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Botulinum toxin type A in pregnancy. QUESTION: My patient received 62 units of botulinum toxin type A (BTX-A) for facial lines. Two weeks later, she found out that she was pregnant. Will this cause any harm to her fetus? ANSWER: Botulinum toxin is not expected to be present in systemic circulation following proper intramuscular or intradermal injection. Moreover, BTX-A, which has a high molecular weight, does not appear to cross the placenta. From the 38 pregnancies reported in the literature, including women who had botulism poisoning during pregnancy, exposure to BTX-A does not appear to increase the risk of adverse outcome in the fetus. | Can botulism poisoning of a pregnant woman harm her fetus? | 554763f0f35db75526000002_001 | no |
DNA binding by epipodophyllotoxins and N-acyl anthracyclines: implications for mechanism of topoisomerase II inhibition. Previous evidence suggests that epipodophyllotoxins, such as etoposide and teniposide, and the N-acyl anthracycline AD41 inhibit topoisomerase II resealing even though they apparently do not bind to DNA. Using experimental conditions designed to detect limited numbers of DNA binding sites, we now report that both epipodophyllotoxins and the N-acyl anthracyclines AD41 and AD32 bind to DNA. Binding was greater to kinetoplast DNA than to pUC18 plasmid DNA. There was also greater etoposide binding to single-stranded DNA than to double-stranded linear or supercoiled DNA. Based on binding competition experiments, etoposide and teniposide appear to have equal affinity for DNA, in spite of the fact that the latter is more potent as a topoisomerase inhibitor. This suggests that the difference in the drugs relates to protein interaction. There are 3- to 7-fold more binding sites for AD41 than for AD32, depending on the DNA substrate employed, and both drugs, unlike adriamycin, exhibit saturation of binding sites over a concentration range of 0-50 microM when kinetoplast DNA is the substrate. Evidence for DNA intercalation by AD41 is provided by the observation that the drug introduces positive supercoils into covalently closed plasmid DNA. Based on these data, a hypothesis is proposed that would provide a general mechanism whereby intercalating agents and epipodophyllotoxins alter topoisomerase function and presumably exert their antitumor effects. | Can DNA intercalators function as topoisomerase inhibitors? | 56c71cb65795f9a73e00000b_021 | yes |
Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. The neuron-specific transcription factor T-box brain 1 (TBR1) regulates brain development. Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). Here, we show that Tbr1 haploinsufficiency results in defective axonal projections of amygdalar neurons and the impairment of social interaction, ultrasonic vocalization, associative memory and cognitive flexibility in mice. Loss of a copy of the Tbr1 gene altered the expression of Ntng1, Cntn2 and Cdh8 and reduced both inter- and intra-amygdalar connections. These developmental defects likely impair neuronal activation upon behavioral stimulation, which is indicated by fewer c-FOS-positive neurons and lack of GRIN2B induction in Tbr1(+/-) amygdalae. We also show that upregulation of amygdalar neuronal activity by local infusion of a partial NMDA receptor agonist, d-cycloserine, ameliorates the behavioral defects of Tbr1(+/-) mice. Our study suggests that TBR1 is important in the regulation of amygdalar axonal connections and cognition. | Is there any role of TBR1 in autism? | 58965ed478275d0c4a000010_005 | yes |
[Indications for steroid and tirilazad treatment in patients with subarachnoid hemorrhage]. Tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, has been used in two randomized, double-blind, vehicle-controlled trials in Europe, Australia, New Zealand, and in North America in patients with aneurysmal subarachnoid hemorrhage. The first trial has been concluded, enrolled 1023 patients, and demonstrated a dramatic reduction in mortality from 27% to 3% (p = 0.01) in males receiving 6 mg/kg/day tirilazad for 10 days, when compared to vehicle-treated patients. There was also a less incidence of symptomatic vasospasm, and the frequency of hypertensive-hypervolemic-hemodilution therapy was significantly reduced. The reduction in mortality rate was remarkable, however the benefits of treatment with tirilazad were predominantly shown in men rather than in women. This clinical trial suggest that tirilazad mesylate, at a dosage of 6 mg/kg/day, improves overall outcome in aneurysmal subarachnoid hemorrhage patients. Further data from the North America trial and the trial in women receiving higher doses of tirilazad are still pending. | Is tirilazad effective for treatment of aneurysmal subarachnoid haemorrhage? | 58ec72a4eda5a5767200000f_003 | no |
Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, Ca(2+) handling and gene transcription. Here, in human, rat and mouse, we identify a novel mechanism linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a key risk factor for heart and neurodegenerative diseases. Acute hyperglycaemia causes covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification of CaMKII at Ser 279 activates CaMKII autonomously, creating molecular memory even after Ca(2+) concentration declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of diabetic humans and rats. In cardiomyocytes, increased glucose concentration significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum Ca(2+) release events that can contribute to cardiac mechanical dysfunction and arrhythmias. These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were aggravated by increased glucose concentration through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signalling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases. | Is Calcium/Calmodulin dependent protein kinase II (CaMKII) involved in cardiac arrhythmias and heart failure? | 5502abd1e9bde69634000008_003 | yes |
Targeting miR-21 for the therapy of pancreatic cancer. Despite tremendous efforts worldwide from clinicians and cancer scientists, pancreatic ductal adenocarcinoma (PDA) remains a deadly disease for which no cure is available. Recently, microRNAs (miRNAs) have emerged as key actors in carcinogenesis and we demonstrated that microRNA-21 (miR-21), oncomiR is expressed early during PDA. In the present study, we asked whether targeting miR-21 in human PDA-derived cell lines using lentiviral vectors (LVs) may impede tumor growth. We demonstrated that LVs-transduced human PDA efficiently downregulated miR-21 expression, both in vitro and in vivo. Consequently, cell proliferation was strongly inhibited and PDA-derived cell lines died by apoptosis through the mitochondrial pathway. In vivo, miR-21 depletion stopped the progression of a very aggressive model of PDA, to induce cell death by apoptosis; furthermore, combining miR-21 targeting and chemotherapeutic treatment provoked tumor regression. We demonstrate herein for the first time that targeting oncogenic miRNA strongly inhibit pancreatic cancer tumor growth both in vitro and in vivo. Because miR-21 is overexpressed in most human tumors; therapeutic delivery of miR-21 antagonists may still be beneficial for a large number of cancers for which no cure is available. | Is miR-21 related to carcinogenesis? | 511a4ec01159fa8212000004_019 | yes |
Genomic regulatory blocks underlie extensive microsynteny conservation in insects. Insect genomes contain larger blocks of conserved gene order (microsynteny) than would be expected under a random breakage model of chromosome evolution. We present evidence that microsynteny has been retained to keep large arrays of highly conserved noncoding elements (HCNEs) intact. These arrays span key developmental regulatory genes, forming genomic regulatory blocks (GRBs). We recently described GRBs in vertebrates, where most HCNEs function as enhancers and HCNE arrays specify complex expression programs of their target genes. Here we present a comparison of five Drosophila genomes showing that HCNE density peaks centrally in large synteny blocks containing multiple genes. Besides developmental regulators that are likely targets of HCNE enhancers, HCNE arrays often span unrelated neighboring genes. We describe differences in core promoters between the target genes and the unrelated genes that offer an explanation for the differences in their responsiveness to enhancers. We show examples of a striking correspondence between boundaries of synteny blocks, HCNE arrays, and Polycomb binding regions, confirming that the synteny blocks correspond to regulatory domains. Although few noncoding elements are highly conserved between Drosophila and the malaria mosquito Anopheles gambiae, we find that A. gambiae regions orthologous to Drosophila GRBs contain an equivalent distribution of noncoding elements highly conserved in the yellow fever mosquito Aëdes aegypti and coincide with regions of ancient microsynteny between Drosophila and mosquitoes. The structural and functional equivalence between insect and vertebrate GRBs marks them as an ancient feature of metazoan genomes and as a key to future studies of development and gene regulation. | Do Conserved noncoding elements act as enhancers? | 5139ec51bee46bd34c000006_006 | yes |
[Immunotherapy for Alzheimer's disease]. Passive anti-beta-amyloid (Aß) immunotherapy has been shown to clear brain Aß deposits. Results from phase III clinical trials in mild-to-moderate Alzheimer's disease (AD) patients with two monoclonal antibodies bapineuzumab and solanezumab and intravenous immunoglobulin have been disappointing. Subsequent analysis of pooled data from both phase III trials with solanezumab showed a reduction in cognitive decline in patients with mild AD. Solanezumab and new monoclonal antibodies are being tested in patients with prodromal and preclinical AD in search for a disease-modifying treatment. | Is Solanezumab effective for Alzheimer's Disease? | 5a70e1d999e2c3af26000007_001 | no |
Citrullination of collagen II affects integrin-mediated cell adhesion in a receptor-specific manner. Citrullinated collagen II (CII) is a well-known autoantigen in rheumatoid arthritis (RA). However, the direct effects of CII citrullination on cell behavior have not been described. To study whether citrullination of CII could affect cellular functions, we measured the adhesion of 3 different cell types (human Saos2 osteosarcoma cells, human synovial fibroblasts, and rat mesenchymal stem cells) with impedance-based technology. The binding of different collagen receptor integrins to citrullinated collagen was studied by CHO cell lines, each overexpressing 1 of the 4 human collagen receptors on the cell surface, and with solid-phase binding assays, using the recombinant human integrin α1I, α2I, α10I, and α11I domains. Collagen citrullination decreased the adhesion of synovial fibroblasts ∼50% (P<0.05) and mesenchymal stem cells ∼40% (P<0.05) by specifically decreasing the binding of integrins α10β1 and α11β1 to arginine-containing motifs, such as GFOGER. In contrast, citrullination had only a minor effect on the function of α1β1 and α2β1 integrins, which have been reported to play a critical role in regulating leukocyte function. Molecular modeling was used to explain the detected functional differences at the structural level. Given that the integrins regulate cell metabolism, proliferation, and migration, we suggest that collagen citrullination modifies the pathogenesis of RA. Here, CII citrullination was shown to decrease the survival of mesenchymal stem cells. | Has protein citrullination been implicated in rheumatoid arthritis? | 54d796f93706e8952800001e_010 | yes |
Lennox-Gastaut syndrome and idiopathic intracranial hypertension. Lennox-Gastaut Syndrome is a severe childhood epilepsy syndrome characterised by the diagnostic triad of a slow spike and wave pattern on electroencephalogram, multiple seizure types and developmental delay. Idiopathic intracranial hypertension is a syndrome characterised by raised cerebrospinal fluid pressure in the absence of an intracranial mass lesion or ventricular dilatation and often headache. We present the first reported case of Lennox-Gastaut Syndrome associated with symptomatic idiopathic intracranial hypertension in a 15 year old male, requiring cerebrospinal fluid diversion by means of ventriculoperitoneal shunting. | Is Lennox-Gastaut Syndrome usually diagnosed in older adults? | 58dbb4f08acda3452900001a_004 | no |
[Miller Fisher syndrome: review of the literature and presentation of 2 cases]. Miller Fisher Syndrome (MFS), which is characterized by ophthalmoplegia, ataxia and tendon areflexia, is generally considered as a clinical variant of Guillain-Barré Syndrome. However some features of the disease are still debated, particularly regarding possible central nervous system involvement. After presenting two new cases of MFS, the authors provide a critical review of the literature and discuss the nosographical position of the disease. The main conclusions can be summarized as follows: MFS is a predominantly axonal inflammatory neuropathy with prevailing involvement of oculomotor nerves. It is associated to spinal multi or polyneuropathy, which in mildly affected cases is manifested by areflexia, while in severe ones it can be responsible of sense and/or motor impairment. In addition to peripheral neuropathy CNS involvement, exclusive or more marked in posterior fossa, occurs not infrequently. The prognosis of the disease is often benign, but disabling or even fatal outcome is possible. Corticosteroid treatment, possibly because of antiinflammatory and/or immunosuppressive action, could be effective in some patients. Finally, in spite of some similarities with GBS, MFS should be considered as a separate entity with its own nosographical position. | Is the Miller-Fisher syndrome considered to be a variant of Guillain-Barré? | 571f59cd0fd6f91b68000008_009 | yes |
Dietary patterns and risk of mortality from cardiovascular disease, cancer, and all causes in a prospective cohort of women. BACKGROUND: The impact of overall dietary patterns that reflect actual eating behaviors on mortality caused by cardiovascular or other chronic diseases is largely unknown. METHODS AND RESULTS: We prospectively evaluated the relation between dietary patterns and risk of cardiovascular, cancer, and all-cause mortality among 72,113 women who were free of myocardial infarction, angina, coronary artery surgery, stroke, diabetes mellitus, or cancer and were followed up from 1984 to 2002. Dietary patterns were derived by factor analysis based on validated food frequency questionnaires administered every 2 to 4 years. Two major dietary patterns were identified: High prudent pattern scores represented high intakes of vegetables, fruit, legumes, fish, poultry, and whole grains, whereas high Western pattern scores reflected high intakes of red meat, processed meat, refined grains, french fries, and sweets/desserts. During 18 years of follow-up, 6011 deaths occurred, including 1154 cardiovascular deaths and 3139 cancer deaths. After multivariable adjustment, the prudent diet was associated with a 28% lower risk of cardiovascular mortality (95% confidence interval [CI], 13 to 40) and a 17% lower risk of all-cause mortality (95% CI, 10 to 24) when the highest quintile was compared with the lowest quintile. In contrast, the Western pattern was associated with a higher risk of mortality from cardiovascular disease (22%; 95% CI, 1 to 48), cancer (16%; 95% CI, 3 to 30), and all causes (21%; 95% CI, 12 to 32). CONCLUSIONS: Greater adherence to the prudent pattern may reduce the risk of cardiovascular and total mortality, whereas greater adherence to the Western pattern may increase the risk among initially healthy women. | Does prudent diet reduce cardiovascular risk? | 53319653d6d3ac6a3400003e_005 | yes |
Subgroups in autism: are there behavioural phenotypes typical of underlying medical conditions? Fifty-nine cases with infantile autism/autistic disorder were subclassified according to associated medical condition (fragile-X, tuberous sclerosis, neurofibromatosis, hypo-melanosis of Ito, Moebius syndrome, Rett syndrome, and a 'new' syndrome associated with a marker chromosome). It was concluded that, even within a group of cases fitting currently accepted criteria for autism, there is considerable variation in symptom profile depending on the exact type of associated medical condition. | Is autism one of the characteristics of Moebius syndrome? | 5727b6410fd6f91b6800001b_004 | yes |
Nucleosome Organization in Human Embryonic Stem Cells. The fundamental repeating unit of eukaryotic chromatin is the nucleosome. Besides being involved in packaging DNA, nucleosome organization plays an important role in transcriptional regulation and cellular identity. Currently, there is much debate about the major determinants of the nucleosome architecture of a genome and its significance with little being known about its role in stem cells. To address these questions, we performed ultra-deep sequencing of nucleosomal DNA in two human embryonic stem cell lines and integrated our data with numerous epigenomic maps. Our analyses have revealed that the genome is a determinant of nucleosome organization with transcriptionally inactive regions characterized by a "ground state" of nucleosome profiles driven by underlying DNA sequences. DNA sequence preferences are associated with heterogeneous chromatin organization around transcription start sites. Transcription, histone modifications, and DNA methylation alter this "ground state" by having distinct effects on both nucleosome positioning and occupancy. As the transcriptional rate increases, nucleosomes become better positioned. Exons transcribed and included in the final spliced mRNA have distinct nucleosome profiles in comparison to exons not included at exon-exon junctions. Genes marked by the active modification H3K4m3 are characterized by lower nucleosome occupancy before the transcription start site compared to genes marked by the inactive modification H3K27m3, while bivalent domains, genes associated with both marks, lie exactly in the middle. Combinatorial patterns of epigenetic marks (chromatin states) are associated with unique nucleosome profiles. Nucleosome organization varies around transcription factor binding in enhancers versus promoters. DNA methylation is associated with increasing nucleosome occupancy and different types of methylations have distinct location preferences within the nucleosome core particle. Finally, computational analysis of nucleosome organization alone is sufficient to elucidate much of the circuitry of pluripotency. Our results, suggest that nucleosome organization is associated with numerous genomic and epigenomic processes and can be used to elucidate cellular identity. | Is DNA methylation correlated with nucleosome occupancy? | 5a43a214966455904c000009_006 | yes |
Treatment of amyotrophic lateral sclerosis with thyrotropin-releasing hormone (TRH). Despite the efforts of many workers, the cause and therapy has not been clarified. We carried out the therapeutic trial of thyrotropin releasing hormone (TRH) for amyotrophic lateral sclerosis (ALS) from January, 1979 to January, 1983. There were 16 subjects. The patients were given a low dose (0.5-2 mg) of TRH intravenously or intramusculary. Mild to moderate improvement was found in 9 (56%) of 16 patients. TRH has been reported to have the activating effects on the pyramidal tract, brainstem motor nuclei, and motoneuron in the spinal cord as a neurotransmitter or neuromodulator. We thought such action of TRH to be useful to the therapy of ALS. | Is there any data to suggest that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients? | 54d76ac63706e89528000016_008 | yes |
Replication of SV40 minichromosomes in vitro. We operationally define two forms of SV40 minichromosomes, a 75S-form, prepared at low salt concentration, referred to as native minichromosomes, and a 50S-form, obtained after treatment with 0.5 M potassium acetate, the salt-treated minichromosomes. Both preparations of minichromosomes serve well as templates for replication in vitro. Their respective replication products are strikingly different: replicated native minichromosomes contain a densely packed array of the maximal number of nucleosomes whereas replicated salt-treated minichromosomes carry, on average, half of the maximal number. We conclude that in both cases parental nucleosomes are transferred to progeny DNA, and, in addition, that an assembly of new nucleosomes occurs during the replication of native minichromosomes. This is apparently due to the presence of a nucleosome assembly factor as a constituent of native minichromosomes that dissociates upon treatment with salt. We further show that preparations of minichromosomes usually contain significant amounts of copurifying hnRNP particles and SV40 virion precursor particles. However, these structures do not detectably affect the replication and the chromatin assembly reactions. | Are hepadnaviral minichromosomes free of nucleosomes? | 58e3d1743e8b6dc87c000001_004 | no |
Metastatic melanoma in an esophagus demonstrating Barrett esophagus with high grade dysplasia. BACKGROUND: Metastatic melanoma involving the esophagus is rare; the occurrence of metastatic melanoma in a background of Barrett esophagus is rarer still. We report a case of an 80 year-old male who presented to our institution for workup of Barrett esophagus with high-grade dysplasia and who proved to have metastatic melanoma occurring in the background of Barrett esophagus, the first report of this kind, to our knowledge, in the English literature. CASE PRESENTATION: An 80 year-old Caucasian male was diagnosed at an outside institution with Barrett's esophagus with high grade dysplasia and presented to our institution for therapy. The patient underwent endoscopic mucosal resection using a band ligation technique of an area of nodularity within the Barrett esophagus. Microscopic examination demonstrated extensive Barrett esophagus with high-grade dysplasia as well as a second tumor which was morphologically different from the surrounding high-grade dysplasia and which was positive for S-100, HMB 45 and Melan-A on immunohistochemistry, consistent with melanoma. Further workup of the patient demonstrated multiple radiologic lesions consistent with metastases. Molecular studies demonstrated that the melanoma was positive for the 1799T>A (V600E) mutation in the BRAF gene. The overall features of the tumor were most consistent with metastatic melanoma occurring in a background of Barrett esophagus with high-grade dysplasia. CONCLUSION: This case demonstrates a unique intersection between a premalignant condition (Barrett esophagus with high grade dysplasia) and a separate malignancy (melanoma). This report also shows the utility of molecular testing to support the hypothesis of primary versus metastatic disease in melanoma. | Are BRAF mutations common in melanoma? | 5512c91b6a8cde6b7200000b_034 | yes |
Carpal tunnel syndrome after epiphysiolysis of the distal radius in a 5-year-old child. Case report. Carpal tunnel syndrome after fracture of the distal radius is a well known complication in adults, but in small children carpal tunnel syndrome is extremely rare. A case of carpal tunnel syndrome in a 5-year-old girl is presented. She had a distal epiphysiolysis of the radius, which was treated conservatively. Eight weeks after removal of the plaster of Paris she had clinical signs of carpal tunnel syndrome after exercise but without new injuries. Conservative treatment with a dorsal splint was effective, and all her symptoms disappeared. So conservative treatment seems worth considering before operation in similar cases. | Can radius fracture cause carpal tunnel syndrome? | 5a72284b2dc08e987e000001_005 | yes |
Poly(ADP-ribose) polymerase inhibitors suppress UV-induced human immunodeficiency virus type 1 gene expression at the posttranscriptional level. Gene expression of human immunodeficiency virus type 1 (HIV-1) is induced not only by trans activation mediated through a gene product (tat) encoded by the virus but also by treatment of virus-carrying cells with DNA-damaging agents such as UV light. Employing an artificially constructed DNA in which the chloramphenicol acetyltransferase gene was placed under the control of the HIV-1 long terminal repeat, we analyzed the induction process in HeLa cells and found that inhibitors of poly(ADP-ribose) polymerase suppressed UV-induced HIV-1 gene expression but not tat-mediated expression. We also found that suppression occurs at the posttranscriptional level. These results indicate that HIV-1 gene expression is activated by at least two different mechanisms, one of which involves poly-ADP ribosylation. A possible new role of poly-ADP ribosylation in the regulation of specific gene expression is also discussed. | Is poly (ADP- ribosylation) involved in transcriptional control? | 53380000d6d3ac6a34000059_000 | yes |
Mowat-Wilson syndrome in a Moroccan consanguineous family. Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum. This disorder is sporadic and is caused by heterozygous mutations or deletions of the ZFHX1B gene located in the 2q22 region. We report here the first Moroccan patient, born to consanguineous parents, with Mowat-Wilson syndrome, due to a de novo, unreported mutation of the ZFHX1B gene. | Is corpus callosum involved in the Mowat–Wilson syndrome? | 5314896adae131f847000001_015 | yes |
Targeting a novel bone degradation pathway in primary bone cancer by inactivation of the collagen receptor uPARAP/Endo180. In osteosarcoma, a primary mesenchymal bone cancer occurring predominantly in younger patients, invasive tumour growth leads to extensive bone destruction. This process is insufficiently understood, cannot be efficiently counteracted and calls for novel means of treatment. The endocytic collagen receptor, uPARAP/Endo180, is expressed on various mesenchymal cell types and is involved in bone matrix turnover during normal bone growth. Human osteosarcoma specimens showed strong expression of this receptor on tumour cells, along with the collagenolytic metalloprotease, MT1-MMP. In advanced tumours with ongoing bone degeneration, sarcoma cells positive for these proteins formed a contiguous layer aligned with the degradation zones. Remarkably, osteoclasts were scarce or absent from these regions and quantitative analysis revealed that this scarcity marked a strong contrast between osteosarcoma and bone metastases of carcinoma origin. This opened the possibility that sarcoma cells might directly mediate bone degeneration. To examine this question, we utilized a syngeneic, osteolytic bone tumour model with transplanted NCTC-2472 sarcoma cells in mice. When analysed in vitro, these cells were capable of degrading the protein component of surface-labelled bone slices in a process dependent on MMP activity and uPARAP/Endo180. Systemic treatment of the sarcoma-inoculated mice with a mouse monoclonal antibody that blocks murine uPARAP/Endo180 led to a strong reduction of bone destruction. Our findings identify sarcoma cell-resident uPARAP/Endo180 as a central player in the bone degeneration of advanced tumours, possibly following an osteoclast-mediated attack on bone in the early tumour stage. This points to uPARAP/Endo180 as a promising therapeutic target in osteosarcoma, with particular prospects for improved neoadjuvant therapy. | Are osteoclasts specialized in bone degradation? | 5aa82180d6d6b54f79000015_004 | yes |
Mitochondrial estrogen receptor β inhibits cell apoptosis via interaction with Bad in a ligand-independent manner. Previous studies reported that estrogen receptor β (ERβ) is localized to mitochondria, whereas little is known about the physiological functions of mitochondrial ERβ. In the present study, we explored the role of mitochondrial ERβ in regulating apoptosis using stable ERβ-expressing and ERβ knockdown cells lines. We found that exogenous ERβ was mainly expressed in mitochondrial but not in nuclear after ERβ overexpression and protected cells from apoptosis induced by hydrogen peroxide (H₂O₂), ultraviolet (UV), and staurosporine (STS). Moreover, overexpression of ERβ prevented Bax activation, cytochrome c release, caspase-3 activation, and PARP cleavage during apoptosis. Furthermore, knockdown of ERβ significantly suppressed the expression of ERβ in mitochondrial and promoted cell apoptosis induced by H₂O₂, UV, and STS. Downregulation of ERβ also enhanced Bax activation, cytochrome c release, caspase-3 activation and PARP cleavage. In addition, our study discovered that mitochondrial ERβ interacted with proapoptotic protein Bad in a ligand-independent manner, which suggests that mitochondrial ERβ inhibits Bad, and prevents Bax activation and cytochrome c release. Collectively, the results of this study support that mitochondrial ERβ prevents cell apoptosis via the mitochondrial apoptotic pathway in a ligand-independent manner. | Can the apoptosis regulator BAX trigger the release of cytochrome c? | 5717bacacb4ef8864c00000d_002 | yes |
Neurovascular complications of cocaine. Use of cocaine in the USA, has reached epidemic proportions since 1983, when "crack" was introduced, its higher potency compared with cocaine HCl has been associated with a tremendous increase in the incidence of strokes. This study reports our experience with 55 cases of neurovascular events (25 ischemic and 30 hemorrhagic) related to cocaine use in 54 patients. Only 15 patients had other risk factors for stroke. Twenty six patients smoked "crack", 10 snorted cocaine and 12 injected it intravenously. Strokes occurred within 3 h of cocaine use in 15 patients with infarcts and 17 with hemorrhages. Ten infarcts occurred after an overnight binge. Of the hemorrhage group 9 were subarachnoid, 16 intracerebral (8 basal ganglia, 7 hemispheric and one brain stem) and 5 intraventricular. Computerized tomography (CT) showed an aneurysm of the anterior communicating artery, as well as one of the vein of Galen. Four aneurysms and 3 AVMs were identified on angiography. CT revealed 15 infarcts; it was normal in 7 patients with pure motor hemiparesis and in 3 with findings consistent with anterior spinal artery infarction. Several mechanisms may be responsible for the cerebrovascular complications. A sudden rise in systemic arterial pressure may cause hemorrhages, frequently in association with an underlying aneurysm or AVM. Vasospasm, arteritis, myocardial infarction with cardiac arrhythmias and increased platelet aggregation may provoke infarcts. | Is cocaine use associated with increased risk for intracerebral hemorrhage? | 5159b990d24251bc050000a3_005 | yes |
Tretinoin and cutaneous photoaging. Guaranteed adverse effects! * A cream containing 0.05% tretinoin (Retinova((R)) is approved for treatment of sun-induced skin damage ("photoaging").* Three trials comparing tretinoin with the excipient show that the effects of tretinoin cream are at best limited and slow to occur. Furthermore, they disappear on treatment cessation, necessitating long-term use.* The 0.05% tretinoin cream has poor local tolerability: most subjects develop irritation and fragile skin and require longer intervals between each application. Systemic adverse effects occur in some circumstances.* There are persistent doubts about whether it is safe to use tretinoin during pregnancy. | Is tretinoin effective for photoaging? | 5a68f2bab750ff4455000017_004 | yes |
A case of Pendred's syndrome presenting with amenorrhea. Pendred's syndrome is manifested by congenital sensorineural deafness in association with familial goiter due to defective organic binding of iodine in the thyroid gland. The majority of patients with Pendred's syndrome are euthyroid. We report on an unusual case of a patient with Pendred's syndrome presenting with amenorrhea and late-onset hypothyroidism. | Do patients with Pendred syndrome present congenital deafness? | 56d8b27651531f7e33000003_017 | yes |
Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics. | Do mutations of AKT1 occur in meningiomas? | 56bf365eef6e39474100000e_003 | yes |
Glutamate dehydrogenase: a reliable marker of liver cell necrosis in the alcoholic. The usefulness of blood enzyme determinations as markers of liver necrosis was tested in 100 alcoholics who underwent biopsy during clinical investigation. Mean values of glutamate dehydrogenase (GDH), serum aspartate and alanine transferase (SGOT and SGPT), ornithine carbamoyltransferase (OCT), and gamma-glutamyltranspeptidase (gamma-GTP) tended to rise with increasing liver cell necrosis, though values of SGOT, SGPT, OCT, and gamma-GTP showed considerable overlap between the 32 patients with histologically proved hepatitis and the 68 without. By contrast, GDH values showed virtually no overlap between patients with and without hepatitis, and a value of two and a half times the normal value discriminated between the two groups. Because of its easy determination and its reliable reflection of liver cell necrosis the GDH concentration should be estimated routinely in alcoholic patients. | SGOT is an abbreviation for an enzyme other wise known as alanine amino transferase, yes or no? | 5a67b48cb750ff4455000010_003 | no |
Selective autophagy regulates insertional mutagenesis by the Ty1 retrotransposon in Saccharomyces cerevisiae. Macroautophagy (autophagy) is a bulk degradation system for cytoplasmic components and is ubiquitously found in eukaryotic cells. Autophagy is induced under starvation conditions and plays a cytoprotective role by degrading unwanted cytoplasmic materials. The Ty1 transposon, a member of the Ty1/copia superfamily, is the most abundant retrotransposon in the yeast Saccharomyces cerevisiae and acts to introduce mutations in the host genome via Ty1 virus-like particles (VLPs) localized in the cytoplasm. Here we show that selective autophagy downregulates Ty1 transposition by eliminating Ty1 VLPs from the cytoplasm under nutrient-limited conditions. Ty1 VLPs are targeted to autophagosomes by an interaction with Atg19. We propose that selective autophagy safeguards genome integrity against excessive insertional mutagenesis caused during nutrient starvation by transposable elements in eukaryotic cells. | Is macroautophagy a selective degradation process? | 51bedaac3148fdcc22da7188_003 | yes |
Methylation of histone H4 lysine 20 by PR-Set7 ensures the integrity of late replicating sequence domains in Drosophila. The methylation state of lysine 20 on histone H4 (H4K20) has been linked to chromatin compaction, transcription, DNA repair and DNA replication. Monomethylation of H4K20 (H4K20me1) is mediated by the cell cycle-regulated histone methyltransferase PR-Set7. PR-Set7 depletion in mammalian cells results in defective S phase progression and the accumulation of DNA damage, which has been partially attributed to defects in origin selection and activation. However, these studies were limited to only a handful of mammalian origins, and it remains unclear how PR-Set7 and H4K20 methylation impact the replication program on a genomic scale. We employed genetic, cytological, and genomic approaches to better understand the role of PR-Set7 and H4K20 methylation in regulating DNA replication and genome stability in Drosophila cells. We find that deregulation of H4K20 methylation had no impact on origin activation throughout the genome. Instead, depletion of PR-Set7 and loss of H4K20me1 results in the accumulation of DNA damage and an ATR-dependent cell cycle arrest. Coincident with the ATR-dependent cell cycle arrest, we find increased DNA damage that is specifically limited to late replicating regions of the Drosophila genome, suggesting that PR-Set7-mediated monomethylation of H4K20 is critical for maintaining the genomic integrity of late replicating domains. | Is H4K20 methylation associated with DNA replication? | 58adbe999ef3c34033000005_003 | yes |
Contrasting chromatin organization of CpG islands and exons in the human genome. BACKGROUND: CpG islands and nucleosome-free regions are both found in promoters. However, their association has never been studied. On the other hand, DNA methylation is absent in promoters but is enriched in gene bodies. Intragenic nucleosomes and their modifications have been recently associated with RNA splicing. Because the function of intragenic DNA methylation remains unclear, I explored the possibility of its involvement in splicing regulation. RESULTS: Here I show that CpG islands were associated not only with methylation-free promoters but also with nucleosome-free promoters. Nucleosome-free regions were observed only in promoters containing a CpG island. However, the DNA sequences of CpG islands predicted the opposite pattern, implying a limitation of sequence programs for the determination of nucleosome occupancy. In contrast to the methylation-and nucleosome-free states of CpG-island promoters, exons were densely methylated at CpGs and packaged into nucleosomes. Exon-enrichment of DNA methylation was specifically found in spliced exons and in exons with weak splice sites. The enrichment patterns were less pronounced in initial exons and in non-coding exons, potentially reflecting a lower need for their splicing. I also found that nucleosomes, DNA methylation, and H3K36me3 marked the exons of transcripts with low, medium, and high gene expression levels, respectively. CONCLUSIONS: Human promoters containing a CpG island tend to remain nucleosome-free as well as methylation-free. In contrast, exons demonstrate a high degree of methylation and nucleosome occupancy. Exonic DNA methylation seems to function together with exonic nucleosomes and H3K36me3 for the proper splicing of transcripts with different expression levels. | Is DNA methylation correlated with nucleosome occupancy? | 5a43a214966455904c000009_011 | yes |
Pentraxin 3 (PTX3) is associated with severe sepsis and fatal disease in emergency room patients with suspected infection: a prospective cohort study. BACKGROUND: Early diagnostic and prognostic stratification of patients with suspected infection is a difficult clinical challenge. We studied plasma pentraxin 3 (PTX3) upon admission to the emergency department in patients with suspected infection. METHODS: The study comprised 537 emergency room patients with suspected infection: 59 with no systemic inflammatory response syndrome (SIRS) and without bacterial infection (group 1), 67 with bacterial infection without SIRS (group 2), 54 with SIRS without bacterial infection (group 3), 308 with sepsis (SIRS and bacterial infection) without organ failure (group 4) and 49 with severe sepsis (group 5). Plasma PTX3 was measured on admission using a commercial solid-phase enzyme-linked immunosorbent assay (ELISA). RESULTS: The median PTX3 levels in groups 1-5 were 2.6 ng/ml, 4.4 ng/ml, 5.0 ng/ml, 6.1 ng/ml and 16.7 ng/ml, respectively (p<0.001). The median PTX3 concentration was higher in severe sepsis patients compared to others (16.7 vs. 4.9 ng/ml, p<0.001) and in non-survivors (day 28 case fatality) compared to survivors (14.1 vs. 5.1 ng/ml, p<0.001). A high PTX3 level predicted the need for ICU stay (p<0.001) and hypotension (p<0.001). AUC(ROC) in the prediction of severe sepsis was 0.73 (95% CI 0.66-0.81, p<0.001) and 0.69 in case fatality (95% CI 0.58-0.79, p<0.001). PTX3 at a cut-off level for 14.1 ng/ml (optimal cut-off value for severe sepsis) showed 63% sensitivity and 80% specificity. At a cut-off level 7.7 ng/ml (optimal cut-off value for case fatality) showed 70% sensitivity and 63% specificity in predicting case fatality on day 28.In multivariate models, high PTX3 remained an independent predictor of severe sepsis and case fatality after adjusting for potential confounders. CONCLUSIONS: A high PTX3 level on hospital admission predicts severe sepsis and case fatality in patients with suspected infection. | Can Pentraxin 3 predict outcomes of sepsis? | 5890eb22621ea6ff7e000006_003 | yes |
Phosphorylation by cAMP-dependent protein kinase modulates the structural coupling between the transmembrane and cytosolic domains of phospholamban. We have used frequency-domain fluorescence spectroscopy to investigate the structural linkage between the transmembrane and cytosolic domains of the regulatory protein phospholamban (PLB). Using an engineered PLB having a single cysteine (Cys(24)) derivatized with the fluorophore N-(1-pyrenyl)maleimide (PMal), we have used fluorescence resonance energy transfer (FRET) to measure the average spatial separation and conformational heterogeneity between PMal bound to Cys(24) in the transmembrane domain and Tyr(6) in the cytosolic domain near the amino terminus of PLB. In these measurements, PMal serves as a FRET donor, and Tyr(6) serves as a FRET acceptor following its nitration by tetranitromethane. The native structure of PLB is retained following site-directed mutagenesis and chemical modification, as indicated by the ability of the derivatized PLB to fully regulate the Ca-ATPase following their co-reconstitution. To assess how phosphorylation modulates the structure of PLB itself, FRET measurements were made following reconstitution of PLB in membrane vesicles made from extracted sarcoplasmic reticulum membrane lipids. We find that the cytosolic domain of PLB assumes a wide range of conformations relative to the transmembrane sequence, consistent with other structural data indicating the presence of a flexible hinge region between the transmembrane and cytosolic domains of PLB. Phosphorylation of Ser(16) by PKA results in a 3 A decrease in the spatial separation between PMal at Cys(24) and nitroTyr(6) and an almost 2-fold decrease in conformational heterogeneity, suggesting a stabilization of the hinge region of PLB possibly through an electrostatic linkage between phosphoSer(16) and Arg(13) that promotes a coil-to-helix transition. This structural transition has the potential to function as a conformational switch, since inhibition of the Ca-ATPase requires disruption of the secondary structure of PLB in the vicinity of the hinge element to permit association with the nucleotide binding domain at a site located approximately 50 A above the membrane surface. Following phosphorylation, the stabilization of the helical content in the hinge domain will disrupt this inhibitory interaction by reducing the maximal dimension of the cytosolic domain of PLB. Thus, stabilization of the structure of PLB following phosphorylation of Ser(16) is part of a switching mechanism, which functions to alter binding interactions between PLB and the nucleotide binding domain of the Ca-ATPase that modulates enzyme inhibition. | Is phospholamban phosphorylated by Protein kinase A? | 54da0c524b1fd0d33c00000b_016 | yes |
Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. BACKGROUND: MicroRNAs (miRNAs/miRs) are small conserved RNA molecules of 22 nucleotides that negatively modulate gene expression primarily through base paring to the 3' untranslated region of target messenger RNAs. The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins. In this study, we investigated the molecular mechanisms through which miR-1 intervenes in regulation of muscle cell growth and differentiation. METHODS AND RESULTS: On the basis of bioinformatics tools, biochemical assays, and in vivo models, we demonstrate that (1) insulin-like growth factor-1 (IGF-1) and IGF-1 receptor are targets of miR-1; (2) miR-1 and IGF-1 protein levels are correlated inversely in models of cardiac hypertrophy and failure as well as in the C2C12 skeletal muscle cell model of differentiation; (3) the activation state of the IGF-1 signal transduction cascade reciprocally regulates miR-1 expression through the Foxo3a transcription factor; and (4) miR-1 expression correlates inversely with cardiac mass and thickness in myocardial biopsies of acromegalic patients, in which IGF-1 is overproduced after aberrant synthesis of growth hormone. CONCLUSIONS: Our results reveal a critical role of miR-1 in mediating the effects of the IGF-1 pathway and demonstrate a feedback loop between miR-1 expression and the IGF-1 signal transduction cascade. | Is micro RNA 1 (miR-1) implicated in cardiac arrhythmias? | 54f4627e64850a5854000007_007 | yes |
[Infantile hemangioma and propranolol: a therapeutic "revolution". Literature review]. Infantile hemangioma (IH) is the most common benign vascular tumour affecting children. Most infantile hemangiomas are self-limiting, but some require specific treatment. Propranolol has been proposed for the treatment of infantile hemangiomas. The aim of this study is to explore the mechanism of action of propranolol for the treatment of infantile hemangiomas and to demonstrate its safety and efficacy through a review of the literature. The non cardioselective bêta-blocker propranolol has been used in a pediatric setting for 40 years and, since 2008, has a new indication. A clearly significant improvement has been observed in the condition of children with complicated IH (10%) treated with propranolol. This new indication has been widely described in the international literature. Various explanations have been put forward for the mechanism of action including a vasoconstrictor, antiangiogenic and apoptotic effect of propranolol on the different cells making up an IH. Overall tolerance is good and the efficacy markedly superior to that of any other treatments used for this purpose. In conclusion, with its good tolerance profile and superior efficacy versus all the other available therapies, propranolol can be considered to be a first-line treatment for complicated IH. | Is propranolol used for treatment of infantile hemangioma? | 5a67a72fb750ff445500000a_001 | yes |
An enigmatic trio of Klinefelter's syndrome, autoimmune hypothyroidism and nephrotic syndrome. Klinefelter's syndrome is the most common chromosomal disorder associated with testicular dysfunction and male infertility. Those affected by Klinefelter's syndrome are at increased risk of systemic lupus erythematosus, breast cancer, non-Hodgkin's lymphoma, and lung cancer. Nephrotic syndrome in association with Klinefelter's syndrome has never been reported in the literature. | Is there an association between Klinefelter syndrome and breast cancer? | 5a68eabab750ff4455000015_008 | yes |
Evaluation of permanent alopecia in pediatric medulloblastoma patients treated with proton radiation. BACKGROUND: To precisely calculate skin dose and thus to evaluate the relationship between the skin dose and permanent alopecia for pediatric medulloblastoma patients treated with proton beams. METHODS: The dosimetry and alopecia outcomes of 12 children with medulloblastoma (ages 4-15 years) comprise the study cohort. Permanent alopecia was assessed and graded after completion of the entire therapy. Skin threshold doses of permanent alopecia were calculated based on the skin dose from the craniospinal irradiation (CSI) plan using the concept of generalized equivalent uniform dose (gEUD) and accounting for chemotherapy intensity. Monte Carlo simulations were employed to accurately assess uncertainties due to beam range prediction and secondary particles. RESULTS: Increasing the dose of the CSI field or the dose given by the boost field to the posterior fossa increased total skin dose delivered in that region. It was found that permanent alopecia could be correlated with CSI dose with a threshold of about 21 Gy (relative biological effectiveness, RBE) with high dose chemotherapy and 30 Gy (RBE) with conventional chemotherapy. CONCLUSIONS: Our results based on 12 patients provide a relationship between the skin dose and permanent alopecia for pediatric medulloblastoma patients treated with protons. The alopecia risk as assessed with gEUD could be predicted based on the treatment plan information. | Is there a role of proton beam therapy in medulloblastoma treatment? | 58850ac7e56acf5176000012_006 | yes |
Role of KCNQ2 and KCNQ3 genes in juvenile idiopathic epilepsy in Arabian foals. Juvenile idiopathic epilepsy (JIE) in Arabian foals resembles benign-familial neonatal convulsion (BFNC) syndrome, a rare idiopathic epilepsy of new-born humans. BFNC syndrome exhibits genetic heterogeneity, as has been hypothesised to occur in Arabian foals, and is known to be caused by mutations in the voltage-gated potassium channel subunit KCNQ2 and KCNQ3 genes. The close phenotypic characteristics of both Arabian foals and children suggest these epileptic syndromes are caused by the same genetic disorder. In horses, the KCNQ2 and KCNQ3 genes are located on the terminal region of chromosomes 22 and 9, respectively, essentially homologous to their location on chromosomes 20q13.3 and 8q24 in humans. Gene trees for the KCNQ2 and KCNQ3 genes between horses and other mammals, particularly humans and mice, were constructed and compared to widely accepted mammalian phylogenetic trees. The KCNQ2 gene tree exhibited close clustering between horses and humans, relative to horses and mice, in contrast to the evolutionary trees of other mammals. Distance values between the horse and human groups were lower as opposed to those found between the horse and mouse groups. The similarity between the horse and the human, especially for the KCNQ2 gene, where the majority of mutations causing BFNC have been found, supports the hypothesis of similar heritable and genetic patterns of the disease in both species and suggests that contrary to the classic mouse-model concept, humans may be a more suitable model for the study of JIE in Arabian foals. | Is the protein KCNQ2 associated with idiopathic epilepsy? | 56c30ce99d3e5f1412000002_007 | yes |
Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland. | Is a CpG island methylator phenotype involved in ependymomas? | 5a86fd5bfaa1ab7d2e00003b_001 | yes |
Promoter regulation by distinct mechanisms of functional interplay between lysine acetylase Rtt109 and histone chaperone Asf1. The promoter activity of yeast genes can depend on lysine 56 (K56) acetylation of histone H3. This modification of H3 is performed by lysine acetylase Rtt109 acting in concert with histone chaperone Asf1. We have examined the contributions of Rtt109, Asf1, and H3 K56 acetylation to nutrient regulation of a well-studied metabolic gene, ARG1. As expected, Rtt109, Asf1, and H3 K56 acetylation are required for maximal transcription of ARG1 under inducing conditions. However, Rtt109 and Asf1 also inhibit ARG1 under repressing conditions. This inhibition requires Asf1 binding to H3-H4 and Rtt109 KAT activity, but not tail acetylation of H3-H4 or K56 acetylation of H3. These observations suggest the existence of a unique mechanism of transcriptional regulation by Rtt109. Indeed, chromatin immunoprecipitation and genetic interaction studies support a model in which promoter-targeted Rtt109 represses ARG1 by silencing a pathway of transcriptional activation that depends on ASF1. Collectively, our results show that ARG1 transcription intensity at its induced and repressed set points is controlled by different mechanisms of functional interplay between Rtt109 and Asf1. | Does the histone chaperone ASF1 interact with histones H1/H2? | 58dcbb8c8acda34529000021_005 | no |
Mowat-Wilson syndrome: the first two Malaysian cases. Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation; a multiple congenital anomaly syndrome characterised by a typical facial gestalt, Hirschsprung disease or severe constipation, genitourinary anomaly, congenital heart defects, agenesis of corpus callosum and eye defects. Some cases also present with epilepsy, growth retardation with microcephaly and speech impairment. MWS was first described in 1998 by Mowat et al, and approximately 180 cases have been reported as of August 2008. The syndrome occurs as a result of heterozygous mutations or deletions in the zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). Most cases reported so far were sporadic occurrences; however, rare cases of sibling recurrence have been cited. The facial phenotype is particularly important for the initial clinical diagnosis and provides the hallmark, warranting ZEB2 mutational analysis even in the absence of Hirschsprung disease. We present the first two molecularly confirmed Malaysian MWS patients, one of whom has a novel mutation. | Is Hirschsprung disease one of the characteristics of the Mowat-Wilson syndrome? | 55001420e9bde69634000005_002 | yes |
CD99 triggers upregulation of miR-9-modulated PRDM1/BLIMP1 in Hodgkin/Reed-Sternberg cells and induces redifferentiation. CD99 is a 32-kDa transmembrane glycoprotein that is encoded by the MIC2 gene. Our study was carried out to examine the role of CD99 in tumor progression of classical Hodgkin lymphoma (cHL). Here, we showed that lowly expressed CD99 protein in cHL cell lines and primary cHL cases correlates with the deficient expression of the positive regulatory domain 1 (PRDM1/BLIMP1). In addition, cHL cell lines showed high levels of miR-9 expression. We determined that the upregulation of CD99 induced expression of transcription factor PRDM1, a master regulator of plasma-cell differentiation, which is also a target for miR-9-mediated downregulation. Indeed, inhibition of miR-9 also triggered upregulation of PRDM1 expression. Furthermore, overexpression of CD99 resulted in changed growth features and reorganization of actin cytoskeleton. As upregulation of CD99 led to a decrease in cHL diagnosis marker CD30 and CD15 and an increase in plasma-cell differentiation marker CD38 and the restoration of B-cell makers PAX5, CD79α and CD19, we suggest that downregulated CD99 leads to the prevention of plasma-cell differentiation in Hodgkin/Reed-Sternberg (H/RS) cells. Furthermore, these data indicate that CD99 may control miR-9 expression, which directly targets PRDM1. Altogether, these results reveal a CD99-miR-9-PRDM1 molecule axis in lymphomagenesis of cHL and suggest that upregulation of CD99 in H/RS cells induces terminal B-cell differentiation, which may provide a novel therapeutic strategies for cHL. | Is CD99 encoded by MIC2 gene? | 55376b37bc4f83e82800000b_018 | yes |
Panoramix enforces piRNA-dependent cotranscriptional silencing. The Piwi-interacting RNA (piRNA) pathway is a small RNA-based innate immune system that defends germ cell genomes against transposons. In Drosophila ovaries, the nuclear Piwi protein is required for transcriptional silencing of transposons, though the precise mechanisms by which this occurs are unknown. Here we show that the CG9754 protein is a component of Piwi complexes that functions downstream of Piwi and its binding partner, Asterix, in transcriptional silencing. Enforced tethering of CG9754 to nascent messenger RNA transcripts causes cotranscriptional silencing of the source locus and the deposition of repressive chromatin marks. We have named CG9754 "Panoramix," and we propose that this protein could act as an adaptor, scaffolding interactions between the piRNA pathway and the general silencing machinery that it recruits to enforce transcriptional repression. | Are piRNAs involved in gene silencing? | 56c6f6005795f9a73e000009_008 | yes |
Effect on weakness and spasticity in amyotrophic lateral sclerosis of thyrotropin-releasing hormone. Very high intravenous doses (2-19 mg/min) of thyrotropin-releasing hormone (TRH, L-pyroglutamyl-L-histidyl-L-prolinamide) given to 12 patients with amyotrophic lateral sclerosis (ALS) produced a moderate to marked improvement of functions caused by deficiency of lower motor neurons (weakness) and upper motor neurons (spasticity). The improvement was sustained throughout the infusion and for about 1 h thereafter; sometimes a slight improvement was evident 20 h after infusion. At a given dose benefits and side-effects were more evident in men than in women. Whether TRH is replacing an ALS-associated deficiency or is simply a symptomatic treatment is unknown. The results of this study raise the possibility of a treatment for ALS, and may provide new insight into its pathogenesis. The potential response to TRH of spasticity and/or lower motor neuron involvement of other causes is proposed. | Is there any data to suggest that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients? | 54d76ac63706e89528000016_015 | yes |
A double-blind, placebo-controlled trial of TRH in amyotrophic lateral sclerosis. A double-blind, placebo-controlled trial of single doses of thyrotropin releasing hormone (TRH) was performed on 12 patients with amyotrophic lateral sclerosis. Each patient was given subcutaneous injections of TRH 150 mg or placebo, and IV infusions of TRH 500 mg or placebo at 72- to 96-hour intervals. Eight motor and functional ratings were scored at regular intervals after each injection. Side effects were seen in all patients and were obvious to patients and examiners, making true blinding impossible. Nevertheless, statistically significant improvement was seen only in dynametric strength 1 hour after subcutaneous injection (p less than 0.05). Significant improvement occurred, in one patient only, on subjective speech testing during IV infusion of TRH. In none of six other ratings was there a significant difference between TRH and placebo. Subjective improvement was noted by 11 of 12 patients. | Is there any data to suggest that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients? | 54d76ac63706e89528000016_027 | yes |
Oral clonidine vs midazolam in the prevention of sevoflurane-induced agitation in children. a prospective, randomized, controlled trial. BACKGROUND: This randomized, double-blind study tested the hypothesis that, in comparison with midazolam, premedication with oral clonidine reduces the incidence of emergence agitation in preschool children anaesthetized with sevoflurane. METHODS: Sixty-eight ASA I-II children undergoing circumcision were randomized into three groups to receive different oral premedication given 30 min before anaesthesia: midazolam 0.5 mg kg-1, clonidine 2 microg kg-1, and clonidine 4 microg kg-1. Sevoflurane anaesthesia was administered via a facemask (O2/N2O: 40/60). Analgesia was with penile block (bupivacaine 0.5% 0.3 ml kg-1) and rectal paracetamol (30 mg kg-1). During the first postoperative hour, children were evaluated using a modified 'objective pain scale'. RESULTS: Only the 4 microg kg-1 dose of clonidine was associated with a significant reduction in emergence agitation. Fewer children in the clonidine 4 microg kg-1 group displayed agitation (25%) than in the midazolam group (60%) (P=0.025). Incidence of hypotension and bradycardia, time to first micturition and first drink did not differ among groups. CONCLUSIONS: In comparison with midazolam, clonidine 4 microg kg-1 reduced sevoflurane-induced emergence agitation without increasing postoperative side-effects. | Can clonidine be used to reduce agitation in children. | 515df89e298dcd4e5100002f_007 | yes |
Pharmacological modulation of the state of awareness in patients with disorders of consciousness: an overview. The neurobiological approach to consciousness moves from the assumption that all phenomenal experiences are based on neuronal activity in the brain. Consciousness has two main components: wakefulness and awareness. While it may be relatively easy to determine the neuronal correlates of wakefulness, it is not the same for awareness, of which the neural correlates are poorly understood. Knowledge of the circuitry and the neurochemistry of the sleep/wake condition is necessary but not sufficient to understand the circuitry and neurochemistry of consciousness. Disorders of consciousness (DOCs) include coma, vegetative state and minimally conscious state. The study of DOCs and of the electrophysiological changes underlying general anaesthesia-induced loss of consciousness may help in understanding the neuronal correlates of consciousness. In turn, the understanding of the neural bases of consciousness may help in designing interventions aimed at restoring consciousness in DOC patients. Sporadic cases of recovery from a DOC have been reported after the administration of various pharmacological agents (baclofen, zolpidem, amantadine etc.). This review provides an overview of such drugs, which are from various and diverging classes but can be grouped into two main categories: CNS stimulants and CNS depressants. The available data seem to suggest an awakening effect obtained with CNS depressants rather than stimulants, the latter being more effective at improving functional cognitive and behavioral recovery in patients who have spontaneously regained an appreciable level of consciousness. There is a need for more rigorous systematic trials and further investigation of the above treatments, with particular attention paid to their mechanisms of action and the neurotransmitters involved. | Is amantadine effective for treatment of disorders conciousness? | 530f7cdde3eabad021000001_001 | yes |
Curcumin Suppresses Metastasis via Sp-1, FAK Inhibition, and E-Cadherin Upregulation in Colorectal Cancer. Colorectal cancer (CRC) is a serious public health problem that results due to changes of diet and various environmental stress factors in the world. Curcumin is a traditional medicine used for treatment of a wide variety of tumors. However, antimetastasis mechanism of curcumin on CRC has not yet been completely investigated. Here, we explored the underlying molecular mechanisms of curcumin on metastasis of CRC cells in vitro and in vivo. Curcumin significantly inhibits cell migration, invasion, and colony formation in vitro and reduces tumor growth and liver metastasis in vivo. We found that curcumin suppresses Sp-1 transcriptional activity and Sp-1 regulated genes including ADEM10, calmodulin, EPHB2, HDAC4, and SEPP1 in CRC cells. Curcumin inhibits focal adhesion kinase (FAK) phosphorylation and enhances the expressions of several extracellular matrix components which play a critical role in invasion and metastasis. Curcumin reduces CD24 expression in a dose-dependent manner in CRC cells. Moreover, E-cadherin expression is upregulated by curcumin and serves as an inhibitor of EMT. These results suggest that curcumin executes its antimetastasis function through downregulation of Sp-1, FAK, and CD24 and by promoting E-cadherin expression in CRC cells. | Is the protein FAK (Focal Adhesion Kinase) phosphorylated? | 54f4c382d0d681a040000006_010 | yes |
New advances in the DNA damage response network of Fanconi anemia and BRCA proteins. FAAP95 replaces BRCA2 as the true FANCB protein. Fanconi anemia (FA) proteins function in a DNA damage response pathway that appears to be part of the network including breast cancer susceptibility gene products, BRCA1 and BRCA2. In response to DNA damage or replication signals, a nuclear FA core complex of at least 6 FA proteins (FANCA, FANCC, FANCE, FANCF, FANCG and FANCL) is activated and leads to monoubiquitination of the downstream FA protein, FANCD2. One puzzling question for this pathway is the role of BRCA2. A previous study has proposed that BRCA2 could be identical to two FA proteins: FANCD1, which functions either downstream or in a parallel pathway; and FANCB, which functions upstream of the FANCD2 monoubiquitination. Now, a new study shows that the real FANCB protein is not BRCA2, but a previously uncharacterized component of the FA core complex, FAAP95, suggesting that BRCA2 does not act upstream of the FA pathway. Interestingly, the newly discovered FANCB gene is X-linked and subject to X-inactivation. The presence of a single active copy of FANCB and its essentiality for a functional FA-BRCA pathway make it a potentially vulnerable component of the cellular machinery that maintains genomic integrity. | Are the Fanconi anemia genes a part of the same signalling pathway? | 54f42f2764850a5854000005_001 | yes |
Human antigen R mediated post-transcriptional regulation of epithelial-mesenchymal transition related genes in diabetic nephropathy. BACKGROUND: Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein that modulates gene expression at the post-transcriptional level. While cytoplasmic HuR expression was identified as a marker in epithelial-mesenchymal transition (EMT) process of several types of cancer, its role in diabetic nephropathy (DN) remains unclear. METHODS: Renal biopsies from Type 2 diabetic patients and STZ-induced DN rats were stained for HuR and EMT markers. Redistribution of HuR was detected by immunostaining and western blot in high glucose stimulated cells. RNAi was used to supress HuR expression. The binding affinity for EMT-related genes was evaluated by immunoprecipitation. RESULTS: Cytoplasmic HuR expression was elevated in human and rat DN specimens along with EMT changes compared to normal controls. HuR shuttling between nucleus and cytoplasm facilitated epithelial to mesenchymal transition in renal epithelial cells. The suppression of HuR partially inhibited EMT of high glucose stimulated HK-2 cells. Furthermore, HuR bound to 3'-UTRs of critical cytokines or transcription factors mRNA involved in EMT process. CONCLUSION: Acquired phenotypic traits of EMT were partially through the enhanced HuR-binding proteins and its post-transcriptional regulation role in DN. | Does HuR bind to the untranslated regions (UTRs) of mRNAs? | 58ce69cd1f5fb2b734000003_000 | yes |
Agitation and changes of Bispectral Index and electroencephalographic-derived variables during sevoflurane induction in children: clonidine premedication reduces agitation compared with midazolam. BACKGROUND: This double-blind randomized study was undertaken to assess agitation, Bispectral Index (BIS) and EEG changes during induction of anaesthesia with sevoflurane in children premedicated with midazolam or clonidine. METHODS: Children were allocated randomly to receive rectal midazolam 0.4 mg kg(-1) (n=20) or oral clonidine 4 microg kg(-1) (n=20) as premedication. Rapid induction of anaesthesia was achieved with inhalation of sevoflurane 8% in nitrous oxide 50%-oxygen 50%. After tracheal intubation, the children's lungs were mechanically ventilated and the inspired sevoflurane concentration was adjusted to achieve an end-tidal fraction of 2.5%. The EEG and BIS were recorded during induction until 10 min after tracheal intubation. The EEG was analysed using spectral analysis at five points: baseline, loss of eyelash reflex, 15 s before the nadir of the BIS (BIS(nadir)), when both pupils returned to the central position (immediately before intubation), and 10 min after intubation. RESULTS: Agitation was observed in 12 midazolam-treated and five clonidine-treated patients (P=0.05). At baseline, EEG rhythms were slower in the clonidine group. Induction of anaesthesia was associated with similar EEG changes in the two groups, with an increase in total spectral power and a shift towards low frequencies; these changes were maximal around the end of the second minute of induction (BIS(nadir)). When the pupils had returned to the central position, fast EEG rhythms increased and BIS was higher than BIS(nadir) (P<0.05). In both groups, agitation was associated with an increase in slow EEG rhythms at BIS(nadir). CONCLUSIONS: Compared with midazolam, clonidine premedication reduced agitation during sevoflurane induction. During induction with sevoflurane 8% (oxygen 50%-nitrous oxide 50%), the nadir of the BIS occurred at the end of the second minute of inhalation. Agitation was associated with a more pronounced slowing of the EEG rhythms at BIS(nadir) compared with inductions in which no agitation was observed. The BIS may not follow the depth of anaesthesia during sevoflurane induction in children. | Can clonidine be used to reduce agitation in children. | 515df89e298dcd4e5100002f_004 | yes |
Perineal cellulitis following trans-obturator sub-urethral tape Uratape. OBJECTIVE: We report two cases of perineal cellulitis due to the surgical treatment of female stress urinary incontinence with a trans-obturator sub-urethral tape of Uratape (Porgés). METHODS: Treatment and follow up of their complication were performed at the CHRU of Lille. RESULTS: In both cases, this complication is related to prolonged vaginal exposition of the tape. Vaginal erosion always occurs next to the silicon coated section of the tape. CONCLUSION: Such a complication has never been described yet. It shows a lack of data concerning human tissue tolerance of sub-urethral tapes constituents. Such examples should call for caution against new materials, all the more so as they have not yet been validated by large scale studies. | Has silicon been used in treatment of incontinence ? | 536172d17d100faa09000009_002 | yes |
Propranolol for infantile hemangiomas. Propranolol has been used successfully in a limited number of children with infantile hemangiomas. This multicenter retrospective study describes the efficacy and adverse effects of propranolol in infantile hemangioma. Seventy-one infants with infantile hemangiomas were treated with oral propranolol, 1 mg/kg/12 hours, for at least 12 weeks. A photograph based severity scoring assessment was performed by five observers to evaluate efficacy, utilizing a scoring system of 10 as the original infantile hemangioma before treatment and 0 as completely normal skin. The mean of the five independent measurements was used in the analysis. Propranolol was a rapid and effective treatment for infantile hemangiomas at 4 weeks (p < 0.001), at 8 weeks (p < 0.001 compared to the 4 wks value), at 12 weeks (p < 0.05 compared to the 8 wks value), and thereafter up to 32 weeks (p < 0.01 compared to the 16 wks value). The response of infantile hemangiomas to propranolol was similar regardless of sex, age at onset of treatment, type of involvement (segmental and nonsegmental), facial segments affected, special locations (eyelid, nasal tip, and parotid region), ulceration, and depth of infantile hemangiomas. Very few side effects were reported; mainly agitated sleep in 10 of 71 patients. In the series of patients in this study, oral propranolol 2 mg/kg/day was a well-tolerated and effective treatment for infantile hemangiomas. Prospective studies are needed to establish the exact role of propranolol in the treatment of infantile hemangiomas. | Is propranolol used for treatment of infantile hemangioma? | 5a67a72fb750ff445500000a_003 | yes |
Effectiveness of antiangiogenic drugs in glioblastoma patients: A systematic review and meta-analysis of randomized clinical trials. BACKGROUND: glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients. PATIENTS AND METHODS: we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. RESULTS: fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001). CONCLUSIONS: antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy. | Is dasatinib effective for treatment of glioblastoma? | 5a760ed883b0d9ea66000019_000 | no |
The circadian clock and tumor suppression by mammalian period genes. Period (Per) genes are key circadian rhythm regulators in mammals. Expression of mouse Per (mPer) genes has a diurnal pattern in the suprachiasmatic nucleus and in peripheral tissues. Genetic ablation mPER1 and mPER2 function results in a complete loss of circadian rhythm control based on wheel-running activity in mice. In addition, these animals also display apparent premature aging and a significant increase in neoplastic and hyperplastic phenotypes. When challenged by gamma radiation, mPer2-deficient mice respond by rapid hair graying, are deficient in p53-mediated apoptosis in thymocytes, and have robust tumor occurrences. Studies have demonstrated that the circadian clock function is very important for cell cycle, DNA damage response, and tumor suppression in vivo. The temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2, and Gadd45alpha, is deregulated in mPer2 mutant mice. Genetic studies have demonstrated that many key regulators of cell cycle and growth control are also important circadian clock regulators, confirming the critical role of circadian function in organismal homeostasis. | Is c-myc subject to regulation by the circadian clock? | 531616bdb166e2b806000003_007 | yes |
Nuclear repulsion enables division autonomy in a single cytoplasm. BACKGROUND: Current models of cell-cycle control, based on classic studies of fused cells, predict that nuclei in a shared cytoplasm respond to the same CDK activities to undergo synchronous cycling. However, synchrony is rarely observed in naturally occurring syncytia, such as the multinucleate fungus Ashbya gossypii. In this system, nuclei divide asynchronously, raising the question of how nuclear timing differences are maintained despite sharing a common milieu. RESULTS: We observe that neighboring nuclei are highly variable in division-cycle duration and that neighbors repel one another to space apart and demarcate their own cytoplasmic territories. The size of these territories increases as a nucleus approaches mitosis and can influence cycling rates. This nonrandom nuclear spacing is regulated by microtubules and is required for nuclear asynchrony, as nuclei that transiently come in very close proximity will partially synchronize. Sister nuclei born of the same mitosis are generally not persistent neighbors over their lifetimes yet remarkably retain similar division cycle times. This indicates that nuclei carry a memory of their birth state that influences their division timing and supports that nuclei subdivide a common cytosol into functionally distinct yet mobile compartments. CONCLUSIONS: These findings support that nuclei use cytoplasmic microtubules to establish "cells within cells." Individual compartments appear to push against one another to compete for cytoplasmic territory and insulate the division cycle. This provides a mechanism by which syncytial nuclei can spatially organize cell-cycle signaling and suggests size control can act in a system without physical boundaries. | Has the fungus Ashbya gossypii got many nuclei that share cytoplasm? | 550e6688a103b7801600000d_009 | yes |
On avoided words, absent words, and their application to biological sequence analysis. BACKGROUND: The deviation of the observed frequency of a word w from its expected frequency in a given sequence x is used to determine whether or not the word is avoided. This concept is particularly useful in DNA linguistic analysis. The value of the deviation of w, denoted by [Formula: see text], effectively characterises the extent of a word by its edge contrast in the context in which it occurs. A word w of length [Formula: see text] is a [Formula: see text]-avoided word in x if [Formula: see text], for a given threshold [Formula: see text]. Notice that such a word may be completely absent from x. Hence, computing all such words naïvely can be a very time-consuming procedure, in particular for large k. RESULTS: In this article, we propose an [Formula: see text]-time and [Formula: see text]-space algorithm to compute all [Formula: see text]-avoided words of length k in a given sequence of length n over a fixed-sized alphabet. We also present a time-optimal [Formula: see text]-time algorithm to compute all [Formula: see text]-avoided words (of any length) in a sequence of length n over an integer alphabet of size [Formula: see text]. In addition, we provide a tight asymptotic upper bound for the number of [Formula: see text]-avoided words over an integer alphabet and the expected length of the longest one. We make available an implementation of our algorithm. Experimental results, using both real and synthetic data, show the efficiency and applicability of our implementation in biological sequence analysis. CONCLUSIONS: The systematic search for avoided words is particularly useful for biological sequence analysis. We present a linear-time and linear-space algorithm for the computation of avoided words of length k in a given sequence x. We suggest a modification to this algorithm so that it computes all avoided words of x, irrespective of their length, within the same time complexity. We also present combinatorial results with regards to avoided words and absent words. | Is there any linear-time and linear-space algorithm for the computation of avoided words in biological sequences? | 5a6d022ab750ff445500002a_000 | yes |
Percutaneous vertebroplasty as treatment for Kummell's disease. We report a case with classic clinical findings and imaging features of Kummell's disease. Kummell's disease is a post-traumatic vertebral body collapse. Initially after the trauma patients are usually asymptomatic but after months they develop a symptomatic and progressive kyphosis of the lower thoracic or lumbar spine. On a conventional radiograph a collapsed vertebral body with a fracture cleft is typical and on MRIT2 weighted images the double line sign is characteristic for Kummell's disease; an increased linear area of hyper-intensity surrounded by an area of low signal. Percutaneous vertebroplasty is an adequate treatment for stabilization of the fracture and pain reduction in patients with Kummell's disease. | Is Kummell’s disease an avascular necrosis of the vertebral body? | 5a787544faa1ab7d2e00000b_001 | yes |
[Diagnostic value of cystatin C and neutrophil gelatinase-associated lipocalin in primary glomerulopathies]. AIM: To study an association between clinical and morphological evidence and the serum and daily urinary levels of cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) in patients with primary glomerulopathies. SUBJECTS AND METHODS: The investigation included 104 patients; morphological examination showed minimal change disease in 15 (14.4%) patients, focal segmental glomerulosclerosis in 24 (23.1%), membrane nephropathy in 32 (30.8%), and IgA nephropathy (mesangioproliferative glomerulonephritis) in 33 (31.7%). The investigators analyzed the clinical type of nephropathy, performed conventional laboratory and instrumental examinations, and determined the level of CysC (by immunoturbodimetry) and NGAL (by enzyme immunoassay) in the serum and daily urine taken before kidney biopsy. The degree of glomerulosclerosis, tubulointerstititial sclerosis, and tubular atrophy was semiquantitatively estimated. RESULTS: Urinary CysC and NGAL excretion correlated with the degree of glomerulosclerosis and proteinuria and the reduced glomerular filtration rate (GFR) regardless of the method of its determination. The urinary level of NGAL positively correlated with the degree of tubular atrophy. The GFR value determined from serum CysC and creatinine levels more precisely reflected the degree of glomerulosclerosis. CONCLUSION: The tubulointerstitial compartment in primary glomerulopathies should be determined not only by morphological changes, but also by tubular function parameters by estimating the urinary excretion of biomarkers. The urinary content of CysC reflects tubular epithelial dysfunction whereas that of NGAL also characterizes tubular atrophy. To estimate the degree of glomerulosclerosis, it is more preferable to use the GFR calculated from the blood concentrations of CysC and creatinine, by keeping in mind clinical findings (using Chronic Kidney Disease Epidemiology Collaboration formula, 2012). | Is cystatin C or cystatin 3 used as a biomarker of kidney function? | 550bf315c2af5d5b7000000e_004 | yes |
[Nervous system lesions in the female workers of hydroponic hothouses]. A follow-up (1985, 1990, 1991) study revealed in female workers of hydroponic hothouses an increase of the incidence of nervous system diseases depending on the length of work (vegeto-vascular dystonia, angiodystonic syndromes, vegeto-sensory polyneuropathy). It is suggested that the main cause of nervous lesions in these cases was the complex effect of pesticides. | Is pesticide exposure associated with polyneuropathy? | 530cefaaad0bf1360c000010_012 | yes |
Channelopathies: Brugada syndrome, long QT syndrome, short QT syndrome, and CPVT. 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 (SQTS), and catecholaminergic polymorphic ventricular tachyarrhythmias (CPVT). 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. Young, otherwise healthy individuals are likely to be involved in sports activity. Therefore, special attention has to be given to advise these patients. Competitive sports and vigorous exercise are contraindications in almost all patients. Even recreational exercise may have to be avoided in phenotypically overt patients or silent gene carriers depending on the underlying disease. | Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
cause sudden cardiac death? | 52e8e96698d023950500001f_011 | yes |
Eight full-length abelson related gene (Arg) isoforms are constitutively expressed in caki-1 cell line and cell distribution of two isoforms has been analyzed after transfection. The human Arg (Abl2) nonreceptor tyrosine kinase has a role in cytoskeletal rearrangements by its C-terminal F-actin- and microtubule-binding sequences. We have previously identified Arg transcripts with different 5'- and 3'-ends, named respectively long and short 1A and 1B (1AL, 1AS, 1BL, 1BS) and long and short C-termini (CTL and CTS), that have different expression patterns in various cell types. The combination of the different ends permits to predict eight putative full-length Arg transcripts and corresponding proteins. By Reverse Transcription-Long PCR we show here that all eight full-length transcripts are endogenously expressed in Caki-1 cells and the two bands, approximately 10 kDa different, shown by 1-D Western blots of Hek293T and Caki-1 lysates correspond to the full-length Arg protein isoforms with different C-termini. 2-D Western blot analysis evidenced different high molecular weight and slight acidic specific spots in Hek293T and Caki-1 lysates. The cellular localization of two Arg isoforms (1BLCTL and 1BLCTS) transfected in Caki-1 and Hek293T cells was cytoplasmic, and some differences in cytoskeleton interactions have been evidenced. Moreover, in Hek293T cells only the transfected 1BLCTS isoform gives rise to a large intracytoplasmic cylindrical structure containing phalloidin-positive amorphous actin aggregates. The presence of eight full-length Arg isoforms with different cellular expression may imply a diverse functional role in normal and neoplastic cells. | Does the Abelson-related gene (ARG) gene encode for a serine kinase? | 58db94948acda34529000017_003 | no |
ATF4 regulates CCL2 expression to promote endometrial cancer growth by controlling macrophage infiltration. Activating transcription factor 4 (ATF4), an endoplasmic reticulum stress-inducible transcription factor, plays important roles in cancer progression and resistance to therapy. However, no report is available about its roles in endometrial cancer (EC). In this study, we found that ATF4 is commonly expressed in EC cell lines. Loss-of-function studies in two EC cell lines showed that ATF4 knockdown suppresses tumor growth of EC in vivo without influencing cell proliferation in vitro. And xenograft tumors derived from ATF4-knockdown cells had reduced M2 macrophage infiltration. In clinical specimens, ATF4-high expressing tumors indeed contained more macrophage infiltration compared to those with lower ATF4 expression. Moreover, we identified that ATF4-mediated chemokine CCL2 expression ultimately results in macrophage infiltration and tumor growth of EC. Taken together, our findings suggest that ATF4 contributes to tumor growth of EC by promoting CCL2 and subsequent recruitment of macrophage, and that ATF4/CCL2 axis might be a potential therapeutic target for EC. | Has ATF4 transcription factor been linked to cancer and neoplastic transformation? | 5a773c50faa1ab7d2e000002_006 | yes |
Differentiation, extracellular matrix synthesis, and integrin assembly by Drosophila embryo cells cultured on vitronectin and laminin substrates. Two contrasting substrates, Drosophila laminin and human vitronectin, caused determined primary Drosophila embryo cells to follow alternate intermediate differentiation steps without affecting the final outcome of differentiation. Integrin alpha PS2 beta PS3 was essential for the initial spreading of myocytes on vitronectin: focal contacts rich in beta PS3 integrins formed and were connected by actin- and myosin-containing stress fibers. While alpha PS2 beta PS3 was unnecessary for myotube formation on laminin, it was required for the subsequent change to a sarcomeric cytoarchitecture. The differentiating primary cultures synthesized integrins and assembled them into detergent-insoluble, cytoskeleton-associated complexes. Collagen IV, laminin, glutactin, papilin, and other extracellular matrix proteins were made primarily by hemocytes and were secreted into the medium. Further differentiation within the cultures was influenced by secreted components and by later addition of vitronectin or bovine serum. Comparison of the differentiation of various cell types on the two substrates showed that vitronectin provided a selective advantage for the differentiation of myocytes, with enrichment over epithelia, epidermal cells, and neurites. | Is the protein Papilin secreted? | 54e25eaaae9738404b000017_007 | yes |
STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome--result of Japanese cohort study. We performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox-Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct-sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause. | Are mutations in the STXBP1 gene associated with epilepsy? | 550748a3bde8548216000001_004 | yes |
Clinical application of adult stem cells for therapy for cardiac disease. INTRODUCTION: Cardiovascular disease is a major cause of death worldwide. Different medical and surgical therapeutic options are well established, but a significant number of patients are not amenable to standard therapeutic options. Cell-based therapies after clinical application have shown different results in recent years. Here, we are giving a comprehensive overview on major available clinical data regarding cell therapy. BACKGROUND: Cell-based therapies and tissue engineering provide new promising platforms to develop upcoming therapeutic options. Initial clinical trials were able to generate promising results. A variety of different stem cell types have been used for the clinical application. Different adult cardiac stem cells and progenitor cells, including mesenchymal, CD34(+) and CD133(+) autologous human bone marrow-derived stem cells (BMCs), human myoblasts, and peripheral blood-derived stem and progenitor cells (PBSCs) have been used for the therapy for end-stage heart failure. Future experiments will show the importance of novel cell populations and clarify the mechanism causing cell therapy-mediated observed effects. CONCLUSION: Several clinical trials have reported on sole therapy, as well as combined application of autologous adult stem cells with conventional revascularization. The reported promising findings encourage further research in the field of the translational research. | Are there clinical trials using stem cells for the treatment of cardiac disease? | 56f160a52ac5ed1459000013_015 | yes |
Ophthalmologic abnormalities in Mowat-Wilson syndrome and a mutation in ZEB2. Mowat-Wilson syndrome is a genetic disorder characterized by a distinct facial appearance, moderate-to-severe mental retardation, microcephaly, agenesis of the corpus callosum, Hirschsprung disease, congenital heart disease, and genital anomalies. Ophthalmological abnormalities have been rarely described in patients with this condition which is caused by mutations in the ZEB2 gene. We report a 9-year-old female with this syndrome who has severe ocular abnormalities including bilateral microphthalmia, cataract, and retinal aplasia. | Is Hirschsprung disease one of the characteristics of the Mowat-Wilson syndrome? | 55001420e9bde69634000005_012 | yes |
Does laryngopharyngeal reflux cause intraoral burning sensations? A preliminary study. Intraoral burning sensations are a common problem in the otolaryngological practice. The aim of this study was to evaluate if laryngopharyngeal reflux can cause intraoral burning sensations by measuring oropharyngeal acid reflux. Patients with recurring intraoral burning sensations underwent oropharyngeal pH monitoring in our outpatient clinic. The pH catheter was placed at the level of the uvula. The catheter contained an externally worn transmitter, which wirelessly sent the data to a monitor. In addition, patients were instructed to indicate meals or the occurrence of burning sensations by pressing provided buttons on the monitor. Corresponding events of burning sensations and a significant decrease in oropharyngeal pH values should be visualized. Twenty two patients suffering from recurring intraoral burning sensations underwent oropharyngeal pH measurement for 21-25 h. We could find oropharyngeal reflux episodes in 11 patients. However, we could not detect any episodes of burning sensations in the mouth corresponding with a decrease in oropharyngeal pH values. Our results suggest that there is no causal connection between LPR episodes and the occurrence of intraoral burning sensations in the examined patients. Although further studies with more patients are necessary in the future, we conclude from our findings that recurring intraoral burning sensations are not an indication for proton pump inhibitor therapy. | Is gastro esophageal reflux related to burning mouth syndrome? | 5321ae889b2d7acc7e000006_001 | no |
Treatment of giant-cell arteritis, a literature review. Giant-cell arteritis (GCA) is the most common vasculitis in people aged more than 50 years. Despite the frequency of this disease, there is currently no international consensus on its therapeutic modalities. The aim of this study was to conduct a review on an international literature about the treatment of GCA, whatever the clinical pattern might be. Oral corticosteroids remain the cornerstone treatment, possibly preceded by intravenous bolus in complicated forms. In cases of glucocorticoid (GC) dependence or GC-related side effects, a GC-sparing agent may be necessary. Methotrexate is one of the most used treatments despite its low level of evidence and mild efficacy. Cyclophosphamide and tocilizumab look promising but require validation in further studies. The results for TNF-α blockers and azathioprine are disappointing. Preventing complications of prolonged corticosteroid therapy is a world challenge and the management of GC-induced osteoporosis is not the same from one country to another. There is a significant risk of arterial thrombosis, mainly at treatment onset, which may encourage to associate an antiplatelet therapy, especially in patients with other cardiovascular risk factors. Place of statins in the treatment of the disease is uncertain. | Is Tocilizumab effective for Giant-Cell Arteritis? | 5a733d2a2dc08e987e000015_009 | yes |
Polyadenylation creates the discriminator nucleotide of chicken mitochondrial tRNA(Tyr). In the chicken mitochondrial genome, the gene for tRNA(Tyr) overlaps by one nucleotide with the downstream tRNA(Cys) gene, which is located on the same strand. The overlapping nucleotide, a guanosine residue, thus encodes both the discriminator base of the tRNA(Tyr) and the 5'base of the tRNA(Cys). When cDNA clones of circularized forms of the tRNA(Tyr) are analyzed, the discriminator nucleotide is an adenosine residue rather than the genomically encoded guanosine. Thus, the tRNA(Tyr) is subjected to an RNA editing activity similar to that shown to exist in the mitochondria of two other animal species. Interestingly, some cDNA clones have several adenosine residues at their 3'-ends instead of the expected CCA-sequence. Furthermore, a review of sequence data from animal mitochondrial genomes suggests that only tRNAs whose discriminator bases are adenosines tend to have genes that overlap with downstream genes. Thus, polyadenylation seems to be a major component of the RNA editing machinery that affects overlapping genes in animal mitochondria. | Is polyadenylation a process that stabilizes a protein by adding a string of Adenosine residues to the end of the molecule? | 5a8714e261bb38fb24000005_018 | no |
Recent advances in plasmepsin medicinal chemistry and implications for future antimalarial drug discovery efforts. Plasmepsins are the aspartic proteases of Plasmodium that play key roles in the survival of the parasite in its host. The plasmepsins of the digestive vacuole play an important role in hemoglobin degradation, providing the parasite with a vital source of nutrients. Recently, plasmepsin V has been shown to be an essential protease, processing hundreds of parasite proteins for export into the host erythrocyte. The functions of the remaining plasmepsins have yet to be discovered. Over the past decade, much effort has been placed towards developing plasmepsin inhibitors as antimalarial agents, particularly targeting the digestive vacuole. This review will highlight some of the recent work in this field with a particular focus on target druggability and strategies for identifying plasmepsins inhibitors as effective antimalarial drugs. Given recent advances in understanding the fundamental roles of the various plasmepsins, it is likely that the most effective antimalarial plasmepsin targets will be the non-digestive vacuole plasmepsins. | Could plasmepsins be used as targets for developing anti-malaria drugs? | 58a6d89660087bc10a00002b_009 | yes |
Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation. The cellular response to Nutlin-3, a small-molecule inhibitor of the p53 repressor MDM2, varies widely among human cancer-derived cell types. Whereas HCT116 colorectal carcinoma cells display sustained cell cycle arrest, BV173 leukemia cells undergo rapid apoptosis and other cell lines show an intermediate response. We found that the expression of the p53 target genes p21, 14-3-3sigma and the microRNA miR-34a correlates tightly with the cell fate choice adopted. All three genes were strongly induced in arresting cells, but silenced in cells undergoing Nutlin-3-induced apoptosis. In contrast, key apoptotic p53 target genes were equally expressed in arresting and apoptotic cells. Interestingly, we establish that miR-34a cooperates with p21 and 14-3-3sigma to override the apoptotic signals generated by p53 activation. Strikingly, p53 binding to chromatin and p53-mediated recruitment of certain coactivators to all three target loci does not vary among cell types. Instead, the cell type-specific silencing of these genes is due to enhanced p21 mRNA degradation, 14-3-3sigma promoter DNA methylation and reduced processing of the miR-34a primary transcript. Thus, p53-independent events regulating expression of protein-coding genes and microRNAs within the network can define the cellular outcome of p53 activation. | Are microRNA (miR) regulated through DNA methylation of their promoters? | 53636e727d100faa0900000d_004 | yes |
Relationship between C-reactive protein, systemic oxygen consumption, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is known to result in elevated systemic oxygen consumption (Vo(2)) and increases in high-sensitivity C-reactive protein (hsCRP), although the relationship among hsCRP, Vo(2), and delayed cerebral ischemia (DCI) after SAH remains unknown. We hypothesized that hsCRP is directly associated with Vo(2) and that elevated Vo(2) is a predictor of DCI after SAH. METHODS: Prospective serial assessments of Vo(2) and hsCRP over 4 prespecified time periods during the first 14 days after bleed in consecutive SAH patients admitted to a single academic medical center for a 2-year period. RESULTS: One hundred ten SAH patients met study criteria (mean age, 55±16 years; 62% women), with a median admission Hunt Hess grade of 3 (interquartile range, 2-4). In multivariate generalized estimating equation model of the first 14 days after bleed, Vo(2) was associated with younger age (P=0.01), male gender (P=0.01), and hsCRP levels (P=0.03). Twenty-four (22%) patients had DCI develop, with a median onset on day 7 after bleed (interquartile range, 5-11). The mean Vo(2) (291±65 mL/min versus 226±55 mL/min; P=0.003) was higher in DCI patients. In a multivariable Cox proportional hazards model, younger age (hazard ratio, 1.2 per 5 years; 95% CI, 1.1-1.3), a higher modified Fisher scale score (hazard ratio, 3.4 per 1-point increase; 95% CI, 1.7-6.9), and higher Vo(2) (HR, 1.2 per 50-mL/min increase; 95% CI, 1.1-1.3) were predictive of DCI. CONCLUSIONS: Systemic oxygen consumption is associated with hsCRP levels in the first 14 days after SAH and is an independent predictor of DCI. | Is there an association between c-reactive protein concentrations and outcomes of subarachnoid hemorrhage patients? | 514cbbf9d24251bc05000065_008 | yes |
Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response. | Is there a relationship between B cells and Multiple Sclerosis? | 58c0836102b8c6095300001c_002 | yes |
Long noncoding RNAs in the p53 network. The tumor-suppressor protein p53 is activated in response to numerous cellular stresses including DNA damage. p53 functions primarily as a sequence-specific transcription factor that controls the expression of hundreds of protein-coding genes and noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). While the role of protein-coding genes and miRNAs in mediating the effects of p53 has been extensively studied, the physiological function and molecular mechanisms by which p53-regulated lncRNAs act is beginning to be understood. In this review, we discuss recent studies on lncRNAs that are directly or indirectly regulated by p53 and how they contribute to the biological outcomes of p53 activation. WIREs RNA 2017, 8:e1410. doi: 10.1002/wrna.1410 For further resources related to this article, please visit the WIREs website. | Is p53 a transcription factor? | 5ac0817cd0c506ce46000001_001 | yes |
With a Little Help from my Enteric Microbial Friends. Although the disciplines of bacteriology and virology frequently come together in the setting of a diagnostic medical microbiology laboratory, the two scientific fields are usually miles apart. The microbiologists basically form two non-overlapping groups of scientists, the bacteriologists and virologists, which go to separate meetings and do not easily intermingle. Some recent research findings about elegant virus-bacterium interactions may change this situation. Obviously, interactions between these two microbes can occur only when they colocalize, which most likely occurs in the gut/intestines where 10(14) commensal bacteria reside (the microbiota). We review findings on the following enteric microbial tandems: norovirus - Enterobacter cloacae, mouse mammary tumor virus (MMTV) - bacterial lipopolysaccharide (LPS), poliovirus and reovirus - intestinal bacteria. The close bacterium-virus interplay may also present options to develop unique therapeutic strategies for those infected, and to prevent further virus spread, and thus minimize the risk for the community. | Is LPS a microbial product? | 56e6f419a12c1fc13b000002_002 | yes |
Chromatin-modifying enzymes as therapeutic targets--Part 2. BACKGROUND: Part 1 of this review described the importance of histone acetylases, deacetylases, methylases and demethylases in transcriptional control and their potential as therapeutic targets. However, precise gene regulation requires the involvement of more than just the addition or removal of acetyl and methyl groups on histones. Histone phosphorylation, ubiquitylation, SUMOylation and poly-ADP-ribosylation, as well as ATP-dependent nucleosome remodeling complexes, play equally pivotal roles in the maintenance of transcriptional fidelity. Accordingly, the enzymes responsible for these modifications are also misregulated in various disease states. OBJECTIVE: To review the complex roles of chromatin-modifying enzymes in gene regulation and to highlight their potential as therapeutic targets. METHODS: This review is based on recent published literature and online resources. RESULTS/CONCLUSION: In this second and final part of the review, we discuss the importance of these other histone and nucleosome modifying enzymes in gene transcription as well as their therapeutic potential. | Is poly (ADP- ribosylation) involved in transcriptional control? | 53380000d6d3ac6a34000059_003 | yes |
Evaluation of archival time on shotgun proteomics of formalin-fixed and paraffin-embedded tissues. There is increasing acceptance of the critical importance of correlating the morphologic features of tissue with the data obtained from various molecular analytic techniques. Access to archived formalin-fixed and paraffin-embedded (FFPE) tissue specimens via shotgun-based proteomic analyses may, therefore, open new avenues for both prospective and retrospective translational research. However, one of the remaining issues in performing comparative proteomic measurements among FFPE tissues relates to potential variability in protein composition and retrieval based on length of storage periods. Optimized protein extraction and digestion procedures for handling FFPE tissues are coupled with the capillary isotachophoresis-based proteome technology to evaluate the effects of length of storage period on archival tissue proteome analysis across 10 archived uterine mesenchymal tumor tissue blocks, including 9 uterine leiomyomas dating from 1990 to 2002 and a single case of alveolar soft part sarcoma (ASPS) from 1980. Several statistical measures, including the Pearson correlation coefficient, coefficient of variance, k-means clustering, and ANOVA, are employed to evaluate the possibility of an archival effect on individual proteins or groups of proteins within nine leiomyomas. Low abundance proteins may be more susceptible to the long-term storage as these proteins are more difficult to be retrieved and extracted as the tissue block ages in paraffin. Despite using tissue blocks stored for as many as 28 years, high confidence and comparative proteome analysis between the leiomyomas and the sarcoma is achieved. Though sharing over 1800 common proteins in a core set, a total of 80 proteins unique to the sarcoma are identified distinguishing the ASPS from the leiomyomas. Vacuolar proton translocating ATPase 116 kDa subunit isoform a3, one of the unique proteins expressed in the ASPS, is further validated by immunohistochemistry (IHC). Although IHC is highly sensitive and provides the subcellular resolution, mass spectrometry-based proteome profiling enables global identification and quantification of thousands of proteins without a priori knowledge of individual proteins being analyzed or the need of validated antibodies. | Is it possible to determine the proteome of a formalin fixed and paraffin embedded (FFPE) tissue? | 511a1e12df1ebcce7d000009_009 | yes |
A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. PURPOSE: The primary goal of this trial was to determine the response rate of single-agent vorinostat in patients with metastatic breast cancer. The secondary goals included assessment of time to progression, evaluation of toxicities, and overall survival. EXPERIMENTAL DESIGN: From June 2005 to March 2006, 14 patients received vorinostat, 200 mg p.o., twice daily for 14 days of each 21 day cycle. Response and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: The median age for all patients was 60.5 years (range, 37-88). Eight patients were estrogen receptor and/or progesterone positive, four were Her-2 positive. Sites of metastatic disease included brain, liver, lungs, bones, pelvis, pleura, chest wall, and distant lymph nodes. Patients received a median of 1.5 prior (range, 0-2) chemotherapeutic regimens for metastatic disease. Fatigue, nausea, diarrhea, and lymphopenia were the most frequent clinically significant adverse effects. The median number of cycles delivered was 2 (range, 1-20). There were no complete or partial responses, and the study was terminated after the first stage; however, 4 patients were observed with stable disease with time to progression of 4, 8, 9, and 14 months. The median number of months that patients received treatment on this study was 1.7 (range, 0.5-14). CONCLUSIONS: Although not meeting the RECIST response criteria for adequate single-agent activity, the observed tolerable toxicities and the potential for clinical benefit in terms of stable disease suggest that further assessment of vorinostat as a part of combination therapy with either chemotherapeutic or targeted agents in metastatic breast might be undertaken. | Are histone deacetylase (HDAC) inhibitors good candidates to control metastasis of solid tumors? | 517404878ed59a060a000023_001 | yes |
ACOG committee opinion. Exercise during pregnancy and the postpartum period. Number 267, January 2002. American College of Obstetricians and Gynecologists. The physiologic and morphologic changes of pregnancy may interfere with the ability to engage safely in some forms of physical activity. A woman's overall health, including obstetric and medical risks, should be evaluated before prescribing an exercise program. Generally, participation in a wide range of recreational activities appears to be safe during pregnancy; however, each sport should be reviewed individually for its potential risk, and activities with a high risk of abdominal trauma should be avoided during pregnancy. Scuba diving also should be avoided throughout pregnancy because the fetus is at an increased risk for decompression sickness during this activity. In the absence of either medical or obstetric complications, 30 minutes or more of moderate exercise a day on most, if not all, days of the week is recommended for pregnant women. | Is scuba diving safe during pregnancy? | 5a70de5199e2c3af26000005_007 | no |
Structural mutants of the spindle pole body cause distinct alteration of cytoplasmic microtubules and nuclear dynamics in multinucleated hyphae. In the multinucleate fungus Ashbya gossypii, cytoplasmic microtubules (cMTs) emerge from the spindle pole body outer plaque (OP) in perpendicular and tangential directions. To elucidate the role of cMTs in forward/backward movements (oscillations) and bypassing of nuclei, we constructed mutants potentially affecting cMT nucleation or stability. Hyphae lacking the OP components AgSpc72, AgNud1, AgCnm67, or the microtubule-stabilizing factor AgStu2 grew like wild- type but showed substantial alterations in the number, length, and/or nucleation sites of cMTs. These mutants differently influenced nuclear oscillation and bypassing. In Agspc72Delta, only long cMTs were observed, which emanate tangentially from reduced OPs; nuclei mainly moved with the cytoplasmic stream but some performed rapid bypassing. Agnud1Delta and Agcnm67Delta lack OPs; short and long cMTs emerged from the spindle pole body bridge/half-bridge structures, explaining nuclear oscillation and bypassing in these mutants. In Agstu2Delta only very short cMTs emanated from structurally intact OPs; all nuclei moved with the cytoplasmic stream. Therefore, long tangential cMTs promote nuclear bypassing and short cMTs are important for nuclear oscillation. Our electron microscopy ultrastructural analysis also indicated that assembly of the OP occurs in a stepwise manner, starting with AgCnm67, followed by AgNud1 and lastly AgSpc72. | Has the fungus Ashbya gossypii got many nuclei that share cytoplasm? | 550e6688a103b7801600000d_013 | yes |
Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity. Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score of 32) and activity against xenografts. Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 cleavage complexes at specific sites in biochemical assays. At higher concentrations, inhibition of Top1 catalytic activity and DNA intercalation is observed. NSC 727357 also induces a limited number of Top2-DNA cleavage complexes. In contrast to the effect of other Top1 inhibitors, cells treated with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle progression in G(1) with no significant inhibition of DNA synthesis after a short exposure to the drug. Moreover, unlike camptothecin and the indenoisoquinoline MJ-III-65 (NSC 706744, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline hydrochloride), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only partially dependent on Top1 and p53, indicating that this drug has additional targets besides Top1 and Top2. | Can DNA intercalators function as topoisomerase inhibitors? | 56c71cb65795f9a73e00000b_007 | yes |
Post-natal erythromycin exposure and risk of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis. PURPOSE: Macrolide antibiotics, erythromycin, in particular, have been linked to the development of infantile hypertrophic pyloric stenosis (IHPS). Our aim was to conduct a systematic review of the evidence of whether post-natal erythromycin exposure is associated with subsequent development of IHPS. METHODS: A systematic review of postnatal erythromycin administration and IHPS was performed. Papers were included if data were available on development (yes/no) of IHPS in infants exposed/unexposed to erythromycin. Data were meta-analysed using Review Manager 5.3. A random effects model was decided on a priori due to heterogeneity of study design; data are odds ratio (OR) with 95 % CI. RESULTS: Nine papers reported data suitable for analysis; two randomised controlled trials and seven retrospective studies. Overall, erythromycin exposure was significantly associated with development of IHPS [OR 2.45 (1.12-5.35), p = 0.02]. However, significant heterogeneity existed between the studies (I = 84 %, p < 0.0001). Data on erythromycin exposure in the first 14 days of life was extracted from 4/9 studies and identified a strong association between erythromycin exposure and subsequent development IHPS [OR 12.89 (7.67-2167), p < 0.00001]. CONCLUSION: This study demonstrates a significant association between post-natal erythromycin exposure and development of IHPS, which seems stronger when exposure occurs in the first 2 weeks of life. | Does erythromycin increase risk of hypertrophic pyloric stenosis? | 5a67ade5b750ff445500000c_005 | yes |
The natural history of B cells. Multiple sclerosis is a common neurological disorder that represents a significant source of disability. B cells have recently emerged as a novel therapeutic target for multiple sclerosis. The natural development of B cells is characterized by an antigen-independent phase that occurs in the bone marrow and an antigen-dependent phase that takes place in the peripheral lymphoid tissue. The stage of B-cell development can be identified by the presence of specific cell surface markers. Checkpoints are in place to prevent self-reactive B cells from further development and activation. Some self-reactive B cells are able to escape these checkpoints, resulting in a loss of tolerance. B cells may contribute to systemic autoimmunity and the development of autoimmune disease via cytokine production, antigen presentation, and complement activation. In addition, B cells may trigger autoimmune disease via molecular mimicry, which occurs when a single B-cell receptor recognizes both a non-self antigen molecule and a self-molecule. Accumulating data suggest that ectopic proliferation of B cells in the central nervous system may also play a role. Further research is needed to elucidate the pathology of B cells and their role in central nervous system autoimmune diseases, including multiple sclerosis. | Is there a relationship between B cells and Multiple Sclerosis? | 58c0836102b8c6095300001c_010 | yes |
New insights into HCV replication: potential antiviral targets. The ultimate goal of hepatitis C virus (HCV) treatment is the eradication of the virus. Ongoing research continues to add to knowledge of the HCV life cycle, revealing new potential viral and host targets for the development of therapy. Understanding of HCV was initially hampered by the inability to achieve viral replication in cell culture. Advances such as the HCV replicon and complete cell culture systems, however, have permitted rapid growth in knowledge and accelerated testing of candidate antiviral agents. Among potential targets are viral entry factors, including scavenger receptor type B1 (SR-B1) and CD81, as well as neutralizing antibodies against the viral glycoproteins. Popular targets related to translation and replication are the NS3/4A protease (inhibited by telaprevir and boceprevir) and the NS5B polymerase, as well as the NS2/3 autoprotease, the NS3 helicase, and nonenzymatic targets such as NS4B and NS5A proteins. Host targets are also available, including microRNAs and cyclophilins. This article summarizes a presentation by Charles M. Rice, PhD, at the IAS-USA live continuing medical education course, Management of Hepatitis C Virus in the New Era: Small Molecules Bring Big Changes, held in New York City in April 2011. | Is there any functional association during viral replication between flaviviridae viral RNA depended RNA polymerase and viral helicase? | 5321b8579b2d7acc7e000008_000 | yes |
A DNA methyltransferase homolog with a chromodomain exists in multiple polymorphic forms in Arabidopsis. Chromodomains are thought to mediate protein-protein interactions between chromatin components. We have detected a chromodomain embedded within the catalytic region of a predicted Arabidopsis DNA methyltransferase that is diverged from other eukaryotic enzymes. The 791 residue "chromomethylase" (CMT1) is encoded by a floral transcript that is spliced from 20 exons and is present at only approximately 1/10(-7) of total mRNA. Genomic sequencing reveals an ancient haplotype split at CMT1 between Col-0 + Metz and the other ecotypes examined. In the Col-0 + Metz haplotype, alternative mRNA processing at intron 13 truncates the coding region. In Ler, RLD, and No-0, similar truncation is caused by insertion of an intact retrotransposon, Evelknievel, which is present as a single copy in Ler and RLD and is currently methylated and inactive. Evelknievel is found at this site on a single branch that connects the Ler, RLD, and No-0 ecotypes but is absent from the genomes of all other ecotypes examined. A stop codon within exon 6 of the Metz ecotype confirms that CMT1 is nonessential. Nevertheless, comparison to CMT1 of Cardaminopsis arenosa, an outcrossing relative, indicates conservation for DNA methyltransferase function. We discuss how allelic diversity of CMT1 may reflect loosened selective constraints in a self-fertilizing species such as Arabidopsis thaliana. | Are chromomethylases present in animal genomes? | 5171833c8ed59a060a00000f_007 | no |
Apremilast for Behçet's syndrome--a phase 2, placebo-controlled study. BACKGROUND: Oral ulcers, the hallmark of Behçet's syndrome, can be resistant to conventional treatment; therefore, alternative agents are needed. Apremilast is an oral phosphodiesterase-4 inhibitor that modulates several inflammatory pathways. METHODS: We conducted a phase 2, multicenter, placebo-controlled study in which 111 patients with Behçet's syndrome who had two or more oral ulcers were randomly assigned to receive 30 mg of apremilast twice daily or placebo for 12 weeks. This regimen was followed by a 12-week extension phase in which the placebo group was switched to apremilast and a 28-day post-treatment observational follow-up phase. The patients and clinicians were unaware of the study assignments throughout the trial. The primary end point was the number of oral ulcers at week 12. Secondary outcomes included pain from these ulcers (measured on a 100-mm visual-analogue scale, with higher scores indicating worse pain), the number of genital ulcers, overall disease activity, and quality of life. RESULTS: The mean (±SD) number of oral ulcers per patient at week 12 was significantly lower in the apremilast group than in the placebo group (0.5±1.0 vs. 2.1±2.6) (P<0.001). The mean decline in pain from oral ulcers from baseline to week 12 was greater with apremilast than with placebo (-44.7±24.3 mm vs. -16.0±32.5 mm) (P<0.001). Nausea, vomiting, and diarrhea were more common in the apremilast group (with 22, 9, and 12 incidents, respectively, among 55 patients) than in the placebo group (with 10, 1, and 2 incidents, respectively, among 56 patients), findings that were similar to those in previous studies of apremilast. There were two serious adverse events in patients receiving apremilast. CONCLUSIONS: Apremilast was effective in treating oral ulcers, which are the cardinal manifestation of Behçet's syndrome. This preliminary study was neither large enough nor long enough to assess long-term efficacy, the effect on other manifestations of Behçet's syndrome, or the risk of uncommon serious adverse events. (Funded by Celgene; ClinicalTrials.gov number, NCT00866359.). | Is Apremilast effective for Behcet’s syndrome? | 5a7340962dc08e987e000017_000 | yes |
[A case of an elderly type 2 diabetes who had severe diabetic nephropathy without retinopathy]. We encountered a man who developed severe diabetic nephropathy without progression of diabetic retinopathy. He had a 14-year history of diabetes, and had been treated with sulfonylurea, and his HbA1c remained around 6.5%. He was admitted because of systemic edema and dyspnea on effort Laboratory data revealed renal failure and nephrotic syndrome, whereas there was no symptom of diabetic retinopathy. Since diabetic nephropathy usually progresses in parallel with retinopathy, it is atypical to develop severe nephropathy without retinopathy. In this case, longstanding hypertension and his genetic background including angiotensin converting enzyme D/I polymorphism might have played an important role in development of diabetic nephropathy. | Is edema a symptom of nephrotic syndrome? | 58da270d8acda34529000013_005 | yes |
A phase II, single-blind, randomized, crossover evaluation of the safety and efficacy of avanafil using visual sexual stimulation in patients with mild to moderate erectile dysfunction. OBJECTIVE: To evaluate the safety, efficacy and time course of three doses of avanafil (50 mg, 100 mg and 200 mg) compared with sildenafil 50 mg or placebo, given in conjunction with visual sexual stimulation (VSS) videos in men with mild to moderate erectile dysfunction (ED). PATIENTS AND METHODS: Male patients, 35-70 years of age, with mild to moderate ED of > 6 months duration, were included in the study. During the course of the study, each patient received placebo, active control (sildenafil 50 mg), and one dose of avanafil (50 mg, 100 mg or 200 mg), all administered in random order at least 72 h apart. RigiScan® (Dacomed Corp., Minneapolis, MN, USA) monitoring was used in conjunction with 20-min VSS videos (20, 60, and 100 min after dosing) to determine the duration of and time to > 60% penile rigidity, maximum rigidity, tumescent activity units (TAUs), rigidity activity units (RAUs), and responses to the five-point Erection Assessment Scale. Safety assessments included adverse events (AEs), vital sign changes in response to dosing, laboratory results (complete blood counts, chemistry panel, prostate-specific antigen, serum testosterone, prothrombin time and urine analysis) and physical examination findings. RESULTS: Eighty-three patients were randomized and received at least one dose of study medication; 82 patients completed the study. Peak response to avanafil occurred in the early interval (20-40 min after dosing), while peak response to sildenafil occurred either in the middle (60-80 min) or late (100-120 min) intervals after dosing. Results were qualitatively similar for all other efficacy endpoints. During the 20-40-min interval, the majority of values for TAUs and RAUs with the avanafil 50-mg, 100-mg and 200-mg treatments were significantly superior to placebo (P < 0.05). Avanafil treatment was generally well tolerated; facial flushing (7-15%) was the most commonly observed AE, and no visual disturbances were reported. CONCLUSION: A favourable safety profile and improvement in sexual function, coupled with rapid onset of action and durability of effect, make avanafil an attractive option for males with ED, especially in the setting of on-demand treatment. | Is avanafil indicated for treatment of erectile dysfunction? | 5895d0457d9090f35300000d_008 | yes |
High-flow nasal cannula: transient fashion or new method of non-invasive ventilatory assistance? Respiratory failure in the premature infants remains a difficult challenge. An alternative to the use of nasal continuous positive airway pressure (NCPAP) as a non-invasive modality to support respiratory distress in premature infants has been the recent introduction of high flow nasal cannula (HFNC) devices in many neonatal units. There has been increased use of HFNC presumably because of anecdotal reports and experience that it is easy to use, and well tolerated by the infants, while experiencing decreased nasal septumerosion. The paucity of evidence regarding its efficacy and safety, would support a caution approach to the use of HFNC. Particular concern has focused on the imprecise regulation and generation of pressure that may occur at higher flows especially in the smallest of infants. | Are high-flow nasal cannulae effective for treatment of preterm infants? | 530cf4c54a5037880c000002_002 | yes |
A case of Mowat-Wilson syndrome caused by a truncating mutation within exon 8 of the ZEB2 gene. Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations. The cause of MWS is a de novo mutation in the ZEB2 gene. This report describes a Turkish boy who was clinically diagnosed with MWS and had his diagnosis confirmed by molecular analysis of the ZEB2 gene. The investigation identified a heterozygous complex rearrangement in exon 8 of ZEB2, specifically a 48-nucleotide deletion and a 44-nucleotide insertion that caused a frameshift. MWS is a relatively newly identified disorder, and even MWS patients without Hirschsprung disease can be diagnosed easily based on clinical findings alone. | Is Hirschsprung disease one of the characteristics of the Mowat-Wilson syndrome? | 55001420e9bde69634000005_001 | yes |
Thyroid hormone analog, diiodothyropropionic acid (DITPA), exerts beneficial effects on chamber and cellular remodeling in cardiomyopathic hamsters. Diiodothyropropionic acid (DITPA) is a thyroid hormone analog that is currently in phase II clinical trials. However, there have not been any studies to comprehensively analyze its effect on myocyte morphology. In addition, long-term studies with DITPA have not been done. This study compares the effects of DITPA with L-thyroxine (T4) on chamber remodeling, cardiac function, cellular morphology, cardiac blood flow, and protein expression. Normal and cardiomyopathic hamsters were treated with T4 or DITPA for 2 months. At the end of the treatment, echos, hemodynamics, coronary blood flow, cell morphology, and protein expression data were collected. Both T4 and DITPA treatment reduced chamber diameter during diastole, suggesting attenuated chamber dilatation in cardiomyopathic hamsters. Wall thickness also tended to increase, which was supported by cell morphology data in which DITPA significantly increased cross-sectional growth of myocytes specifically in the minor dimension, which is oriented transmurally. T4 and DITPA also increased myocardial blood flow both at baseline and after maximal dilation. This suggests there was increased angiogenesis or reduced loss of arterioles. Both T4 and DITPA had beneficial effects on chamber remodeling, which was most likely due to beneficial changes in cell shape and improved vascular supply. | Is DITPA a thyroid hormone analog utilized in experimental and clinical studies | 52fb4b462059c6d71c00005f_006 | yes |
Drosophila Bicoid is a substrate of sumoylation and its activator function is subject to inhibition by this post-translational modification. Bicoid (Bcd) is a Drosophila morphogenetic protein and a transcriptional activator. Genetic studies have suggested a role of sumoylation in Bcd function, but it is unknown how Bcd activity is affected specifically by its own sumoylation status. Here we show that Bcd is sumoylated in Drosophila cells. We identify a lysine residue of Bcd as the primary sumoylation site. Using a Bcd mutant defective in being sumoylated, we show that sumoylation of Bcd is inhibitory to its ability to activate transcription. We provide evidence suggesting that the SUMO moiety has an intrinsic inhibitory activity for the activator function of Bcd. | Is SUMOylation a post-translational modification in eukaryotes? | 58a6b98860087bc10a000028_004 | yes |
Quantification of HER expression and dimerization in patients' tumor samples using time-resolved Förster resonance energy transfer. Following the development of targeted therapies against EGFR and HER2, two members of the human epidermal receptor (HER) family of receptor tyrosine kinases, much interest has been focused on their expression in tumors. However, knowing the expression levels of individual receptors may not be sufficient to predict drug response. Here, we describe the development of antibody-based time-resolved Förster resonance energy transfer (TR-FRET) assays for the comprehensive analysis not only of EGFR and HER2 expression in tumor cryosections, but also of their activation through quantification of HER homo- or heterodimers. First, EGFR and HER2 expression levels were quantified in 18 breast tumors and the results were compared with those obtained by using reference methods. The EGFR number per cell determined by TR-FRET was significantly correlated with EGFR mRNA copy number (P<0.0001). Moreover, our method detected HER2 overexpression with 100% specificity and sensibility, as confirmed by the standard IHC, FISH and qPCR analyses. EGFR and HER2 dimerization was then assessed, using as controls xenograft tumors from cell lines with known dimer expression profiles. Our results show that quantification of HER dimerization provides information about receptor activation that cannot be obtained by quantification of single receptors. Quantifying HER expression and dimerization by TR-FRET assays might help identifying novel clinical markers for optimizing patients' treatment in oncology. | Is HER2 active only when it dimerizes? | 5509ec41c2af5d5b70000006_000 | yes |
Mechanisms and clinical management of inherited channelopathies: long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. The following briefly reviews features and management of long QT syndrome (LQTS), Brugada Syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome (SQTS). LQTS is marked by QT prolongation, syncope and sudden death due to torsades de pointes. Risk stratification is based on age, gender, history of symptoms, QT interval, and genetic subtype of LQTS. In addition to avoidance QT-prolonging drugs and high intensity sports, standard treatment for LQTS involves anti-adrenergic therapy, with implantable cardioverter-defibrillator (ICD) use in high risk subgroups. Brugada Syndrome is associated with right ventricular conduction delay and ST elevation in the right precordial leads, syncope, and sudden death from ventricular fibrillation. The electrocardiographic abnormality can be accentuated by sodium channel blocker, vagal stimulation or fever. Patients with aborted cardiac arrest and those with syncope and a spontaneous or sodium channel blocker-inducible type I Brugada ECG pattern are at high risk and should receive an ICD. The role of electrophysiologic testing is controversial. Although there is no reliable drug therapy for Brugada Syndrome, quinidine, which suppresses I(to) current, can reduce the incidence of arrhythmias. Patients with CPVT present with exercise-induced syncope and sudden cardiac death but normal resting electrocardiograms. Exercise or isoproterenol infusion may cause increased ventricular ectopy or bidirectional ventricular tachycardia. Treatment modalities include anti-adrenergic therapy and ICD implantation. Congenital SQTS is a relatively recently described disorder characterized by a very short QT interval and by susceptibility to atrial and ventricular fibrillation. ICD implantation is the primary therapy; quinidine may be a useful adjunctive therapy. | Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cause sudden cardiac death? | 530cf4fe960c95ad0c000003_003 | yes |
The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells. Androgen ablation therapy is the most common strategy for suppressing prostate cancer progression; however, tumor cells eventually escape androgen dependence and progress to an androgen-independent phase. The androgen receptor (AR) plays a pivotal role in this transition. To address this transition mystery in prostate cancer, we established an androgen-independent prostate cancer cell line (LNCaPdcc), by long-term screening of LNCaP cells in androgen-deprived conditions, to investigate changes of molecular mechanisms before and after androgen withdrawal. We found that LNCaPdcc cells displayed a neuroendocrine morphology, less aggressive growth, and lower expression levels of cell cycle-related factors, although the cell cycle distribution was similar to parental LNCaP cells. Notably, higher protein expression of AR, phospho-Ser(81)-AR, and PSA in LNCaPdcc cells were observed. The nuclear distribution and protein stability of AR increased in LNCaPdcc cells. In addition, cell proliferation results exhibited the biphasic nature of the androgen (R1881) effect in two cell lines. On the other hand, LNCaPdcc cells expressed higher levels of Her2, phospho-Tyr(1221/1222)-Her2, ErbB3, and ErbB4 proteins than parental LNCaP cells. These two cell lines exhibited distinct responses to Her2 activation (by heregulin treatment) on Her2 phosphorylation and Her2 inhibition (by AG825 or Herceptin treatments) on proliferation. In addition, the Her2 inhibitor more effectively caused AR degradation and diminished AR Ser(81) phosphorylation in LNCaPdcc cells. Taken together, our data demonstrate that Her2 plays an important role in the support of AR protein stability in the transition of androgen requirement in prostate cancer cells. We hope these findings will provide novel insight into the treatment of hormone-refractory prostate cancer. | Is the monoclonal antibody Trastuzumab (Herceptin) of potential use in the treatment of prostate cancer? | 5313b049e3eabad021000013_032 | yes |
Neuroprotective electrical stimulation of cerebellar fastigial nucleus attenuates expression of periinfarction depolarizing waves (PIDs) and inhibits cortical spreading depression. In rat, electrical stimulation of the cerebellar fastigial nucleus (FN) for 1 h reduces the volume of focal ischemic infarctions produced by occluding the middle cerebral artery (MCAO), even 10 days later. The mechanism by which this 'central neurogenic neuroprotection' salvages ischemic brain is not known but does not result from changes in cerebral perfusion. MCAO also triggers periodic periinfarction depolarizing waves (PIDs) in the ischemic penumbra, the territory of salvage. These may contribute to neuronal death and promote infarct expansion. Conceivably, FN stimulation, which can otherwise modify cortical excitability, may alter the development of PIDs. We investigated in anesthetized rats whether FN stimulation modifies PIDs expression and, if so, the threshold for evoking cortical spreading depression (CSD), a process sharing characteristics with PIDs and an index of cortical excitability. Stimulation of FN immediately or 72 h before MCAO decreased infarction volumes by approximately 45% (p<0.01), increased PID latency >10-fold, and decreased the number of PIDs by >50% (p<0.001). In normal rats, stimulation of FN increased the threshold current for eliciting CSD by 175% and slowed its propagation velocity by 35% (p<0.01 for each) immediately, but not 72 h, after FN stimulation. We conclude: FN stimulation elicits long-lasting suppression of PIDs in parallel with neuroprotection. However, PIDs suppression over time is unlikely to result from a major increase in cortical tolerance to depolarization and probably is not the principal mechanism of salvage. | Does cortical spreading depression appear in ischemic penumbra following ischemic stroke? | 514b335dd24251bc05000061_006 | yes |
Pulsed electromagnetic field stimulates osteoprotegerin and reduces RANKL expression in ovariectomized rats. Pulsed electromagnetic field (PEMF) has been shown to increase bone mineral density in osteoporosis patients and prevent bone loss in ovariectomized rats. But the mechanisms through which PEMF elicits these favorable biological responses are still not fully understood. Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) are cytokines predominantly secreted by osteoblasts and play a central role in differentiation and functional activation of osteoclasts. The purpose of this study was to investigate the effects of PEMF on RANKL and OPG expression in ovariectomized rats. Thirty 3-month-old female Sprague-Dawley rats were randomly divided into three groups: sham-operated control (Sham), ovariectomy control (OVX), and ovariectomy with PEMF treatment (PEMF). After 12-week interventions, the results showed that PEMF increased serum 17β-estradiol level, reduced serum tartrate-resistant acid phosphatase level, increased bone mineral density, and inhibited deterioration of bone microarchitecture and strength in OVX rats. Furthermore, PEMF could suppress RANKL expression and improve OPG expression in bone marrow cells of OVX rats. In conclusion, this study suggests that PEMF can prevent ovariectomy-induced bone loss through regulating the expression of RANKL and OPG. | Is RANKL secreted from the cells? | 55262a9787ecba3764000009_000 | yes |
B- and T-cell prolymphocytic leukemia: antibody approaches. B- and T-cell subtypes of prolymphocytic leukemia (PLL) are rare, aggressive lymphoid malignancies with characteristic morphologic, immunophenotypic, cytogenetic, and molecular features. Prognosis for these patients remains poor, with short survival times and no curative therapy. The advent of mAbs has improved treatment options. In B-PLL, rituximab-based combination chemoimmunotherapy is effective in fitter patients. TP53 abnormalities are common and, as for chronic lymphocytic leukemia, these patients should generally be managed using an alemtuzumab-based therapy. Currently, the best treatment for T-PLL is IV alemtuzumab, which has resulted in very high response rates of more than 90% when given as frontline treatment and a significant improvement in survival. Consolidation of remissions with autologous or allogeneic stem cell transplantation further prolongs survival times, and the latter may offer potential cure. The role of allogeneic transplantation with nonmyeloablative conditioning needs to be explored further in both T- and B-PLL to broaden the patient eligibility for what may be a curative treatment. | Is alemtuzumab effective for remission induction in patients diagnosed with T-cell prolymphocytic leukemia? | 530cefaaad0bf1360c000001_000 | yes |
[PCSK9 inhibitors. A new approach for treatment of hypercholesterolemia]. To date HMG-CoA-reductase inhibitors are the most effective drugs for reduction of LDL-cholesterol levels and for prevention of cardiovascular events. Inhibition of the enzyme PCSK9 (proprotein convertase subtilisin/kexin type 9), which is involved in depletion of the LDL-receptor, is a new pharmacologic approach. Inhibition of PCSK9 by monoclonal antibodies provokes an additional reduction of LDL-cholesterol levels by 50-60 % in addition to statins. Previous phase III studies indicate good compatibility. Ongoing long-term studies will answer questions of safety and influence on cardiovascular events. Although those results are not available yet, alirocumab and evolocumab have already been recommendd for approval. | Does PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds with HDL-receptor (HDL-R)? | 58db9aa28acda34529000018_009 | no |
Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. Nintedanib (BIBF 1120) is a small, orally available, triple angiokinase inhibitor in phase III development (various indications) that targets VEGFR 1-3, FGFR 1-3, and PDGFR-α/β. This open-label, uncontrolled, phase II study assessed the efficacy and safety of nintedanib in patients with recurrent glioblastoma multiforme (GBM) who had previously failed radiotherapy plus temozolomide as first-line therapy (STUPP), or the same regimen with subsequent bevacizumab-based therapy as second-line treatment (BEV). Patients with a performance status of 0-1, histologically proven GBM, and measurable disease (by RANO) were enrolled. Nintedanib was given orally at a dose of 200 mg twice daily (bid), with magnetic resonance imaging undertaken every 8 weeks. The primary endpoint was objective response rate. The study was stopped prematurely following a preplanned futility analysis after inclusion of 13 patients in the STUPP arm and 12 in the BEV arm. Best response was stable disease (SD) in three patients (12 %); all other patients progressed within the first four 28-day cycles. One patient in the BEV arm has had SD for 17+ months. Median progression-free survival was 1 month and median overall survival was 6 months. Nintedanib had an acceptable safety profile, with no CTCAE grade 3-4 adverse events. Common adverse events were CTCAE grade 1-2 fatigue, loss of appetite, diarrhea, and nausea. Single-agent nintedanib (200 mg bid) demonstrated limited, but clinically non-relevant antitumor activity in patients with recurrent GBM who had failed 1-2 prior lines of therapy. | Is fatigue prevalent in patients receiving treatment for glioblastoma? | 530e42e65937551c09000007_014 | yes |