Datasets:

nirantk

/

geneticsQA-train

like 0

Which enzyme is inhibited by Imetelstat?

['The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells.', 'The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines.', 'Imetelstat inhibited telomerase activity in both subpopulations. ', 'Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells.', "GRN163L (Imetelstat) is a lipid-conjugated N3'→P5' thio-phosphoramidate oligonucleotide that blocks the template region of telomerase. ", 'We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. ', 'Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53.', 'The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.', ' Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. ', 'PURPOSE: Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. ', 'Imetelstat inhibited telomerase activity in both subpopulations.', 'Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro.', 'Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells.', 'When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited.', 'Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations.', 'Imetelstat (a telomerase antagonist) exerts off‑target effects on the cytoskeleton.', 'The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation.', 'We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT.', "This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. ", 'Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks.', 'Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.', 'Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. ', 'When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. ', 'Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. ', 'Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia.', 'The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines.', 'A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis.', 'We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. ', 'In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. ', 'Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. ', 'BACKGROUND: Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. ', 'Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase.METHODS: We sought to obtain preliminary information on the therapeutic activity and safety of imetelstat in patients with high-risk or intermediate-2-risk myelofibrosis. ', 'Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. ']

['Imetelstat works by inhibiting telomerase.']

['telomerase']

Which genes does thyroid hormone receptor beta1 regulate in the liver?

['our data suggests that TRbeta1-mediated down regulation of hepatic LDLr gene may play a critical role in iodine excess-induced hypercholesterolemic effects.', 'These data suggest that ChREBP mRNA expression is positively regulated by TR-beta1 and TH at the transcriptional level in mammals. This novel observation indicates that TH fine-tunes hepatic lipogenesis via regulating SREBP-1c and ChREBP gene expression reciprocally.', 'In contrast treatment with L-T3 produced an increase in S14 and ME but no change in TR beta-/- mice. From these results, it can be concluded that regulation of HR and EE are independent of TR beta. With the exception of serum cholesterol concentration and liver ME mRNA accumulation, all other markers of TH action examined during TH deprivation exhibited the expected responses in the absence of TR beta.', 'However, the T3-activated expression of the GH gene in GH3-PV and ME gene in SK-Hep-1-PV was repressed by approximately 30% and 90%, respectively, indicating the lack of correlation of PV/TRpbeta1 protein ratio with the dominant negative potency of mutant PV.', 'Transient cotransfection of P450R promoter/chloramphenicol acetyl transferase (CAT) constructs and the thyroid hormone receptor beta1 (TR beta1) expression plasmid into rat hepatoma H4IIE cells resulted in a 2.4-fold induction of promoter activity that was both T3 and TR beta1 dependent.', 'At the molecular level, we detected a dose-dependent attenuation of hepatic low density lipoprotein receptor (LDLr) and thyroid hormone receptor beta1 (TRbeta1) expression in parallel to the change of serum cholesterol.']

['LDL receptor"//\n"ChREBP"//\n"ME", "malic enzyme"//\n"cytochrome P450 oxidoreductase"//']

['LDL receptor', 'ChREBP', 'Carbohydrate response element binding protein', 'ME', 'malic enzyme', 'cytochrome P450 oxidoreductase']

What is the evolutionary process described by the "Muller's ratchet" model?

["Muller's ratchet is a paradigmatic model for the accumulation of deleterious mutations in a population of finite size. A click of the ratchet occurs when all individuals with the least number of deleterious mutations are lost irreversibly due to a stochastic fluctuation.", 'Population bottlenecks can have major effects in the evolution of RNA viruses, but their possible influence in the evolution of DNA viruses is largely unknown.', "The accumulation of deleterious mutations of a population directly contributes to the fate as to how long the population would exist, a process often described as Muller's ratchet with the absorbing phenomenon.", "Genetic diversity is thought to be important in allowing RNA viruses to explore sequence space, facilitating adaptation to changing environments and hosts. Some arboviruses that infect both a mosquito vector and a mammalian host are known to experience population bottlenecks in their vectors, which may constrain their genetic diversity and could potentially lead to extinction events via Muller's ratchet.", "The accumulation of deleterious mutations is driven by rare fluctuations that lead to the loss of all mutation free individuals, a process known as Muller's ratchet.", "The vast majority of mutations are deleterious and are eliminated by purifying selection. Yet in finite asexual populations, purifying selection cannot completely prevent the accumulation of deleterious mutations due to Muller's ratchet: once lost by stochastic drift, the most-fit class of genotypes is lost forever.", "Primary bacterial endosymbionts of insects (p-endosymbionts) are thought to be undergoing the process of Muller's ratchet where they accrue slightly deleterious mutations due to genetic drift in small populations with negligible recombination rates.", 'Computer simulations of substitution of favorable mutants and of the long-term increase of deleterious mutants verified the essential correctness of the original Fisher-Muller argument and the reality of the Muller ratchet mechanism.', "The theory of Muller' Ratchet predicts that small asexual populations are doomed to accumulate ever-increasing deleterious mutation loads as a consequence of the magnified power of genetic drift and mutation that accompanies small population size.", 'It also predicts the "ratchet mechanism" discovered by Muller, who pointed out that deleterious mutants would more readily increase in a population without recombination.', 'We also demonstrate that during repeated genetic bottleneck passages, accumulation of deleterious mutations does occur in a stepwise (ratchet-like) manner as originally proposed by Muller.', 'Muller proposed that an asexual organism will inevitably accumulate deleterious mutations, resulting in an increase of the mutational load and an inexorable, ratchet-like, loss of the least mutated class [Muller, H.', 'In asexual populations, as Muller noted, the loss is irreversible and the load of deleterious mutations increases in a ratchet-like manner with the successive loss of the least-mutated individuals.', 'BACKGROUND: The accumulation of deleterious mutations of a population directly contributes to the fate as to how long the population would exist, a process often described as Mullers ratchet with the absorbing phenomenon.', 'The accumulation of deleterious mutations is driven by rare fluctuations that lead to the loss of all mutation free individuals, a process known as Mullers ratchet.', "Deleterious mutations can accumulate in asexual haploid genomes through the process known as Muller's ratchet.", "Deleterious mutations can accumulate in asexual haploid genomes through the process known as Muller's ratchet", "The accumulation of deleterious mutations of a population directly contributes to the fate as to how long the population would exist, a process often described as Muller's ratchet with the absorbing phenomenon"]

["The vast majority of mutations are deleterious and are eliminated by purifying selection. Yet in finite populations, purifying selection cannot completely prevent the accumulation of deleterious mutations. Muller's ratchet is a paradigmatic model for the accumulation of deleterious mutations in a population of finite size, due to genetic drift. Muller's ratchet suggests that population bottlenecks, which may constrain the genetic diversity of a population, could lead to extinction of all individuals with the least number of deleterious mutations, due to a stochastic fluctuation. When the most-fit class of genotypes is lost, it is lost irreversibly."]

[]

What are the skeletal muscle satellite cells?

['Skeletal muscle satellite cells (SCs) are Pax7(+) myogenic stem cells that reside between the basal lamina and the plasmalemma of the myofiber. In mature muscles, SCs are typically quiescent, but can be activated in response to muscle injury. Depending on the magnitude of tissue trauma, SCs may divide minimally to repair subtle damage within individual myofibers or produce a larger progeny pool that forms new myofibers in cases of overt muscle injury', 'Satellite cells (SC) are quiescent adult muscle stem cells critical for postnatal development', 'Satellite cells are multipotential stem cells that mediate postnatal muscle growth and respond differently to temperature based upon aerobic versus anaerobic fiber-type origin', 'Skeletal muscle mass, function, and repair capacity all progressively decline with aging, restricting mobility, voluntary function, and quality of life. Skeletal muscle repair is facilitated by a population of dedicated muscle stem cells (MuSCs), also known as satellite cells, that reside in anatomically defined niches within muscle tissues. In adult tissues, MuSCs are retained in a quiescent state until they are primed to regenerate damaged muscle through cycles of self-renewal divisions', 'Muscle satellite cells are a stem cell population required for postnatal skeletal muscle development and regeneration, accounting for 2-5% of sublaminal nuclei in muscle fibers.', 'Skeletal muscle satellite cells are adult muscle-derived stem cells receiving increasing attention.', 'Skeletal muscle satellite cells are quiescent mononucleated myogenic cells, located between the sarcolemma and basement membrane of terminally-differentiated muscle fibres.', 'The acquisition of a proliferating-cell status from a quiescent state as well as the shift between proliferation and differentiation are key developmental steps in skeletal-muscle stem cells (satellite cells) to provide proper muscle regeneration', 'Satellite cells are essential for skeletal muscle regeneration as they ultimately provide the myogenic precursors that rebuild damaged muscle tissue', 'Skeletal muscle satellite cells are committed to myogenesis and do not spontaneously adopt nonmyogenic fates.', 'These are normally quiescent in adult muscle, but act as a reserve population of cells, able to proliferate in response to injury and give rise to regenerated muscle and to more satellite cells.', 'Satellite cell-derived muscle precursor cells may be used to repair and regenerate damaged or myopathic skeletal muscle, or to act as vectors for gene therapy.', '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.', ' Skeletal muscle satellite cells, located between the basal lamina and plasma membrane of myofibers, are required for skeletal muscle regeneration. The capacity of satellite cells as well as other cell lineages including mesoangioblasts, mesenchymal stem cells, and side population (SP) cells to contribute to muscle regeneration has complicated the identification of a satellite stem cell.', ' Muscle satellite cells are a stem cell population required for postnatal skeletal muscle development and regeneration, accounting for 2-5% of sublaminal nuclei in muscle fibers. In adult muscle, satellite cells are normally mitotically quiescent.', ' Skeletal muscle is a highly specialized tissue composed of non-dividing, multi-nucleated muscle fibres that contract to generate force in a controlled and directed manner. Skeletal muscle is formed during embryogenesis from a subset of muscle precursor cells, which generate both differentiated muscle fibres and specialized muscle-forming stem cells known as satellite cells.', ' Skeletal muscle satellite cells are adult muscle-derived stem cells receiving increasing attention. Sheep satellite cells have a greater similarity to human satellite cells with regard to metabolism, life span, proliferation and differentiation, than satellite cells of the rat and mouse.', 'Skeletal muscle satellite cells are adult muscle-derived stem cells receiving increasing attention.', 'Skeletal muscle satellite cells play key roles in postnatal muscle growth and regeneration.', 'Muscle satellite cells are a stem cell population required for postnatal skeletal muscle development and regeneration, accounting for 2-5% of sublaminal nuclei in muscle fibers.', 'Skeletal muscle satellite cells are quiescent mononucleated myogenic cells, located between the sarcolemma and basement membrane of terminally-differentiated muscle fibres.', 'Skeletal muscle satellite cells, located between the basal lamina and plasma membrane of myofibers, are required for skeletal muscle regeneration.', 'Skeletal muscle is formed during embryogenesis from a subset of muscle precursor cells, which generate both differentiated muscle fibres and specialized muscle-forming stem cells known as satellite cells.']

['Skeletal muscle satellite cells (SCs) are Pax7(+) myogenic stem cells that reside between the basal lamina and the plasmalemma of the myofiber. In mature muscles, SCs are typically quiescent, but can be activated in response to muscle injury. Depending on the magnitude of tissue trauma, SCs may divide minimally to repair subtle damage within individual myofibers or produce a larger progeny pool that forms new myofibers in cases of overt muscle injury', 'Skeletal muscle satellite cells (SCs) are Pax7(+) myogenic stem cells that reside between the basal lamina and the plasmalemma of the myofiber. In mature muscles, SCs are typically quiescent, but can be activated in response to muscle injury. Depending on the magnitude of tissue trauma, SCs may divide minimally to repair subtle damage within individual myofibers or produce a larger progeny pool that forms new myofibers in cases of overt muscle injury.']

[]

What are some treatment options for stress urinary incontinence (SUI) that persist after 12 months?

['["The initial treatment for SUI that persists after 12 months consists of conservative measures such as pelvic floor muscle exercises and behavioral therapy. Properly selected and informed patients can also be treated efficiently with minimally invasive procedures such as the implantation of a male suburethral sling, although the experience with such devices is not extensive. However, the implantation of artificial urinary sphincter is the gold standard therapy.", "treatments such as periurethral injection of bulking agents, artificial urinary sphincter (AUS) implantation, and sub-urethral sling positioning. The artificial urethral sphincter has represented, until today, the gold standard but, in the recent years, sling systems have been investigated as minimally invasive alternative options.", "Today, three different sling procedures are commonly performed: bone-anchored, readjustable, and trans-obturator slings systems.", "The bone anchored suburethral synthetic sling is a simple and attractive procedure that can produce immediate good results with low morbidity, especially when strictly selected patients are treated. ", "BAUS implantation is a safe, effective, minimally invasive option for iatrogenic male incontinence due to ISD. It compares favourably with AUS."]']

Some treatment options for stress urinary incontinence (SUI) that persist after 12 months include conservative measures such as pelvic floor muscle exercises and behavioral therapy, as well as minimally invasive procedures like the implantation of a male suburethral sling. The gold standard therapy is the implantation of an artificial urinary sphincter.

[]

How could iPSCs be used for the treatment of diabetes?

['Human induced pluripotent stem cells (hiPSCs) have raised the possibility that patient-specific insulin-secreting cells might be derived from somatic cells through cell fate reprogramming.', 'We demonstrated for the first time that miRNAs might be ideal substitutes to induce pancreatic differentiation in hiPSCs.', 'Pluripotent stem cells as a potential tool for disease modelling and cell therapy in diabetes.', 'One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs). ESCs and iPSCs have a great potential to differentiate into all cell types, and they have a high ability to differentiate into insulin-secreting β cells. ', 'Several iPSC lines have been recently generated from patients with different types of diabetes, and most of these cell lines are able to differentiate into insulin-secreting β cells. In this review, we summarize recent advances in the differentiation of pancreatic β cells from PSCs, and describe the challenges for their clinical use in diabetes cell therapy.', 'The aim of this study was to evaluate the effect of PDX-1 (pancreatic and duodenal homeobox-1), NeuroD1 (neurogenic differentiation-1) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homolog A) in the differentiation of induced pluripotent stem cells (iPSCs) into insulin-producing cells and to explore this new approach of cell transplantation therapy for type 1 diabetes in mice.', ' iPSCs were infected with adenovirus (Ad-Mouse PDX-1-IRES-GFP, Ad-Mouse NeuroD1-IRES-GFP and Ad-Mouse Mafa-IRES-GFP) and then differentiated into insulin-producing cells in vitro. ', 'The insulin-producing cells we obtained from three-gene-modified EBs may be used as seed cells for tissue engineering and may represent a cell replacement strategy for the production of β cells for the treatment of type 1 diabetes.', 'To date, the pathogenesis of diabetes is far to be understood, and there is no permanent treatment available for diabetes. One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs).']

['One of the promising approaches to cure diabetes is to use induced PCSs (iPSCs) and to differentiate them into insulin-secreting β cells. The induction of iPSC differentiation into insulin-secreting cells can be achieved in several ways, such as with the use of microRNAs, or adenoviral transfection with selected genes.']

[]

Is TREM2 associated with Alzheimer's disease?

["Absence of TREM2 polymorphisms in patients with Alzheimer's disease and Frontotemporal Lobar Degeneration", ' These data demonstrate that TREM2 coding region is highly conserved, implying a crucial role of this receptor. Further studies, including a functional analysis, are certainly required to clarify the role of TREM2 in neurodegenerative processes', "Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4", 'We observed an enrichment of rare variants across TREM2 in both AD and FTD patients compared to controls, most notably in the extracellular IgV-set domain', 'None of the rare variants individually reached significant association, but the frequency of p.R47H was increased ~ 3-fold in both AD and FTD patients compared to controls, in line with previous reports', 'Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general.', "non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimer's disease (AD)", 'These data strongly support the important role of p.R47H in AD risk, and suggest that this rare genetic variant is not related to FTD.', ' Higher levels of TREM2 mRNA (p = 0.002) and protein (p < 0.001) were identified in AD patients', 'Our results indicate that TREM2 might serve as a novel noninvasive biomarker for AD diagnosis', "studies have identified the rs75932628 (R47H) variant in TREM2 as an Alzheimer's disease risk factor with estimated odds ratio ranging from 2.9 to 5.1", "This study replicates the association between R47H and Alzheimer's disease risk in a large, population-based sample, and estimates the population frequency and attributable risk of this rare variant", 'Moreover, mutation scanning of the five exons of TREM2 failed to detect the presence of novel polymorphisms', "A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland", "We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers", "Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes", "rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD)", 'These results confirm the association between this variant and AD and underline its involvement in early-onset cases', "recent studies have reported the association of rs75932628-T in the TREM2 gene with the risk for Alzheimer's disease (AD)", 'Rs75932628-T is a rare nonsynonymous variant (p.R47H) that confers a high risk of AD with an effect size similar to that of the APOE ɛ4 allele', 'Here, we report the first positive replication study in a Spanish population and confirm that TREM2 rs75932628-T is associated with the risk for AD', "works have demonstrated a rare functional variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer's disease (AD), with an odds ratio similar to that of the apolipoprotein E ε4 allele", 'The reduced function of TREM2 was speculated to be the main cause in the pathogenic effects of this risk variant, and TREM2 is highly expressed in white matter, as well as in the hippocampus and neocortex, which is partly consistent with the pathological features reported in AD brain, indicating the possible involvement of TREM2 in AD pathogenesis', 'Emerging evidence has demonstrated that TREM2 could suppress inflammatory response by repression of microglia-mediated cytokine production and secretion, which may prevent inflammation-induced bystander damage of neurons', 'TREM2 also participates in the regulation of phagocytic pathways that are responsible for the removal of neuronal debris', 'Based on the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2 might provide new opportunities for AD treatment', 'Under the hypothesis that low-prevalence variants showing moderate-to-high effect size may be associated with risk for sAD, two independent research groups have demonstrated that a rare variant (rs75932628, encoding a substitution of arginine by histidine at residue 47 (R47H), in the TREM2 gene, which encodes the triggering receptor expressed on myeloid cells 2) is significantly associated with an increased susceptibility to sAD', 'Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD', 'TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk', "evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease", 'These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease', "The association of TREM2 variants with AD brings innate immune signaling into the light, affirming innate immunity's role as a significant factor in AD pathogenesis", 'The purpose of this paper is to discuss these recent developments including the potential role that TREM2 normally plays and how loss of function may contribute to AD pathogenesis by enhancing oxidative stress and inflammation within the CNS', 'Even though we are more at the beginning than at the end of sAD genetics, there is some reason for optimism given the recent identification of novel risk or protective variants (such as rare TREM2 and APP mutations) showing strong statistical associations with sAD']

["A rare variant of the TREM2 gene, which encodes the triggering receptor encoded in myeloid cells 2 (rs75932628-T) causing a R47H substitution has been associated with both early and late onset Alzheimer's disease in various populations. Emerging evidence has demonstrated that TREM2 could suppress inflammatory response by repression of microglia-mediated cytokine production and secretion, which may prevent inflammation-induced bystander damage of neurons. Higher levels of TREM2 mRNA (p = 0.002) and protein (p < 0.001) were identified in AD patients which indicates that TREM2 might serve as a novel noninvasive biomarker for AD diagnosis. Based on the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2 might provide new opportunities for AD treatment."]

['yes']

What is DECKO?

['DECKO: Single-oligo, dual-CRISPR deletion of genomic elements including long non-coding RNAs', 'We present a dual CRISPR tool, DECKO, which is cloned using a single starting oligonucleotide, thereby affording simplicity and scalability to CRISPR knockout studies of non-coding genomic elements, including long non-coding RNAs.', ' We present a vector system adapted for this purpose called DECKO (Double Excision CRISPR Knockout), which applies a simple two-step cloning to generate lentiviral vectors expressing two guide RNAs (gRNAs) simultaneously. The key feature of DECKO is its use of a single 165 bp starting oligonucleotide carrying the variable sequences of both gRNAs, making it fully scalable from single-locus studies to complex library cloning.', 'DECKO: Single-oligo, dual-CRISPR deletion of genomic elements including long non-coding RNAs.', 'We present a vector system adapted for this purpose called DECKO (Double Excision CRISPR Knockout), which applies a simple two-step cloning to generate lentiviral vectors expressing two guide RNAs (gRNAs) simultaneously.', 'The key feature of DECKO is its use of a single 165 bp starting oligonucleotide carrying the variable sequences of both gRNAs, making it fully scalable from single-locus studies to complex library cloning.', 'We present a vector system adapted for this purpose called DECKO (Double Excision CRISPR Knockout), which applies a simple two-step cloning to generate lentiviral vectors expressing two guide RNAs (gRNAs) simultaneously', 'The key feature of DECKO is its use of a single 165 bp starting oligonucleotide carrying the variable sequences of both gRNAs, making it fully scalable from single-locus studies to complex library cloning.We apply DECKO to deleting the promoters of one protein-coding gene and two oncogenic lncRNAs, UCA1 and the highly-expressed MALAT1, focus of many previous studies employing RNA interference approaches', 'These clones have reductions in steady-state MALAT1 RNA levels of up to 98 % and display reduced proliferation rates.We present a dual CRISPR tool, DECKO, which is cloned using a single starting oligonucleotide, thereby affording simplicity and scalability to CRISPR knockout studies of non-coding genomic elements, including long non-coding RNAs', 'We present a vector system adapted for this purpose called DECKO (Double Excision CRISPR Knockout), which applies a simple two-step cloning to generate lentiviral vectors expressing two guide RNAs (gRNAs) simultaneously.', 'The key feature of DECKO is its use of a single 165 bp starting oligonucleotide carrying the variable sequences of both gRNAs, making it fully scalable from single-locus studies to complex library cloning.We apply DECKO to deleting the promoters of one protein-coding gene and two oncogenic lncRNAs, UCA1 and the highly-expressed MALAT1, focus of many previous studies employing RNA interference approaches.', 'These clones have reductions in steady-state MALAT1 RNA levels of up to 98 % and display reduced proliferation rates.We present a dual CRISPR tool, DECKO, which is cloned using a single starting oligonucleotide, thereby affording simplicity and scalability to CRISPR knockout studies of non-coding genomic elements, including long non-coding RNAs.', 'DECKO: Single-oligo, dual-CRISPR deletion of genomic elements including long non-coding RNAs.', 'We present a dual CRISPR tool, DECKO, which is cloned using a single starting oligonucleotide, thereby affording simplicity and scalability to CRISPR knockout studies of non-coding genomic elements, including long non-coding RNAs..']

['DECKO (Double Excision CRISPR Knockout) is a dual CRISPR tool, which is cloned using a single starting oligonucleotide, thereby affording simplicity and scalability to CRISPR knockout studies of non-coding genomic elements, including long non-coding RNAs.']

[]

Which polymerase transcribes pri-miRNAs?

['Previous studies in vivo reported that processing of primary microRNA (pri-miRNA) is coupled to transcription by RNA polymerase II (RNAP II) and can occur co-transcriptionally. ', 'we have established a robust in vivo system in which pri-miRNA is transcribed by RNAP II and processed to pre-miRNA in HeLa cell nuclear extracts.', 'In addition, obvious enrichments of three histone modifications (H2BK5me1, H3K36me3 and H4K20me1) as well as RNA Polymerase II (RNAPII) were observed on pre-miRNA genomic sequences corresponding to the active-promoter miRNAs and expressed miRNAs', 'Because the transcripts of most miRNA genes are the products of type-II RNA polymerase, pri-miRNA has a poly(A) tail and appears in expressed sequence tags (EST)', 'Recent evidence indicates that miRNA genes are transcribed by RNA polymerase II (Pol II)', 'Since Pol II transcripts are capped, we hypothesized that CBP (cap-binding protein) 20 and 80 may bind to capped primary miRNA (pri-miRNA) transcripts and play a role in their processing. Here, we show that cbp20 and cbp80 mutants have reduced miRNA levels and increased pri-miRNA levels.', " Analogously to mRNAs, the non-protein-encoding pri-miRNAs are synthesized by RNA polymerase II and post-transcriptionally modified by addition of a 5'-cap and a 3'-poly (A) tail.", 'Plant miRNAs are first transcribed as stem-loop primary miRNAs (pri-miRNAs) by RNA polymerase II,then cleaved in the nucleus into mature miRNAs by Dicer-like 1 (DCL1).', 'miRNAs are excised in a stepwise process from double-stranded RNA precursors that are embedded in long RNA polymerase II primary transcripts (pri-miRNA).', 'Plant pri-miRNAs are transcribed by DNA-dependent RNA polymerase II (Pol II) and their levels are determined through transcription and degradation, whereas pri-miRNA processing is affected by its structure, splicing, alternative splicing, loading to the processor and the processor activity, which involve in many accessory proteins.', 'Specifically, MHV68 miRNAs are transcribed from RNA polymerase III promoters located within adjacent viral tRNA-like sequences.', 'Mammalian miRNA biogenesis begins with cotranscriptional cleavage of RNA polymerase II (Pol II) transcripts by the Microprocessor complex.', 'miRNAs are excised in a stepwise process from double-stranded RNA precursors that are embedded in long RNA polymerase II primary transcripts (pri-miRNA).', 'Canonical primary microRNA (pri-miRNA) precursors are transcribed by RNA polymerase II and then processed by the Drosha endonuclease to generate approximately 60 nt pre-miRNA hairpins.', 'Treatment of cells overexpressing NF90 and NF45 with an RNA polymerase II inhibitor, alpha-amanitin, did not reduce the amounts of pri-miRNAs, suggesting that the accumulation of pri-miRNAs is not due to transcriptional activation.', 'Plant miRNAs are first transcribed as stem-loop primary miRNAs (pri-miRNAs) by RNA polymerase II,then cleaved in the nucleus into mature miRNAs by Dicer-like 1 (DCL1)', 'Plant pri-miRNAs are transcribed by DNA-dependent RNA polymerase II (Pol II) and their levels are determined through transcription and degradation, whereas pri-miRNA processing is affected by its structure, splicing, alternative splicing, loading to the processor and the processor activity, which involve in many accessory proteins', 'The majority of human miRNA genes is transcribed by polymerase II and can be classified as class II genes similar to protein-coding genes.', 'Plant pri-miRNAs are transcribed by DNA-dependent RNA polymerase II (Pol II) and their levels are determined through transcription and degradation, whereas pri-miRNA processing is affected by its structure, splicing, alternative splicing, loading to the processor and the processor activity, which involve in many accessory proteins.', 'In plant, primary transcripts (pri-miRNAs) transcribed from miRNA genes by RNA polymerase II are first processed into stem-loop pre-miRNAs and further chopped into ∼21\u2009nt long miRNAs by RNase III-like enzyme DCL1.', 'These small RNAs are first transcribed by RNA polymerase II as a primary miRNA (pri-miRNA) transcript, which is then cleaved into the precursor miRNA (pre-miRNA).', 'Here we present the first direct evidence that miRNA genes are transcribed by RNA polymerase II (pol II).', 'Plant miRNAs are first transcribed as stem-loop primary miRNAs (pri-miRNAs) by RNA polymerase II,then cleaved in the nucleus into mature miRNAs by Dicer-like 1 (DCL1).', 'MicroRNA genes are transcribed by RNA polymerase II.', 'Here we have established a robust in vivo system in which pri-miRNA is transcribed by RNAP II and processed to pre-miRNA in HeLa cell nuclear extracts.', 'Although it is assumed that miRNA promoters are similar in structure to gene promoters, since both are transcribed by RNA polymerase II (Pol II), computational validations exhibit poor performance of gene promoter prediction methods on miRNAs.']

['Recent evidence indicates that miRNA genes are transcribed by RNA polymerase II (Pol II) we have established a robust in vivo system in which pri-miRNA is transcribed by RNAP II and processed to pre-miRNA in HeLa cell nuclear extracts.', 'Previous studies in vivo reported that processing of primary microRNA (pri-miRNA) is coupled to transcription by RNA polymerase II (RNAP II) and can occur co-transcriptionally. ', "The non-protein-encoding pri-miRNAs are synthesized by RNA polymerase II and post-transcriptionally modified by addition of a 5'-cap and a 3'-poly (A) tail.", " Analogously to mRNAs, the non-protein-encoding pri-miRNAs are synthesized by RNA polymerase II and post-transcriptionally modified by addition of a 5'-cap and a 3'-poly (A) tail. Recent evidence indicates that miRNA genes are transcribed by RNA polymerase II (Pol II)", 'Previous studies in vivo reported that processing of primary microRNA (pri-miRNA) is coupled to transcription by RNA polymerase II (RNAP II) and can occur co-transcriptionally. we have established a robust in vivo system in which pri-miRNA is transcribed by RNAP II and processed to pre-miRNA in HeLa cell nuclear extracts.', "Because the transcripts of most miRNA genes are the products of type-II RNA polymerase, pri-miRNA has a poly(A) tail and appears in expressed sequence tags (EST). Analogously to mRNAs, the non-protein-encoding pri-miRNAs are synthesized by RNA polymerase II and post-transcriptionally modified by addition of a 5'-cap and a 3'-poly (A) tail."]

['RNA polymerase II', 'RNAPII']

Describe clinical presentation of Ambras syndrome.

['In 1993, Baumister et al. described congenital hypertrichosis lanuginose or Ambras syndrome: a distinct form of congenital hypertrichosis characterized by excessive hair growth over the body and face associated with facial and occasional dental anomalies. ', 'Ambras syndrome (AS) is a rare form of congenital hypertrichosis with excessive hair on the shoulders, face and ears. ', 'Ambras syndrome (AMS) is a unique form of universal congenital hypertrichosis. In patients with this syndrome, the whole body is covered with fine long hair, except for areas where normally no hair grows. There is accompanying facial dysmorphism and teeth abnormalities, including retarded first and second dentition and absence of teeth. ', 'We report two siblings with congenital generalized hypertrichosis and distinctive facial appearance consistent with the dysmorphic facial features described in Ambras syndrome.', 'Ambras syndrome is a rare and special form of congenital hypertrichosis, characterized by dysmorphic facial features and familial pattern of inheritance.', 'Ambras syndrome (AS) is a special form of congenital universal hypertrichosis described for the first time by Baumeister et al. (1). ', 'Ambras syndrome (AMS) is a unique form of universal congenital hypertrichosis. ', 'Ambras syndrome (AMS) is a unique form of congenital universal hypertrichosis. ', 'Ambras syndrome (AMS) is a unique form of universal congenital hypertrichosis.', 'Ambras syndrome (AMS) is a unique form of congenital universal hypertrichosis.', '[Ambras syndrome--a form of generalised congenital hypertrichosis].', 'described congenital hypertrichosis lanuginose or Ambras syndrome: a distinct form of congenital hypertrichosis characterized by excessive hair growth over the body and face associated with facial and occasional dental anomalies.']

['Ambras syndrome is a distinct form of congenital hypertrichosis characterized by excessive hair growth over the body and face associated with facial and occasional dental anomalies. In patients with this syndrome, the whole body is covered with fine long hair, except for areas where normally no hair grows. There is accompanying facial dysmorphism and teeth abnormalities, including retarded first and second dentition and absence of teeth.']

[]

Which markers are screened with the triple test for the detection of syndromes in fetus?

['Our study aimed at calculation and validation of the triple marker medians used in screening Egyptian females as well as to recommend programme conventions to unify screening in this country.', 'Chorionic gonadotropin (CG), α-fetoprotein (AFP) and unconjugated oestriol (uE3) were measured on Siemens Immulite analyzer.', 'Triple test screening for Down syndrome: an Egyptian-tailored study.', 'The purpose of this article was to evaluate the reliability of maternal serum triple marker screening of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol for the prenatal diagnosis of fetal chromosomal abnormalities in Turkish pregnant women.', 'Second trimester triple test is an effective screening tool for detecting fetal Down syndrome in Turkish women.', "The aim of this prospective study was to compare triple test screening (alpha-fetoprotein, beta-chorionic gonadotrophin and unconjugated oestriol) with amniocentesis in the detection of fetuses with Down's syndrome in women of 35 years of age or more. ", "The aim of this prospective study was to compare triple test screening (alpha-fetoprotein, beta-chorionic gonadotrophin and unconjugated oestriol) with amniocentesis in the detection of fetuses with Down's syndrome in women of 35 years of age or more.", 'None of the other five markers added more than 2% detection for the same false-positive rate.The performance of screening using maternal age and serum-free beta-hCG and PAPP-A at 10 weeks of pregnancy was better than the double test (alpha-fetoprotein and hCG with maternal age) and similar to the triple test (alpha-fetoprotein, unconjugated oestriol and hCG with maternal age) at 15-22 weeks.', 'To make recommendations to physicians providing prenatal care on (1) whether prenatal screening for and diagnosis of Down syndrome (DS) is advisable and (2) alternative screening and diagnosis manoeuvres."Triple-marker" screening of maternal serum levels of alpha-fetoprotein, human chorionic gonadotropin and unconjugated estriol; fetal ultrasonographic examination; amniocentesis; and chorionic villus sampling (CVS).Accuracy of detection of DS in fetuses, and risks to the mother, including psychologic distress, and to the fetus from the screening and diagnostic interventions.A MEDLINE search for relevant a', 'A decision analytic model was designed for women at increased risk for a DS fetus due to either advanced maternal age (AMA) or a positive expanded maternal serum alpha fetoprotein (MSAFP) screening test, also known as a triple screen (+triple) test.', 'These tests have a limited detection rate for Down syndrome: approximately 40% for hCG or free beta-subunit alone, approximately 60% for the triple screen test, and approximately 70% for the quadruple marker test, all at 5%, or a relatively high, false-positive rate.', 'Serum human chorionic gonadotropin (hCG) and hCG free beta-subunit tests are used in combination with unconjugated estriol and alpha-fetoprotein in the triple screen test, and with the addition of inhibin-A in the quadruple marker test for detecting Down syndrome in the second trimester of pregnancy.', 'Initial and revised screen-positive rates and detection rates were reviewed for women undergoing triple-marker testing (maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol).']

['The markers that are screened with the triple test for the detection of syndromes in fetus are:\n1) alpha-fetoprotein (AFP), \n2) beta-chorionic gonadotrophin (beta-CG) and \n3) unconjugated oestriol (uE3).']

['alpha-fetoprotein', 'AFP', 'α-fetoprotein', 'beta-chorionic gonadotrophin', 'beta-CG', 'unconjugated oestriol', 'uE3']

What is the application of the ASSET algorithm in C.elegans?

['ASSET: a robust algorithm for the automated segmentation and standardization of early Caenorhabditis elegans embryos.', 'The early Caenorhabditis elegans embryo is an attractive model to investigate evolutionarily conserved cellular mechanisms. However, there is a paucity of automated methods to gather quantitative information with subcellular precision in this system. We developed ASSET (Algorithm for the Segmentation and the Standardization of C. elegans Time-lapse recordings) to fill this need. ASSET automatically detects the eggshell and the cell cortex from DIC time-lapse recordings of live one-cell-stage embryos and can also track subcellular structures using fluorescent time-lapse microscopy. Importantly, ASSET standardizes the data into an absolute coordinate system to allow robust quantitative comparisons between embryos. We illustrate how ASSET can efficiently gather quantitative data on the motion of centrosomes and precisely track cortical invaginations, revealing hitherto unnoticed differences between wild-type and saps-1(RNAi) embryos. In summary, we establish ASSET as a novel tool for the efficient quantification and standardization of images from early C. elegans embryos.', 'In summary, we establish ASSET as a novel tool for the efficient quantification and standardization of images from early C. elegans embryos.', 'We developed ASSET (Algorithm for the Segmentation and the Standardization of C. elegans Time-lapse recordings) to fill this need. ASSET automatically detects the eggshell and the cell cortex from DIC time-lapse recordings of live one-cell-stage embryos and can also track subcellular structures using fluorescent time-lapse microscopy. Importantly, ASSET standardizes the data into an absolute coordinate system to allow robust quantitative comparisons between embryos. ', 'In summary, we establish ASSET as a novel tool for the efficient quantification and standardization of images from early C. elegans embryos.']

['ASSET (Algorithm for the Segmentation and the Standardization of C. elegans Time-lapse recordings) is a robust algorithm for the automated segmentation and standardization of early Caenorhabditis elegans embryos. It gathers quantitative information with subcellular precision in the early Caenorhabditis elegans embryo, which is an attractive model to investigate evolutionarily conserved cellular mechanisms. ASSET automatically detects the eggshell and the cell cortex from DIC time-lapse recordings of live one-cell-stage embryos and can also track subcellular structures using fluorescent time-lapse microscopy. Importantly, ASSET standardizes the data into an absolute coordinate system to allow robust quantitative comparisons between embryos.', 'The early Caenorhabditis elegans embryo is an attractive model to investigate evolutionarily conserved cellular mechanisms. In summary, we establish ASSET as a novel tool for the efficient quantification and standardization of images from early C. elegans embryos.']

[]

Which interleukin is blocked by Siltuximab?

['This review also summarizes the biologics targeting either IL-6 or the IL-6 receptor, including tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab, and siltuximab. ', 'Siltuximab, a chimeric monoclonal antibody with high affinity and specificity for interleukin-6, has been shown to enhance anti-multiple myeloma activity of bortezomib and corticosteroid in vitro.', 'A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma.', 'We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. ', 'Currently, there are more effective therapeutic alternatives in multicentric Castleman disease: treatment with monotherapy of rituximab or in combination therapy with immunomodulatory drugs (thalidomide or lenalidomide, treatment with anti-IL-6 (siltuximab) or against its receptor (tocilizumab). ', 'PURPOSE: Siltuximab is a monoclonal antibody that binds to interleukin (IL)-6 with high affinity and specificity; C-reactive protein (CRP) is an acute-phase protein induced by IL-6. ', 'Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma.', 'Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer.', 'An interleukin-6 neutralizing antibody, siltuximab (CNTO 328) could inhibit STAT3 tyrosine phosphorylation in a cell-dependent manner.', 'Pharmacokinetic and pharmacodynamic modeling of an anti-interleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma.', 'The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study.', 'A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer.', '[Effects of siltuximab on the interleukin-6/Stat3 signaling pathway in ovarian cancer].', 'Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients.', 'A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma.', "We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease. ", 'CONCLUSIONS: These results demonstrated that siltuximab effectively block the IL-6 signaling pathways, which. ', 'CONCLUSIONS: These results show that siltuximab effectively block the IL-6 signaling pathways and IL-6-induced gene expression. ', 'A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer.', 'Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD.', "Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease.", 'To study the effects of siltuximab on the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) signaling pathway in ovarian epithelial carcinoma.', 'These results demonstrated that siltuximab effectively block the IL-6 signaling pathways,', 'These results show that siltuximab effectively block the IL-6 signaling pathways and IL-6-induced gene expression.', 'The IL6 regulation of IRF9 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti-IL6 antibody Siltuximab.', ' Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel.', 'These results demonstrated that siltuximab effectively block the IL-6 signaling pathways, which.', 'Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients.', 'Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman&apos;s disease..', 'Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts.']

['Siltuximab is a monoclonal antibody that binds to interleukin-6 with high affinity and specificity.']

['interleukin-6']

What is the generic name of Gliolan?

['BACKGROUND: Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. ', 'OBJECTIVE: This study evaluates the cost-effectiveness of 5-aminolevulinic acid (5-ALA, Gliolan®) in patients undergoing surgery for malignant glioma, in standard clinical practice conditions in Spain. ', 'OBJECTIVE: To assess effectiveness of 5-aminolevulinic acid (5-ALA, Gliolan(®)) in patients treated for malignant glioma under typical daily practice conditions in Spain, using complete resection rate (CR) and progression free survival at 6 months (PFS6). ', 'Today, ALA is approved as Levulan for actinic keratoses, the ALA-methyl ester Metvix for actinic keratoses and basal cell carcinoma, the ALA-hexyl ester Hexvix for the diagnosis of bladder cancer and Gliolan for malignant glioma. ', 'MATERIAL AND METHODS: All patients who had undergone 5-ALA fluorescence-guided surgery due to suspected malignant glioma were included. Patients received a standard preoperative dose of Gliolan. ', 'Today, ALA is approved as Levulan for actinic keratoses, the ALA-methyl ester Metvix for actinic keratoses and basal cell carcinoma, the ALA-hexyl ester Hexvix for the diagnosis of bladder cancer and Gliolan for malignant glioma']

['5-aminolevulinic acid (or 5-ALA) is the generic name of Gliolan. It is approved for fluorescence-guided resections of adult malignant gliomas.']

['5-aminolevulinic acid']

What is the inheritance of Barth syndrome?

['Barth syndrome (BTHS) is an X-linked recessive disease primarily affecting males.', 'The results of our study should not only be applicable to BTHS families, but also to families with other X-linked diseases.', 'Barth syndrome, an X-linked disorder that is characterized by cardiomyopathy, neutropenia, skeletal myopathy, and growth delay, is caused by mutations in the taffazin gene at Xq28 that result in cardiolipin deficiency and abnormal mitochondria. ', 'Barth syndrome should be considered when boys present with cardiomyopathy, especially when associated with increased left ventricular trabeculations, neutropenia, skeletal muscle weakness, or family history indicating an X-linked pattern of inheritance.', 'Mutations in the G4.5 gene result in a wide spectrum of severe infantile X-linked cardiomyopathic phenotypes including Barth syndrome with dilated cardiomyopathy and INVM.', 'X-linked mode of inheritance is seen in Menkes disease, Barth syndrome, and in deficiencies of the E1 alpha subunit of the pyruvate dehydrogenase complex. ', 'X-linked mode of inheritance is seen in Menkes disease, Barth syndrome, and in deficiencies of the E1 alpha subunit of the pyruvate dehydrogenase complex.', 'OBJECTIVE: Barth syndrome is a rare, X-linked recessive disorder that affects only boys.', 'Barth syndrome, an X-linked mitochondrial cardioskeletal myopathy, was diagnosed by genetic testing at autopsy.', 'Barth syndrome is an X-linked cardiomyopathy with neutropenia and 3-methylglutaconic aciduria.', 'Barth syndrome is an X-linked cardiac and skeletal mitochondrial myopathy.', 'Barth syndrome should be considered when boys present with cardiomyopathy, especially when associated with increased left ventricular trabeculations, neutropenia, skeletal muscle weakness, or family history indicating an X-linked pattern of inheritance', 'X-linked mode of inheritance is seen in Menkes disease, Barth syndrome, and in deficiencies of the E1 alpha subunit of the pyruvate dehydrogenase complex', 'Although the cardiomyopathy was familial in two siblings, two of three cases were female, ruling out Barth syndrome (with sex-linked recessive inheritance)', 'Barth syndrome is an X-linked genetic disorder caused by mutations in the tafazzin (taz) gene and characterized by dilated cardiomyopathy, exercise intolerance, chronic fatigue, delayed growth, and neutropenia', 'Barth syndrome should be considered when boys present with cardiomyopathy, especially when associated with increased left ventricular trabeculations, neutropenia, skeletal muscle weakness, or family history indicating an X-linked pattern of inheritance.', 'X-linked mode of inheritance is seen in Menkes disease, Barth syndrome, and in deficiencies of the E1 alpha subunit of the pyruvate dehydrogenase complex.', 'Although the cardiomyopathy was familial in two siblings, two of three cases were female, ruling out Barth syndrome (with sex-linked recessive inheritance).', 'Although the cardiomyopathy was familial in two siblings, two of three cases were female, ruling out Barth syndrome (with sex-linked recessive inheritance).', 'Barth syndrome should be considered when boys present with cardiomyopathy, especially when associated with increased left ventricular trabeculations, neutropenia, skeletal muscle weakness, or family history indicating an X-linked pattern of inheritance..']

['Barth syndrome (BTHS) has an X-linked recessive pattern of inheritance.']

['X-linked recessive pattern of inheritance']

Are CpG islands located close to housekeeping genes?

['our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated', 'CpG islands are preferentially located at the start of transcription of housekeeping genes and are associated with tissue-specific genes', 'It has been envisaged that CpG islands are often observed near the transcriptional start sites (TSS) of housekeeping genes.', 'These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes.', 'CpG islands are stretches of DNA sequence that are enriched in the (CpG)n repeat and are present in close association with all housekeeping genes as well as some tissue-specific genes in the mammalian genome.', "CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes", 'In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island.', 'All housekeeping and widely expressed genes have a CpG island covering the transcription start, whereas 40% of the genes with a tissue-specific or limited expression are associated with islands', 'Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences.', 'Unmethylated CpG rich islands are a feature of vertebrate DNA: they are associated with housekeeping and many tissue specific genes.', "CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes."]

["Our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated. These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes. In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island. Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences. All housekeeping and widely expressed genes have a CpG island covering the transcription start, whereas 40% of the genes with a tissue-specific or limited expression are associated with islands. It has been envisaged that CpG islands are often observed near the transcriptional start sites (TSS) of housekeeping genes. CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes. ", 'Yes, CpG islands are preferentially located at the start of transcription of housekeeping genes and are associated with tissue-specific genes.', "These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes. Our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated. In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island. Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences. All housekeeping and widely expressed genes have a CpG island covering the transcription start, whereas 40% of the genes with a tissue-specific or limited expression are associated with islands. It has been envisaged that CpG islands are often observed near the transcriptional start sites (TSS) of housekeeping genes. CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes. "]

['yes']

Where is base J found in the genome of Leishmania tarentolae?

['Base J (β-D-glucosyl-hydroxymethyluracil) replaces 1% of T in the Leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops.', 'Base J is found predominantly in repetitive DNA and correlates with epigenetic silencing of telomeric variant surface glycoprotein genes in Trypanosoma brucei.', 'J is enriched at sites involved in RNA polymerase (RNAP) II initiation and termination.', 'Base J (β-D-glucosyl-hydroxymethyluracil) replaces 1% of T in the Leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops', 'Telomeric localization of the modified DNA base J in the genome of the protozoan parasite Leishmania', 'Base J is found predominantly in repetitive DNA and correlates with epigenetic silencing of telomeric variant surface glycoprotein genes in Trypanosoma brucei. ', 'Base J is a hypermodified DNA base localized primarily to telomeric regions of the genome of Trypanosoma brucei.']

['Base J (β-D-glucosyl-hydroxymethyluracil) replaces 1% of T in the Leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops. Base J is found predominantly in repetitive DNA and correlates with epigenetic silencing of telomeric variant surface glycoprotein genes in Trypanosoma brucei.', 'Base J (-D-glucosyl-hydroxymethyluracil) replaces 1% of T in the Leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops. Base J is found predominantly in repetitive DNA and correlates with epigenetic silencing of telomeric variant surface glycoprotein genes in Trypanosoma brucei. J is enriched at sites involved in RNA polymerase (RNAP) II initiation and termination. ', 'Base J (β-D-glucosyl-hydroxymethyluracil) replaces 1% of T in the Leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops. Base J is found predominantly in repetitive DNA and correlates with epigenetic silencing of telomeric variant surface glycoprotein genes in Trypanosoma brucei.', 'Base J (β-D-glucosyl-hydroxymethyluracil) replaces 1% of T in the Leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops.', 'j (β-d-glucosyl-hydroxymethyluracil) replaces 1% of t in the leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops. . j is found predominantly in repetitive dna and correlates with epigenetic silencing of telomeric variant surface glycoprotein genes in trypanosoma brucei. . ', 'base j (β-d-glucosyl-hydroxymethyluracil) replaces 1% of t in the leishmania genome and is only found in telomeric repeats (99%) and in regions where transcription starts and stops.']

['telomeric repeats']

What states the second parity rule (PR2)?

["Chargaff' s second parity rule (PR2) states that complementary nucleotides are met with almost equal frequencies in single stranded DNA.", 'Sueoka and Lobry declared respectively that, in the absence of bias between the two DNA strands for mutation and selection, the base composition within each strand should be A=T and C=G (this state is called Parity Rule type 2, PR2)', 'The intra-strand Parity Rule 2 of DNA (PR2) states that A=T and G=C within each strands.', 'deviations from the PR2 is a sign of strand-specific (or asymmetric) mutation and/or selection pressures.', 'PR2 is an intra-strand rule where A=T and G=C are expected when there are no biases between the two complementary strands of DNA in mutation and selection rates (substitution rates)', 'When there are no biases in mutation and selection between the two strands of DNA, the 12 possible substitution rates of the four nucleotides reduces to six (type 1 parity rule or PR1), and the intrastrand average base composition is expected to be A = T and G = C at equilibrium without regard to the G + C content of DNA (type 2 parity rule or PR2)', 'The second method was to plot the intrastrand bias of the third codon position from Parity Rule 2 (PR2), where A = T and G = C.', 'The extent of deviation from intra-strand equality rule of A = T and G = C (Parity Rule 2, or PR2) is specific for individual amino acids and has been expressed as the PR2-bias fingerprint.', 'When there are no biases in mutation and selection between the two strands of DNA, the 12 possible substitution rates of the four nucleotides reduces to six (type 1 parity rule or PR1), and the intrastrand average base composition is expected to be A = T and G = C at equilibrium without regard to the G + C content of DNA (type 2 parity rule or PR2).', 'Chargaff s second parity rule (PR2) states that complementary nucleotides are met with almost equal frequencies in single stranded DNA.', 'The second parity rule of Chargaff (AHT and GHC within one strand) holds all over the living world with minor exceptions.', 'The second method was to plot the intrastrand bias of the third codon position from Parity Rule 2 (PR2), where A = T and G = C.', 'The extent of deviation from intra-strand equality rule of A = T and G = C (Parity Rule 2, or PR2) is specific for individual amino acids and has been expressed as the PR2-bias fingerprint.', "Chargaff' s second parity rule (PR2) states that complementary nucleotides are met with almost equal frequencies in single stranded DNA", 'The intra-strand Parity Rule 2 of DNA (PR2) states that A=T and G=C within each strands', 'The second method was to plot the intrastrand bias of the third codon position from Parity Rule 2 (PR2), where A = T and G = C', 'The extent of deviation from intra-strand equality rule of A = T and G = C (Parity Rule 2, or PR2) is specific for individual amino acids and has been expressed as the PR2-bias fingerprint']

["The second parity rule (PR2), also known as Chargaff' s second parity rule, is an intra-strand rule which states that, when there are no biases between the two complementary strands of DNA in mutation and selection rates (substitution rates), complementary nucleotides are expected to have almost equal frequencies within single stranded DNA, namely A = T and G = C at equilibrium, without regard to the G + C content of the DNA."]

[]

Which amino acid residue appears mutated in most of the cases reported with cadasil syndrome?

['missense mutations and small deletions in the NOTCH3 gene, not involving cysteine residues, have been described in patients considered to be affected by paucisymptomatic CADASIL. However, the significance of such molecular variants is still unclear', 'CADASIL is caused mostly by missense mutations in the NOTCH3 gene, invariably involving a cysteine residue.', 'Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported', 'The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue']

['CADASIL is caused mostly by missense mutations in the NOTCH3 gene, invariably involving a cysteine residue.']

['Cysteine']

Is lenvatinib effective for renal cell carcinoma?

['However, the combination of lenvatinib, a multitargeted agent that inhibits VEGF as well as FGF receptors, and everolimus demonstrated promising results in a randomized phase II trial. ', 'The FDA has approved the combination of lenvatinib and everolimus to treat advanced or metastatic renal cell carcinoma.', 'Moreover, a recent Phase II study demonstrated a significant benefit for the second-line combination treatment with everolimus plus lenvatinib (a novel TKI) in terms of progression-free survival and overall survival compared to the single-agent everolimus.', 'We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC. ', 'INTERPRETATION: Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. ', 'Lenvatinib therapy for the treatment of patients with advanced renal cell carcinoma.', 'Lenvatinib therapy for the treatment of patients with advanced renal cell carcinoma.']

['Yes, combination of lenvatinib and everolimus is approved to treat advanced or metastatic renal cell carcinoma.']

['yes']

Do brown fat cells produce heat?

['WAT and BAT are both involved in energy balance. WAT is mainly involved in the storage and mobilization of energy in the form of triglycerides, whereas BAT specializes in dissipating energy as heat during cold- or diet-induced thermogenesis.', 'Because brown adipose\xa0tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications.', 'Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes.', 'Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation.', 'Brown fat biology and thermogenesis.', 'Brown fat (brown adipose tissue, BAT) primary function is to produce heat. ', 'Brown fat cells were classified into 6 types: Type 1 cells are fat-depleted cells filled with granular cytoplasm and are believed to be produced after oxidation of fat for heat production.', 'Calorimetric measurements from cell suspensions showed that ATP increased basal heat production of isolated brown fat cells by approximately 40% but had no effect on the greater than fivefold increase in heat production seen with maximal adrenergic stimulation.', 'Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1.', 'Brown adipocytes oxidize fatty acids to produce heat in response to cold or to excessive energy intake; stimulation of brown fat development and function may thus counteract obesity.', 'The occurrence of Types 1 and/or 6 cells that has been revealed in 65 out of the total 180 samples (36%), suggests that the oxidation of fat for the thermogenesis proceeds in the brown fat tissue and that brown fat cells partially undergo fat depletion.', 'Brown fat cells were classified into 6 types: Type 1 cells are fat-depleted cells filled with granular cytoplasm and are believed to be produced after oxidation of fat for heat production.', 'In response to cold, both classical brown fat and the newly identified "beige" or "brite" cells are activated by β-adrenergic signaling and catabolize stored lipids and carbohydrates to produce heat via UCP1', 'The ability of brown adipocytes (fat cells) to dissipate energy as heat shows great promise for the treatment of obesity and other metabolic disorders', 'Inappropriate heat dissipation ignites brown fat thermogenesis in mice with a mutant thyroid hormone receptor α1', 'Brown fat and vascular heat dissipation: The new cautionary tail', 'Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. ', 'In the same manner, marked ability to produce a considerable amount of heat was evidenced in brown fat tissue of children and teenagers. ', 'Brown fat cells were classified into 6 types: Type 1 cells are fat-depleted cells filled with granular cytoplasm and are believed to be produced after oxidation of fat for heat production. ', 'It is inferred that brown-adipose-tissue heat production is reduced during (and probably also some time after) anesthesia. ', 'Parallel measurements of heat production and thermogenin content in brown fat cells during cold acclimation of rats.', 'The classical white adipose tissue builds up energy in the form of triglycerides and is useful for preventing fatigue during periods of low caloric intake and the brown adipose tissue instead of inducing fat accumulation can produce energy as heat.', 'In response to cold, both classical brown fat and the newly identified "beige" or "brite" cells are activated by β-adrenergic signaling and catabolize stored lipids and carbohydrates to produce heat via UCP1.', 'White adipose tissue stores energy reserves as fat, whereas the metabolic function of brown adipose tissue is lipid oxidation to produce heat.', 'The main function of brown adipose tissue (BAT) is to produce heat in response to cold.', 'Brown adipocytes oxidize fatty acids to produce heat in response to cold or caloric overfeeding.', 'Brown fat (brown adipose tissue, BAT) primary function is to produce heat.', 'Adipose tissue plays an active role in energy balance because it is not only a lipid storing and mobilizing tissue but consists of functionally specialized tissues able to produce heat (in brown adipose tissue) and to produce or release a vast number of so called adipokines or adipocytokines.', 'Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, plays an important role in the regulation of energy balance.', 'Brown adipose cells are specialized to dissipate chemical energy in the form of heat, as a physiological defence against cold and obesity.', 'In the present study, the thermogenesis of human brown fat tissue was suggested chiefly with regard to the occurrence of Types 1 and/or 6 cells.', 'In the same manner, marked ability to produce a considerable amount of heat was evidenced in brown fat tissue of children and teenagers.', 'Adult humans have heat-producing and energy-consuming brown adipose tissue in the clavicular region of the neck.', 'Brown and beige adipocytes expend chemical energy to produce heat and are therefore important in regulating body temperature and body weight.', "In human perirenal brown fat tissue, darkly stained fat-depleted cells (D) occupy, with other cell types (CR, CR'), an important part in the reversible heat production cycle of the brown fat tissue.", 'Brown fat is a specialized fat depot that can increase energy expenditure and produce heat.']

['Yes, brown fat cells produce heat.']

['yes']

What is the "wearing-off" phenomenon in levodopa-treated patients with Parkinson's Disease?

['It is unlike the "wearing-off" phenomenon that occurs when dopaminergic drug levels decline and responds to dopaminergic rescue drugs. ', 'Unfortunately, chronic use of traditional levodopa/dopa decarboxylase inhibitor formulations is associated with the development of complications, such as wearing-off and dyskinesia.', 'One of the first complications observed with levodopa therapy is wearing-off, which can emerge within 1-3 years of initiation of levodopa treatment. Wearing-off is characterized by the predictable emergence of motor and nonmotor PD symptoms before the next scheduled dose of medication. Despite effective treatment options to tackle wearing-off, it remains underrecognized and under treated. ', "Shortness of breath, a 'wearing-off' symptom in Parkinson's disease.", "Although levodopa is considered the gold standard for Parkinson's disease therapy, prolonged use of this drug can result in motor complications such as a 'wearing-off' phenomenon. This outcome is seen in a significant number of patients with Parkinson's disease taking levodopa and, in some cases, is observed only a few hours after intake of the last dose of levodopa. Patients experiencing the wearing-off period may present with sensory, autonomic, psychiatric and motor fluctuations. Although infrequent, shortness of breath is an important non-motor wearing-off symptom experienced by patients with Parkinson's disease.", "We report here on a patient with Parkinson's disease who was taking levodopa and developed both shortness of breath and hyperventilation during wearing-off periods.", 'His shortness of breath was determined to be a wearing-off phenomenon and his condition improved with the addition of a catechol-O-methyltransferase inhibitor (entacapone).', "The wearing-off phenomenon in patients with Parkinson's disease (PD) is a complication of prolonged levodopa usage. During this phenomenon, motor symptoms such as rigidity and freezing re-emerge. This is often accompanied by non-motor symptoms, including anxiety, the so-called wearing-off related anxiety (WRA). ", 'Patients with wearing-off tended to receive higher L-dopa dosage and endure longer duration of L-dopa treatment. ', "The wearing-off phenomenon frequently complicates levodopa therapy of Parkinson's disease (PD).", "The effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson's disease (PD), 8 of whom showed signs of daily motor fluctuations (wearing-off phenomenon).", "Although infrequent, shortness of breath is an important non-motor wearing-off symptom experienced by patients with Parkinson's disease.", "Although levodopa is considered the gold standard for Parkinson's disease therapy, prolonged use of this drug can result in motor complications such as a 'wearing-off' phenomenon.", 'More than 50% of patients with Parkinsons disease develop motor response fluctuations (the wearing off" phenomenon) after more than five years of levodopa therapy', 'More than 50% of patients with Parkinsons disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy', 'The wearing-off phenomenon in patients with Parkinsons disease (PD) is a complication of prolonged levodopa usage', 'Short-term effect of a single levodopa dose on micturition disturbance in Parkinsons disease patients with the wearing-off phenomenon', 'To evaluate the effectiveness of entacapone in the management of levodopa wearing-off in Parkinsons disease (PD) in a naturalistic, real-life setting.This prospective, open-label, observational study included patients with idiopathic PD. Patients were eligible for inclusion if they had been taking 3-5 doses of levodopa per day for ≥2 months and had shown signs of levodopa wearing-off for ≥1 month', 'The duration of clinical control of motor symptoms of Parkinson disease (PD) treated with levodopa/carbidopa preparations eventually starts to shorten, a phenomenon known as end-of-dose "wearing off." The involvement of core nonmotor symptoms of "wearing off" (depressed mood, pain/aching, anxiety, and cloudy/slowed thinking) is not well understood.', 'Efficacy and tolerability of entacapone in patients with Parkinsons disease treated with levodopa plus a dopamine agonist and experiencing wearing-off motor fluctuations', 'The efficacy and tolerability of entacapone was investigated in a randomized, double-blind, placebo-controlled, 3-month study of 162 patients with Parkinsons disease (PD) treated with levodopa and a dopamine agonist and experiencing wearing-off motor fluctuations', 'Efficacy and safety of entacapone in levodopa/carbidopa versus levodopa/benserazide treated Parkinsons disease patients with wearing-off', 'We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off " phenomenon in levodopa-treated parkinsonian patients.', 'We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off" phenomenon in levodopa-treated parkinsonian patients.', 'Our data also support the involvement of postsynaptic dopamine receptor mechanisms in the wearing-off phenomenon seen in levodopa-treated parkinsonian patients.', "Short-term effect of a single levodopa dose on micturition disturbance in Parkinson's disease patients with the wearing-off phenomenon.", 'It is unlike the "wearing-off" phenomenon that occurs when dopaminergic drug levels decline and responds to dopaminergic rescue drugs. ', 'More than 50% of patients with Parkinson\'s disease develop motor response fluctuations (the \'wearing off" phenomenon) after more than five years of levodopa therapy.', 'The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose "wearing-off" phenomenon has been controlled with more frequent levodopa dosage.', 'More than 50% of patients with Parkinson\'s disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy.', "To evaluate the role of the practicing pharmacist in the identification and current treatment of the levodopa wearing-off phenomenon experienced by patients with Parkinson's disease (PD) who are receiving chronic levodopa therapy.Literature retrieval was accessed through MEDLINE (1967-June 2007) using the terms levodopa, wearing-off, and Parkinson's disease.", "This study investigated the effects of OPC in comparison with placebo on levodopa pharmacokinetics, tolerability and safety, COMT activity and motor response to levodopa in Parkinson's disease (PD) patients with motor fluctuations.This was a randomized, multicentre, double-blind and placebo-controlled study in four parallel groups of PD patients treated with standard-release 100/25 mg levodopa/carbidopa or levodopa/benserazide and with motor fluctuations (wearing-OFF phenomenon).", "Patients experiencing the wearing-off period may present with sensory, autonomic, psychiatric and motor fluctuations. Although infrequent, shortness of breath is an important non-motor wearing-off symptom experienced by patients with Parkinson's disease.", "This outcome is seen in a significant number of patients with Parkinson's disease taking levodopa and, in some cases, is observed only a few hours after intake of the last dose of levodopa. Patients experiencing the wearing-off period may present with sensory, autonomic, psychiatric and motor fluctuations. Although infrequent, shortness of breath is an important non-motor wearing-off symptom experienced by patients with Parkinson's disease.", "Although levodopa is considered the gold standard for Parkinson's disease therapy, prolonged use of this drug can result in motor complications such as a 'wearing-off' phenomenon. This outcome is seen in a significant number of patients with Parkinson's disease taking levodopa and, in some cases, is observed only a few hours after intake of the last dose of levodopa. Patients experiencing the wearing-off period may present with sensory, autonomic, psychiatric and motor fluctuations.", 'It is suggested that tolcapone may be useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.', 'It is suggested that tolcapone may be useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena..', "Levodopa-treated Parkinson's disease is often complicated by the occurrence of motor fluctuations, which can be predictable ('wearing-off') or unpredictable ('on-off').", 'She was treated with 400 mg/day of levodopa-carbidopa, which improved her symptoms, however, she developed wearing off phenomenon 3 years after the initiation of levodopa treatment.', "[Benefit of L-DOPA-without-DCI (decarboxylase inhibitor) therapy on wearing-off phenomenon in advanced stages of Parkinson's disease patients].", "To evaluate the role of the practicing pharmacist in the identification and current treatment of the levodopa wearing-off phenomenon experienced by patients with Parkinson's disease (PD) who are receiving chronic levodopa therapy.", "However, once the decision to initiate levodopa therapy has been made, studies generally support the use of entacapone as an adjunct to levodopa in patients with Parkinson's disease and the 'wearing off' phenomenon..", 'These results suggest that wearing-off phenomenon may arise as a consequence of the degeneration of dopamine terminals due to natural disease progression with a resultant inability to buffer variations in levodopa availability; on-off phenomenon, may reflect additional postsynaptic dopamine receptor dysregulation, possibly in response to the resultant, nonphysiologic fluctuations in synaptic dopamine..', 'Conversion from oral to intravenous levodopa treatment immediately stabilized plasma levodopa levels in both the wearing-off and on-off groups; motor variability also decreased, especially in those with wearing-off phenomenon.']

["Chronic administration of traditional levodopa/dopa decarboxylase inhibitor formulations to Paskinson's Disease patients is associated with the development of complications, such as wearing-off phenomenon. Wearing-off phenomenon is characterized by the predictable emergence of motor symptoms (e.g. rigidity and freezing) and nonmotor PD symptoms (e.g. anxiety and shortness of breath), before the next scheduled dose of medication."]

[]

Do proton pump inhibitors affect thyroxine absorption?

['Proton-pump inhibitors, antacids and a long list of drugs may decrease thyroxine absorption', 'Many commonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine.', 'Pantoprazole did not influence endocrine function in healthy male volunteers during short-term treatment.', 'PPIs should be added to the list of medications affecting the level of thyroid hormone in patients with hypothyroidism treated with LT4 replacement. Patients with hypothyroidism and normal TSH values during LT4 replacement therapy may need additional thyroid function testing after treatment with PPIs and may need adjustment of their LT4 dose.']

['Proton-pump inhibitors, antacids and a long list of drugs may decrease thyroxine absorption.\nPatients with hypothyroidism and normal TSH values during LT4 replacement therapy may need additional thyroid function testing after treatment with PPIs and may need adjustment of their LT4 dose.']

['yes']

Is aganglionic megacolon a feature of Down syndrome?

['Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS', 'Of the 17 patients with HD who were studied, 10 were isolated (58.8%) and seven (41.1%) were associated to other structural abnormalities and psychomotor retardation. Three of the cases in this latter group were due to chromosome pathology (trisomy 21, Down syndrome)', 'The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy. The patient condition improved after a colostomy performed in the setting of the treatment of Hirschprung disease', 'Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed to be a sex-modified multifactorial trait. To test this hypothesis, complex segregation analysis was performed on data on 487 probands and their families. Demographic information on probands and the recurrence risk to relatives of probands are presented. An increased sex ratio (3.9 male:female) and an elevated risk to sibs (4%), as compared with the population incidence (0.02%), are observed, with the sex ratio decreasing and the recurrence risk to sibs increasing as the aganglionosis becomes more extensive. Down syndrome was found at an increased frequency among affected individuals but not among their unaffected sibs, and the increase was not associated with maternal age', 'Intestinal microvillous atrophy in a patient with Down syndrome and aganglionic megacolon.', ' The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy.', 'The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy.', 'The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy']

['Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS.']

['yes']

When did the polio vaccine becomes available?

['Inactivated poliovirus vaccine (IPV), developed in the USA by Jonas Salk in the early 1950s, was field tested in 1954,', 'the use of an oral polio vaccine (OPV) during a vaccination campaign launched by the Wistar Institute, Philadelphia, PA, USA, in the Belgian Congo in 1958 and 1959. ']

['Inactivated poliovirus vaccine (IPV), developed in the USA by Jonas Salk in the early 1950s, was field tested in 1954,', 'The Salk polio Vaccine was field tested in 1954.']

['1954']

Is Calcium/Calmodulin dependent protein kinase II (CaMKII) involved in cardiac arrhythmias and heart failure?

['In human hypertrophy, both CaMKII and PKA functionally regulate RyR2 and may induce SR Ca(2+) leak. In the transition from hypertrophy to HF, the diastolic Ca(2+) leak increases and disturbed Ca(2+) cycling occurs. This is associated with an increase in CaMKII- but not PKA-dependent RyR2 phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic target for the treatment of arrhythmias and contractile dysfunction.', '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.', 'In the recent years, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) was suggested to be associated with cardiac hypertrophy and heart failure but also with arrhythmias both in animal models as well as in the human heart.', 'Calcium-calmodulin-dependent protein kinase II (CaMKII) has emerged as a central mediator of cardiac stress responses which may serve several critical roles in the regulation of cardiac rhythm, cardiac contractility and growth. Sustained and excessive activation of CaMKII during cardiac disease has, however, been linked to arrhythmias, and maladaptive cardiac remodeling, eventually leading to heart failure (HF) and sudden cardiac death. ', 'Overexpression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in transgenic mice results in heart failure and arrhythmias.', 'From recent studies, it appears evident that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a central role in the arrhythmogenic processes in heart failure by sensing intracellular Ca(2+) and redox stress, affecting individual ion channels and thereby leading to electrical instability in the heart. ', 'CaMKII activation is proarrhythmic in heart failure where myocardium is stretched.', 'The Ca-calmodulin dependent kinase II (CaMKII) seems to be involved in the development of heart failure and arrhythmias and may therefore be a promising target for the development of antiarrhythmic therapies.', 'Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is up-regulated in heart failure and has been shown to cause I(Na) gating changes that mimic those induced by a point mutation in humans that is associated with combined long QT and Brugada syndromes.', 'CaMKII-dependent phosphorylation of Na(V)1.5 at multiple sites (including Thr-594 and Ser-516) appears to be required to evoke loss-of-function changes in gating that could contribute to acquired Brugada syndrome-like effects in heart failure.', 'Because CaMKII expression and activity are increased in cardiac hypertrophy, heart failure, and during arrhythmias both in animal models as well as in the human heart a clinical significance of CaMKII is implied.', 'The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure, and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease.', "In our opinion, the multifunctional Ca and calmodulin-dependent protein kinase II (CaMKII) has emerged as a molecule to watch, in part because a solid body of accumulated data essentially satisfy Koch's postulates, showing that the CaMKII pathway is a core mechanism for promoting myocardial hypertrophy and heart failure. Multiple groups have now confirmed the following: (1) that CaMKII activity is increased in hypertrophied and failing myocardium from animal models and patients; (2) CaMKII overexpression causes myocardial hypertrophy and HF and (3) CaMKII inhibition (by drugs, inhibitory peptides and gene deletion) improves myocardial hypertrophy and HF", ' In contrast, inhibiting the CaMKII pathway appears to reduce arrhythmias and improve myocardial responses to pathological stimuli. ', 'In this review, we discuss the important role of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in the regulation of RyR2-mediated Ca(2+) release. In particular, we examine how pathological activation of CaMKII can lead to an increased risk of sudden arrhythmic death. Finally, we discuss how reduction of CaMKII-mediated RyR2 hyperactivity might reduce the risk of arrhythmias and may serve as a rationale for future pharmacotherapeutic approaches.', 'Transgenic (TG) Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) δ(C) mice develop systolic heart failure (HF). CaMKII regulates intracellular Ca(2+) handling proteins as well as sarcolemmal Na(+) channels. We hypothesized that CaMKII also contributes to diastolic dysfunction and arrhythmias via augmentation of the late Na(+) current (late I(Na)) in early HF (8-week-old TG mice).', 'Thus, late I(Na) inhibition appears to be a promising option for diastolic dysfunction and arrhythmias in HF where CaMKII is found to be increased.', 'We tested the hypothesis that increased RyR2 phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias.', 'CONCLUSIONS: our results suggest that Ca(2+)/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca(2+) release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.', 'Excessive activation of calmodulin kinase II (CaMKII) causes arrhythmias and heart failure, but the cellular mechanisms for CaMKII-targeted proteins causing disordered cell membrane excitability and myocardial dysfunction remain uncertain.', 'Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo.', 'We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIdelta(C) mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.', 'Ca2+/calmodulin dependent protein kinase II (CaMKII) can phosphorylate RyR2 and modulate its activity. This phosphorylation positively modulates cardiac inotropic function but in extreme situations such as heart failure, elevated CaMKII activity can adversely increase Ca2+ release from the SR and lead to arrhythmogenesis. ', 'Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase expressed abundantly in the heart. CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias.', 'Under stress conditions, excessive CaMKII activity promotes heart failure and arrhythmias, in part through actions at Ca(2+) homeostatic proteins.', 'Ca-calmodulin-dependent protein kinase II (CaMKII) was recently shown to alter Na(+) channel gating and recapitulate a human Na(+) channel genetic mutation that causes an unusual combined arrhythmogenic phenotype in patients: simultaneous long QT syndrome and Brugada syndrome. CaMKII is upregulated in heart failure where arrhythmias are common, and CaMKII inhibition can reduce arrhythmias. Thus, CaMKII-dependent channel modulation may contribute to acquired arrhythmic disease. ', 'In heart failure (HF), Ca(2+)/calmodulin kinase II (CaMKII) expression is increased. Altered Na(+) channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na(+) channel gating, in part perhaps via CaMKII.', 'Thus, CaMKII-dependent regulation of Na(+) channel function may contribute to arrhythmogenesis in HF.', 'Recent findings that CaMKII expression in the heart changes during hypertrophy, heart failure, myocardial ischemia, and infarction suggest that CaMKII may be a viable therapeutic target for patients suffering from common forms of heart disease.', ' Overexpression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in transgenic mice results in heart failure and arrhythmias.', 'Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias.', 'BACKGROUND: Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias.', 'CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias.', 'Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure.', 'From recent studies, it appears evident that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a central role in the arrhythmogenic processes in heart failure by sensing intracellular Ca(2+) and redox stress, affecting individual ion channels and thereby leading to electrical instability in the heart.', 'Ryanodine receptor phosphorylation, calcium/calmodulin-dependent protein kinase II, and life-threatening ventricular arrhythmias.', 'CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias', 'The Ca-calmodulin dependent kinase II (CaMKII) seems to be involved in the development of heart failure and arrhythmias and may therefore be a promising target for the development of antiarrhythmic therapies', 'Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias.', 'Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias']

['Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase expressed abundantly in the heart. CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias. ', 'Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase expressed abundantly in the heart. CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias.', 'Overexpression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in transgenic mice results in heart failure and arrhythmias.The Ca-calmodulin dependent kinase II (CaMKII) seems to be involved in the development of heart failure and arrhythmias and may therefore be a promising target for the development of antiarrhythmic therapies.']

['yes']

Is there an association between borna virus and brain tumor?

['Borna disease virus (BDV), a nonsegmented, negative-strand RNA virus, infects a wide variety of mammalian species and readily establishes a long-lasting, persistent infection in brain cells. ', 'To investigate the biological characteristics of field isolates of Borna disease virus (BDV), as well as to understand BDV infections outside endemic countries, we isolated the virus from brain samples of a heifer with Borna disease in Japan.', 'Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to the certain neuronal populations.', 'In addition, compared to uninfected mixed cultures, activation of microglia in BDV-infected mixed cultures was associated with a significantly greater lipopolysaccharide-induced release of tumor necrosis factor alpha, interleukin 1beta, and interleukin 10. Taken together, the present data are the first in vitro evidence that persistent BDV infection of neurons and astrocytes rather than direct exposure to the virus or dying neurons is critical for activating microglia.', 'Usually, Borna disease virus is not cleared from the brain but rather persists in neural cells.', 'Varied persistent life cycles of Borna disease virus in a human oligodendroglioma cell line.', 'Borna disease virus (BDV) establishes a persistent infection in the central nervous system of vertebrate animal species as well as in tissue cultures. ', 'Thus, our findings show that BDV may have established a persistent infection at low levels of viral expression in OL cells with the possibility of a latent infection.', 'These results suggested that BDV infection may cause direct damage in the developing brain by inhibiting the function of amphoterin due to binding by the p24 phosphoprotein.', 'We describe a model for investigating disorders of central nervous system development based on neonatal rat infection with Borna disease virus, a neurotropic noncytolytic RNA virus. ', 'Borna disease virus (BDV) replicates in brain cells. The neonatally infected rat with BDV exhibits developmental-neuromorphological abnormalities, neuronal cytolysis, and multiple behavioral and physiological alterations. ', 'Borna disease virus (BDV) causes central nervous system (CNS) disease in several vertebrate species, which is frequently accompanied by behavioral abnormalities.', 'Intrinsic responses to Borna disease virus infection of the central nervous system.', 'Immune cells invading the central nervous system (CNS) in response to Borna disease virus (BDV) antigens are central to the pathogenesis of Borna disease (BD). ', 'We report here the partial purification and characterization of cell-free BDV from the tissue culture supernatant of infected human neuroblastoma SKNSH cells.', 'We have used the reverse transcriptase-polymerase chain reaction technique to gain insight into the pathogenesis of encephalitis caused by Borna disease virus (BDV). ', 'In contrast, in the BDV-infected primary mixed cultures, we observed proliferation of microglia cells that acquired the round morphology and expressed major histocompatibility complex molecules of classes I and II.']

['There is no data to suggest an association between borna virus and brain tumor. Borna disease virus establishes a persistent infection in the central nervous system of vertebrate animal species as well as in tissue cultures causing cellular damage. Infected neural cells, include astrocytes, neurons, oligodendroglioma cell line. Borna disease virus replicates and can cause damage of brain cells.']

['no']

Which are the main brain dysfunctions caused by hyperbilirubinemia?

['Bilirubin-induced neurologic dysfunction (BIND) and classical kernicterus are clinical manifestations of moderate to severe hyperbilirubinemia whenever bilirubin levels exceed the capacity of the brain defensive mechanisms in preventing its entrance and cytotoxicity. In such circumstances and depending on the associated co-morbidities, bilirubin accumulation may lead to short- or long-term neurodevelopmental disabilities, which may include deficits in auditory, cognitive, and motor processing. Neuronal cell death, astrocytic reactivity, and microglia activation are part of the bilirubin-induced pathogenesis. ', 'Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia.', 'Bilirubin-induced neurologic dysfunction (BIND) and kernicterus has been used to describe moderate to severe neurologic dysfunction observed in children exposed to excessive levels of total serum bilirubin (TSB) during the neonatal period.', 'Histologic studies of brain tissue demonstrate that the onset of severe neonatal hyperbilirubinemia, characterized by seizures, leads to alterations in myelination and glia reactivity. ', 'Thus, kernicterus in this model displays not only axonal damage but also myelination deficits and glial activation in different brain regions that are usually related to the neurologic sequelae observed after severe hyperbilirubinemia.', 'Advances in the care of neonatal hyperbilirubinemia have led to a decreased incidence of kernicterus. However, neonatal exposure to high levels of bilirubin continues to cause severe motor symptoms and cerebral palsy (CP). Exposure to moderate levels of unconjugated bilirubin may also cause damage to the developing central nervous system, specifically the basal ganglia and cerebellum. ', 'High levels of serum unconjugated bilirubin (UCB) in newborns are associated with axonal damage and glial reactivity that may contribute to subsequent neurologic injury and encephalopathy (kernicterus). ', 'Hyperbilirubinemia remains one of the most frequent clinical diagnoses in the neonatal period. This condition may lead to the deposition of unconjugated bilirubin (UCB) in the central nervous system, causing nerve cell damage by molecular and cellular mechanisms that are still being clarified. ', '"Kernicterus" is a term currently used to describe bilirrubin induced brain injury in the neuro-pathological studies. This is a confusing term and nowadays we prefer bilirrubin encephalopathy or bilirrubin induced neurological dysfunction. ', 'We then review the possible alteration of the neuroprotective and trophic barrier functions in the course of bilirubin-induced neurological dysfunctions resulting from hyperbilirubinemia.', 'It has been suggested recently that there is an association between hyperbilirubinemia and long-term neurologic dysfunctions.', "In this article, we review computational insights into the brain dysfunctions underlying Parkinson's disease, Huntington's disease, and dystonia, with particular foci on dysfunctions of the dopamine system, basal ganglia pathways, and neuronal oscillations.", 'Hyperbilirubinemia may accompany harmful effects such as jaundice, brain dysfunction, and pharmacokinetic alterations of drugs.', 'Neonatal jaundice is a common cause of sensorneural hearing loss in children.We aimed to detect the neurotoxic effects of pathologic hyperbilirubinemia on brain stem and auditory tract by auditory brain stem evoked response (ABR) which could predict early effects of hyperbilirubinemia.This case-control study was performed on newborns with pathologic hyperbilirubinemia', 'For example, the mean latencies time of wave I was significantly higher in right ear of the case group than in controls (2.16 ± 0.26 vs. 1.77 ± 0.15 milliseconds, respectively) (P &lt; 0.001).Pathologic hyperbilirubinemia causes acute disorder on brain stem function; therefore, early diagnosis of neonatal jaundice for prevention of bilirubin neurotoxic effects is essential', 'Wave amplitudes are valuable BAER variables to detect functional impairment of the brainstem and auditory pathway in neonatal hyperbilirubinemia, and are recommended to be used in assessing bilirubin neurotoxicity to the neonatal brain.<CopyrightInformation>Copyright © 2013 European Paediatric Neurology Society', 'Histologic studies of brain tissue demonstrate that the onset of severe neonatal hyperbilirubinemia, characterized by seizures, leads to alterations in myelination and glia reactivity', '[Characteristics of auditory brain stem response in neonatal hyperbilirubinemia induced by different causes].', 'Excessive hyperbilirubinemia in human neonates can cause permanent dysfunction of the auditory system, as assessed with brainstem auditory evoked potentials (BAEPs).', 'A recent surge in reported cases of classical kernicterus, due in part to earlier hospital discharge and relaxation of treatment criteria for hyperbilirubinemia, and new reports of hyperbilirubinemia-induced auditory dysfunction using evoked potential based infant testing and hearing screening, underscore the need to better understand how hyperbilirubinemia causes brain damage in some infants, especially because the damage is preventable.', 'Pathologic hyperbilirubinemia causes acute disorder on brain stem function; therefore, early diagnosis of neonatal jaundice for prevention of bilirubin neurotoxic effects is essential.']

['Bilirubin-induced neurologic dysfunction (BIND) and classical kernicterus are the main dysfunctions of hyperbilirubinemia, whenever bilirubin levels exceed the capacity of the brain defensive mechanisms in preventing its entrance and cytotoxicity. Bilirubin accumulation may lead to deficits in auditory, cognitive, and motor processing, due to neuronal cell death, reduced myelination and glial activation.']

[]

What is the role of venous angioplasty in multiple sclerosis?

['Balloon angioplasty corrects blood pressure deviation in multiple sclerosis patients undergoing internal jugular vein dilation.', 'PURPOSE: To investigate prevalence of extracranial abnormalities in azygos and internal jugular (IJ) veins using conventional venography and intravascular ultrasound (IVUS) in patients with multiple sclerosis (MS) being evaluated for chronic cerebrospinal venous insufficiency, a condition of vascular hemodynamic dysfunction', 'Feasibility and safety of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.', 'CONCLUSIONS: Endovascular treatment for CCSVI appears feasible and safe. ', 'This report presents the case of a 45-year-old man with known MS and suspected CCSVI who had undergone previous internal jugular angioplasty and stenting. The patient reported dramatic improvement of symptoms after intervention. ', "Open venous reconstruction of the internal jugular vein was performed with a spiral graft from the saphenous vein. The patient's symptoms improved for several weeks until the venous reconstruction occluded. This case is the first reported open venous reconstruction for suspected CCSVI.", 'Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency in people with multiple sclerosis: a summary of a Cochrane systematic review.', "BACKGROUND: It has been recently hypothesised that chronic cerebrospinal venous insufficiency (CCSVI) may be an important factor in the pathogenesis of multiple sclerosis (MS). The proposed treatment for CCSVI is percutaneous transluminal angioplasty, also known as the 'liberation procedure', which is claimed to improve the blood flow in the brain, thereby alleviating some of the symptoms of MS.", 'CONCLUSIONS: There is currently no high level evidence to support or refute the efficacy or safety of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS.', 'CONCLUSION: The results of the current study suggest that endovascular evaluation and management of chronic cerebrospinal venous insufficiency is safe, with low morbidity and no procedure-related mortality.', 'There are clinical trials ongoing or planned to treat chronic cerebrospinal venous insufficiency (CCSVI) through angioplasty. ', 'Percutaneous transluminal angioplasty for chronic cerebrospinal venous insufficiency in multiple sclerosis: dichotomy between subjective and objective outcome scores.', 'Some multiple sclerosis (MS) patients reported an improvement after percutaneous transluminal angioplasty (PTA) for chronic cerebrospinal venous insufficiency (CCSVI), despite the lack of correspondence with objective outcome scores. ', ' Spontaneously performed approach to CCSVI does not improve clinical and MRI parameters, despite frequent subjective perception of quality of life improvement.', 'Percutaneous angioplasty of internal jugular and azygous veins in patients with chronic cerebrospinal venous insufficiency and multiple sclerosis: early and mid-term results.', 'Purpose: To assess the safety of endovascular treatment of chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis (MS).', '.Conclusion: Endovascular treatment of the IJV and azygous veins in patients with CCSVI and MS is a safe procedure with no post-procedural complications followed by significant improvement of IJV flow haemodynamic parameters and decrease in the EDSS score. Whether CCSVI percutaneous treatment might affect clinical improvement in patients suffering from MS is yet to be seen after completion of major multicentric clinical trials, still it seems like that this procedure is not negligible.', ' CONCLUSIONS: PTA in patients with MS with CCSVI increased CSF flow and decreased CSF velocity, which are indicative of improved venous parenchyma drainage.', 'BACKGROUND: It has been postulated that Multiple sclerosis (MS) stems from a narrowing in the veins that drain blood from the brain, known medically as chronic cerebrospinal venous insufficiency, or CCSVI. It has been proposed that balloon angioplasty should alleviate the symptoms of MS.', " The revival of this concept has generated major interest in media and patient groups, mainly driven by the hope that endovascular treatment of 'CCSVI' could alleviate MS.", " The data obtained here do generally not support the 'CCSVI' concept. Moreover, there are no methodologically adequate studies to prove or disprove beneficial effects of endovascular treatment in MS. ", "RATIONALE: It is estimated that some hundreds of Canadian patients with multiple sclerosis (MS) have journeyed abroad to avail themselves of 'liberation therapy' (venoplasty) following the initial report by Zamboni et al in 2009. ", 'CONCLUSION: No objective improvement was found at one year in thirty MS subjects who had undergone venoplasty, although many reported a degree of subjective benefit.', 'Zamboni et al. reported significant improvement in neurological outcomes in MS patients who underwent percutaneous transluminal angioplasty (PTA).', 'CONCLUSION: The study revealed that PTA in relapsing remitting MS patients was not associated with any neurological improvement. However, there was an increase in disease activity irrespective of the adherence to DMTs.', 'Serious complication of percutaneous angioplasty with stent implantation in so called "chronic cerebrospinal venous insufficiency" in multiple sclerosis patient.', 'We strongly ask for restriction of PTA procedure in so called CCSVI, which concept was not proven to be relevant to MS.', 'Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients.', "The proposed treatment for CCSVI is percutaneous transluminal angioplasty, also known as the 'liberation procedure', which is claimed to improve the blood flow in the brain thereby alleviating some of the symptoms of MS. ", "AUTHORS' CONCLUSIONS: There is currently no high level evidence to support or refute the efficacy or safety of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS. ", 'Significant improvement of clinical disability in relapsing-remitting patients was (P < 0.001) achieved.', 'Data from a few small case series suggest possible improvement of the clinical course and quality of life by performing percutaneous balloon angioplasty (PTA) of the stenotic veins. ', 'CONCLUSION: In the case presented, PTA of the IJV confluence resulted in haemodynamic improvement despite the presence of IJV external compression.', 'CONCLUSIONS: Endovascular treatment of CCSVI in patients with MS appears to be a safe procedure resulting in significant clinical improvement.', 'Endovascular treatment of concurrent CCSVI seems to be safe and repeatable and may reduce annual relapse rates and cumulative disability in patients with relapsing-remitting MS.', 'Therefore, any potentially harmful interventional treatment such as transluminal angioplasty and/or stenting should be strongly discouraged.', 'The work of Dr. Zamboni, et al, who reported that treating the venous stenoses causing CCSVI with angioplasty resulting in significant improvement in the symptoms and quality of life of patients with MS (2) has led to further interest in this theory and potential treatment. ', 'Regardless of this continued uncertainty surrounding the safety and efficacy of this therapy, MS patients from Canada, and other jurisdictions, are traveling abroad to receive central venous angioplasty and, unfortunately, some also receive venous stents. ', 'Finally, no proven (i.e., based on strict scientific methodology and on the rules of evidence-based medicine) therapeutic effect of the "liberation" procedure (unblocking the extracranial venous obstruction using angioplasty) has been shown up to date.', 'The angiographic and hemodynamic improvement was associated with improvement in symptomatology, most particularly in cognitive and constitutional symptoms that may be related to cerebrovenous flow. ', ' In conclusion, in this series, endovascular intervention to correct venous stenosis associated with multiple sclerosis was associated with improvement in symptoms possibly related to disturbed venous hemodynamics. ', 'Some investigators have proceeded to unblinded nonrandomized angioplasty and stenting procedures in patients with CCSVI, with anecdotal reports of symptom improvement. Because of conflicting data on the presence of CCSVI and the absence of controlled trials of CCSVI intervention, the current standard of clinical care is neither to evaluate multiple sclerosis (MS) patients for CCSVI anomalies, nor to intervene with procedures to alter such anomalies.', 'Endovascular treatment (percutaneous transluminal angioplasty (PTA) with or without stenting) of CCSVI was reported to be feasible with a minor complication rate.', 'PTA seems to be an effective treatment for patients with CCVI and multiple sclerosis, However, randomized studies are warranted to establish the efficacy of this new treatment for MS.', 'CONCLUSIONS: Endovascular treatment of CCSVI is a safe procedure; there is a 1.6% risk of major complications.', "CONCLUSIONS: The endovascular treatment in patients with MS and concomitant CCSVI did not have an influence on the patient's neurological condition; however, in the mid-term follow-up, an improvement in some quality-of-life parameters was observed.", 'Although there is no methodologically rigorous evidence to support this hypothesis presently, a considerable number of MS patients have undergone endovascular CCSVI procedures. Such procedures include angioplasty or stent placement in jugular and azygous veins. The safety and efficacy of these procedures is unknown, but not without risk. ', 'CONCLUSIONS: As the debate about CCSVI and its relationship to MS continues, the complications and risks associated with venous stenting and angioplasty in jugular and azygous veins are becoming clearer. ', 'CONCLUSIONS: This study further confirms the safety of PTA treatment in patients with CCSVI associated with MS. ', 'This review aims to describe the proposed association between CCSVI and MS, summarize the current data, and discuss the role of endovascular therapy and the need for rigorous randomized clinical trials to evaluate this association and treatment.', 'CONCLUSION: Endovascular therapy appears to be a safe and reliable method for treating CCSVI.', 'In particular, the potential shift in treatment concepts possibly leading to an interventional treatment approach including balloon angioplasty and venous stent placement is currently being debated. ', 'In conclusion, the present conclusive data confuting the theory of CCSVI in MS should lead to reluctance with respect to the interventional treatment of possible venous anomalies in MS patients.', 'Although balloon angioplasty and stenting seem to be safe procedures, there are currently no data on the treatment of a large group of patients with this vascular pathology. ', 'CONCLUSIONS: The procedures appeared to be safe and well tolerated by the patients, regardless of the actual impact of the endovascular treatments for venous pathology on the clinical course of multiple sclerosis, which warrants long-term follow-up.', 'Two pilot studies demonstrated the safety and feasibility in Day Surgery of the endovascular treatment of CCSVI by means of balloon angioplasty (PTA). It determines a significant reduction of postoperative venous pressure. ', 'However, PTA seems to positively influence clinical and QoL parameters of the associated MS and warrants further randomized control trials.', 'Furthermore, they have obtained apparent clinical improvement or stabilization by endovascular ballooning of points of obstruction in the great veins in some, at least temporarily.', 'A potential shift in the treatment paradigm of MS involving endovascular balloon angioplasty or venous stent placement has been proposed as well as conducted in small patient series. In some cases, it may have resulted in serious injury. ', ' At present, invasive and potentially dangerous endovascular procedures as therapy for patients with MS should be discouraged until such studies have been completed, analyzed, and debated in the scientific arena.', 'She underwent percutaneous balloon angioplasty of the associated chronic cerebrospinal venous insufficiency (CCSVI), due to membranous obstruction of the proximal azygous vein, with severe stenosis of the left internal jugular vein. Treatment of the associated CCSVI made a parallel improvement in both clinical and neurophysiological parameters, allowing us to avoid high dose steroid therapy. ', 'CONCLUSIONS: PTA of venous strictures in patients with CCSVI is safe, and especially in patients with RR, the clinical course positively influenced clinical and QOL parameters of the associated MS compared with the preoperative assessment.', 'In particular, the potential shift in treatment concepts possibly leading to an interventional treatment approach including balloon angioplasty and venous stent placement is currently being debated']

["Chronic cerebrospinal venous insufficiency (CCSVI) may be an important factor in the pathogenesis of multiple sclerosis (MS). The proposed treatment for CCSVI is percutaneous transluminal angioplasty, also known as the 'liberation procedure', which is claimed to improve the blood flow in the brain, thereby alleviating some of the symptoms of MS. There have been reports to suggest that venous angioplasty in MS patients is a feasible and safe procedure and is associated with improved disease symptom severity, quality of life, and corrects blood pressure deviation, improves CSF dynamics. Open venous reconstruction of the internal jugular vein has also been tried with good results.\nHowever, some authors have failed to document beneficial value of venous angioplasty in MS patients and systematic review has suggested that there is currently no high level evidence to support or refute the efficacy or safety of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS."]

[]

What are PD-1 inhibitors?

[' The programmed death-1 (PD-1) pathway negatively regulates T-cell activation and has an important role in regulating antitumor host immunity. Monoclonal antibodies directed against PD-1 or the PD-1 ligand (PD-L1) have shown activity in several tumor types with preliminary data suggesting a relationship between PD-L1 expression and response.', 'Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment.', 'Checkpoint inhibitors with monoclonal antibodies targeting the CTLA-4 or PD-1 axis have revolutionized treatment in some solid tumors, especially melanoma and lung', 'In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma.', 'Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. T', 'The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma', 'PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkins lymphoma', 'PD-1 inhibitors raise survival in NSCLC', 'PD-1 inhibitors raise survival in NSCLC.', 'PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma.', 'The development of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) checkpoint inhibitors has changed the landscape of non-small-cell lung cancer (NSCLC) therapy, with 2 approvals from the US Food and Drug Administration of PD-1 inhibitors for second-line therapy.', 'In this article, we will review the unique biologic features that predispose cHL to PD-1 inhibition, current data regarding the safety and efficacy of PD-1 inhibitors in the treatment of cHL, biomarkers of immune response, ongoing clinical trials with PD-1 inhibitors, as well as areas of uncertainty.', 'To determine how PD-1 signaling inhibits T cell proliferation, we used human CD4(+) T cells to examine the effects of PD-1 signaling on the molecular control of the cell cycle.', 'PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A.', 'The field of immuno-oncology has witnessed unprecedented success in recent years, with several programmed cell death 1 and PD-L1 inhibitors obtaining US FDA registration and breakthrough drug therapy designation in multiple tumor types.', 'The use of antibodies against programmed cell death 1 (PD-1), such as nivolumab and pembrolizumab, has dramatically improved the prognosis of patients with advanced melanoma.', ' Since 2010, treatment options for metastatic melanoma have been developed including chemotherapies, checkpoint inhibition immunotherapies, e.g., anti‑cytotoxic T‑lymphocyte antigen‑4\xa0(CTLA‑4) and anti‑programmed death‑1\xa0(PD‑1), and molecular-targeted therapies, e.g., BRAF and MEK inhibitors. ', 'his strategy may be particularly advantageous for vaccines targeting prostate cancer, a disease for which antitumor vaccines have demonstrated clinical benefit and yet PD-1 pathway inhibitors alone have shown little efficacy to dat', 'Manipulation of co-stimulatory or co-inhibitory checkpoint proteins allows for the reversal of tumor-induced T-cell anergy observed in cancer', 'Colorectal cancers (CRCs) have been identified as potential targets for immunotherapy with programmed cell death (PD)-1 inhibitors', 'Blockading the interaction of programmed death-1 (PD-1) protein with its ligands (PD-Ls, such as PD-L1) was proved to be a pathway for suppressing the development of tumors and other degradations of biological species. Thus, finding PD-1 inhibitors situated at the convergence point of drug discovery', 'Anti-programmed cell death receptor-1 (PD-1) antibodies have demonstrated antitumor activity in many cancer entitie', ' Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carci', 'The effectiveness of a CTLA-targeted antibody in treating melanoma was an impetus for the use of programmed cell death-1 (PD-1) inhibitors in cancer treatmen', ' Monoclonal antibodies that target the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) pathway have shown antitumour activity in metastatic renal cell carcinoma (mRCC)']

['The programmed death-1 (PD-1) pathway negatively regulates T-cell activation and has an important role in regulating antitumor host immunity. Monoclonal antibodies directed against PD-1 or the PD-1 ligand (PD-L1) are used to treat cancer. ']

[]

Is valproic acid effective for glioblastoma treatment?

['A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.', 'PURPOSE: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models.', ' Median overall survival (OS) was 29.6\xa0months (range: 21-63.8\xa0months), and median progression-free survival (PFS) was 10.5\xa0months (range: 6.8-51.2\xa0months). OS at 6, 12, and 24\xa0months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24\xa0months was 70%, 43%, and 38% respectively. ', 'CONCLUSIONS: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.', 'Treatment of GDSCs with histone deacetylase inhibitors, TSA and VPA, significantly reduced proliferation rates of the cells and expression of the stem cell markers, indicating differentiation of the cells. Since differentiation into GBM makes them susceptible to the conventional cancer treatments, we posit that use of histone deacetylase inhibitors may increase efficacy of the conventional cancer treatments for eliminating GDSCs.', 'Several clinical studies have reported that valproic acid could prolong survival of GBM patients. ', 'Our meta-analysis confirmed the benefit of using VPA (HR, 0.56; 95% CI, 0.44-0.71). Sub-group analysis shows that patients treated with VPA had a hazard ratio of 0.74 with a 95% confidence interval of 0.59-0.94 vs. patients treated by other-AEDs and a hazard ratio of 0.66 with a 95% confidence interval of 0.52-0.84 vs. patients treated by administration of non-AEDs. ', '.CONCLUSION: The results of our study suggest that glioblastoma patients may experience prolonged survival due to VPA administration. ', 'A new and exciting insight is the potential contribution of VPA to prolonged survival, particularly in glioblastomas. ', 'Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models', 'Valproic acid use during radiation therapy for glioblastoma associated with improved survival', 'Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT)', 'Valproic acid use during radiation therapy for glioblastoma associated with improved survival.', 'Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.', 'PURPOSE: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS).METHODS AND MATERIALS: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS.RESULTS: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. ', 'When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, -0.09 to 1.17), independently of RTOG RPA class and seizure history.', 'Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7-67.3) compared with 61 weeks (95% CI: 52.5-69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43-0.92; P = .016), adjusting for age, extent of resection, and O(6)-DNA methylguanine-methyltransferase promoter methylation status.', "Use of VPA together with chemoradiation with temozolomide results in a 2-months' longer survival of patients with GBM."]

['Yes, valproic acid prolong survival of glioblastoma patients. Valproic acid is an antiepileptic agent with histone deacetylase inhibitor activity shown to sensitize glioblastoma cells to radiation in preclinical models.']

['yes']

Which kinases does baricitinib inhibit?

['Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib.', 'A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome.', 'Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders.', 'A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib.', 'Phase II data for four JAK inhibitors (baricitinib,', 'Positive clinical trial results have also been reported for several other JAK inhibitors including baricitinib. Several other JAK inhibitors and other small molecular entities are also being developed in studies ranging from preclinical models to large clinical trials.']

['Baricitinib is an inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2.']

['JAK1', 'JAK2']

Is dupilumab an antibody targeting the IL-1 receptor?

['Atopic dermatitis (AD) is characterized by type 2 helper T (Th2) cell-driven inflammation. Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that blocks the signaling of IL-4 and IL-13, both key cytokines in Th2-mediated pathways.', "Dupilumab, a humanized monoclonal antibody to the interteukin-4R is the first antibody (i.e. 'biological') with published efficacy shown in controlled prospective studies in atopic dermatitis. ", 'Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis.', 'Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players.', ' Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. ', 'Dupilumab was also introduced as a possible treatment for patients with severe pemphigus. It can directly inhibit IL-4 by targeting IL-4 α-chain receptor.', 'We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor']

['No, Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that blocks the signaling of IL-4 and IL-13, both key cytokines in Th2-mediated pathways.']

['no']

Is the optogenetics tool ChR2 light-sensitive?

['Channelrhodospin-2 (ChR2), a light-sensitive ion channel, and its variants have emerged as new excitatory optogenetic tools not only in neuroscience, but also in other areas, including cardiac electrophysiology.', 'Light-sensitive genes chiefly including the genetically targeted light-gated channels channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR) cause intracellular ion flow during optical illumination.', 'Computational optogenetics: empirically-derived voltage- and light-sensitive channelrhodopsin-2 model.', 'The versatility and the electrophysiologic characteristics of the light-sensitive ion-channels channelrhodopsin-2 (ChR2), halorhodopsin (NpHR), and the light-sensitive proton pump archaerhodopsin-3 (Arch) make these optogenetic tools potent candidates in controlling neuronal firing in models of epilepsy and in providing insights into the physiology and pathology of neuronal network organization and synchronization.', 'Channelrhodopsins-2 (ChR2) are a class of light sensitive proteins that offer the ability to use light stimulation to regulate neural activity with millisecond precision.', 'The most widely used optogenetic tool, Channelrhodopsin2 (ChR2), is both light- and voltage-sensitive.', 'Channelrhodospin-2 (ChR2), a light-sensitive ion channel, and its variants have emerged as new excitatory optogenetic tools not only in neuroscience, but also in other areas, including cardiac electrophysiology. ', 'Optogenetic methods have emerged as a powerful tool for elucidating neural circuit activity underlying a diverse set of behaviors across a broad range of species. Optogenetic tools of microbial origin consist of light-sensitive membrane proteins that are able to activate (e.g., channelrhodopsin-2, ChR2) or silence (e.g., halorhodopsin, NpHR) neural activity ingenetically-defined cell types over behaviorally-relevant timescales. ', 'Virus-mediated expression of a ChR2 variant with greater light sensitivity in SGNs reduced the amount of light required for responses and allowed neuronal spiking following stimulation up to 60 Hz. ', 'Channelrhodopsin-2 (ChR2) from the green alga Chlamydomonas reinhardtii functions as a light-gated cation channel that has been developed as an optogenetic tool to stimulate specific nerve cells in animals and control their behavior by illumination. ', 'Here, we used animal models to characterize optogenetic stimulation, which is the optical stimulation of neurons genetically engineered to express the light-gated ion channel channelrhodopsin-2 (ChR2). ', 'The versatility and the electrophysiologic characteristics of the light-sensitive ion-channels channelrhodopsin-2 (ChR2), halorhodopsin (NpHR), and the light-sensitive proton pump archaerhodopsin-3 (Arch) make these optogenetic tools potent candidates in controlling neuronal firing in models of epilepsy and in providing insights into the physiology and pathology of neuronal network organization and synchronization.', 'The most widely used optogenetic tool, Channelrhodopsin2 (ChR2), is both light- and voltage-sensitive. A light-triggered action potential or light-driven perturbations of ongoing electrical activity provide instant voltage feedback, shaping ChR2 current.', ' Optogenetic methods have emerged as a powerful tool for elucidating neural circuit activity underlying a diverse set of behaviors across a broad range of species. Optogenetic tools of microbial origin consist of light-sensitive membrane proteins that are able to activate (e.g., channelrhodopsin-2, ChR2) or silence (e.g., halorhodopsin, NpHR) neural activity ingenetically-defined cell types over behaviorally-relevant timescales.', 'Channelrhodospin-2 (ChR2), a light-sensitive ion channel, and its variants have emerged as new excitatory optogenetic tools not only in neuroscience, but also in other areas, including cardiac electrophysiology.', 'It allows neurons to express light-sensitive genes that enable the identification, dissection, and manipulation of specific neural populations and their connections in the tissues and organs of awake animals with unprecedented spatial and temporal precision. Light-sensitive genes chiefly including the genetically targeted light-gated channels channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR) cause intracellular ion flow during optical illumination.', 'Channelrhodopsin-2 (ChR2) from the green alga Chlamydomonas reinhardtii functions as a light-gated cation channel that has been developed as an optogenetic tool to stimulate specific nerve cells in animals and control their behavior by illumination. The molecular mechanism of ChR2 has been extensively studied by a variety of spectroscopic methods, including light-induced difference Fourier transform infrared (FTIR) spectroscopy, which is sensitive to structural changes in the protein upon light activation.']

['Channelrhodospin-2 (ChR2) is a light-sensitive ion channel that has emerged as new optogenetics tool.']

['yes']

Which could be some of the possible causes of hypersomnia?

['Sleep-wake disturbances (SWD) are common after traumatic brain injury (TBI). In acute TBI, we recently found decreased CSF levels of hypocretin-1, a wake-promoting neurotransmitter', 'Hypocretin levels 6 months after TBI were significantly lower in patients with post-traumatic EDS', 'These results suggest that sleep-wake disturbances, particularly EDS, fatigue and hypersomnia are common after TBI, and significantly impair quality of life', 'When sleepiness is excessive, undesirable, inappropriate or unexplained, it often indicates a clinical disorder that is generically termed hypersomnia. One of the leading causes of hypersomnia is sleep apnea', "A clinically relevant sleep-wake disturbance is found in up to half the patients with dementia, and the sundowning agitation is a common cause of institutionalisation of demented geriatric patients. The circadian rhythm of demented patients is levelled off with increased daytime sleep and disrupted night sleep. Particularly in vascular dementia, Korsakow syndrome, Parkinson's disease, and depression the alteration of sleep architecture may be pronounced, whereas in Alzheimer's disease prominent hypersomnolence or insomnia is typically only found in later stages of the diseases", 'We report on an 83 yr old man with hypersomnia and central sleep apnoea (CSA)', 'One of the leading causes of hypersomnia is sleep apnea.', 'In this article, the causes of hypersomnia are detailed following the conventional classification of hypersomnic syndromes: narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, insufficient sleep syndrome, medication- and toxin-dependent sleepiness, hypersomnia associated with psychiatric disorders, hypersomnia associated with neurological disorders, posttraumatic hypersomnia, infection (with a special emphasis on the differences between bacterial and viral diseases compared with parasitic diseases, such as sleeping sickness) and hypersomnia, hypersomnia associated with metabolic or endocrine diseases, breathing-related sleep disorders and sleep apnea syndromes, and periodic limb movements in sleep.', 'In the absence of sleep deprivation (either because of behavioral or medical causes) or pharmacologically induced sleepiness, hypersomnia is a manifestation of one of the central disorders of hypersomnolence, such as narcolepsy types 1 and 2, idiopathic hypersomnia, and recurrent hypersomnias such as Kleine-Levin syndrome.', 'Sleep apnea syndrome (SAS), narcolepsy, chronic sleep deprivation (insufficiency), and restless legs/periodic limb movements in sleep syndrome (RLS/PLMS) represent the most common causes of hypersomnia.', 'Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia.', 'One of the leading causes of hypersomnia is sleep apnea.']

["Sleep-wake disturbances (SWD) with hypersomnia are common after traumatic brain injury (TBI), with decreased CSF levels of hypocretin-1, a wake-promoting neurotransmitter, in cases of sleep apnea, as well as in up to half the patients with dementia, particularly in vascular dementia, Korsakow syndrome, Parkinson's disease, and depression, where the alteration of sleep architecture may be pronounced, whereas in Alzheimer's disease prominent hypersomnolence or insomnia is typically only found in later stages of the diseases."]

['traumatic brain injury (TBI)', 'sleep apnea', 'dementia']

Is NOD1 activated in inflammation?

['Nod1 and Nod2 control bacterial infections and inflammation', 'The Nod proteins Nod1 and Nod2 are two NLR family members that trigger immune defense in response to bacterial peptidoglycan', 'Nod proteins fight off bacterial infections by stimulating proinflammatory signaling and cytokine networks and by inducing antimicrobial effectors, such as nitric oxide and antimicrobial peptides.', 'Nod1 is also critically implicated in shaping adaptive immune responses towards bacterial-derived constituents.', 'Together, Nod1 and Nod2 represent central players in the control of immune responses to bacterial infections and inflammation.', 'The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis.', 'we show that Nod1 deficiency results in the increased development of both colitis-associated and Apc tumor suppressor-related colon tumors. In the absence of Nod1 signaling, there is a greater disruption of the intestinal epithelial cell barrier due to chemically induced injury as manifested by increased surface epithelial apoptosis early on during chemically induced colitis and increased intestinal permeability.', 'The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice.', 'Depletion of the gut microbiota suppressed tumor development in Nod1-deficient mice, thus highlighting a link between the commensal bacteria within the intestine and the host innate immune Nod1 signaling pathway in the regulation inflammation-mediated colon cancer development.', ' NOD1 protein is expressed in the eye and promotes ocular inflammation in a dose- and time-dependent fashion. ', 'NOD1 expression in the eye and functional contribution to IL-1beta-dependent ocular inflammation in mice', "Polymorphisms in NOD1 are associated with autoinflammatory diseases characterized by uveitis such as Crohn's disease and sarcoidosis", 'NOD1 is homologous to NOD2, which is responsible for an autosomal dominant form of uveitis. Nonetheless, the role of NOD1 in intraocular inflammation has not been explored.', 'Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model', 'mice deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue', 'The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis.', 'Nod1 ligands induce site-specific vascular inflammation', 'Phenotyping of Nod1/2 double deficient mice and characterization of Nod1/2 in systemic inflammation and associated renal disease', 'The present study analyzed Nod1 and Nod2 double deficient (Nod1/2 DKO) mice under physiological and inflammatory conditions', "Several inflammatory disorders, such as Crohn's disease and asthma, are linked to genetic changes in either Nod1 or Nod2.", 'Systematic analysis of Nod1/2 DKO mice revealed a possible role of Nod1/2 in the development of renal disease during systemic inflammation.', 'NOD1 and NOD2 Signaling in Infection and Inflammation', 'NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. ', 'In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. ', 'This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.', 'NOD1 expression elicited by iE-DAP in first trimester human trophoblast cells and its potential role in infection-associated inflammation', 'This study aimed to investigate the expression and function of NOD1 in first trimester trophoblast cells, and evaluate the potential role of trophoblast cells in infection-associated inflammation', 'NOD1 may have a role in mediating infection-associated inflammation. Once iE-DAP is recognized by NOD1, the inflammatory response may be induced via NOD1-RICK-NF-κB-mediated pathways.', 'NOD1/2(-/-) mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance.', 'In contrast, Nod1 gene-deficient mice developed enhanced joint inflammation with concomitant elevated levels of proinflammatory cytokines and cartilage damage, consistent with a model in which Nod1 controls the inflammatory reaction.', 'These data indicate that the NLR family members Nod1 and Nod2 have different functions in controlling inflammation, and that intracellular Nod1-Nod2 interactions may determine the severity of arthritis in this experimental model.', 'Whereas the lymphotoxin pathway was critical for the induction of the B cell chemoattractant CXCL13 in response to Nod1 agonists, B cell accumulation within the spleen following Nod1-induced systemic inflammation was independent of the lymphotoxin pathway.', 'The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed.', 'Nonetheless, the role of NOD1 in intraocular inflammation has not been explored.', 'A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses.', 'We previously demonstrated that human first-trimester trophoblasts express Nod1 and Nod2, which trigger inflammation upon stimulation.', 'In addition, recent studies have revealed a role for intracellular NOD1 receptors in the regulation of vascular inflammation and metabolism.', 'In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM.', 'Phenotyping of Nod1/2 double deficient mice and characterization of Nod1/2 in systemic inflammation and associated renal disease.', 'Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor.', 'The nucleotide-binding oligomerisation domain (NOD) intracellular molecules recognise a wide range of microbial products, as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor κB (NFκB). ', 'Nod1 ligands induce site-specific vascular inflammation.', 'The nucleotide oligomerization domain (NOD) intracellular molecules recognize a wide range of microbial products as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor KB (NFKB), a central regulator of the terminal processes of human labor and delivery. ', 'CONCLUSIONS: We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. ', 'Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model.', 'In particular, muramyl peptides trigger inflammation, contribute to host defense against microbial infections, and modulate the adaptive immune response to antigens. ', 'Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand-injected mice. ', 'CONCLUSIONS: We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. ', 'Interferon-gamma (IFN gamma), which is a potent pro-inflammatory cytokine in intestinal mucosal inflammation, activates CARD4/NOD1 mRNA transcription in a time- and dose-dependent manner and results in augmentation of CARD4/NOD1 protein in SW480 cells.', 'These studies suggest that the Th1 cytokine, IFN gamma, activates CARD4/NOD1 transcription and regulate innate immune mechanisms in the condition of intestinal mucosal inflammation.', 'NOD1 activation triggers inflammation,', 'In contrast to enhanced leptin mRNA by LPS and TNFα, NOD1 activation suppressed leptin mRNA in adipocytes, suggesting the differential effects of NOD1 activation in adipocytes. Overall, our results suggest that NOD1 represents a novel target for adipose inflammation in obesity.', 'NOD1 activation triggers inflammation, antimicrobial mechanisms and autophagy in both epithelial cells and murine macrophages.', 'NOD1 is an intracellular immune receptor that senses peptidoglycan from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering peptidoglycan structure.', 'Bacterial NOD1 activation is positioned as a component of metabolic endotoxemia that can contribute to hyperlipidemia, systemic inflammation and insulin resistance by acting directly on adipocytes.', 'NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1(-/-), mice.', 'We conclude that NOD1 activation reduced AHR in allergen-induced lung inflammation, which was accompanied by a reduction of allergen-specific T-cell proliferation.', 'The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed.', 'Interferon-gamma (IFN gamma), which is a potent pro-inflammatory cytokine in intestinal mucosal inflammation, activates CARD4/NOD1 mRNA transcription in a time- and dose-dependent manner and results in augmentation of CARD4/NOD1 protein in SW480 cells.']

["Nod proteins fight off bacterial infections by stimulating proinflammatory signaling and cytokine networks and by inducing antimicrobial effectors, such as nitric oxide and antimicrobial peptides. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways and several inflammatory disorders, such as Crohn's disease and asthma, are linked to genetic changes in either Nod1 or Nod2. Nod1 is also critically implicated in shaping adaptive immune responses towards bacterial-derived constituents. Together, Nod1 and Nod2 represent central players in the control of immune responses to bacterial infections and inflammation. Mice deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue", 'Nod1/2 DKO mice show increased susceptibility for intestinal permeability while vascular permeability was not affected. The present study analyzed Nod1 and Nod2 double deficient (Nod1/2 DKO) mice under physiological and inflammatory conditions. The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice. However, the influence of Rip2 was strictly dependent on infection conditions that favored expression of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS), as Rip2 was dispensable for inflammation when mice were infected with bacteria grown under conditions that promoted expression of the SPI-1 TTSS.', 'Nod1 and Nod2 control bacterial infections and inflammation']

['yes']

Do normal cells express the protein TERT?

['Since telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells, it has become a very promising target for anti-cancer therapy', 'Telomerase plays a pivotal role in cellular immortality and tumorigenesis. Its activity is normally not detectable in most somatic cells while it is reactivated in the vast majority of cancer cells. Therefore, inhibition of telomerase has been viewed as a promising anticancer approach due to its specificity for cancer cells.', 'Telomerase activity is found in 85%-90% of all human cancers but not in their adjacent normal cells. Human telomerase reverse transcriptase (hTERT) is an essential component in the telomerase complex that plays an important role in telomerase activity.', 'elomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication']

['Νο, telomerase activity is found in 85%-90% of all human cancers but not in their adjacent normal cells. Human telomerase reverse transcriptase (hTERT) is an essential component in the telomerase complex that plays an important role in telomerase activity.']

['no']

What happens to H2AX upon DNA bouble strand breaks?

['Histone H2AX phosphorylation as a measure of DNA double-strand breaks and a marker of environmental stress and disease activity in lupus', 'DSBs were quantified in peripheral blood mononuclear cell subsets from patients with SLE, healthy controls, and patients with rheumatoid arthritis (RA) by measuring phosphorylated H2AX (phospho-H2AX) levels with flow cytometry', 'Most hydrogen peroxide-induced histone H2AX phosphorylation is mediated by ATR and is not dependent on DNA double-strand breaks.', 'The nuclear foci of phosphorylated histone H2AX (γH2AX) are frequently used as a marker for DNA double-strand breaks (DSBs) following ionizing radiation (IR)', 'These results suggest that a major fraction of γH2AX induced by oxidative stress is not associated with DSBs. Single-stranded DNA arisen from stalled replication forks can cause the ATR-mediated induction of γH2AX', 'H2AX phosphorylation at the sites of DNA double-strand breaks in cultivated mammalian cells and tissues', 'A sequence variant of histone H2A called H2AX is one of the key components of chromatin involved in DNA damage response induced by different genotoxic stresses', ' Phosphorylated H2AX (γH2AX) is rapidly concentrated in chromatin domains around DNA double-strand breaks (DSBs) after the action of ionizing radiation or chemical agents and at stalled replication forks during replication stress', 'DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin', 'he cellular response to DSBs depends on damage signaling including the phosphorylation of the histone H2AX (γH2AX). However, a lack of γH2AX formation in heterochromatin (HC) is generally observed after DNA damage induction. Here, we examine γH2AX and repair protein foci along linear ion tracks traversing heterochromatic regions in human or murine cells and find the DSBs and damage signal streaks bending around highly compacted DNA. ']

[' Phosphorylated H2AX (γH2AX) is rapidly concentrated in chromatin domains around DNA double-strand breaks (DSBs) after the action of ionizing radiation or chemical agents and at stalled replication forks during replication stress The nuclear foci of phosphorylated histone H2AX (γH2AX) are frequently used as a marker for DNA double-strand breaks (DSBs) following ionizing radiation (IR)', ' phosphorylated h2ax (γh2ax) is rapidly concentrated in chromatin domains around dna double-strand breaks (dsbs) after the action of ionizing radiation or chemical agents and at stalled replication forks during replication stress.', 'Defective or inefficient DNA double-strand break (DSB) repair results in failure to preserve genomic integrity leading to apoptotic cell death, a hallmark of systemic lupus erythematosus (SLE). Phosphorylated H2AX (γH2AX) is rapidly concentrated in chromatin domains around DNA double-strand breaks (DSBs) after the action of ionizing radiation or chemical agents and at stalled replication forks during replication stress.', 'The nuclear foci of phosphorylated histone H2AX (γH2AX) are frequently used as a marker for DNA double-strand breaks (DSBs) following ionizing radiation (IR). Phosphorylated H2AX (γH2AX) is rapidly concentrated in chromatin domains around DNA double-strand breaks (DSBs) after the action of ionizing radiation or chemical agents and at stalled replication forks during replication stress. DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin', 'Histone H2AX phosphorylation as a measure of DNA double-strand breaks and a marker of environmental stress and disease activity in lupus. DSBs were quantified in peripheral blood mononuclear cell subsets from patients with SLE, healthy controls, and patients with rheumatoid arthritis (RA) by measuring phosphorylated H2AX (phospho-H2AX) levels with flow cytometry. Most hydrogen peroxide-induced histone H2AX phosphorylation is mediated by ATR and is not dependent on DNA double-strand breaks. The nuclear foci of phosphorylated histone H2AX (H2AX) are frequently used as a marker for DNA double-strand breaks (DSBs) following ionizing radiation (IR). These results suggest that a major fraction of H2AX induced by oxidative stress is not associated with DSBs. ', 'Defective or inefficient DNA double-strand break (DSB) repair results in failure to preserve genomic integrity leading to apoptotic cell death, a hallmark of systemic lupus erythematosus (SLE). The nuclear foci of phosphorylated histone H2AX (γH2AX) are frequently used as a marker for DNA double-strand breaks (DSBs) following ionizing radiation (IR). A sequence variant of histone H2A called H2AX is one of the key components of chromatin involved in DNA damage response induced by different genotoxic stresses. DNA double-strand breaks (DSBs) can induce chromosomal aberrations and carcinogenesis and their correct repair is crucial for genetic stability.', 'DSBs were quantified in peripheral blood mononuclear cell subsets from patients with SLE, healthy controls, and patients with rheumatoid arthritis (RA) by measuring phosphorylated H2AX (phospho-H2AX) levels with flow cytometry DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin']

['it is rapidly concentrated']

How do Ecm22 and Upc2 impact filamentation in Saccharomyces cerevisiae via sterol biosynthesis pathways?

['["Here, we examine the role of the related transcription factors Ecm22 and Upc2 in Saccharomyces cerevisiae filamentation.", "The zinc cluster proteins Upc2 and Ecm22 promote filamentation in Saccharomyces cerevisiae by sterol biosynthesis-dependent and -independent pathways.", "Upc2, a zinc-cluster transcription factor, is a regulator of ergosterol biosynthesis in yeast.", "The zinc cluster proteins Ecm22, Upc2, Sut1 and Sut2 have initially been identified as regulators of sterol import in the budding yeast Saccharomyces cerevisiae.", "Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes.", "Ecm22 and Upc2 positively control the expression of FHN1, NPR1, PRR2 and sterol biosynthesis genes.", "RNA-seq analysis shows that hypoxic regulation of sterol synthesis genes in Y. lipolytica is predominantly mediated by Upc2.", "However, in yeasts such as Saccharomyces cerevisiae and Candida albicans sterol synthesis is instead regulated by Upc2, an unrelated transcription factor with a Gal4-type zinc finger.", "Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression.", "One such factor could be the mammalian equivalent of the gene product of UPC2.", "Simultaneous deletion of ECM22 and UPC2 as well as mutation of the three Ste12-binding sites in the PRM1 promoter completely abolishes basal and pheromone-induced PRM1 expression, indicating that Ste12 and Ecm22/Upc2 control PRM1 transcription through distinct pathways.", "Ecm22 and Upc2 positively regulate basal expression of PRM1 and PRM4.", "Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place.", "A yeast mutant (upc2-1) with a defect in the aerobic exclusion of sterols was found to have increased sensitivity to LiCl and NaCl.", "The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function.", "Secretion of apoE was achieved only by the use of a mutant (upc2) strain of yeast with the phenotype of enhanced uptake and intracellular esterification of exogenous cholesterol.", "Gas chromatographic analysis of the nonsaponifiable fractions of the various strains showed that the major sterol for all YLR228c and UPC2 combinations was ergosterol, the consensus yeast sterol..", "In the pathogenic yeast Candida albicans, the zinc cluster transcription factor Upc2p has been shown to regulate the expression of ERG11 and other genes involved in ergosterol biosynthesis upon exposure to azole antifungals.", "By comparing the gene expression profiles of the fluconazole-resistant isolate and of strains carrying wild-type and mutated UPC2 alleles, we identified target genes that are controlled by Upc2p."]', '["Here, we examine the role of the related transcription factors Ecm22 and Upc2 in Saccharomyces cerevisiae filamentation.", "The zinc cluster proteins Upc2 and Ecm22 promote filamentation in Saccharomyces cerevisiae by sterol biosynthesis-dependent and -independent pathways.", "Upc2, a zinc-cluster transcription factor, is a regulator of ergosterol biosynthesis in yeast.", "The zinc cluster proteins Ecm22, Upc2, Sut1 and Sut2 have initially been identified as regulators of sterol import in the budding yeast Saccharomyces cerevisiae.", "Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes.", "Ecm22 and Upc2 positively control the expression of FHN1, NPR1, PRR2 and sterol biosynthesis genes.", "RNA-seq analysis shows that hypoxic regulation of sterol synthesis genes in Y. lipolytica is predominantly mediated by Upc2.", "However, in yeasts such as Saccharomyces cerevisiae and Candida albicans sterol synthesis is instead regulated by Upc2, an unrelated transcription factor with a Gal4-type zinc finger.", "Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression.", "One such factor could be the mammalian equivalent of the gene product of UPC2.", "Simultaneous deletion of ECM22 and UPC2 as well as mutation of the three Ste12-binding sites in the PRM1 promoter completely abolishes basal and pheromone-induced PRM1 expression, indicating that Ste12 and Ecm22/Upc2 control PRM1 transcription through distinct pathways.", "Ecm22 and Upc2 positively regulate basal expression of PRM1 and PRM4.", "Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place.", "A yeast mutant (upc2-1) with a defect in the aerobic exclusion of sterols was found to have increased sensitivity to LiCl and NaCl.", "The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function.", "Secretion of apoE was achieved only by the use of a mutant (upc2) strain of yeast with the phenotype of enhanced uptake and intracellular esterification of exogenous cholesterol.", "Gas chromatographic analysis of the nonsaponifiable fractions of the various strains showed that the major sterol for all YLR228c and UPC2 combinations was ergosterol, the consensus yeast sterol..", "In the pathogenic yeast Candida albicans, the zinc cluster transcription factor Upc2p has been shown to regulate the expression of ERG11 and other genes involved in ergosterol biosynthesis upon exposure to azole antifungals.", "By comparing the gene expression profiles of the fluconazole-resistant isolate and of strains carrying wild-type and mutated UPC2 alleles, we identified target genes that are controlled by Upc2p."]']

Ecm22 and Upc2 impact filamentation in Saccharomyces cerevisiae through sterol biosynthesis-dependent and -independent pathways. They promote filamentation by directing transcription of sterol biosynthetic genes and positively controlling the expression of sterol biosynthesis genes.

[]

Is the H3K4me3 histone mark related to transcriptional initiation or elongation?

['The histone marks appeared mainly in generic regions and were enriched around the transcription start sites (TSSs) of genes', 'Trimethylation of histone H3 Lys 4 (H3K4me3) is a mark of active and poised promoters.', 'Histone H3 lysine 4 trimethylation (H3K4me3) is well known to occur in the promoter region of genes for transcription activation', "3'-H3K4me3 is associated with ~15% of protein-coding genes in both tissues", "Furthermore, 3'-H3K4me3 modification levels correlate positively with the antisense expression levels of the associated sense genes, implying that 3'-H3K4me3 is involved in the activation of antisense transcription.", 'Among these are forms of histone 3 that are mono- or tri-methylated at lysine 4 (H3K4me1 or H3K4me3, respectively), which bind preferentially to promoter and enhancer elements in the mammalian genome', 'we find that H3K4me1 and H3K4me3 are enriched at transcriptional start sites in the genome', 'H3K4me1 and H3K4me3 generally mark cis regulatory elements']

['H3K4me3 is associated with transcriptionally active genes, but its function in the transcription process is still unclear. It is well known to occur in the promoter region of genes for transcription activation but its levels correlate positively with the antisense expression levels of the associated sense genes implying that it may be also involved in the activation of antisense transcription. Although it is mostly associated with transcription initiation H3K4me3 levels determine the efficiency of transcription elongation.']

['transcriptional initiation']

Which depression rating scales were shown to have acceptable psychometric properties for screening of poststroke depression?

['The Center of Epidemiological Studies-Depression Scale (CESD) (sensitivity: 0.75; 95% CI 0.60 to 0.85; specificity: 0.88; 95% CI 0.71 to 0.95), the Hamilton Depression Rating Scale (HDRS) (sensitivity: 0.84; 95% CI 0.75 to 0.90; specificity:0.83; 95% CI 0.72 to 0.90) and the Patient Health Questionnaire (PHQ)-9 (sensitivity: 0.86; 95% CI 0.70 to 0.94; specificity: 0.79; 95% CI 0.60 to 0.90) appeared to be the optimal measures for screening measures.', 'There are a number of possible instruments that may help in screening for poststroke depression but none are satisfactory for case-finding.', 'Preliminary data suggests the CESD, HDRS or the PHQ-9 as the most promising options.', 'The Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale-depression subscale (HADS-D), Hamilton Rating Scale for Depression (HAMD), and Montgomery-Asberg Depression Rating Scale (MADRS) were administered. The balance of sensitivity and specificity was assessed using receiver operating characteristics (ROC) analysis. RESULTS: Discriminating abilities of all the scales for major and all PSD were good (area under ROC values 0.88-0.93 and 0.88-0.92 at 2 weeks; and 0.93-0.96 and 0.89-0.91 at 1 year, respectively).', 'We compared the Beck Depression Inventory, Hamilton Rating Scale for Depression, Visual Analogue Mood Scale, proxy assessment, and Clinical Global Impression of the nursing and study personnel, together with Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised diagnosis, in assessing depression after stroke in a follow-up study of 100 patients.', 'The sensitivity and specificity against the Diagnostic and Statistical Manual of Mental Disorders criteria were acceptable with the Clinical Global Impression, Beck Depression Inventory, and Hamilton Rating Scale for Depression, mostly in the range of 0.70 to 1.00.', 'The Visual Analogue Mood Scale was not a sensitive instrument (sensitivity, 0.20 to 0.60) and did not correlate with the Beck Depression Inventory during the first year after stroke.', 'Beck Depression Inventory, Hamilton Rating Scale for Depression, and Clinical Global Impression assessment by professionals, in addition to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised diagnosis, are useful in assessing depression, but none of these instruments clearly stood apart from the others.', 'Proxy ratings should be used with caution, and the use of the Visual Analogue Mood Scale among patients with aphasia and other cognitive impairments cannot be recommended.', 'This study evaluated the diagnostic accuracy of the Poststroke Depression Rating Scale (PSDRS), a diagnostic tool specifically devised to assess depression after stroke, in comparison to the Hamilton Depression Rating Scale (Ham-D).', 'At their optimum cut-off points, the Ham-D and PSDRS showed good sensitivity and specificity for MDL or MDL + MDDM; the PSDRS had a higher positive predictive value for MDL in respect of the Ham-D (78 vs. 59%).', 'Furthermore, the diagnostic accuracy of the PSDRS was higher in respect of the Ham-D in aphasic patients.', 'The Ham-D and PSDRS are both reliable diagnostic tools for the diagnosis of PSD.', 'We suggest that the PSDRS could be a useful tool in clinical practice and in therapeutic trials.', 'The psychiatrist classified 25/71 (35.2%) patients as depressed. Using the recommended cut-point of 2 or more on the Signs of Depression Scale, the nurse and carer respectively rated 27/71 (38.0%) and 18/30 (60.0%) patients as potentially depressed. The proportion of patients correctly identified as depressed by the test (sensitivity) when rated by nurses was 64%, and the proportion of patients not depressed who were correctly identified by the test (specificity) was 61%, whereas carers achieved sensitivity 90% and specificity 35%.', 'The Signs of Depression Scale is easily completed by clinical staff, although we found the sensitivity when completed by nurses to be low. Information from carers shows potential to improve screening and it is important for nurses to value the knowledge and skills of carers in detecting depression following a stroke. Further refinement of the Signs of Depression Scale, with accompanying research, is required.', 'The VAMS was not useful in screening for depression in Chinese stroke patients while both the HADS and the GDS demonstrated satisfactory accuracy in detecting depression in Chinese stroke patients.', 'At their respective optimum cutoff values, the sensitivity of the self-rated scales varied between 80% and 90%, while the specificity was about 60%. For the observer-rated scale (Hamilton Depression Rating Scale), sensitivity was 78.1%, and specificity was 74.6%.', 'The hypothesis was supported: in contrast to psychiatric interview (68% depressed) and self-report (Beck Depression Inventory, 50% depressed), none of the patients were described as depressed in chart notes by the rehabilitation team (excluding the psychiatrists).', 'Although there were no marked differences in the screening abilities for PSD between the scales, differences were found in factors influencing misclassification. Assessment scales with less somatic items may be recommended for the screening of PSD, particularly at the acute phase of stroke.']

['The Center of Epidemiological Studies-Depression Scale, Hamilton Depression Rating Scale, and the Patient Health Questionnaire, The Beck Depression Inventory, Hospital Anxiety and Depression Scale-depression subscale, Montgomery-Asberg Depression Rating Scale, Poststroke Depression Rating Scale and Clinical Global Impression scale appeared to have acceptable psychometric properties for identifying depression in patients after stroke. Therefore, these scales can be used for screening of post-stroke depression. Signs of Depression Scale and Visual Analogue Mood Scale showed inferior psychometric properties and therefore should not be used for screening for post-stroke depression.']

[]

What is the typical rash associated with gluten ?

['Dermatitis herpetiformis (DH) is an autoimmunity-driven inflammatory blistering dermatosis associated with a gluten-dependent enteropathy. ', 'Dermatitis herpetiformis is an autoimmune blistering disease that appears as a cutaneous manifestation of gluten intolerance. ', 'Treatment of dermatitis herpetiformis is based on a life-long, strict gluten-free diet, which improves all clinical aspects of gluten sensitivity, and dapsone, a drug that is only effective for the skin manifestations.', 'Dermatitis herpetiformis and coeliac disease are gluten-sensitive diseases that share immunopathological mechanisms.', 'We report the unusual case of an 8-month-old child presenting to his general practitioner with pruritic skin lesions, subsequently proven to be dermatitis herpetiformis (DH) as the first sign of gluten-sensitive disease.', 'Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity. ', ' These findings may relate to the fact, that dermatitis herpetiformis is associated with gluten sensitive enteropathy, coeliac disease, which is characterised by IgA type autoantibodies to a closely related enzyme, tissue transglutaminase.', ' There is growing evidence that dermatitis herpetiformis should be considered as the skin manifestation of gluten sensitivity developing in those patients with mild coeliac disease, who produce epidermal transglutaminase autoantibodies of high avidity and affinity.', 'BACKGROUND: A life-long gluten-free diet is the treatment of choice for dermatitis herpetiformis, which is considered to be coeliac disease of the skin. ', 'We report long-term clinical and histological remissions in seven patients with dermatitis herpetiformis after the reintroduction of dietary gluten.', 'Gluten sensitive enteropathy has various manifestations, of which the two major forms are classical coeliac disease (cCD) and dermatitis herpetiformis (DH).', 'The major significant advances in our understanding of DH have been the demonstration that DH patients also have coeliac diseases (CD) and that the rash is also gluten dependent. ', 'Despite the fact that it has been known for over fifty years that gluten causes the enteropathy of CD, and for over thirty years the rash of DH, it is still not known how gluten produces these effects.', 'BACKGROUND: Dermatitis herpetiformis (DH) is a specific dermatological manifestation of coeliac disease and 80% of DH patients have gluten sensitive enteropathy manifested by crypt hyperplasia and villous atrophy. ', 'The presence of a rash is also a sensitive indicator of gluten ingestion in dermatitis herpetiformis, and this was used to study whether patients with this disease could also tolerate oats. PATIENTS/METHODS: Eleven patients with dermatitis herpetiformis in remission on a gluten-free diet were challenged daily with 50 g oats for six months.', 'Dermatitis herpetiformis (DH) is a lifelong, gluten-sensitive, blistering skin disease with pathognomonic immunoglobulin (Ig)A deposits in the papillary dermis.', 'CONCLUSIONS: Patients with dermatitis herpetiformis can include moderate amounts of oats in their gluten-free diets without deleterious effects to the skin or intestine.', 'BACKGROUND: Dermatitis herpetiformis (DH) is a chronic papulovesicular immune-mediated disorder associated with gluten-sensitive enteropathy. ', 'Serum IgA class antigliadin antibodies (IgA-AGA) are increased in untreated patients with coeliac disease and dermatitis herpetiformis (DH), and it has been suggested that salivary IgA-AGA measurements could be used as a non-invasive screening test for gluten-sensitive enteropathy. ', 'Despite the fact that it has been known for over fifty years that gluten causes the enteropathy of CD, and for over thirty years the rash of DH, it is still not known how gluten produces these effects.', 'The central role of gluten in childhood dermatitis herpetiformis is evidenced by the fact that a gluten free diet helps the damaged jejunal mucosa to recover and controls the rash even in those children who do not have an abnormal jejunal biopsy.', 'The major significant advances in our understanding of DH have been the demonstration that DH patients also have coeliac diseases (CD) and that the rash is also gluten dependent.', 'The results confirm the absence of oat toxicity on the gluten sensitive small bowel mucosa and suggest that the rash in patients with dermatitis herpetiformis is not activated by eating oats.', 'The presence of a rash is also a sensitive indicator of gluten ingestion in dermatitis herpetiformis, and this was used to study whether patients with this disease could also tolerate oats.', 'Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity.', 'This contrasts to the situation in dermatitis herpetiformis, where both the rash and the enteropathy are gluten dependent.', 'Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity', 'Dermatitis herpetiformis (DH) is a chronic papulovesicular immune-mediated disorder associated with gluten-sensitive enteropathy']

['Dermatitis herpetiformis is a lifelong, gluten-sensitive, blistering skin disease with pathognomonic immunoglobulin (Ig)A deposits in the papillary dermis.']

['dermatitis herpetiformis']

What is the mode of inheritance of Facioscapulohumeral muscular dystrophy (FSHD)?

['autosomal dominant mode of inheritance']

['The mode of inheritance of Facioscapulohumeral muscular dystrophy is autosomal dominant.']

['autosomal dominant']

Are optogenetics tools used in the study and treatment of epilepsy?

['The emerging revolutionary technique of optogenetics enables manipulation of the activity of specific neuronal populations in vivo with exquisite spatiotemporal resolution using light. We used optogenetic approaches to test the role of hippocampal excitatory neurons in the lithium-pilocarpine model of acute elicited seizures in awake behaving rats.', 'This chapter focuses on the development of optogenetics and on-demand technologies for the study of epilepsy and the control of seizures.', 'We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research.', 'Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy.', ' 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.', '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.', 'Recently, a number of experiments have explored the treatments for epilepsy with optogenetic control of neurons. Here, we discuss the possibility that an optogenetic approach could be used to control the release of gliotransmitters and improve astrocyte function such as glutamate and K(+) uptake, and thereby offer a potential strategy to investigate and treat astrocyte-related epilepsy.', 'Optogenetic and designer receptor technologies provide unprecedented and much needed specificity, allowing for spatial, temporal and cell type-selective modulation of neuronal circuits. Using such tools, it is now possible to begin to address some of the fundamental unanswered questions in epilepsy, to dissect epileptic neuronal circuits and to develop new intervention strategies. ', 'We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research.', 'Moreover, optogenetics may be considered for developing potential treatment strategies for brain diseases, particularly for excitability disorders such as epilepsy.', 'This chapter focuses on the development of optogenetics and on-demand technologies for the study of epilepsy and the control of seizures.', 'How might novel technologies such as optogenetics lead to better treatments in epilepsy?', 'WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis.', 'Finally, optogenetic tools allow rapid and reversible suppression of epileptic electroencephalography (EEG) activity upon photoactivation.', 'Our data suggest that epileptiform activity in the hippocampus caused by impaired inhibition may be controlled by optogenetic silencing of principal neurons and potentially can be developed as an alternative treatment for epilepsy.', 'Seizure suppression by high frequency optogenetic stimulation using in vitro and in vivo animal models of epilepsy.', 'Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy. ', 'We first discuss the benefits and caveats to using optogenetic approaches and recent advances in optogenetics related tools. We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research.']

['Using optogenetics tools it is possible to begin to address some of the fundamental unanswered questions in epilepsy, to dissect epileptic neuronal circuits and to develop new intervention strategies.']

['yes']

Has depression been shown to be a predictor of frailty?

['significant role of frailty as a predictor of depression in a relatively younger old Chinese population', 'significant relationships between frailty and depressive symptoms and mortality at 1 year', 'These findings suggest that malnutrition is a major predictor of frailty or the "failure to thrive" syndrome in older persons. Depression is a major cause of poor nutritional status in older persons.', 'Depressed mood was associated with increased risk of steep strength decline, in particular in older men with low body weight. Low body weight in combination with depressed mood may be an indicator of frailty or severe disease status that leads to accelerated strength loss and disability.', 'Longitudinally, depressed mood was the only independent predictor of decline in cognition, functional ability, physician-rated health, and mortality;']

['Yes']

['yes']

Which factors activate zygotic gene expression during the maternal-to-zygotic transition in zebrafish?

['Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition.', 'Our results demonstrate that maternal Nanog, Pou5f1 and SoxB1 are required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR-430 expression.', 'Here we show that Nanog, Pou5f1 (also called Oct4) and SoxB1 regulate zygotic gene activation in zebrafish.', 'Here we show that Nanog, Pou5f1 (also called Oct4) and SoxB1 regulate zygotic gene activation in zebrafish. We identified several hundred genes directly activated by maternal factors, constituting the first wave of zygotic transcription.']

['Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Maternal Nanog, Pou5f1 and SoxB1 are required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR-430 expression.']

['Nanog', 'Pou5f1', 'SoxB1']

What are the clinical manifestations of bilateral lens dislocation?

['["bilateral lens dislocation", "Clinical manifestations include mental retardation, dislocation of the optic lens (ectopia lentis)", "Ectopia lentis is a genetically heterogeneous condition that is characterized by the subluxation of the lens resulting from the disruption of the zonular fibers. "]']

Clinical manifestations of bilateral lens dislocation include mental retardation and dislocation of the optic lens (ectopia lentis). Ectopia lentis is characterized by the subluxation of the lens due to disruption of the zonular fibers.

[]

What is magnetoreception?

['The ability to perceive geomagnetic fields (GMFs) represents a fascinating biological phenomenon. Studies on transgenic flies have provided evidence that photosensitive Cryptochromes (Cry) are involved in the response to magnetic fields (MFs). ', 'Cryptochromes, blue-light absorbing proteins involved in the circadian clock, have been proposed to be the receptor molecules of the avian magnetic compass. ', "Although it has been known for almost half a century that migratory birds can detect the direction of the Earth's magnetic field, the primary sensory mechanism behind this remarkable feat is still unclear. The leading hypothesis centers on radical pairs-magnetically sensitive chemical intermediates formed by photoexcitation of cryptochrome proteins in the retina. ", 'Biogenic magnetic particles have been detected in some migratory insects, which implies the basis of magnetoreception mechanism for orientation and navigation. ', 'Magnetoreception is essential for magnetic orientation in animal migration. The molecular basis for magnetoreception has recently been elucidated in fruitfly as complexes between the magnetic receptor magnetoreceptor (MagR) and its ligand cryptochrome (Cry). MagR and Cry are present in the animal kingdom.', 'Magnetoreception is an enigmatic, poorly understood sensory ability, described mainly on the basis of behavioural studies in animals of diverse taxa. ', 'The photoreceptor protein cryptochrome is thought to host, upon light absorption, a radical pair that is sensitive to very weak magnetic fields, endowing migratory birds with a magnetic compass sense.']

['Magnetoreception is an enigmatic, poorly understood sensory ability, described mainly on the basis of behavioural studies in animals of diverse taxa. The ability to perceive geomagnetic fields (GMFs) represents a fascinating biological phenomenon. Studies on transgenic flies have provided evidence that photosensitive Cryptochromes (Cry) are involved in the response to magnetic fields (MFs). The photoreceptor protein cryptochrome is thought to host, upon light absorption, a radical pair that is sensitive to very weak magnetic fields, endowing migratory birds with a magnetic compass sense.']

[]

Which are the most common methods for ctDNA (circulating tumour DNA) detection?

['existing methods for ctDNA detection are restricted to genetic mutations.', 'Recently, nanoplasmonics has emerged as a platform for one-step dual detection with high sensitivity and specificity.', 'These results demonstrate that the sensor can simultaneously detect the hot-spot mutation and epigenetic changes on the ctDNA. Promisingly, other specific-tumor mutants and epigenetic changes can be detected at low concentration with this platform.', 'The practice of "liquid biopsy" as a diagnostic, prognostic and theranostic tool in non-small cell lung cancer (NSCLC) patients is an appealing approach, at least in theory, since it is noninvasive and easily repeated', 'Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. ', 'Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.', 'Synthesis of a new Ni-phenanthroline complex and its application as an electrochemical probe for detection of nucleic acid', 'A new DNA sensor using a nickel(II) phenanthroline complex ([Ni(phen)(2)PHPIP]·2ClO(4)) as the electrochemical probe was developed. The sensor is very sensitive and selective for calf thymus DNA (ctDNA) detection in aqueous medium. ']

['Recently, nanoplasmonics has emerged as a platform for one-step dual detection with high sensitivity and specificity. The practice of "liquid biopsy" as a diagnostic, prognostic and theranostic tool in non-small cell lung cancer (NSCLC) patients is an appealing approach, at least in theory, since it is noninvasive and easily repeated. Cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. A new DNA sensor using a nickel(II) phenanthroline complex ([Ni(phen)(2)PHPIP]·2ClO(4)) as the electrochemical probe was developed. The sensor is very sensitive and selective for calf thymus DNA (ctDNA) detection in aqueous medium.', 'A new DNA sensor using a nickel(II) phenanthroline complex ([Ni(phen)(2)PHPIP]·2ClO(4)) as the electrochemical probe was developed. The calculated dynamics parameters of the electrode process indicate that there are obvious interactions between the probe and the ctDNA in aqueous solution. Under constant potential conditions, the redox current peak of the probe (Ni-complex) decreases obviously as the probe interacts/binds with ctDNAs. These results demonstrate that the sensor can simultaneously detect the hot-spot mutation and epigenetic changes on the ctDNA.']

['nanoplasmonics', 'biosensors', 'liquid biopsy', 'Cancer personalized profiling by deep sequencing', 'CAPP-Seq', 'electrochemical sensors']

Which enzymes are involved in global genome nucleotide excision repair (GG-NER) in bacteria?

['we evaluated the in vivo role of NER in the repair of DNA adducts generated by psoralens (mono- or bi-functional) and UV-A light (PUVA) in E. coli. Cultures of wild-type E. coli K12 and mutants for uvrA, uvrB, uvrC or uvrAC genes were treated with PUVA and cell survival was determined.', 'Nucleotide excision repair (NER) is universally used to recognize and remove many types of DNA damage. In eubacteria, the NER system typically consists of UvrA, UvrB, UvrC, the UvrD helicase, DNA polymerase I, and ligase.', 'During nucleotide excision repair (NER) in bacteria the UvrC nuclease and the short oligonucleotide that contains the DNA lesion are removed from the post-incision complex by UvrD, a superfamily 1A helicase.', 'UvrD interacts with UvrB, a component of the post-incision complex.', 'PcrA helicase from Bacillus stearothermophilus can also displace UvrC and the excised oligonucleotide from a post-incision NER complex, which supports the idea that PcrA performs a UvrD-like function during NER in gram-positive organisms.', 'Cho rather than UvrC seems to be an effective nuclease for the NER of DPCs.', 'Nucleotide excision repair consists of excinuclease protein UvrABC endonuclease, multi-enzymatic complex which carries out repair of damaged DNA in sequential manner.', 'Escherichia coli K12 mutant strains deficient in nucleotide excision repair (NER) were submitted to increasing concentrations of cisplatin, and the results revealed that uvrA and uvrB mutants are sensitive to this agent, while uvrC and cho mutants remain as the wild type strain.', 'we used a genetic approach to investigate the roles of nucleotide excision repair (NER) pathway components in H. pylori mutation and recombination. RESULTS: Inactivation of any of the four uvr genes strongly increased the susceptibility of H. pylori to DNA damage by ultraviolet light. Inactivation of uvrA and uvrB significantly decreased mutation frequencies whereas only the uvrA deficient mutant exhibited a significant decrease of the recombination frequency after natural transformation. A uvrC mutant did not show significant changes in mutation or recombination rates; however, inactivation of uvrC promoted the incorporation of significantly longer fragments of donor DNA (2.2-fold increase) into the recipient chromosome. A deletion of uvrD induced a hyper-recombinational phenotype.', 'Transcription-coupled DNA repair (TCR) is a subpathway of nucleotide excision repair (NER) that is triggered when RNA polymerase is stalled by DNA damage. Lesions targeted by TCR are repaired more quickly than lesions repaired by the transcription-independent "global" NER pathway, but the mechanism underlying this rate enhancement is not understood. Damage recognition during bacterial NER depends upon UvrA, which binds to the damage and loads UvrB onto the DNA. Bacterial TCR additionally requires the Mfd protein, a DNA translocase that removes the stalled transcription complexes.']

['Nucleotide excision repair (NER) is universally used to recognize and remove many types of DNA damage. In eubacteria, the NER system typically consists of UvrA, UvrB, UvrC, the UvrD helicase, DNA polymerase I, and ligase. Damage recognition during bacterial NER depends upon UvrA, which binds to the damage and loads UvrB onto the DNA. Subsequently, UvrA, UvrB and UvrC form the excinuclease protein UvrABC endonuclease, a multi-enzymatic complex which carries out repair of damaged DNA in sequential manner. In some cases, Cho may be the effective nuclease for NER, rather than UvrC. UvrC nuclease and the short oligonucleotide that contains the DNA lesion are removed from the post-incision complex by UvrD, a superfamily 1A helicase. In gram-positive organisms, PcrA helicase can also displace UvrC and the excised oligonucleotide from a post-incision NER complex.']

['UvrA', 'UvrB', 'UvrC nuclease', 'UvrD 1A helicase', 'DNA polymerase I', 'Ligase', 'Cho nuclease (instead of UvrC)', 'PcrA helicase (instead of Uvrd, in gram-positive bacteria)']

Which treatment leads to an increase in neutrophil counts in severe congenital neutropenia?

['This chapter focuses on cyclic and congenital neutropenia, two very interesting and rare hematological conditions causing severe chronic neutropenia. Both disorders respond well to treatment with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF)', 'Data on more than 600 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) demonstrate that, regardless of the particular CN subtype, more than 95% of these patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 x 10(9)/L.', 'Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias', 'In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections', 'A sustained ANC response was seen in 40/44 severe congenital neutropenia patients and 10/10 cyclic neutropenia patients', 'We examined peripheral blood mononuclear cells (PBMC) of SCN patients who demonstrated normalization of their blood neutrophil counts in a phase II clinical study with recombinant human granulocyte colony-stimulating factor (rhG-CSF)', 'Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized by severe neutropenia secondary to a maturational arrest at the level of promyelocytes', 'In contrast to rhGM-CSF treatment, all five patients responded to rhG-CSF during the first 6 weeks of treatment with an increase in the ANC to above 1,000/microL. The level of ANC could be maintained during maintenance treatment', 'Treatment of these patients with granulocyte colony-stimulating factor (G-CSF) leads to a significant increase in circulating neutrophils and a reduction in infection-related events in more than 95% of the patients', 'In patients with chronic neutropenia, rhGM-CSF may increase neutrophil counts']

['In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections ', 'In patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections.']

[]

List the existing methods for genetic manipulation of cells.

['For efficient genetic transformation, Agrobacterium-mediated as well as direct delivery methods have been used successfully. However, these methods suffer from many disadvantages especially in terms of transfer of large genes, gene complexes and gene silencing. To overcome these problems, recently, some efforts have been made to develop genetic transformation systems based on engineered plant chromosomes called minichromosomes or plant artificial chromosomes. ', 'Existing methods for site-directed plasmid mutagenesis are restrained by the small spectrum of modifications that can be introduced by mutagenic primers and the amplicon size limitations of in vitro DNA synthesis. As demonstrated here, the combined use of Red/ET recombination and unique restriction site elimination enables extensive manipulation regardless of plasmid size and DNA sequence elements.', 'Bacterial artificial chromosomes (BACs) derived from genomes of large DNA viruses are powerful tools for functional delineation of viral genes.', 'Here, we describe a novel method for cloning the genomes of large DNA viruses as BACs, which entails direct in vitro transposition of viral genomes with a BAC cassette, and subsequent recovery in Escherichia coli. Determination of insertion sites and adjacent viral sequences identify the BAC clones for genetic manipulation and functional characterization.', 'Here, we describe a vector system for efficient multigene assembly and transformation. The system consists of a transformation-competent artificial chromosome (TAC)-based acceptor vector together with two donor vectors. By exploiting the CreloxP recombination system and homing endonucleases, multiple rounds of gene assembly cycling were carried out with alternate use of the donor vectors, and multiple genes were sequentially delivered into the TAC vector.']

['Genetic engineering, also called genetic modification, is the direct manipulation of an organism\'s genome using biotechnology. New DNA may be inserted in the host genome by first isolating and copying the genetic material of interest using molecular cloning methods to generate a DNA sequence, or by synthesizing the DNA, and then inserting this construct into the host organism. Genes may be removed, or "knocked out", using a nuclease. Gene targeting is a different technique that uses homologous recombination to change an endogenous gene, and can be used to delete a gene, remove exons, add a gene, or introduce point mutations. Based on results there are developed many methods for genetic manipulation of cells such as Microinjection, electroporation, liposomes and via viral vectors.', 'The existing methods for genetic manipulation of cells include Agrobacterium-mediated or direct delivery methods, as well as methods using plant artificial chromosomes, site-directed plasmid mutagenesis, combined use of Red/ET recombination and unique restriction site elimination, Bacterial artificial chromosomes (BACs), direct in vitro transposition of viral genomes with a BAC cassette, and subsequent recovery in Escherichia coli, as well as transformation-competent artificial chromosome (TAC)-based acceptor vector, by exploiting the CreloxP recombination system and homing endonucleases.']

['Agrobacterium-mediated delivery', 'direct delivery methods', 'methods using plant artificial chromosomes', 'site-directed plasmid mutagenesis', 'combined use of Red/ET recombination and unique restriction site elimination', 'Bacterial artificial chromosomes (BACs)', 'direct in vitro transposition of viral genomes with a BAC cassette, and subsequent recovery in Escherichia coli', 'transformation-competent artificial chromosome (TAC)-based acceptor vector, by exploiting the CreloxP recombination system and homing endonucleases', 'Microinjection', 'electroporation', 'viral vectors', 'liposomes']

Are there any clinical trials of the effect of evening primrose oil on postmenopausal symptoms ?

['To analyze whether the time (morning/evening) of administration of a compound containing 60 mg of dry soy seed extract (glycine max) with 40% of total isoflavones, primrose oil and α-tocopherol modifies the effect on the climacteric syndrome.', 'The object of this study was to evaluate the effect of different doses of a compound containing isoflavones 60 mg, primrose oil 440 mg and vitamin E 10 mg. (IOVE) on menopausal complaints. This was an open, multicentre, randomised, group comparative, efficacy and safety trial.', 'Emphasis was placed on randomized, double-blind, placebo-controlled clinical trials, as these provide the best efficacy and safety data', 'Nonprescription therapies reviewed include black cohosh, dong quai, evening primrose oil, physical activity, phytoestrogens, and red clover', 'The effect of oral evening primrose oil on menopausal hot flashes: a randomized clinical trial.', 'The aim of this study was to compare the efficacy of evening primrose with placebo in improvement of menopausal hot flashes. ', ' The application of oral evening primrose oil compared with placebo for controlling hot flashes may decrease more the intensity of attacks ', 'Our search identified 58 randomised controlled trials of which 11 involved the use of clonidine, six for SSRIs, four for gabapentin, seven for black cohosh, seven for red clover, 18 for phytoestrogens, two for ginseng, one for evening primrose,', 'Single clinical trials have found no benefit for dong quai, evening primrose oil,', 'Single clinical trials have found that dong quai, evening primrose oil,', 'To evaluate the efficacy of gamolenic acid provided by evening primrose oil in treating hot flushes and sweating associated with the menopause. DESIGN: Randomised, double blind, placebo controlled study.']

['Yes']

['yes']

When was empagliflozin FDA approved?

['To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).', 'To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM)', 'To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).']

['Empagliflozin was approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).']

['2014']

What is the INSURE procedure in premature babies.

[' intubation-surfactant-extubation (INSURE) method in the treatment of neonatal respiratory distress syndrome (NRDS)', 'INSURE method can improve the oxygenation function of the lung, decrease the incidence of VAP and shorten the duration of oxygen therapy in neonates with NRDS', 'intubation, surfactant, and extubation (InSurE)', 'Nasal continuous positive airway pressure (NCPAP) plus intubation, surfactant, and extubation (InSurE) with the option of back-up ventilation for those infants for whom noninvasive ventilatory support failed resulted in a significant increase in survival in extremely low birth weight (ELBW) infants.', 'The INSURE method, which consists of an intubation-surfactant-extubation sequence, is effective in reducing the need for mechanical ventilation (MV), the duration of respiratory support, and the need for surfactant replacement in preterm infants with respiratory distress syndrome', 'intubation-surfactant-extubation (INSURE) procedures', ' INSURE (Intubation SURfactant Extubation) procedure in preterm neonates.', 'INtubation-SURfactant-Extubation (INSURE) treatment', 'Surfactant given during brief intubation followed by immediate extubation on nasal continuous positive airway pressure [Intubation-Surfactant-Extubation (InSurE) approach] is used to treat respiratory distress syndrome in newborns.', 'INSURE (intubatio-surfactant-extubation) method ', 'In preterm infants with respiratory distress syndrome (RDS) nasal continuous positive airway pressure (nCPAP) with the "InSurE" procedure (intubation, surfactant, extubation) is increasingly used. ', 'INSURE method ( INtubation- SURfactant- Extubation) during nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome', 'a method for surfactant administration by transient intubation, INSURE (i.e. INtubation SURfactant Extubation) during nasal continuous positive airway pressure (nCPAP) for moderately preterm infants with respiratory distress syndrome (RDS)', '(INSURE method: INtubation-SURfactant-Extubation) during treatment with nasal Continuous Positive Airway Pressure (CPAP).', 'INSURE (Intubation-SURfactant-Extubation) approach--i.e., surfactant therapy during brief intubation, immediately followed by extubation and continuous positive airway pressure (CPAP) treatment', 'InSurE (Intubate, Surfactant, Extubate) procedure.']

['The INSURE procedure includes intubation, surfactant administration, and extubation (InSurE). It is used to treat respiratory distress syndrome in newborns.', 'InSurE stands for Intubation-surfactant-extubation and is a method in the treatment of neonatal respiratory distress syndrome (NRDS)']

[]

Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?

['Transcription downstream of Ca(2+) influx is in large part funneled through the transcription factor nuclear factor of activated T cells (NFAT), a heavily phosphorylated protein that is cytoplasmic in resting cells, but that enters the nucleus when dephosphorylated by the calmodulin-dependent serine/threonine phosphatase calcineurin.', 'Calcineurin signaling has been implicated in a broad spectrum of developmental processes in a variety of organ systems. Calcineurin is a calmodulin-dependent, calcium-activated protein phosphatase composed of catalytic and regulatory subunits. The serine/threonine-specific phosphatase functions within a signal transduction pathway that regulates gene expression and biological responses in many developmentally important cell types. Calcineurin signaling was first defined in T lymphocytes as a regulator of nuclear factor of activated T cells (NFAT) transcription factor nuclear translocation and activation.', 'NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. ', 'Calcium activated gene transcription through Nuclear Factor of Activated T-cells, (NFAT) proteins, is emerging as a ubiquitous mechanism for the control of important physiological processes. Of the five mammalian NFAT isoforms, transcriptional activities of NFATs 1-4 are stimulated by a calcium driven association between the ubiquitous phosphatase calcineurin and the calcium-sensing protein calmodulin.', 'Transcription factors of the NFAT (nuclear factor of activated T cells) family are expressed in most immune system cells and in a range of other cell types. Signaling through NFAT is implicated in the regulation of transcription for the immune response and other processes, including differentiation and apoptosis. NFAT normally resides in the cytoplasm, and a key aspect of the NFAT activation pathway is the regulation of its nuclear import by the Ca(2+)/calmodulin-dependent phosphatase calcineurin. ', 'The nuclear factor of activated T cells (NFAT) group of transcription factors is retained in the cytoplasm of quiescent cells. NFAT activation is mediated in part by induced nuclear import. This process requires calcium-dependent dephosphorylation of NFAT caused by the phosphatase calcineurin.', 'The calcium-regulated protein phosphatase calcineurin (PP2B) functions as a regulator of gene expression in diverse tissues through the dephosphorylation and activation of a family of transcription factors known as nuclear factor of activated T cells (NFAT).', 'Calcineurin, a Ca(2+)/calmodulin-stimulated protein phosphatase, plays a key role in T-cell activation by regulating the activity of NFAT (nuclear factor of activated T cells), a family of transcription factors required for the synthesis of several cytokine genes.', 'The calcium/calmodulin-dependent phosphatase calcineurin, which signals to nuclear factor of activated T cells (NFAT) transcription factors, serves as a transducer of calcium signals and is sufficient and necessary for pathologic cardiac hypertrophy and remodeling.', 'Upon activation, Cn directly binds to, and dephosphorylates nuclear factor of activated T cells (NFAT) transcription factors within the cytoplasm allowing them to translocate to the nucleus and participate in the regulation of gene expression.', 'The functions of NFAT proteins are directly controlled by the calcium- and calmodulin-dependent phosphatase calcineurin.', 'Transcription downstream of Ca(2+) influx is in large part funneled through the transcription factor nuclear factor of activated T cells (NFAT), a heavily phosphorylated protein that is cytoplasmic in resting cells, but that enters the nucleus when dephosphorylated by the calmodulin-dependent serine/threonine phosphatase calcineurin', 'The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN)', 'The functions of NFAT proteins are directly controlled by the calcium- and calmodulin-dependent phosphatase calcineurin']

['The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN).Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization.']

['Calcineurin', 'CaN', 'phosphatase 2b']

What is the major adverse effect of Doxorubicin-induced cardiotoxicity in cancer patients?

['["It remains to be seen whether inhibition by adriamycin of these systems is related to the severe cardiotoxicity, the major adverse effect of the drug that limits its clinical usefulness.", "Leukocytopenia was the major adverse effect among patients undergoing systemic THP administration", "The major adverse effect was bone-marrow suppression;", "The major adverse effect was bone marrow suppression;", "Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic;", "chronic cardiotoxicity represents a serious adverse effect that may be lethal due to the development of irreversible, cumulative dose-dependent, congestive cardiomyopathy", "Myelosuppression, predominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepatopathy, characterised by elevated bilirubin concentrations, occurs less frequently", "In spite of the routine use of this drug its major adverse effect, the dose-dependent cardiotoxicity, cannot be prevented yet", "The major adverse effect was myelosuppression", "Cardiac toxicity is a major adverse effect caused by doxorubicin (DOX) therapy", "Antioxidative and cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity", "The major adverse effect of DOX treatment in cancer patients is the onset of cardiomyopathy and heart failure"]']

The major adverse effect of DOX treatment in cancer patients is the onset of cardiomyopathy and heart failure

[]

Which are the main clinical features of Fanconi anemia?

['The clinical features of cytopenia, developmental defects, and tumor predisposition are similar in each group, suggesting that the gene products participate in a common pathway.', 'Fanconi anemia (FA) is a genetically and phenotypically heterogeneous recessive disorder characterized by diverse congenital malformations, progressive pancytopenia and predisposition to both hematologic malignancies and solid tumors', 'Patients with FA exhibit a heterogeneous spectrum of clinical features. The most significant and consistent phenotypic characteristics are stem cell loss, causing progressive bone marrow failure and sterility, diverse developmental abnormalities and a profound predisposition to neoplasia', 'Fanconi anemia (FA) is an autosomal recessive, cancer susceptibility disorder characterized by diverse clinical features, such as short stature, skeletal or skin abnormalities, progressive bone marrow (BM) failure, and increased risk of malignancies', 'Fanconi anaemia (FA) is an autosomal recessive disease characterised by congenital abnormalities, defective haemopoiesis, and a high risk of developing acute myeloid leukaemia and certain solid tumours', 'Fanconi anemia (FA), a recessive syndrome with both autosomal and X-linked inheritance, features diverse clinical symptoms, such as progressive bone marrow failure, hypersensitivity to DNA cross-linking agents, chromosomal instability and susceptibility to cancer.', 'Fanconi anemia (FA) consists of a group of at least five autosomal recessive disorders that share both clinical (e.g., birth defects and hematopoietic failure) and cellular (e.g., sensitivity to cross-linking agents and predisposition to apoptosis) features with each other.', 'Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia.', 'Progressive bone marrow failure starting in the first decade of life is one of the main characteristics of Fanconi anemia', 'FA is an autosomal recessive disease with three main features: chromosome instability, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), cisplatin and so on, and susceptible to a number of cancer types, mainly leukemia and squamous cell carcinomas of the head and neck or gynecologic system', 'Bone marrow failure resulting in pancytopenia is the main cause of death of FA patients']

['Fanconi anaemia (FA) is an autosomal recessive disease characterised by congenital abnormalities, defective haemopoiesis, and increased risk of malignancies.', 'Fanconi anemia (FA) is a genetically and phenotypically heterogeneous recessive disorder characterized by diverse congenital malformations, progressive pancytopenia and predisposition to both hematologic malignancies and solid tumors']

['congenital abnormalities', 'defective haemopoiesis', 'increased risk of malignancies', 'cellular hypersensitivity to DNA crosslinking agents']

Is it possible to detect survivin protein expression in normal human adult tissues?

['Survivin (BIRC5) is one of the members of IAP-family apoptosis inhibitors. The BIRCS gene is expressed in most human embryonic tissues and malignant tumors but not in normal differentiated tissues of adult human.', 'Survivin is an inhibitor of apoptosis that is undetectable in most terminally differentiated normal human tissues, strongly expressed in embryonic and fetal organs and is strongly expressed in many different human cancers.', 'Survivin is a member of the inhibitor apoptosis family that is overexpressed in many malignancies. It has five known alternative splice forms, some of which differ in their antiapoptotic properties and expression levels in human cancers.', 'survivin is usually not expressed in normal adult tissues,', 'AZD1152-hQPA induced caspase-dependent apoptosis of some cell lines, demonstrated by loss of mitochondrial membrane potential, activation of caspase-9, followed by activation of caspase-3. This effect was accompanied by the inhibition of survivin expression. In vivo efficacy was determined in NOD/SCID/γc(null) mice implanted with the Ramos human BL cell line. AZD1152 had anti-tumour effects in this murine xenograft model. There preclinical data suggest that the inhibition of Aurora B kinase is a potentially useful therapeutic strategy in BL and HL.', 'a novel antiapoptosis gene, i.e., survivin, was identified as a structurally unique member of the inhibitor of apoptosis protein family. Survivin expression is turned off during fetal development and not found in non-neoplastic adult human tissues but is again turned on in the most common human cancers. The antiapoptotic properties of survivin might provide a significant growth advantage in tumors and possibly also contribute to chemoresistance of cancer.', 'Further comparison of the distribution of PDEF with other widely recognized cancer-associated molecules showed that PDEF has more restricted distributions than Her-2/neu, Bcl-2, survivin or telomerase in cDNA libraries from normal human tissues and more increased distribution than Her-2/neu, CA-125, Bcl-2, survivin and telomerase in cDNA libraries from brain (except survivin), breast, lung and ovarian tumors. These data together show a better tumor-association for PDEF and suggest that PDEF is a more suitable target for developing specific cancer therapies.', 'we identified decreased FHIT expression resulting in apoptosis inhibition and decreasing apoptosis associated with abnormal levels of some pro- and anti-apoptotic proteins (Bax, Bcl-2 and Survivin) by TUNEL and TMA. Our results demonstrated that the mutation in the FHIT gene significantly reduced FHIT expression in human CRC. Both TUNEL and TMA experiments demonstrated significantly inhibited apoptosis by down-regulation of Bax and up-regulation of Survivin and Bcl-2. Collectively, these studies identify the mechanism by which an important tumor suppressor gene, FHIT, inactivated specifically in human CRC, and contributes to our understanding of the mechanism of colorectal carcinogenesis.']

['No. Survivin is an inhibitor of apoptosis that is undetectable in normal differentiated tissues of adult human.', 'Most normal adult tissues do not express survivin, thymus and testis are the only exceptions.']

['no']

Does molindone affect body weight?

['Mean weight increased by 0.54 kg, and mean body mass index by 0.24 kg/m(2). ', 'A large-scale trial comparing a first-generation antipsychotic (molindone) with newer agents did not find significant differences in treatment response, although the newer antipsychotics were associated with more severe weight gain. ', 'No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. ', 'The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment. ', 'Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. ', 'Molindone is no more or less likely than typical drugs to cause movement disorders, but it does cause significantly more weight loss (2RCTs n=60 RR 2.78, CI 1.10 to 6.99, NNH 5 CI 2 to 77). ', 'Molindone may be an effective antipsychotic but its adverse effect profile does not differ significantly from that of typical antipsychotics (apart from the event of weight loss). ', 'Convergent evidence suggests a hierarchy in the magnitude of BWG that may be induced by diverse agents, being very high for clozapine and olanzapine; high for quetiapine, zotepin, chlorpromazine, and thioridazine; moderate for risperidone and sertindole; and low for ziprazidone, amisulpiride, haloperidol, fluphenazine, pimozide, and molindone. ', 'Loxapine and molindone induce weight decreases, and these exceptions are difficult to explain.', 'It is no more or less likely than typical drugs to cause movement disorders, but causes significantly more weight loss (RR 2.78, CI 1.10 to 6.99).', 'Molindone may be an effective antipsychotic; however, its adverse effect profile does not differ significantly from that of typical antipsychotics, apart from the event of weight loss. ', 'Among conventional agents, mean weight change ranged from a reduction of 0.39 kg with molindone to an increase of 3.19 kg with thioridazine.', 'Weight gain has been reported with nearly every antipsychotic drug on the market (molindone is an exception). ', 'Although almost all antipsychotics induce bodyweight gain, molindone and loxapine appear to induce bodyweight loss. ', 'Clozapine and low-potency phenothiazines are associated with the largest gains and molindone with weight loss, but the mechanism is not known. ', 'On average, molindone patients lost 5 pounds over the 6 weeks of treatment, whereas thioridazine patients gained 6 pounds. ', 'Clinically, molindone has a tendency to cause weight loss and may have less effect on seizure threshold than conventional antipsychotic agents', ' Monthly weights and neuroleptic dosages during the first three months of psychiatric hospitalization were compared between matched groups of patients receiving molindone, a combination of molindone and other neuroleptics, or other neuroleptic drugs. We found no significant differences in weight gain among the three groups. ', 'The weight-reducing property of molindone, a recently introduced antipsychotic drug, was tested in 9 hospitalized chronic schizophrenic patients. There was an average weight loss of 7.6 kg after 3 months on molindone; most of the loss occurred during the first month.']

['Yes, molindone has a tendency to cause weight loss or limited weight gain.']

['yes']

What is the role of IL-18BP?

['Interleukin 18--binding protein ameliorates liver ischemia--reperfusion injury.', ' IL-18BP exhibited anti-inflammatory, antioxidant, and protective effects in I/R-mediated hepatic injury via regulating some liver enzyme activities and cytokine levels. ', "Because of IL-18's potential pro-inflammatory and tissue destructive effects, its biological activities are tightly controlled in the body by its naturally occurring antagonist called IL-18BP. The antagonist is produced in the body both constitutively and in response to an increased production of IL-18 as a negative feedback mechanism. Under physiological conditions, most of IL-18 in the circulation is bound with IL-18BP and is inactive. However, an imbalance in the production of IL-18 and its antagonist (an increase in the production of IL-18 with a decrease, no increase or an insufficient increase in the production of IL-18BP) has been described in many chronic inflammatory diseases in humans.", 'L-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. ', 'Platelets also contain the IL-18 antagonist, the IL-18-Binding Protein (IL-18BP)', 'The natural inhibitor IL-18BP , whose production is enhanced by IFN-γ and IL-27, further regulates IL-18 activity in the extracellular environment. ', 'IL-18 binding protein (IL-18BP) is a naturally occurring inhibitor of IL-18. ', 'IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. The balance between IL-18 and IL-18BP has an important role in the inflammatory setting.']

['IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. The balance between IL-18 and IL-18BP has an important role in the inflammatory setting.']

['IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. The balance between IL-18 and IL-18BP has an important role in the inflammatory setting.']

How does the organic cation transporter 3 (OCT3) play a role in the regulation of neurotransmission in the brain?

['["The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. ", "The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain.", "In agreement with this distribution, OCT3/Slc22a3-deficient mice show evidence of altered monoamine neurotransmission in the brain, with decreased intracellular content and increased turnover of aminergic transmitters.", "CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF.", "The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain", "The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain. ", "CRT may be a key factor facilitating blood-to-brain guanidinoacetate transport in patients deficient in S-adenosylmethionine:guanidinoacetate N-methyltransferase, the creatine biosynthetic enzyme, resulting in cerebral accumulation of guanidinoacetate. CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF.", "Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain.", "CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF. Interestingly, BBB efflux transport of GCs, including guanidinoacetate and creatinine, is negligible, though the BBB has a variety of efflux transport systems for synthetic precursors of GCs, such as amino acids and neurotransmitters.", " The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission.", "CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF.", "Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission.", "The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain.", "OCT2-OCT-3 display differential tissue distribution: OCT1 is predominantly found in liver of humans, and liver and kidney in rodents; OCT2 is most strongly expressed in both human and rodent kidney, whereas is OCT3 primarily expressed in placenta, but also more widely detected in various tissues, including brain and lung."]']

Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission.

[]

How is bladder wall thickness measured?

['Modifications of the bladder wall (organ damage) in patients with bladder outlet obstruction: ultrasound parameters.', 'Early identification of bladder changes by noninvasive transabdominal ultrasound', 'Measurement of the bladder wall thickness (BWT) or detrusor wall thickness (DWT) by US is reliable,', 'Also conventional US detects established signs of bladder damage: diverticulosis, trabecolations in the bladder wall (pseudo-diverticula),', 'non-invasive US of the bladder wall', 'BladderScan BVM 9500 device (Diagnostic Ultrasound, Bothell, WA) was used to measure bladder wall thickness', 'ultrasonography-estimated bladder weight and bladder wall thickness ', 'To identify measurements of ultrasonography (US)-derived bladder wall thickness (BWT) ', 'transabdominal US measurements of BWT and', 'Transvaginal ultrasound measurement of bladder wall thickness: ', 'ultrasound (US) techniques to measure bladder wall thickness (BWT).', 'Women underwent US measurement of BWT', 'Transabdominal and transperineal US for measuring BWT', 'ultrasound bladder and detrusor wall thickness', 'Ultrasonic measurements of urinary bladders are suitable to quantify bladder wall hypertrophy', 'ultrasonic bladder wall measurements t', 'Preliminary data on the automatic measurement of bladder wall thickness were reported, suggesting a good repeatability and agreement with conventional ultrasound imaging', ' conventional ultrasound bladder wall thickness (BWT) measurements ', 'Ultrasonographic measurement of bladder wall thickness ', 'All children underwent ultrasonography to measure bladder wall thickness', 'Ultrasonographic assessment of bladder wall thickness is a sensitive screening tool ', 'ultrasound for bladder wall thickness (BWT)', 'transabdominal ultrasonography for bladder volume and detrusor muscle thickness', 'Transabdominal ultrasonography with a high-frequency probe was performed to obtain the anterior, posterior, and lateral bladder wall thicknesses.', 'ultrasonographic estimate of bladder wall thickness. ', 'ultrasonographic estimate of bladder wall thickness. ', 'there are marked differences in sonographic findings in male and female neonates in regard to renal pelvic dilatation, renal size and bladder wall thickness', 'BWT was measured by suprapubic ultrasonography.', 'transvaginal ultrasound measurement of bladder wall thickness', 'The measurement of a mean bladder wall thickness greater than 5 mm with transvaginal ultrasound ']

['Ultrasound']

['Ultrasound']

What roles do zinc-dependent endopeptidases play in physiological and pathological processes through ECM cleavage?

['["matrix metalloproteinase (MMP)-9", "matrix metalloproteinase-3 (MMP-3) gene ", "matrix metalloproteinases (MMPs)", "Matrix metalloproteinase-9 (MMP-9) is a secreted glycoprotein with a major role in shaping the extracellular matrix and a detailed understanding of the secretory mechanism could help identify methods to correct diseases resulting from dysregulation of secretion.", "Gelatinase B/matrix metalloproteinase-9 (MMP-9) (EC 3.4.24.35) cleaves many substrates and is produced by most cell types\\u00a0as a zymogen", "Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix.", "Extracellular matrix metalloproteinases (MMPs) are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity."]', '["matrix metalloproteinase (MMP)-9", "matrix metalloproteinase-3 (MMP-3) gene ", "matrix metalloproteinases (MMPs)", "Matrix metalloproteinase-9 (MMP-9) is a secreted glycoprotein with a major role in shaping the extracellular matrix and a detailed understanding of the secretory mechanism could help identify methods to correct diseases resulting from dysregulation of secretion.", "Gelatinase B/matrix metalloproteinase-9 (MMP-9) (EC 3.4.24.35) cleaves many substrates and is produced by most cell types\\u00a0as a zymogen", "Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix.", "Extracellular matrix metalloproteinases (MMPs) are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity."]']

Zinc-dependent endopeptidases, specifically extracellular matrix metalloproteinases (MMPs), are involved in physiological and pathological processes through the cleavage of the extracellular matrix. These enzymes play a crucial role in remodeling the ECM and regulating various cellular functions.

[]

Are there enhancer RNAs (eRNAs)?

['active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription', ' eRNAs may then facilitate enhancer-promoter interaction or activate promoter-driven transcription', 'Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers', 'Enhancer RNAs and regulated transcriptional programs', 'enhancers have been found to be broadly transcribed, resulting in the production of enhancer-derived RNAs, or eRNAs', 'The emerging roles of eRNAs in transcriptional regulatory networks', 'we found certain enhancer RNAs (eRNAs) regulate chromatin accessibility of the transcriptional machinery at loci encoding master regulators of myogenesis (i.e., MyoD/MyoG), thus suggesting their significance and site-specific impact in cellular programming', 'Enhancer RNAs: the new molecules of transcription', ' the discovery that distal regulatory elements known as enhancers are transcribed and such enhancer-derived transcripts (eRNAs) serve a critical function in transcriptional activation has added a new dimension to transcriptional regulation', 'eRNAs reach the heart of transcription', 'Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation.', 'Since the discovery that many transcriptional enhancers are transcribed into long noncoding RNAs termed "enhancer RNAs" (eRNAs), their putative role in enhancer function has been debated.', 'Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs).', 'Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established.', 'In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs).', 'In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). ', 'A subset of enhancers are occupied by RNA polymerase II (RNAP II) and transcribed to produce long non-coding RNAs termed eRNAs. ', 'Very recent evidence has indicted that some eRNAs play a role in initiating or activating transcription, possibly by helping recruit and/or stabilize binding of the general transcription machinery to the proximal promoter of their target genes. ', 'In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation. ', 'Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis.', 'A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4.', ' Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established. Here we show that eRNAs facilitate the transition of paused RNA polymerase II (RNAPII) into productive elongation by acting as a decoy for the negative elongation factor (NELF) complex upon induction of immediate early genes (IEGs) in neurons.', 'Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation.', 'Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription.', 'Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers,', 'In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation.', ' Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription.']

['Yes. Active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription.']

['yes']

Does smoking increase risk for glioblastoma?

['Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility.', 'No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. ', 'Non-smokers with G/A and A/A genotype showed increased glioma risk compared with G/G genotype (adjusted OR = 1.72, 95%CI: 1.29-2.30, p = 0.0002 and adjusted OR = 1.81, 95%CI: 1.10-2.99, p = 0.020, respectively). This association was not found in ever- or current-smokers. ', 'There was no significant association between glioma and alcohol consumption, smoking and mobile phone use. ', 'RESULTS: We found no associations between the GSTM3, GSTP1, NQO1, CYP1A1, GSTM1, or GSTT1 polymorphisms and adult brain tumor risk with the possible exception of a weak association between the G-C (Val-Ala) GSTP1 105/114 haplotype and glioma [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54, 0.99], nor was there an interaction between the effects of the GSTM3 or GSTP1 polymorphisms and cigarette smoking.', 'We did not find any evidence for an association with life-style characteristics such as cigarette smoking, alcohol consumption, use of drugs of any kind, or dietary intake of cured or smoked meat or fish.', 'No relation was observed between glioma risk and smoking (odds ratio = 0', 'Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility', 'Compared with nonsmokers, duration of cigarette smoking, number of cigarettes smoked per day and pack-years of smoking were associated with increased glioma risk, although the increases in risk were relatively modest', 'Among ever smokers, women who reported having quit smoking had a 51% increase in risk of glioma compared with never smokers (HR = 1.51, 95% CI = 0.97-2.34), while current smokers did not appear to have an increase in risk']

['No. Smoking does not increase risk for glioblastoma.']

['no']

Can tetracycline affect tooth formation?

['he results of that study, reported earlier (Rebich et al., 1983), indicated that over one-fifth of the American Indian children had discoloration of the dentition due to ingestion of tetracycline during the years of tooth formatio', 'ale Wistar rats prelabeled with tetracycline to mark surfaces of bone and tooth formation-mineralization were placed into orbit for 18.5 days aboard the Soviet COSMOS-1129 Biosatellit', 'It was concluded that the increased tetracycline incorporation reflected a higher rate of mineralization associated with faster tooth formation in the unimpeded toot', 'n this investigation an attempt has been made to determine the relationship between the staining of permanent teeth by tetracycline administered during the period of tooth formation with the dosage of the drug and the duration of therap', ' definite relationship between total dosage and staining and duration of administration and staining was established; the condition occurred with greater frequency (in more than one-third of the children) when the total dosage exceeded 3 g. or the duration of treatment was longer than 10 days', 'This case report suggests the possibility that discoloration from tetracycline may not be limited to tooth development in the child, but may also affect the adult dentition']

['Tetracycline is incorporated in the teeth during their formation and leads to their permanent staining. A definite relationship between total dosage and staining and duration of administration and staining was established; the condition occurred with greater frequency (in more than one-third of the children) when the total dosage exceeded 3 g. or the duration of treatment was longer than 10 days.']

['yes']

Is myasthenia gravis associated with osteoporosis?

['We performed PVP in 4 patients with generalized MG associated with recent steroid-induced symptomatic VFs. ', 'In this case report, we used tacrolimus to successfully treat a 13-year-old boy with ocular MG who had suffered from severe steroid complications, including a failure of thrive and osteoporosis.', ' INTRODUCTION: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk. ', 'RESULTS: Compared to the control cohort, there was no statistically significant increased risk observed in patients with MG for any fracture (adjusted hazard ratio [AHR] 1.11; 95 % confidence interval [CI], 0.84-1.47) or osteoporotic fractures (AHR 0.98 [95 % CI 0.67-1.41]). Further, use of oral glucocorticoids up to a cumulative dose exceeding 5 g prednisolone equivalents did not increase risk of osteoporotic fracture (AHR 0.99 [95 % CI, 0.31-3.14]) compared with MG patients without glucocorticoid exposure.', 'The RANKL/OPG ratio and indices of bone metabolisms are also not affected by THX, although THX increases the levels of IL-7 and RANKL.', 'Both disorders had been controlled for around 15 years by oral prednisolone and a cholinesterase inhibitor following surgical removal of invasive thymoma and radiotherapy, but muscular weakness due to myalgia and an increase in serum levels of myogenic enzymes, mainly ascribable to the recurrence of PM, reappeared immediately after cessation of these drugs, which was done because the patient had multiple bone fractures and severe osteoporosis due to the long-term corticosteroid therapy. ', 'We measured bone density in 36 patients (26 females and 10 males) who had undergone long-term prednisolone administration, and found a decrease in bone density in 31% of female patients and osteoporosis in only 11.5% (three cases).', 'In conclusion, prednisolone-treated patients with myasthenia gravis have an acceptable risk of bone loss if prophylactic medication is administered.', 'INTRODUCTION: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk.', 'Alendronate should be used with caution in patients with myasthenia gravis who have corticosteroid-induced osteoporosis', 'In this paper we present two cases of young women who developed severe PAO with vertebral fractures: a 42-year-old woman with a family history of osteoporosis, and a 21-year-old woman affected with myasthenia gravis', 'Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk']

['Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased risk of glucocorticoid-induced osteoporosis. Thymectomy can also increase risk for osteoporosis. Appropriate osteoporosis preventive measures can reduce osteoporosis risk in MG patients.']

['yes']

Magnetic beads has been used in numerous applications. List some coatings used.

['aptamer-based magnetic separation system ', 'enzymes coated to magnetic beads', ' Aptamers are short, single-stranded (ss) oligonucleotidesable to recognize target molecules with high affinity. ', ' Recent developments involve immobilization of tagged enzymes onto magnetic nanoparticles. ', 'Using magnetic beads to immobilize DNAs containing various types of structures, we evaluated the in vitro binding activities of two well-characterized DNA repair proteins, Escherichia coli MutS and human p53.', 'An affinity capture involved enzymatic assay for thrombin by using peptide aptamers as affinity ligands on magnetic beads', 'During phage selection the biotinylated antigens are bound to streptavidin coupled magnetic beads, ', ' aptamer-functionalized magnetic beads ', 'native antibody immobilized to magnetic beads', 'Plasma membrane isolation using immobilized concanavalin A magnetic beads.', 'streptavidin magnetic beads', ' Digoxin was coated onto the surface of streptavidin magnetic beads. ', "covalent immobilization of the antigen onto carboxylic-modified magnetic beads (HOOC-MBs) activated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and N-hydroxysulfosuccinimide (sulfo-NHS), and further incubation in a mixture solution containing variable concentrations of the antigen and a fixed concentration of an HRP-labeled detection antibody. ", 'Aptamers against HNE were immobilized on magnetic beads', 'The high specificity was obtained by using the magnetic beads and aptamers,', 'Multiple targets (maltase, invertase, lipase) were immobilized on the magnetic beads by covalent linkage using 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide (EDC) and N-hydroxysuccinimide (NHS) as reaction reagents, respectively.', 'TiO2 -coated magnetic beads', 'antibody-targeted magnetic beads', 'A special SELEX library was constructed with the aim to immobilize this library on magnetic beads', 'streptavidin-coupled magnetic beads', 'aptamers loaded on the magnetic beads ', 'His-affinity magnetic beads', 'treptavidin-coated magnetic beads', ', synthesized DNA is bound to magnetic beads', 'streptavidin-modified magnetic microbeads ', 'oligo(dT) magnetic beads']

['aptamers\nenzymes\nstreptavidin\nconcanavalin A\ncarboxylic-modified \nTiO2\nantibodies\nSELEX library\nsynthesized DNA\nC18\nC8\noligo(dT)']

['aptamers', 'enzymes', 'streptavidin', 'concanavalin A', 'carboxylic-modified', 'TiO2', 'antibodies', 'SELEX library', 'synthesized DNA', 'C18', 'C8', 'oligo(dT)']

Can telomere length shortening be reversed by telomerase?

['Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease; thus, it is important to understand the mechanisms that regulate length at the molecular level. ', 'High telomerase activity is detected in nearly all human cancers but most human cells are devoid of telomerase activity. There is well-documented evidence that reactivation of telomerase occurs during cellular transformation. In humans, tumors can rely in reactivation of telomerase or originate in a telomerase positive stem/progenitor cell, or rely in alternative lengthening of telomeres, a telomerase-independent telomere-length maintenance mechanism.', ' Together, these observations may provoke a re-evaluation of telomere and telomerase based therapies, both in telomerase inhibition for cancer therapy and telomerase activation for tissue regeneration and anti-ageing strategies.', 'Telomeres progressively shorten throughout life. A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase.', 'Telomerase-mediated telomere elongation provides cell populations with the ability to proliferate indefinitely. Telomerase is capable of recognizing and extending the shortest telomeres in cells;', 'Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.']

['Yes, telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.']

['yes']

Which R package is used for visualization of linear and circular karyotypes?

['chromDraw: an R package for visualization of linear and circular karyotypes.', 'The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.', 'The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix.', 'chromDraw: an R package for visualization of linear and circular karyotypes.', 'The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix.']

['The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.', 'The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.']

['chromDraw']

Which medication should be administered when managing patients with suspected acute opioid overdose?

['Opioid overdose has a high mortality, but is often reversible with appropriate overdose management and naloxone (opioid antagonist). ', 'Training clinicians how to manage an opioid overdose and administer naloxone was effective.', 'For patients who have ingested dextromethorphan and are sedated or comatose, naloxone, in the usual doses for treatment of opioid overdose, can be considered for prehospital administration, particularly if the patient has respiratory depression', 'Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. ', 'Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. ', 'Patients who received naloxone for known or presumed opioid overdose were formally evaluated one hour later for multiple potential predictor variables. ', 'Patients with presumed opioid overdose can be safely discharged one hour after naloxone administration', 'To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.).', 'Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of <10 breaths/min. ', 'There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. ', 'To illustrate this problem, we report the case of a patient inappropriately treated with naloxone and the results of a retrospective review of the medical records of 15 consecutive patients with cancer treated with naloxone in the emergency department over a 5-month period. ', 'Management of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid antagonists. ', ' The proportion of clinicians willing to use naloxone in an opioid overdose rose from 77% to 99% after training. Barriers to implementing training were clinician time and confidence, service resources, client willingness and naloxone formulation.', 'Opioid overdose is rarely the primary cause of altered mental status in cancer patients receiving opioid therapy. The inappropriate administration of naloxone to reverse an abnormal mental status can cause severe withdrawal symptoms and pain. ']

['Naloxone is opioid anagonist that should be administered for all patients with suspected acute opioid overdose. Intravenous naltrexone hydrochloride is usually administered, however, other formulations, including enteral methylnaltrexone, nebulized naloxone and subcutaneous naloxone, are under investigation and can be used under certain circumstances.']

['naloxone']

Which residue of alpha-synuclein was found to be phosphorylated in Lewy bodies?

["Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies", "Approximately 90% of α-syn deposited in Lewy bodies is phosphorylated at serine 129 (Ser129). In contrast, only 4% or less of total α-syn is phosphorylated at this residue in the normal brain. This suggests that the accumulation of Ser129-phosphorylated α-syn leads to the formation of Lewy bodies and dopaminergic neurodegeneration in Parkinson's disease", 'Alpha-synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies. These inclusion bodies are the characteristic pathologic lesions of Parkinson disease', 'Alpha-synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies.', '�-Synuclein is causative for autosomal dominant familial Parkinson disease and dementia with Lewy bodies, and the phosphorylation of �-synuclein at residue Ser-129 is a key posttranslational modification detected in Parkinson disease/dementia with Lewy bodies lesions.', 'Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions.', 'Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions.', 'alpha-Synuclein is a major protein component deposited in Lewy bodies and Lewy neurites that is extensively phosphorylated at Ser(129), although its role in neuronal degeneration is still elusive.', 'These observations are most consistent with a model in which preferential accumulation of normally produced Ser-129 phosphorylated alpha-synuclein is the key event responsible for the formation of Lewy bodies in various Lewy body diseases.', 'The predominant modification of alpha-synuclein in Lewy bodies is a single phosphorylation at Ser-129.', 'Approximately 90% of α-syn deposited in Lewy bodies is phosphorylated at serine 129 (Ser129).', "This suggests that the accumulation of Ser129-phosphorylated α-syn leads to the formation of Lewy bodies and dopaminergic neurodegeneration in Parkinson's disease.", 'Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions', 'Alpha-synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies']

["Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodiesApproximately 90% of α-syn deposited in Lewy bodies is phosphorylated at serine 129 (Ser129). In contrast, only 4% or less of total α-syn is phosphorylated at this residue in the normal brain. This suggests that the accumulation of Ser129-phosphorylated α-syn leads to the formation of Lewy bodies and dopaminergic neurodegeneration in Parkinson's disease", 'Alpha-synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies, which are characteristic pathologic lesions of Parkinson disease.', 'Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinsons disease patients where it mainly accumulates in the Lewy bodies', 'Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson s disease patients where it mainly accumulates in the Lewy bodies ']

['Serine 129']

Could Arimidex (anastrozole) cause hot flashes?

['More than a third of breast cancer patients undergoing aromatase inhibitor (AI) treatment report joint pain.', 'In the first 6 weeks, emergence of joint pain was associated with increase in general pain, fatigue, disturbed sleep, hot flashes, vaginal dryness, and decreased sexual activity.', 'Antiestrogen therapy can cause vasomotor symptoms similar to those occurring during menopause, including hot flashes.', 'The purpose of this study was to assess the feasibility and safety of acupuncture for treatment of hot flashes in Korean patients with breast cancer receiving antiestrogen therapy.', '10 patients with breast cancer who were undergoing antiestrogen therapy with tamoxifen or anastrozole and who were suffering from hot flashes.', 'During treatment, severity of hot flashes was reduced by 70%-95% in all patients.', 'anastrozole has been widely used in Japan as an adjuvant treatment for postmenopausal, hormone-responsive breast cancer patients.', 'The aim of this study is to evaluate the rate of bone fracture and bone mineral density (BMD) during anastrozole treatment in Japanese patients.', 'Musculoskeletal disorders were the most common (26.1\xa0%), and hot flashes were the second most common adverse event (7.9\xa0%).', 'To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer.', 'fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone.', 'Incidences of prespecified adverse events (AEs) were similar. Hot flashes were more common in the experimental arm: 63 patients (24.6%) versus 35 patients (13.8%) in the standard arm (P = .0023).', 'The third-generation agents (anastrozole, letrozole, and exemestane) have been shown to be more effective and safer than the selective estrogen receptor modulators tamoxifen and raloxifen.', 'AIs are well tolerated and cause a lower incidence of gynecological symptoms (vaginal bleeding, discharge, and endometrial neoplasia), venous thromboembolic events, and hot flashes compared with tamoxifen.', 'Mood disturbances, somnolence, anxiety, fatigue, hot flashes, and memory impairment have been reported among patients receiving anastrozole as adjuvant therapy.', 'Twenty-five PM-BC patients received, in sequence, leuprorelin, taxane-anthracycline induction chemotherapy, radiation therapy, a platinum-based intensification high-dose CT, followed by leuprorelin and anastrazole for five years.', 'Grade 4 hematologic toxicity was observed in all patients, no patient showed a decrease of cardiac ejection fraction and hot flashes and arthralgias were of moderate intensity.', 'Of the patients treated with anastrozole, 3 (37.5%) reported toxicity, with 1 report each of decreased libido, leg swelling, and depression (12.5%). Toxicity was reported in 2 patients taking letrozole (40%), with both reporting peripheral edema, and 1 reporting hot flashes.', 'Patients were treated with goserelin 3.6 mg subcutaneous monthly and began anastrozole 1-mg daily 21 days after the first injection of goserelin.', 'The most common adverse events were fatigue (50%), arthralgias (53%), and hot flashes (59%).', 'These studies were designed to evaluate the safety and efficacy of AIs in the following clinical settings: 1) as initial adjuvant therapy (the Arimidex, Tamoxifen, Alone or in Combination trial, Breast International Group Trial 1-98),', 'AIs were tolerated well, and patients who received them experienced fewer thrombolic events and less endometrial cancer, hot flashes, night sweats, and vaginal bleeding compared with patients who receive tamoxifen.', 'It has been suggested that the association of AI and GnRh analogues and AI could block the two routes of oestrogen production in males, and therefore this approach could increase efficacy. However, it could also enhance the rate of adverse events (hot flashes, sexual impotence, etc.).', 'We reviewed therapeutic effects and harmful side effects in 33 patients with advanced or recurrent breast cancer who underwent treatment with Anastrozole 1 mg/day in our department.', 'The most frequent harmful side effects were rise in total cholesterol, general fatigue, hot flashes and arthralgia (9.1%).', 'We analyzed the changes in frequency and severity of menopausal symptoms in patients receiving tamoxifen or aromatase inhibitors and identified factors influencing these symptoms.', 'Both first-line tamoxifen and aromatase inhibitors induced an increase in the occurrence and severity of hot flashes (p<0.0001 and p=0.014, respectively).', 'To evaluate the efficacy and toxicity of the selective aromatase inhibitor anastrozole (Arimidex), we conducted a phase II trial in 53 women with asymptomatic recurrent/persistent müllerian cancer.', 'Toxicity was modest (grade I) and infrequent, with the most common toxicities being fatigue and hot flashes.', 'The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC).', 'in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group.', 'reduced nausea, hot flashes, and abdominal discomfort caused almost twice as many patients to prefer to continue with letrozole therapy than with anastrozole']

['Yes. Hot flashes are one of the most common adverse effects of Arimidex.']

['yes']

Is Weaver syndrome similar to Sotos?

['Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. NSD1 and EZH2 are both histone-modifying enzymes', 'NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression', 'Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap', 'Clinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1', 'Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia.', 'Thus, it is not surprising that prenatal overgrowth occurs in several syndromes, including the Sotos and Weaver syndromes.', 'NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes.', 'We conclude therefore that NSD1 mutations account for most cases of Sotos syndrome and a significant number of Weaver syndrome cases in our series.', 'We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.', 'Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia', 'NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes', 'We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes', 'Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. ', 'Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes.', ' Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia. Two previous cases of neuroblastoma have been reported in children with Weaver syndrome.', 'Weaver syndrome is closely related to Sotos syndrome,', 'Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia.', 'Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident.', 'Clinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1.']

['Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. NSD1 and EZH2 are both histone-modifying enzymes', 'Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling.']

['yes']

Are there any HCV replication inhibitors available?

['We report here the discovery of the first small-molecule HCV infectivity inhibitor, GS-563253, also called HCV infectivity inhibitor 1 (HCV II-1). ', 'Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferred by the NS5B S282T mutation.', "We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells", 'The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers.', 'Vaniprevir (phase III clinical trials) and MK-5172 (phase II clinical trials) are two potent antiviral compounds that target NS3/4A protease', 'treatment for hepatitis C virus (HCV) infection has been significantly improved with the approval of the first two HCV NS3/4A protease inhibitors, telaprevir (Incivek) and boceprevir (Victrelis). ', 'Combination therapy with telaprevir and BMS-788329 (NS5A inhibitor) reduced serum HCV RNA to undetectable levels. The presence of an NS3-V36A telaprevir resistance mutation resulted in poor response to telaprevir monotherapy but showed significant HCV reduction when telaprevir was combined with BMS-788329. However, a BMS-788329-resistant strain emerged at low frequency. Infection with a BMS-788329-resistant NS5A-L31V mutation rapidly resulted in gain of an additional NS5A-Y93A mutation that conferred telaprevir resistance during combination therapy', 'HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (BMS-790052), represent a new class of DAA', 'ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). ', 'Telaprevir and boceprevir are the first two protease inhibitor (PI) DAAs to be approved for combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). ', 'symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed', 'In vitro, boceprevir is more active than telaprevir against the HCV G3 NS3/4A enzyme in cell-based and biochemical assays and against G3 isolates in replicon assays', 'Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A', 'Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration']

['Chronic hepatitis C virus (HCV) infection is a worldwide health problem causing serious complications, such as liver cirrhosis and hepatoma. Small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) have been reported to suppress gene expression significantly. HCV seems a suitable candidate for targets of siRNAs, as HCV is a positive single-strand RNA virus and replicates in the cytoplasm. Based on results, nowadays there are few HCV replication inhibitors such as GS-563253, PSI-6130, NA-808, BMS-790052, GS-9132 and BMS-788329.']

['yes']

Which infection can be prevented with Dapivirine?

['OBJECTIVES: The objectives of this study were to comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and six representative cell lines, and to investigate the alteration of drug transporter gene expression after exposure to three candidate microbicidal antiretroviral (ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. The outcome of the objectives informs development of optimal ARV-based microbicidal formulations for prevention of HIV-1 infection.', 'We evaluated the adherence and acceptability of a vaginal ring containing dapivirine, maraviroc, or both drugs for 28\xa0days during a Phase I placebo-controlled trial in 48 HIV-negative sexually abstinent U.S. women aged 18-40.', 'Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women.', 'Methods We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. Results Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.05) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group.', 'Conclusions A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. ', 'BACKGROUND: This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women.OBJECTIVES: The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa.', 'CONCLUSIONS: The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women.', 'PURPOSE: To develop polymeric films containing dual combinations of anti-HIV drug candidate tenofovir, maraviroc and dapivirine for vaginal application as topical microbicides.', 'Efficacy trials with a dapivirine-containing vaginal ring for HIV prevention are ongoing and plans to develop multi-purpose vaginal rings for prevention of both HIV and pregnancy have been elaborated.', 'Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.', 'The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group.', 'In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group.', 'Within this study the in vitro bioactivity of dapivirine as compared to the NNRTI UC781 was further established and a quick dissolve film was developed for vaginal application of dapivirine for prevention of HIV infection.', 'Dapivirine, a nonnucleoside reverse transcriptase inhibitor, is in development as a microbicide for the protection of women against HIV infection.', 'Dapivirine is a nonnucleoside reverse transcriptase inhibitor being developed as a topical microbicide for the prevention of human immunodeficiency virus infection.', 'Dapivirine from both IVRs was successfully distributed throughout the lower genital tract at concentrations>1000x the EC(50) against wild-type HIV-1 (LAI) in MT4 cells suggesting that IVR delivery of microbicides is a viable option meriting further study.', 'The nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 (Dapivirine) effectively prevented human immunodeficiency virus (HIV) infection in cocultures of monocyte-derived dendritic cells and T cells, representing primary targets in sexual transmission.', 'To assess the potential of polymeric nanoparticles (NPs) to affect the genital distribution and local and systemic pharmacokinetics (PK) of the anti-HIV microbicide drug candidate dapivirine after vaginal delivery.Dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) NPs were prepared by a nanoprecipitation method', 'The nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 (Dapivirine) effectively prevented human immunodeficiency virus (HIV) infection in cocultures of monocyte-derived dendritic cells and T cells, representing primary targets in sexual transmission', 'Dapivirine is a nonnucleoside reverse transcriptase inhibitor being developed as a topical microbicide for the prevention of human immunodeficiency virus infection. ', 'CONCLUSIONS: The study demonstrates proof of concept for a dapivirine-releasing diaphragm with daily release quantities potentially capable of preventing HIV transmission. ', 'Antiretroviral-containing vaginal microbicide rings, which release medication over a month or longer, may reduce these adherence challenges.ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection.', 'Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades.', 'Two large efficacy trials of a vaginal ring containing the investigational drug dapivirine demonstrated efficacy and safety in preventing HIV infections in women in Africa.', 'In doing so, we discovered that dapivirine and maraviroc, a non-nucleoside reverse transcriptase inhibitor and an entry inhibitor currently in development as microbicides for HIV PrEP, are differentially metabolized in colorectal tissue and vaginal tissue.', 'Plasma dapivirine concentrations were low (<1 ng/ml) and remained well below those observed at the maximum tolerated dose for oral treatment (mean Cmax of 2286 \u200ang/ml).CONCLUSION: The dapivirine vaginal ring has a safety and pharmacokinetic profile that supports its use as a sustained-release topical microbicide for HIV-1 prevention in women.', 'ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection.', 'Dual segment polyurethane intravaginal rings (IVRs) were fabricated to enable sustained release of antiretroviral agents dapivirine and tenofovir to prevent the male to female sexual transmission of the human immunodeficiency virus.', 'The study demonstrates proof of concept for a dapivirine-releasing diaphragm with daily release quantities potentially capable of preventing HIV transmission.']

['Vaginal ring containing Dapivirine is used for HIV prevention in women.']

['HIV']

Does TGF-beta play a role in cardiac regeneration after myocardial infarction?

['We then performed a chemical screen and identified several small molecules that increase or reduce cardiomyocyte proliferation during heart development. These compounds act via Hedgehog, Insulin-like growth factor or Transforming growth factor β signaling pathways. ', 'Here, we report that the balance between the reparative and regenerative processes is achieved through Smad3-dependent TGFβ signaling. ', 'Thus, TGFβ signaling orchestrates the beneficial interplay between scar-based repair and cardiomyocyte-based regeneration to achieve complete heart regeneration.', 'As expected, transforming growth factor (TGF)-beta, a profibrotic cytokine, was dramatically upregulated in MI hearts, but its phosphorylated comediator (pSmad) was significantly downregulated in the nuclei of Cx43-deficient hearts post-MI, suggesting that downstream signaling of TGF-beta is diminished substantially in Cx43-deficient hearts. This diminution in profibrotic TGF-beta signaling resulted in the attenuation of adverse structural remodeling as assessed by echocardiography.', 'Potentially beneficial changes include increases in the HSMP secretory-leucocyte-protease-inhibitor (SLPI) and cytokine transforming growth factor (TGF)-beta(1). Targeting these proteins may mitigate enhanced LV remodeling and dysfunction with aging.', 'After injury, the presence of macrophages, which secreted high levels of transforming growth factor-beta and vascular endothelial growth factor-A, led to rapid removal of cell debris and replacement by granulation tissue containing inflammatory cells and blood vessels, followed by myofibroblast infiltration and collagen deposition.', 'Secretion of transforming growth factor-beta and vascular endothelial growth factor-A as well as neovascularization, myofibroblast infiltration, and collagen deposition decreased. ', 'Repression of proinflammatory cytokine and chemokine synthesis, mediated in part through Transforming Growth Factor (TGF)-beta and Interleukin (IL)-10, is critical for resolution of the inflammatory infiltrate and transition to fibrous tissue deposition.', 'TGF-beta conducted the myogenic differentiation of CD117+ stem cells by upregulating GATA-4 and NKx-2.5 expression. Therefore, the intramyocardial implantation of TGF-beta-preprogrammed CD117+ cells effectively assisted the myocardial regeneration and induced therapeutic angiogenesis, contributing to functional cardiac regeneration.', 'These results indicate that TGF-beta/Smad signaling may be involved in the remodeling of the infarct scar after the completion of wound healing per se, via ongoing stimulation of matrix deposition.']

['TGFβ signaling orchestrates the beneficial interplay between scar-based repair and cardiomyocyte-based regeneration to achieve complete heart regeneration.']

['yes']

How is CBX1/M31 related to position-effect variegation?

['First, forced expression of full-length SUV39H1 (412 amino acids) redistributes endogenous M31 (HP1beta) and induces abundant associations with inter- and metaphase chromatin', 'Together, our data reveal a dominant role(s) for the SET domain of SUV39H1 in the distribution of prominent heterochromatic proteins and suggest a possible link between a chromosomal SU(VAR) protein and histone H3', 'Using this motif, termed chromo box, we have cloned a mouse candidate modifier gene, M31, that also shows considerable sequence homology to Drosophila HP1', 'Here we report evidence of at least four independently segregating loci in the mouse homologous to the M31 cDNA. One of these loci--Cbx-rs1--maps to the X Chromosome (Chr), 1 cM proximal to Amg and outside the X-inactivation center region', 'Although there is significant heterochromatic overlap between SUV39H1 and M31 (HP1(beta)) during interphase, mitotic SUV39H1 displays a more restricted spatial and temporal association pattern with metaphase chromosomes than M31 (HP1(beta)), or the related HP1(&agr;) gene product', 'which complex with the heterochromatin component M31.', 'In addition, Suv39h1/SUV39H1 proteins associate with M31, currently the only other characterized mammalian SU(VAR) homologue', 'M31, a murine homolog of Drosophila HP1, is concentrated in the XY body during spermatogenesis', 'The HP1 class of chromobox genes are thought to encode proteins involved in the packaging of chromosomal DNA into repressive heterochromatin domains, as seen, for example, in position-effect variegation', 'Study of the distribution of a murine HP1-like chromodomain protein, M31, during spermatogenesis revealed spreading from the tip of the XY body in mid-stage pachytene spermatocytes to include the whole of the XY body in late-pachytene spermatocytes', 'We also demonstrate that the formation of the XY body during spermatogenic progression in neonatal mice coincides with the expression of a novel nuclear isoform of M31, M31(p21', 'Furthermore, by overexpressing a mammalian homologue (M31) of Drosophila melanogaster heterochromatin protein 1 (HP1; refs 7,8) in transgenic mouse lines that exhibit PEV, it is possible to modify the proportion of cells that silence the transgene in a dose-dependent manner', 'Thus, we show M31 overexpression to have two contrasting effects which are dependent on chromosomal context: (i) it enhanced PEV in those lines with centromeric or pericentromeric transgene locations; and (ii) it suppressed PEV when the transgene was non-centromeric']

['M31 is a heterochromatin component, that is concentrated in the XY body during spermatogenesis. M31 overexpression has two contrasting effects which are dependent on chromosomal context: (i) it enhanced PEV in those lines with centromeric or pericentromeric transgene locations; and (ii) it suppressed PEV when the transgene was non-centromeric.']

[]

Is marijuana use associated with increased risk for stroke?

['The illicit drugs more commonly associated with stroke are psychomotor stimulants, such as amphetamine and cocaine. Less commonly implicated are opioids and psychotomimetic drugs, including cannabis.', 'Among 326 patients (184 males), the most frequent stroke risk factors overall were dyslipidaemia (187), smoking (161), hypertension (105) and obesity (92). Fifty-one patients used illicit drugs, mostly comprising marijuana and amphetamines.', 'Patients in Adelaide are more likely to be obese, to be misusing marijuana and amphetamines, to suffer a cardioembolic event and to have a stroke that concurrently affects both the anterior and posterior cerebral circulation.', 'RCVS was spontaneous in 37% of patients and secondary in the 63% others, to postpartum in 5 and to exposure to various vasoactive substances in 37, mainly cannabis, selective serotonin-recapture inhibitors and nasal decongestants.', 'We reported two cases of young stroke associated with drug misuse. Case 1 used amphetamine, cocaine, marijuana and LSD for few yaers, and developed occlusion of a middle cerebral artery. Case 2 presented aphasia shortly after marijuana smoking.', 'Marijuana may have accelerated stroke onset, but essential cause of stroke in this case must be protein S mutation.', 'Cannabis is the most widely consumed among the illicit drugs worldwide, but it has only exceptionally been associated to cerebrovascular disease.', 'We here describe 2 young patients (26 and 29 years, respectively) who suffered from ischemic stroke in temporal relation with cannabis consumption.', 'The review of the literature on this topic reveals another 18 patients with stroke in association to cannabis use.', 'Although a causal relationship is difficult to establish due to the widespread use of cannabis, this drug may play an etiologic role in ischemic stroke.', 'Marijuana may trigger a myocardial infarction and have a vasospastic effect.', 'Despite the fact that cannabis is the most widely used illicit drug, there are only a few reports associating its use with cerebrovascular disease.', 'We describe a patient who suffered three ischaemic strokes immediately after cannabis consumption.', 'Cannabis use may be associated with ischaemic stroke in young patients, but its mechanism is unclear.', 'A right occipital ischemic stroke occurred in a 37-year-old Albanese man with a previously uneventful medical history, 15 min after having smoked a cigarette with approximately 250 mg of marijuana.', 'Therefore, as the family history for cerebrovascular events, blood pressure, clotting tests, examinations for thrombophilia, vasculitis, extracranial and intracranial arteries and cardiac investigations were normal or respectively negative, the stroke was attributed to the chronic cannabis consumption.', 'Three adolescent males had similar presentations of headache, fluctuating level of consciousness or lethargy, visual disturbance, and variable ataxia after self-administration of marijuana.', 'Episodic marijuana use may represent a risk factor for stroke in childhood, particularly in the posterior circulation.', 'Although several mechanisms exist by which marijuana use might contribute to the development of chronic cardiovascular conditions or acutely trigger cardiovascular events, there are few data regarding marijuana/THC use and cardiovascular disease outcomes.', 'Reported here is the case of a previously healthy young man who smoked marijuana on a daily basis and had an occipital lobe stroke; he was found to be heterozygous for factor V Leiden.', 'This case suggests that marijuana smoking may increase the risk of arterial thrombosis in otherwise healthy individuals who are heterozygous for factor V Leiden.', 'Thus, chronic abuse of marijuana might be a risk factor for stroke.', 'A 22-year-old man with a five-year history of drug and alcohol abuse presented with a left hemiparesis preceded by three transient ischaemic attacks, two of which occurred whilst smoking cannabis. Substance abuse was the only identifiable risk factor for cerebrovascular disease.', 'Chronic marijuana smoking, however, seems to reduce CBF.', 'Research directions might include more studies of cardiovascular disease outcomes and relationships of marijuana with cardiovascular risk factors, studies of metabolic and physiologic effects of chronic marijuana use that may affect cardiovascular disease risk, increased understanding of the role of the cannabinoid receptor system in cardiovascular regulation, and studies to determine if there is a therapeutic role for cannabinoids in blood pressure control or for neuroprotection after stroke.']

['Yes, the use of marijuana is associated with increased risk for ischemic stroke, especially in young adults. The mechanisms underlying such association remain largely unclear, but increased vascular reactivity and increased cerebrovascular resistance were implicated.']

['yes']

Which factors are considered in the ABCD2 score?

["The 'accuracy' of age, blood pressure, clinical features, duration and diabetes (ABCD(2)) scoring by non-stroke specialists referring patients to a daily Rapid Access Stroke Prevention (RASP) service is unclear, as is the accuracy of ABCD(2) scoring by trainee residents. ", ' Classification of low risk was based on an age, blood pressure, clinical features, duration of symptoms and diabetes (ABCD2) score <4 and the absence of high risk features, including known carotid disease, crescendo TIA, or atrial fibrillation. ', 'Our goal was to compare the very early predictive accuracy of the most relevant clinical scores [age, blood pressure, clinical features and duration of symptoms (ABCD) score, ABCD and diabetes (ABCD2) score, ABCD and brain infarction on imaging score, ABCD2 and brain infarction on imaging score, ABCD and prior TIA within 1 week of the index event (ABCD3) score, California Risk Score, Essen Stroke Risk Score and Stroke Prognosis Instrument II] in consecutive transient ischemic attack (TIA) patients. ', 'We examined the association of the age, blood pressure, clinical features, duration of symptoms and diabetes (ABCD2) score, a validated risk prediction model for stroke after TIA, and the presence of ICS or ECS. ', 'BACKGROUND: The ABCD2 score (Age, Blood pressure, Clinical features, Duration of symptoms and Diabetes) is used to identify patients having a transient ischemic attack who are at high risk for imminent stroke. ', 'BACKGROUND AND PURPOSE: The risk of stroke after a transient ischaemic attack (TIA) can be predicted by scores incorporating age, blood pressure, clinical features, duration (ABCD-score), and diabetes (ABCD2-score). ', 'BACKGROUND: Modifications to the age, blood pressure, clinical symptoms, duration of symptoms, and diabetes (ABCD2) score, which incorporate history of hypertension and acute hyperglycemia in addition to acute blood pressure (BP) elevation and history of diabetes, have been proposed to increase the predictive value of the score. ', 'ABCD2 (Age, Blood pressure, Clinical features, Duration, Diabetes) score and magnetic resonance imaging abnormalities help to identify patients at high risk of stroke.', 'METHODS: We prospectively calculated the ABCD(2) score (age [> or = 60 years: 1 point]; blood pressure [systolic >140 mm Hg or diastolic >90 mm Hg: 1[; clinical features [unilateral weakness: 2, speech disturbance without weakness: 1, other symptom: 0]; duration of symptoms [ <10 minutes: 0, 10-59 minutes: 1, > or = 60 minutes: 2]; diabetes mellitus [yes: 1]) in consecutive TIA patients hospitalized in 3 tertiary care neurology departments across 2 different racial populations (white and Asian). ', 'Early stroke risk is especially high in TIA patients with a high ABCD2 score of 4 or more (A age over 60 years [1 point]: B blood pressure > 140/90 mmHg [1 point]: C Clinical features, including unilateral weakness [2 points] and speech disturbance without weakness [1 point] D2: Diabetes [1 point] and Duration of symptoms [1 point for < 60 min and 2 points for > 60 min]), acute ischemic lesions on diffusion weighted image, > 50% carotid stenosis, severe intracranial artery stenosis, microembolic signals on transcranial Doppler, atrial fibrillation, or hypercoagulable states.', 'STUDY OBJECTIVE: We evaluate, in admitted patients with transient ischemic attack, the accuracy of the ABCD(2) (age [A], blood pressure [B], clinical features [weakness/speech disturbance] [C], transient ischemic attack duration [D], and diabetes history [D]) score in predicting ischemic stroke within 7 days. ', 'Our goal was to compare the very early predictive accuracy of the most relevant clinical scores [age, blood pressure, clinical features and duration of symptoms (ABCD) score, ABCD and diabetes (ABCD2) score, ABCD and brain infarction on imaging score, ABCD2 and brain infarction on imaging score, ABCD and prior TIA within 1 week of the index event (ABCD3) score, California Risk Score, Essen Stroke Risk Score and Stroke Prognosis Instrument II] in consecutive transient ischemic attack (TIA) patients.', 'The risk of stroke after a transient ischaemic attack (TIA) can be predicted by scores incorporating age, blood pressure, clinical features, duration (ABCD-score), and diabetes (ABCD2-score).', 'BACKGROUND AND PURPOSE: The risk of stroke after a transient ischaemic attack (TIA) can be predicted by scores incorporating age, blood pressure, clinical features, duration (ABCD-score), and diabetes (ABCD2-score).']

['Age, Blood pressure, Clinical features, Duration of symptoms and Diabetes are included in the ABCD2 score, which is used to identify patients having a transient ischemic attack who are at high risk for imminent stroke.']

['Age', 'Blood pressure', 'Clinical features', 'Duration of symptoms', 'Diabetes']

Which is the most common editing modification in eukaryotic mRNA?

['One of the most common forms of pre-mRNA editing is A-to-I editing, in which adenosine is deaminated to inosine, which is read as guanosine during translation.', 'Deamination of adenine by adenosine deaminases that act on RNA (ADARs) leads to the conversion of adenine into inosine (A-I editing) recognized by the splicing and translation systems as guanine.', 'denosine deaminases editing adenines in transport RNAs (ADATs) convert adenine into inosine in tRNAs of all eukaryotes; as a result, the diversity of tRNA forms in the cell increases.', 'A-to-I editing events in normal and cancerous human keratinocytes', 'A-to-I RNA editing can alter codons, substitute amino acids and affect protein sequence, structure, and function.', '-to-I RNA editing is a post-transcriptional mechanism frequently used to expand and diversify transcriptome and proteome repertoire in eukaryotic cells', 'This study describes for the first time A-to-I editing in the coding sequence of a tumor suppressor gene in humans, and suggests that IGFBP7 editing serves as a fine-tuning mechanism to maintain the equilibrium between proliferation and senescence in normal skin.', 'Adenosine deaminases that act on RNA (ADARs) catalyze the adenosine-to-inosine (A-to-I) conversion, the most common type of RNA editing in higher eukaryotes. ', 'RNA editing is observed in eukaryotic mRNA, transfer RNA, ribosomal RNA, and non-coding RNAs (ncRNA). The most common RNA editing in the mammalian central nervous system is a base modification, where the adenosine residue is base-modified to inosine (A to I).', 'It occurs in a wide variety of eukaryotic organisms and in some viruses. One of the most common forms of pre-mRNA editing is A-to-I editing, in which adenosine is deaminated to inosine, which is read as guanosine during translation.', 'The most common RNA editing in the mammalian central nervous system is a base modification, where the adenosine residue is base-modified to inosine (A to I).', 'One of the most common forms of pre-mRNA editing is A-to-I editing, in which adenosine is deaminated to inosine, which is read as guanosine during translation.', 'RNA editing by adenosine deamination (A-to-I) is widespread in humans and can lead to a variety of biological effects depending on the RNA type or the RNA region involved in the editing modification.']

['One of the most common forms of pre-mRNA editing is A-to-I editing, in which adenosine is deaminated to inosine, which is read as guanosine during translation.']

['A-to-I']

What is the link between TB (Turbeculosis) infection and TNFa inhibition?

['The use of TNFalpha blockers is associated with reactivation of tuberculosis (TB)', 'We present two patients with inflammatory bowel disease who, despite negative tuberculosis screening, developed a de novo tuberculosis infection after the start of anti tumor necrosis factor alpha treatment.', 'To compare the performance of two interferon gamma release assays (IGRAs) and conventional screening tests in patients with inflammatory arthritis undergoing screening for latent tuberculosis infection (LTBI) before treatment with anti-tumour necrosis factor alpha (anti-TNFalpha) compounds.', 'The occurrence of tuberculosis (TB) in patients treated with immunosuppressive drugs (ISD) is an old problem that has been highlighted by cases occurring in patients using anti-TNFalpha drugs.', 'TNFalpha plays a pivotal role not only in the inflammatory process but also in the normal response against pathogens and therefore, interfering with this cytokine may increase the risk of infection.']

['The occurrence of tuberculosis (TB) in patients treated with immunosuppressive drugs (ISD) is an old problem that has been highlighted by cases occurring in patients using anti-TNFalpha drugs.']

[]

Which receptors are targeted by a drug Macitentan?

['Macitentan is a novel dual endothelin receptor antagonist with sustained receptor binding in clinical development for pulmonary arterial hypertension. ', 'This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. ', 'Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects.', 'Macitentan is a potent, orally active, non-peptide antagonist of endothelin receptors with tissue-targeting properties, currently undergoing clinical development for the treatment of pulmonary arterial hypertension. ', 'Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro.', 'Macitentan is a new non-selective endothelin-1 receptor antagonist under development for the treatment of pulmonary arterial hypertension. ', 'This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.', 'Dual ETRA/ETRB blockade with macitentan (or the combination of the ETRA and ETRB antagonists BQ123 and BQ788) did not enhance antitumor immune cell recruitment. ', 'The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortality clinical trial in PAH patients. ', 'Given that the newest PAH drugs include a receptor tyrosine kinase antagonist (imatinib), a soluble guanylate cyclase stimulator (riociguat), an oral analog of prostacyclin (selexipag), and a tissue targeting ERA (macitentan) determination of appropriate combinations for various etiologies and clinical stages is urgently required. ', "The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist.", 'Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET(A) with significant affinity for the ET(B) receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. ', 'Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist.', 'Here we investigated the effects of macitentan, an orally-active, tissue-targeting dual ET receptor antagonist on chronic complications in type 2 diabetes. ', 'Several specific therapeutic agents were developed for the medical management of PAH including prostanoids (epoprostenol, trepoprostenil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan, macitentan soon available) and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). ', 'The aim of the present study is to evaluate the in vitro effect of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist, and its major metabolite (ACT-132577) on alpha smooth muscle actin (alphaSMA) expression, evaluated on dermal fibroblasts from healthy subjects and on dermal fibroblasts from lesional and non-lesional skin from sclerodermic patients. ', 'Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects.', 'This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor antagonist (ERA) with sustained receptor binding and enhanced tissue penetration properties compared to other ERAs.', 'We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial.', 'Many clinical studies targeting the vasoconstrictor ET-1 pathway with receptor antagonists like bosentan and ambrisentan have shown strong results, even more optimism coming from macitentan, the newest drug.', 'Promising candidates include tyrosine kinase antagonists (e.g. imatinib); soluble guanylate cyclase stimulators (riociguat); an oral analog of prostacyclin (selexipag); and a tissue targeting endothelin receptor antagonist (macitentan).', 'Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment.', 'Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension.', 'Macitentan is a novel dual endothelin receptor antagonist (ERA) showing sustained receptor occupancy. ', 'Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd. ', 'Endothelin (ET)-1 influences pathological changes via two ET receptor subtypes (ETA and ETB), to which it binds with high affinity. ', 'Macitentan was developed by modifying the structure of bosentan in the search for an optimal dual ERA with improved efficacy and tolerability compared with other ERAs. ', 'Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans.', 'Macitentan is a tissue-targeting, dual endothelin receptor antagonist, currently under phase 3 investigation in pulmonary arterial hypertension. ', 'Antivascular therapy for multidrug-resistant ovarian tumors by macitentan, a dual endothelin receptor antagonist.', 'The nonselective endothelin type A and B receptor antagonists bosentan (100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted rings by 30±5% and 24±3%, respectively. ', 'Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension.', 'This rise could largely be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). ', 'Promising study results for the treatment of IPF were published for the triple tyrosine kinase inhibitor intedanib, other drugs such as the endothelin receptor antagonist (ERA) macitentan are currently investigated in clinical trials.', 'To study the pharmacokinetics, pharmacodynamics, and tolerability of rising single doses of macitentan, an endothelin receptor antagonist, in healthy male subjects. ', 'Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist, enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer.', 'We investigated the therapeutic efficacy of the dual ETR antagonist, macitentan, on human ovarian cancer cells, SKOV3ip1 and IGROV1, growing orthotopically in nude mice. ', 'Macitentan, a tissue-targeting endothelin receptor antagonist for the potential oral treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis.', 'Macitentan (ACT-064992), under development by Actelion Ltd in collaboration with Japanese licensee Nippon Shinyaku Co Ltd, is an orally active, non-peptide dual endothelin (ET)(A) and ET(B) receptor antagonist for the potential treatment of idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). ', 'Macitentan, because of its ability to target the tissues and to block both ET(A) and ET(B) receptors, is emerging as a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation. ', 'Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan.', 'Macitentan (ACT-064992) is an orally active endothelin receptor antagonist. ', 'Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist.', "Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N'-propylaminosulfonamide], is a new dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting.", 'Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ET(A) and ET(B) receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET(A) receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET(B) receptors). ', 'In conclusion, macitentan, by its tissue-targeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats.']

['Endothelin receptor A and endothelin receptor B are targeted by a drug Macitentan. Macitentan is a potent, orally active, non-peptide dual antagonist of endothelin receptors A and B that is approved for the treatment of pulmonary arterial hypertension.']

['endothelin receptor A', 'endothelin receptor B']

Which are the 3 basic transcription factors that have been used for the direct reprogramming of fibroblasts into cardiomyocytes or cardiomyocyte like-cells?

['Direct reprogramming of human cardiac fibroblasts (HCFs) into cardiomyocytes may hold great potential for this purpose. We reported previously that induced cardiomyocyte-like cells (iCMs) can be directly generated from mouse cardiac fibroblasts in vitro and vivo by transduction of three transcription factors: Gata4, Mef2c, and Tbx5, collectively termed GMT.', 'Cardiac fibroblasts can be reprogrammed to cardiomyocyte-like cells by the introduction of three transcription factors: Gata4, Mef2c and Tbx5 (collectively referred to here as GMT).', 'Here we describe a detailed step-by-step protocol for in vitro cardiac reprogramming using retroviruses encoding GMT.', 'Overexpression of transcription factors MYOCD and SRF alone or in conjunction with Mesp1 and SMARCD3 enhanced the basal but necessary cardio-inducing effect of the previously reported GATA4, TBX5, and MEF2C.', ' Using calcium activity as our primary outcome measure, we compared several published combinations of transcription factors along with novel combinations in mouse embryonic fibroblasts. The most effective combination consisted of Hand2, Nkx2.5, Gata4, Mef2c, and Tbx5 (HNGMT). This combination is >50-fold more efficient than GMT alone and produces iCMs with cardiomyocyte marker expression, robust calcium oscillation, and spontaneous beating that persist for weeks following inactivation of reprogramming factors.', 'Here we show that four human cardiac transcription factors, including GATA binding protein 4, Hand2, T-box5, and myocardin, and two microRNAs, miR-1 and miR-133, activated cardiac marker expression in neonatal and adult human fibroblasts. ', 'We found that functional cardiomyocytes can be directly induced from fibroblasts by a combination of three cardiac transcription factors, Gata4, Mef2c and Tbx5, in vitro and in vivo.', 'To assess the efficiency of direct fibroblast reprogramming via viral overexpression of GATA4, Mef2c, and Tbx5 (GMT). ', ' In addition, transplantation of GMT infected CFs into injured mouse hearts resulted in decreased cell survival with minimal induction of cardiomyocyte genes.', 'Here, to identify a cardiac transcription factor combination facilitating mouse fibroblast reprogramming into cardiomyocytes, we directly screened all triplet combinations of 10 candidate factors combined with a Q-PCR assay reporting induction of multiple cardiac-specific genes. Through this screening method the combination of Tbx5, Mef2c, and Myocd was identified to upregulate a broader spectrum of cardiac genes compared to the combination of Tbx5, Mef2c, and Gata4 that was recently shown to induce reprogramming of fibroblasts into cardiomyocytes.', 'We reported previously that cardiac fibroblasts,which represent 50%of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT).', 'Here, we report that a combination of three developmental transcription factors (i.e., Gata4, Mef2c, and Tbx5) rapidly and efficiently reprogrammed postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells. Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously.', 'More recently, we showed that reprogramming of cardiac fibroblasts to cardiomyocyte-like cells in vivo after coronary artery ligation using three cardiac transcription factors (Gata4/Mef2c/Tbx5) offers an alternative approach to regenerate heart muscle.', 'Here, we report that a combination of three developmental transcription factors (i.e., Gata4, Mef2c, and Tbx5) rapidly and efficiently reprogrammed postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells.', "Srivastava's group reported the first direct reprogramming of mouse fibroblast cells into mesoderm lineage cells (cardiomyocytes) with the enforced expression of three cardiac transcriptional factors: Gata4, Mef2c, and Tbx5.", "Srivastava's group reported the first direct reprogramming of mouse fibroblast cells into mesoderm lineage cells (cardiomyocytes) with the enforced expression of three cardiac transcriptional factors: Gata4, Mef2c, and Tbx5", 'Cardiac fibroblasts can be reprogrammed to cardiomyocyte-like cells by the introduction of three transcription factors: Gata4, Mef2c and Tbx5 (collectively referred to here as GMT)']

['Direct reprogramming of human cardiac fibroblasts (HCFs) into cardiomyocytes may hold great potential for this purpose. We found that functional cardiomyocytes can be directly induced from fibroblasts by a combination of three cardiac transcription factors, Gata4, Mef2c and Tbx5, in vitro and in vivo.', 'Direct reprogramming of human cardiac fibroblasts (HCFs) into cardiomyocytes may hold great potential for this purpose. We reported previously that induced cardiomyocyte-like cells (iCMs) can be directly generated from mouse cardiac fibroblasts in vitro and vivo by transduction of three transcription factors: Gata4, Mef2c, and Tbx5, collectively termed GMT. ', 'Cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT). Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously.']

['Gata4', 'Mef2c', 'Tbx5']

Does dasatinib promote or inhibit T-cell proliferation?

['Dasatinib inhibited antigen-specific proliferation of murine CD4(+) and CD8(+) transgenic T cells in vitro and in vivo', 'Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses. ', 'Both dasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and degranulation in a dose-dependent manner. ', 'Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses', 'Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation', 'Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation.', 'Dasatinib inhibits the proliferation and function of CD4+CD25+ regulatory T cells.', 'T-cell functions including proliferation, activation and cytokine production were all uniformly inhibited in the presence of dasatinib. We also demonstrated inhibition of TCR signalling through Src-family kinase LCK, and predicted that inhibition of LCK and other kinases involved in T-cell signalling by dasatinib is responsible for the suppression of T-cell function. ']

['Dasatinib inhibits T-cell proliferation']

['inhibits']

What is the effect of enamel matrix derivative on pulp regeneration?

['Among the human studies, two studies reported that EMD is a more efficient DPC procedure compared with calcium hydroxide (Ca(OH)2 ). One study reported Ca(OH)2 to be more efficient for DPC than EMD. One study reported no difference in the efficacies between EMD and Ca(OH)2 for DPC. All animal studies reported EMD to be more effective in reparative dentine formation in comparison with Ca(OH)2 . EMD can provide favourable results in DPC procedures', 'EMD increased the osteogenic potential of hDPCs', ' the expression levels of osteogenesis-related genes, such as ALP, DSPP, BMP, and OPN were also upregulated. In addition, the expression levels of odontogenesis-related transcription factors Osterix and Runx2 were upregulated', 'EMD could enhance the mineralization of hDPSCs upregulated the expression of markers for odontoblast/osteoblast-like cells. Further studies are required to determine if EMD can improve pulp tissue repair and regeneration', 'In both the scaffold groups, dentin sialophosphoprotein, dentin matrix protein-1, and osteopontin messenger RNA was up-regulated significantly in EMD-treated hDPCs when compared with the nontreated cells', 'Proliferated pulp tissue partly filled the space initially occupied by EMDgel and DSP-stained hard tissue was observed alongside exposed dentine surfaces as well as in isolated masses within the proliferated pulp tissue, although the new hard tissue did not cover the pulp exposure', 'In the EMD-treated teeth, large amounts of newly formed dentin-like hard tissue with associated formative cells outlined the pulpal wound separating the cavity area from the remaining pulp tissue', 'Inflammatory cells were present in the wound area but not subjacent to the newly formed hard tissue. Morphometric analysis showed that the amount of hard tissue formed in EMD-treated teeth was more than twice that of the calcium-hydroxide-treated control teeth (p < 0.001), suggesting that EMD is capable of promoting reparative processes in the wounded pulp more strongly than is calcium hydroxide']

['EMD increased the osteogenic potential of hDPCs. The expression levels of osteogenesis-related genes, such as ALP, DSPP, BMP, and OPN were also upregulated. In addition, the expression levels of odontogenesis-related transcription factors Osterix and Runx2 were upregulated. Proliferated pulp tissue partly filled the space initially occupied by EMDgel and isolated masses within the proliferated pulp tissue.']

['increase of the osteogenic potential of hDPCs']

What is the anatomical structure crucial in optic nerve glioma surgery, named after Johann Gottfried Zinn?

['["Should the annular tendon of the eye be named \'annulus of Zinn\' or \'of Valsalva\'?", "The annular tendon is commonly named \'annulus of Zinn\', from the German anatomist and botanist Johann Gottfried Zinn (1727-1759) who described this structure in his Descriptio anatomica oculi humani (Anatomical Description of the Human Eye, 1755).", "It arose at the annulus of Zinn, passing forwards between the inferior rectus muscle and lateral rectus muscle, and insert directly on the sclera. ", "Drilling was continued toward the annulus of Zinn (AZ) and optic nerve superiorly and over the intracavernous ICA posteriorly.", "Measurements before and after resection of the ACP included the length of C6 segment of the ICA on its lateral aspect; C6 segment length on its medial aspect; and medial length of the optic nerve from the optic chiasm to falciform ligament (before ACP resection) then to the annulus of Zinn (after ACP resection).", "The muscles, situated between the optic nerve and the lateral rectus muscle, originated from the annulus of Zinn and branched off two heads; one inserted into the medial inferior side of the superior rectus muscle and the other inserted into the central superior side of the inferior rectus muscle. ", " In 30 cadavers, the superior division of the oculomotor nerve was severed en bloc 1.5 cm anterior to the annulus of Zinn with the levator palpebrae superioris (LPS) and the superior rectus muscles. ", "The optic canal was subsequently removed en bloc, beginning at the annulus of Zinn and extending to the optic chiasm.", "PURPOSE: To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis.DESIGN: A retrospective, noncomparative, interventional case series.STUDY POPULATION: All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010.PROCEDURE: A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn.", "No patients had tumor recurrence or developed postoperative paralytic ptosis.CONCLUSIONS: The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis.", "To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis.A retrospective, noncomparative, interventional case series.All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010.A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn", "Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn", "A simulation of the procedure in a cadaver and en bloc resection of the orbital apex are performed to demonstrate the subdural plane of dissection within the annulus of Zinn.Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence.Eleven patients underwent resection of optic nerve gliomas using this technique", "No patients had tumor recurrence or developed postoperative paralytic ptosis.The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis", "The orbital surface of the medial rectus and inferior rectus are exposed from the annulus of Zinn to a position close to where the muscles penetrate Tenons capsule", "The orbital surface of the medial rectus and inferior rectus are exposed from the annulus of Zinn to a position close to where the muscles penetrate Tenon\'s capsule. ", "The muscles, situated between the optic nerve and the lateral rectus muscle, originated from the annulus of Zinn and branched off two heads; one inserted into the medial inferior side of the superior rectus muscle and the other inserted into the central superior side of the inferior rectus muscle.", "']

annulus of Zinn

[]

How does saxagliptin compare to other DPP-4 inhibitors in treating type 2 diabetes?

[' up to October 1st, 2013.", "Saxagliptin.", "Vildagliptin.", "an extensive Medline, Embase and Cochrane Database search for \'vildagliptin\', \'sitagliptin\', \'saxagliptin\', \'alogliptin\', \'linagliptin\' and \'dutogliptin\' was performed up to 1 March 2013.", "An extensive Medline and Embase search for \'vildagliptin\', \'sitagliptin\', \'saxagliptin\', \'alogliptin\', \'linagliptin\', and \'dutogliptin\' was performed, collecting all randomized clinical trials on humans up to March 1, 2011.", "An extensive Medline, Embase, and Cochrane Database search for \\"vildagliptin\\", \\"sitagliptin\\", \\"saxagliptin\\", \\"alogliptin\\", \\"linagliptin\\", and \\"dutogliptin\\" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013.", "the words \\"sitagliptin,\\" \\"vildagliptin,\\" \\"saxagliptin,\\" \\"alogliptin,\\" \\"linagliptin,\\" and/or \\"dutogliptin.\\" Completed but unpublished trials were identified through a search of the ClinicalTrials.gov website,", "Sitagliptin (MK- 0431), Saxagliptin, Melogliptin, Linagliptin (BI-1356), Dutogliptin, Carmegliptin, Alogliptin and Vildagliptin (LAF237).", "Of these, two have been approved for clinical use in the United States: sitagliptin and saxagliptin. Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2).", "We conducted a search on MEDLINE, Embase and Cochrane Collaborative database for randomized controlled trials (RCTs) of DPP-4 inhibitors and metformin as initial combination therapy or as monotherapy in patients with T2DM by the end of December 2012, using the key words \'alogliptin\', \'dutogliptin\', \'linagliptin\', \'saxagliptin\', \'sitagliptin\', \'vildagliptin\' and \'metformin\'.", "Given as monotherapy, linagliptin, sitagliptin, and vildagliptin (but not saxagliptin) met the equivalence criterion when compared with one another. Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion.", "Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2). Alogliptin was approved for use in Japan under the trade name Nesina\\u00ae in April 2010 (3).", "Any DPP-4 inhibitor (vildagliptin, sitagliptin, saxagliptin, linagliptin or alogliptin).", "An extensive search of Medline and the Cochrane Library (any date up to December 31, 2010, restricted to randomized clinical trials, published in English) was performed for all trials containing, in any field, the words \\"sitagliptin,\\" \\"vildagliptin,\\" \\"saxagliptin,\\" \\"alogliptin,\\" \\"linagliptin,\\" and/or \\"dutogliptin.\\" Completed but unpublished trials were identified through a search of the ClinicalTrials.gov website, using the same keywords as above.", "A systematic review and meta-analysis of randomised controlled trials (RCTs) of DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin and alogliptin) on HbA1c were conducted.", "Several clinical trials have studied the addition of GLP-1 receptor agonists [exenatide BID (twice daily), lixisenatide, albiglutide] or DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, alogliptin, linagliptin) to ongoing insulin therapy or adding insulin to ongoing therapy with a GLP-1 receptor agonist (liraglutide).", "Testing the therapeutic equivalence of alogliptin, linagliptin, saxagliptin, sit']

Saxagliptin has been compared to other DPP-4 inhibitors in clinical trials, showing similar efficacy and safety profiles. In some studies, saxagliptin has been found to be non-inferior or equivalent to other DPP-4 inhibitors like sitagliptin, vildagliptin, linagliptin, and alogliptin in treating type 2 diabetes.

[]

Is corpus callosum involved in the Mowat–Wilson syndrome?

[' The syndrome is characterized by typical facial features, moderate-to-severe mental retardation, epilepsy and variable congenital malformations, including Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of the corpus callosum, and eye defects. ', 'Mowat-Wilson syndrome in a fetus with antenatal diagnosis of short corpus callosum: advocacy for standard autopsy.', 'It is mainly characterized by moderate-to-severe intellectual disability, epilepsy, facial dysmorphism and various malformations including Hirschsprung disease and corpus callosum anomalies. ', 'The association of a corpus callosum hypoplasia with a histological Hirschsprung disease and a typical facial gestalt allowed the guiding of genetic testing.', 'Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). ', '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.', 'Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations.', 'The striking facial phenotype in addition to other features such as severely impaired speech, hypotonia, microcephaly, short stature, seizures, corpus callosum agenesis, congenital heart defects, hypospadias, and Hirschsprung disease are particularly important clues for the initial clinical diagnosis. ', '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. ', 'It is characterized by a distinctive facial appearance in association with intellectual disability (ID) and variable other features including agenesis of the corpus callosum, seizures, congenital heart defects, microcephaly, short stature, hypotonia, and Hirschsprung disease. ', 'Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies.', '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. ', 'Agenesis or hypogenesis of the corpus callosum.', 'The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. ', 'Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects.', 'In 11 of the 28 patients with ACC, the following diagnoses could be established: Mowat-Wilson syndrome (n = 2), Walker-Warburg syndrome (n = 1), oro-facial-digital syndrome type 1 (n = 1), and chromosomal rearrangements (n = 7), including a patient with an apparently balanced reciprocal translocation, which led to the disruption and a predicted loss of function in the FOXG1B gene.', 'Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies.', '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. ', 'Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, characterized by typical facies, severe MR, epilepsy, and variable congenital malformations, including Hirschsprung disease (HSCR), genital anomalies, congenital heart disease (CHD), and agenesis of the corpus callosum (ACC). ', 'Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). ', 'Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease.', 'ACC is found in 40% of the cases of Mowat-Wilson syndrome (MWS), a polytopic embryonic defect including a distinctive facial gestalt, severe mental retardation, epilepsy and postnatal microcephaly as constant features. ', 'However, analysis of MWS should be considered in the differential diagnosis of ACC, especially when the facial features raise the possibility of MWS.', 'Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome).', 'We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome).', 'Congenital anomalies, including Hirschsprung disease (HSCR), congenital heart disease, hypospadias, genitourinary anomalies, agenesis of the corpus callosum, and short stature are common. ']

['Yes, agenesis of the corpus callosum is common patients with Mowat–Wilson syndrome. Other characteristic features of Mowat–Wilson syndrome include typical facial features, moderate-to-severe mental retardation, epilepsy and variable congenital malformations, including Hirschsprung disease, genital anomalies, congenital heart disease, and eye defects.']

['yes']

Which drugs are included in the FEC-75 regimen?

['Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial.', 'Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group.', 'In May 2008, the patient underwent preoperative chemotherapy consisting of 4 courses of FEC 75(fluororracil, epirubicin, and cyclophosphamide).', 'Stage II-IIIC HER2-positive breast cancer patients, including inflammatory disease, were treated with weekly-trastuzumab for 24 weeks administered concurrently with all primary chemotherapy containing paclitaxel (80 mg/m(2)) for 12 weeks and 4 cycles of FEC-75 (fluorouracil 500 mg/m(2), epirubicine 75 mg/m(2), and cyclophosphamide 500 mg/m(2)) followed by surgery. ', 'Further improvements can be achieved with dose-dense regimens, but densification of fluorouracil/epirubicin/cyclophosphamide (FEC) has proved difficult, with FEC(60) providing little benefit over standard chemotherapy and FEC(100) associated with toxicity. We investigated the feasibility of two intermediate dose-dense FEC regimens. Patients were randomised to six cycles of FEC(75) or FEC(90), with all three drugs given on day 1 of each 14-day cycle. ', 'BACKGROUND: A previously published prospective randomized phase 3 trial showed that administration of 24 weeks of primary systemic chemotherapy (PST) with paclitaxel and FEC(75) (fluorouracil, epirubicin, cyclophosphamide) concurrently with trastuzumab in patients with HER2-positive primary breast cancer resulted in a 60% pathologic complete response rate (PCR) with no associated severe cardiac toxicity. ', 'Maintenance chemotherapy was FEC 75 (fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) on Day 1 every 21 days for 4 cycles). ', 'The French Epirubicin Study Group carried out a randomized trial comparing epirubicin alone 75 mg/m2 with fluorouracil (5FU) 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 50 mg/m2 (FEC 50) and 5FU 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 75 mg/m2 (FEC 75) as first treatment for advanced breast cancer patients.', 'Patients were randomised to 1 of 3 treatment groups: Group A (n = 207) received FEC 50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 6 cycles; Group B (n = 193) received FEC 50 every 21 days for 3 cycles; Group C (n = 195) received FEC 75 (fluorouracil 500 mg/m2, epirubicin 75 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 3 cycles.', 'Sixty chemotherapy-naive breast cancer patients of 30 to 71 years in age, P.S. = 0-1, receiving 5-fluorouracil-epirubicin-cyclophosphamide (FEC 75) q 21 days or cyclophosphamide-methotrexate-5-fluorouracil (CMF) or 120 mg/m2 epirubicin or high dose mitomycin-methotrexate-mitoxantrone (MMM) q 14 days (+ G-CSF) or 100 mg/m2 epirubicin (+ G-CSF) were randomized to receive, 15 min before chemotherapy, 8 mg i.v. bolus of ondansetron or 3 mg i.v. granisetron or 5 mg i.v. tropisetron and no further antiemetic therapy in the following days.', 'PATIENTS AND METHODS: Four hundred seventeen anthracycline-naive MBC patients were randomized to receive one of the following regimens: arm A: 11 cycles of fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC 75) every 21 days; arm B: four cycles of FEC 100 (same regimen but with epirubicin 100 mg/m(2)) then eight cycles of FEC 50 (epirubicin 50 mg/m(2)); and arm C: four cycles of FEC 100 then restart the same regimen at disease progression in case of prior response or stabilization.', 'The aim of this study, using a Fleming single-stage design, was to explore the efficacy and safety of Taxotere 100 x mg x m(-2) docetaxel and FEC 75 cyclophosphamide 500 mg x m(-2), fluorouracil 500 x mg x m(-2) and epirubicin 75 mg x m(-2), in alternating and sequential schedules for the first-line treatment of metastatic breast cancer.', 'PATIENTS AND METHODS: Between 1986 and 1990, 621 patients with operable breast cancer were randomly assigned to receive fluorouracil (Roche SA, Basel, Switzerland) 500 mg/m2, epirubicin (Pharmacia SA, Milan, Italy) 50 mg/m2, and cyclophosphamide (Asta Medica AG, Frankfurt, Germany) 500 mg/m2 every 21 days (FEC 50) for six cycles (6 FEC 50); FEC 50 for three cycles (3 FEC 50); or the same regimen with epirubicin 75 mg/m2 (FEC 75) for three cycles (3 FEC 75).', 'We studied the feasibility of FEC (75) (fluorouracil: 500 mg/m(2), epirubicin: 75 mg/m(2), and cyclophosphamide:500 mg/m(2), q 3 w, 6 cycles) as adjuvant chemotherapy for 59 primary breast cancer patients.', 'Between 1986 and 1990, 621 patients with operable breast cancer were randomly assigned to receive fluorouracil (Roche SA, Basel, Switzerland) 500 mg/m2, epirubicin (Pharmacia SA, Milan, Italy) 50 mg/m2, and cyclophosphamide (Asta Medica AG, Frankfurt, Germany) 500 mg/m2 every 21 days (FEC 50) for six cycles (6 FEC 50); FEC 50 for three cycles (3 FEC 50); or the same regimen with epirubicin 75 mg/m2 (FEC 75) for three cycles (3 FEC 75)', 'Four hundred seventeen anthracycline-naive MBC patients were randomized to receive one of the following regimens: arm A: 11 cycles of fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC 75) every 21 days; arm B: four cycles of FEC 100 (same regimen but with epirubicin 100 mg/m(2)) then eight cycles of FEC 50 (epirubicin 50 mg/m(2)); and arm C: four cycles of FEC 100 then restart the same regimen at disease progression in case of prior response or stabilization.', 'The French Epirubicin Study Group carried out a randomized trial comparing epirubicin alone 75 mg/m2 with fluorouracil (5FU) 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 50 mg/m2 (FEC 50) and 5FU 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 75 mg/m2 (FEC 75) as first treatment for advanced breast cancer patients']

['Fluorouracil, epirubicin, and cyclophosphamide are included in the FEC-75 regimen. This chemotherapy regiment is used for breast cancer treatment.']

['fluorouracil', 'epirubicin', 'cyclophosphamide']

Which enzyme is crucial for protein function regulation and tumorigenesis by interacting with partners needed for sumoylation in the pathway?

['oylation and plays a central role by interacting with almost all of the partners required for sumoylation", "Here we demonstrate that the synaptic diffusion of Ubc9, the sole conjugating enzyme of the sumoylation pathway, is regulated by synaptic activity", "Here, we investigated inhibition of sumoylation as a novel antifibrotic approach.Sumoylation was inhibited by siRNA-mediated knockdown of the Small Ubiquitin-like MOdifiers (SUMO) E2-conjugating enzyme Ubc9, which is essential for sumoylation", "Here we have identified host cell proteins involved with the cellular SUMOylation pathway, SUMO-1 (small ubiquitin-like modifier) and UBC9, a SUMO-1 conjugating enzyme that interact with classical swine fever virus (CSFV) Core protein", "A new pathway that contributes to mutant CFTR degradation is mediated by the small heat shock protein, Hsp27, which cooperates with Ubc9, the E2 enzyme for SUMOylation, to selectively conjugate mutant CFTR with SUMO-2/3", "Using transfection of Ets-1 wildtype (WT) or its sumoylation deficient version (Ets-1 K15R/K227R), as well as WT or mutant proteins of the SUMO pathway, we further demonstrated that the E2 SUMO-conjugating enzyme Ubc9 and a E3 SUMO ligase, PIASy, can enhance Ets-1 sumoylation, while a SUMO protease, SENP1, can desumoylate Ets-1", "The results show that basal SUMO modification is required for stimuli-induced p100 phosphorylation and that blocking SUMOylation of p100, either by site-directed mutation or by short interfering RNA-targeted diminution of E2 SUMO-conjugating enzyme Ubc9, inhibits various physiological stimuli-induced p100 processing and ultimate activation of the alternative NF-kappaB pathway", "Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different E1-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme", "SUMO-conjugating enzyme E2 UBC9 mediates viral immediate-early protein SUMOylation in crayfish to facilitate reproduction of white spot syndrome virus.", "OBJECTIVE: To determine the role of ubiquitin-conjugating enzyme 9 (UBC9), a small ubiquitin-like modifier-conjugating enzyme, in cardiomyocyte protein quality control. ", "Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays a key role in tumorigenesis. ", "UBC9 is the only E2 conjugating enzyme involved in this process, and loss of UBC9 completely abolishes the SUMOylation pathway.", "Here we demonstrate that the synaptic diffusion of Ubc9, the sole conjugating enzyme of the sumoylation pathway, is regulated by synaptic activity.", "Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different E1-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme.", "Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1), Ubc9 (the only known conjugating enzyme for the sumoylation pathway) or HIF-1\\u03b1, augmented sumoylation of HIF-1\\u03b1, nucleus-bound translocation and enhanced transcriptional activity of HIF-1\\u03b1 in RVLM neurons took place preferentially during the pro-life phase of experimental brain death.", "In this study, we found that the SUMOylation pathway was involved in the DENV life cycle, since DENV replication was reduced by silencing the cellular gene Ubc9, which encodes the sole E2-conjugating enzyme required for SUMOylation.", "In this study, we revisited the role of Tax SUMOylation using a strategy based on the targeting of Ubc9, the unique E2 SUMO-conjugating enzyme.", "Taken together, these findings provide evidence for regulated sumoylation as a mechanism to modulate the activity of Tec1 and validate Ubc9 fusion-directed sumoylation as a useful approach for studying']

Ubiquitin-conjugating enzyme 9 (Ubc9)

[]

Which is the target of the drug Denosumab?

['Denosumab is a human monoclonal antibody which specifically blocks receptor activator of nuclear factor κB ligand and is a very potent antiresorptive drug. ', 'denosumab, a monoclonal antibody against RANKL', 'Denosumab is a human monoclonal antibody indicated for the treatment of osteoporosis in postmenopausal women with a high risk of fractures. ', 'Denosumab (Dmab) is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), which, through the prevention of the RANKL/RANK interaction, inhibits osteoclast-mediated bone resorption and significantly reduces the risk of vertebral, nonvertebral, and hip fractures. ']

['Denosumab (Dmab) is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL).']

['receptor activator of nuclear factor-κB ligand', 'RANKL']

What is the mechanism of action of Osimertinib?

['In addition, mutations leading to resistance to first-line EGFR and ALK TKIs can now be successfully inhibited by soon to be approved third-generation EGFR TKIs (osimertinib, rociletinib) and second-generation ALK TKIs (ceritinib, alectinib). ', 'Gefitinib, erlotinib, and afatinib are the EGFR tyrosine kinase inhibitors that are presently in clinical use. Understanding resistance mechanisms has led to the identification of a secondary mutational target, T790M, in more than half of patients, for which osimertinib has been approved. ', 'Third-generation EGFR TKIs against the T790M mutation have been in active clinical development. These agents include osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. ', 'PURPOSE: Osimertinib (AZD9291) 80\xa0mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure.', 'RECENT FINDINGS: Third-generation TKIs in clinical development include osimertinib, rociletinib, and HM61713.', 'In this study, we investigated the interaction between ABCB1 and osimertinib, a novel selective, irreversible third-generation EGFR TKI that has recently been approved by the U.S. Food and Drug Administration. ', 'Considering that osimertinib is a clinically approved third-generation EGFR TKI, our findings suggest that a combination therapy with osimertinib and conventional anticancer drugs may be beneficial to patients with MDR tumors.', 'In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo Our results showed that osimertinib significantly increased the sensitivity of ABCB1- and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. ', 'The potency of 1st (erlotinib), 2nd (afatinib) and 3rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR', 'Osimertinib (AZD9291, Tagrisso™), an oral, third-generation EGFR TKI, has been designed to target the EGFR T790M mutation, while sparing wild-type EGFR.', 'Early phase clinical data suggest the third generation EGFR TKIs such as osimertinib, rociletinib, and HM61713 are highly efficacious and well tolerated.', 'We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.']

['Osimertinib is a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation.']

[]

What is adhesive capsulitis

['Adhesive capsulitis (frozen shoulder) is a common cause of shoulder pain and disability', 'Adhesive capsulitis is characterized by painful, gradual loss of active and passive shoulder motion resulting from fibrosis and contracture of the joint capsule.', "Painful stiffening of the shoulder, 'frozen shoulder' is a common cause of shoulder pain and disability.", 'Current adhesive capsulitis was defined as restriction of external rotation and one or more additional directional restrictions with history of shoulder pain.', 'Adhesive capsulitis is a clinical syndrome of pain and severely decreased joint motion ("frozen shoulder") caused by thickening and contraction of the joint capsule and synovium.', 'Adhesive capsulitis is, in most cases, a self-limiting condition of poorly understood etiology that results in shoulder pain and large mobility deficits. ', 'Adhesive capsulitis of the shoulder is a condition of unknown etiology that results in the development of restriction of active and passive glenohumeral motion.', 'Adhesive capsulitis of the shoulder is an idiopathic condition characterized clinically by pain and limitation of movement']

['Adhesive capsulitis also known as "frozen shoulder" is characterized by painful, gradual loss of active and passive shoulder motion resulting from fibrosis and contracture of the joint capsule.']

[]

Is microRNA(miRNA) 30 involved in post-ischemic cardiac remodeling?

['The myocardium of the failing heart undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosi', 'Connective tissue growth factor (CTGF) is a key molecule in the process of fibrosis and therefore seems an attractive therapeutic target', 'CTGF is importantly regulated by 2 major cardiac microRNAs (miRNAs), miR-133 and miR-30.', 'the expression of both miRNAs was inversely related to the amount of CTGF in 2 rodent models of heart disease and in human pathological left ventricular hypertrophy. Second, in cultured cardiomyocytes and fibroblasts, knockdown of these miRNAs increased CTGF levels. Third, overexpression of miR-133 or miR-30c decreased CTGF levels, which was accompanied by decreased production of collagens.', 'miR-30 importantly limit the production of CTGF', 'miR-30 directly downregulate CTGF, a key profibrotic protein, and thereby establish an important role for these miRNAs in the control of structural changes in the extracellular matrix of the myocardium.']

['Myocardial remodeling after an ischemic insult involves extracellular matrix proteins with increased fibrosis\nInitial experimental data indicate that miRNA 30 decreases CTGF a key molecule in the process of fibrosis, by directly downregulating the production of CTGF']

['yes']

What is known as Von Hippel–Lindau disease or syndrome?

['Von Hippel-Lindau syndrome is an autosomal dominant inherited phacomatosis with a predisposition for the central nervous system and retina. There is variable expression with hemangioblastomas in the brain, medulla oblongata, spinal chord, renal carcinoma, pheochromocytoma, pancreatic cysts and islet cell tumors as well as tumors of the endolymphatic sac of the inner ear. Clinical symptoms occur first after an age of approximately 30\xa0years.', 'Von Hippel-Lindau Disease (VHL) is an autosomal dominant inherited systemic cancer syndrome that gives rise to cystic and highly vascularized tumors in many organs, including the eye.', 'Von Hippel-Lindau (VHL) disease is a hereditary, autosomal dominant syndrome which is manifested by a range of different benign and malignant tumors. This disease can present with different clinical presentations such as; retinal angioma (RA), hemangioblastoma (HB) of the central nervous system (CNS), pheochromocytoma (Pheo), and epididymal cystadenoma. Tumors are usually accompanied with cysts.', 'von Hippel-Lindau (VHL) disease is an autosomal-dominant familial cancer syndrome associated with mutations of the VHL tumor suppressor gene (3p25-26). Its estimated incidence ranges from 1 in 36,000 to 1 in 53,000 with a penetrance of up to 95% by age 60. Genotype-phenotype correlation divides VHL into two broad clinical subtypes. Type 1 VHL is predominantly associated with large deletion or truncation mutations which result in an encoded protein with very little or no activity. It is associated with retinal and CNS hemangioblastoma and renal cell carcinoma but not pheochromocytoma. Type 2 is usually associated with missense mutations encoding a protein with limited activity and includes pheochromocytoma. It is further classified into three other subtypes (2A, 2B, 2C) based on the presence of hemangioblastoma and renal cell carcinoma. Visceral cysts in the kidney, pancreas and epididymis, nonfunctioning pancreatic neuroendocrine tumors which often show distinctive clear cell cytology, endolymphatic sac tumors and head and neck paragangliomas are well recognized but less common presenting features.', 'von Hippel-Lindau (VHL) disease is an inheritable multisystem tumor syndrome characterized by multiple benign and malignant tumors affecting multiple organs. VHL is the result of a germline mutation in the VHL tumor suppressor gene. Molecular genomic analysis routinely confirms the clinical diagnosis.', 'Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome (1/36,000 live births) with highly penetrance that predispose to the development of a panel of highly vascularized tumors (model of tumoral angiogenesis). Main manifestations include central nervous system (CNS) and retinal haemangioblastomas, endolymphatic sac tumors, clear-cell renal cell carcinomas (RCC), phaeochromocytomas and pancreatic neuroendocrine tumors.', 'Von Hippel-Lindau (VHL) disease is an inherited syndrome caused by germline mutations in the VHL tumor suppressor gene, predisposing to a variety of neoplasms including pancreatic neuroendocrine tumors (PanNET). ', 'Von Hippel-Lindau disease is an autosomal dominant disorder involving the development of specific tumours in multiple organs, both benign and malignant. In the CNS, the syndrome is characterized by haemangioblastomas of the retina, spinal cord and brain. ', 'Patients with von Hippel-Lindau disease (VHL) often harbor significant disease burden within the CNS, specifically craniospinal-axis hemangioblastomas and endolymphatic sac tumors (ELSTs). The majority (60-80%) of patients with VHL harbor hemangioblastomas, and 10-15% will develop ELSTs.', 'Von Hippel-Lindau (VHL) syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs.', 'von Hippel-Lindau disease (VHL) disease increases susceptibility to several malignancies, including renal cell carcinoma, haemangioblastomas of the central nervous system or retina and phaeochromocytomas. The VHL tumour suppressor gene, responsible for the disease, encodes for a major regulator of the hypoxic response by targeting the transcription factor hypoxia inducible factor (HIF) for degradation.', 'Von Hippel-Lindau syndrome (VHLS) is an autosomal dominant familial cancer syndrome arising from germ-line inactivation of the VHL gene on the short arm of chromosome 3. VHLS manifests in a myriad of hyper-vascular tumors of both benign and malignant nature. Incidence of VHLS is roughly 1 in 36,000 live births and has over 90% penetrance by the age of 65. ', 'Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene is responsible for the development of renal carcinomas, pheochromocytomas and tumours in other organs. The gene product (pVHL) is a central component in the oxygen-sensing pathway through its role in the regulation of the hypoxia-inducible factor (HIF). Loss of pVHL leads to activation of the HIF pathway in normoxia with the concomitant increase in tumour vascularisation due to the up-regulation of pro-angiogenic genes.', 'Germ line inactivation of the von-Hippel-Lindau (VHL) tumor suppressor gene causes von Hippel-Lindau hereditary cancer syndrome, and somatic mutations of this gene have been linked to the development of sporadic hemangioblastomas and clear cell renal carcinomas. The protein encoded by VHL, pVHL, has no known enzymatic activities but interacts with various partner proteins.', 'pVHL acts as a multi-purpose adaptor protein that controls different gene expression programs. Through its oxygen-dependent regulation of hypoxia-inducible factor alpha (HIFalpha), pVHL plays a central role in the oxygen-sensing pathway. In addition, many HIFalpha-independent functions of pVHL have recently been identified. These include microtubule-based processes, extracellular matrix assembly and suppression of kidney cyst formation. ', 'von Hippel-Lindau (VHL) disease is an inherited multisystem familial cancer syndrome caused by mutations of the VHL gene on chromosome 3p25. A wide variety of neoplastic processes are known to be associated with VHL disease. ', 'von Hippel-Lindau (VHL) disease is a rare, autosomal dominantly inherited multisystem disorder characterized by development of a variety of benign and malignant tumors. The spectrum of clinical manifestations of the disease is broad and includes retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renal cysts and tumors, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas. The most common causes of death in VHL disease patients are renal cell carcinoma and neurologic complications from cerebellar hemangioblastomas. ', 'Von Hippel-Lindau disease (VHL disease) is a hereditary cancer predisposition syndrome caused by mutations of the von Hippel-Lindau tumor suppressor gene.', 'von Hippel-Lindau disease is an inherited, multisystemic cancer syndrome often involving the retina.', 'von Hippel-Lindau (VHL) disease is an autosomal-dominant familial cancer syndrome associated with mutations of the VHL tumor suppressor gene (3p25-26).', 'Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome (1/36,000 live births) with highly penetrance that predispose to the development of a panel of highly vascularized tumors (model of tumoral angiogenesis).', 'Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome with a variety of benign and malignant tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renal cysts and tumors, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas.', 'Von Hippel-Lindau (VHL) disease type 2A is an inherited tumor syndrome characterized by predisposition to pheochromocytoma (pheo), retinal hemangioma (RA), and central nervous system hemangioblastoma (HB).', 'von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germ line mutation of the von Hippel-Lindau tumor suppressor gene (VHL).', 'von Hippel-Lindau (VHL) disease is an inherited multisystem familial cancer syndrome caused by mutations of the VHL gene on chromosome 3p25.', 'von Hippel-Lindau (VHL) disease is an inherited multisystem familial cancer syndrome caused by mutations of the VHL gene on chromosome 3p25', 'von Hippel-Lindau disease is an inherited, multisystemic cancer syndrome often involving the retina', 'Von Hippel-Lindau disease is an inherited syndrome of multiorgan neoplasia caused by a germline mutation in the von Hippel-Lindau gene and can include central nervous system tumors, renal cell carcinomas and benign pancreatic cystic tumors.', 'von Hippel-Lindau (VHL) disease is a dominantly inherited, multisystemic tumor syndrome caused by mutations in the VHL gene.']

['von Hippel-Lindau (VHL) disease is a rare, autosomal dominantly inherited multisystem disorder characterized by development of a variety of benign and malignant tumors, which are usually accompanied with cysts. The spectrum of clinical manifestations of the disease is broad and includes retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renal cysts and tumors, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas. The most common causes of death in VHL disease patients are renal cell carcinoma and neurologic complications from cerebellar hemangioblastomas. von Hippel-Lindau (VHL) syndrome is associated with mutations of the VHL tumor suppressor gene (3p25-26). Its estimated incidence ranges from 1 in 36,000 to 1 in 53,000 with a penetrance of up to 95% by age 60. The VHL tumour suppressor gene, responsible for the disease, encodes for a major regulator of the hypoxic response by targeting the transcription factor hypoxia inducible factor (HIF) for degradation. Loss of pVHL leads to activation of the HIF pathway in normoxia with the concomitant increase in tumour vascularisation due to the up-regulation of pro-angiogenic genes.In addition, many HIFalpha-independent functions of pVHL have recently been identified. These include microtubule-based processes, extracellular matrix assembly and suppression of kidney cyst formation.', 'VHL is the result of a germline mutation in the VHL tumor suppressor gene. Loss of pVHL leads to activation of the HIF pathway in normoxia with the concomitant increase in tumour vascularisation due to the up-regulation of pro-angiogenic genes. These include microtubule-based processes, extracellular matrix assembly and suppression of kidney cyst formation. Clinical symptoms occur first after an age of approximately 30\xa0years. Main manifestations include central nervous system (CNS) and retinal haemangioblastomas, endolymphatic sac tumors, clear-cell renal cell carcinomas (RCC), phaeochromocytomas and pancreatic neuroendocrine tumors. Type 1 VHL is predominantly associated with large deletion or truncation mutations which result in an encoded protein with very little or no activity. It is further classified into three other subtypes (2A, 2B, 2C) based on the presence of hemangioblastoma and renal cell carcinoma. In addition, many HIFalpha-independent functions of pVHL have recently been identified. It is associated with retinal and CNS hemangioblastoma and renal cell carcinoma but not pheochromocytoma. Incidence of VHLS is roughly 1 in 36,000 live births and has over 90% penetrance by the age of 65. ']

[]

Which is the underlying mechanism for exon skipping used to treat Duchenne muscular dystrophy?

['Antisense-mediated exon skipping therapy is a promising therapeutic approach that uses short DNA-like molecules called antisense oligonucleotides (AOs) to skip over/splice out the mutated part of the gene to produce a shortened but functional dystrophin protein', 'many DMD patients need exon skipping of multiple exons in order to restore the reading frame, depending on how many base pairs the mutated exon(s) and adjacent exons have. Theoretically, multiple exon skipping could be used to treat approximately 90%, 80%, and 98% of DMD patients with deletion, duplication, and nonsense mutations, respectively', 'Antisense oligonucleotides (AONs) that bind to complementary sequences of the dystrophin pre-mRNA to induce skipping of the targeted exon by modulating pre-mRNA splicing are promising therapeutic agents for DMD. Such AONs can restore the open reading frame of the DMD gene and produce internally deleted, yet partially functional dystrophin protein isoforms in skeletal muscle', "Of all novel molecular interventions currently being investigated for Duchenne muscular dystrophy, perhaps the most promising method aiming to restore dystrophin expression to diseased cells is known as 'exon skipping' or splice-modulation, whereby antisense oligonucleotides eliminate the deleterious effects of DMD mutations by modulating dystrophin pre-messenger RNA splicing, such that functional dystrophin protein is produced.", 'We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection', 'Using antisense oligonucleotides (AONs), the disrupted DMD reading frame is restored, allowing generation of partially functional dystrophin and conversion of a severe Duchenne into a milder Becker muscular dystrophy phenotype. ', 'Using antisense oligonucleotides (AONs) targeting specific exons the DMD reading frame is restored and partially functional dystrophins are produced. ']

['Antisense-mediated exon skipping therapy is a promising therapeutic approach that uses short DNA-like molecules called antisense oligonucleotides (AOs) to skip over/splice out the mutated part of the gene to produce a shortened but functional dystrophin protein. Many Duchenne Muscular Dystrophy patients need exon skipping of multiple exons in order to restore the reading frame, depending on how many base pairs the mutated exon(s) and adjacent exons have.', 'Antisense-mediated exon skipping therapy is a promising therapeutic approach that uses short DNA-like molecules called antisense oligonucleotides (AOs) to skip over/splice out the mutated part of the gene to produce a shortened but functional dystrophin protein ', 'Antisense-mediated exon skipping therapy is a promising therapeutic approach that uses short DNA-like molecules called antisense oligonucleotides (AOs) to skip over/splice out the mutated part of the gene to produce a shortened but functional dystrophin protein', 'Antisense oligonucleotides (AONs) that bind to complementary sequences of the dystrophin pre-mRNA to induce skipping of the targeted exon by modulating pre-mRNA splicing are promising therapeutic agents for DMD. In addition, multiple exon skipping could be used to select deletions that optimize the functionality of the truncated dystrophin protein. Theoretically, multiple exon skipping could be used to treat approximately 90%, 80%, and 98% of DMD patients with deletion, duplication, and nonsense mutations, respectively. One major challenge has been its limited applicability.']

[]

How are GRBs (Genomic Regulatory Blocks) defined?

['Reporter insertions distal to zebrafish developmental regulatory genes pax6.1/2, rx3, id1, and fgf8 and miRNA genes mirn9-1 and mirn9-5 recapitulate the expression patterns of these genes even if located inside or beyond bystander genes, suggesting that the regulatory domain of a developmental regulatory gene can extend into and beyond adjacent transcriptional units. We termed these chromosomal segments genomic regulatory blocks (GRBs).', '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', 'Although gene order in hox and other gene clusters has long been known to be conserved because of shared regulatory sequences or overlapping transcriptional units, the chromosomal areas found through insertional hotspots contain only one or a few developmental regulatory genes as well as phylogenetically unrelated genes. We have termed these regions genomic regulatory blocks (GRBs), and show that they underlie the phenomenon of conserved synteny through all sequenced vertebrate genomes.', 'Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region.', 'The target genes are most often transcription factors involved in embryonic development and differentiation.', "GRBs often contain extensive gene deserts, as well as additional 'bystander' genes intertwined with HCNEs but whose expression and function are unrelated to those of the target gene. ", 'We show evidence that GRB target genes have properties that set them apart from their bystanders as well as other genes in the genome: longer CpG islands, a higher number and wider spacing of alternative transcription start sites, and a distinct composition of transcription factor binding sites in their core/proximal promoters.', 'GRB targets are genes with a number of unique features that are the likely cause of their ability to respond to regulatory inputs from very long distances', 'Genomic regulatory blocks are chromosomal regions spanned by long clusters of highly conserved noncoding elements devoted to long-range regulation of developmental genes, often immobilizing other, unrelated genes into long-lasting syntenic arrangements.', 'Specifically, we discuss the recently discovered genomic regulatory blocks which we argue are principal units of vertebrate genome evolution and serve as the foundations onto which evolutionary innovations are built through sequence evolution and insertion of new cis-regulatory elements.', 'We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. ', 'Using a comparative genomics approach to reconstruct the fate of genomic regulatory blocks (GRBs) and identify exonic remnants that have survived the disappearance of their host genes after whole-genome duplication (WGD) in teleosts, we discover a set of 38 candidate cis-regulatory coding exons (RCEs) with predicted target genes. ', 'They are therefore functionally related to a number of key protein coding developmental genes, that form genomic regulatory blocks (GRBs) with arrays of highly conserved non-coding elements (HCNEs) functioning as long-range enhancers that collaboratively regulate the expression of their target genes.', ' In this paper, we therefore systematically investigate the regulatory landscape around conserved self-transcribed miRNAs (ST miRNAs), with their own known or computationally inferred promoters, by analyzing the hallmarks of GRB target genes', 'Based on these results we used both an elevated HCNE density in the genomic vicinity as well as the presence of a bivalent promoter to identify 29 putative GRB target miRNAs/miRNA clusters, over two-thirds of which are known to play a role during development and differentiation.', 'Furthermore these predictions include miRNAs of the miR-9 family, which are the only experimentally verified GRB target miRNAs.', 'A subset of the conserved miRNA loci we investigated exhibits typical characteristics of GRB target genes, which may partially explain their complex expression profiles during development.', 'Developmental genes are regulated by complex, distantly located cis-regulatory modules (CRMs), often forming genomic regulatory blocks (GRBs) that are conserved among vertebrates and among insects.', 'We have investigated GRBs associated with Iroquois homeobox genes in 39 metazoans. ', 'Integrating sequence conservation, gene expression data, gene function, epigenetic marks, and other genomic features, we provide extensive evidence that many conserved ancient linkages involve (1) the coordinated transcription of neighboring genes, or (2) genomic regulatory blocks (GRBs) in which transcriptional enhancers controlling developmental genes are contained within nearby bystander genes.', 'As most of them occur as clusters near potential target genes, the database is organized along two hierarchical levels: individual UCNEs and ultra-conserved genomic regulatory blocks (UGRBs). ', 'Detailed synteny maps between the human and other genomes are provided for all UGRBs.', 'Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region.', 'Integrating sequence conservation, gene expression data, gene function, epigenetic marks, and other genomic features, we provide extensive evidence that many conserved ancient linkages involve (1) the coordinated transcription of neighboring genes, or (2) genomic regulatory blocks (GRBs) in which transcriptional enhancers controlling developmental genes are contained within nearby bystander genes.', 'We have termed these regions genomic regulatory blocks (GRBs), and show that they underlie the phenomenon of conserved synteny through all sequenced vertebrate genomes.', 'They are therefore functionally related to a number of key protein coding developmental genes, that form genomic regulatory blocks (GRBs) with arrays of highly conserved non-coding elements (HCNEs) functioning as long-range enhancers that collaboratively regulate the expression of their target genes.', 'These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes.', 'The Sonic Hedgehog (Shh) genomic regulatory block (GRB) is one of the best functionally characterized examples, with several discrete enhancers reported within its introns, vast upstream gene-free region and neighboring genes (Lmbr1 and Rnf32).', 'BACKGROUND: Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. ', 'These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. ', 'Developmental genes are regulated by complex, distantly located cis-regulatory modules (CRMs), often forming genomic regulatory blocks (GRBs) that are conserved among vertebrates and among insects.']

["Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. The target genes are most often transcription factors involved in embryonic development and differentiation. GRBs often contain extensive gene deserts, as well as additional 'bystander' genes intertwined with HCNEs but whose expression and function are unrelated to those of the target gene.", 'Genomic regulatory blocks are chromosomal regions spanned by long clusters of highly conserved noncoding elements devoted to long-range regulation of developmental genes, often immobilizing other, unrelated genes into long-lasting syntenic arrangements. Integrating sequence conservation, gene expression data, gene function, epigenetic marks, and other genomic features, we provide extensive evidence that many conserved ancient linkages involve (1) the coordinated transcription of neighboring genes, or (2) genomic regulatory blocks (GRBs) in which transcriptional enhancers controlling developmental genes are contained within nearby bystander genes. Although gene order in hox and other gene clusters has long been known to be conserved because of shared regulatory sequences or overlapping transcriptional units, the chromosomal areas found through insertional hotspots contain only one or a few developmental regulatory genes as well as phylogenetically unrelated genes. In addition, we generated ChIP-seq data for key histone modifications in zebrafish embryos, which provided further evidence of putative GRBs in embryonic development.', 'Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. ']

[]

Is p100 the precursor protein molecule of the NF-kappaB transcription factor subunit p50?

['We previously reported that alymphoplasia (aly/aly) mice, which have a natural loss-of-function mutation in the Nik gene, which encodes a kinase essential for the processing of p100 to p52 in the alternative nuclear factor-κB (NF-κB) pathway, show mild osteopetrosis with an increase in several parameters of bone formation: ', 'Proteolytic processing of the nuclear factor (NF)-kappaB2 precursor protein p100 generates the active NF-kappaB2 subunit p52, which in turn transcriptionally up-regulates p100 expression. ', 'The mammalian Rel/NF-kappaB family of transcription factors, including RelA, c-Rel, RelB, NF-kappaB1 (p50 and its precursor p105), and NF-kappaB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation.', 'NF-kappaB functions as a hetero- or homo-dimer which can be formed from five NF-kappaB subunits, NF-kappaB1 (p50 and its precursor p105), NF-kappaB2 (p52 and its precursor p100), RelA (p65), RelB and c-Rel.', 'The non-canonical pathway based on processing of NF-kappaB2 precursor protein p100 to generate p52 plays a critical role in controlling B cell function and lymphoid organogenesis.', 'Processing of NF-kappaB2 precursor protein p100 to generate p52 is tightly controlled, which is important for proper function of NF-kappaB.', 'Processing of NF-kappa B2 precursor protein p100 to generate p52 is tightly regulated. ', 'Processing of the NF-kappaB2 precursor protein p100 to generate p52 is an important step of NF-kappaB regulation.', 'Targeted disruption of the Rel/NF-kappaB family members NF-kappaB2, encoding p100/p52, and RelB in mice results in anatomical defects of secondary lymphoid tissues.', 'Here, we show that in T cells infected with the human T-cell leukemia virus (HTLV), IKKalpha is targeted to a novel signaling pathway that mediates processing of the nfkappab2 precursor protein p100, resulting in active production of the NF-kappaB subunit, p52.', 'nfkb2 encodes two members of the NF-kappa B/Rel family of proteins: p52 and p100. The p100 polypeptide has been proposed to serve as a precursor of p52, which corresponds to the N-terminal half of p100.', 'In most cells, small amounts of p52 are produced relative to the levels of p100, unlike the usually balanced production of nfkb1-derived p50 and p105. ', 'The alternative or second pathway proceeded via NF-kappaB-inducing kinase (NIK)-, IKKalpha-, and protein synthesis-dependent processing of the inhibitory NF-kappaB2 p100 precursor protein to the p52 form and resulted in a delayed but sustained activation of primarily RelB-containing NF-kappaB dimers.', 'In one exceptional case, generation of the p50 subunit of the transcriptional regulator NF-kappaB, the precursor protein p105 is processed in a limited manner: the N-terminal domain yields the p50 subunit, whereas the C-terminal domain is degraded', 'Proteolytic processing of the p105 precursor (NF-kappa B1) generates the p50 subunit of NF-kappa B', 'p105 (NFKB1) acts in a dual way as a cytoplasmic IkappaB molecule and as the source of the NF-kappaB p50 subunit upon processing', 'The p50 subunit of NF-kappa B is derived from the amino terminus of a 105 kilodalton precursor', 'Regulation of the transcription factor NF-kappaB involves proteasome-mediated processing of the NF-kappaB1 p105 precursor protein, which generates the p50 subunit of NF-kappaB', 'This effort identified NF-kappaB1 (p105), an atypical IkappaB molecule and the precursor of NF-kappaB subunit p50', 'NF-kappaB functions as a hetero- or homo-dimer which can be formed from five NF-kappaB subunits, NF-kappaB1 (p50 and its precursor p105), NF-kappaB2 (p52 and its precursor p100), RelA (p65), RelB and c-Rel', 'The mammalian Rel/NF-kappaB family of transcription factors, including RelA, c-Rel, RelB, NF-kappaB1 (p50 and its precursor p105), and NF-kappaB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation']

['No, the precursor molecule for NF-kappaB p50 is p105 and not p100. Nfkb2 encodes two members of the NF-kappa B/Rel family of proteins: p52 and p100. The p100 polypeptide has been proposed to serve as a precursor of p52 (and not of p50), which corresponds to the N-terminal half of p100. NF-kappaB functions as a hetero- or homo-dimer which can be formed from five NF-kappaB subunits, NF-kappaB1 (p50 and its precursor p105), NF-kappaB2 (p52 and its precursor p100), RelA (p65), RelB and c-Rel.']

['no']