, we showed that macroautophagy is necessary for conidiation in the rice-blast fungus Magnaporthe oryzae. Here, we analyzed the physiological function(s) of selective autophagy in Magnaporthe through targeted deletion of MGG_12832, an ortholog of yeast SNX41 and ATG20/SNX42. Loss of MGG_12832 (hereafter SNX41) abolished conidia formation and pathogenesis in M. oryzae. Snx41-GFP localized as dynamic puncta or short tubules that are partially associated with autophagosomes and/or autophagic vacuoles. PX domain, but not macroautophagy per se, was required for such localization of Snx41-GFP in Magnaporthe. Although not required for nonselective autophagy, Snx41 was essential for pexophagy in Magnaporthe. We identified Oxp1, an ATP-dependent oxoprolinase in the gamma-glutamyl cycle, as a binding partner and potential retrieval target of Snx41-dependent protein sorting. The substrate of Oxp1, 5-oxoproline, could partially restore conidiation in the snx41Δ. Exogenous glutathione, a product of the gamma-glutamyl cycle, significantly restored pathogenicity in the snx41Δ mutant, likely through counteracting the oxidative stress imposed by the host. We propose that the gamma-glutamyl cycle and glutathione biosynthesis are subject to regulation by Snx41-dependent vesicular trafficking, and mediate antioxidant defense crucial for in planta growth and pathogenic differentiation of Magnaporthe at the onset of blast disease in rice.", "On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDx BRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation-associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44-64], and median duration of response was 9.2 months (95% CI, 6.6-11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval. Clin Cancer Res; 23(23); 7165-70. ©2017 AACRSee related commentary by Kohn et al., p. 7155.", "Coleoid cephalopods (octopus, squid and cuttlefish) are active, resourceful predators with a rich behavioural repertoire. They have the largest nervous systems among the invertebrates and present other striking morphological innovations including camera-like eyes, prehensile arms, a highly derived early embryogenesis and a remarkably sophisticated adaptive colouration system. To investigate the molecular bases of cephalopod brain and body innovations, we sequenced the genome and multiple transcriptomes of the California two-spot octopus, Octopus bimaculoides. We found no evidence for hypothesized whole-genome duplications in the octopus lineage. The core developmental and neuronal gene repertoire of the octopus is broadly similar to that found across invertebrate bilaterians, except for massive expansions in two gene families previously thought to be uniquely enlarged in vertebrates: the protocadherins, which regulate neuronal development, and the C2H2 superfamily of zinc-finger transcription factors. Extensive messenger RNA editing generates transcript and protein diversity in genes involved in neural excitability, as previously described, as well as in genes participating in a broad range of other cellular functions. We identified hundreds of cephalopod-specific genes, many of which showed elevated expression levels in such specialized structures as the skin, the suckers and the nervous system. Finally, we found evidence for large-scale genomic rearrangements that are closely associated with transposable element expansions. Our analysis suggests that substantial expansion of a handful of gene families, along with extensive remodelling of genome linkage and repetitive content, played a critical role in the evolution of cephalopod morphological innovations, including their large and complex nervous systems.", "Diffuse intrinsic pontine glioma is a pediatric oncologic disease with dismal prognosis and no effective treatment. Since 2007, our patients have been using valproic acid as prophylactic anticonvulsant. We have undertaken a retrospective study in order to evaluate the influence of valproate in the outcomes of children with this disease in our center. Patients were treated with weekly carboplatin and vincristine and received conformal radiotherapy, either concurrent or sequential. Event-free survival and overall survival of patients not treated with valproic acid were 6.5 and 7.8 months. Accelerated failure time model (a parametric multivariate regression test for time-to-failure data) showed a statistically significant superiority of the median event-free survival of treated patients (6.5 vs. 9.5 months in treated patients; HR 0.54-95 % CI 0.33-0.87; p < 0.05) and also of overall survival (7.8 vs. 13.4 months in treated patients; HR 0.60-95 % CI 0.37-0.98; p = 0.05)." ]

[ "In the last few weeks, the FDA approved three new therapies for multiple myeloma: ixazomib, the first oral proteasome inhibitor; and daratumumab and elotuzumab, two monoclonal antibodies that target CD38 and SLAMF7, respectively.", "Our understanding of the highly specialized functions for small non-coding single-stranded RNA (ssRNA) in the transcriptome of the human central nervous system (CNS) continues to evolve. Circular RNAs (circRNAs), a recently discovered class of ssRNA enriched in the brain and retina, are extremely stable and intrinsically resilient to degradation by exonuclease. Conventional methods of ssRNA, microRNA (miRNA), or messenger RNA (mRNA) detection and quantitation requiring free ribonucleotide ends may have considerably underestimated the quantity and significance of CNS circRNA in the CNS. Highly-specific small ssRNAs, such as the ~23 nucleotide (nt) Homo sapien microRNA-7 (hsa-miRNA-7; chr 9q21.32), are not only abundant in the human limbic system but are, in addition, associated with a ~1400 nt circRNA for miRNA-7 (ciRS-7) in the same anatomical region. Structurally, ciRS-7 contains about ~70 tandem anti-miRNA-7 sequences and acts as an endogenous, anti-complementary miRNA-7 \"sponge\" that attracts, binds, and, hence, quenches, natural miRNA-7 functions. Using a combination of DNA and miRNA array technologies, enhanced LED-Northern and Western blot hybridization, and the magnesium-dependent exoribonuclease and circRNA-sensitive probe RNaseR, here we provide evidence of a significantly misregulated ciRS-7-miRNA-7-UBE2A circuit in sporadic Alzheimer's disease (AD) neocortex (Brodmann A22) and hippocampal CA1. Deficits in ciRS-7-mediated \"sponging events\", resulting in excess ambient miRNA-7 appear to drive the selective down-regulation in the expression of miRNA-7-sensitive mRNA targets, such as that encoding the ubiquitin conjugating enzyme E2A (UBE2A; chr Xq24). UBE2A, which normally serves as a central effector in the ubiquitin-26S proteasome system, coordinates the clearance of amyloid peptides via proteolysis, is known to be depleted in sporadic AD brain and, hence, contributes to amyloid accumulation and the formation of senile plaque deposits. Dysfunction of circRNA-miRNA-mRNA regulatory systems appears to represent another important layer of epigenetic control over pathogenic gene expression programs in the human CNS that are targeted by the sporadic AD process.", "Gregor Mendel, an Augustinian monk and part-time school teacher, undertook a series of brilliant hybridisation experiments with garden peas between 1857 and 1864 in the monastery gardens and, using statistical methods for the first time in biology, established the laws of heredity, thereby establishing the discipline of genetics.", "The life and personality of Johann Gregor Mendel (1822-1884), the founder of scientific genetics, are reviewed against the contemporary background of his times. At the end are weighed the benefits for Mendel (as charged by Sir Ronald Fisher) to have documented his results on hand of falsified data. Mendel was born into a humble farm family in the \"Kuhländchen\", then a predominantly German area of Northern Moravia. On the basis of great gifts Mendel was able to begin higher studies; however, he found himself in serious financial difficulties because of his father's accident and incapacitation. His hardships engendered illness which threatened continuation and completion of his studies until he was afforded the chance of absolving successfully theological studies as an Augustinian monk in the famous chapter of St. Thomas in Altbrünn (Staré Brno). Psychosomatic indisposition made Mendel unfit for practical pastoral duties. Thus, he was directed to teach but without appropriate state certification; an attempt to pass such an examination failed. At that point he was sent to the University of Vienna for a 2-year course of studies, with emphasis on physics and botany, to prepare him for the exam. His scientific and methodologic training enabled him to plan studies of the laws of inheritance, which had begun to interest him already during his theology training, and to choose the appropriate experimental plant. In 1865, after 12 years of systematic investigations on peas, he presented his results in the famous paper \"Versuche über Pflanzenhybriden.\" Three years after his return from Vienna he failed to attain his teaching certification a second time. Only by virtue of his exceptional qualifications did he continue to function as a Supplementary Professor of Physics and Natural History in the two lowest classes of a secondary school. In 1868 he was elected Abbot of his chapter, and freed from teaching duties, was able to pursue his many scientific interests with greater efficiency. This included meteorology, the measurement of ground water levels, further hybridization in plants (a.o. involving the hawk week Hieracium up to about 1873), vegetable and fruit tree horticulture, apiculture, and agriculture in general. This involved Mendel's active participation in many organizations interested in advancing these fields at a time when appropriate research institutes did not exist in Brünn. Some of the positions he took in his capacity of Abbot had severe repercussions and further taxed Mendel's already over-stressed system. The worst of these was a 10-year confrontation with the government about the taxation of the monastery.(ABSTRACT TRUNCATED AT 400 WORDS)", "Fibroblast growth factors are structurally related proteins associated with cell growth, differentiation, migration, wound healing, angiogenesis, and oncogenesis. At the cellular level, their function is mediated by transmembrane tyrosinekinase receptors, fibroblast growth factor receptors. Four genes encoding fibroblast growth factor receptors have been identified, and mutations in three of these, FGFR1, FGFR2, and FGFR3, can cause different congenital, autosomal dominant disorders affecting the craniofacial and skeletal development: craniosynostosis and chondrodysplasias. The craniosynostosis syndromes: Apert syndrome, Beare-Stevenson syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Muenke syndrome, Pfeiffer syndrome and Saethre-Chotzen syndrome can be caused by mutation in either FGFR1, FGFR2, or FGFR3. Saethre-Chotzen syndrome can also be caused by mutation in a functionally related gene, ACS. The same mutation can cause different syndromes, and the same syndrome can be caused by mutations in different genes. The chondrodysplasias: achondroplasia, hypochondroplasia, and thanatophoric dysplasia are all caused by mutations in FGFR3.", "Author information:(1)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; Research Centre of the Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic address: chen199001207@163.com.(2)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; Research Centre of the Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China.(3)Research Centre of the Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic address: yangqw@jlu.edu.cn.(4)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic address: lyz18@mails.jlu.edu.cn.(5)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic address: songyangjlu@foxmail.com.", "The Saccharomyces cerevisiae RRM3 gene encodes a 5' to 3' DNA helicase. While replication of most of the yeast genome was not dependent upon Rrm3p, in its absence, replication forks paused and often broke at an estimated 1400 discrete sites, including tRNA genes, centromeres, inactive replication origins, and transcriptional silencers. These replication defects were associated with activation of the intra-S phase checkpoint. Activation of the checkpoint was critical for viability of rrm3Delta cells, especially at low temperatures. Each site whose replication was affected by Rrm3p is assembled into a nonnucleosomal protein-DNA complex. At tRNA genes and the silent mating type loci, disruption of these complexes eliminated dependence upon Rrm3p. These data indicate that the Rrm3p DNA helicase helps replication forks traverse protein-DNA complexes, naturally occurring impediments that are encountered in each S phase.", "This article explains what methicillin-resistant Staphylococcus aureus (MRSA) is, how it is spread and what the real challenges are in healthcare settings in the UK. It explores the different strains of MRSA and points out the main ways to control their spread. It is intended to be a reference source for all nurses." ]

[ "BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNT/DNET) are rare epileptogenic tumors. Microsurgery remains the best treatment option, although case reports exist on the use of gamma knife radiosurgery (GKRS) in selected cases. We investigated the long-term outcome of GKRS-treated DNTs at our institution in the context of current diagnostic and treatment options.CASE DESCRIPTIONS: We conducted a retrospective review of three consecutive adult patients (≥18 years) treated with salvage GKRS between 2002 and 2010 at Karolinska University Hospital, Stockholm, Sweden. The case series was supplemented by a review of current literature. A 20-year-old male underwent subtotal resection (STR) in 1997 and 2002 of DNT resulting in temporary control of intractable epilepsy despite antiepileptic drug treatment (AED). Long-term seizure control was obtained after GKRS of two separate residual DNT components along the surgical margin (2005 and 2010). A 27-year-old male undergoing gross total resection of the contrast-enhancing portion of a DNT (1999) resulted in temporary control of intractable epilepsy despite AEDs; lasting clinical control of seizures was achieved in 2002 after GKRS of a small, recurrent DNT component. A 28-year-old male underwent STR of DNT (1994 and 2004) resulting in temporary control of intractable epilepsy. Lasting seizure control was gained after GKRS of a residual tumor (2005).CONCLUSION: GKRS as performed in our series was effective in terms of tumor and seizure control. No adverse radiation effects were recorded. Prospective studies are warranted to establish the role of GKRS in the treatment of DNTs.", "Ribosome biogenesis is an energy consuming process which takes place mainly in the nucleolus. By producing ribosomes to fuel protein synthesis, it is tightly connected with cell growth and cell cycle control. Perturbation of ribosome biogenesis leads to the activation of p53 tumor suppressor protein promoting processes like cell cycle arrest, apoptosis or senescence. This ribosome biogenesis stress pathway activates p53 through sequestration of MDM2 by a subset of ribosomal proteins (RPs), thereby stabilizing p53. Here, we identify human HEATR1, as a nucleolar protein which positively regulates ribosomal RNA (rRNA) synthesis. Downregulation of HEATR1 resulted in cell cycle arrest in a manner dependent on p53. Moreover, depletion of HEATR1 also caused disruption of nucleolar structure and activated the ribosomal biogenesis stress pathway - RPL5 / RPL11 dependent stabilization and activation of p53. These findings reveal an important role for HEATR1 in ribosome biogenesis and further support the concept that perturbation of ribosome biosynthesis results in p53-dependent cell cycle checkpoint activation, with implications for human pathologies including cancer.", "BACKGROUND/PURPOSE: Although hepatic tumors are uncommon in the perinatal period they are associated with significant morbidity and mortality in affected patients. The purpose of this review is to focus on the fetus and neonate in an attempt to determine the various ways liver tumors differ clinically and pathologically from those found in the older child and adult and to show that certain types of tumors have a better prognosis than others.METHODS: The author conducted a retrospective review of perinatal hepatic tumors reported in the literature and of patients treated and followed up at Children's Hospital San Diego and Children's Hospital Los Angeles. Only fetuses and infants younger than 2 months with adequate clinical and pathologic data ere accepted for review. The period of patient accrual was from 1970 to 2005. Length of follow-up varied from 1 week to more than 5 years. Elevated alpha-fetoprotein level was defined as one significantly higher than that of the reporting institution's normal level for age group; laboratory values for this protein vary from one institution to the next and therefore it was not possible to assign one figure as a standard reference number. Discussion of the differential diagnosis and pathologic findings of hepatic tumors in the fetus and neonate are described elsewhere and will not be discussed here in detail (Perspect Pediatr Pathol 1978;4:217; Weinberg AG, Finegold MJ. Primary hepatic tumors in childhood. In: Finegold M, editor. Pathology of neoplasia in children and adolescents. Philadelphia, PA: WB Saunders, 1986; Am J Surg Pathol 1982;6:693; Pediatr Pathol 1983;1:245; Arch Surg 1990;125:598; Semin Neonatol 2003;8:403; Pediatr Pathol 1985;3:165; Isaacs H Jr. Liver tumors. In: Isaacs H Jr, editor. Tumors of the fetus and newborn. Philadelphia, PA: WB Saunders, 1997; Isaacs H Jr. Liver tumors. In: Isaacs H Jr, editor. Tumors of the fetus and infant: an atlas. Philadelphia, PA: WB Saunders, 2002).RESULTS: One hundred ninety-four fetuses and neonates presented with hepatic tumors diagnosed prenatally (n = 56) and in the neonatal period (n = 138). The study consisted of 3 main tumors: hemangioma (117 cases, 60.3%), mesenchymal hamartoma (45 cases, 23.2%), and hepatoblastoma (32 cases, 16.5%). The most common initial finding was a mass found either by antenatal sonography or by physical examination during the neonatal period. Overall, hydramnios was next followed by fetal hydrops, respiratory distress, and congestive heart failure, which were often related to the cause of death. Half of the fetuses and neonates with hepatoblastoma had abnormally elevated serum alpha-fetoprotein levels compared with 16 (14%) of 117 of those with hemangioma and 1 neonate with mesenchymal hamartoma. There were 76 (65%) examples of solitary (unifocal) hemangiomas and 41 (35%) of multifocal (which included the entity diffuse hemangiomatosis) with 86% and 71% survival rates, respectively. Of 45 patients with mesenchymal hamartoma, of the 29 (64%) who had surgical resections, 23 (79%) survived. Patients with hepatoblastoma had the worst outcome of the group, for only 8 (25%) of 32 were alive. Half of patients with either stage 1 or 3 hepatoblastoma died; no patient with stage 4 survived. There was some relationship between histologic type and prognosis. For example, half of the patients with the pure fetal hepatoblastoma histology survived compared with those with fetal and embryonal histology where 30% survived. Fifteen of 32 hepatoblastoma patients received surgical resection with or without chemotherapy, resulting in 7 (47%) of 15 cures. The 56 fetuses and 138 neonates with hepatic tumors (hemangioma, mesenchymal hamartoma, and hepatoblastoma) had survival rates of 75%, 64%, and 25%, respectively. The overall survival of the entire group consisting of 194 tumors was 125 or 64%.CONCLUSIONS: The study shows that clinical findings in fetuses and neonates with hepatic tumors are less well defined than in older children. Survival rates are much lower as well. When the clinical course is complicated by associated conditions such as stillbirth, fetal hydrops, congestive heart failure, severe anemia, or thrombocytopenia, the mortality rate is much greater. If the patient is mature enough and in a clinical condition where he or she can be operated on, survival figures approach those of the older child. Some hepatic tumors have a better prognosis than others. Neonates with focal (solitary) hepatic hemangiomas have the best outcome and fetuses with hepatoblastoma the worst. Although infantile hemangioma undergoes spontaneous regression, it may be life threatening when congestive heart failure and/or consumptive coagulopathy occur. Mesenchymal hamartoma is a benign lesion best treated by surgical resection, which usually results in cure. However, there are fatal complications associated with this tumor, ie, fetal hydrops, respiratory distress, and circulatory problems owing to a large space occupying abdominal lesion and sometimes stillbirth, all contributing to the death rate. Hepatoblastoma, the major malignancy of the fetus and neonate, is treated primarily by surgical resection. Pre- or postoperative chemotherapy is reserved for those patients with unresectable tumors or metastatic disease. The survival rate is much lower than that reported by multigroup prospective trials. Patients die from the mass effect caused by the tumor, which lead to abdominal distension, vascular compromise, anemia, hydrops, respiratory distress, and stillbirth. Metastases to the abdominal cavity, lungs, and placenta are other causes of death. Because of the danger of labor-induced rupture of the tumor and potentially fatal intraabdominal hemorrhage, cesarean delivery is recommended when a hepatic tumor is found on prenatal ultrasound.", "RATIONALE: Ubiquitin-proteasome system (UPS) dysfunction has been implicated in cardiac pathogenesis. Understanding how cardiac UPS function is regulated will facilitate delineating the pathophysiological significance of UPS dysfunction and developing new therapeutic strategies. The COP9 (constitutive photomorphogenesis mutant 9) signalosome (CSN) may regulate the UPS, but this has not been tested in a critical vertebrate organ. Moreover, the role of CSN in a postmitotic organ and the impact of cardiomyocyte-restricted UPS dysfunction on the heart have not been reported.OBJECTIVE: We sought to determine the role of CSN-mediated deneddylation in UPS function and postnatal cardiac development and function.METHODS AND RESULTS: Cardiomyocyte-restricted Csn8 gene knockout (CR-Csn8KO) in mice was achieved using a Cre-LoxP system. CR-Csn8KO impaired CSN holocomplex formation and cullin deneddylation and resulted in decreases in F-box proteins. Probing with a surrogate misfolded protein revealed severe impairment of UPS function in CR-Csn8KO hearts. Consequently, CR-Csn8KO mice developed cardiac hypertrophy, which rapidly progressed to heart failure and premature death. Massive cardiomyocyte necrosis rather than apoptosis appears to be the primary cause of the heart failure. This is because (1) massive necrotic cell death and increased infiltration of leukocytes were observed before increased apoptosis; (2) increased apoptosis was not detectable until overt heart failure was observed; and (3) cardiac overexpression of Bcl2 failed to ameliorate CR-Csn8KO mouse premature death.CONCLUSIONS: Csn8/CSN plays an essential role in cullin deneddylation, UPS-mediated degradation of a subset of proteins, and the survival of cardiomyocytes and, therefore, is indispensable in postnatal development and function of the heart. Cardiomyocyte-restricted UPS malfunction can cause heart failure.", "A significant percentage of Duchenne muscular dystrophy (DMD) cases are caused by premature termination codon (PTC) mutations in the dystrophin gene, leading to the production of a truncated, non-functional dystrophin polypeptide. PTC-suppressing compounds (PTCSC) have been developed in order to restore protein translation by allowing the incorporation of an amino acid in place of a stop codon. However, limitations exist in terms of efficacy and toxicity. To identify new compounds that have PTC-suppressing ability, we selected and clustered existing PTCSC, allowing for the construction of a common pharmacophore model. Machine learning (ML) and deep learning (DL) models were developed for prediction of new PTCSC based on known compounds. We conducted a search of the NCI compounds database using the pharmacophore-based model and a search of the DrugBank database using pharmacophore-based, ML and DL models. Sixteen drug compounds were selected as a consensus of pharmacophore-based, ML, and DL searches. Our results suggest notable correspondence of the pharmacophore-based, ML, and DL models in prediction of new PTC-suppressing compounds.", "Propionic acidemia (PA) is a metabolic disorder that causes mental retardation and that can be fatal if untreated. PA is inherited in an autosomal recessive fashion involving mutations in PCCA or PCCB encoding the alpha and beta subunits of propionyl-CoA carboxylase (PCC). Current treatment is based on dietary restriction of substrate amino acids, which attenuates symptoms. However, patients still experience episodes of hyperammonemia that can cause progressive neurologic damage. In this paper, we have tested gene therapy approaches to PA in a stringent mouse model of PCCA deficiency, in which homozygous knockout mice are born but die within 36 hr. In this work, we have delivered first-generation and helper-dependent adenovirus serotype 5 (Ad5) vectors expressing the human PCCA cDNA by intraperitoneal injection into newborn mice. Unmodified Ad5 vectors mediated extensive transduction of the peritoneum with weak liver transduction as determined by luciferase imaging and dsRed expression. In contrast, modification of Ad5 with polyethylene glycol detargeted the virus from the peritoneum and retargeted it for transduction in the liver. When vectors expressing PCCA were injected, significant increases in life span were observed for both the unmodified and polyethylene glycol (PEG)-modified Ad5 vectors. However, this rescue was transient. Similarly, adeno-associated virus serotype 8-mediated transduction also produced only transient rescue. These data show first proof of principle for gene therapy of PA and demonstrate the potential utility of PEG to modify viral tropism in an actual gene therapy application.", "Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from activated trigeminal sensory afferents in headache and facial pain disorders. There are a handful of CGRP-targeted therapies currently in phase 3 studies for migraine acute treatment or prevention. Currently, 4 monoclonal antibodies targeting either the CGRP ligand or receptor are being studied for migraine prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab), and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in clinical trials for cluster headache prevention as well. Several other small-molecular CGRP receptor antagonists are in earlier stages of development for acute migraine treatment or prevention. In this review, we will discuss the growing body of clinical trials studying CGRP-targeted therapies for migraine and cluster headache." ]

[ "The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway.", "This paper discusses the problematic and sometimes implicit nature of some central notions and criteria used in debates about inclusion (or exclusion) of health care services in the health care benefit package. An analysis of discussions about four health care services--lungtransplantation, statins, (sildenafil (viagra) and rivastigmine--illustrates a case-by-case approach and inconsistent use of criteria, which present a challenge to develop a decision-making procedure in which important criteria or central notions can be discussed explicitly.", "Author information:(1)Groupe Francophone de Cytogénétique Hématologique (GFCH).(2)Laboratoire de Cytogénétique Hématologique, Centre Hospitalier Universitaire (CHU) de Marseille, Aix-Marseille University, Marseille, France.(3)Centre de Recherches en Cancérologie de Toulouse (CRCT), Team 16, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.(4)Groupe Francophone d'Hématologie Cellulaire (GFHC) and.(5)Laboratoire d'hématologie, CHU de Guadeloupe, Inserm Unité Mixte de Recherche 1134, Pointe à Pitre, France.(6)Laboratoire d'Hématologie, Institut Universitaire de Cancérologie de Toulouse, CHU Toulouse, France.(7)Department of Hematology, University Toulouse III, Toulouse, France.(8)Centre de Recherches en Cancérologie de Toulouse (CRCT), Team 8, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.(9)Gene Editing, Wellcome Sanger Institute, Hinxton, Cambridge, UK.(10)Stem Cell Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.(11)Wellcome Sanger Institute, Hinxton, UK.(12)Department of Haematology, Cambridge University Hospitals National Health Service Trust, Cambridge, UK.(13)Wellcome-Medical Research Council Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.(14)Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.(15)Institute of Medical Informatics, University of Münster, Münster, Germany.(16)Institut Cochin, Université de Paris, Inserm U1016, Centre National de la Recherche Scientifique UMR8104, Paris, France.(17)Belgium Cancer Registry, Brussels, Belgium.(18)Department of Human Genetics, Katholieke Universiteit Leuven and Universitair Ziekenhuis, Leuven, Belgium.(19)Laboratoire de Cytogénétique, CHU de Tours, France.(20)Laboratoire d'Hématologie, CHU de Bordeaux, Bordeaux, France.(21)Laboratoire de Cytogénétique, CHU de Besançon, Besançon, France.(22)Laboratoire de Cytogénétique, CHU de Strasbourg, Strasbourg, France.(23)Département de Biopathologie, Institut Paoli-Calmettes, Marseille, France.(24)Laboratoire de Cytogénétique, CHU de Grenoble, Grenoble, France.(25)Laboratoire de Cytogénétique, CHU de Reims, Reims, France.(26)Laboratoire de Cytogénétique, CHU de Saint-Etienne, Saint-Etienne, France.(27)Laboratoire de Cytogénétique, CHU de Paris-Necker, Paris, France.(28)Laboratoire d'Hématologie, CHU d'Angers, Angers, France.(29)Laboratoire de Cytogénétique, CHU de Nantes, Nantes, France.(30)Laboratoire de Cytogénétique, CH de Versailles, Le Chesnay, France.(31)Laboratoire de Cytogénétique, CHU de Lyon, Lyon, France.(32)Laboratoire de Cytogénétique, Centre Henri-Becquerel, Rouen, France.(33)Laboratoire d'Hématologie, CHU Avicenne, Bobigny, France.(34)Groupe Francophone des Myélodysplasies (GFM); and.(35)Laboratoire d'hématologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Paris, France.", "The CpG island methylator phenotype (CIMP), characterized by an exceptionally high frequency of methylation of discrete CpG islands, is observed in 18% to 25% of sporadic colorectal cancers. Another hypermethylation pattern found in colorectal cancers, termed long-range epigenetic silencing, is associated with DNA/histone methylation in three distinct gene clusters at chromosome 2q14.2, showing that DNA hypermethylation can span larger chromosomal domains and lead to the silencing of flanking, unmethylated genes. We investigated whether these two phenotypes are interrelated in colorectal cancers. The CIMP status of 148 sporadic colorectal cancers was determined by methylation-specific PCR. We determined the BRAF V600E mutation by mutant allele-specific PCR amplification. The methylation status of the MLH1 gene and of three CpG islands (EN1, SCTR, and INHBB), corresponding to three distinct clusters along 2q14.2, was determined by methylation-specific PCR. The average number of sites showing methylation in CIMP+ tumors was 2.21, compared with 1.22 for CIMP- individuals, and this difference was highly significant (P = 3.6 x 10(-8), Mann-Whitney test). Moreover, all CIMP+ tumors showed hypermethylation of at least one of these loci, in contrast to CIMP- tumors, where 18 (16%) samples remained unmethylated. The mean number of simultaneously hypermethylated CpG islands at 2q14.2 differs significantly between CIMP- and CIMP+ tumors, suggesting varying effects of domain silencing in this region. Given that the number of hypermethylated loci at 2q14.2 likely affects the range of silenced flanking genes, high frequency of simultaneous hypermethylation of three CpG islands (EN1, SCTR, and INHBB) may have potential influence on specific characteristics of CIMP+ colorectal cancers.", "Kusunokinin, a lignan compound, inhibits cancer cell proliferation and induces apoptosis; however, the role of kusunokinin is not fully understood. Here, we aimed to identify a target protein of (-)-kusunokinin and determine the protein levels of its downstream molecules. We found that (-)-kusunokinin bound 5 possible target proteins, including CSF1R, MMP-12, HSP90-α, CyclinB1 and MEK1 with ΔGbind less than -10.40 kcal/mol. MD simulation indicated (-)-kusunokinin and pexidartinib (P31, a specific CSF1R binding compound) shared some extents of functional similarity in which (-)-kusunokinin bound CSF1R at the juxtamembrane (JM) region with aromatic amino acids similar to pexidartinib using π-π interaction, as well as hydrogen bond. Both P31 and (-)-kusunokinin moved into the same CSF1R region and W7 was a mutual key residue. However, the P31 binding site differed from the (-)-kusunokinin binding site. For in vitro study, the synthetic (±)-kusunokinin exhibited stronger cytotoxicity than picropodophyllotoxin, silibinin and etoposide on MCF-7 cells and represented less toxicity than picropodophyllotoxin and doxorubicin on L-929 and MCF-12A cells. Knocking down CSF1R using a specific siRNA combination with (±)-kusunokinin demonstrated levels of cell proliferation proteins slightly higher than siRNA-CSF1R treatment. However, siRNA-CSF1R combination with P31 represented the number of cell viability and cell proliferation proteins, like in the control groups (Lipofectamine and siRNA-Luciferase). Moreover, (±)-kusunokinin suppressed CSF1R and its downstream proteins, including AKT, CyclinD1 and CDK1. Meanwhile, both P31 and siRNA-CSF1R dramatically suppressed CSF1R, MEK1, AKT, ERK, CyclinB1, CyclinD1 and CDK1. Our overall results indicate that the mechanism of (±)-kusunokinin differed fairly from P31. We have concluded that (±)-kusunokinin inhibited breast cancer cell proliferation partially through the binding and suppression of CSF1R, which consequently affected AKT and its downstream molecules.", "The COP9 (Constitutive photomorphogenesis 9) signalosome (CSN), a large multiprotein complex that resembles the 19S lid of the 26S proteasome, plays a central role in the regulation of the E3-cullin RING ubiquitin ligases (CRLs). The catalytic activity of the CSN complex, carried by subunit 5 (CSN5/Jab1), resides in the deneddylation of the CRLs that is the hydrolysis of the cullin-neural precursor cell expressed developmentally downregulated gene 8 (Nedd8)isopeptide bond. Whereas CSN-dependent CSN5 displays isopeptidase activity, it is intrinsically inactive in other physiologically relevant forms. Here we analyze the crystal structure of CSN5 in its catalytically inactive form to illuminate the molecular basis for its activation state. We show that CSN5 presents a catalytic domain that brings essential elements to understand its activity control. Although the CSN5 active site is catalytically competent and compatible with di-isopeptide binding, the Ins-1 segment obstructs access to its substrate-binding site, and structural rearrangements are necessary for the Nedd8-binding pocket formation. Detailed study of CSN5 by molecular dynamics unveils signs of flexibility and plasticity of the Ins-1 segment. These analyses led to the identification of a molecular trigger implicated in the active/inactive switch that is sufficient to impose on CSN5 an active isopeptidase state. We show that a single mutation in the Ins-1 segment restores biologically relevant deneddylase activity. This study presents detailed insights into CSN5 regulation. Additionally, a dynamic monomer-dimer equilibrium exists both in vitro and in vivo and may be functionally relevant.", "BACKGROUND: There has been much debate about the appropriate statistical methodology for the evaluation of malaria field studies and the challenges in interpreting data arising from these trials.METHODS: The present paper describes, for a pivotal phase III efficacy of the RTS, S/AS01 malaria vaccine, the methods of the statistical analysis and the rationale for their selection. The methods used to estimate efficacy of the primary course of vaccination, and of a booster dose, in preventing clinical episodes of uncomplicated and severe malaria, and to determine the duration of protection, are described. The interpretation of various measures of efficacy in terms of the potential public health impact of the vaccine is discussed.CONCLUSIONS: The methodology selected to analyse the clinical trial must be scientifically sound, acceptable to regulatory authorities and meaningful to those responsible for malaria control and public health policy." ]

[ "Migraine is the third-most prevalent disease in the world and affects approximately 39 million individuals in the United States alone. Migraine occurs in nearly 1 in 7 individuals between 15 and 49 years of age and is 3 times more frequent in women than in men. The Food and Drug Administration (FDA) recently approved 3 new humanized monoclonal antibodies that target calcitonin gene-related peptide (CGRP): erenumab, fremanezumab, and galcanezumab. The agents either bind to the CGRP receptor (erenumab) or bind to the CGRP ligand (fremanezumab and galcanezumab) and block its binding to the receptor. All 3 products are indicated for preventative treatment of episodic or chronic migraine in adults. The available studies to date document that these agents reduce migraine attacks. The CGRP monoclonal antibodies offer patients new options once they have exhausted other treatments.", "AIMS: To prospectively validate the SYNTAX Score II and forecast the outcomes of the randomized Evaluation of the Xience Everolimus-Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) Trial.METHODS AND RESULTS: Evaluation of the Xience Everolimus Eluting Stent vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization is a prospective, randomized multicenter trial designed to establish the efficacy and safety of percutaneous coronary intervention (PCI) with the everolimus-eluting stent compared with coronary artery bypass graft (CABG) surgery in subjects with unprotected left-main coronary artery (ULMCA) disease and low-intermediate anatomical SYNTAX scores (<33). After completion of patient recruitment in EXCEL, the SYNTAX Score II was prospectively applied to predict 4-year mortality in the CABG and PCI arms. The 95% prediction intervals (PIs) for mortality were computed using simulation with bootstrap resampling (10 000 times). For the entire study cohort, the 4-year predicted mortalities were 8.5 and 10.5% in the PCI and CABG arms, respectively [odds ratios (OR) 0.79; 95% PI 0.43-1.50). In subjects with low (≤22) anatomical SYNTAX scores, the predicted OR was 0.69 (95% PI 0.34-1.45); in intermediate anatomical SYNTAX scores (23-32), the predicted OR was 0.93 (95% PI 0.53-1.62). Based on 4-year mortality predictions in EXCEL, clinical characteristics shifted long-term mortality predictions either in favour of PCI (older age, male gender and COPD) or CABG (younger age, lower creatinine clearance, female gender, reduced left ventricular ejection fraction).CONCLUSION: The SYNTAX Score II indicates at least an equipoise for long-term mortality between CABG and PCI in subjects with ULMCA disease up to an intermediate anatomical complexity. Both anatomical and clinical characteristics had a clear impact on long-term mortality predictions and decision making between CABG and PCI.", "OBJECTIVE: MicroRNAs (miRNA) have recently emerged as a new class of modulators of gene expression. In this study we investigated the expression, regulation, and function of miR-155 and miR-146a in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) and RA synovial tissue.METHODS: Locked nucleic acid microarray was used to screen for differentially expressed miRNA in RASFs treated with tumor necrosis factor alpha (TNFalpha). TaqMan-based real-time polymerase chain reaction was applied to measure the levels of miR-155 and miR-146a. Enforced overexpression of miR-155 was used to investigate the function of miR-155 in RASFs.RESULTS: Microarray analysis of miRNA expressed in RASFs treated with TNFalpha revealed a prominent up-regulation of miR-155. Constitutive expression of both miR-155 and miR-146a was higher in RASFs than in those from patients with osteoarthritis (OA), and expression of miR-155 could be further induced by TNFalpha, interleukin-1beta, lipopolysaccharide, poly(I-C), and bacterial lipoprotein. The expression of miR-155 in RA synovial tissue was higher than in OA synovial tissue. Enforced expression of miR-155 in RASFs was found to repress the levels of matrix metalloproteinase 3 (MMP-3) and reduce the induction of MMPs 3 and 1 by Toll-like receptor ligands and cytokines. Moreover, compared with monocytes from RA peripheral blood, RA synovial fluid monocytes displayed higher levels of miR-155.CONCLUSION: This study provides the first description of increased expression of miRNA miR-155 and miR-146a in RA. Based on these findings, we postulate that the inflammatory milieu may alter miRNA expression profiles in resident cells of the rheumatoid joints. Considering the repressive effect of miR-155 on the expression of MMPs 3 and 1 in RASFs, we hypothesize that miR-155 may be involved in modulation of the destructive properties of RASFs.", "Author information:(1)Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain and Behavior Institute Columbia University, New York, NY 10027, USA.(2)Mortimer B. Zuckerman Mind Brain and Behavior Institute Columbia University, New York, NY 10027, USA.(3)Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.(4)Mortimer B. Zuckerman Mind Brain and Behavior Institute Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Neuroscience, Columbia University, New York, NY 10032, USA.(5)Department of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan.(6)Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA.(7)Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain and Behavior Institute Columbia University, New York, NY 10027, USA; Department of Neuroscience, Columbia University, New York, NY 10032, USA. Electronic address: jag90@columbia.edu.", "Transcription regulation in multicellular eukaryotes is orchestrated by a number of DNA functional elements located at gene regulatory regions. Some regulatory regions (e.g. enhancers) are located far away from the gene they affect. Identification of distal regulatory elements is a challenge for the bioinformatics research. Although existing methodologies increased the number of computationally predicted enhancers, performance inconsistency of computational models across different cell-lines, class imbalance within the learning sets and ad hoc rules for selecting enhancer candidates for supervised learning, are some key questions that require further examination. In this study we developed DEEP, a novel ensemble prediction framework. DEEP integrates three components with diverse characteristics that streamline the analysis of enhancer's properties in a great variety of cellular conditions. In our method we train many individual classification models that we combine to classify DNA regions as enhancers or non-enhancers. DEEP uses features derived from histone modification marks or attributes coming from sequence characteristics. Experimental results indicate that DEEP performs better than four state-of-the-art methods on the ENCODE data. We report the first computational enhancer prediction results on FANTOM5 data where DEEP achieves 90.2% accuracy and 90% geometric mean (GM) of specificity and sensitivity across 36 different tissues. We further present results derived using in vivo-derived enhancer data from VISTA database. DEEP-VISTA, when tested on an independent test set, achieved GM of 80.1% and accuracy of 89.64%. DEEP framework is publicly available at http://cbrc.kaust.edu.sa/deep/.", "Burkholderia pseudomallei is a soil-dwelling bacterium and the cause of melioidosis, which kills an estimated 89,000 people per year worldwide. Agricultural workers are at high risk of infection due to repeated exposure to the bacterium. Little is known about the soil physicochemical properties associated with the presence or absence of the organism. Here, we evaluated the soil physicochemical properties and presence of B. pseudomallei in 6,100 soil samples collected from 61 rice fields in Thailand. The presence of B. pseudomallei was negatively associated with the proportion of clay, proportion of moisture, level of salinity, percentage of organic matter, presence of cadmium, and nutrient levels (phosphorus, potassium, calcium, magnesium, and iron). The presence of B. pseudomallei was not associated with the level of soil acidity (P = 0.54). In a multivariable logistic regression model, the presence of B. pseudomallei was negatively associated with the percentage of organic matter (odds ratio [OR], 0.06; 95% confidence interval [CI], 0.01 to 0.47; P = 0.007), level of salinity (OR, 0.06; 95% CI, 0.01 to 0.74; P = 0.03), and percentage of soil moisture (OR, 0.81; 95% CI, 0.66 to 1.00; P = 0.05). Our study suggests that B. pseudomallei thrives in rice fields that are nutrient depleted. Some agricultural practices result in a decline in soil nutrients, which may impact the presence and amount of B. pseudomallei bacteria in affected areas.IMPORTANCE: Burkholderia pseudomallei is an environmental Gram-negative bacillus and the cause of melioidosis. Humans acquire the disease following skin inoculation, inhalation, or ingestion of the bacterium in the environment. The presence of B. pseudomallei in soil defines geographic regions where humans and livestock are at risk of melioidosis, yet little is known about the soil properties associated with the presence of the organism. We evaluated the soil properties and presence of B. pseudomallei in 61 rice fields in East, Central, and Northeast Thailand. We demonstrated that the organism was more commonly found in soils with lower levels of organic matter and nutrients, including phosphorus, potassium, calcium, magnesium, and iron. We also demonstrated that crop residue burning after harvest, which can reduce soil nutrients, was not uncommon. Some agricultural practices result in a decline in soil nutrients, which may impact the presence and amount of B. pseudomallei bacteria in affected areas.", "BACKGROUND: Structural variants (SVs) affecting non-coding cis-regulatory elements are a common cause of congenital limb malformation. Yet, the functional interpretation of these non-coding variants remains challenging. The human Liebenberg syndrome is characterised by a partial transformation of the arms into legs and has been shown to be caused by SVs at the PITX1 locus leading to its misregulation in the forelimb by its native enhancer element Pen. This study aims to elucidate the genetic cause of an unsolved family with a mild form of Liebenberg syndrome and investigate the role of promoters in long-range gene regulation.METHODS: Here, we identify SVs by whole genome sequencing (WGS) and use CRISPR-Cas9 genome editing in transgenic mice to assign pathogenicity to the SVs.RESULTS: In this study, we used WGS in a family with three mildly affected individuals with Liebenberg syndrome and identified the smallest deletion described so far including the first non-coding exon of H2AFY. To functionally characterise the variant, we re-engineered the 8.5 kb deletion using CRISPR-Cas9 technology in the mouse and showed that the promoter of the housekeeping gene H2afy insulates the Pen enhancer from Pitx1 in forelimbs; its loss leads to misexpression of Pitx1 by the pan-limb activity of the Pen enhancer causing Liebenberg syndrome.CONCLUSION: Our data indicate that housekeeping promoters may titrate promiscuous enhancer activity to ensure normal morphogenesis. The deletion of the H2AFY promoter as a cause of Liebenberg syndrome highlights this new mutational mechanism and its role in congenital disease." ]

[ "Expression of the E3 ubiquitin ligase Triad1 is greater in mature granulocytes than in myeloid progenitor cells. HoxA10 actives transcription of the gene encoding Triad1 (ARIH2) during myeloid differentiation, but the contribution of increased Triad1 expression to granulocyte production or function is unknown. Mice with bone marrow-specific disruption of the ARIH2 gene exhibit constitutive inflammation with tissue infiltration by granulocytes and B cells. In contrast, disruption of the HOXA10 gene in mice neither constitutively activates the innate immune response nor significantly alters steady-state granulopoiesis. This study explores the impact of HoxA10-induced Triad1 expression on emergency (stress) granulopoiesis. We found that mice with HOXA10 gene disruption exhibited an overwhelming and fatal emergency granulopoiesis response that was characterized by tissue infiltration with granulocytes, but reversed by re-expression of Triad1 in the bone marrow. We determined that HoxA9 repressed ARIH2 transcription in myeloid progenitor cells, antagonizing the effect of HoxA10 on Triad1 expression. Also, we found that differentiation-stage-specific ARIH2 transcription was regulated by the tyrosine phosphorylation states of HoxA9 and HoxA10. Our studies demonstrate a previously undescribed role for HoxA10 in terminating emergency granulopoiesis, suggesting an important contribution by Hox proteins to the innate immune response.", "Oxidative stress appears to be of fundamental relevance to diseases as diverse as atherosclerosis, cancer, and Alzheimer's disease. Observational data in humans have suggested that antioxidant vitamin intake is associated with reduced cardiovascular disease. Animal studies are largely consistent with the concept that dietary supplementation with antioxidant vitamins reduces the progression of atherosclerosis. However, recent prospective, controlled clinical trials of vitamin E, including the Cardiovascular Disease, Hypertension and Hyperlipidemia, Adult-Onset Diabetes, Obesity, and Stroke (CHAOS) study, the Heart Outcomes Prevention Evaluation (HOPE) trial, Gruppo Italiano per lo Studio della Sopravvivvenza nell'Infarto Miocardico (GISSI)-Prevenzione trial, the Secondary Prevention with Antioxidants of Cardiovascular Disease in End Stage Renal Disease (SPACE) trial, and the Heart Protection Study (HPS) present a confused picture. The various possibilities that have been advanced to explain this discrepancy are discussed in this review. A striking feature of these and other trials of antioxidants is the absence of a biochemical basis for patient inclusion or, indeed, dose selection. Patients with high levels of oxidant stress or depletion of natural antioxidant defense systems may be the most likely to benefit from antioxidant therapy. If this is the case, then reliable, quantitative indices of in vivo oxidant stress such as urinary isoprostane levels should be considered as an inclusion criterion for patient selection. Future trials of antioxidant therapy in cardiovascular disease should then be targeted toward such patients with high levels of oxidant stress or patients with depletion of natural antioxidant defense systems. Furthermore, the dose of antioxidant should be chosen based on a surrogate readout that is a reliable, reproducible, and easily obtainable in vivo measure of oxidant stress. In the interim, although the safety of vitamin E up to doses of 800 IU/day has been determined, the conflicting nature of the results published to date encourages us to avoid making premature recommendations with respect to vitamin E supplementation in the prevention and treatment of cardiovascular disease.", "Soluble-fiber breakfast cereals were examined for their cholesterol-lowering ability in 58 male patients with mild to moderate hypercholesterolemia in a randomized, double-blind, placebo-controlled study. Patients followed a step 1 diet for a minimum of 6 wk, then were randomly assigned to groups incorporating either corn flakes or one of two soluble-fiber cereals (pectin enriched or psyllium enriched) in the diet for an additional 6 wk. During the diet-only phase, total cholesterol dropped 3.8%. During the cereal-plus-diet phase, total and LDL cholesterol values of the pectin-enriched cereal group dropped an additional 2.1% (P = 0.243) and 3.9% (P = 0.16), respectively, and they dropped 5.9% (P = 0.005) and 5.7% (P = 0.034), respectively, in the psyllium-enriched cereal group. During the cereal-plus-diet phase, no significant effects on HDL cholesterol, triglyceride, or body weight were found within or between any cereal groups. These results support use of soluble-fiber cereals as an effective and well-tolerated part of a prudent diet in the treatment of mild to moderate hypercholesterolemia.", "OBJECTIVE: In this study, we investigated the effect of small interfering RNA (siRNA) of connective tissue growth factor (CTGF) by pRetro-Super (PRS) retrovirus vector on the expression of CTGF and related extracellular matrix molecules in human renal proximal tubular cells (HKCs) induced by high glucose, to provide help for renal tubulointerstitial fibrosis therapy.METHODS: HKCs were exposed to d-glucose to observe their dose and time effect, while the mannitol as osmotic control. Retrovirus producing CTGF siRNA were constructed from the inverted oligonucleotides and transferred into packaging cell line PT67 with lipofectamine, and the virus supernatant was used to infect HKC. The expression of CTGF, fibronectin (FN) and collagen-type I (col1) were measured by semi-quantitative RT-PCR and Western blot.RESULTS: In response to high glucose, CTGF expression in HKCs was increased in a dose- and time-dependent manner, whereas the increase did not occur in the osmotic control. Introduction of PRS-CTGF-siRNA resulted in the significant reduction of CTGF, FN, col1 mRNA (p < 0.01, respectively) and CTGF, col1 protein (p < 0.05, respectively) expression, while PRS void vector group did not have these effects (p > 0.05).CONCLUSIONS: CTGF siRNA therapy can effectively reduce the levels of CTGF, FN and col1 induced by high glucose in cultured HKCs, which suggested that it may be a potential therapeutic strategy to prevent the renal interstitial fibrosis in the future.", "OBJECTIVE: Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption.RESEARCH DESIGN AND METHODS: This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, (3)H-glucose, (14)C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal.RESULTS: Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0-2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0-6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups.CONCLUSIONS: Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition.", "The stable transgenesis of genes encoding functional or spatially localized proteins, fused to fluorescent proteins such as green fluorescent protein (GFP) or red fluorescent protein (RFP), is an extremely important research tool in cell and developmental biology. Transgenic organisms constructed with fluorescent labels for cell membranes, subcellular organelles, and functional proteins have been used to investigate cell cycles, lineages, shapes, and polarity, in live animals and in cells or tissues derived from these animals. Genes of interest have been integrated and maintained in generations of transgenic animals, which have become a valuable resource for the cell and developmental biology communities. Although the use of Xenopus laevis as a transgenic model organism has been hampered by its relatively long reproduction time (compared to Drosophila melanogaster and Caenorhabditis elegans), its large embryonic cells and the ease of manipulation in early embryos have made it a historically valuable preparation that continues to have tremendous research potential. Here, we report on the Xenopus laevis transgenic lines our lab has generated and discuss their potential use in biological imaging.", "It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH." ]

[ "PROBLEM: Several studies indicate that RANTES (regulated on activation, normal T cell expressed and secreted) is able to downregulate T-cell responses which suggest it might be relevant for fetal tolerance induction. However, the role of RANTES in pregnancy had not been established. Here we investigate RANTES regulation during early pregnancy and potential failures leading to losses of pregnancies.METHOD OF STUDY: RANTES and progesterone levels were determined in sera and feto-placental units from high resorption rate CBA/JxDBA/2 pregnant females and compared with CBA/JxBALB/c normal pregnant mice. RANTES in vitro modulation was also studied in nulliparous, primiparous and multiparous CBA/J and BALB/c cells in response to paternal alloantigen and progesterone stimulation.RESULTS: Nulliparous CBA/J females were quantitatively deficient in RANTES sera levels, whereas pregnancies with male BALB/c or DBA/2 increased its production. However, feto-placental units from CBA/J females are high producers of progesterone and RANTES.CONCLUSION: These data suggest that the beneficial effect of RANTES on feto-maternal interface requires an optimal concentration range and might be modulated by progesterone, hence exacerbated placental expression could be associated with high resorption rate.", "PROBLEM: Previous studies have demonstrated a requirement for RANTES (regulated on activated normal T-cell expressed, and secreted) at immune privileged sites; we have investigated the role of RANTES in the induction of maternal-fetal tolerance.METHOD OF STUDY: Endometrial and peripheral T lymphocytes were obtained from women with recurrent pregnancy losses (RPLs) and fertile women. RANTES modulation by progesterone or paternal alloantigens was measured by enzyme-linked immunosorbent assay or flow cytometry analysis.RESULTS: Progesterone significantly increased intracellular RANTES expression in CD4+ and CD8+ endometrial T cells. Moreover, alloreactive lymphocytes from RPL patients produced lower RANTES levels when compared with those from fertile women. At the local level, treatment with recombinant RANTES induced a decrease in CCR5 and CXCR4 messenger RNA that correlated with an increase in T-bet expression. RPL patients and normally fertile women express RANTES similarly, but differ in their patterns of RANTES receptor expression.CONCLUSION: RANTES may be implicated in the local induction of a Th1-type response necessary for successful implantation. Altered response to RANTES stimulation among some RPL patients may be responsible for poor pregnancy outcomes.", "BACKGROUND: With the advancement in high-throughput technologies, researchers can simultaneously investigate gene expression and copy number alteration (CNA) data from individual patients at a lower cost. Traditional analysis methods analyze each type of data individually and integrate their results using Venn diagrams. Challenges arise, however, when the results are irreproducible and inconsistent across multiple platforms. To address these issues, one possible approach is to concurrently analyze both gene expression profiling and CNAs in the same individual.RESULTS: We have developed an open-source R/Bioconductor package (iGC). Multiple input formats are supported and users can define their own criteria for identifying differentially expressed genes driven by CNAs. The analysis of two real microarray datasets demonstrated that the CNA-driven genes identified by the iGC package showed significantly higher Pearson correlation coefficients with their gene expression levels and copy numbers than those genes located in a genomic region with CNA. Compared with the Venn diagram approach, the iGC package showed better performance.CONCLUSION: The iGC package is effective and useful for identifying CNA-driven genes. By simultaneously considering both comparative genomic and transcriptomic data, it can provide better understanding of biological and medical questions. The iGC package's source code and manual are freely available at https://www.bioconductor.org/packages/release/bioc/html/iGC.html .", "Biological analyses traditionally probe cell ensembles in the range of 103-106 cells, thereby completely averaging over relevant individual cell responses, such as differences in cell proliferation, responses to external stimuli or disease onset. In past years, this fact has been realized and increasing interest has evolved for single-cell analytical methods, which could give exciting new insights into genomics, proteomics, transcriptomics and systems biology. Microfluidic or lab-on-a-chip devices are the method of choice for single-cell analytical tools as they allow the integration of a variety of necessary process steps involved in single-cell analysis, such as selection, navigation, positioning or lysis of single cells as well as separation and detection of cellular analytes. Along with this advantageous integration, microfluidic devices confine single cells in compartments near their intrinsic volume, thus minimizing dilution effects and increasing detection sensitivity. This review overviews the developments and achievements of microfluidic single-cell analysis of intracellular compounds in the past few years, from proof-of-principle devices to applications demonstrating a high biological relevance.", "Metabolic and inflammatory pathways crosstalk at many levels, and, while required for homeostasis, interaction between these pathways can also lead to metabolic dysregulation under conditions of chronic stress. Thus, we hypothesized that mechanisms might exist to prevent overt inflammatory responses during physiological fluctuations in nutrients or under nutrient-rich conditions, and we identified the six-transmembrane protein STAMP2 as a critical modulator of this integrated response system of inflammation and metabolism in adipocytes. Lack of STAMP2 in adipocytes results in aberrant inflammatory responses to both nutrients and acute inflammatory stimuli. Similarly, in whole animals, visceral adipose tissue of STAMP2(-/-) mice exhibits overt inflammation, and these mice develop spontaneous metabolic disease on a regular diet, manifesting insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease. We conclude that STAMP2 participates in integrating inflammatory and metabolic responses and thus plays a key role in systemic metabolic homeostasis.", "Cytokines such as monocyte chemotactic peptide-1 (MCP-1), interleukin-8 (IL-8), RANTES (Regulated on Activation and Normally T-cells Expressed and presumably Secreted) and interleukin-10 (IL-10) are thought to play pivotal roles in immune recognition, acceptance of the fetal allograft, maintenance of pregnancy and parturition. Their secretion and regulation within the third trimester uterus is, however, less well defined. We therefore investigated the release of these cytokines by third trimester amnion, chorion, placenta and decidua, and studied the influence of prostaglandin E2 (PGE2) infusion on their release in a dynamic placental cotyledon perfusion system. MCP-1 was released predominately by the chorion (78.2 +/- 7.3 pg/mg wet tissue weight; mean +/- SEM), decidua (112.4 +/- 5.2 pg/mg) and placenta (101.8 +/- 5.0 pg/mg) with low amounts from the amnion (1.3 +/- 0.4 pg/mg). High concentrations of IL-8 were released by the amnion (39.9 +/- 5.3 pg/mg), chorion (52.8 +/- 1.9 pg/mg), decidua (42.2 +/- 1.5 pg/mg) and placenta (45 +/- 1.3 pg/mg). Release of RANTES was not detectable from the amnion but was detected in moderate amounts from the chorion (6.0 +/- 1.2 pg/mg), decidua (15.2 +/- 1.4 pg/mg) and placenta (26.9 +/- 1.6 pg/mg). Low concentrations of IL-10 were secreted by the chorion (6.8 +/- 0.8 pg/mg), decidua (9.0 +/- 0.9 pg/mg) and placenta (3.3 +/- 0.3 pg/mg) with none detectable from the amnion. MCP-1, IL-8, RANTES and IL-10 were all released by perfused placental cotyledons. PGE2 stimulated release of MCP-1, IL-8 and IL-10 into the maternal and of MCP-1 and IL-8 into the fetal circulation of the placenta but had no effect on RANTES release. It is suggested that MCP-1 and IL-8 may be involved in the inflammatory process of parturition and IL-10 in the protection of the fetal allograft. In addition, PGE2 may have an important immunomodulatory role within the uterus at term.", "Metaproteomic studies of whole microbial communities from environmental samples (e.g., soil, sediments, freshwater, seawater, etc.) have rapidly increased in recent years due to many technological advances in mass spectrometry (MS). A single 24-h liquid chromatograph-tandem mass spectrometry (LC-MS/MS) measurement can potentially detect and quantify thousands of proteins from many dominant and subdominant naturally occurring microbial populations. Importantly, amino acid sequences and relative abundance information for detected peptides are determined, which allows for the characterization of expressed protein functions within communities and specific matches to be made to microbial lineages, with potential subspecies resolution. Continued optimization of protein extraction and fractionation protocols, development of quantification methods, and advances in mass spectrometry instrumentation are enabling more accurate and comprehensive peptide detection within samples, leading to wider research applicability, greater ease of use, and overall accessibility. This chapter provides a brief overview of metaproteomics experimental options, including a general protocol for sample handling and LC-MS/MS measurement.", "Several lines of evidence suggest that the mechanism underlying drug-induced neuronal apoptosis is initiated by the increased production of reactive oxygen species (ROS). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, has been shown to initiate an apoptotic cascade by increasing ROS in the dopaminergic neurons of the substantia nigra, leading to the morphological and physiological features associated with Parkinson's disease. Recently, it has been reported that autophagy, a type of programmed cell death independent of the apoptotic cascade, also plays a role in neuronal damage. Although autophagy is negatively regulated by the mammalian target of rapamycin receptor (mTOR), there is some evidence showing a novel function for the anti-apoptotic protein Bcl-2. Bcl-2 is proposed to play a role in negatively regulating autophagy by blocking an essential protein in the signaling pathway, Beclin 1. Nevertheless, it is unclear whether autophagy is also correlated with apoptotic signaling in 1-methyl-4-phenylpyridinium (MPP(+)) toxicity. Therefore, we hypothesized that the MPP(+) toxicity generally associated with initiating the apoptotic signaling cascade also increases an autophagic phenotype in neuronal cells. Using the SK-N-SH dopaminergic cell lines, we demonstrate that MPP(+) increases the expression of microtubule-associated protein light chain 3 (LC3-II), an autophagosome membrane marker and the mTOR signaling pathway, and Beclin 1 while decreasing the Bcl-2 levels. Moreover, these expressions correlate with a decreased binding ratio between Bcl-2 and Beclin 1, in effect limiting the regulation of the downstream autophagic markers, such as LC3-II. Our results indicate that MPP(+) can induce autophagy in SK-N-SH cells by decreasing the Bcl-2/Beclin 1 complex.", "A review of 775 normally pigmented Africans and 18 African albinos with malignant skin tumours showed that squamous cell carcinoma was the most common tumour type, in contrast to Caucasians, in whom basal cell carcinoma is most frequent. In African albinos squamous cell carcinoma of the head and neck region was most frequent. However, the proportion of basal cell carcinomas was low also among albinos but higher than among normally pigmented patients. In contrast to the normally pigmented patients, there were no squamous cell carcinomas on the limbs in albino patients. We suggest that this difference was due to environmental factors, such as chronic leg ulcers, which might have been less influential in the albinos, who seldom lived more than 30 years. No cases of cutaneous melanoma or Kaposi sarcoma were found in the albino group.", "The hallmark of Ewing's sarcoma (EWS) is a translocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 aberrant chimeric gene. Because EWS afflicts young patients, it stands out among the diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic chemotherapy regimens produce minimal benefit in patients with metastases at presentation or those with relapsed disease. While the outcomes of chemorefractory EWS patients are generally poor, recent developments have led to the promising use of targeted therapy. Specifically, inhibition of insulin-like growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin (mTOR) pathways has emerged as a targeted therapy in EWS, with select patients experiencing dramatic therapeutic responses. However, targeted therapies in general, and these responders in particular, are faced with the ultimate conundrum of eventual resistance. To optimize response, combining IGF1R and mTOR inhibitor-based regimens with chemotherapy in the upfront setting in newly diagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in these patients. Another option is to explore novel targeted multikinase inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have experienced a surge in supporting preclinical data. Drugs inhibiting the downstream targets of EWS/FLI1 are also in preclinical development. However, ultimately, the underlying biomarker correlates of resistance and response must be delineated along with ways to overcome them. Novel agents, together with integration of advances in multimodal approaches (including surgery and radiation), as well as offering targeted therapies early in the disease course represent new strategies for confronting the challenges of EWS.", "Male pseudohermaphroditism caused by steroid 5alpha-reductase deficiency is an autosomal recessive disorder. The enzyme steroid 5alpha-reductase 2 (encoded by the SRD5A2 gene) catalyses the conversion of testosterone to dihydrotestosterone, which is required for normal differentiation of the external male genitalia. This report describes the molecular analysis of the 5alpha-reductase type 2 gene in a Brazilian patient who was raised as a female, underwent a reversal of gender role behavior, and is now a married man. This patient is a compound heterozygote bearing an A-->G mutation within exon 2, changing codon 126 from Glu to Arg on one allele and a novel single base deletion (418delT) causing a frameshift mutation at codon 140 in the same exon, on the other allele. This last mutation probably leads to the synthesis of a truncated protein, because a premature termination signal is created at codon 159.", "One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD." ]

[ "Deamination of cytidine residues in viral DNA is a major mechanism by which APOBEC3G (A3G) inhibits vif-deficient human immunodeficiency virus type 1 (HIV-1) replication. dC-to-dU transition following RNase-H activity leads to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis. Here, we demonstrate that A3G provides an additional layer of defense against HIV-1 infection dependent on inhibition of proviral transcription. HIV-1 transcription elongation is regulated by the trans-activation response (TAR) element, a short stem-loop RNA structure required for elongation factors binding. Vif-deficient HIV-1-infected cells accumulate short viral transcripts and produce lower amounts of full-length HIV-1 transcripts due to A3G deamination of the TAR apical loop cytidine, highlighting the requirement for TAR loop integrity in HIV-1 transcription. We further show that free single-stranded DNA (ssDNA) termini are not essential for A3G activity and a gap of CCC motif blocked with juxtaposed DNA or RNA on either or 3'+5' ends is sufficient for A3G deamination. These results identify A3G as an efficient mutator and that deamination of (-)SSDNA results in an early block of HIV-1 transcription.", "DNA methylation is involved in fundamental cellular processes such as silencing of genes and transposable elements, but the underlying mechanism of regulation of DNA methylation is largely unknown. DNA methyltransferase 3-like protein (Dnmt3L), a member of the Dnmt3 family of proteins, is required during the establishment of DNA methylation patterns in germ cells. Dnmt3L does not possess enzymatic activity. Rather, in vitro analysis indicates that Dnmt3L stimulates DNA methylation by both Dnmt3a and Dnmt3b through direct binding to these proteins. In the current study, we demonstrated that in vivo, Dnmt3L physically and functionally interacted with the Dnmt3 isoform Dnmt3a2. In wild-type embryonic stem (ES) cells, but not in cells lacking Dnmt3a, endogenous Dnmt3L was concentrated in chromatin foci. In ES cells deficient in both Dnmt3a and Dnmt3b, Dnmt3L was distributed diffusely throughout the nucleus and cytoplasm, and ectopic expression of Dnmt3a2, but not Dnmt3a or Dnmt3b, restored wild-type Dnmt3L localization. We showed that endogenous Dnmt3L physically interacted with Dnmt3a2, but not Dnmt3a or Dnmt3b, in ES cells and embryonic testes. We also found that specific CpG sites were demethylated upon depletion of either Dnmt3a or Dnmt3L, but not Dnmt3b, in ES cells. These results provide evidence for a physical and functional interaction between Dnmt3L and Dnmt3a2 in the nucleus. We propose that Dnmt3a2 recruits Dnmt3L to chromatin, and induces regional DNA methylation in germ cells.", "3'-untranslated regions of various mRNAs have been shown to contain sequence motifs which control mRNA stability, translatability, and efficiency of translation as well as intracellular localization. We aimed to identify protein binding regions of the long and highly conserved 3'UTR of the mRNA coding for neurofibromin, a well-known tumor suppressor protein, whose genetic deficiency causes the autosomal dominant disease neurofibromatosis type 1 (NF1). We discovered five RNA fragments that were able to undergo specific binding to proteins from cell lysates (NF1-PBRs, NF1-protein-binding regions). Additionally we identified the Elav-like protein HuR binding to NF1-PBR1. HuR interacts with AU-rich elements in the 3'UTR of many protooncogenes, cytokines, and transcription factors, thereby regulating the expression of these mRNAs on the posttranscriptional level. Transfection assays with a CAT reporter construct revealed reduced expression of the reporter, suggesting that HuR may be involved in the fine-tuning of the expression of the NF1 gene.", "Bortezomib (Velcade™) is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM). Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ~30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response.", "Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.", "Although the mechanisms underlying striatal neurodegeneration are poorly understood, we have shown that striatal pathogenesis may be initiated by high synaptic levels of extracellular dopamine (DA). Here we investigated in rat striatal primary neurons the mobilization of the mitogen-activated protein kinase (MAPK) signaling pathways after treatment with DA. Instead of observing an elevation of the archetypical pro-cytotoxic MAPKs, p-JNK and p-p38 MAPK, we found that DA, acting through D1 DA receptors, induced a sustained stimulation of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via a cAMP/protein kinase A (PKA)/Rap1/B-Raf / MAPK/ERK kinase (MEK) pathway. Blockade of D2 DA receptors, beta-adrenergic receptors or N-methyl-D-aspartate receptors with receptor-specific antagonists had no significant effect on this process. Activation of D1 DA receptors and PKA by DA caused phosphorylation and inactivation of the striatal-enriched tyrosine phosphatase, an important phosphatase for the dephosphorylation and subsequent inactivation of p-ERK in the striatum. Interestingly, p-ERK was primarily retained in the cytoplasm, with only low amounts translocated to the nucleus. The scaffold protein beta-arrestin2 interacted with both p-ERK and D1 DA receptor, triggering the cytosolic retention of p-ERK and inducing striatal neuronal apoptotic death. These data provide unique insight into a novel role of p-ERK in striatal neurodegeneration.", "Multiple classes of small RNAs (sRNAs) are expressed in the blood and are involved in the regulation of pivotal cellular processes. We aimed to elucidate the expression patterns and functional roles of sRNAs in the systemic response to intracranial aneurysm (IA) rupture. We used next-generation sequencing to analyze the expression of sRNAs in patients in the acute phase of IA rupture (first 72 h), in the chronic phase (3-15 months), and controls. The patterns of alterations in sRNA expression were analyzed in the context of clinically relevant information regarding the biological consequences of IA rupture. We identified 542 differentially expressed sRNAs (108 piRNAs, 99 rRNAs, 90 miRNAs, 43 scRNAs, 36 tRNAs, and 32 snoRNAs) among the studied groups with notable differences in upregulated and downregulated sRNAs between the groups and sRNAs categories. piRNAs and rRNAs showed a substantial decrease in RNA abundance that was sustained after IA rupture, whereas miRNAs were largely upregulated. Downregulated sRNA genes included piR-31080, piR-57947, 5S rRNA, LSU-rRNA, and SSU-rRNA s. Remarkable enrichment in the representation of transcription factor binding sites was revealed in genomic locations of the regulated sRNA. We found strong overrepresentation of glucocorticoid receptor, retinoid x receptor alpha, and estrogen receptor alpha binding sites at the locations of downregulated piRNAs, tRNAs, and rRNAs. This report, although preliminary and largely proof-of-concept, is the first to describe alterations in sRNAs abundance levels in response to IA rupture in humans. The obtained results indicate novel mechanisms that may constitute another level of control of the inflammatory response. KEY MESSAGES: A total of 542 sRNAs were differentially expressed after aneurysmal SAH comparing with controls piRNAs and rRNAs were upregulated and miRNAs were downregulated after IA rupture The regulated sRNA showed an enrichment in the representation of some transcription factor binding sites piRNAs, tRNAs, and rRNAs showed an overrepresentation for GR, RXRA, and ERALPHA binding sites." ]

[ "Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma (PCa) on core biopsy (NBX) is critical because it is associated with disease progression and the worst clinical outcome. We evaluated 1557 consecutive and prospectively collected NBXs to determine the frequency of diagnosis, morphologic subpatterns, and their relation to the amount and pattern distribution of GP5 PCa based on the 2005 modified Gleason grading system. Tertiary GP5 was upgraded to a secondary pattern to derive the final Gleason score. GP5 accounted for 6% of all NBXs and 14% of PCa cases. GP5 PCas were associated with high-risk preoperative clinical and biopsy characteristics, regardless of the amount of GP5. Most patients (85%) with % GP5 greater than 5% of PCa had the final Gleason score of 9 to 10, compared with % GP5 of 5% or less of PCa (P < .0001). The morphologic subpatterns of GP5 PCas were as follows: infiltrating cords (96%), single cells (76%), solid sheets (29%), and comedocarcinoma (2%). Infiltrating cords and single-cell patterns frequently coexisted (76%). The GP5 was distributed in a tertiary (66%), followed by secondary (32%) and primary (2%) components of PCa. Infiltrating cords and single cells were the 2 most frequently encountered patterns, specifically when GP5 involved 5% or less of PCa and represented secondary or tertiary component of PCa. GP5 PCa is a relatively frequent presentation in the contemporary NBX practice. Because of its important prognostic and therapeutic implications, pathologists must be aware of its varied morphologic presentations and to the fact that most cases with GP5 represent a tertiary component of PCa.", "Marfan's syndrome is an autosomal dominant disorder of connective tissue, commonly involving the cardiovascular, ocular, and skeletal systems. Revised criteria for the clinical diagnosis of Marfan's syndrome regard skeletal involvement as a major criterion if at least four of eight typical skeletal manifestations are present, one of which is protrusio acetabuli. Using Kulman's method to determine the presence of protrusio, we analysed the pelvic X-rays of 15 patients with Marfan's syndrome and 15 controls. Protrusio was present in 47% (7/15) of Marfan patients, compared with 7% (1/15) of controls (P = 0.035). Using the revised criteria, the presence of protrusio would have affected the final diagnosis of Marfan's syndrome in only one patient out of 15. Therefore, we recommend that a pelvic X-ray is reserved for those cases in which the presence of protrusio will alter the final diagnosis. With regard to the radiological assessment of protrusio, in our opinion this can be performed simply and reliably using the position of the acetabular line alone.", "It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activation in a PI3K dependent manner. However, the functionality of PAK4 in pancreatic cancer and the contribution made by HGF signalling to pancreatic cancer cell motility remain to be elucidated. We now find that elevated PAK4 expression is coincident with increased expression levels of c-Met and the p85α subunit of PI3K. Furthermore, we demonstrate that pancreatic cancer cells have a specific motility response to HGF both in 2D and 3D physiomimetic organotypic assays; which can be suppressed by inhibition of PI3K. Significantly, we report a specific interaction between PAK4 and p85α and find that PAK4 deficient cells exhibit a reduction in Akt phosphorylation downstream of HGF signalling. These results implicate a novel role for PAK4 within the PI3K pathway via interaction with p85α. Thus, PAK4 could be an essential player in PDAC progression representing an interesting therapeutic opportunity.", "Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.", "The carnitine/acylcarnitine transporter (CACT; SLC25A20) mediates an antiport reaction allowing entry of acyl moieties in the form of acylcarnitines into the mitochondrial matrix and exit of free carnitine. The transport function of CACT is crucial for the β-oxidation pathway. In this work, it has been found that CACT is partially acetylated in rat liver mitochondria as demonstrated by anti-acetyl-lys antibody immunostaining. Acetylation was reversed by the deacetylase Sirtuin 3 in the presence of NAD+. After treatment of the mitochondrial extract with the deacetylase, the CACT activity, assayed in proteoliposomes, increased. The half-saturation constant of the CACT was not influenced, while the V max was increased by deacetylation. Sirtuin 3 was not able to deacetylate the CACT when incubation was performed in intact mitoplasts, indicating that the acetylation sites are located in the mitochondrial matrix. Prediction on the localization of acetylated residues by bioinformatics correlates well with the experimental data. Recombinant CACT treated with acetyl-CoA was partially acetylated by non-enzymatic mechanism with a corresponding decrease of transport activity. The experimental data indicate that acetylation of CACT inhibits its transport activity, and thus may contribute to the regulation of the mitochondrial β-oxidation pathway.", "BACKGROUND: Lbx/ladybird genes originated as part of the metazoan cluster of Nk homeobox genes. In all animals investigated so far, both the protostome genes and the vertebrate Lbx1 genes were found to play crucial roles in neural and muscle development. Recently however, additional Lbx genes with divergent expression patterns were discovered in amniotes. Early in the evolution of vertebrates, two rounds of whole genome duplication are thought to have occurred, during which 4 Lbx genes were generated. Which of these genes were maintained in extant vertebrates, and how these genes and their functions evolved, is not known.RESULTS: Here we searched vertebrate genomes for Lbx genes and discovered novel members of this gene family. We also identified signature genes linked to particular Lbx loci and traced the remnants of 4 Lbx paralogons (two of which retain Lbx genes) in amniotes. In teleosts, that have undergone an additional genome duplication, 8 Lbx paralogons (three of which retain Lbx genes) were found. Phylogenetic analyses of Lbx and Lbx-associated genes show that in extant, bony vertebrates only Lbx1- and Lbx2-type genes are maintained. Of these, some Lbx2 sequences evolved faster and were probably subject to neofunctionalisation, while Lbx1 genes may have retained more features of the ancestral Lbx gene. Genes at Lbx1 and former Lbx4 loci are more closely related, as are genes at Lbx2 and former Lbx3 loci. This suggests that during the second vertebrate genome duplication, Lbx1/4 and Lbx2/3 paralogons were generated from the duplicated Lbx loci created during the first duplication event.CONCLUSION: Our study establishes for the first time the evolutionary history of Lbx genes in bony vertebrates, including the order of gene duplication events, gene loss and phylogenetic relationships. Moreover, we identified genetic hallmarks for each of the Lbx paralogons that can be used to trace Lbx genes as other vertebrate genomes become available. Significantly, we show that bony vertebrates only retained copies of Lbx1 and Lbx2 genes, with some Lbx2 genes being highly divergent. Thus, we have established a base on which the evolution of Lbx gene function in vertebrate development can be evaluated.", "Leptin, an adipocyte-released hormone, modifies food intake and energy expenditure regulating hypothalamic-pituitary-thyroid axis function. We previously reported that thyrotropin-releasing hormone (TRH) precursor gene overexpression induces hypertension in the normal rat and that spontaneously hypertensive rats have central TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number. In both models, intracerebroventricular antisense (AS) treatment against the TRH precursor produced a dose-dependent reduction of the increased diencephalic TRH content while normalizing high arterial blood pressure. In this article, we report that male Wistar rats that were made hypertensive by intracerebroventricular injection of a eucaryotic expression plasmid containing the pre-TRH cDNA showed decreased leptin plasma levels and that pre-TRH AS treatment reversed this phenomenon. In addition, male and female spontaneously hypertensive rats showed lower levels of circulating leptin than did sex-matched Wistar-Kyoto control rats. This difference also was abated by the pre-TRH AS treatment. Conversely, 20 microg ICV leptin induced a long-lasting pressor effect (18 +/- 5 mm Hg, n=6, P<0.01, >60 minutes) that was not observed in pre-TRH AS pretreated rats (2 +/- 3 mm Hg, n=6) but persisted in rats used as controls that were treated with inverted oligonucleotide (20 +/- 6 mm Hg, n=4, P<0.01). These data suggest that in rats with TRH-induced hypertension, leptin is decreased, inducing compensatory adiposity. We propose that because leptin produces central TRH synthesis and release, obesity may induce hypertension through TRH system activation and that the TRH-leptin interaction may thus contribute to the strong association between hypertension and obesity." ]

[ "TFIIS is a transcription elongation factor that stimulates transcript cleavage activity of arrested RNA polymerase II (Pol II). Recent studies revealed that TFIIS has also a role in Pol II transcription initiation. To improve our understanding of TFIIS function in vivo, we performed genome-wide location analysis of this factor. Under normal growth conditions, TFIIS was detected on Pol II-transcribed genes, and TFIIS occupancy was well correlated with that of Pol II, indicating that TFIIS recruitment is not restricted to NTP-depleted cells. Unexpectedly, TFIIS was also detected on almost all Pol III-transcribed genes. TFIIS and Pol III occupancies correlated well genome-wide on this novel class of targets. In vivo, some dst1 mutants were partly defective in tRNA synthesis and showed a reduced Pol III occupancy at the restrictive temperature. In vitro transcription assays suggested that TFIIS may affect Pol III start site selection. These data provide strong in vivo and in vitro evidence in favor of a role of TFIIS as a general Pol III transcription factor.", "Persistent hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma and the major indication for liver transplantation in adults. Current standard of care treatment (SOC) with pegylated-interferon-α 2 and ribavirin (RBV) has a limited efficacy and is associated with significant side effects frequently associated with poor compliance or treatment discontinuation, requiring specialized and frequent monitoring. To overcome the limited efficacy of SOC, more than 50 direct-acting antiviral agents (DAA) designed to target viral-encoded proteins essential in the HCV life cycle are currently under development. The rapid selection of resistant mutants associated with the quasispecies nature of HCV with high mutation and replication rates is one of the main challenges for the new HCV therapies. Predictive host and viral factors together with combination of DAAs with or without IFN and/or RBV need to be accurately evaluated to design the most effective individualized treatment strategy within the shortest time interval and with minimum side effects.", "Hot water epilepsy is a reflex epilepsy. Seizures are provoked by hot water, and result from the association of both cutaneous and heat stimuli. Described mainly in India and Japan, the condition seems to be rare in Europe, where it occurs in young children. We report five infants aged from 6 months to 2 years. They had brief seizures during bathing with activity arrest, hypotonia, and vasoactive modification; clonic movements were observed. A simple treatment-decreasing the bath temperature-can be sufficient. Sometimes an antiepileptic drug is required. Seizure course and psychomotor development are favorable. Hot water epilepsy is a benign form of epilepsy. Its incidence could be underestimated because of confusion with febrile convulsions, vagal fits, or aquagenic urticaria.", "Circular RNAs (circRNAs) are a type of single-stranded RNA molecules that normally do not encode proteins. circRNAs are involved in many physiological processes as well as the pathogenesis of diseases. Cardiac fibrosis is increasingly recognized as a pathological force in advanced heart diseases. A growing number of studies have reported that the occurrence and development of cardiac fibrosis is closely associated with the regulation of circRNAs. This review summarizes the current understanding of circRNA biogenesis and function and will highlight the recent updates regarding the involvement of circRNAs in cardiac fibrosis, and their potential as emerging biomarkers and therapeutic targets.", "Delivery of small interfering RNAs (siRNAs) into cells is a key obstacle to their therapeutic application. We designed a protamine-antibody fusion protein to deliver siRNA to HIV-infected or envelope-transfected cells. The fusion protein (F105-P) was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. siRNAs bound to F105-P induced silencing only in cells expressing HIV-1 envelope. Additionally, siRNAs targeted against the HIV-1 capsid gene gag, inhibited HIV replication in hard-to-transfect, HIV-infected primary T cells. Intratumoral or intravenous injection of F105-P-complexed siRNAs into mice targeted HIV envelope-expressing B16 melanoma cells, but not normal tissue or envelope-negative B16 cells; injection of F105-P with siRNAs targeting c-myc, MDM2 and VEGF inhibited envelope-expressing subcutaneous B16 tumors. Furthermore, an ErbB2 single-chain antibody fused with protamine delivered siRNAs specifically into ErbB2-expressing cancer cells. This study demonstrates the potential for systemic, cell-type specific, antibody-mediated siRNA delivery.", "Frontline chemotherapy is successful against chronic lymphocytic leukemia (CLL), but results in untoward toxicity. Further, prognostic factors, cytogenetic anomalies, and compensatory cellular signaling lead to therapy resistance or disease relapse. Therefore, for the past few years, development of targeted therapies is on the rise. PI3K is a major player in the B-cell receptor (BCR) signaling axis, which is critical for the survival and maintenance of B cells. Duvelisib, a PI3K δ/γ dual isoform specific inhibitor that induces apoptosis and reduces cytokine and chemokine levels in vitro, holds promise for CLL. Areas covered: Herein, we review PI3K isoforms and their inhibitors in general, and duvelisib in particular; examine literature on preclinical investigations, pharmacokinetics and clinical studies of duvelisib either as single agent or in combination, for patients with CLL and other lymphoid malignancies. Expert opinion: Duvelisib targets the PI3K δ isoform, which is necessary for cell proliferation and survival, and γ isoform, which is critical for cytokine signaling and pro-inflammatory responses from the microenvironment. In phase I clinical trials, duvelisib as a single agent showed promise for CLL and other lymphoid malignancies. Phase II and III trials of duvelisib alone or in combination with other agents are ongoing.", "This report presents the first example of male transmission of Apert acrocephalosyndactyly syndrome. Female transmission has been reported in the five previous well-documented cases of dominant inheritance of the syndrome." ]

[ "Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated the role of JAKs in colorectal cancer in order to develop effective therapeutic targets for INCB018424, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of INCB018424 on the phosphorylation of JAK1/2 using western blot analysis. Cell viability was determined using the trypan blue exclusion assay. The cell death mechanism was identified by the activation of caspase 3 using western blot and annexin V staining. The basal levels of phospho-JAK1 and phospho-JAK2 were cancer cell type dependent. Colorectal cancer cell lines that phosphorylate both JAK1 and JAK2 include DLD-1 and RKO. INCB018424 inactivates both JAK1 and JAK2 in DLD-1 cells but inactivates only JAK1 in RKO cells. Cell death was proportional to the inactivation of JAK1 but not JAK2. INCB018424 causes caspase-dependent cell death, which is prevented by treatment with z-VAD. The inhibition of JAK1 phosphorylation seemed sufficient to allow INCB018424-mediated apoptosis. JAK1 is a key molecule that is involved in colon cancer cell survival and the inhibition of JAK1 by INCB01424 results in caspase-dependent apoptosis in colorectal cancer cells. The use of selective JAK1 inhibitors could be an attractive therapy against colorectal cancer, but further clinical investigations are needed to test this possibility.", "OBJECTIVE: To determine the better approach for weaning preterm infants from nasal continuous positive airway pressure (NCPAP) with or without transitioning to nasal cannula (NC).DESIGN/METHODS: This is a randomized, open label, controlled trial. Preterm infants born at ≥28 weeks gestation who were clinically stable on NCPAP of 5 cm H(2)O with FiO(2)<0.30 for at least 24 h were randomly assigned to one of 2 groups. The no-NC group were kept on NCPAP until they were on FiO(2)=0.21 for 24 h, and then were weaned off NCPAP completely without any exposure to NC. If they met failing criteria, NCPAP was re-instituted. The NC-group was weaned off NCPAP when FiO(2) was ≤0.30 to NC (2 L/min) followed by gradual weaning from oxygen. Infants who failed NC were supported back with NCPAP for 24 h before making a second attempt of NC.RESULTS: Sixty neonates were enrolled; 30 in each group. The two groups were similar in birthweight, gestational age, sex, antenatal steroids, mode of delivery, use of surfactant and xanthines, and duration of mechanical ventilation. After randomization, the no-NC group had fewer days on oxygen [median (interquartile range): 5 (1-8) vs 14 (7.5-19.25) days, p<0.001] and shorter duration of respiratory support [10.5 (4-21) vs 18 (11.5-29) days, p=0.03]. There were no differences between groups regarding success of weaning from NCPAP.CONCLUSIONS: Weaning preterm infants from NCPAP to NC is associated with increased exposure to oxygen and longer duration of respiratory support.", "Alzheimer's disease (AD) is the most common cause of dementia in humans. A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The \"Swedish\" mutations (APP(SW)) and the \"London\" mutation (APP(LON)) are examples of these mutants. Selective silencing of these mutant alleles holds therapeutic promise for AD. Here we show that the expression of the mutant APPs was selectively inhibited by RNA interference. The best selectivity was obtained when the mismatches were centrally placed in the antisense strand of small interfering RNAs. Introducing an additional mismatch in the antisense strand may improve the selectivity. The addition of a G at 5' end of the antisense strand may enhance the efficacy of gene silencing by RNA interference. Our results illustrate the guiding principles for selection of targeted sequences to achieve allele-specific silencing. The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.", "INTRODUCTION: Atherosclerotic Coronary Artery Disease (ASCAD) is the leading cause of mortality worldwide. Novel therapeutic approaches aiming to improve the atheroprotective functions of High Density Lipoprotein (HDL) include the use of reconstituted HDL forms containing human apolipoprotein A-I (rHDL-apoA-I). Given the strong atheroprotective properties of apolipoprotein E3 (apoE3), rHDL-apoE3 may represent an attractive yet largely unexplored therapeutic agent.OBJECTIVE: To evaluate the atheroprotective potential of rHDL-apoE3 starting with the unbiased assessment of global transcriptome effects and focusing on endothelial cell (EC) migration as a critical process in re-endothelialization and atherosclerosis prevention. The cellular, molecular and functional effects of rHDL-apoE3 on EC migration-associated pathways were assessed, as well as the potential translatability of these findings in vivo.METHODS: Human Aortic ECs (HAEC) were treated with rHDL-apoE3 and total RNA was analyzed by whole genome microarrays. Expression and phosphorylation changes of key EC migration-associated molecules were validated by qRT-PCR and Western blot analysis in primary HAEC, Human Coronary Artery ECs (HCAEC) and the human EA.hy926 EC line. The capacity of rHDL-apoE3 to stimulate EC migration was assessed by wound healing and transwell migration assays. The contribution of MEK1/2, PI3K and the transcription factor ID1 in rHDL-apoE3-induced EC migration and activation of EC migration-related effectors was assessed using specific inhibitors (PD98059: MEK1/2, LY294002: PI3K) and siRNA-mediated gene silencing, respectively. The capacity of rHDL-apoE3 to improve vascular permeability and hypercholesterolemia in vivo was tested in a mouse model of hypercholesterolemia (apoE KO mice) using Evans Blue assays and lipid/lipoprotein analysis in the serum, respectively.RESULTS: rHDL-apoE3 induced significant expression changes in 198 genes of HAEC mainly involved in re-endothelialization and atherosclerosis-associated functions. The most pronounced effect was observed for EC migration, with 42/198 genes being involved in the following EC migration-related pathways: 1) MEK/ERK, 2) PI3K/AKT/eNOS-MMP2/9, 3) RHO-GTPases, 4) integrin. rHDL-apoE3 induced changes in 24 representative transcripts of these pathways in HAEC, increasing the expression of their key proteins PIK3CG, EFNB2, ID1 and FLT1 in HCAEC and EA.hy926 cells. In addition, rHDL-apoE3 stimulated migration of HCAEC and EA.hy926 cells, and the migration was markedly attenuated in the presence of PD98059 or LY294002. rHDL-apoE3 also increased the phosphorylation of ERK1/2, AKT, eNOS and p38 MAPK in these cells, while PD98059 and LY294002 inhibited rHDL-apoE3-induced phosphorylation of ERK1/2, AKT and p38 MAPK, respectively. LY had no effect on rHDL-apoE3-mediated eNOS phosphorylation. ID1 siRNA markedly decreased EA.hy926 cell migration by inhibiting rHDL-apoE3-triggered ERK1/2 and AKT phosphorylation. Finally, administration of a single dose of rHDL-apoE3 in apoE KO mice markedly improved vascular permeability as demonstrated by the reduced concentration of Evans Blue dye in tissues such as the stomach, the tongue and the urinary bladder and ameliorated hypercholesterolemia.CONCLUSIONS: rHDL-apoE3 significantly enhanced EC migration in vitro, predominantly via overexpression of ID1 and subsequent activation of MEK1/2 and PI3K, and their downstream targets ERK1/2, AKT and p38 MAPK, respectively, and improved vascular permeability in vivo. These novel insights into the rHDL-apoE3 functions suggest a potential clinical use to promote re-endothelialization and retard development of atherosclerosis.", "Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4), orally active, that improves glycemic control in patients with type 2 diabetes (T2DM) primarily by enhancing pancreatic (alpha and beta) islet function. Thus vildagliptin has been shown both to improve insulin secretion and to suppress the inappropriate glucagon secretion seen in patients with T2DM. Vildagliptin reduces HbA(1c) when given as monotherapy, without weight gain and with minimal hypoglycemia, or in combination with the most commonly prescribed classes of oral hypoglycemic drugs: metformin, a sulfonylurea, a thiazolidinedione, or insulin. Metformin, with a different mode of action not addressing beta-cell dysfunction, has been used for about 50 years and still represents the universal first line therapy of all guidelines. However, given the multiple pathophysiological abnormalities in T2DM and the progressive nature of the disease, intensification of therapy with combinations is typically required over time. Recent guidelines imply that patients will require pharmacologic combinations much earlier to attain and sustain the increasingly stringent glycemic targets, with careful drug selection to avoid unwanted adverse events, especially hypoglycemia. The combination of metformin and vildagliptin offers advantages when compared to currently used combinations with additive efficacy and complimentary mechanisms of action, since it does not increase the risk of hypoglycemia and does not promote weight gain. Therefore, by specifically combining these agents in a single tablet, there is considerable potential to achieve better blood glucose control and to improve compliance to therapy.", "Molecular chaperones are proteins that assist the folding, unfolding, and remodeling of other proteins. In eukaryotes, heat shock protein 90 (Hsp90) proteins are essential ATP-dependent molecular chaperones that remodel and activate hundreds of client proteins with the assistance of cochaperones. In Escherichia coli, the activity of the Hsp90 homolog, HtpG, has remained elusive. To explore the mechanism of action of E. coli Hsp90, we used in vitro protein reactivation assays. We found that E. coli Hsp90 promotes reactivation of heat-inactivated luciferase in a reaction that requires the prokaryotic Hsp70 chaperone system, known as the DnaK system. An Hsp90 ATPase inhibitor, geldanamycin, inhibits luciferase reactivation demonstrating the importance of the ATP-dependent chaperone activity of E. coli Hsp90 during client protein remodeling. Reactivation also depends upon the ATP-dependent chaperone activity of the DnaK system. Our results suggest that the DnaK system acts first on the client protein, and then E. coli Hsp90 and the DnaK system collaborate synergistically to complete remodeling of the client protein. Results indicate that E. coli Hsp90 and DnaK interact in vivo and in vitro, providing additional evidence to suggest that E. coli Hsp90 and the DnaK system function together.", "Recent reports of microRNA (miR) modulators of both neuronal and immune processes (here termed NeurimmiRs) predict therapeutic potential for manipulating NeurimmiR levels in diseases affecting both the immune system and higher brain functions, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and anxiety-related disorders. In our opinion, NeurimmiRs that function within both the nervous and the immune systems, such as miR-132 and miR-124, may act as 'negotiators' between these two interacting compartments. We suggest that NeurimmiRs primarily target transcriptional or other regulatory genes, which enables modulation of both immune and cognitive processes through direct or indirect alterations of neuron-glia and/or brain-to-body signaling. Thus, manipulating NeurimmiR control over the immune contributions to cognitive pathways may offer new therapeutic targets." ]

[ "The IL-17 pathway is an established driver of psoriasis pathogenesis. We examined the detailed molecular and cellular effects of blockade of IL-17 signaling in human psoriatic skin before and following treatment with brodalumab, a competitive inhibitor of the IL-17 Receptor A subunit. Thousands of aberrantly expressed genes in lesional skin normalized within 2 weeks following brodalumab treatment, with conversion of the lesional psoriasis transcriptome to resemble that seen in nonlesional skin. Keratinocyte-expressed genes appeared to normalize rapidly, whereas T cell-specific normalization occurred over six weeks. The three IL-17 ligand genes that are upregulated in lesional skin, IL17A, IL17C, and IL17F, were all downregulated in a dose-dependent manner following brodalumab treatment. Cellular measures also showed a similar pattern with dramatic decreases in keratinocyte hyperplasia within one week, and decreases in infiltrating leukocytes occurred over a longer timescale. Individuals with the highest brodalumab exposure showed normalization of both IL-17-responsive genes and the psoriasis transcriptome, whereas subjects with lower exposures showed transient or incomplete molecular responses. Clinical and molecular response appeared dependent on the extent of brodalumab exposure relative to the expression of IL-17 ligand genes, and reduction of IL-17 signaling into the nonlesional range was strongly correlated with normalization of the psoriasis transcriptome. These data indicate that blockade of IL-17 signaling in psoriatic skin leads to rapid transcriptomal changes initially in keratinocyte-expressed genes, followed by normalization in the leukocyte abnormalities, and demonstrates the essential role of the IL-17R on keratinocytes in driving disease pathogenesis.", "Some patients with nickel (Ni) allergic contact dermatitis suffer from systemic (intestinal or cutaneous) symptoms after ingestion of Ni-rich foods and experience symptoms reduction with low-Ni diet, a condition termed Systemic Ni Allergy Syndrome (SNAS). We aimed at evaluating whether oral administration of low nickel doses improved clinical conditions and modulated immunological aspects of SNAS, without significant side effects. Thirty-six SNAS patients were enrolled. Treatment started after 1-month of low-Ni diet and consisted in an incremental oral NiOH dose phase (0.3ng to 1.5 microg/week) followed by a 12-months maintenance phase (1.5 microg/week). Randomly, twenty-four patients added Ni therapy to low-Ni diet and 12 remained with diet alone. All patients were allowed rescue medications (antihistamines and topical steroids). After 4 months, Ni-rich foods were gradually reintroduced. In vitro allergen-driven IL13, IL5 and IFN-gamma release by peripheral blood mononuclear cells was evaluated before and after treatment. Twenty-three patients receiving NiOH and the 12 control patients completed the study. Evaluation of SNAS clinical severity (by VAS and drug consumption) showed a significant difference in favor of NiOH-treated patients compared to controls. Twenty of 23 patients in the NiOH group and none in the control group tolerated Ni-rich food reintroduction. Release of all studied cytokines in culture supernatants was significantly lower after NiOH treatment. In conclusion NiOH is effective in reducing symptoms and drug consumption in SNAS and is able to modulate inflammatory parameters.", "Proteins and their interactions govern virtually all cellular processes, such as regulation, signaling, metabolism, and structure. Most experimental findings pertaining to such interactions are discussed in research papers, which, in turn, get curated by protein interaction databases. Authors, editors, and publishers benefit from efforts to alleviate the tasks of searching for relevant papers, evidence for physical interactions, and proper identifiers for each protein involved. The BioCreative II.5 community challenge addressed these tasks in a competition-style assessment to evaluate and compare different methodologies, to make aware of the increasing accuracy of automated methods, and to guide future implementations. In this paper, we present our approaches for protein-named entity recognition, including normalization, and for extraction of protein-protein interactions from full text. Our overall goal is to identify efficient individual components, and we compare various compositions to handle a single full-text article in between 10 seconds and 2 minutes. We propose strategies to transfer document-level annotations to the sentence-level, which allows for the creation of a more fine-grained training corpus; we use this corpus to automatically derive around 5,000 patterns. We rank sentences by relevance to the task of finding novel interactions with physical evidence, using a sentence classifier built from this training corpus. Heuristics for paraphrasing sentences help to further remove unnecessary information that might interfere with patterns, such as additional adjectives, clauses, or bracketed expressions. In BioCreative II.5, we achieved an f-score of 22 percent for finding protein interactions, and 43 percent for mapping proteins to UniProt IDs; disregarding species, f-scores are 30 percent and 55 percent, respectively. On average, our best-performing setup required around 2 minutes per full text. All data and pattern sets as well as Java classes that extend- - third-party software are available as supplementary information (see Appendix).", "Since the first unequivocal description of RNA interference (RNAi) in 1998, it has remained one of the hottest topics under investigation, culminating in the award of a Nobel Prize to its discoverers in 2006. Excitement over this technique derives from the ease with which it can be used to switch-off a specific gene in almost any organism, thereby allowing the role of that gene to be identified. More importantly, it offers the potential to treat certain diseases by switching-off the causative genes. Key to the RNAi pathway are the small-interfering RNAs (siRNAs), which at 21-23 nucleotides in length are very amenable to analogue development by chemists. However in comparison to the use of oligonucleotides as antisense agents, an area where many chemists first developed an interest in nucleic acids, the RNAi pathway is exceedingly complex. The literature is also complicated by the fact that the phenomenon has been studied in a wide range of organisms. In this tutorial review we have presented the subject from a more chemical perspective, incorporating a glossary to give a clear explanation of the specialist terms. However, the coverage of the biology remains sufficiently detailed to give the reader the necessary insight that we believe will be essential for the successful design of chemically modified siRNA.", "The SPRY domain is a protein interaction module found in 77 murine and ~100 human proteins, and is implicated in important biological pathways, including those that regulate innate and adaptive immunity. The current definition of the SPRY domain is based on a sequence repeat discovered in the splA kinase and ryanodine receptors. The greater SPRY family is divided into the B30.2 (which contains a PRY extension at the N-terminus) and \"SPRY-only\" sub-families. In this brief review, we examine the current structural and biochemical literature on SPRY/B30.2 domain involvement in key immune processes and highlight a PRY-like 60 amino acid region in the N-terminus of \"SPRY-only\" proteins. Phylogenetic, structural, and functional analyses suggest that this N-terminal region is related to the PRY region of B30.2 and should be characterized as part of an extended SPRY domain. Greater understanding of the functional importance of the N-terminal region in \"SPRY only\" proteins will enhance our ability to interrogate SPRY interactions with their respective binding partners.", "OBJECTIVE: The 6-question EuroQol 5-Dimension Health Assessment (EQ-5D) is a widely used, simple instrument that monitors general health-related quality of life (HRQoL) in chronic disease. It has not previously been applied to US patients undergoing endoscopic sinus surgery (ESS).STUDY DESIGN: Prospective cohort study.SETTING: Academic Medical Center.SUBJECTS AND METHODS: The study population consisted of 267 patients with chronic rhinosinusitis (CRS) who completed 2 disease-specific instruments-the Chronic Sinusitis Survey (CSS) and the Sinonasal Outcomes Test-22 (SNOT-22)-and 1 general health-related quality-of-life instrument-the EQ-5D-before and after ESS for CRS. Baseline scores were compared to those collected 3 and 12 months after surgery and to the general US population.RESULTS: Surveys were completed at all time points by 186 patients, for a response rate of 69.7%. Patients with CRS, when compared to the US population, reported more problems in the domains of pain/discomfort (73.1% vs 40.8%, P < .01), anxiety/depression (50.5% vs 26.4%, P < .01), and usual activities (30.6% vs 15.0%, P < .01). One year following ESS, there was a significant decrease in patients who reported problems with pain/discomfort (54.3%, P < .001), anxiety/depression (30.6%, P < .001), and usual activities (21.5%, P < .01). After surgery, CRS anxiety/depression scores were no different from those of the US general population. Chronic Sinusitis Survey and SNOT-22 scores demonstrated similar postoperative improvements.CONCLUSION: The EQ-5D assessment provides meaningful general health outcomes data with low patient burden. Application of this instrument demonstrated long-term improvement in the quality of life of patients who undergo sinus surgery.", "Cytokines and thyroid hormones are involved in the biochemical changes associated to heart failure (HF).AIM: Aims of the study were to investigate: plasma circulating levels of the cytokines Interleukine-6 (IL-6) TNF alpha and C reactive protein (CRP) in patients with stable HF in relation to the severity of left ventricular dysfunction; the relationship between these inflammatory markers and thyroid hormones.METHODS: One-hundred and sixty-six patients (121 males, age 64+/-12), with non-ischemic cardiomyopathy, were admitted to the Institute of Clinical Physiology for progressive deterioration of symptoms. Forty-eight healthy subjects (30 males, age range 26-75 years) were also enrolled as control group (Group N). High sensitivity (hs)-IL-6 and hs-TNFalpha were quantified using solid phase sandwich ELISA kits. Hs-CRP was measured by Immulite System.RESULTS: In the whole population (HF and N), the association between inflammatory markers and age resulted statistically significant only for IL-6 serum concentration (p<0.001) but not for TNFalpha and CRP. IL-6 and TNFalpha were strongly higher in the HF in comparison with N (p<0.001) while CRP showed a less significant difference (p<0.05). Whole population showed a negative association between IL-6 and EF% and between CRP and EF% (respectively p<0.01, r=-0.23; p<0.05, r=0.19). Comparing normal subjects with two classes of patients, respectively with EF>35% and EF<35%, we clearly observed the progressive enhancement of the inflammatory markers. Considering normal subjects, patients without and with low T3 syndrome, IL-6 and TNFalpha increased progressively from normal to patients with fT3<2 pg/ml (p<0.01 and p<0.01) while CRP only respect to the group with low T3 syndrome (p<0.01). The inflammatory markers were all inversely correlated with FT3 levels.CONCLUSION: Because low FT3 serum concentration represents a negative prognostic index, it is likely that impairment of T3 production and enhanced inflammation represent pathogenic mechanisms linked to HF progression." ]

[ "Alterations in microRNAs expression have been proposed to play role in endometrial cancer pathogenesis. Dicer and Drosha are main regulators of microRNA biogenesis and deregulation of their expression has been indicated as a possible cause of microRNAs alterations observed in various cancers. The objective of this study was to investigate Dicer and Drosha genes expression in endometrial cancer and to analyze the impact of clinicopathological characteristics on their expression. Fresh tissue samples were collected from 44 patients (26 endometroid endometrial carcinoma and 18 controls). Clinical and pathological data were acquired from medical documentation. Dicer and Drosha genes expressions were assessed by qRT-PCR using validated reference genes. Dicer and Drosha expression levels were significantly lower in endometrial cancer samples comparing to controls. Dicer was down-regulated by the factor of 1.54 (p=0.009) and Drosha gene mean expression value was 1.4 times lower in endometrial cancer group versus control group (p=0.008). Down-regulation of Dicer significantly correlated with decreased expression of Drosha (coefficient value 0.75). Decreased expression of Drosha correlated with higher histological grade and was influenced by BMI. Lower Dicer expression was found in nulli- and uniparous females comparing to multiparous individuals (p=0.002). Neither the FIGO stage nor the menstrual status had significant influence on the expression of studied genes. This study revealed for the first time that expression alterations of main regulators of microRNAs biogenesis are present in endometrial cancer tissue and could be potentially responsible for altered microRNAs profiles observed in this malignancy.", "BACKGROUND: Injury severity measures are based either on the Abbreviated Injury Scale (AIS) or the International Classification of diseases (ICD). The latter is more convenient because routinely collected by clinicians for administrative reasons. To exploit this advantage, a proprietary program that maps ICD-9-CM into AIS codes has been used for many years. Recently, a program called ICDPIC trauma and developed in the USA has become available free of charge for registered STATA users. We compared the ICDPIC calculated Injury Severity Score (ISS) with the one from direct, prospective AIS coding by expert trauma registrars (dAIS).METHODS: The administrative records of the 289 major trauma cases admitted to the hospital of Udine-Italy from 1 July 2004 to 30 June 2005 and enrolled in the Italian Trauma Registry were retrieved and ICDPIC-ISS was calculated. The agreement between ICDPIC-ISS and dAIS-ISS was assessed by Cohen's Kappa and Bland-Altman charts. We then plotted the differences between the 2 scores against the ratio between the number of traumatic ICD-9-CM codes and the number of dAIS codes for each patient (DIARATIO). We also compared the absolute differences in ISS among 3 groups identified by DIARATIO. The discriminative power for survival of both scores was finally calculated by ROC curves.RESULTS: The scores matched in 33/272 patients (12.1%, k 0.07) and, when categorized, in 80/272 (22.4%, k 0.09). The Bland-Altman average difference was 6.36 (limits: minus 22.0 to plus 34.7). ICDPIC-ISS of 75 was particularly unreliable. The differences increased (p < 0.01) as DIARATIO increased indicating incomplete administrative coding as a cause of the differences. The area under the curve of ICDPIC-ISS was lower (0.63 vs. 0.76, p = 0.02).CONCLUSIONS: Despite its great potential convenience, ICPIC-ISS agreed poorly with its conventionally calculated counterpart. Its discriminative power for survival was also significantly lower. Incomplete ICD-9-CM coding was a main cause of these findings. Because this quality of coding is standard in Italy and probably in other European countries, its effects on the performances of other trauma scores based on ICD administrative data deserve further research. Mapping ICD-9-CM code 862.8 to AIS of 6 is an overestimation.", "Observational studies have found that persons who consume large amounts of fruit and vegetables have lower rates of coronary heart disease. The strength of epidemiologic evidence, however, differs for each of the antioxidant vitamins. High intake of vitamin E from food or supplements has generally been associated with a lower incidence of coronary heart disease. The evidence for beta-carotene intake is inconsistent, with several studies finding a modest reduction in risk among persons with high intake, and others failing to find an association. Although many studies have examined the relationship between vitamin C intake and cardiovascular disease, no significant benefit was seen in any of the large studies that were able to control for other antioxidant intake or multivitamin use. Observational studies cannot discern whether the decreased risk observed is caused by the antioxidants themselves or other characteristics of the individuals who consume them. The epidemiologic associations may be due to other nutrients in antioxidant-rich foods, or other dietary or lifestyle factors. Randomized controlled trials are necessary to confirm or refute the observational data. On the basis of available evidence, we should recommend a healthy diet, rich in fruit and vegetables, but should not endorse vitamin supplementation unless conclusive evidence of benefit is demonstrated in clinical trials.", "BACKGROUND: Diagnosis of pyoderma gangrenosum can be difficult, leading to overdiagnosis or underdiagnosis.OBJECTIVE: To identify clinical features helpful in establishing a diagnosis of pyoderma gangrenosum and to compare the characteristics of patients with pyoderma gangrenosum with those of patients with chronic venous ulcers.METHOD: A retrospective chart review was performed in 28 patients with typical pyoderma gangrenosum and compared with the clinical features in 28 patients with chronic venous ulcers.RESULTS: (1) Even when other body sites are affected, pyoderma gangrenosum usually affects the upper and lower legs and feet or peristomal sites compared with chronic venous ulcers that are limited to the lower legs and feet. (2) Pyoderma gangrenosum can be associated with systemic diseases, especially inflammatory bowel disease. (3) Pustules and purulent discharge are features of pyoderma gangrenosum but not of chronic venous ulcers. (4) Crater-like holes or cribriform scarring is commonly seen in pyoderma gangrenosum but not in chronic venous ulcers. (5) Pathergy is a specific but not sensitive finding of pyoderma gangrenosum. It does not occur in patients with chronic venous ulcers.CONCLUSIONS: Diagnosis of pyoderma gangrenosum should be considered in patients with purulent ulcers affecting the legs or peristomal sites. To confirm the diagnosis, specific features should be sought, including pathergy, crater-like holes or cribriform scarring, and association with inflammatory bowel disease. Other causes of ulceration should be excluded.", "BACKGROUND: To determine the prevalence of urinary incontinence in female long-distance runners and to compare it with the presence or not of eating disorders. Methods - A total of 37 women have completed the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and the short version of the Eating Attitudes Test (EAT-26). A one-hour pad test was performed to determine urine loss. Mean values of continuous variables were compared using an independent sample t-test or the Mann-Whitney U test.RESULTS: 23 athletes (62.2%) reported urine loss. The mean of the ICIQ-SF was 4.03 +/- 5.06. There was a significant relation between the 1-hour pad test (p=0.02) and eating disorders (p=0.03).CONCLUSIONS: There was urinary incontinence in female long-distance runners and a correlation with eating disorders. Coaches should improve their knowledge about this problem and establish cooperation with a multidisciplinary team.", "A 60-kDa glucosamine binding lectin, white kidney bean lectin (WKBL), was purified from Phaseolus vulgaris cv. white kidney beans, by application of anion exchange chromatography on Q-Sepharose, affinity chromatography on Affi-gel blue gel, and FPLC-size exclusion on Superdex 75. The anti-proliferative activity of WKBL on HONE1 cells and HepG2 cells was stronger than the activity on MCF7 cells and WRL68 cells (IC50 values for a 48-h treatment with WKBL on HONE1 cells: 18.8 μM; HepG2 cells: 19.7 μM; MCF7 cells: 26.9 μM; and WRL68 cells: >80 μM). The activity could be reduced by addition of glucosamine, which occupies the binding sites of WKBL, indicating that carbohydrate binding is crucial for the activity. Annexin V-FITC and PI staining, JC-1 staining and Hoechst 33342 staining revealed that apoptosis was induced on WKBL-treated HONE1 cells and HepG2 cells, but not as obviously on MCF7 cells. Cell cycle analysis also showed a slight cell cycle arrest on HONE1 cells after WKBL treatment. Western blotting suggested that WKBL induced apoptosis of HONE1 cells occurred through the extrinsic apoptosis pathway, with detection of increased level of active caspase 3, 8 and 9.", "Pyoderma gangrenosum is a skin disease characterized by wounds with blue-to-purple undermined borders surrounding purulent necrotic bases. This article reports on a patient with a circumferential, full-thickness, and partially necrotic lower-extremity ulceration of unknown etiology. Results of laboratory tests and arterial and venous imaging studies were found to be within normal limits. The diagnosis of pyoderma gangrenosum was made on the basis of the histologic appearance of the wound tissue after biopsy as a diagnosis of exclusion. Negative pressure wound therapy was undertaken, which saved the patient's leg from amputation. Although negative pressure wound therapy has demonstrated efficacy in the treatment of chronic wounds in a variety of circumstances, this is the first documented use of this technique to treat an ulceration secondary to pyoderma gangrenosum.", "Crocin is a water-soluble carotenoid pigment that is primarily used in various cuisines as a seasoning and coloring agent, as well as in traditional medicines for the treatment of edema, fever, and hepatic disorder. In this study, we demonstrated that crocin markedly induces the expression of heme oxygenase-1 (HO-1) which leads to an anti-inflammatory response. Crocin inhibited inducible nitric oxide synthase (iNOS) expression and nitric oxide production via downregulation of nuclear factor kappa B activity in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. These effects were abrogated by blocking of HO-1 expression or activity. Crocin also induced Ca(2+) mobilization from intracellular pools and phosphorylation of Ca(2+)/calmodulin-dependent protein kinase 4 (CAMK4). CAMK4 knockdown and kinase-dead mutant inhibited crocin-mediated HO-1 expression, Nrf2 activation, and phosphorylation of Akt, indicating that HO-1 expression is mediated by CAMK4 and that Akt is a downstream mediator of CAMK4 in crocin signaling. Moreover, crocin-mediated suppression of iNOS expression was blocked by CAMK4 inhibition. Overall, these results suggest that crocin suppresses LPS-stimulated expression of iNOS by inducing HO-1 expression via Ca(2+)/calmodulin-CAMK4-PI3K/Akt-Nrf2 signaling cascades. Our findings provide a novel molecular mechanism for the inhibitory effects of crocin against endotoxin-mediated inflammation." ]

[ "AIM: Ezetimibe selectively blocks intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1 (NPC1L1) and reducing LDL cholesterol (LDL-C). In animals, ezetimibe reversed diet-induced obesity, liver steatosis, and insulin resistance. In humans, its potential effects on liver steatosis and insulin resistance have been suggested. We investigated the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia in obese subjects with dyslipidaemia in a double-blind randomized crossover trial.METHODS: Twenty obese men with hypertriglyceridaemia were assigned randomly to an ezetimibe- or a placebo-precedence-treated group. Subjects in the ezetimibe group were treated with ezetimibe (10 mg/day) for the first 4 weeks, followed by a 4-week interval and then treated with placebo for another 4 weeks. The placebo group received these treatments in reverse order. Subjects were requested to fast for at least 12 hours and then received a standard meal. Blood samples were collected at 0, 30, 60, 120, 240, 360 and 480 minutes after the meal on Days 0, 28, 56 and 84 and were used to measure the lipid and glucose metabolism markers.RESULTS: Ezetimibe significantly decreased the postprandial serum triglyceride excursion (p=0.01) and fasting serum LDL-C, remnant-like particles(RLP) and ApoB48 levels (p<0.05). Postprandial glucose excursion, serum insulin levels, serum glucose-dependent insulinotropic polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) were not significantly affected by ezetimibe treatment.CONCLUSION: Ezetimibe restored the postprandial dysregulation of lipid but did not affect glucose metabolism in a double-blind randomized crossover trial.", "Transposable elements (TEs) are the main component of eukaryotic genomes. Besides their impact on genome size, TEs are also functionally important as they can alter gene expression and influence phenotypic variation. In plants, most top-down studies focus on extremely clear phenotypes such as the shape or the color of individuals and do not explore fully the role of TEs in evolution. Assessing the impact of TEs in a more systematic manner, however, requires identifying active TEs to further study their impact on phenotypes. In this chapter, we describe an in planta approach that consists in activating TEs by interfering with pathways involved in their silencing. It enables to directly investigate the functional impact of single TE families at low cost.", "BACKGROUND: Our aim was to define predictors of late radiation-induced lung injury (RILI) in Hodgkin's lymphoma (HL) survivors treated with bleomycin-containing chemotherapy and radiotherapy.MATERIAL AND METHODS: Eighty consecutive patients treated with chemotherapy and subsequent supradiaphragmatic radiation therapy for HL were retrospectively reviewed for symptoms and/or radiological signs of RILI. Median patient age was 26 years (range 14-55). Left, right, and total lung dosimetric parameters along with clinical, disease, and treatment-related characteristics were analyzed. Multivariate logistic regression analyses were performed. A receiver operator characteristic (ROC) curve analysis was performed to find possible cutoff values dividing patients into high- and low-risk groups.RESULTS: Seven of 80 (9%) patients had lung disease at baseline. Four of 80 (5%) had toxicity after chemotherapy and before the beginning of radiotherapy. These patients were excluded from further evaluation. At a median time of 10 months (range 9-18), 9/69 patients (13%) developed lung radiological changes on computed tomography (CT) after treatment. Four of nine patients were diagnosed RTOG grade ≥ 2. On multivariate analyses, left-lung V30 (p = 0.004, OR = 1.108 95% CI 1.033-1.189) and total-lung V30 (p = 0.009, OR = 1.146 95% CI 1.035-1.270) resulted to be predictors of lung CT changes with a cutoff value of 16% and 15%, respectively. When only symptomatic RILI was considered a left-lung V30 cutoff value of 32% was estimated.CONCLUSION: Bleomycin and RT may cause lung injury in a small, but significant fraction of HL patients. Left-lung V30 predicts the risk of developing asymptomatic or symptomatic RILI after sequential chemo-radiotherapy.", "Retrotransposons are mobile genetic elements abundant in plant and animal genomes. While efficiently silenced by the epigenetic machinery, they can be reactivated upon stress or during development. Their level of transcription not reflecting their transposition ability, it is thus difficult to evaluate their contribution to the active mobilome. Here we applied a simple methodology based on the high throughput sequencing of extrachromosomal circular DNA (eccDNA) forms of active retrotransposons to characterize the repertoire of mobile retrotransposons in plants. This method successfully identified known active retrotransposons in both Arabidopsis and rice material where the epigenome is destabilized. When applying mobilome-seq to developmental stages in wild type rice, we identified PopRice as a highly active retrotransposon producing eccDNA forms in the wild type endosperm. The mobilome-seq strategy opens new routes for the characterization of a yet unexplored fraction of plant genomes.", "The methyl-cytosine binding domain 2 (MBD2)-nucleosome remodeling and deacetylase (NuRD) complex recognizes methylated DNA and silences expression of associated genes through histone deacetylase and nucleosome remodeling functions. Our previous structural work demonstrated that a coiled-coil interaction between MBD2 and GATA zinc finger domain containing 2A (GATAD2A/p66α) proteins recruits the chromodomain helicase DNA-binding protein (CHD4/Mi2β) to the NuRD complex and is necessary for MBD2-mediated DNA methylation-dependent gene silencing in vivo (Gnanapragasam, M. N., Scarsdale, J. N., Amaya, M. L., Webb, H. D., Desai, M. A., Walavalkar, N. M., Wang, S. Z., Zu Zhu, S., Ginder, G. D., and Williams, D. C., Jr. (2011) p66α-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Proc. Natl. Acad. Sci. U.S.A. 108, 7487-7492). The p66α-MBD2 interaction differs from most coiled-coils studied to date by forming an anti-parallel heterodimeric complex between two peptides that are largely monomeric in isolation. To further characterize unique features of this complex that drive heterodimeric specificity and high affinity binding, we carried out biophysical analyses of MBD2 and the related homologues MBD3, MBD3-like protein 1 (MBD3L1), and MBD3-like protein 2 (MBD3L2) as well as specific mutations that modify charge-charge interactions and helical propensity of the coiled-coil domains. Analytical ultracentrifugation analyses show that the individual peptides remain monomeric in isolation even at 300 μM in concentration for MBD2. Circular dichroism analyses demonstrate a direct correlation between helical content of the coiled-coil domains in isolation and binding affinity for p66α. Furthermore, complementary electrostatic surface potentials and inherent helical content of each peptide are necessary to maintain high-affinity association. These factors lead to a binding affinity hierarchy of p66α for the different MBD2 homologues (MBD2 ≈ MBD3 > MBD3L1 ≈ MBD3L2) and suggest a hierarchical regulatory model in tissue and life cycle stage-specific silencing by NuRD complexes.", "BACKGROUND: HER2 status is a predictive biomarker of response to trastuzumab in advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. However, there is relatively little known about the role of HER2 in resected gastric or GEJ adenocarcinoma in the Western population.METHODS: Retrospective, observational, single centre study of patients with gastric or GEJ adenocarcinoma undergoing surgery with curative intent between January 2007 and June 2014 in the University Hospital Complex of Santiago de Compostela. The expression of HER2 was determined by immunohistochemistry (IHC) using DAKO-HercepTest™ and gene amplification with DuoCISH using a DAKO-DuoCISH kit. The study of HER2 expression and amplification was carried out in all the patients and it was correlated with classic clinicopathological parameters, survival and recurrence pattern.RESULTS: 106 patients were included. HER2 expression was as follows: 71.7% HER2 negative, 21.7% HER2 equivocal and 6.6% HER2 positive, or with HER2 overexpression. 13.2% of patients (14/106) had HER2 amplification by DuoCISH. A significant association was seen between overexpression and amplification of HER2 (p < 0.001).HER2 positivity was associated with the intestinal subtype (p = 0.010) and a low grade of differentiation (p = 0.018). Likewise, HER2 was significantly associated with a worse prognosis: overall survival (OS) 32.3 months HER2 positive versus 93.9 months HER2 negative (HR 0.42; confidence interval 95% 0.18-0.93; p = 0.028); and the presence of distant metastasis without accompanying locoregional recurrence (p = 0.048).CONCLUSION: HER2 status defines a subgroup with differentiated clinicopathological characteristics, worse prognosis and distant dissemination, without accompanying locoregional recurrence, in patients with resected gastric or GEJ adenocarcinoma operated on in a Western population.", "Controlling activity of defined populations of neurons without affecting other neurons in the brain is now possible by a new gene- and neuroengineering technology termed optogenetics. Derived from microbial organisms, opsin genes encoding light-activated ion channels and pumps (channelrhodopsin-2 [ChR2]; halorhodopsin [NpHR], respectively), engineered for expression in the mammalian brain, can be genetically targeted into specific neural populations using viral vectors. When exposed to light with appropriate wavelength, action potentials can be triggered in ChR2-expressing neurons, whereas inhibition of action potentials can be obtained in NpHR-expressing neurons, thus allowing for powerful control of neural activity. Optogenetics is now intensively used in laboratory animals, both in vitro and in vivo, for exploring functions of complex neural circuits and information processing in the normal brain and during various neurological conditions. The clinical perspectives of adopting optogenetics as a novel treatment strategy for human neurological disorders have generated considerable interest, largely because of the enormous potential demonstrated in recent rodent and nonhuman primate studies. Restoration of dopamine-related movement dysfunction in parkinsonian animals, amelioration of blindness and recovery of breathing after spinal cord injury are a few examples of such perspectives.", "Human Scribble (Scrib) is an evolutionary-conserved cell polarity protein, but its potential role in human cancer is controversial. Herein, we show that Scrib is nearly universally overexpressed in cultured tumor cell lines and genetically disparate cancer patient series compared with matched normal tissues in vivo. Instead of a membrane association seen in normal epithelia, tumor-associated Scrib is mislocalized and found predominantly in the cytosol. Small-interfering RNA silencing of Scrib in model lung adenocarcinoma A549 cells inhibited cell migration in wound-healing assays, suppressed tumor cell invasion across Matrigel-coated inserts, and down-regulated the expression of cell motility markers and mediators of epithelial-mesenchymal transition. These data uncover a previously unrecognized exploitation of Scrib for aberrant tumor cell motility and invasion, thus potentially contributing to disease progression in humans.", "Circular RNAs (circRNAs) are noncoding RNAs that form covalently closed loop structures. CircRNAs are dysregulated in cancer and play key roles in tumorigenesis, diagnosis, and tumor therapy. CircRNAs function as competing endogenous RNAs or microRNA sponges that regulate transcription and splicing, binding to proteins, and translation. CircRNAs may serve as novel biomarkers for cancer diagnosis, and they show potential as therapeutic targets in cancers including breast cancer (BC). In women, BC is the most common malignant tumor worldwide and the second leading cause of cancer death. Although evidence indicates that circRNAs play a critical role in BC, the mechanisms regulating the function of circRNAs in BC remain poorly understood. Here, we provide literature review aiming to clarify the role of circRNAs in BC and summarize the latest research. We provide a systematic overview of the biogenesis and biological functions of circRNAs, elaborate on the functional roles of circRNAs in BC, and highlight the value of circRNAs as diagnostic and therapeutic targets in BC.", "Active transposable elements (TEs) generate insertion polymorphisms that can be detected through genome resequencing strategies. However, these techniques may have limitations for organisms with large genomes or for somatic insertions. Here, we present a method that takes advantage of the extrachromosomal circular DNA (eccDNA) forms of actively transposing TEs in order to detect and characterize active TEs in any plant or animal tissue. Mobilome-seq consists in selectively amplifying and sequencing eccDNAs. It relies on linear digestion of genomic DNA followed by rolling circle amplification of circular DNA. Both active DNA transposons and retrotransposons can be identified using this technique.", "PURPOSE: To provide an overview of burning mouth syndrome (BMS), describe the role of the clinician when a patient presents with the burning mouth complaint, offer guidance in differentiating the cause of the complaint, and identify potential treatment options for the patient suffering from BMS.DATA SOURCES: A search of MD Consult, Medline, and EBSCO Host Research Databases with the terms \"burning mouth\" and \"BMS.\"CONCLUSIONS: BMS is a common, chronic disorder of unknown etiology with no underlying or systemic causes or oral signs identified. It affects more than 1 million people in the United States, predominantly postmenopausal women. Despite the common nature of the disorder, it is often misunderstood. Palliative treatment, education, and support should be offered to the patient with idiopathic BMS. A variety of treatment options exist, including benzodiazepines, tricyclic antidepressants, anticonvulsants, alpha-lipoic acid, topical capsaicin, and cognitive therapy can be added to the medication regimen for greater benefit.IMPLICATIONS FOR PRACTICE: The role of the clinician is to obtain a meticulous history and physical examination of the patient, order relevant diagnostic tests, and rule out treatable conditions that may be causing the burning mouth symptom. If secondary causes of BMS are ruled out, the clinician should present treatment options to the patient and consider referral to specialists as necessary. A combination of medications may be more effective than a single medication.", "Restless-legs syndrome (RLS) is a sensorimotor disorder, characterized by an irresistible urge to move the legs usually accompanied or caused by uncomfortable and unpleasant sensations. It begins or worsens during periods of rest or inactivity, is partially or totally relieved by movements and is exacerbated or occurs at night and in the evening. RLS sufferers represent 2 to 3% of the general population in Western countries. Supportive criteria include a family history, the presence of periodic-leg movements (PLM) when awake or asleep and a positive response to dopaminergic treatment. The RLS phenotypes include an early onset form, usually idiopathic with a familial history and a late onset form, usually secondary to peripheral neuropathy. Recently, an atypical RLS phenotype without PLM and l-DOPA resistant has been characterized. RLS can occur in childhood and should be distinguished from attention deficit/hyperactivity disorder, growing pains and sleep complaints in childhood. RLS should be included in the diagnosis of all patients consulting for sleep complaints or discomfort in the lower limbs. It should be differentiated from akathisia, that is, an urge to move the whole body without uncomfortable sensations. Polysomnographic studies and the suggested immobilization test can detect PLM. Furthermore, an l-DOPA challenge has recently been validated to support the diagnosis of RLS. RLS may cause severe-sleep disturbances, poor quality of life, depressive and anxious symptoms and may be a risk factor for cardiovascular disease. In most cases, RLS is idiopathic. It may also be secondary to iron deficiency, end-stage renal disease, pregnancy, peripheral neuropathy and drugs, such as antipsychotics and antidepressants. The small-fiber neuropathy can mimic RLS or even trigger it. RLS is associated with many neurological and sleep disorders including Parkinson's disease, but does not predispose to these diseases. The pathophysiology of RLS includes an altered brain-iron metabolism, a dopaminergic dysfunction, a probable role of pain control systems and a genetic susceptibility with nine loci and three polymorphisms in genes serving developmental functions. RLS treatment begins with the elimination of triggering factors and iron supplementation when deficient. Mild or intermittent RLS is usually treated with low doses of l-DOPA or codeine; the first-line treatment for moderate to severe RLS is dopaminergic agonists (pramipexole, ropinirole, rotigotine). In severe, refractory or neuropathy-associated RLS, antiepileptic (gabapentin, pregabalin) or opioid (oxycodone, tramadol) drugs can be used." ]

[ "Autosomal Dominant Leukodystrophy (ADLD), a fatal adult onset demyelinating disorder, is the only human disease that has been linked to mutations of the nuclear lamina protein, lamin B1, and is primarily caused by duplications of the LMNB1 gene. Why CNS myelin is specifically targeted and the mechanisms underlying ADLD are unclear. Recent work from our group has demonstrated that over expression of lamin B1 in oligodendrocytes, the myelin producing cells in the CNS, resulted in age dependent epigenetic modifications, transcriptional down-regulation of lipogenic gene expression and significant reductions of myelin-enriched lipids. Given the high lipid content of meylin, we hypothesize that lipid loss is one of the primary drivers of the demyelination phenotype. These results can, at least partially, explain the age dependence and cell type specificity in ADLD and are discussed in the context of the existing literature, in an attempt to delineate potential pathways underlying the disease phenotype.", "BACKGROUND: Cellulitis has many clinical mimickers (pseudocellulitis), which leads to frequent misdiagnosis.OBJECTIVE: To create a model for predicting the likelihood of lower extremity cellulitis.METHODS: A cross-sectional review was performed of all patients admitted with a diagnosis of lower extremity cellulitis through the emergency department at a large hospital between 2010 and 2012. Patients discharged with diagnosis of cellulitis were categorized as having cellulitis, while those given an alternative diagnosis were considered to have pseudocellulitis. Bivariate associations between predictor variables and final diagnosis were assessed to develop a 4-variable model.RESULTS: In total, 79 (30.5%) of 259 patients were misdiagnosed with lower extremity cellulitis. Of the variables associated with true cellulitis, the 4 in the final model were asymmetry (unilateral involvement), leukocytosis (white blood cell count ≥10,000/uL), tachycardia (heart rate ≥90 bpm), and age ≥70 years. We converted these variables into a points system to create the ALT-70 cellulitis score as follows: Asymmetry (3 points), Leukocytosis (1 point), Tachycardia (1 point), and age ≥70 (2 points). With this score, 0-2 points indicate ≥83.3% likelihood of pseudocellulitis, and ≥5 points indicate ≥82.2% likelihood of true cellulitis.LIMITATIONS: Prospective validation of this model is needed before widespread clinical use.CONCLUSION: Asymmetry, leukocytosis, tachycardia, and age ≥70 are predictive of lower extremity cellulitis. This model might facilitate more accurate diagnosis and improve patient care.", "Commercial inulinase from Aspergillus niger was immobilized in montmorillonite and then treated in pressurized propane and liquefied petroleum gas (LPG). Firstly, the effects of system pressure, exposure time, and depressurization rate, using propane and LPG, on enzymatic activity were evaluated through central composite design 2³. Residual activities of 145.1 and 148.5% were observed for LPG (30 bar, 6 h, and depressurization rate of 20 bar min⁻¹) and propane (270 bar, 1 h, and depressurization rate of 100 bar min⁻¹), respectively. The catalysts treated at these conditions in both fluids were then used for the production of fructooligosaccharides (FOS) using sucrose and inulin as substrates in aqueous and organic systems. The main objective of this step was to evaluate the yield and productivity in FOS, using alternatives for enhancing enzyme activity by means of pressurized fluids and also using low-cost supports for enzyme immobilization, aiming at obtaining a stable biocatalyst to be used for synthesis reactions. Yields of 18% were achieved using sucrose as substrate in aqueous medium, showing the potential of this procedure, hence suggesting a further optimization step to increase the process yield.", "Histone lysine methylation is a critical marker for controlling gene expression. The position and extent of methylation (mono-, di-, or tri-) controls the binding of effector proteins that determine whether the associated DNA is expressed or not. Dysregulation of histone protein methylation has been associated with a number of types of cancer, and development of inhibitors for the effector proteins is becoming an active area of research. For this reason, understanding the mechanism by which effector proteins obtain selectivity for the different methylation states of lysine is of great interest. To this end, we have performed mutation studies on the Drosophila HP1α chromodomain, which binds H3K9Me(2) and H3K9Me(3) with approximately equal affinities. The selectivity of HP1α chromodomain for H3K9Me(3) over H3K9Me(2) was investigated by mutating E52 to remove or weaken the hydrogen bond to K9Me(2) while maintaining affinity for K9Me(3,) including E52F, E52I, E52V, E52D, an E52Q. The E52Q mutant exhibited the greatest degree of selectivity for KMe3, with 3.5-fold weaker binding to the dimethylated peptide (K(D) =52 μM) compared to the trimethylated peptide (K(D) =15 μM). These studies provide insight into the role of electrostatic interactions and hydrogen bonding in the differentiation of methylation states and have implications regarding the evolutionary pressure for selectivity in this protein-protein interaction. Moreover, the information from this study may help guide inhibitor development for this class of proteins.", "DOPA was measured in the anterior pituitary and hypothalamic-hypophysial portal blood after treatment with NSD-1015, a DOPA decarboxylase inhibitor. NSD-1015 caused DOPA to accumulate in the anterior pituitary of mice and rats, and increased DOPA in the hypothalamic-hypophysial portal blood of rat. Serum prolactin was also increased. Interruption of the anterior pituitary blood supply from the hypothalamic-hypophysial system by cannulation of the entire pituitary stalk eliminated the NSD-1015-induced DOPA accumulation in the rat pituitary. We conclude that DOPA can be taken into the anterior pituitary from the portal blood of NSD-1015-treated rodents and that the anterior pituitary lacks tyrosine hydroxylase activity in both mice and rats.", "Transcription has the capacity to mechanically modify DNA topology, DNA structure and nucleosome arrangement. Resulting from ongoing transcription, these modifications in turn may provide instant feedback to the transcription machinery. To substantiate the connection between transcription and DNA dynamics, we charted an ENCODE map of transcription-dependent dynamic supercoiling in human Burkitt's lymphoma cells by using psoralen photobinding to probe DNA topology in vivo. Dynamic supercoils spread ~1.5 kilobases upstream of the start sites of active genes. Low- and high-output promoters handled this torsional stress differently, as shown by using inhibitors of transcription and topoisomerases and by chromatin immunoprecipation of RNA polymerase and topoisomerases I and II. Whereas lower outputs are managed adequately by topoisomerase I, high-output promoters additionally require topoisomerase II. The genome-wide coupling between transcription and DNA topology emphasizes the importance of dynamic supercoiling for gene regulation.", "Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was -0.36 overall and -0.15 in those patients completing > or =1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease. We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis." ]

[ "OBJECTIVES: To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC).SUMMARY BACKGROUND DATA: To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene.METHODS: A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival.RESULTS: Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05).CONCLUSIONS: Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01836432.", "Mal de debarquement syndrome (MdDS) is a chronic disorder of imbalance characterized by a feeling of rocking and swaying. The medical treatment for MdDS is still limited. Motivated by our previous pilot study that demonstrates the promising clinical efficacy of repetitive transcranial stimulation (rTMS) in MdDS patients, a novel rTMS paradigm, i.e., 1 Hz stimulation over ipsilateral dorsal lateral prefrontal cortex (DLPFC) with respect to the dominant hand followed by 10 Hz stimulation over contralateral DLPFC, was proposed and conducted in MdDS in the present study. To evaluate the potential efficacy, we examined the changes before and after rTMS in both subjective reported symptom using visual analogue scale (VAS) and direct brain activity in resting state electroencephalography (rsEEG). To disentangle activity from distinct brain substrates and/or local networks in rsEEG signals, a group-wise independent component analysis was employed and the corresponding spectral power changes were examined in the identified components. In general, reduction in rocking sensation was reported in five of ten subjects (with dramatic reductions (changes > 30) in three subjects) after rTMS using the present paradigm, while no changes and slight increases in rocking sensation were reported in the remaining subjects. In rsEEG, significant elevated spectral powers in low frequency bands (i.e., theta and alpha) over broad areas of occipital, parietal, motor, and prefrontal cortices were induced by rTMS, reflecting the enhancement of cortical inhibition over these areas. Meanwhile, the significant correlations between changes in rsEEG and VAS scores were detected in the high frequency bands (i.e., high alpha and beta) over posterior parietal and left visual areas, reflecting the suppression of spatial information processing. Therefore, the present findings demonstrate the promising clinical efficacy of a new rTMS paradigm for MdDS, and suggest its merit for further studies in more patients.", "Discovery-based proteomic studies aim to answer important biological questions by identifying as many proteins as possible. In order to accomplish this lofty goal, an effort must be placed on determining an optimal workflow that maximizes protein identifications. In this study, we compare protein extraction, digestion and fractionation methods for bottom-up proteomics using a human colon cancer cell line as our model system. Four different buffers for protein extraction, two digestion approaches, as well as three sample fractionation methods were evaluated in order to determine an accessible workflow that gives maximal protein identifications. Samples comparing these workflows were analyzed via UPLC paired with tandem MS on a Q-Exactive mass spectrometer. Our goal is to determine an optimal workflow to enable users to maximize protein identifications. Our results show that an increased number of confident protein identifications are attained with a filter-aided digestion approach as compared to an in-solution digestion. Overall SDS-PAGE fractionation leads to higher numbers of identifications than SCX SpinTip and reverse phased cartridge platforms. The novel aspect of this work is the comparison of two readily available, offline platforms for fractionation in reference to a traditional technique, SDS-PAGE.", "Arginine vasotocin (AVT) and its mammalian homologoue arginine vasopressin (AVP) influence male sexual and aggressive behaviors in many species. We tested the effects of AVT and an AVP-V(1a) receptor antagonist on the display of alternative male tactics in a tropical coral reef fish, the bluehead wrasse Thalassoma bifasciatum. We gave AVT injections to territorial and nonterritorial males of the large and colorful phenotype (terminal phase) and an AVP-V(1a) receptor antagonist, Manning compound, to territorial males in the field. AVT increased courtship independent of status, while its effects on territoriality and aggression were dependent upon male status. In territorial males, AVT increased courtship and tended to decrease the number of chases toward initial phase individuals. In nonterritorial males, AVT increased courtship, chases toward initial phase individuals, and territorial behavior while decreasing feeding. These are all behaviors rarely seen in nonterritorial males, so AVT made these males act like territorial TP males. The AVP-V(1a) receptor antagonist had opposite effects. It decreased courtship and territorial defense, making these males act more like nonterritorial males. Manipulations of the AVT system shifted males within a single phenotype from the nonterritorial social status to the territorial social status and vice versa. Since the entire suite of behaviors related to territoriality was affected by AVT system manipulations, our results suggest that the AVT system may play a key role in motivation of behaviors related to mating.", "BACKGROUND: No approved systemic therapy exists for von Hippel-Lindau disease, an autosomal dominant disorder with pleiotropic organ manifestations that include clear cell renal cell carcinomas; retinal, cerebellar, and spinal haemangioblastomas; pheochromocytomas; pancreatic serous cystadenomas; and pancreatic neuroendocrine tumours. We aimed to assess the activity and safety of pazopanib in patients with von Hippel-Lindau disease.METHODS: In this non-randomised, single-centre, open-label, phase 2 trial, adult patients with clinical manifestations of von Hippel-Lindau disease were recruited from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and were treated with pazopanib (800 mg orally daily) for 24 weeks, with an option to continue treatment if desired by the patient and treating physician. Primary endpoints were the proportion of patients who achieved an objective response and safety in the per-protocol population. The objective response was measured for each patient and each lesion type. Radiographic assessments were done at baseline and every 12 weeks throughout the study. Activity and safety were assessed with continuous monitoring and a Bayesian design. This study is registered with ClinicalTrials.gov, number NCT01436227, and is closed to accrual.FINDINGS: Between Jan 18, 2012, and Aug 10, 2016, we screened 37 patients with genetically confirmed or clinical features consistent with von Hippel-Lindau disease, of whom 31 eligible patients were treated with pazopanib. The proportion of patients who achieved an objective response was 42% (13 of 31 patients). By lesion sites responses were observed in 31 (52%) of 59 renal cell carcinomas, nine (53%) of 17 pancreatic lesions, and two (4%) of 49 CNS haemangioblastomas. Seven (23%) of 31 patients chose to stay on the treatment after 24 weeks. Four (13%) of 31 patients withdrew from the study because of grade 3 or 4 transaminitis, and three (10%) discontinued study treatment because of treatment intolerance with multiple intercurrent grade 1-2 toxicities. Treatment-related serious adverse events included one case each of appendicitis and gastritis and one patient had a fatal CNS bleed.INTERPRETATION: Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side-effect profile consistent with that seen in previous trials. Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients. The safety and activity of pazopanib in this setting warrants further investigation.FUNDING: Novartis Inc and NIH National Cancer Institute core grant.", "BACKGROUND: Despite continued investigation, limited progress has been made in the adjuvant treatment of resected pancreatic cancer. Novel or targeted therapies are needed.METHODS: Multi-institutional, open-label, dose-finding, phase 2 trial evaluating the use of algenpantucel-L (NewLink Genetics Corporation, Ames, IA) immunotherapy in addition to chemotherapy and chemoradiotherapy in the adjuvant setting for resected pancreatic cancer (ClinicalTrials.gov identifier, NCT00569387). The primary outcome was 12-month disease-free survival. Secondary outcomes included overall survival and toxicity.RESULTS: Seventy patients were treated with gemcitabine and 5-fluorouracil-based chemoradiotherapy as well as algenpantucel-L (mean 12 doses, range 1-14). After a median follow-up of 21 months, the 12-month disease-free survival was 62 %, and the 12-month overall survival was 86 %. The most common adverse events were injection site pain and induration.CONCLUSIONS: The addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival. A multi-institutional, phase 3 study is ongoing (ClinicalTrials.gov identifier, NCT01072981).", "BACKGROUND: The TβRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of TGFβ signalling. We have examined peroxisome proliferator-activated receptor (PPAR) pathway perturbation in this model and explored the impact of the pan-PPAR agonist lanifibranor on the cardiorespiratory phenotype.METHODS: PPAR pathway gene and protein expression differences from TG and WT sex-matched littermate mice were determined at baseline and following administration of one of two doses of lanifibranor (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. The prevention of bleomycin-induced lung fibrosis and SU5416-induced pulmonary hypertension by lanifibranor was explored.RESULTS: Gene expression data were consistent with the downregulation of the PPAR pathway in the TβRII∆k-fib mouse model. TG mice treated with high-dose lanifibranor demonstrated significant protection from lung fibrosis after bleomycin and from right ventricular hypertrophy following induction of pulmonary hypertension by SU5416, despite no significant change in right ventricular systolic pressure.CONCLUSIONS: In the TβRII∆k-fib mouse strain, treatment with 100 mg/kg lanifibranor reduces the development of lung fibrosis and right ventricular hypertrophy induced by bleomycin or SU5416, respectively. Reduced PPAR activity may contribute to the exaggerated fibroproliferative response to tissue injury in this transgenic model of scleroderma and its pulmonary complications.", "Impetigo is a common, superficial, bacterial infection of the skin characterized by an inflamed and infected epidermis. The rarer variant, bullous impetigo, is characterized by fragile fluid-filled vesicles and flaccid blisters and is invariably caused by pathogenic strains of Staphylococcus aureus. Bullous impetigo is at the mild end of a spectrum of blistering skin diseases caused by a staphylococcal exfoliative toxin that, at the other extreme, is represented by widespread painful blistering and superficial denudation (the staphylococcal scalded skin syndrome). In bullous impetigo, the exfoliative toxins are restricted to the area of infection, and bacteria can be cultured from the blister contents. In staphylococcal scalded skin syndrome the exfoliative toxins are spread hematogenously from a localized source causing widespread epidermal damage at distant sites. Both occur more commonly in children under 5 years of age and particularly in neonates. It is important to swab the skin for bacteriological confirmation and antibiotic sensitivities and, in the case of staphylococcal scalded skin syndrome, to identify the primary focus of infection. Topical therapy should constitute either fusidic acid (Fucidin, Leo Pharma Ltd) as a first-line treatment, or mupirocin (Bactroban, GlaxoSmithKline) in proven cases of bacterial resistance. First-line systemic therapy is oral or intravenous flucloxacillin (Floxapen, GlaxoSmithKline). Nasal swabs from the patient and immediate relatives should be performed to identify asymptomatic nasal carriers of Staphylococcus aureus. In the case of outbreaks on wards and in nurseries, healthcare professionals should also be swabbed." ]

[ "Ascomycetes develop four major types of fruiting bodies that share a common ancestor, and a set of common core genes most likely controls this process. One way to identify such genes is to search for conserved expression patterns. We analysed microarray data of Fusarium graminearum and Sordaria macrospora, identifying 78 genes with similar expression patterns during fruiting body development. One of these genes was asf1 (anti-silencing function 1), encoding a predicted histone chaperone. asf1 expression is also upregulated during development in the distantly related ascomycete Pyronema confluens. To test whether asf1 plays a role in fungal development, we generated an S. macrospora asf1 deletion mutant. The mutant is sterile and can be complemented to fertility by transformation with the wild-type asf1 and its P. confluens homologue. An ASF1-EGFP fusion protein localizes to the nucleus. By tandem-affinity purification/mass spectrometry as well as yeast two-hybrid analysis, we identified histones H3 and H4 as ASF1 interaction partners. Several developmental genes are dependent on asf1 for correct transcriptional expression. Deletion of the histone chaperone genes rtt106 and cac2 did not cause any developmental phenotypes. These data indicate that asf1 of S. macrospora encodes a conserved histone chaperone that is required for fruiting body development.", "We studied the role of the L-arginine-nitric oxide (NO) pathway in non-adrenergic, non-cholinergic (NANC) relaxation of the rabbit sphincter of Oddi by recording changes in isometric tension in response to electrical field stimulation in two series of experiments. In a first set of experiments, biliary sphincters of Oddi removed from New Zealand white rabbits were placed horizontally in an organ bath containing oxygenized, buffered (pH 7.4) Krebs solution. Contractile responses of the whole sphincter to field stimulation were determined. In the second set of experiments, sphincter of Oddi was divided into two parts and the effects of field stimulation were studied separately on areas close to the duodenal papilla (area I) and areas close to the common bile duct (area II). In the whole sphincter of Oddi, field stimulation induced an initial twitch-like contraction followed by relaxation proportional to the number of stimuli (3 and 10 stimuli at 20 Hz, 50 V, 0.1 ms). The magnitude of the contractile responses was considerably reduced by 1 microM atropine, phentolamine and oxprenolol (NANC solution). Field stimulation produced dose-dependent contractions of both segments of sphincter of Oddi in response to the same protocol as used with whole sphincter of Oddi. However, preincubation with NANC solution produced monophasic relaxations in response to field stimulation in area I, whereas area II preparations such as the whole sphincter of Oddi responded with contractions followed by minimal relaxations. Field stimulation failed to induce either contractions or relaxations in the presence of 1 microM tetrodotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)", "A 63-year-old woman previously stable on a regimen of atorvastatin 40 mg daily, carvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily, spironolactone 25 mg daily, rivaroxaban 15 mg daily, and enalapril 20 mg twice daily for heart failure developed rhabdomyolysis 26 days after enalapril was stopped and sacubitril/valsartan (Entresto™) started. The patient received sacubitril/valsartan at 24/26 mg twice daily for heart failure; however, after 26 days she developed muscle and skin pain. Investigations revealed elevated creatine kinase and liver function tests, and rhabdomyolysis with raised transaminases was diagnosed. Sacubitril/valsartan and atorvastatin were discontinued and the patient was hydrated. She returned to baseline in 23 days and has not had any reoccurrence of rhabdomyolysis and elevated transaminases for 46 days. A Naranjo assessment score of 5 was obtained, indicating a probable relationship between the patient's rhabdomyolysis and her use of sacubitril/valsartan. The Drug Interaction Probability Scale score was 3, consistent with a possible interaction as a cause for the reaction, with sacubitril/valsartan as the precipitant drug and atorvastatin as the object drug.", "Acrokeratosis paraneoplastic (Bazex syndrome) is a rare, but distinctive paraneoplastic dermatosis characterized by erythematosquamous lesions located at the acral sites and is most commonly associated with carcinomas of the upper aerodigestive tract. We report a 58-year-old female with a history of a pigmented rash on her extremities, thick keratotic plaques on her hands, and brittle nails. Chest imaging revealed a right upper lobe mass that was proven to be small cell lung carcinoma. While Bazex syndrome has been described in the dermatology literature, it is also important for the radiologist to be aware of this entity and its common presentations.", "BACKGROUND: Preclinical data suggest that dual blockade of the insulin-like growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC selected for high IGF-1 serum levels.PATIENTS AND METHODS: CARRIE was an international, randomized, double-blind, placebo-controlled phase II study for patients with previously untreated metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 : 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or placebo combined with gemcitabine/nab-paclitaxel at approved dose schedule. The co-primary endpoints were progression-free survival (PFS) in patients with high IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin (HRG)+ tumors. Key secondary endpoints were overall survival (OS), objective response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate.RESULTS: A total of 317 patients were screened, with 88 patients randomized in part 2 (experimental arm n = 43; control n = 45). In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental versus control arms, respectively [hazard ratio (HR) = 1.88, P = 0.027]. In the high IGF-1/HRG+ subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39, P = 0.42). Median OS and ORR for the overall population were similar between two arms. No significant difference in serious or grade ≥3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) versus control arm (24.4%).CONCLUSIONS: Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls.CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02399137; EUDRA CT: 2014-004572-34.", "The use of trastuzumab in the adjuvant and metastatic treatment of breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The long-term significance of these events, isolating known cardiotoxic effects of anthracyclines from those of trastuzumab, and the appropriateness of referring to trastuzumab-related cardiotoxicity as reversible rather than responsive to trastuzumab withdrawal and heart failure medical therapy, are issues that continue to be debated. This article provides an overview of the available cardiac safety data from the major trastuzumab clinical trials in breast cancer, highlighting areas of ongoing controversy. Important recent data documenting the occurrence and prognostic use of cardiac troponin I elevations among patients treated with trastuzumab are placed into context with the mechanistic insight these data provide and the implications for clinical practice today.", "Antiretroviral preexposure prophylaxis (PrEP; emtricitabine and tenofovir disoproxil fumarate [Truvada]) prevents HIV without penalizing sexual pleasure, and may even enhance pleasure (e.g., by reducing HIV-related anxiety). However, concern about sexual risk behavior increasing with PrEP use (risk compensation) and corresponding stereotypes of promiscuity may undermine PrEP's preventive potential. In this commentary, we review literature on sexual behavior change accompanying PrEP use, discuss risk compensation concerns and the \"Truvada whore\" stereotype as PrEP barriers, question the appropriateness of restricting PrEP access because of risk compensation, and consider sexual pleasure as a benefit of PrEP, an acceptable motive for seeking PrEP, and a core element of health. It is essential for science to trump stereotypes and sex-negative messaging in guiding decision-making affecting PrEP access and uptake." ]

[ "Hemophilic pseudotumor is an uncommon complication seen in approximately 1-2% of patients with severe hemophilia. Hemophilic pseudotumors are distinguished into two subdivisions based on location, proximal or distal. Plain x-rays and CT are useful in diagnosis, but MR imaging is the diagnostic test of choice because of its sensitivity to the various blood products. The choice of therapy depends on many parameters, such as the size of the tumor, the age of the patient, and the relation with underlying organs. In most cases of asymptomatic hemophilic pseudotumor, conservative treatment with administration of missing factor as well as immobilization is recommended. The authors describe a 13-year-old boy with severe hemophilia A, who presented with a tibial pseudotumor a few months after an injury. He was conservatively treated for a long period, with daily administration of recombinant factor VIII. His clinical condition improved shortly after therapy induction, but radiological improvement has been moderate. Case history, imaging findings, and therapeutic options are discussed.", "Bacteroides, a predominant commensal bacteria in the gut, are thought to be responsible for the development of inflammatory bowel disease (IBD). In the present study, we examined whether or not bifidobacteria suppress B. vulgatus, a representative pathogenic Bacteroides species, in both the coculture system and the gnotobiotic murine model. As a result, Bifidobacterium infantis 1222 highly inhibited the growth of B. vulgatus in the coculture and also significantly suppressed the systemic antibody response raised by B. vulgatus colonizing the gut in gnotobiotic mice. Colonization of the mice by B. vulgatus increased the number of Peyer's patch (PP) cells bearing PNA (peanut agglutinin)+/anti-kappa+ phenotype, which represents plasma cell-like B cells. Moreover, treatment of those B. vulgatus-implanted mice with B. infantis 1222 abrogated such increase in the number of PNA+/anti-kappa+ cells. These results thus suggested that B. infantis 1222 protected the gut epithelial layer including the PP from being invaded by Bacteroides, thereby suppressing the systemic antibody response raised by Bacteroides.", "Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric neuro-metabolic disease in children. Due to the lack of an animal model, its pathogenetic mechanism is poorly understood. To study the role of AADC in brain development, a zebrafish model of AADC deficiency was generated. We identified an aadc gene homolog, dopa decarboxylase (ddc), in the zebrafish genome. Whole-mount in situ hybridization analysis showed that the ddc gene is expressed in the epiphysis, locus caeruleus, diencephalic catecholaminergic clusters, and raphe nuclei of 36-h post-fertilization (hpf) zebrafish embryos. Inhibition of Ddc by AADC inhibitor NSD-1015 or anti-sense morpholino oligonucleotides (MO) reduced brain volume and body length. We observed increased brain cell apoptosis and loss of dipencephalic catecholaminergic cluster neurons in ddc morphants (ddc MO-injected embryos). Seizure-like activity was also detected in ddc morphants in a dose-dependent manner. ddc morphants had less sensitive touch response and impaired swimming activity that could be rescued by injection of ddc plasmids. In addition, eye movement was also significantly impaired in ddc morphants. Collectively, loss of Ddc appears to result in similar phenotypes as that of ADCC deficiency, thus zebrafish could be a good model for investigating pathogenetic mechanisms of AADC deficiency in children.", "The past 15 years opened new avenues for retrovirus and retroelement research. Not surprisingly, they stemmed from essential knowledge collected in the past, which remains the ground of the present and therefore should be remembered. However, a short supplement of new break-through discoveries and ideas should be recollected. Using selected examples of recent works, I tried to extend and supplement my original article published in Folia Biologica (1996).", "The steroidogenic acute regulatory protein-related lipid transfer (START) domain family is defined by a conserved 210-amino acid sequence that folds into an α/β helix-grip structure. Members of this protein family bind a variety of ligands, including cholesterol, phospholipids, sphingolipids, and bile acids, with putative roles in nonvesicular lipid transport, metabolism, and cell signaling. Among the soluble START proteins, STARD4 is expressed in most tissues and has previously been shown to transfer sterol, but the molecular mechanisms of membrane interaction and sterol binding remain unclear. In this work, we use biochemical techniques to characterize regions of STARD4 and determine their role in membrane interaction and sterol binding. Our results show that STARD4 interacts with anionic membranes through a surface-exposed basic patch and that introducing a mutation (L124D) into the Omega-1 (Ω1) loop, which covers the sterol binding pocket, attenuates sterol transfer activity. To gain insight into the attenuating mechanism of the L124D mutation, we conducted structural and biophysical studies of wild-type and L124D STARD4. These studies show that the L124D mutation reduces the conformational flexibility of the protein, resulting in a diminished level of membrane interaction and sterol transfer. These studies also reveal that the C-terminal α-helix, and not the Ω1 loop, partitions into the membrane bilayer. On the basis of these observations, we propose a model of STARD4 membrane interaction and sterol binding and release that requires dynamic movement of both the Ω1 loop and membrane insertion of the C-terminal α-helix.", "The mechanism of cardiolipin (diphosphatidylglycerol) biosynthesis was examined in mitochondria and outer and inner mitochondrial membranes prepared from guinea pig and rat livers to determine whether this formation from phosphatidylglycerol was absolutely dependent on cytidinediphosphodiglyceride, as previously reported for intact mitochondria. Experimental results confirmed that the biosynthesis of cardiolipin, from the membrane-bound radioactive phosphatidylglycerol in intact mitochondria isolated from guinea pig and rat liver, was absolutely dependent on CDP-diglycerides and required the addition of divalent cations. Furthermore, the same mechanism for the biosynthesis of cardiolipin was operational in the outer and inner mitochondrial membranes. This biosynthesis was associated with both the outer and inner mitochondrial membranes prepared from guinea pig liver, but only with the inner mitochondrial membranes prepared from rat liver. The release of radioactive glycerol was also measured, but the amount obtained did not satisfy the stoichiometric requirement for CDP-diglyceride-independent biosynthesis of cardiolipin from 2 mol of phosphatidylglycerol with the liberation of 1 mol of glycerol. Therefore, it was concluded that this mechanism is not involved in the biosynthesis of cardiolipin in mitochondrial and submitochondrial membranes prepared from guinea pig and rat liver.", "BACKGROUND: The novel simplified out-of-hospital cardiac arrest (sOHCA) and simplified cardiac arrest hospital prognosis (sCAHP) scores used for prognostication of hospitalised patients have not been externally validated. Therefore, this study aimed to externally validate the sOHCA and sCAHP scores in a Japanese population.METHODS: We retrospectively analysed data from a prospectively maintained Japanese database (January 2012 to March 2013). We identified adult patients who had been resuscitated and hospitalised after intrinsic out-of-hospital cardiac arrest (OHCA) (n=2428, age ≥18 years). We validated the sOHCA and sCAHP scores with reference to the original scores in predicting 1-month unfavourable neurological outcomes (cerebral performance categories 3-5) based on the discrimination and calibration measures of area under the receiver operating characteristic curves (AUCs) and a Hosmer-Lemeshow goodness-of-fit test with a calibration plot, respectively.RESULTS: In total, 1985/2484 (82%) patients had a 1-month unfavourable neurological outcome. The original OHCA, sOHCA, original cardiac arrest hospital prognosis (CAHP) and sCAHP scores were available for 855/2428 (35%), 1359/2428 (56%), 1130/2428 (47%) and 1834/2428 (76%) patients, respectively. The AUCs of simplified scores did not differ significantly from those of the original scores, whereas the AUC of the sCAHP score was significantly higher than that of the sOHCA score (0.88 vs 0.81, p<0.001). The goodness of fit was poor in the sOHCA score (ν=8, χ2=19.1 and Hosmer-Lemeshow test: p=0.014) but not in the sCAHP score (ν=8, χ2=13.5 and Hosmer-Lemeshow test: p=0.10).CONCLUSION: The performances of the original and simplified OHCA and CAHP scores in predicting neurological outcomes in successfully resuscitated OHCA patients were acceptable. With the highest availability, similar discrimination and good calibration, the sCAHP score has promising potential for clinical implementation, although further validation studies to evaluate its clinical acceptance are necessary." ]