Datasets:

BastienHot
/

BioASQ-Task-B-Revised

Dataset card Viewer Files Files and versions Community

Split (2)

train · 34.7k rows

context stringlengths 5 6.31k ⌀	question stringlengths 13 640	answer stringlengths 4 2.42k ⌀
Cross-linking and immunoprecipitation (CLIP) is increasingly used to map transcriptome-wide binding sites of RNA-binding proteins. We developed a method for CLIP data analysis, and applied it to compare CLIP with photoactivatable ribonucleoside-enhanced CLIP (PAR-CLIP) and to uncover how differences in cross-linking and ribonuclease digestion affect the identified sites. We found only small differences in accuracies of these methods in identifying binding sites of HuR, which binds low-complexity sequences, and Argonaute 2, which has a complex binding specificity. We found that cross-link-induced mutations led to single-nucleotide resolution for both PAR-CLIP and CLIP. Our results confirm the expectation from original CLIP publications that RNA-binding proteins do not protect their binding sites sufficiently under the denaturing conditions used during the CLIP procedure, and we show that extensive digestion with sequence-specific RNases strongly biases the recovered binding sites. This bias can be substantially reduced by milder nuclease digestion conditions.	What is the principle of the PAR-CLIP methodology?	ross-linking and immunoprecipitation (CLIP) is increasingly used to map transcriptome-wide binding sites of RNA-binding proteins.
Antibody therapy has been used to treat a variety of diseases and the success of ZMapp and other monoclonal antibody-based therapies during the 2014-2016 West African Ebola outbreak has shown this countermeasure can be a successful therapy for Ebola hemorrhagic fever. This study utilized transchromosomal bovines (TcB) vaccinated with a DNA plasmid encoding Ebola virus glycoprotein sequence to produce human polyclonal antibodies directed against Ebola virus glycoprotein. When administered 1 day postinfection, these TcB polyclonal antibodies provided partial protection and resulted in a 50% survival rate following a lethal challenge of Ebola virus Makona in rhesus macaques.	Which disease is treated with ZMapp?	Antibody therapy has been used to treat a variety of diseases and the success of ZMapp and other monoclonal antibody-based therapies during the 2014-2016 West African Ebola outbreak has shown this countermeasure can be a successful therapy for Ebola hemorrhagic fever.
Over a half of patients with Systemic Lupus Erythematosus will develop lupus nephritis (LN). The diagnosis of LN, suspected based on clinical data (proteinuria, active urinary sediment, renal dysfunction), is confirmed with renal biopsy. The immunosuppressive treatment of proliferative classes of LN is based on an induction phase, where high-dose steroids are used in conjunction with mycophenolate mofetil (MMF) or cyclophosphamide, and a subsequent maintenance phase, that combines low-dose steroids with MMF or azathioprine. Different classes of drugs (calcineurin inhibitors, anti-CD20) can be used as an alternative, or in resistant forms of LN, although their role is less well-established. Recently published (or nearing completion) studies have opened up the possibility of using new drugs in LN. In particular, depletion (Obinutuzumab, anti-CD20 monoclonal antibody) or neutralization (Belimumab, anti-"B-cell activating factor" monoclonal antibody) of B lymphocytes, and the use of a calcineurin inhibitor with a low profile of renal and systemic toxicity (Voclosporin) demonstrated an improvement in renal response in addition to standard therapy.	Is Belimumab used for lupus nephritis?	In particular, depletion (Obinutuzumab, anti-CD20 monoclonal antibody) or neutralization (Belimumab, anti-"B-cell activating factor" monoclonal antibody) of B lymphocytes, and the use of a calcineurin inhibitor with a low profile of renal and systemic toxicity (Voclosporin) demonstrated an improvement in renal response in addition to standard therapy.
We tested the effect of two different concentrations (150μg/l and 0.15μg/l) of mycotoxin zearalenone (ZEA) on the reproductive parameters and expression of testicular genes in male mice. In adult males, no reduction of body or reproductive organ weight was observed, and the seminiferous tubules were morphologically normal with ongoing spermatogenesis. However, we found decreased sperm concentration, increase of morphologically abnormal spermatozoa and increased binding of apoptotic marker annexin V. This study was also focused on the evaluation of gene expression profiles of 28 genes playing important roles during the processes occurring in the testicular tissue. We detected changes in the expression of genes important for proper spermatogenesis. Surprisingly, we observed a stronger effect after exposure to the lower dose of ZEA.	Is Annexin V an apoptotic marker?	However, we found decreased sperm concentration, increase of morphologically abnormal spermatozoa and increased binding of apoptotic marker annexin V.
The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant treatment decisions. The aim of this study was to assess its value to predict chemosensitivity in the neoadjuvant setting. We obtained the 70-gene profile of stage II-III patients prior to neoadjuvant chemotherapy and classified the prognosis-signatures. Pathological complete remission (pCR) was used to measure chemosensitivity. Among 167 patients, 144 (86%) were having a poor and 23 (14%) a good prognosis-signature. None of the good prognosis-signature patients achieved a pCR (0/23), whereas 29/144 patients (20%) in the poor prognosis-signature group did (P = 0.015). All triple-negative tumors (n = 38) had a poor prognosis-signature. Within the non triple-negative subgroup, the response of the primary tumor remained associated with the classification of the prognosis-signature (P = 0.023). A pCR is unlikely to be achieved in tumors that have a good prognosis-signature. Tumors with a poor prognosis-signature are more sensitive to chemotherapy.	How many genes are in the gene signature screened by MammaPrint?	the 70-gene profile
Apixaban is a direct inhibitor of factor Xa, and is a potential alternative for the treatment of acute venous thromboembolism. This study sought to evaluate the efficacy and safety of apixaban versus enoxaparin. A systematic search of the literature for randomized controlled trials of apixaban thromboprophylaxis versus enoxaparin was conducted using three databases: PubMed, EMBASE, and the Cochrane library. Five studies that included a total of 12,938 patients were analyzed using Bayesian random-effects meta-analysis. To evaluate efficacy, a composite of venous thromboembolism and death during follow-up was measured. To evaluate safety, major and total bleeding events were considered. The odds ratio (OR) for the composite outcome of efficacy was 0.66 (95 % CI 0.33-1.29) for apixaban compared to enoxaparin, while there was a similar risk of major bleeding (OR 1.03, 95 % CI 0.36-3.73) and total bleeding (OR 0.92, 95 % CI 0.64-1.20). These results suggest a lack of clear superiority of apixaban relative to enoxaparin. Apixaban is an oral alternative with similar efficacy and safety to existing anticoagulant therapies.	Is apixaban effective for treatment of acute venous thromboembolism?	Apixaban is a direct inhibitor of factor Xa, and is a potential alternative for the treatment of acute venous thromboembolism.
Pluripotency denotes the flexible capacity of single cells to give rise to all somatic lineages and typically also the germline. Mouse ES cells and post-implantation epiblast-derived stem cells (EpiSC) are widely used pluripotent cell culture systems. These two in vitro stem cell types have divergent characteristics. They are considered as representative of distinct developmental stages, distinguished by using the terms "naïve" and "primed". A binary description is an over-simplification, however. Here, we discuss an intermediate stage of pluripotency that we term "formative". Formative pluripotency features a gene regulatory network switch from the naïve state and comprises capacitation of enhancers, signaling pathways and epigenetic machinery in order to install competence for lineage specification.	What is formative pluripotency?	Here, we discuss an intermediate stage of pluripotency that we term "formative". Formative pluripotency features a gene regulatory network switch from the naïve state and comprises capacitation of enhancers, signaling pathways and epigenetic machinery in order to install competence for lineage specification
Peroxiredoxin-2 (Prdx2), a potent peroxide reductant, is the third most abundant protein in the erythrocyte and might be expected to play a major role in the cell's oxidative defenses. However, in this study, experiments with erythrocytes from mice with a disrupted Prdx2 gene found that the cells were not more sensitive to exogenous H(2)O(2) or organic peroxides than wild type. Intraerythrocytic H(2)O(2) was increased, however, indicating an important role for Prdx2 in detoxifying endogenously generated H(2)O(2). These results are consistent with proposals that red cell Prdx2 acts stoichiometrically, not catalytically, in reducing peroxides. Additional experiments with mice with disrupted catalase or glutathione peroxidase (Gpx1) genes showed that Gpx1 is the only erythrocyte enzyme that reduces organic peroxides. Catalase(-/-) cells were readily oxidized by exogenous H(2)O(2). Cells lacking both catalase and Gpx1 were more sensitive to exogenous H(2)O(2) than cells lacking only catalase. A kinetic model proposed earlier to rationalize results with Gpx1(-/-) erythrocytes also fits the data with Prdx2(-/-) cells and indicates that although Gpx1 and Prdx2 both participate in removing endogenous H(2)O(2), Prdx2 plays a larger role. Although the rate of H(2)O(2) production in the red cell is quite low, Prdx2-deficient mice are anemic, suggesting an important role in erythropoiesis.	What type of enzyme is peroxiredoxin 2 (PRDX2)?	Peroxiredoxin-2 (Prdx2), a potent peroxide reductant, is the third most abundant protein in the erythrocyte and might be expected to play a major role in the cell's oxidative defenses.
Pre- and postnatal growth retardation of unknown pathogenesis is a common clinical feature in patients with Williams-Beuren syndrome (WBS). However, growth hormone deficiency (GHD) has not been considered a major cause of growth retardation. There is only one patient in the literature with confirmed GHD who responded well to human growth hormone (hGH) therapy. We report a female infant with confirmed WBS who, through provocative testing, was found to have GHD and who responded satisfactorily to hGH therapy. Height SDS was -4.2 at the age of 12 months when hGH was initiated and increased to -0.8 at the age of 4.25 years. The pathogenesis of GHD in our patient is unclear. Nevertheless, the elevated levels of prolactin and the response of hGH to growth hormone releasing hormone (GHRH) administration are indicative of a hypothalamic rather than pituitary defect. In conclusion, GH deficiency might contribute to the growth failure in a number of patients with WBS and in such cases hGH therapy will most likely improve final height.	Which hormone abnormalities are common in Williams syndrome	the elevated levels of prolactin and the response of hGH to growth hormone releasing hormone (GHRH) administration are indicative of a hypothalamic rather than pituitary defect. In conclusion, GH deficiency might contribute to the growth failure in a number of patients with WBS
Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.	Is RET the major gene involved in Hirschsprung disease?	The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease
The neuronal RNA-binding protein (RBP) HuD plays an important role in brain development, synaptic plasticity and neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD). Bioinformatics analysis of the human SOD1 mRNA 3' untranslated region (3'UTR) demonstrated the presence of HuD binding adenine-uridine (AU)-rich instability-conferring elements (AREs). Using differentiated SH-SY5Y cells along with brain tissues from sporadic amyotrophic lateral sclerosis (sALS) patients, we assessed HuD-dependent regulation of SOD1 mRNA. In vitro binding and mRNA decay assays demonstrate that HuD specifically binds to SOD1 ARE motifs promoting mRNA stabilization. In SH-SY5Y cells, overexpression of full-length HuD increased SOD1 mRNA and protein levels while a dominant negative form of the RBP downregulated its expression. HuD regulation of SOD1 mRNA was also found to be oxidative stress (OS)-dependent, as shown by the increased HuD binding and upregulation of this mRNA after HO exposure. This treatment also induced a shift in alternative polyadenylation (APA) site usage in SOD1 3'UTR, increasing the levels of a long variant bearing HuD binding sites. The requirement of HuD for SOD1 upregulation during oxidative damage was validated using a specific siRNA that downregulated HuD protein levels to 36% and prevented upregulation of SOD1 and 91 additional genes. In the motor cortex from sALS patients, we found increases in SOD1 and HuD mRNAs and proteins, accompanied by greater HuD binding to this mRNA as confirmed by RNA-immunoprecipitation (RIP) assays. Altogether, our results suggest a role of HuD in the post-transcriptional regulation of SOD1 expression during ALS pathogenesis.	Do RNA binding Proteins that bind to adenine uridine (AU)-rich elements (AREs) in the 5' untranslated region (UTR) of mRNAs (AU-RBPs) regulate the DNA Damage Response?	Bioinformatics analysis of the human SOD1 mRNA 3' untranslated region (3'UTR) demonstrated the presence of HuD binding adenine-uridine (AU)-rich instability-conferring elements (AREs).
Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.	Which molecule is targeted by the drug Gevokizumab?	In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II).
Treatment of childhood uveitis associated with juvenile idiopathic arthritis (JIA) is a challenge for both, ophthalmologists and pediatricians. In this study, we use the tools of evidence based medicine (EBM) to analyse studies concerning disease-modifying antirheumatic drugs (DMARD)/ immunosuppressive drugs and tumor necrosis factor alpha (TNFalpha) blocking agents. Most experience among DMARD's/ immunosuppressive drugs has been obtained with methotrexate (MTX) in juvenile idiopathic arthritis. However, controlled studies in uveitis are still missing, so that treatment with MTX and all other immunosuppressive drugs (ciclosporine A, azathioprine, mycophenolate mofetil) only reaches an evidence level III (expert opinion, clinical experience or descriptive study). Studies on TNFalpha-blocking agents reach an evidence level II-III, depending on the substance. In future, MTX will have to be examined in comparison to the new biological substance classes (e.g., tumor necrosis factor-alpha-blockers) for the treatment of uveitis in juvenile idiopathic arthritis. Controlled studies which have led to the approval of drugs for JIA are needed for uveitis in order to have the most effective and safe therapy for children with uveitis, who do not respond to conventional therapy with local and systemic steroids.	What is the effect of methotrexate in treating uveitis due to juvenile idiopathic arthritis ?	Most experience among DMARD's/ immunosuppressive drugs has been obtained with methotrexate (MTX) in juvenile idiopathic arthritis. However, controlled studies in uveitis are still missing, so that treatment with MTX and all other immunosuppressive drugs (ciclosporine A, azathioprine, mycophenolate mofetil) only reaches an evidence level III (expert opinion, clinical experience or descriptive study)
Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.	Is sacituzumab govitecan effective for breast cancer?	Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC.
Coactivators represent a large class of proteins that partner with nuclear receptors and other transcription factors to regulate gene expression. Given their pleiotropic roles in the control of transcription, coactivators have been implicated in a broad range of human disease states, including cancer. This is best typified by the three members of the steroid receptor coactivator (SRC) family, each of which integrates steroid hormone signaling and growth factor pathways to drive oncogenic gene expression programs in breast, endometrial, ovarian, prostate, and other cancers. Because of this, coactivators represent emerging targets for cancer therapeutics, and efforts are now being made to develop SRC-targeting agents, such as the SI-2 inhibitor and the novel SRC stimulator, MCB-613, that are able to block cancer growth in cell culture and animal model systems. Here, we will discuss the mechanisms through which coactivators drive cancer progression and how targeting coactivators represent a novel conceptual approach to combat tumor growth that is distinct from the use of other targeted therapeutic agents. We also will describe efforts to develop next-generation SRC inhibitors and stimulators that can be taken into the clinic for the treatment of recurrent, drug-resistant cancers. Clin Cancer Res; 22(22); 5403-7. ©2016 AACR.	What are coactivators?	Coactivators represent a large class of proteins that partner with nuclear receptors and other transcription factors to regulate gene expression.
EMT (epithelial-mesenchymal transition) is crucial for cancer cells to acquire invasive phenotypes. In A549 lung adenocarcinoma cells, TGF-β elicited EMT in Smad-dependent manner and TNF-α accelerated this process, as confirmed by cell morphology, expression of EMT markers, capacity of gelatin lysis and cell invasion. TNF-α stimulated the phosphorylation of Smad2 linker region, and this effect was attenuated by inhibiting MEK or JNK pathway. Comprehensive expression analysis unraveled genes differentially regulated by TGF-β and TNF-α, such as cytokines, chemokines, growth factors and ECM (extracellular matrices), suggesting the drastic change in autocrine/paracrine signals as well as cell-to-ECM interactions. Integrated analysis of microRNA signature enabled us to identify a subset of genes, potentially regulated by microRNAs. Among them, we confirmed TGF-β-mediated induction of miR-23a in lung epithelial cell lines, target genes of which were further identified by gene expression profiling. Combined with in silico approaches, we determined HMGN2 as a downstream target of miR-23a. These findings provide a line of evidence that the effects of TGF-β and TNF-α were partially mediated by microRNAs, and shed light on the complexity of molecular events elicited by TGF-β and TNF-α.	Which growth factors are known to be involved in the induction of EMT?	Comprehensive expression analysis unraveled genes differentially regulated by TGF-β and TNF-α, such as cytokines, chemokines, growth factors and ECM (extracellular matrices), suggesting the drastic change in autocrine/paracrine signals as well as cell-to-ECM interactions.
Phospholamban (PLN) is a type II membrane protein that inhibits the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), thereby regulating calcium homeostasis in cardiac muscle. In membranes, PLN forms pentamers that have been proposed to function either as a storage for active monomers or as ion channels. Here, we report the T-state structure of pentameric PLN solved by a hybrid solution and solid-state NMR method. In lipid bilayers, PLN adopts a pinwheel topology with a narrow hydrophobic pore, which excludes ion transport. In the T state, the cytoplasmic amphipathic helices (domains Ia) are absorbed into the lipid bilayer with the transmembrane domains arranged in a left-handed coiled-coil configuration, crossing the bilayer with a tilt angle of approximately 11° with respect to the membrane normal. The tilt angle difference between the monomer and pentamer is approximately 13°, showing that intramembrane helix-helix association forces dominate over the hydrophobic mismatch, driving the overall topology of the transmembrane assembly. Our data reveal that both topology and function of PLN are shaped by the interactions with lipids, which fine-tune the regulation of SERCA.	Is phospholamban a regulatory/inhibitory protein of the Ca ATPase SERCA?	Phospholamban (PLN) is a type II membrane protein that inhibits the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), thereby regulating calcium homeostasis in cardiac muscle. In membranes, PLN forms pentamers that have been proposed to function either as a storage for active monomers or as ion channels.
The products of the human Arg gene and human, mouse, Drosophila, and nematode Abl genes characterize the Abelson family of nonreceptor tyrosine protein kinase. The Arg gene, expressed as a 12-kb transcript, codes a protein highly related to c-abl in the tyrosine kinase, SH2, and SH3 domains, and both proteins have a myristoylated isoform. The C-terminal domains of Arg and c-abl, poorly similar to each other, may account for their different functions. Arg is cytoplasmic, c-abl also has nuclear localization, and their products have different transforming activity. To gain insight about the role of Arg in myeloid differentiation we investigated Arg gene expression in HL-60 cells differentiated with all-trans retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate. With a semiquantitative reverse transcriptase-polymerase chain reaction assay it was evident that the Arg transcript level in HL-60 cells differentiated toward granulocyte and macrophage-like lineage was, respectively, 3.5- and 2.8-fold the Arg level evidenced in undifferentiated HL-60 cells. In the HL-60 cells, under the same differentiating conditions, the c-abl RNA level did not change significantly, showing that Arg and c-abl responded in a different way to the inducers of differentiation used.	Does the Abelson-related gene (ARG) gene encode for a serine kinase?	The products of the human Arg gene and human, mouse, Drosophila, and nematode Abl genes characterize the Abelson family of nonreceptor tyrosine protein kinase.
Nephrotic syndrome is an unusual manifestation of IgA Nephropathy (IgAN). Some cases respond to steroid treatment. Here we describe a case-series of IgAN patients with steroid-responsive nephrotic syndrome. Twelve patients with IgAN with steroid-responsive nephrotic syndrome were evaluated and followed up. All patients presented with generalized edema. Renal insufficiency was found in two patients. The renal biopsy of eight patients revealed wide foot process effacement in addition to the typical features of IgAN. They showed complete remission after steroid therapy. Seven relapses were reported in five patients; six of the relapsed cases responded to steroid therapy. Compared with steroid-non-responsive patients, the patients with steroid-responsive nephrotic syndrome had shorter symptom duration, more weight gain, more proteinuria, and lower histologic grade than did those that had steroid-non-responsive nephrotic syndrome at presentation. None of the responders progressed to end stage renal disease, whereas five (38%) non-responders required dialysis or renal transplantation. Patients with IgAN who have steroid-responsive nephrotic syndrome likely have both minimal change disease and IgAN. The clinical features of sudden onset of generalized edema, initial heavy proteinuria and initial severe hypoalbuminemia might help identify the subset of patients, especially in low grade IgAN.	Is edema a symptom of nephrotic syndrome?	Nephrotic syndrome is an unusual manifestation of IgA Nephropathy (IgAN).
Prolactinoma is the most common secreting pituitary adenoma. It is typically diagnosed in women of reproductive age and is common cause of infertility. Currently the treatment of choice is pharmacotherapy with dopamine agonists, whereas surgical treatment is reserved for a selected group of patients. Pituitary-tumor apoplexy is a rare, life-threatening condition associated with significant morbidity and mortality. The authors present the case of a 25-year-old woman with prolactinoma treated with dopamine agonist. In course of such a treatment the patient became pregnant. The bromocriptine was gradually withdrawn. In the 14th week of pregnancy she was admitted for symptoms suggesting pituitary tumor apoplexy. The treatment with bromocriptine was reinitiated. In the 20th week of pregnancy further deterioration of the patient's neurological condition and visual-field abnormalities were observed. The patient was qualified for surgical treatment - selective transsphenoidal adenomectomy. The successful surgery led to improvement of neurological condition. The early postoperative PRL level decreased significantly and hormonal function of the pituitary was preserved. The pregnancy ended in 38th week with a caesarean section. Endocrinological evaluation conducted after the uneventful delivery confirmed normal function of the pituitary. Magnetic resonance imaging (MRI) did not reveal tumor re-growth. The patient is kept under constant medical care. In this case study the authors discussed therapeutic management and reviewed literature regarding gestational pituitary-tumor apoplexy with particular emphasis on surgical treatment.	Which pituitary adenoma is common cause of infertility is women?	Prolactinoma is the most common secreting pituitary adenoma. It is typically diagnosed in women of reproductive age and is common cause of infertility.
Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy. In particular, the possibility to specifically activate by light-determined interneuron populations expressing channelrhodopsin-2 provides an unprecedented opportunity of exploring their contribution to physiological and pathological network activity. There are several subclasses of interneurons in cortical areas with different functional connectivity to the principal neurons (e.g., targeting their perisomatic or dendritic compartments). Therefore, one could optogenetically activate specific or a mixed population of interneurons and dissect their selective or concerted inhibitory action on principal cells. We chose to explore a conceptually novel strategy involving simultaneous activation of mixed populations of interneurons by optogenetics and study their impact on ongoing epileptiform activity in mouse acute hippocampal slices. Here we demonstrate that such approach results in a brief initial action potential discharge in CA3 pyramidal neurons, followed by prolonged suppression of ongoing epileptiform activity during light exposure. Such sequence of events was caused by massive light-induced release of GABA from ChR2-expressing interneurons. The inhibition of epileptiform activity was less pronounced if only parvalbumin- or somatostatin-expressing interneurons were activated by light. Our data suggest that global optogenetic activation of mixed interneuron populations is a more effective approach for development of novel therapeutic strategies for epilepsy, but the initial action potential generation in principal neurons needs to be taken in consideration.	Are optogenetics tools used in the study and treatment of epilepsy?	Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy.
TET2 haplo-insufficiency occurs through different molecular mechanisms and is promptly revealed by array comparative genomic hybridization, single nucleotide polymorphism (SNP) array, and next-generation sequencing (NGS). Fluorescence in situ hybridization (FISH) can effectively demonstrate TET2 deletions and is often used to validate molecular results. In the present study 41 MDS patients with and without 4q abnormalities were analyzed with a series of bacterial artificial chromosome (BAC) probes spanning the 4q22.3-q25 region. On conventional cytogenetic (CC) studies, a structural defect of the long arm of chromosome 4 (4q) was observed in seven patients. In three, one each with a t(1;4)(p21;q24), an ins(5;4)(q23;q24qter), and a t(4;17)(q31;p13) as the sole chromosomal abnormality, FISH with the RP11-356L5 and RP11-16G16 probes, which cover the TET2 locus, produced one signal only. Unexpectedly, this same result was achieved in 3 of the remaining 34 patients. Thus, a TET2 deletion was observed in a total of six patients (14.6%). TET2 deletion was not correlated with any particular clinical findings or outcome. These findings demonstrate that 1) FISH is an effective and economical method to reveal cryptic abnormalities of band 4q22-q24 resulting in TET2 deletions; 2) in these patients, TET2 deletion is the unifying genetic event; and 3) the different breakpoints within the 4q22-q25 region suggest that deletions are not mediated by repetitive sequences.	Which human syndromes have been detected with Fluorescence in situ hybridization (FISH)?	These findings demonstrate that 1) FISH is an effective and economical method to reveal cryptic abnormalities of band 4q22-q24 resulting in TET2 deletions;
Tom Beauchamp and James Childress have always maintained that their four principles approach (otherwise known as principlism) is a globally applicable framework for biomedical ethics. This claim is grounded in their belief that the principles of respect for autonomy, non-maleficence, beneficence and justice form part of a 'common morality', or collection of very general norms to which everyone who is committed to morality subscribes. The difficulty, however, has always been how to demonstrate, at least in the absence of a full-blooded analysis of the concept of morality, whether the four principles are foundational, and so globally applicable, in this way. In the recently published sixth edition of Principles of Biomedical Ethics, an imaginative and non-question-begging empirical method of determining the common morality's norms is suggested. In this paper, I outline this method, before arguing that it is difficult to see how it might be thought to achieve its purpose.	List four principles of medical ethics.	Tom Beauchamp and James Childress have always maintained that their four principles approach (otherwise known as principlism) is a globally applicable framework for biomedical ethics. This claim is grounded in their belief that the principles of respect for autonomy, non-maleficence, beneficence and justice form part of a 'common morality', or collection of very general norms to which everyone who is committed to morality subscribes.
Chronic myeloid leukemia (CML) is characterized by the presence of a BCR-ABL fusion gene, which is the result of a reciprocal translocation between chromosomes 9 and 22, and is cytogenetically visible as a shortened chromosome 22 (Philadelphia). Research during the past two decades has established that BCR-ABL is probably the pathogenetic pathway leading to CML, and that constitutive tyrosine kinase activity is central to BCR-ABL capacity to transform hematopoietic cells in vitro and in vivo. The tyrosine kinase inhibitor imatinib mesylate was introduced into the treatment regimen for CML in 1998. During the last few years, reports on chromosomal changes during imatinib treatment have been described. In this study, we evaluated the random aneuploidy rate with chromosomes 9 and 18 in bone marrow from treated and untreated patients. We found higher aneuploidy rates in both treated and untreated patients compared to the control group. In three patients who were treated with imatinib mesylate for more than 1.5 years, triploidy also appeared in some nuclei. To our knowledge, this is the first report on new chromosomal changes such as random aneuploidy and triploidy under imatinib treatment, but more studies are needed to investigate the long-term effect of the imatinib treatment on genetic instability.	What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?	imatinib mesylate was introduced into the treatment regimen for CML
Heterochromatin assembly in budding yeast requires the SIR complex, which contains the NAD-dependent deacetylase Sir2 and the Sir3 and Sir4 proteins. Sir3 binds to nucleosomes containing deacetylated histone H4 lysine 16 (H4K16) and, with Sir4, promotes spreading of Sir2 and deacetylation along the chromatin fiber. Combined action of histone modifying and binding activities is a conserved hallmark of heterochromatin, but the relative contribution of each activity to silencing has remained unclear. Here, we reconstitute SIR-chromatin complexes using purified components and show that the SIR complex efficiently deacetylates chromatin templates and promotes the assembly of altered structures that silence Gal4-VP16-activated transcription. Silencing requires all three Sir proteins, even with fully deacetylated chromatin, and involves the specific association of Sir3 with deacetylated H4K16. These results define a minimal set of components that mediate heterochromatic gene silencing and demonstrate distinct contributions for histone deacetylation and nucleosome binding in the silencing mechanism.	How histone deacetylation causes transcriptional gene silencing?	Silencing requires all three Sir proteins, even with fully deacetylated chromatin, and involves the specific association of Sir3 with deacetylated H4K16. These results define a minimal set of components that mediate heterochromatic gene silencing and demonstrate distinct contributions for histone deacetylation and nucleosome binding in the silencing mechanism
Finding and characterizing mRNAs, their transcription start sites (TSS), and their associated promoters is a major focus in post-genome biology. Mammalian cells have at least 5-10 magnitudes more TSS than previously believed, and deeper sequencing is necessary to detect all active promoters in a given tissue. Here, we present a new method for high-throughput sequencing of 5' cDNA tags-DeepCAGE: merging the Cap Analysis of Gene Expression method with ultra-high-throughput sequence technology. We apply DeepCAGE to characterize 1.4 million sequenced TSS from mouse hippocampus and reveal a wealth of novel core promoters that are preferentially used in hippocampus: This is the most comprehensive promoter data set for any tissue to date. Using these data, we present evidence indicating a key role for the Arnt2 transcription factor in hippocampus gene regulation. DeepCAGE can also detect promoters used only in a small subset of cells within the complex tissue.	What is DeepCAGE?	Mammalian cells have at least 5-10 magnitudes more TSS than previously believed, and deeper sequencing is necessary to detect all active promoters in a given tissue. Here, we present a new method for high-throughput sequencing of 5' cDNA tags-DeepCAGE: merging the Cap Analysis of Gene Expression method with ultra-high-throughput sequence technology.
Chemotherapeutic regimens in present use for recurrent glioma have substantial toxicity. Activity against recurrent gliomas has been reported for both tamoxifen and interferon alpha, agents that have more acceptable toxicity profiles and that can be administered in an outpatient setting. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Eligible patients had radiographically measurable recurrent gliomas of any grade after initial radiation therapy. Interferon-alpha [6 x 10(6) U subcutaneously three times per week] and tamoxifen (240 mg/m2/day orally) were administered continuously. Treatment response was assessed at 6 week intervals using clinical and radiographic criteria. Eighteen patients (11 males and 7 females) were enrolled. Median age was 41 years (range 23-61 years). All patients had gliomas that progressed after radiation therapy and nitrosourea chemotherapy. The histologic diagnosis of the original tumor was glioblastoma multiforme in 8 patients, anaplastic astrocytoma in 5 patients, astrocytoma in 4 patients and mixed malignant glioma in 1 patient. Reversible moderate to severe neurological toxicity manifested by dizziness and unsteady gait was seen at tamoxifen doses of 240 mg/m2/day. Although the initial tamoxifen dose was reduced to 120 mg/m2/day, moderate neurotoxicity was noted at this dose as well and the trial was closed early. The combination of oral tamoxifen (120 to 240 mg/m2/day) and subcutaneous interferon-alpha [6 x 10(6) U three times per week] was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure. Of 16 evaluable patients, 12 had progressive disease after one cycle of treatment, 3 had stable disease, and there was one minor response. Gradual dose escalation may be required if similar patients are to be treated with high dose tamoxifen in conjunction with interferon.	Was tamoxifen tested for treatment of glioma patients?	The combination of oral tamoxifen (120 to 240 mg/m2/day) and subcutaneous interferon-alpha [6 x 10(6) U three times per week] was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure.
Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.	Is CD84 genetically associated with arthritis?	The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients)
Benralizumab is a humanized anti-IL5 receptor α (IL5Rα) monoclonal antibody (mAb) with enhanced (afucosylation) antibody-dependent cell-mediated cytotoxicity (ADCC) function. An ADCC reporter cell-based neutralizing antibody (NAb) assay was developed and characterized to detect NAb against benralizumab in human serum to support the clinical development of benralizumab. The optimal ratio of target cells to effector cells was 3:1. Neither parental benralizumab (fucosylated) nor benralizumab Fab resulted in ADCC activity, confirming the requirement for ADCC activity in the NAb assay. The serum tolerance of the cells was determined to be 2.5%. The cut point derived from normal and asthma serum samples was comparable. The effective range of benralizumab was determined, and 35 ng/mL [80% maximal effective concentration (EC80)] was chosen as the standard concentration to run in the assessment of NAb. An affinity purified goat anti-benralizumab polyclonal idiotype antibody preparation was shown to have NAb since it inhibited ADCC activity in a dose-dependent fashion. The low endogenous concentrations of IL5 and soluble IL5 receptor (sIL5R) did not demonstrate to interfere with the assay. The estimated assay sensitivities at the cut point were 1.02 and 1.10 μg/mL as determined by the surrogate neutralizing goat polyclonal and mouse monoclonal anti-drug antibody (ADA) controls, respectively. The assay can detect NAb (at 2.5 μg/mL) in the presence of 0.78 μg/mL benralizumab. The assay was not susceptible to non-specific matrix effects. This study provides an approach and feasibility of developing an ADCC cell-based NAb assay to support biopharmaceuticals with an ADCC function.	What is mechanism of action of Benralizumab?	Benralizumab is a humanized anti-IL5 receptor α (IL5Rα) monoclonal antibody (mAb) with enhanced (afucosylation) antibody-dependent cell-mediated cytotoxicity (ADCC) function.
The classic concept of the viability thresholds of ischemia differentiates between two critical flow rates, the threshold of electrical failure and the threshold of membrane failure. These thresholds mark the upper and lower flow limits of the ischemic penumbra which is thought to suffer only functional but not structural injury. Recent studies of the functional and metabolic disturbances suggest a more complex pattern of thresholds. At declining flow rates, protein synthesis is inhibited at first (at a threshold of about 0.55 ml/gm/min), followed by a stimulation of anaerobic glycolysis (at 0.35 ml/gm/min), the release of neurotransmitters and the beginning disturbance of energy metabolism (at about 0.20 ml/min), and finally the anoxic depolarization (< 0.15 ml/gm/min). The penumbra, as defined by the classic flow thresholds, does not remain viable for extended periods. Since viability of the tissue requires maintenance of energy-dependent metabolic processes, penumbra is redefined as a region of constrained blood supply in which the energy metabolism is preserved. Imaging of the penumbra by combining autoradiographic cerebral blood flow measurements with bioluminescent images of adenosine triphosphate (ATP) demonstrates a gradual expansion of the infarct core (in which ATP is depleted) into the penumbra until, after a few hours, the penumbra has disappeared. It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply. This explains pharmacological suppression of periinfarct depolarizations lowering the threshold of metabolic disturbances and reducing the volume of the ischemic infarct.	Does cortical spreading depression appear in ischemic penumbra following ischemic stroke?	It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply.
Thyroid involvement in Williams syndrome (WS) was recently reported in two small groups of patients, both showing an increased prevalence of elevation of TSH serum concentration; in one of the two reports, 70% of the patients demonstrated a hypoplasia of thyroid gland as well. In our institution, we currently follow a large population of WS patients who periodically undergo a multispecialist clinical evaluation that includes ultrasound evaluation of the thyroid gland, and levels of FT3, FT4, TSH, and anti-thyroid antibodies. Here, we report on the prevalence of thyroid structural and functional anomalies, in a population of 95 WS patients, half of them followed for more than 5 years. Our study confirms the increased incidence of both elevated TSH serum values (37.9% in our sample) and thyroid gland hypoplasia (74.7%). Moreover, we demonstrated that TSH elevation declines with age. For this reason, we suggest that a complete thyroid evaluation be performed in every patient with WS, and that this medical complication should be periodically searched for in follow-up visits.	Which hormone abnormalities are common in Williams syndrome ?	Our study confirms the increased incidence of both elevated TSH serum values (37.9% in our sample) and thyroid gland hypoplasia (74.7%).
Research focusing on the canonical adult myogenic progenitor, the skeletal muscle satellite cell, is still an ever-growing field 46 years from their initial description. Recent publications revealed numerous new aspects of satellite cell biology, starting from their developmental life to their role as the principal self-renewing myogenic stem cell in adult skeletal muscle and finally their loss during aging. The myogenic potential of satellite cells is under the molecular control of specific paired-box and bHLH transcription factors whose tightly orchestrated balance accounts for an effective skeletal muscle regeneration. New reports also demonstrate satellite cells relationships with blood vessels and the high myogenic potential of stem cell subsets related to both lineages.	What are the skeletal muscle satellite cells?	Research focusing on the canonical adult myogenic progenitor, the skeletal muscle satellite cell, is still an ever-growing field 46 years from their initial description.
The Melkersson-Rosenthal syndrome consists of a triad of recurrent lip and/or face swelling, fissured tongue, and intermittent facial palsy. Onset of the symptoms may occur during childhood, and treatment of the condition is difficult. We describe two children with Melkersson-Rosenthal syndrome in whom combination treatment with prednisone and minocycline proved effective and well tolerated.	List the classical triad of symptoms of the Melkersson–Rosenthal syndrome.	The Melkersson-Rosenthal syndrome consists of a triad of recurrent lip and/or face swelling, fissured tongue, and intermittent facial palsy.
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are activated by environmental stress. JNK is also activated by proinflammatory cytokines, such as TNF and IL-1, and Toll-like receptor ligands. This pathway, therefore, can act as a critical convergence point in immune system signaling for both adaptive and innate responses. Like other MAPKs, the JNKs are activated via the sequential activation of protein kinases that includes two dual-specificity MAP kinase kinases (MKK4 and MKK7) and multiple MAP kinase kinase kinases. MAPKs, including JNKs, can be deactivated by a specialized group of phosphatases, called MAP kinase phosphatases. JNK phosphorylates and regulates the activity of transcription factors other than c-Jun, including ATF2, Elk-1, p53 and c-Myc and non-transcription factors, such as members of the Bcl-2 family. The pathway plays a critical role in cell proliferation, apoptosis, angiogenesis and migration. In this review, an overview of the functions that are related to rheumatic diseases is presented. In addition, some diseases in which JNK participates will be highlighted.	Which MAP kinase phosphorylates the transcription factor c-jun?	The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are activated by environmental stress.
Active enhancers in mammals produce enhancer RNAs (eRNAs) that are bidirectionally transcribed, unspliced, and unstable. Enhancer regions are also enriched with long noncoding RNA (lncRNA) transcripts, which are typically spliced and substantially more stable. In order to explore the relationship between these two classes of RNAs, we analyzed DNase hypersensitive sites with evidence of bidirectional transcription, which we termed eRNA-producing centers (EPCs). EPCs found very close to transcription start sites of lncRNAs exhibit attributes of both enhancers and promoters, including distinctive DNA motifs and a characteristic chromatin landscape. These EPCs are associated with higher enhancer activity, driven at least in part by the presence of conserved, directional splicing signals that promote lncRNA production, pointing at a causal role of lncRNA processing in enhancer activity. Together, our results suggest that the conserved ability of some enhancers to produce lncRNAs augments their activity in a manner likely mediated through lncRNA maturation.	What are the eRNA-producing centers (EPCs)?	In order to explore the relationship between these two classes of RNAs, we analyzed DNase hypersensitive sites with evidence of bidirectional transcription, which we termed eRNA-producing centers (EPCs).
The diagnosis and treatment of multiple myeloma (MM) are progressing continuously. This article aims at summarizing the current status in the diagnosis and treatment of MM, emphasizing a clinical point of view. Prognostic factors can be determined by clinical parameters, molecular analyses and patient characteristics (e.g. age and comorbidities). The international staging system (ISS) and cytogenetics, such as the high-risk aberrations 17p deletion, translocation (4;14) and insertion 1q21 > 2 copies, are key factors in risk stratification of MM patients. Induction therapy based on novel agents, namely bortezomib, followed by subsequent high-dose melphalan and autologous stem cell transplantation is considered the standard of care for younger, newly diagnosed MM patients (≤ 70 years). Transplant-ineligible patients should receive thalidomide or bortezomib-based chemotherapy. The combination of bortezomib, melphalan and prednisone (VMP) was shown to significantly improve overall survival (OS) compared to melphalan and prednisone (MP, 56.4 vs. 43.1 months, p = < 0.01). Recent results suggest that lenalidomide-based therapy not incorporating alkylating agents might be a competitive alternative with a favorable toxicity profile for transplant-ineligible patients. Maintenance therapies are of increasing clinical significance in MM as they have the ability to prolong overall survival; however, thalidomide maintenance therapy should not be used in MM patients with high-risk cytogenetics as it shortens OS. Refractory or relapsed MM treatment continues to improve with the development of second and third generation immunomodulatory agents and proteasome inhibitors. For example, pomalidomide and dexamethasone vs. high-dose dexamethasone significantly improved OS (12.7 vs. 8.1 months, p = 0.03). Novel therapy strategies include targeted and stroma-directed approaches. Antibodies targeting CS-1 (elotuzumab) and CD38 (daratumumab) in particular are currently undergoing advanced clinical phase II/III trials.	Which molecule is targeted by Daratumumab?	Antibodies targeting CS-1 (elotuzumab) and CD38 (daratumumab) in particular are currently undergoing advanced clinical phase II/III trials.
Polycystic kidney disease (PKD) includes a group of disorders that are characterized by the presence of cysts in the kidney and other organs, including the pancreas. Here we show that in orpk mice, a model system for PKD that harbors a mutation in the gene that encodes the polaris protein, pancreatic defects start to occur at the end of gestation, with an initial expansion of the developing pancreatic ducts. Ductal dilation continues rapidly after birth and results in the formation of large, interconnected cysts. Expansion of pancreatic ducts is accompanied by apoptosis of neighboring acinar cells, whereas endocrine cell differentiation and islet formation appears to be unaffected. Polaris has been shown to co-localize with primary cilia, and these structures have been implicated in the formation of renal cysts. In the orpk pancreas, cilia numbers are reduced and cilia length is decreased. Expression of polycystin-2, a protein involved in PKD, is mislocalized in orpk mice. Furthermore, the cellular localization of beta-catenin, a protein involved in cell adhesion and Wnt signaling, is altered. Thus, polaris and primary cilia function are required for the maturation and maintenance of proper tissue organization in the pancreas.	Which is the most common disease attributed to malfunction or absence of primary cilia?	Polaris has been shown to co-localize with primary cilia, and these structures have been implicated in the formation of renal cysts
Allgrove syndrome (triple A syndrome) is an autosomal recessive disorder characterised by adrenocortical insufficiency, achalasia and alacrima. Patients also suffer from diverse neurological disorders. Allgrove syndrome is caused by mutations in the AAAS gene located at chromosome 12q13, which encodes for a tryptophan-aspartic acid (WD) repeat protein (aladin). The exact function of this protein is still not known.	List symptoms of Allgrove syndrome.	Allgrove syndrome (triple A syndrome) is an autosomal recessive disorder characterised by adrenocortical insufficiency, achalasia and alacrima.
Hereditary angioedema (HAE) manifests as intermittent, painful attacks of submucosal oedema affecting the larynx, gastrointestinal tract or limbs. Currently, acute treatment is available in Europe but not USA, and requires intravenous administration of a pooled blood product. HAE is most likely caused by dysinhibition of the contact cascade, resulting in overproduction of bradykinin. DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously. In a placebo-controlled Phase II trial in patients with HAE, DX-88 resulted in significant improvement in symptoms compared with placebo. A Phase III trial is ongoing. This review explains the pathophysiology of HAE and the mechanism by which DX-88, a non-intravenous, nonplasma-derived therapy, might improve the disease, and discusses the clinical course of HAE and available treatments. Finally, it explores the potential value and efficacy of DX-88 in treating HAE.	DX-88 is investigational name of which drug?	DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously.
In animals, RNA binding proteins (RBPs) and microRNAs (miRNAs) post-transcriptionally regulate the expression of virtually all genes by binding to RNA. Recent advances in experimental and computational methods facilitate transcriptome-wide mapping of these interactions. It is thought that the combinatorial action of RBPs and miRNAs on target mRNAs form a post-transcriptional regulatory code. We provide a database that supports the quest for deciphering this regulatory code. Within doRiNA, we are systematically curating, storing and integrating binding site data for RBPs and miRNAs. Users are free to take a target (mRNA) or regulator (RBP and/or miRNA) centric view on the data. We have implemented a database framework with short query response times for complex searches (e.g. asking for all targets of a particular combination of regulators). All search results can be browsed, inspected and analyzed in conjunction with a huge selection of other genome-wide data, because our database is directly linked to a local copy of the UCSC genome browser. At the time of writing, doRiNA encompasses RBP data for the human, mouse and worm genomes. For computational miRNA target site predictions, we provide an update of PicTar predictions.	What is the doRiNA database?	At the time of writing, doRiNA encompasses RBP data for the human, mouse and worm genomes