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Structural alterations in cardiac calcium release units resulting from overexpression of junctin. Junctin is a 26 kDa membrane protein that binds to calsequestrin, triadin, and ryanodine receptors (RyRs) within the junctional sarcoplasmic reticulum of calcium release units. The sequence of junctin includes a short N-terminal cytoplasmic domain a single transmembrane domain, and a highly charged C-terminal domain located in the sarcoplasmic reticulum lumen. Dog and mouse junctins are highly conserved at the transmembrane domains, but the luminal domains are more divergent. To probe the contribution of junctin to the architecture of calcium release units in heart, we engineered transgenic mice overexpressing canine junctin and examined the left ventricular myocardium by electron microscopy. Overall architecture of calcium release units is similar in control myocardium and in myocardium overexpressing junctin by 5-10-fold. In both myocardia, junctional SR cisternae are closely associated with exterior membranes (plasmalemma and transverse tubules). The cisternae are flat; they contain a string of calsequestrin beads and are lined by a row of feet, or RyRs, on the side facing the exterior membranes. T tubule surface density, measured as the perimeter of T tubule profiles v area of section, is the same in transgenic and control myocardia (305 v 289 nm/nm(2)). Three changes affecting the junctional SR architecture are apparent in the myocardium overexpressing junctin. One is a more tightly zippered appearance of the junctional SR cisternae. The width of the junctional SR is narrower and less variable in overexpressing than in control myocardium and the calsequestrin content is more compact. A second change is the extension of zippered junctional SR domains to non-junctional regions, which we term "frustrated" junctional SR. A third change is an increase in the extent of association between SR and T tubules. In junctin overexpressing myocardium junctional SR cisternae cover approximately 45% of the surface of all T tubule profiles, while in control myocardium the coverage approximately 30%. Junctional associations between SR and T tubules are increased in size. We conclude that the increase in junctin expression affects the packing of calsequestrin in the junctional SR and facilitates the association of SR and T tubules. | Is there a relationship between junctin and ryanodine receptors? | 52b2f3b74003448f5500000c_005 | yes |
The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase. Depressed Ca-handling in cardiomyocytes is frequently attributed to impaired sarcoplasmic reticulum (SR) function in human and experimental heart failure. Phospholamban (PLN) is a key regulator of SR and cardiac function, and PLN mutations in humans have been associated with dilated cardiomyopathy (DCM). We previously reported the deletion of the highly conserved amino acid residue arginine 14 (nucleic acids 39, 40 and 41) in DCM patients. This basic amino acid is important in maintaining the upstream consensus sequence for PKA phosphorylation of Ser 16 in PLN. To assess the function of this mutant PLN, we introduced the PLN-R14Del in cardiac myocytes of the PLN null mouse. Transgenic lines expressing mutant PLN-R14Del at similar protein levels to wild types exhibited no inhibition of the initial rates of oxalate-facilitated SR Ca uptake compared to PLN-knockouts (PLN-KO). The contractile parameters and Ca-kinetics also remained highly stimulated in PLN-R14Del cardiomyocytes, similar to PLN-KO, and isoproterenol did not further stimulate these hyper-contractile basal parameters. Consistent with the lack of inhibition on SR Ca-transport and contractility, confocal microscopy indicated that the PLN-R14Del failed to co-localize with SERCA2a. Moreover, PLN-R14Del did not co-immunoprecipitate with SERCA2a (as did WT-PLN), but rather co-immunoprecipitated with the sarcolemmal Na/K-ATPase (NKA) and stimulated NKA activity. In addition, studies in HEK cells indicated significant fluorescence resonance energy transfer between PLN-R14Del-YFP and NKAα1-CFP, but not with the NKA regulator phospholemman. Despite the enhanced cardiac function in PLN-R14Del hearts (as in PLN-knockouts), there was cardiac hypertrophy (unlike PLN-KO) coupled with activation of Akt and the MAPK pathways. Thus, human PLN-R14Del is misrouted to the sarcolemma, in the absence of endogenous PLN, and alters NKA activity, leading to cardiac remodeling. | Can PLN mutations lead to dilated cardiomyopathy? | 5148e42cd24251bc0500003b_012 | yes |
Compromised metabolic recovery following spontaneous spreading depression in the penumbra. Spreading depression (SD) has been demonstrated following focal ischemia, and the additional workload imposed by SD on a tissue already compromised by a marked reduction in blood flow may contribute to the evolution of irreversible damage in the ischemic penumbra. SD was elicited in one group of rats by injecting KCl directly into a frontal craniectomy and the wave of depolarization was recorded in two craniectomies 3 and 6 mm posterior to the first one. In a second group, the middle cerebral artery was occluded using the monofilament technique and a recording electrode was placed 5 mm lateral to the midline and 0.2 mm posterior to bregma. To determine the metabolic response in the penumbral region of the cortex ipsilateral to the occlusion, brains from both groups were frozen in situ when the deflection of the SD was maximal. The spatial metabolic response of SD in the ischemic cortex was compared to that in the non-ischemic cortex. Coronal sections of the brains were lyophilized, pieces of the dorsolateral cortex were dissected and weighed, and analyzed for ATP, P-creatine, inorganic phosphate (Pi), glucose, glycogen and lactate at varying distances anterior and posterior to the recording electrode. ATP and P-creatine levels were significantly decreased at the wavefront in both groups and the levels recovered after passage of the wavefront in the normal brain, but not in the ischemic brain. Glucose and glycogen levels were significantly decreased and lactate levels significantly increased in the tissue after the passage of the wavefront. While the changes in the glucose-related metabolites persisted during recovery even in anterior portions of the cortex in both groups in the aftermath of the SD, the magnitude of the changes was greater in the penumbra than in the normal cortex. SD appears to impose an equivalent increase in energy demands in control and ischemic brain, but the ability of the penumbra to recover from the insult is compromised. Thus, increasing the energy imbalance in the penumbra after multiple SDs may hasten the deterioration of the energy status of the tissue and eventually contribute to terminal depolarization and cell death, particularly in the penumbra. | Does cortical spreading depression appear in ischemic penumbra following ischemic stroke? | 514b335dd24251bc05000061_007 | yes |
Altered microRNA regulation in Huntington's disease models. Huntington's disease (HD) is a genetic neurodegenerative disease caused by abnormal CAG expansion. MicroRNAs (miRNAs) are short RNA molecules regulating gene expression, and are implicated in a variety of diseases including HD. However, the profiles and regulation of miRNAs in HD are not fully understood. Here, we analyzed the miRNA expression and miRNA regulators in two transgenic models of HD, YAC128 and R6/2 mice, and in a 3-nitropropionic acid (3NP)-induced striatal degeneration rat model. After characterizing the phenotypes by behavioral tests and histological analyses, we profiled striatal miRNAs using a miRNA microarray and we measured the key molecules involved in miRNA biogenesis and function. YAC128 mice showed upregulation-dominant miRNA expressions at 5 months and downregulation-dominant expressions at 12 months. Concomitantly, the expressions of Drosha-DGCR8, Exportin-5, and Dcp1 were increased at 5months, and the expression of Dicer was decreased at 12 months. In 10-week-old R6/2 mice, downregulation was dominant in the miRNA expressions and the level of Drosha decreased concomitantly. Nine miRNAs (miR-22, miR-29c, miR-128, miR-132, miR-138, miR-218, miR-222, miR-344, and miR-674*) were commonly down-regulated in both the 12-month-old YAC128 and 10-week-old R6/2 mice. Meanwhile, 3NP rats showed dynamic changes in the miRNA profiles during disease development and a few miRNAs with altered expression. Our results show that transgenic HD mice have abnormal miRNA biogenesis. This information should aid in future studies on therapeutic application of miRNAs in HD. | Is the microRNA 132 (miR-132) involved in brain pathologies? | 5156be5ed24251bc05000087_003 | yes |
Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation. | Is the gene DUX4 epigenetically regulated in somatic cells? | 55152c2946478f2f2c000005_003 | yes |
JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. The Polycomb group (PcG) proteins have an important role in controlling the expression of genes essential for development, differentiation and maintenance of cell fates. The Polycomb repressive complex 2 (PRC2) is believed to regulate transcriptional repression by catalysing the di- and tri-methylation of lysine 27 on histone H3 (H3K27me2/3). At present, it is unknown how the PcG proteins are recruited to their target promoters in mammalian cells. Here we show that PRC2 forms a stable complex with the Jumonji- and ARID-domain-containing protein, JARID2 (ref. 4). Using genome-wide location analysis, we show that JARID2 binds to more than 90% of previously mapped PcG target genes. Notably, we show that JARID2 is sufficient to recruit PcG proteins to a heterologous promoter, and that inhibition of JARID2 expression leads to a major loss of PcG binding and to a reduction of H3K27me3 levels on target genes. Consistent with an essential role for PcG proteins in early development, we demonstrate that JARID2 is required for the differentiation of mouse embryonic stem cells. Thus, these results demonstrate that JARID2 is essential for the binding of PcG proteins to target genes and, consistent with this, for the proper differentiation of embryonic stem cells and normal development. | Does Jarid2 play a role in early embryo development? | 5883781b2305cd7e21000001_002 | yes |
FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth. Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer. | Are the Fanconi anemia genes a part of the same signalling pathway? | 54f42f2764850a5854000005_002 | yes |
NOD1 expression is increased in the adipose tissue of women with gestational diabetes. Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies, complicated by gestational diabetes mellitus (GDM). 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). The aim of this study was to determine whether levels of NOD1 and NOD2 are increased in adipose tissue of women with GDM. The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed. NOD1, but not NOD2, expression was higher in omental and subcutaneous adipose tissues obtained from women with GDM when compared with those from women with normal glucose tolerance (NGT). In both omental and subcutaneous adipose tissues from NGT and GDM women, the NOD1 ligand g-d-glutamyl-meso-diaminopimelic acid (iE-DAP) significantly induced the expression and secretion of the pro-inflammatory cytokine interleukin 6 (IL6) and chemokine IL8; COX2 (PTGS2) gene expression and subsequent prostaglandin production; the expression and secretion of the extracellular matrix remodelling enzyme matrix metalloproteinase 9 (MMP9) and the gene expression and secretion of the adhesion molecules ICAM1 and VCAM1. There was no effect of the NOD2 ligand muramyl dipeptide on any of the endpoints tested. The effects of the NOD1 ligand iE-DAP were mediated via NFκB, as the NFκB inhibitor BAY 11-7082 significantly attenuated iE-DAP-induced expression and secretion of pro-inflammatory cytokines, COX2 gene expression and subsequent prostaglandin production, MMP9 expression and secretion and ICAM1 and VCAM1 gene expression and secretion. In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM. | Is NOD1 activated in inflammation? | 57091eefcf1c325851000016_004 | yes |
C-reactive protein as predictor for poor outcome after aneurysmal subarachnoid haemorrhage. BACKGROUND: Aneurysmal subarachnoid haemorrhage (SAH) is a severe disease with high case-fatality and morbidity rates. After SAH, the value of C-reactive protein (CRP)--an acute phase sensitive inflammatory marker--as a prognostic factor has been poorly studied, with conflicting results. In this prospective study, we tested whether increased CRP levels increase independently the risk for cerebral infarct and poor outcome. METHODS: Previous diseases as well as clinical, laboratory and radiological variables were recorded for 178 patients with SAH admitted within 48 h and with aneurysms occluded within 60 h after bleeding. Plasma CRP was measured, as well as computed tomography (CT) scans routinely obtained on admission, in the morning after aneurysm occlusion, and at discharge during second week after SAH. Factors predicting occurrence of cerebral infarct and poor outcome at 3 months after SAH were tested with multiple logistic regression. RESULTS: CRP levels increased significantly (p < 0.001) between hospital admission (mean ± SD, 11.4 ± 21.3 mg/l) and the postoperative morning (27.0 ± 31.0 mg/l) and then decreased (p < 0.001) during the the second week (19.8 ± 25.0 mg/l). Admission (18.0 ± 35.7 vs 8.5 ± 8.4 mg/l) and postoperative (41.0 ± 40.2 vs 21.1 ± 24.1 mg/l) CRP levels were higher (p < 0.001) in those with a poor outcome than in those with a favourable outcome, but CRP values did not predict delayed cerebral ischaemia or cerebral infarction. CRP levels did not independently predict outcome, since these correlated with admission clinical grade and occurrence of intraventricular haemorrhage. Higher increase in CRP level between admission and postoperative morning, however, independently predicted poor outcome (p = 0.004). Part of this increased risk was likely due to an appearance of early postoperative cerebral infarction. CONCLUSIONS: CRP levels correlate with outcome but do not seem to predict delayed cerebral ischaemia or infarction after SAH. | Is there an association between c-reactive protein concentrations and outcomes of subarachnoid hemorrhage patients? | 514cbbf9d24251bc05000065_004 | yes |
Relationship between cerebral injury and inflammatory responses in patients undergoing cardiac surgery with cardiopulmonary bypass. This study was performed to evaluate whether cytokines, adhesion molecules, ghrelin and S-100B are useful markers in predicting the cerebral infarction after cardiac surgery with cardioplumomary bypass (CPB). The patients (n=20) were classified into two groups; group A (n=4) showed postoperative organized cerebral damage, while group B (n=16) consisted of patients without occurrence of postoperative strokes. Before CPB, serum levels of S-100B in both groups A and B were low (<0.5 ng/mL), while ghrelin concentrations in group A (all patients had history of strokes) were much higher than those in group B. After CPB, when serum levels of S-100B in group A at 24h were higher than those in group B, ghrelin in group A at same time point showed high levels in comparison to group B. At 12 and 24h after CPB, levels of tumor necrosis factor (TNF)-alpha, interleukin-10 and soluble TNF-receptor I in group A were significantly higher than those in group B. In conclusion, it is considered that ghrelin as well as S-100B can be a useful marker for the prediction of stoke after CPB. Increase of TNF-alpha, interleukin-10 and soluble TNF-receptor I after CPB may be involved in the pathogenesis of stroke after CPB. | Does ghrelin play a role in ischemic stroke? | 551c2c276b348bb82c00000c_005 | yes |
N-terminal proB-type natriuretic peptide (NT-proBNP) concentrations in elite rugby players at rest and after active and passive recovery following strenuous training sessions. BACKGROUND: The serum biomarker N-terminal proB-type natriuretic peptide (NT-proBNP), a cleaved fragment of the brain natriuretic peptide (BNP) precursor (amino acids 1-76), is accepted as a standard marker for evaluating and monitoring cardiac injury characterized by myocardial wall stress. Strenuous exercise may generate transitory ischemia, myocardial stress and diastolic left ventricular dysfunction, possibly inducing increased concentrations of NT-proBNP. A purported caveat to prolonged strenuous exercise is based on evidence for biochemical and structural signs of heart dysfunction in recreational athletes after continuous exertion. METHODS: We compared NT-proBNP levels in three groups of physically fit subjects: top-level rugby players, professional soccer players and healthy controls. NT-proBNP concentrations were measured at rest and after an intensive training session followed by two different recovery strategies (passive or active). RESULTS: A comparison of the three samples showed that NT-proBNP concentrations in the rugby players were lower than those in controls at rest and were similar to those in professional soccer players. Elevated post-training NT-proBNP levels were unaffected by the type of recovery. The relatively high NT-proBNP levels after active recovery when psychophysical stress is higher, because of cycling and cold water immersion, suggest that not only endurance exercise, but also strenuous, stressful short exercise can induce an increase in NT-proBNP concentrations. CONCLUSIONS: In this sample of professional athletes, NT-proBNP was low at rest, and the increase after physical exercise was physiological. | Does BNP increase after intensive exercise in athletes? | 531d2aa5267d7dd053000003_008 | yes |
Haplotypes of the human RET proto-oncogene associated with Hirschsprung disease in the Italian population derive from a single ancestral combination of alleles. The RET proto-oncogene is the major gene involved in the complex genetics of Hirschsprung disease (HSCR), or aganglionic megacolon, showing causative loss-of-function mutations in 15-30% of the sporadic cases. Several RET polymorphisms and haplotypes have been described in association with the disease, suggesting a role for this gene in HSCR predisposition, also in the absence of mutations in the coding region. Finally, the presence of a functional variant in intron 1 has repeatedly been proposed to explain such findings. Here we report a case-control study conducted on 97 Italian HSCR sporadic patients and 85 population matched controls, using 13 RET polymorphisms distributed throughout the gene, from the basal promoter to the 3'UTR. Linkage disequilibrium and haplotype analyses have shown increased recombination between the 5' and 3' portions of the gene and an over-representation, in the cases studied, of two haplotypes sharing a common allelic combination that extends from the promoter up to intron 5. We propose that these two disease-associated haplotypes derive from a single founding locus, extending up to intron 19 and successively rearranged in correspondence with a high recombination rate region located between the proximal and distal portions of the gene. Our results suggests the possibility that a common HSCR predisposing variant, in linkage disequilibrium with such haplotypes, is located further downstream than the previously suggested interval encompassing intron 1. | Is RET the major gene involved in Hirschsprung disease? | 5503121de9bde69634000019_002 | yes |
Magnesium sulfate in the management of patients with aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, dose-adapted trial. BACKGROUND: Recent studies suggest that high-dose MgSO4 therapy is safe and reduces the incidence of DIND and subsequent poor outcome after SAH. We intended to assess the safety and efficacy of high-dose MgSO4 therapy after SAH as means to prevent DIND and to evaluate the impact on clinical outcome. METHODS: This was a prospective, randomized, single-blind, placebo-controlled study. The MgSO4 infusion was adjusted every 12 hours until day 12 according to the target serum Mg2+ level. The occurrence of DIND, secondary infarction, side effects, and the outcome after 3 and 12 months were assessed. RESULTS: Fifty-eight patients were randomized; 27 received placebo and 31 MgSO4. The difference in occurrence of DIND and secondary infarction was not significant. The intention-to-treat analysis revealed a trend toward better outcome (P = .083) after 3 months. On-treatment analysis showed a significantly better outcome after 3 months (P = .017) and a trend toward better outcome after 1 year (P = .083). Significantly more often hypotension (P = .040) and hypocalcemia (P = .005) occurred as side effects in the treatment group. In 16 patients (52%), the MgSO4 therapy had to be stopped before day 12 because of side effects. No predictive factor leading to termination was found in a postrandomization analysis. CONCLUSIONS: High-dose MgSO4 therapy might be efficient as a prophylactic adjacent therapy after SAH to reduce the risk for poor outcome. Nevertheless, because of the high frequency of the side effects, patients should be observed in an intensive or intermediate care setting. | Does magnesium sulfate improve outcomes of subarachnoid hemorrhage patients? | 54d62ede3706e89528000002_003 | no |
Intrathecal administration of triptolide, a T lymphocyte inhibitor, attenuates chronic constriction injury-induced neuropathic pain in rats. Triptolide is a potent immunosuppressive drug capable of inhibiting T cell activation and proliferation. Recent studies show that T cells play an important role in neuropathic pain following nerve injury in rats. In this study, we investigated the effect of triptolide on T cell activation and development of neuropathic pain. Neuropathic pain by chronic constriction injury (CCI) was induced by loose ligation of the sciatic nerve in Sprague-Dawley rats. Triptolide (5 or 10 μg/kg) or vehicle (DMSO) was administered intrathecally after surgery for 7 days (n=8 per group). The right hind paw withdrawal threshold to von Frey filament stimuli and withdrawal latency to radiant heat were determined before and after the surgery (days 0 to 7). NF-κB activation and pro-inflammatory cytokine (TNF-α and IL-2) expression were determined by ELISA, Western blot, and real time-PCR. CCI of the sciatic nerve induced mechanical allodynia and thermal hyperalgesia in these rats. Intrathecal triptolide (5 and 10 μg/kg) suppressed the development of allodynia and thermal hyperalgesia. It also inhibited CCI-induced inflammation and T cell activation, by decreasing spinal cord TNF-α, IL-2 and NF-κB p65 levels. Motor dysfunction was not observed after triptolide treatment. In the present study, we demonstrated the suppressive effect of triptolide on the development of neuropathic pain. Therefore, triptolide could be a promising immunosuppressive agent in the treatment of neuropathic pain. Further studies are required to examine the safety of intrathecal triptolide for clinical application. | Do T-Cells regulate neuropathic pain? | 58c0825502b8c6095300001b_003 | yes |
TDP-43 is recruited to stress granules in conditions of oxidative insult. Transactive response DNA-binding protein 43 (TDP-43) forms abnormal ubiquitinated and phosphorylated inclusions in brain tissues from patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. TDP-43 is a DNA/RNA-binding protein involved in RNA processing, such as transcription, pre-mRNA splicing, mRNA stabilization and transport to dendrites. We found that in response to oxidative stress and to environmental insults of different types TDP-43 is capable to assemble into stress granules (SGs), ribonucleoprotein complexes where protein synthesis is temporarily arrested. We demonstrated that a specific aminoacidic interval (216-315) in the C-terminal region and the RNA-recognition motif 1 domain are both implicated in TDP-43 participation in SGs as their deletion prevented the recruitment of TDP-43 into SGs. Our data show that TDP-43 is a specific component of SGs and not of processing bodies, although we proved that TDP-43 is not necessary for SG formation, and its gene silencing does not impair cell survival during stress. The analysis of spinal cord tissue from ALS patients showed that SG markers are not entrapped in TDP-43 pathological inclusions. Although SGs were not evident in ALS brains, we speculate that an altered control of mRNA translation in stressful conditions may trigger motor neuron degeneration at early stages of the disease. | Are stress granules involved in the pathogenesis of Amyotrophic Lateral Sclerosis? | 56c81fd15795f9a73e00000c_015 | yes |
Thyronamines--past, present, and future. Thyronamines (TAMs) are a newly identified class of endogenous signaling compounds. Their structure is identical to that of thyroid hormone and deiodinated thyroid hormone derivatives, except that TAMs do not possess a carboxylate group. Despite some initial publications dating back to the 1950s, TAMs did not develop into an independent area of research until 2004, when they were rediscovered as potential ligands to a class of G protein-coupled receptors called trace-amine associated receptors. Since this discovery, two representatives of TAMs, namely 3-iodothyronamine (3-T(1)AM) and thyronamine (T(0)AM), have been detected in vivo. Intraperitoneal or central injection of 3-T(1)AM or T(0)AM into mice, rats, or Djungarian hamsters caused various prompt effects, such as metabolic depression, hypothermia, negative chronotropy, negative inotropy, hyperglycemia, reduction of the respiratory quotient, ketonuria, and reduction of fat mass. Although their physiological function remains elusive, 3-T(1)AM and T(0)AM have already revealed promising therapeutic potential because they represent the only endogenous compounds inducing hypothermia as a prophylactic or acute treatment of stroke and might thus be expected to cause fewer side effects than synthetic compounds. This review article summarizes the still somewhat scattered data on TAMs obtained both recently and more than 20 yr ago to yield a complete and updated picture of the current state of TAM research. | Have thyronamines effects on fat tissue? | 534bf050aeec6fbd07000015_000 | yes |
Role of the arabidopsis DRM methyltransferases in de novo DNA methylation and gene silencing. Proper DNA methylation patterning requires the complementary processes of de novo methylation (the initial methylation of unmethylated DNA sequences) and maintenance methylation (the faithful replication of preexisting methylation). Arabidopsis has two types of methyltransferases with demonstrated maintenance activity: MET1, which maintains CpG methylation and is homologous to mammalian DNMT1, and CHROMOMETHYLASE 3 (CMT3), which maintains CpNpG (N = A, T, C, or G) methylation and is unique to the plant kingdom. Here we describe loss-of-function mutations in the Arabidopsis DOMAINS REARRANGED METHYLASE (DRM) genes and provide evidence that they encode de novo methyltransferases. drm1 drm2 double mutants retained preexisting CpG methylation at the endogenous FWA locus but blocked de novo CpG methylation that is normally associated with FWA transgene silencing. Furthermore, drm1 drm2 double mutants blocked de novo CpNpG and asymmetric methylation and gene silencing of the endogenous SUPERMAN (SUP) gene, which is normally triggered by an inverted SUP repeat. However, drm1 drm2 double mutants did not show reactivation of previously established SUPERMAN epigenetic silenced alleles. Thus, drm mutants prevent the establishment but not the maintenance of gene silencing at FWA and SUP, suggesting that the DRMs encode the major de novo methylation enzymes affecting these genes. | Are chromomethylases present in animal genomes? | 5171833c8ed59a060a00000f_002 | no |
Papilin in development; a pericellular protein with a homology to the ADAMTS metalloproteinases. Papilin is an extracellular matrix glycoprotein that we have found to be involved in, (1) thin matrix layers during gastrulation, (2) matrix associated with wandering, phagocytic hemocytes, (3) basement membranes and (4) space-filling matrix during Drosophila development. Determination of its cDNA sequence led to the identification of Caenorhabditis and mammalian papilins. A distinctly conserved 'papilin cassette' of domains at the amino-end of papilins is also the carboxyl-end of the ADAMTS subgroup of secreted, matrix-associated metalloproteinases; this cassette contains one thrombospondin type 1 (TSR) domain, a specific cysteine-rich domain and several partial TSR domains. In vitro, papilin non-competitively inhibits procollagen N-proteinase, an ADAMTS metalloproteinase. Inhibiting papilin synthesis in Drosophila or Caenorhabditis causes defective cell arrangements and embryonic death. Ectopic expression of papilin in Drosophila causes lethal abnormalities in muscle, Malpighian tubule and trachea formation. We suggest that papilin influences cell rearrangements and may modulate metalloproteinases during organogenesis. | Is the protein Papilin secreted? | 54e25eaaae9738404b000017_001 | yes |
Ripples from neighbouring transcription. Transcriptional initiation of each gene is assumed to be independently controlled in mammals. On the other hand, recent large-scale transcriptome analyses have shown that the genome is pervasively transcribed, such that the most of its DNA gives rise to RNAs. This raises the question of whether it is possible to pinpoint and activate a particular locus without perturbing numerous neighbouring transcripts. Here we show that intensive transcription at one locus frequently spills over into its physical neighbouring loci. Rapid induction of immediate-early genes (IEGs) in response to growth factor stimulations is accompanied by co-upregulation of their neighbouring genes. Profiling the primary transcripts in the nucleus with whole-genome tiling arrays delineated simultaneous activation of transcription centred on IEGs. Even in surrounding intergenic regions, transcriptional activation took place at the same time. Acetylation levels of histone H3 and H4 are elevated along with the IEG induction and neighbouring co-upregulation. Inhibition of the mitogen-activated protein kinase (MAPK) pathway or the transcription factor SRF suppresses all transcriptional upregulation. These results suggest that transcriptional activation has a ripple effect, which may be advantageous for coordinated expression. | Do IEG create a ripple effect of transcription? | 58c276bc02b8c60953000020_000 | yes |
CYLD is a crucial negative regulator of innate immune response in Escherichia coli pneumonia. Bacteraemic pneumonia is a common cause of sepsis in critically ill patients today and is characterized by dysregulation of inflammation. The genetic factors predisposing to bacteraemic pneumonia are not yet fully understood. Innate immunity is pivotal for host defence against invading bacteria, and nuclear factor-kappa B (NF-kappaB) is central to bacteria-induced inflammation and immune responses. The deubiquitinating enzyme CYLD has been identified as a key negative regulator for NF-kappaB. In the present study, we investigated the role of CYLD in innate immune response in Escherichia coli pneumonia. Upon E. coli inoculation, Cyld(-/-) mice were hypersusceptible to E. coli pneumonia with higher mortality. Innate immune response to E. coli was enhanced in Cyld(-/-) cells and mice. Cyld(-/-) cells exhibited enhanced NF-kappaB activation upon E. coli inoculation, and the enhanced NF-kappaB activation by E. coli was abolished by perturbing IkappaB kinase (IKK) signalling. Furthermore, IKK inhibitor rescued Cyld(-/-) mice from lethal infection during E. coli pneumonia along with reduced inflammation. Taken together, these data showed that CYLD acts as a crucial negative regulator for E. coli pneumonia by negatively regulating NF-kappaB. These findings provide novel insight into the regulation of bacteraemic pneumonia and related diseases and may help develop novel therapeutic strategies for these diseases. | Is the protein product of the cylindromatosis gene (CYLD) a deubiquitinating enzyme? | 550aef0ec2af5d5b7000000a_020 | yes |
Stretch current-induced abnormal impulses in CaMKIIδ knockout mouse ventricular myocytes. BACKGROUND: CaMKII activation is proarrhythmic in heart failure where myocardium is stretched. However, the arrhythmogenic role of CaMKII in stretched ventricle has not been well understood. OBJECTIVE: We tested abnormal impulse inducibility by stretch current in myocytes isolated from CaMKIIδ knockout (KO) mouse left ventricle (LV) where CaMKII activity is reduced by = 62%. METHODS AND RESULTS: Action potentials were recorded by whole-cell patch clamp, and abnormal impulses were induced in LV myocytes by a simulation of stretch-activated channel (SAC) current. SAC activation failed to induce abnormal impulses in wild type (WT) myocytes but steadily produced early after-depolarizations and automaticity in KO myocytes in which an increase in L-type calcium channel (LTCC) current (I(Ca)) and a reduction of sarcoplasmic reticulum Ca(2+) leak and action potential duration (APD) were observed. The abnormal impulses were not suppressed by CaMKII inhibitor AIP whereas a low concentration of nifedipine eliminated abnormal impulses without shortening APD, implicating I(Ca) in promoting stretch-induced abnormal impulses. In addition, APD prolongation by LTCC opener S(-)Bay K 8644 or isoproterenol facilitated abnormal impulse induction in WT ventricular myocytes even in the presence of CaMKII inhibitor AIP, whereas APD prolongation by K(+) channel blocker 4-aminopyridine promoted abnormal impulses in KO myocytes but not in WT myocytes. CONCLUSION: I(Ca) activation plays a central role in stretch-induced abnormal impulses and APD prolongation is arrhythmogenic only when I(Ca) is highly activated. At increased I(Ca) activation, CaMKII inhibition cannot suppress abnormal impulse induction. | Is Calcium/Calmodulin dependent protein kinase II (CaMKII) involved in cardiac arrhythmias and heart failure? | 5502abd1e9bde69634000008_016 | yes |
Formin-like 2 Promotes β1-Integrin Trafficking and Invasive Motility Downstream of PKCα. Regulated turnover of integrin receptors is essential for cell adhesion and migration. Pathways selectively regulating β1-integrin recycling are implicated in cancer invasion and metastasis, yet proteins required for the internalization of this pro-invasive integrin remain to be identified. Here, we uncover formin-like 2 (FMNL2) as a critical regulator of β1-integrin internalization downstream of protein kinase C (PKC). PKCα associates with and phosphorylates FMNL2 at S1072 within its Diaphanous autoregulatory region, leading to the release of formin autoinhibition. Phosphorylation of FMNL2 triggers its rapid relocation and promotes its interaction with the cytoplasmic tails of the α-integrin subunits for β1-integrin endocytosis. FMNL2 drives β1-integrin internalization and invasive motility in a phosphorylation-dependent manner, while a FMNL2 mutant defective in actin assembly interferes with β1-integrin endocytosis and cancer cell invasion. Our data establish a role for FMNL2 in the regulation of β1-integrin and provide a mechanistic understanding of the function of FMNL2 in cancer invasiveness. | Is the protein β1-integrin recycled? | 56e5b445edfc094c1f000001_004 | yes |
A case-control study of stroke risk factors and outcomes in African American stroke patients with and without crack-cocaine abuse. BACKGROUND: Stroke in crack-cocaine abusers is increasingly recognized. We aimed to identify significant differences in stroke risk factors, characteristics, and outcomes between hospitalized stroke patients with and without crack-cocaine abuse. METHODS: This was a retrospective study that compared stroke patients with crack-cocaine abuse (cases) to stroke patients without crack-cocaine (controls). RESULTS: We identified 93 crack-cocaine cases and 93 controls admitted between January 2004 and May 2006 to one teaching hospital. There were significant differences between crack-cocaine cases and controls in age (48.7 years vs. 55 years) (P = 0.0001), male gender (65.6% vs. 40.9%) (odds ratios, OR = 1.64, 95% CI 1.22-2.21), arterial hypertension (61.1% vs. 83.9%) (OR = 0.30, 95% CI 0.15-0.60), hypercholesterolemia (18.7% vs. 68.5%) (OR = 0.10, 95% CI 0.05-0.21), diabetes (20.9% vs. 41.9%) (OR = 0.36, 95% CI 0.19-0.70), cigarette smoking (70.6% vs. 29%) (OR = 5.86, 95% CI 3.07-11.20), ischemic stroke (61.3% vs. 79.6%) (OR = 0.40, 95% CI 0.21-0.78), and intracerebral hemorrhage (33.3% vs. 17.2%) (OR = 3.03, 95% CI 1.53-6.00). Also, there were significant differences in National Institutes of Health Stroke Scale scores (3.3 vs. 7) (P < 0.0001), and MRS scores (1.8 vs. 2.5) (P = 0.0022) at hospital discharge. Using univariable and multivariable logistic regression, we found that crack-cocaine abusers had 2.28 higher odds of having a favorable functional outcome (MRS score < 2) at hospital discharge, after adjusting for stroke risk factors and characteristics. CONCLUSIONS: Our study suggests that crack-cocaine abusers with stroke had fewer traditional risk factors, and more favorable functional outcome as compared to non-crack-cocaine abusers. | Is cocaine use associated with increased risk for intracerebral hemorrhage? | 5159b990d24251bc050000a3_006 | yes |
Impaired Na+,K+ATPase activity in red blood cells in euthyroid women treated with levothyroxine after total thyroidectomy for Graves' disease. In patients suffering from hyperthyroidism dependent on Graves' disease, a reduction in Na+,K+ATPase activity has been demonstrated in red blood cells (RBCs), as well as an inverse correlation between this enzymatic action and free triiodothyronine (FT3) levels. The restoration of normal FT3 values also brings about a normalization of Na+,K+ATPase activity in erythrocytes. These results have made it possible to hypothesize that the thyroid hormones control Na+,K+ATPase activity and that this control is manifested by means of variations in the number of ouabain-binding sites. For this reason, the measurement of the activity of the Na/K pump can be considered as a further indicator of the peripheral effects of thyroid hormones. With a view to assess the relation between the course of treated hyperthyroidism and Na+,K+ATPase activity during antithyroid therapy and after surgical thyroidectomy followed by replacement therapy, we studied 24 patients affected by Graves' disease (group Graves [GG]). They were compared with 24 female Graves' patients who underwent total thyroidectomy for nontoxic and diffuse nodular goiter (NDNG) (group control [GC]) and with 24 normal healthy women (group normal [GN]). When Graves' hyperthyroidism was diagnosed, the Na+,K+ATPase activity in RBCs was impaired in all GG patients. Thionamide treatment restored the normal activity of the Na/K pump, accompanied by normalization of the number of ouabain-binding sites. One hundred eighty days after thyroidectomy, in conditions of clinical and biochemical euthyroidism due to replacement therapy with levothyroxine, the activity of Na+,K+ATPase in RBCs was once again reduced in GG, while appearing normal in GC and GN (1.77 +/- 0.16 mmol Pi h(-1) L(-1) RBCs v 2.09 +/- 0.26 v 2.09 +/- 0.24, P < .05). Different instrumental or biochemical parameters, such as glycemia, serum lipids, ions, serum alkaline phosphatase (AIPh), serum creatine phosphokinase (CPK), blood pressure, and heart rate, were evaluated and appeared normalized in GG and GC 180 days after surgery. We conclude that (1) in patients suffering from Graves' disease, subjected to total thyroidectomy followed by levothyroxine replacement therapy, there is a reduction in the activity of the Na+,K+ATPase on erythrocytes 6 months after the surgical approach; and (2) a similar alteration is not observed in patients subjected to thyroidectomy for NDNG. These findings allow the formulation of the hypothesis that (1) treatment with levothyroxine for 180 days after thyroidectomy in GG is not long enough to restore the normality of all the peripheral indicators of action of the thyroid hormones; and (2) levothyroxine replacement therapy is unable to guarantee euthyroidism in all the tissues in GG (eg, during hematopoiesis in the bone marrow). | Does triiodothyronine stimulate red blood cell sodium potassium pump? | 517a8a718ed59a060a00003e_001 | no |
Differential regulation of M3/6 (DUSP8) signaling complexes in response to arsenite-induced oxidative stress. Mitogen-activated protein kinase (MAPK) cascades are involved in the regulation of cellular proliferation, differentiation, survival, apoptosis, as well as in inflammatory responses. Signal intensity and duration have been recognized as crucial parameters determining MAPK signaling output. Phosphatases play a particularly important role in this respect, by tightly controlling MAPK phosphorylation and activation. M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs and is found in a complex with these kinases, along with other pathway components, held together by scaffold proteins. The JNK family consists of three genes, giving rise to at least ten different splice variants. Some functional differences between these gene products have been demonstrated, but the underlying molecular mechanisms and the roles of individual splice variants are still incompletely understood. We have investigated the interaction of M3/6 with JNK isoforms, as well as scaffold proteins of the JNK interacting protein (JIP) family, in order to elucidate the contribution of M3/6 to the regulation of distinct JNK signaling modules. M3/6 exhibited stronger binding towards JNK1β and JNK2α isoforms and this was reflected in higher enzymatic activity towards JNK2α2 when compared to JNK1α1 in vitro. After activation of the pathway by exposure of cells to arsenite, the interaction of M3/6 with JNK1α and JNK3 was enhanced, whereas that with JNK1β or JNK2α decreased. The modulation of binding affinities was found to be independent of JNK-mediated M3/6 phosphorylation. Furthermore, arsenite treatment resulted in an inducible recruitment of M3/6 to JNK-interacting protein 3 (JIP3) scaffold complexes, while its interaction with JIP1 or JIP2 was constitutive. The presented data suggest an isoform-specific role for the M3/6 phosphatase and the dynamic targeting of M3/6 towards distinct JNK-containing signaling complexes. | Is protein M3/6 a dual specificity phosphatase? | 5512cce26a8cde6b7200000c_001 | yes |
Differential ubiquitination defines the functional status of the tumor suppressor Smad4. Smad4 is an essential signal transducer of all transforming growth factor-beta (TGF-beta) superfamily pathways that regulate cell growth and differentiation, and it becomes inactivated in human cancers. Receptor-activated (R-) Smads can be poly-ubiquitinated in the cytoplasm or the nucleus, and this regulates their steady state levels or shutdown of the signaling pathway. Oncogenic mutations in Smad4 and other Smads have been linked to protein destabilization and proteasomal degradation. We analyzed a panel of missense mutants derived from human cancers that map in the N-terminal Mad homology (MH) 1 domain of Smad4 and result in protein instability. We demonstrate that all mutants exhibit enhanced poly-ubiquitination and proteasomal degradation. In contrast, wild type Smad4 is a relatively stable protein that undergoes mono- or oligo-ubiquitination, a modification not linked to protein degradation. Analysis of Smad4 deletion mutants indicated efficient mono- or oligo-ubiquitination of the C-terminal MH2 domain. Mass spectrometric analysis of mono-ubiquitinated Smad4 MH2 domain identified lysine 507 as a major target for ubiquitination. Lysine 507 resides in the conserved L3 loop of Smad4 and participates in R-Smad C-terminal phosphoserine recognition. Mono- or oligo-ubiquitinated Smad4 exhibited enhanced ability to oligomerize with R-Smads, whereas mutagenesis of lysine 507 led to inefficient Smad4/R-Smad hetero-oligomerization and defective transcriptional activity. Finally, overexpression of a mutant ubiquitin that only leads to mono-ubiquitination of Smad4 enhanced Smad transcriptional activity. These data suggest that oligo-ubiquitination positively regulates Smad4 function, whereas poly-ubiquitination primarily occurs in unstable cancer mutants and leads to protein degradation. | Is there any protein that undergoes both mono-ubiquitination and poly-ubiquitination? | 530c7cfd970c65fa6b00000c_004 | yes |
Spreading depression in focal ischemia: a computational study. When a cerebral infarction occurs, surrounding the core of dying tissue there usually is an ischemic penumbra of nonfunctional but still viable tissue. One current but controversial hypothesis is that this penumbra tissue often eventually dies because of the metabolic stress imposed by multiple cortical spreading depression (CSD) waves, that is, by ischemic depolarizations. We describe here a computational model of CSD developed to study the implications of this hypothesis. After simulated infarction, the model displays the linear relation between final infarct size and the number of CSD waves traversing the penumbra that has been reported experimentally, although damage with each individual wave progresses nonlinearly with time. It successfully reproduces the experimental dependency of final infarct size on midpenumbra cerebral blood flow and potassium reuptake rates, and predicts a critical penumbra blood flow rate beyond which damage does not occur. The model reproduces the dependency of CSD wave propagation on N-methyl-D-aspartate activation. It also makes testable predictions about the number, velocity, and duration of ischemic CSD waves and predicts a positive correlation between the duration of elevated potassium in the infarct core and the number of CSD waves. These findings support the hypothesis that CSD waves play an important causal role in the death of ischemic penumbra tissue. | Does cortical spreading depression appear in ischemic penumbra following ischemic stroke? | 514b335dd24251bc05000061_005 | yes |
Mammalian target of rapamycin (mTOR) inhibition: potential for antiseizure, antiepileptogenic, and epileptostatic therapy. New epilepsy treatments are needed that not only inhibit seizures symptomatically (antiseizure) but also prevent the development of epilepsy (antiepileptogenic). The mammalian target of rapamycin (mTOR) pathway may mediate mechanisms of epileptogenesis and serve as a rational therapeutic target. mTOR inhibitors have antiepileptogenic and antiseizure effects in animal models of the genetic disease, tuberous sclerosis complex. The mTOR pathway is also implicated in epileptogenesis in animal models of acquired epilepsy and infantile spasms, although the effects of mTOR inhibitors are variable depending on the specific conditions and model. Furthermore, beneficial effects on seizures are lost when treatment is withdrawn, suggesting that mTOR inhibitors are "epileptostatic" in only stalling epilepsy progression during treatment. Clinical studies of rapamycin in human epilepsy are limited, but suggest that mTOR inhibitors at least have antiseizure effects in tuberous sclerosis patients. Further studies are needed to assess the full potential of mTOR inhibitors for epilepsy treatment. | Is Tuberous Sclerosis a genetic disease? | 52b06a68f828ad283c000005_008 | yes |
Zyxin is a transforming growth factor-β (TGF-β)/Smad3 target gene that regulates lung cancer cell motility via integrin α5β1. Although TGF-β acts as a tumor suppressor in normal tissues and in early carcinogenesis, these tumor suppressor effects are lost in advanced malignancies. Single cell migration and epithelial-mesenchymal transition (EMT), both of which are regulated by TGF-β, are critical steps in mediating cancer progression. Here, we sought to identify novel direct targets of TGF-β signaling in lung cancer cells and have indentified the zyxin gene as a target of Smad3-mediated TGF-β1 signaling. Zyxin concentrates at focal adhesions and along the actin cytoskeleton; as such, we hypothesized that cytoskeletal organization, motility, and EMT in response to TGF-β1 might be regulated by zyxin expression. We show that TGF-β1 treatment of lung cancer cells caused rapid phospho-Smad3-dependent expression of zyxin. Zyxin expression was critical for the formation and integrity of cell adherens junctions. Silencing of zyxin decreased expression of the focal adhesion protein vasodilator-activated phospho-protein (VASP), although the formation and morphology of focal adhesions remained unchanged. Zyxin-depleted cells displayed significantly increased integrin α5β1 levels, accompanied by enhanced adhesion to fibronectin and acquisition of a mesenchymal phenotype in response to TGF-β1. Zyxin silencing led to elevated integrin α5β1-dependent single cell motility. Importantly, these features are mirrored in the K-ras-driven mouse model of lung cancer. Here, lung tumors revealed decreased levels of both zyxin and phospho-Smad3 when compared with normal tissues. Our data thus demonstrate that zyxin is a novel functional target and effector of TGF-β signaling in lung cancer. By regulating cell-cell junctions, integrin α5β1 expression, and cell-extracellular matrix adhesion, zyxin may regulate cancer cell motility and EMT during lung cancer development and progression. | Is zyxin a focal adhesion protein? | 54f4b319d0d681a040000005_013 | yes |
Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Down syndrome (DS) is a major cause of mental retardation and heart disease. Although it is usually caused by the presence of an extra chromosome 21, a subset of the diagnostic features may be caused by the presence of only band 21q22. We now present evidence that significantly narrows the chromosomal region responsible for several of the phenotypic features of DS. We report a molecular and cytogenetic analysis of a three-generation family containing four individuals with clinical DS as manifested by the characteristic facial appearance, endocardial cushion defect, mental retardation, and probably dermatoglyphic changes. Autoradiograms of quantitative Southern blots of DNAs from two affected sisters, their carrier father, and a normal control were analyzed after hybridization with two to six unique DNA sequences regionally mapped on chromosome 21. These include cDNA probes for the genes for CuZn-superoxide dismutase (SOD1) mapping in 21q22.1 and for the amyloid precursor protein (APP) mapping in 21q11.2-21.05, in addition to six probes for single-copy sequences: D21S46 in 21q11.2-21.05, D21S47 and SF57 in 21q22.1-22.3, and D21S39, D21S42, and D21S43 in 21q22.3. All sequences located in 21q22.3 were present in three copies in the affected individuals, whereas those located proximal to this region were present in only two copies. In the carrier father, all DNA sequences were present in only two copies. Cytogenetic analysis of affected individuals employing R and G banding of prometaphase preparations combined with in situ hybridization revealed a translocation of the region from very distal 21q22.1 to 21qter to chromosome 4q. Except for a possible phenotypic contribution from the deletion of chromosome band 4q35, these data provide a molecular definition of the minimal region of chromosome 21 which, when duplicated, generates the facial features, heart defect, a component of the mental retardation, and probably several of the dermatoglyphic changes of DS. This region may include parts of bands 21q22.2 and 21q22.3, but it must exclude the genes S0D1 and APP and most of band 21q22.1, specifically the region defined by S0D1, SF57 and D21S47. | Down's syndrome occurs when an individual has an extra copy or part of a copy of chromosome 21, yes or no? | 5a76016683b0d9ea6600000d_012 | yes |
Tretinoin therapy in photoageing: historical perspective. Tretinoin was shown in the late 1960s to be useful for the treatment of disorders associated with abnormal epithelial differentiation; however, because of irritation, retinoids were only slowly accepted. In the 1970s, evidence accumulated to show that topical tretinoin could modulate many of the abnormalities in the epidermis and dermis associated with photoageing. It has been shown in hairless mice that tretinoin can reverse dermal elastosis with the formation of new collagen and this has led to clinical trials being carried out in man. Randomized, controlled trials have shown that topical tretinoin is effective in the treatment of photoaged skin. | Is tretinoin effective for photoaging? | 5a68f2bab750ff4455000017_006 | yes |
Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. BACKGROUND AND OBJECTIVES: Voltage-sensitive calcium channel conductance is essential for the nervous system to signal a painful event. However, intrathecal administration of L-type calcium channel blockers does not provide analgesia. The present investigation was designed to assess the safety and analgesic efficacy of ziconotide, a new N-type calcium channel blocker, when administered intrathecally to patients with acute postoperative pain. METHODS: This randomized, double-blind, pilot study included patients undergoing elective total abdominal hysterectomy, radical prostatectomy, or total hip replacement. After intrathecal injection of local anesthetic and before surgical incision, a continuous intrathecal infusion of either placebo or 1 of 2 doses of ziconotide (0.7 microg/h or 7.0 microg/h) was started and continued for 48 to 72 hours postoperatively. Primary and secondary efficacy variables were the mean daily patient controlled analgesia (PCA) morphine equivalent consumption and visual analog pain intensity (VASPI) scores, respectively. RESULTS: Thirty patients received study drug; 26 were evaluable for efficacy. Mean daily PCA morphine equivalent consumption was less in patients receiving ziconotide than in placebo-treated patients, and the difference was statistically significant between 24 and 48 hours (P = .040). VASPI scores during the first 8 hours postoperatively were markedly lower in ziconotide-treated than in placebo-treated patients. In 4 of 6 patients receiving the high-dose of ziconotide (7 microg/h), adverse events, such as dizziness, blurred vision, nystagmus, and sedation contributed to study drug being discontinued after 24 hours. After ziconotide discontinuation, these symptoms resolved. CONCLUSIONS: Ziconotide showed analgesic activity, as shown by decreased PCA morphine equivalent consumption and lower VASPI scores. Because of a favorable trend of decreased morphine consumption with an acceptable side-effect profile in the low-dose ziconotide group, 0.7 microg/h may be closer to the ideal dose than 7 microg/h. Large-scale studies are required to clarify this issue. | Does ziconotide bind to N-type calcium channels? | 56cf27293975bb303a000003_009 | yes |
Interstitial pneumonitis probably induced by cyclophosphamide in nephrosis. A case of interstitial shadows associated with oral cyclophosphamide therapy in a 32-month-old girl with steroid-resistant nephrotic syndrome, who was admitted to the Nishi-Kobe Medical Center with systemic edema, is reported. Due to the lack of response to prednisolone, cyclophosphamide was also administered orally at a dose of 3 mg/kg per day, 4 weeks after the start of steroid therapy. Approximately 3 weeks after the combination treatment she developed a fever, dry cough and cyanosis. Radiographic examination showed diffuse ground-glass shadow in both lungs, presumably indicating that she had interstitial pneumonitis. Her pulmonary signs and symptoms deteriorated despite various antimicrobial treatments. A discontinuation of cyclophosphamide and the administration of high-dose methylprednisolone yielded a dramatic improvement. These findings suggest that the diffuse pulmonary disease in this case was induced by cyclophosphamide. Since interstitial pneumonitis may be fatal and irreversible, attention should be paid to this rare complication even in patients undergoing low-dose oral cyclophosphamide treatment. | Is edema a symptom of nephrotic syndrome? | 58da270d8acda34529000013_004 | yes |
The protomap is propagated to cortical plate neurons through an Eomes-dependent intermediate map. The cortical area map is initially patterned by transcription factor (TF) gradients in the neocortical primordium, which define a "protomap" in the embryonic ventricular zone (VZ). However, mechanisms that propagate regional identity from VZ progenitors to cortical plate (CP) neurons are unknown. Here we show that the VZ, subventricular zone (SVZ), and CP contain distinct molecular maps of regional identity, reflecting different gene expression gradients in radial glia progenitors, intermediate progenitors, and projection neurons, respectively. The "intermediate map" in the SVZ is modulated by Eomes (also known as Tbr2), a T-box TF. Eomes inactivation caused rostrocaudal shifts in SVZ and CP gene expression, with loss of corticospinal axons and gain of corticotectal projections. These findings suggest that cortical areas and connections are shaped by sequential maps of regional identity, propagated by the Pax6 → Eomes → Tbr1 TF cascade. In humans, PAX6, EOMES, and TBR1 have been linked to intellectual disability and autism. | Is there any role of TBR1 in autism? | 58965ed478275d0c4a000010_006 | yes |
Monocular deprivation delays the dynamic changes of phosphorylated synapsin Ia/b at site-1 in contralateral visual cortex of juvenile mice. Synapsins as a family of presynaptic terminal phosphoprotein participates in neuronal development, but their role in the synaptic plasticity of visual cortex is unclear. In this study, the impact of monocular deprivation (MD) on dynamic changes of isoform-specific protein expression and site 1 phosphorylation of synapsins in visual cortex of the postnatal mice were observed by using the technique of Western blot analysis. The results showed that the total (T-) protein levels of synapsins including the isoform of Ia/b, IIa/b and IIIa were about 21-26% of adult level in visual cortex of mice at postnatal 7 days (P7), and then the T-synapsin Ia/b and IIb could quickly reach adult level at P35. However, the T-synapsin IIa and IIIa increased more slowly (71-74% at P35), and then kept increasing in the visual cortex of mice at P60. Unlike to the changes of T-synapsins, the level of phosphorylated (P-) synapsin Ia/b (not IIa/b and IIIa) at site 1 increased with development to the highest level at P21, and then decreased rapidly to a low level in visual cortex of mice at P35-60. In addition, we found that the levels of P-synapsin Ia/b increased significantly in left visual cortex of P28 and P35 (not P21 and P42) mice with 1-week MD of right eye; and no significant changes of T-synapsins were observed in both left and right sides of visual cortex in P21-42 mice with MD treatment. These results suggested that the isoform-specific protein expression and site-1 phosphorylation of synapsins might play a different role in the synaptic plasticity of visual cortex, and MD delays the dynamic changes of phosphorylated synapsin Ia/b at site-1 in contralateral visual cortex of juvenile mice. | Is synapsin a phosphoprotein? | 58a8962338c171fb5b000007_000 | yes |
Modafinil and unconstrained motor activity in schizophrenia: double-blind crossover placebo-controlled trial. Avolition affects quality of life in chronic schizophrenia. We investigated the effect of modafinil upon unconstrained motor activity in 18 male patients. In a randomised crossover design study, wrist-worn actigraphic monitors were used to objectively record motor activity over a 20 h period. Patients' total activity was significantly greater when given the drug. These data suggest that modafinil increases quantifiable motor behaviour in schizophrenia and may have an impact on avolition. | Was modafinil tested for schizophrenia treatment? | 54fc845e6ea36a810c000005_018 | yes |
A multicenter cohort study of pregnancy outcomes among women with laboratory-confirmed H1N1 influenza. OBJECTIVE: To evaluate associations between laboratory-confirmed 2009 H1N1 influenza infection and obstetric and neonatal outcomes. STUDY DESIGN: A multicenter cohort study was performed comparing laboratory-confirmed cases of 2009 H1N1 infection during pregnancy (N=142) with matched controls (N=710). Subanalysis was also performed comparing severely infected (hospitalized) women with controls. RESULT: No outcome differences were noted in comparing all women with H1N1 with controls. Women with severe infection had a higher incidence of delivering a small for gestational age (SGA) infant: 18.8% (6/32) versus 7.4% (52/707), adjusted odds ratio 2.35 (95% confidence interval 1.03, 5.36, P=0.02). Mean birth weight was 3013.0 g among severely infected women and 3223.3 g in controls (P=0.08), and incidence of preterm delivery was 25.0% (8/32) and 11.6% (82/710) (P=0.08), respectively. CONCLUSION: Pregnant women with mild clinical illness secondary to 2009 H1N1 were not at a greater risk of adverse pregnancy outcomes. However, severely infected women were more likely to deliver SGA infants. | Is pregnancy an additional risk during during H1N1 infection? | 531a3fe3b166e2b806000038_008 | yes |
Accelerated growth in the absence of DNA replication origins. DNA replication initiates at defined sites called origins, which serve as binding sites for initiator proteins that recruit the replicative machinery. Origins differ in number and structure across the three domains of life and their properties determine the dynamics of chromosome replication. Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins. Initiation mechanisms that rely on homologous recombination operate in some viruses. Here we show that such mechanisms also operate in archaea. We use deep sequencing to study replication in Haloferax volcanii and identify four chromosomal origins of differing activity. Deletion of individual origins results in perturbed replication dynamics and reduced growth. However, a strain lacking all origins has no apparent defects and grows significantly faster than wild type. Origin-less cells initiate replication at dispersed sites rather than at discrete origins and have an absolute requirement for the recombinase RadA, unlike strains lacking individual origins. Our results demonstrate that homologous recombination alone can efficiently initiate the replication of an entire cellular genome. This raises the question of what purpose replication origins serve and why they have evolved. | Do all archaea possess multiple origins of DNA replication? | 5547d72ef35db75526000008_003 | no |
High flow nasal cannula for respiratory support in preterm infants. BACKGROUND: High flow nasal cannulae (HFNC) are small, thin, tapered cannulae used to deliver oxygen or blended oxygen and air at flow rates of > 1 L/min. HFNC can be used to provide high concentrations of oxygen and may deliver positive end-expiratory pressure. OBJECTIVES: To compare the safety and efficacy of HFNC with other forms of non-invasive respiratory support in preterm infants. SEARCH STRATEGY: The strategy included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010), MEDLINE, CINAHL, EMBASE and abstracts from conference proceedings. SELECTION CRITERIA: Randomised or quasi-randomised trials comparing HFNC with other non-invasive forms of respiratory support in preterm infants immediately after birth or following extubation. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed by the authors. Relative risk, risk difference and number needed to treat were calculated. MAIN RESULTS: Four studies were identified for inclusion in the review. The studies differed in the interventions compared (nasal continuous positive airway pressure (CPAP), humidified HFNC, non-humidified HFNC), the flow rates provided and the indications for respiratory support. Meta-analysis and subgroup analysis were not possible. When used as primary respiratory support after birth, one trial found similar rates of treatment failure in infants treated with HFNC and nasal CPAP. Following extubation, one trial found that infants treated with HFNC had a significantly higher rate of reintubation than those treated with nasal CPAP. Another trial found similar rates of reintubation for humidified and non-humidified HFNC, and the fourth trial found no difference between two different models of equipment used to deliver humidified HFNC. AUTHORS' CONCLUSIONS: There is insufficient evidence to establish the safety or effectiveness of HFNC as a form of respiratory support in preterm infants. When used following extubation, HFNC may be associated with a higher rate of reintubation than nasal CPAP. Further adequately powered randomised controlled trials should be undertaken in preterm infants comparing HFNC with nasal CPAP and with other means of respiratory support; or of support following extubation. These trials should measure clinically important outcomes. | Are high-flow nasal cannulae effective for treatment of preterm infants? | 530cf4c54a5037880c000002_009 | yes |
Nonestrogen treatment modalities for vasomotor symptoms associated with menopause. OBJECTIVE: To systematically review the literature regarding the efficacy and safety of nonestrogen treatments for menopause-associated vasomotor symptoms not due to cancer or chemotherapy. DATA SOURCES: Pertinent literature and clinical studies were identified by searching MEDLINE (1966-February 2004) and EMBASE (1959-February 2004) using the key search terms vasomotor symptoms, hot flashes, and menopause. Bibliographies of relevant articles were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: English-language articles reporting efficacy and safety of nonestrogen treatment modalities for perimenopausal and postmenopausal vasomotor symptoms were evaluated. All articles identified from the data sources were evaluated, and all information deemed relevant was included. Emphasis was placed on randomized, double-blind, placebo-controlled clinical trials, as these provide the best efficacy and safety data. Studies evaluating treatment of vasomotor symptoms from other causes, such as cancer or chemotherapy, were excluded. DATA SYNTHESIS: Prescription medications reviewed for efficacy and safety in postmenopausal vasomotor symptoms include clonidine hydrochloride, danazol, gabapentin, methyldopa, mirtazapine, progestins, propranolol hydrochloride, selective serotonin-reuptake inhibitors (SSRIs), and venlafaxine. Nonprescription therapies reviewed include black cohosh, dong quai, evening primrose oil, physical activity, phytoestrogens, and red clover. CONCLUSIONS: According to this systematic literature review, postmenopausal vasomotor treatments that have been shown to be safe and effective in short-term use include black cohosh, exercise, gabapentin, medroxyprogesterone acetate, SSRIs (ie, paroxetine hydrochloride), and soy protein. Initial, small reports are suggestive for efficacy in menopausal vasomotor symptoms with megestrol acetate and venlafaxine. | Are there any clinical trials of the effect of evening primrose oil on postmenopausal symptoms ? | 5324cf869b2d7acc7e000020_003 | yes |
Effect of competitive marathon cycling on plasma N-terminal pro-brain natriuretic peptide and cardiac troponin T in healthy recreational cyclists. For a further depiction of exercise-induced cardiac dysfunction, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and cardiac troponin T (cTnT) were measured in recreational cyclists (n = 29) during the Otztal Radmarathon 2004. In all subjects, NT-pro-BNP significantly increased from 28 +/- 21 to 278 +/- 152 ng/L immediately after the race (p <0.001), decreased again on the following day, and returned to baseline values 1 week later. The mean percentage increase in NT-pro-BNP was 1,128 +/- 803%. CTnT, negative in all subjects before the race, increased transiently in 13 athletes (45%), with levels ranging from 0.043 to 0.224 mug/L in 8 of them (28%). One day after competition, cTnT had normalized in all athletes. Because of the typical release of kinetics, the deflection of NT-pro-BNP is considered to be the adequate volume regulatory response of a hemodynamically stressed heart to prolonged strenuous exercise. The observed kinetics of cTnT substantiate a release from the free cytoplasmatic pool due to the half-life of cytosolic cTnT. In healthy cyclists, transient increases in NT-pro-BNP and cTnT are more likely to reflect cardiac fatigue than injury. | Does BNP increase after intensive exercise in athletes? | 531d2aa5267d7dd053000003_010 | yes |
EGFRvIII/integrin β3 interaction in hypoxic and vitronectinenriching microenvironment promote GBM progression and metastasis. Glioblastoma (GBM) is one of the most lethal brain tumors with a short survival time. EGFR amplification and mutation is the most significant genetic signature in GBM. About half of the GBMs with EGFR amplification express a constitutively autophosphorylated variant of EGFR, known as EGFRvIII. Our in vitro data demonstrated further enhanced EGFRvIII activity and tumor cell invasion in the tumor microenvironment of hypoxia plus extracellular matrix (ECM) vitronectin, in which EGFRvIII and integrin β3 tended to form complexes. The treatment with ITGB3 siRNA or the integrin antagonist cilengetide preferentially interrupted the EGFRvIII/integrin β3 complex, effectively reduced tumor cell invasion and activation of downstream signaling effectors. Cilengitide is recently failed in Phase III CENTRIC trial in unselected patients with GBM. However, we found that cilengitide demonstrated efficacious tumor regression via inhibition of tumor growth and angiogenesis in EGFRvIII orthotopic xenografts. Bioinformatics analysis emphasized key roles of integrin β3, hypoxia and vitronectin and their strong correlations with EGFRvIII expression in malignant glioma patient samples in vivo. In conclusion, we demonstrate that EGFRvIII/integrin β3 complexes promote GBM progression and metastasis in the environment of hypoxia and vitronectin-enrichment, and cilengitide may serve as a promising therapeutics for EGFRvIII-positive GBMs. | Is cilengitide effective for treatment of glioblastoma? | 5a76080683b0d9ea66000015_004 | no |
Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia. Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the body. Bilirubin elimination is a multifaceted process consisting of uptake of bilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the hepatocytes, it is extensively glucuronidated by UGT1A1. Eventually, the glucuronide metabolite is excreted into the bile via MRP2. UGT1A1 inhibition has been previously shown to be linked with hyperbilirubinemia. However, because drug transporters also contribute to bilirubin elimination, the purpose of this work was to investigate the in vitro inhibition of OATP1B1, OATP1B3, MRP2, and BSEP of select test drugs known to elicit hyperbilirubinemia. Test drugs investigated in this study were atazanavir and indinavir, which are associated with hyperbilirubinemia and elevations in serum transaminase; ritonavir and nelfinavir, which are not associated with hyperbilirubinemia; and bromfenac, troglitazone, and trovafloxacin, which are associated with severe idiosyncratic hepatotoxicity exhibiting elevations in serum bilirubin and transaminase. Due to limited solubility and poor ionization of bilirubin and its glucuronide, the formation of estradiol 3-glucuronide was used as a surrogate to assess UGT1A1 activity, while the transport of pitavastatin, CDCF, and taurocholate were used as surrogate probe substrates to monitor the function of OATP1B1/OATP1B3, MRP2, and BSEP, respectively. It was assumed that any inhibition of the surrogate probe substrates by test drugs is indicative of the potential impact of test drugs to modulate the function of proteins involved in bilirubin disposition. In vitro inhibition was determined by calculating IC50. Moreover, Cmax and Cmax,free were integrated with IC50 values to calculate R and Rfree, respectively, which represents the ratio of probe drug glucuronidation/transport in the absence and presence of test drugs. Analysis of the data showed that Rfree demonstrated the best correlation to hyperbilirubinemia. Specifically, Rfree was above the 1.1 target threshold against UGT1A1, OATP1B1, and BSEP for atazanavir and indinavir. In contrast, Rfree was below this threshold for ritonavir and nelfinavir as well as for bromfenac, troglitazone, and trovafloxacin. For all test drugs examined, only minor inhibition against OATP1B3 and MRP2 were observed. These data suggest that the proposed surrogate probe substrates to evaluate the in vitro inhibition of UGT1A1, OATP1B1, and BSEP may be suitable to assess bilirubin disposition. For protease inhibitors, inclusion of OATP1B1 and BSEP inhibition may improve the predictability of hyperbilirubinemia. | Are OATP1B1 and OATP1B3 associated with bilirubin transport? | 571e3e2abb137a4b0c000008_001 | yes |
In Vitro Studies Reveal a Sequential Mode of Chain Processing by the Yeast SUMO (Small Ubiquitin-related Modifier)-specific Protease Ulp2. Sumoylation is a post-translational modification essential in most eukaryotes that regulates stability, localization, activity, or interaction of a multitude of proteins. It is a reversible process wherein counteracting ligases and proteases, respectively, mediate the conjugation and deconjugation of SUMO molecules to/from target proteins. Apart from attachment of single SUMO moieties to targets, formation of poly-SUMO chains occurs by the attachment of additional SUMO molecules to lysine residues in the N-terminal extensions of SUMO. In Saccharomyces cerevisiae there are apparently only two SUMO(Smt3)-specific proteases: Ulp1 and Ulp2. Ulp2 has been shown to be important for the control of poly-SUMO conjugates in cells and to dismantle SUMO chains in vitro, but the mechanism by which it acts remains to be elucidated. Applying an in vitro approach, we found that Ulp2 acts sequentially rather than stochastically, processing substrate-linked poly-SUMO chains from their distal ends down to two linked SUMO moieties. Furthermore, three linked SUMO units turned out to be the minimum length of a substrate-linked chain required for efficient binding to and processing by Ulp2. Our data suggest that Ulp2 disassembles SUMO chains by removing one SUMO moiety at a time from their ends (exo mechanism). Apparently, Ulp2 recognizes surfaces at or near the N terminus of the distal SUMO moiety, as attachments to this end significantly reduce cleavage efficiency. Our studies suggest that Ulp2 controls the dynamic range of SUMO chain lengths by trimming them from the distal ends. | Is SUMOylation a post-translational modification in eukaryotes? | 58a6b98860087bc10a000028_001 | yes |
Evidence-based cerebral vasospasm management. Cerebral vasospasm and delayed cerebral ischemia remain common complications of aneurysmal subarachnoid hemorrhage (SAH), and yet therapies for cerebral vasospasm are limited. Despite a large number of clinical trials, only calcium antagonists have strong evidence supporting their effectiveness. The purpose of this work was to perform a systematic review of the literature on the treatment of cerebral vasospasm. A literature search for randomized controlled trials of therapies used for prevention or treatment of cerebral vasospasm and/or delayed cerebral ischemia was conducted, and 41 articles meeting the review criteria were found. Study characteristics and primary results of these articles are reviewed. Key indicators of quality were poor when averaged across all studies, but have improved greatly over time. The only proven therapy for vasospasm is nimodipine. Tirilazad is not effective, and studies of hemodynamic maneuvers, magnesium, statin medications, endothelin antagonists, steroid drugs, anticoagulant/antiplatelet agents, and intrathecal fibrinolytic drugs have yielded inconclusive results. The following conclusions were made: nimodipine is indicated after SAH and tirilazad is not effective. More study of hemodynamic maneuvers, the effectiveness of other calcium channel antagonists such as nicardipine delivered by other routes (for example intrathecally), magnesium, statin drugs, endothelin antagonists, and intrathecal fibrinolytic therapy is warranted. There is less enthusiasm for the study of steroid drugs and anticoagulant/antiplatelet agents because they entail more risks and investigations so far have shown little evidence of efficacy. The study of rescue therapy such as balloon angioplasty and intraarterial vasodilating agents will be difficult. The quality of clinical trials should be improved. | Is nimodipine recommended for prevention of vasospasm in aneurysmal subarachnoid hemorrhage patients? | 51490275d24251bc0500003d_014 | yes |
Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia. Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are late complications of cytotoxic therapy used in the treatment of malignant diseases. The most common subtype of t-AML ( approximately 75% of cases) develops after exposure to alkylating agents, and is characterized by loss or deletion of chromosome 5 and/or 7 [-5/del(5q), -7/del(7q)], and a poor outcome (median survival 8 months). In the University of Chicago's series of 386 patients with t-MDS/t-AML, 79 (20%) patients had abnormalities of chromosome 5, 95 (25%) patients had abnormalities of chromosome 7, and 85 (22%) patients had abnormalities of both chromosomes 5 and 7. t-MDS/t-AML with a -5/del(5q) is associated with a complex karyotype, characterized by trisomy 8, as well as loss of 12p, 13q, 16q22, 17p (TP53 locus), chromosome 18, and 20q. In addition, this subtype of t-AML is characterized by a unique expression profile (higher expression of genes) involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), loss of expression of IRF8, and overexpression of FHL2. Haploinsufficiency of the RPS14, EGR1, APC, NPM1, and CTNNA1 genes on 5q has been implicated in the pathogenesis of MDS/AML. In previous studies, we determined that Egr1 acts by haploinsufficiency and cooperates with mutations induced by alkylating agents to induce myeloid leukemias in the mouse. To identify mutations that cooperate with Egr1 haploinsufficiency, we used retroviral insertional mutagenesis. To date, we have identified two common integration sites involving genes encoding transcription factors that play a critical role in hematopoiesis (Evi1 and Gfi1b loci). Of note is that the EVI1 transcription factor gene is deregulated in human AMLs, particularly those with -7, and abnormalities of 3q. Identifying the genetic pathways leading to t-AML will provide new insights into the underlying biology of this disease, and may facilitate the identification of new therapeutic targets. | Is Growth factor independence 1b (GFI1B) important for hematopoiesis? | 553bd2f0f321868558000008_007 | yes |
Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha. p105 (NFKB1) acts in a dual way as a cytoplasmic IkappaB molecule and as the source of the NF-kappaB p50 subunit upon processing. p105 can form various heterodimers with other NF-kappaB subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the IkappaB kinase (IKK) complex invokes p105 degradation and p50 homodimer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKKbeta phosphorylation of p105 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site located in a death domain, which is separate from the substrate site. The substrate residues were identified as serines 923 and 927, the latter of which was previously assumed to be a threonine. S927 is part of a conserved DSGPsi motif and is functionally most critical. The region containing both serines is homologous to the N-terminal destruction box of IkappaBalpha, -beta, and -epsilon. Upon phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate recognition molecules betaTrCP1 and betaTrCP2, resulting in polyubiquitination and complete degradation by the proteasome. However, processing of p105 is independent of IKK signaling. In line with this and as a physiologically relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B cells lacking IKKgamma, processing was unaffected, but LPS-induced p105 degradation was abolished. Thus, a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing. | Is p100 the precursor protein molecule of the NF-kappaB transcription factor subunit p50? | 55088e412e93f0133a000001_008 | no |
Treatment for Restless Legs Syndrome [Internet]. CONTEXT: Restless legs syndrome (RLS) is a neurological disorder characterized by unpleasant sensations in the legs and a distressing, irresistible urge to move them. RLS severity and burden vary widely, and the condition may require long-term treatment. OBJECTIVE: To review the comparative effectiveness, efficacy, and safety of pharmacologic and nonpharmacologic treatments for RLS. DATA SOURCES: We searched bibliographic databases MEDLINE (via OVID), Embase, and Natural Standards through June 2012. REVIEW METHODS: Eligible efficacy studies included randomized controlled trials (RCTs) of individuals with RLS published in English that lasted at least 4 weeks and compared pharmacologic and/or nonpharmacologic treatments with placebo or active treatment. We assessed RLS symptom impact, sleep scale scores, disease-specific quality of life, withdrawals, and adverse effects. We included observational studies that assessed long-term (>6 months) treatment adverse effects and withdrawals. RESULTS: Of the 53 studies included, one active comparator and 33 placebo-controlled RCTs provided efficacy and harms data, and 18 observational studies assessed long-term harms and adherence. RCTs were typically small and of short duration, and enrolled adult subjects with severe primary RLS of long duration. Placebo-controlled RCTs (18 trials) demonstrated that dopamine agonists (pramipexole, rotigotine, ropinirole, and cabergoline) increased the percentage of subjects who had a clinically important response defined as ≥50 percent reduction from baseline in mean International RLS symptom scale scores (IRLS responders) (risk ratio [RR]=1.60; [95% confidence interval [CI]: 1.38 to 1.86], k=7), improved RLS symptom scores, patient-reported sleep scale scores (effect size=0.38; [95% CI: 0.29 to 0.46], k=8), and disease-specific quality of life (effect size=−0.37; [95% CI: −0.48 to −0.27], k=9). Dopamine agonists resulted in more patients who experienced at least one adverse event (high-strength evidence for all outcomes). Long-term augmentation (drug-induced worsening of symptoms) and treatment withdrawal were common. Alpha-2-delta ligands (gabapentin enacarbil, gabapentin, and pregabalin) increased the number of IRLS responders (RR=1.66; [95% CI: 1.33 to 2.09], k=3, high strength of evidence) and mean change in IRLS symptom scores (k=3, high strength of evidence). Intravenous ferric carboxymaltose reduced IRLS symptom scale scores versus placebo (k=1, moderate strength of evidence). Four studies assessed nonpharmacologic interventions. Compression stockings but not the botanical extract valerian improved IRLS symptom scale scores more than sham or placebo treatments. Strength of evidence was moderate for compression stockings and low for valerian. Exercise improved symptoms more than control (low-strength evidence). Near-infrared light treatment improved IRLS symptom scores more than sham (low-strength evidence). Two trials compared active treatments. In one small crossover trial, pramipexole and levodopa/benserazide resulted in similar improvements in IRLS scores (low-strength evidence). Cabergoline improved IRLS scores and resulted in less augmentation than levodopa (moderate-strength evidence). Iron improved symptoms in adults with iron deficiency (k=2) (low-strength evidence). No studies enrolled pregnant women, children, or those with end-stage renal disease. Withdrawal from mostly dopamine agonist and levodopa treatment at 1 year or more ranged from 13 to 57 percent. Treatment withdrawals were due to lack of efficacy (6% to 37%) as well as augmentation and other adverse events. CONCLUSION: Compared to placebo, dopamine agonists and alpha-2-delta ligands reduce RLS symptoms and improve patient-reported sleep outcomes and disease-specific quality of life. Adverse effects of pharmacologic therapies and long-term treatment withdrawals due to adverse effects or lack of efficacy are common. Long-term effectiveness as well as applicability for adults with milder or less frequent RLS symptoms, individuals with secondary RLS, and children is unknown. | Is Rucaparib effective for ovarian cancer? | 5a7379a83b9d13c70800000a_010 | yes |
H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas. Brain tumors are one of the most common childhood malignancies. Diffuse high-grade gliomas represent approximately 10% of pediatric brain tumors. Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors. We performed a pyrosequencing-based analysis for the identification of H3F3A codon 27 and codon 34 mutations in 338 pediatric brain tumors. The K27M mutation occurred in 35 of 129 glioblastomas (27.1%) and in 5 of 28 (17.9%) anaplastic astrocytomas. None of the other tumor entities showed H3F3A K27M mutation. Because H3F3A K27M mutations occur exclusively in pediatric diffuse high-grade astrocytomas, analysis of codon 27 mutational status could be useful in the differential diagnosis of these neoplasms. | Is there an association between Histone H3.3 mutations and glioma? | 5890ede0621ea6ff7e000007_000 | yes |
Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo. OBJECTIVES: The antimycobacterial activities of RS-112997, RS-124922 and RS-118641, three capuramycin analogues that inhibit phospho-N-acetylmuramyl-pentapeptide translocase, were tested against clinical isolates of Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare. METHODS AND RESULTS: MICs were determined by the broth microdilution method using a modified Middlebrook 7H9 broth. RS-118641 was the most potent compound overall. The MIC50/90 (mg/L) results for RS-118641 were: M. tuberculosis, 1/2; multidrug-resistant (MDR) M. tuberculosis, 0.5/2; M. avium, 4/8; and M. intracellulare, 0.06/0.5. No statistically significant differences in MIC distributions were observed between non-MDR and MDR M. tuberculosis for any of the capuramycin analogues tested. In order to evaluate the therapeutic efficacy of RS-112997 and RS-124922 in a murine lung model of tuberculosis, both compounds were administered intranasally at 0.1 or 1 mg/mouse/day for 12 days. The mycobacterial load in the lungs was significantly lower in all treatment groups than in the untreated controls. Additional experiments were performed to evaluate the therapeutic efficacy of the three compounds against the M. intracellulare infection in mice. All compounds were administered intranasally at 0.1 mg/mouse/day for 21 days. The mycobacterial load in the lungs was significantly lower in all treatment groups than in the untreated controls. CONCLUSIONS: These results suggest that capuramycin analogues exhibit strong antimycobacterial potential and should be considered for further evaluation in the treatment of M. tuberculosis and M. avium-M. intracellulare complex infections in humans. | Is Mycobacterium avium less susceptible to antibiotics than Mycobacterium tuberculosis? | 5710a650cf1c32585100002b_008 | yes |
The Fanconi anemia protein interaction network: casting a wide net. It has long been hypothesized that a defect in the repair of damaged DNA is central to the etiology of Fanconi anemia (FA). Indeed, an increased sensitivity of FA patient-derived cells to the lethal effects of various forms of DNA damaging agents was described over three decades ago [A.J. Fornace, Jr., J.B. Little, R.R. Weichselbaum, DNA repair in a Fanconi's anemia fibroblast cell strain, Biochim. Biophys. Acta 561 (1979) 99-109; Y. Fujiwara, M. Tatsumi, Repair of mitomycin C damage to DNA in mammalian cells and its impairment in Fanconi's anemia cells, Biochem. Biophys. Res. Commun. 66 (1975) 592-598; A.J. Rainbow, M. Howes, Defective repair of ultraviolet- and gamma-ray-damaged DNA in Fanconi's anaemia, Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 31 (1977) 191-195]. Furthermore, the cytological hallmark of FA, the DNA crosslink-induced radial chromosome formation, exemplifies an innate impairment in the repair of these particularly cytotoxic DNA lesions [A.D. Auerbach, Fanconi anemia diagnosis and the diepoxybutane (DEB) test, Exp. Hematol. 21 (1993) 731-733]. Precisely defining the collective role of the FA proteins in DNA repair, however, continues to be one of the most enigmatic and challenging questions in the FA field. The first six identified FA proteins (A, C, E, F, G, and D2) harbored no recognizable enzymatic features, precluding association with a specific metabolic process. Consequently, our knowledge of the role of the FA proteins in the DNA damage response has been gleaned primarily through biochemical association studies with non-FA proteins. Here, we provide a chronological discourse of the major FA protein interaction network discoveries, with particular emphasis on the DNA damage response, that have defined our current understanding of the molecular basis of FA. | Is hypersensitivity to DNA crosslinking agents a hallmark of Fanconi anemia? | 54ecb66d445c3b5a5f000002_005 | yes |
Transient activation of autophagy via Sox2-mediated suppression of mTOR is an important early step in reprogramming to pluripotency. Autophagy is an essential cellular mechanism that degrades cytoplasmic proteins and organelles to recycle their components. Here we show that autophagy is required for reprogramming of somatic cells to form induced pluripotent stem cells (iPSCs). Our data indicate that mammalian target of rapamycin (mTOR) is downregulated by Sox2 at an early stage of iPSC generation and that this transient downregulation of mTOR is required for reprogramming to take place. In the absence of Sox2, mTOR remains at a high level and inhibits autophagy. Mechanistically, Sox2 binds to a repressive region on the mTOR promoter and recruits the NuRD complex to mediate transcriptional repression. We also detected enhanced autophagy at the four- to eight-cell stage of embryonic development, and a similar Sox2 and mTOR-mediated regulatory pathway seems to operate in this context as well. Thus, our findings reveal Sox2-dependent temporal regulation of autophagy as a key step in cellular reprogramming processes. | Does the protein mTOR regulate autophagy? | 5505ad7ff73303d458000007_008 | yes |
T-Brain-1--A Potential Master Regulator in Autism Spectrum Disorders. T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs. In addition, one gene, Kiaa0319, is a known causative gene for dyslexia, a disorder frequently associated with autism. A change in expression level in 10 of these 24 genes has been previously confirmed. We further validated the alteration of RNA expression levels of Kiaa0319, Baiap2, and Gad1 in Tbr1 deficient mice. Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism. | Is there any role of TBR1 in autism? | 58965ed478275d0c4a000010_001 | yes |
Shadow enhancers foster robustness of Drosophila gastrulation. Critical developmental control genes sometimes contain "shadow" enhancers that can be located in remote positions, including the introns of neighboring genes [1]. They nonetheless produce patterns of gene expression that are the same as or similar to those produced by more proximal primary enhancers. It was suggested that shadow enhancers help foster robustness in gene expression in response to environmental or genetic perturbations [2, 3]. We critically tested this hypothesis by employing a combination of bacterial artificial chromosome (BAC) recombineering and quantitative confocal imaging methods [2, 4]. Evidence is presented that the snail gene is regulated by a distal shadow enhancer located within a neighboring locus. Removal of the proximal primary enhancer does not significantly perturb snail function, including the repression of neurogenic genes and formation of the ventral furrow during gastrulation at normal temperatures. However, at elevated temperatures, there is sporadic loss of snail expression and coincident disruptions in gastrulation. Similar defects are observed at normal temperatures upon reductions in the levels of Dorsal, a key activator of snail expression (reviewed in [5]). These results suggest that shadow enhancers represent a novel mechanism of canalization whereby complex developmental processes "bring about one definite end-result regardless of minor variations in conditions" [6]. | Are shadow enhancers associated with development? | 56a292ae496b62f23f000001_001 | yes |
Abnormal division and gene expression in cultured cells from a patient with tuberous sclerosis. Tuberous sclerosis is a dominant hereditary disease characterized by the appearance of angiofibromas on the face, epileptic attacks, and mental retardation. Attention has been paid to the atypical cells observed histologically in the stroma of the angiofibroma as they may play an important role in forming lesions. We have established a cell line from an angiofibroma to clarify the nature of these cells at the cellular and biochemical levels. The cultured cells have been stably maintained for four years and show an abnormal morphology resembling that of neuronal cells. In culture, these cells divide into daughter cells, which consist of both normal cells and abnormal ones whose nuclei disintegrate and cannot divide further. The cells resemble normal fibroblasts in their pattern of staining with antibodies against tubulin, actin, vimentin, and fibronectin. However, they also stain with an antibody against the glia-specific acidic protein, which is thought to be a specific marker protein for glial cells. The gel profile of cyclic-AMP binding proteins was not fibroblastic, but rather of the neuron cell type. These results indicate the gene expression of these cells is also abnormal. They are a useful tool for understanding this specific genetic disease. | Is Tuberous Sclerosis a genetic disease? | 52b06a68f828ad283c000005_032 | yes |
The behavioral phenotype of Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is caused by a heterozygous mutation or deletion of the ZEB2 gene. 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. The current study investigated the behavioral phenotype of MWS. Parents and carers of 61 individuals with MWS completed the Developmental Behavior Checklist. Data were compared with those for individuals selected from an epidemiological sample of people with ID from other causes. The behaviors associated with MWS included a high rate of oral behaviors, an increased rate of repetitive behaviors, and an under-reaction to pain. Other aspects of the MWS behavioral phenotype are suggestive of a happy affect and sociable demeanor. Despite this, those with MWS displayed similarly high levels of behavioral problems as those with intellectual disabilities from other causes, with over 30% showing clinically significant levels of behavioral or emotional disturbance. These findings have the potential to expand our knowledge of the role of the ZEB2 gene during neurodevelopment. Furthermore, they are a foundation for informing interventions and management options to enhance the independence and quality of life for persons with MWS. | Is corpus callosum involved in the Mowat–Wilson syndrome? | 5314896adae131f847000001_010 | yes |
Sumoylated SnoN represses transcription in a promoter-specific manner. The transcriptional modulator SnoN controls a diverse set of biological processes, including cell proliferation and differentiation. The mechanisms by which SnoN regulates these processes remain incompletely understood. Recent studies have shown that SnoN exerts positive or negative regulatory effects on transcription. Because post-translational modification of proteins by small ubiquitin-like modifier (SUMO) represents an important mechanism in the control of the activity of transcriptional regulators, we asked if this modification regulates SnoN function. Here, we show that SnoN is sumoylated. Our data demonstrate that the SUMO-conjugating E2 enzyme Ubc9 is critical for SnoN sumoylation and that the SUMO E3 ligase PIAS1 selectively interacts with and enhances the sumoylation of SnoN. We identify lysine residues 50 and 383 as the SUMO acceptor sites in SnoN. Analyses of SUMO "loss-of-function" and "gain-of-function" SnoN mutants in transcriptional reporter assays reveal that sumoylation of SnoN contributes to the ability of SnoN to repress gene expression in a promoter-specific manner. Although this modification has little effect on SnoN repression of the plasminogen activator inhibitor-1 promoter and only modestly potentiates SnoN repression of the p21 promoter, SnoN sumoylation robustly augments the ability of SnoN to suppress transcription of the myogenesis master regulatory gene myogenin. In addition, we show that the SnoN SUMO E3 ligase, PIAS1, at its endogenous levels, suppresses myogenin transcription. Collectively, our findings suggest that SnoN is directly regulated by sumoylation leading to the enhancement of the ability of SnoN to repress transcription in a promoter-specific manner. Our study also points to a physiological role for SnoN sumoylation in the control of myogenin expression in differentiating muscle cells. | Is sumoylation implicated in myogenesis? | 56cca4da5795f9a73e000034_000 | yes |
[What type of adjuvant chemotherapy should be proposed for the initial treatment of glioblastoma?]. Carmustine wafers (Gliadel) and temozolomide (Temodal) were recently approved for initial management of glioblastoma. Gliadel) is a polymer wafer containing carmustine. These wafers are designed to be placed in the surgical cavity after glioblastoma resection to deliver local chemotherapy. This treatment is intended for tumors for which gross total resection is possible. Temozolomide is administered concomitantly with radiotherapy for six weeks followed by six cycles of adjuvant temozolomide (EORTC 26981, also known as "Stupp's protocol"). Temozolomide administered according to this protocol produced a median survival benefit of 2 months in glioblastomas, and carmustine a similar benefit in high-grade gliomas. The two-year survival rate was 26.5% with radiotherapy plus temozolomide compared with 10.4% with radiotherapy alone. In patients with complete resection, two-year survival reached 38%. These two new treatments are essentially intended for patients younger than 70 years and with a Karnofsky index>70. Ongoing studies are evaluating the possible value of combining these two treatments. | Do carmustine wafers improve survival of glioblastoma patients? | 54d630283706e89528000004_006 | yes |
Bioprinting is coming of age: Report from the International Conference on Bioprinting and Biofabrication in Bordeaux (3B'09). The International Conference on Bioprinting and Biofabrication in Bordeaux (3B'09) demonstrated that the field of bioprinting and biofabrication continues to evolve. The increasing number and broadening geography of participants, the emergence of new exciting bioprinting technologies, and the attraction of young investigators indicates the strong growth potential of this emerging field. Bioprinting can be defined as the use of computer-aided transfer processes for patterning and assembling living and non-living materials with a prescribed 2D or 3D organization in order to produce bio-engineered structures serving in regenerative medicine, pharmacokinetic and basic cell biology studies. The use of bioprinting technology for biofabrication of in vitro assay has been shown to be a realistic short-term application. At the same time, the principal feasibility of bioprinting vascularized human organs as well as in vivo bioprinting has been demonstrated. The bioprinting of complex 3D human tissues and constructs in vitro and especially in vivo are exciting, but long-term, applications. It was decided that the 5th International Conference on Bioprinting and Biofabrication would be held in Philadelphia, USA in October 2010. The specially appointed 'Eploratory Committee' will consider the possibility of turning the growing bioprinting community into a more organized entity by creating a new bioprinting and biofabrication society. The new journal Biofabrication was also presented at 3B'09. This is an important milestone per se which provides additional objective evidence that the bioprinting and biofabrication field is consolidating and maturing. Thus, it is safe to state that bioprinting technology is coming of age. | Can bioprinting use human cells? | 571394141174fb175500000b_004 | yes |
Transcription-associated R-loop formation across the human FMR1 CGG-repeat region. Expansion of a trinucleotide (CGG) repeat element within the 5' untranslated region (5'UTR) of the human FMR1 gene is responsible for a number of heritable disorders operating through distinct pathogenic mechanisms: gene silencing for fragile X syndrome (>200 CGG) and RNA toxic gain-of-function for FXTAS (∼ 55-200 CGG). Existing models have focused almost exclusively on post-transcriptional mechanisms, but co-transcriptional processes could also contribute to the molecular dysfunction of FMR1. We have observed that transcription through the GC-rich FMR1 5'UTR region favors R-loop formation, with the nascent (G-rich) RNA forming a stable RNA:DNA hybrid with the template DNA strand, thereby displacing the non-template DNA strand. Using DNA:RNA (hybrid) immunoprecipitation (DRIP) of genomic DNA from cultured human dermal fibroblasts with both normal (∼ 30 CGG repeats) and premutation (55<CGG<200 repeats) alleles, we provide evidence for FMR1 R-loop formation in human genomic DNA. Using a doxycycline (DOX)-inducible episomal system in which both the CGG-repeat and transcription frequency can be varied, we further show that R-loop formation increases with higher expression levels. Finally, non-denaturing bisulfite mapping of the displaced single-stranded DNA confirmed R-loop formation at the endogenous FMR1 locus and further indicated that R-loops formed over CGG repeats may be prone to structural complexities, including hairpin formation, not commonly associated with other R-loops. These observations introduce a new molecular feature of the FMR1 gene that is directly affected by CGG-repeat expansion and is likely to be involved in the associated cellular dysfunction. | Do RNA:DNA hybrids preferentially form in high or low GC regions? | 56e310a151531f7e33000017_004 | yes |
The good and bad effects of statins on insulin sensitivity and secretion. AIMS: Statins are the main lipid-lowering treatment in both primary and secondary prevention populations. Whether statins deteriorates glycemic control, predisposing to the onset of diabetes mellitus has been a matter of recent concern. Statins may accelerate progression to diabetes via molecular mechanisms that impact insulin sensitivity and secretion. In this review, we debate the relative effect of statins in driving insulin resistance and the impairment of insulin secretion. METHODS: Narrative overview of the literature synthesizing the findings of literature was retrieved from searches of computerized databases, hand searches, and authoritative texts employing the key words "Statins", "Randomized Clinical Trial", "Insulin sensitivity", "Insulin resistance", "Insulin Secretion", "Diabetes Mellitus" alone and/or in combination. RESULTS: The weight of clinical evidence suggests a worsening effect of statins on insulin resistance and secretion, anyway basic science studies did not find a clear molecular explanation, providing conflicting evidence regarding both the beneficial and the adverse effects of statin therapy on insulin sensitivity. CONCLUSIONS: Although most of the clinical studies suggest a worsening of insulin resistance and secretion, the cardiovascular benefits of statin therapy outweigh the risk of developing insulin resistance, thus the data suggest the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control. | Do statins cause diabetes? | 58a341eb60087bc10a000018_011 | yes |
[Atypical neuroradiological features of microcystic meningioma: case report]. We report a rare case of microcystic meningioma presenting with atypical neuroradiological features. A 76-year-old woman was admitted to our hospital in October, 1996 because of head heaviness without obvious neurological deficits. Previous CT scan in 1989 revealed no abnormality, but a subsequent scan in 1992 showed a low-density area in the right frontal region. Since then the patient has been followed up as a case of cerebral infarction. At the time of the current admission, CT scan disclosed the low-density area as having grown to the size of 4 cm and heterogeneously enhanced after injection of contrast medium. On MRI the mass lesion was depicted as low-intensity on T1-weighted image and high-intensity on T2-weighted image. The mass was heterogeneously enhanced after administration of Gd-DTPA. Right internal and external carotid angiograms revealed neither tumor feeder nor tumor stain. Craniogram showed neither hyperostosis nor bone erosion, and yet bone scintigram demonstrated markedly increased uptake involving the right frontal bone near the tumor. At surgery the tumor was found to have originated from the dura in the right frontal convexity, which was well demarcated and separated from the surrounding brain tissue. Total removal designated as Simpson grade I procedure was accomplished. Light microscopy revealed abundant microcysts of varied size throughout the tumor tissue with the presence of whorl formation and psammoma body, but no malignancy was indicated. Electron microscopy further demonstrated interdigitation of the neighboring cell membranes, desmosomes, and intracytoplasmic filaments, which are pathognomonic findings of meningiomas. The microcysts were seen to reside in the extracellular spaces rather than in the cytoplasm. With these pathological findings, the tumor was finally diagnosed as microcystic meningioma. | Are psammoma bodies characteristic to meningiomas? | 514a4679d24251bc0500005b_002 | yes |
Upregulated expression of C-X-C chemokine receptor 4 is an independent prognostic predictor for patients with gastric cancer. Aberrant chemokine (C-X-C motif) receptor CXCR4 expressions in malignant tissues have been reported, but its role in gastric cancer prognosis remains unknown. Our studies were designed to investigate the expression and prognostic significance of CXCR4 in patients with gastric cancer. CXCR4 expression was retrospectively analyzed by immunohistochemistry in 97 patients with gastric adenocarcinoma from China. Results were assessed for association with clinical features and overall survival by using Kaplan-Meier analysis. Prognostic values of CXCR4 expression and clinical outcomes were evaluated by Cox regression analysis. A molecular prognostic stratification scheme incorporating CXCR4 expression was determined by using receiver operating characteristic (ROC) analysis. The results show that CXCR4 predominantly localized in the cell membranes and cytoplasm. The protein level of CXCR4 was upregulation in gastric cancer tissues and upregulated expression of CXCR4 was only significantly associated with Lauren classification (P<0.001). Increased CXCR4 expression in gastric cancer tissues was positively correlated with poor overall survival of gastric cancer patients (P<0.001). Further multivariate Cox regression analysis suggested that intratumoral CXCR4 expression was an independent prognostic indicator for the disease. Applying the prognostic value of intratumoral CXCR4 density to TNM stage system showed a better prognostic value in patients with gastric cancer. In conclusion, intratumoral CXCR4 expression was recognized as an independent prognostic marker for the overall survival of patients with gastric cancer. On the basis of TNM stage, detection of CXCR4 expression will be helpful for predicting prognosis for patients with gastric cancer. | Is protein CXCR4 used as a prognostic marker of cancer? | 56e68967edfc094c1f000002_002 | yes |
Characterization of human and mouse TRPM2 genes: identification of a novel N-terminal truncated protein specifically expressed in human striatum. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable cation channel activated by ADP-ribose or reactive oxygen species. In human, a major transcript of 6.5 kb is expressed in various tissues, whereas a minor transcript of 5.5 kb is detected only in striatum (caudate nucleus and putamen). We found that the 5.5-kb shorter transcript is transcribed from the intron 4 of the TRPM2 gene and encodes the striatum short form protein (SSF-TRPM2) with 1289 amino acid residues as compared to the long form protein (LF-TRPM2), in which the N-terminal 214 amino acid residues are removed. The SSF-TRPM2 protein still maintained H2(O2)-induced Ca2+ influx activity. In addition, we found that the major transcripts in human and mouse start from a novel 5' non-coding exon; however, we could not detect any striatum short transcript in mouse brain. These new findings are invaluable to further study the regulation of TRPM2 gene expression and to examine the possible involvement of the TRPM2 gene in the pathophysiology of bipolar disorder. | The TRPM2 gene is associated with development of spontaneous thromboembolism? | 5ab144fefcf4565872000012_008 | no |
C-Jun N-terminal kinase 2 promotes graft injury via the mitochondrial permeability transition after mouse liver transplantation. The c-Jun N-terminal kinase (JNK) pathway enhances graft injury after liver transplantation (LT). We hypothesized that the JNK2 isoform promotes graft injury via the mitochondrial permeability transition (MPT). Livers of C57BL/6J (wild-type, WT) and JNK2 knockout (KO) mice were transplanted into WT recipients after 30 h of cold storage in UW solution. Injury after implantation was assessed by serum ALT, histological necrosis, TUNEL, Caspase 3 activity, 30-day survival, and cytochrome c and 4-hydroxynonenal immunostaining. Multiphoton microscopy after LT monitored mitochondrial membrane potential in vivo. After LT, ALT increased three times more in WT compared to KO (p < 0.05). Necrosis and TUNEL were more than two times greater in WT than KO (p < 0.05). Immunostaining showed a >80% decrease of mitochondrial cytochrome c release in KO compared to WT (p < 0.01). Lipid peroxidation was similarly decreased. Every KO graft but one survived longer than all WT grafts (p < 0.05, Kaplan-Meier). After LT, depolarization of mitochondria occurred in 73% of WT hepatocytes, which decreased to 28% in KO (p < 0.05). In conclusion, donor JNK2 promotes injury after mouse LT via the MPT. MPT inhibition using specific JNK2 inhibitors may be useful in protecting grafts against adverse outcomes from ischemia/reperfusion injury. | Is the JNK pathway activated during liver regeneration? | 53455e0caeec6fbd0700000f_008 | yes |
Drug abuse and stroke. Cerebrovascular disorders contribute to the morbidity and disability associated with illicit drug use. Drug abusers have an increased risk of both hemorrhagic and ischemic stroke. In geographic areas with a high prevalence of illicit drug use, drug abuse is a frequent cause of stroke in the young adult. 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. Toxicology screening for illicit drugs should be done in young patients with stroke with no obvious cause, or if suggested by history or examination. Although in some patients the mechanism of stroke is identified using neuroimaging and other modern diagnostic tools, in a sizeable fraction of cases the mechanism of stroke remains unclear. Further studies are needed to elucidate the role of hemodynamic and immunologic mechanisms in these cases. | Is marijuana use associated with increased risk for stroke? | 5149e23dd24251bc0500004b_005 | yes |
Challenges and pitfalls in the introduction of pharmacogenetics for cancer. There have been several success stories in the field of pharmacogenetics in recent years, including the analysis of HER2 amplification for trastuzumab selection in breast cancer and VKORC1 genotyping for warfarin dosing in thrombosis. Encouraging results from these studies suggest that genetic factors may indeed be important determinants of drug response and toxicity for at least some drugs. However, to apply pharmacogenetics appropriately, a thorough understanding of the scope and limitations of this field is required. The challenges include an appreciation of biological variability, logistical issues pertaining to the proper management of information, the need for robust methods and adequate sample quality with well-designed workflows. At the same time, the economics of pharmacogenetic testing from the perspective of clinicians, patients, governments, insurance companies and pharmaceutical companies will play an important role in determining its future use. Ethical considerations such as informed consent and patient privacy, as well as the role of regulatory bodies in addressing these issues, must be fully understood. Only once these issues are properly dealt with can the full benefits of pharmacogenetics begin to be realised. | Is there a pharmacogenetic test for trastuzumab? | 514a1469d24251bc05000056_014 | yes |
Phospholamban overexpression in rabbit ventricular myocytes does not alter sarcoplasmic reticulum Ca transport. Phospholamban has been suggested to be a key regulator of cardiac sarcoplasmic reticulum (SR) Ca cycling and contractility and a potential therapeutic target in restoring the depressed Ca cycling in failing hearts. Our understanding of the function of phospholamban stems primarily from studies in genetically altered mouse models. To evaluate the significance of this protein in larger mammalian species, which exhibit Ca cycling properties similar to humans, we overexpressed phospholamban in adult rabbit cardiomyocytes. Adenoviral-mediated gene transfer, at high multiplicities of infection, resulted in an insignificant 1.22-fold overexpression of phospholamban. There were no effects on twitch Ca-transient amplitude or decay under basal or isoproterenol-stimulated conditions. Furthermore, the SR Ca load and Na/Ca exchanger function were not altered. These apparent differences between phospholamban overexpression in rabbit compared with previous findings in the mouse may be due to a significantly higher (1.5-fold) endogenous phospholamban-to-sarco(endo)plasmic reticulum Ca-ATPase (SERCA) 2a ratio and potential functional saturation of SERCA2a by phospholamban in rabbit cardiomyocytes. The findings suggest that important species-dependent differences in phospholamban regulation of SERCA2a occur. In larger mammals, a higher fraction of SERCA2a pumps are regulated by phospholamban, and this may influence therapeutic strategies to enhance cardiac contractility and functional cardiac reserve. | Is phospholamban a regulatory/inhibitory protein of the Ca ATPase SERCA? | 5501b3b3e9bde69634000007_008 | yes |
Laser ablation electrospray ionization for atmospheric pressure molecular imaging mass spectrometry. Laser ablation electrospray ionization (LAESI) is a novel method for the direct imaging of biological tissues by mass spectrometry. By performing ionization in the ambient environment, this technique enables in vivo studies with potential for single-cell analysis. A unique aspect of LAESI mass spectrometric imaging (MSI) is depth profiling that, in combination with lateral imaging, permits 3D molecular imaging for the first time under native conditions. With current lateral and depth resolutions of approximately 100 and approximately 40 microm, respectively, LAESI MSI helps to explore the molecular architecture of live tissues. | Is single-cell analysis (SCA) possible in proteomics? | 5144bc8fd24251bc0500000e_001 | no |
Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain. BACKGROUND: Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM). There is a wide variation in the prevalence of MTHFR polymorphisms and homocysteine (Hcy) plasma levels among populations around the world. The present study was undertaken to investigate the possible association between hyperhomocysteinemia and its causative genetic or acquired factors and RM in Catalonia, a Mediterranean region in Spain. METHODS: Sixty consecutive patients with > 3 unexplained RM and 30 healthy control women having at least one child but no previous miscarriage were included. Plasma Hcy levels, MTHFR gene mutation, red blood cell (RBC) folate and vitamin B12 serum levels were measured in all subjects. RESULTS: No significant differences were observed neither in plasma Hcy levels, RBC folate and vitamin B12 serum levels nor in the prevalence of homozygous and heterozygous MTHFR gene mutation between the two groups studied. CONCLUSIONS: In the present study RM is not associated with hyperhomocysteinemia, and/or the MTHFR gene mutation. | Can methylenetetrahydrofolate reductase (MTHFR) gene mutations cause homocystinuria? | 58d8d0cc8acda34529000008_013 | yes |
Clinical and economic choices in anaesthesia for day surgery: a prospective randomised controlled trial. We compared the cost-effectiveness of general anaesthetic agents in adult and paediatric day surgery populations. We randomly assigned 1063 adult and 322 paediatric elective patients to one of four (adult) or two (paediatric) anaesthesia groups. Total costs were calculated from individual patient resource use to 7 days post discharge. Incremental cost-effectiveness ratios were expressed as cost per episode of postoperative nausea and vomiting (PONV) avoided. In adults, variable secondary care costs were higher for propofol induction and propofol maintenance (propofol/propofol; p < 0.01) than other groups and lower in propofol induction and isoflurane maintenance (propofol/isoflurane; p < 0.01). In both studies, predischarge PONV was higher if sevoflurane/sevoflurane (p < 0.01) was used compared with use of propofol for induction. In both studies, there was no difference in postdischarge outcomes at Day 7. Sevoflurane/sevoflurane was more costly with higher PONV rates in both studies. In adults, the cost per extra episode of PONV avoided was pound 296 (propofol/propofol vs. propofol/ sevoflurane) and pound 333 (propofol/sevoflurane vs. propofol/isoflurane). | Are there randomised controlled trials on sevoflurane? | 515d9e5c298dcd4e5100000e_001 | yes |
Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability. INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors are indicated for the treatment of erectile dysfunction (ED); however, they can also inhibit other PDE isozymes, affecting their target tissues (e.g., PDE1: heart; PDE6: retina; and PDE11: skeletal muscle), which in some cases can cause unwanted side effects and therapy discontinuation. Data from in vitro studies showed that avanafil, a PDE5 inhibitor for the treatment of ED, exhibited strong selectivity toward PDE5 and against all other PDE isozymes. AIM: To review the inhibitory effects of avanafil for PDE isozymes compared with those of sildenafil, tadalafil, and vardenafil and to discuss these results within the context of clinical trial safety observations. METHODS: Review of in vitro selectivity data for avanafil (published primary data from a peer-reviewed journal and scientific congress abstracts); PubMed search for pertinent publications on PDE5 inhibitor safety data; and review of published articles and abstracts from avanafil phase 1, 2, and 3 clinical trials. MAIN OUTCOME MEASURES: A low incidence of some PDE-related adverse events may be reflected by the high selectivity of avanafil against non-PDE5 isozymes. RESULTS: Avanafil is highly selective toward PDE5 and against all other PDE isozymes tested. Lower selectivity against PDE1, PDE6, and PDE11 is consistent with results from randomized, placebo-controlled, phase 3 trials in which musculoskeletal and hemodynamic adverse events were reported in <2% of patients and no color vision-related abnormalities were reported with avanafil doses up to 200 mg once daily. CONCLUSIONS: Data suggest that avanafil may confer a safety benefit, in terms of a lower incidence of specific adverse events, by virtue of its high specificity to PDE5 and its overall selectivity against other PDE isozymes. | Is avanafil indicated for treatment of erectile dysfunction? | 5895d0457d9090f35300000d_014 | yes |
Kikuchi's disease accompanied by lupus-like butterfly rash. Kikuchi's disease (KD) is a benign and self-limiting lymphadenitis, particularly affecting young women. KD is often associated with fever, arthralgia, and leukopenia, features also found in systemic lupus erythematosus (SLE). Lymphadenitis associated with SLE is indistinguishable from that in KD, and the association of KD and SLE has been previously reported. We describe a case of KD who developed a typical butterfly rash, reminiscent of SLE. However, histological and laboratory findings excluded the diagnosis of SLE. This case emphasizes that careful differential diagnosis between KD and SLE is required. | Is butterfly rash a symptom of Systemic lupus erythematosus? | 58bfeb2b02b8c6095300001a_001 | yes |
Serum and cerebrospinal fluid C-reactive protein levels as predictors of vasospasm in aneurysmal subarachnoid hemorrhage. Clinical article. OBJECT: Cerebral vasospasm is a common and potentially devastating complication of aneurysmal subarachnoid hemorrhage (aSAH). Inflammatory processes seem to play a major role in the pathogenesis of vasospasm. The C-reactive protein (CRP) constitutes a highly sensitive inflammatory marker. The association of elevated systemic CRP and coronary vasospasm has been well established. Additionally, elevation of the serum CRP levels has been demonstrated in patients with aSAH. The purpose of the current study was to evaluate the possible relationship between elevated CRP levels in the serum and CSF and the development of vasospasm in patients with aSAH. METHODS: A total of 41 adult patients in whom aSAH was diagnosed were included in the study. Their demographics, the admitting Glasgow Coma Scale (GCS) score, Hunt and Hess grade, Fisher grade, CT scans, digital subtraction angiography studies, and daily neurological examinations were recorded. Serial serum and CSF CRP measurements were obtained on Days 0, 1, 2, 3, 5, 7, and 9. All patients underwent either surgical or endovascular treatment within 48 hours of their admission. The outcome was evaluated using the Glasgow Outcome Scale and the modified Rankin Scale. RESULTS: The CRP levels in serum and CSF peaked on the 3rd postadmission day, and the CRP levels in CSF were always higher than the serum levels. Patients with lower admission GCS scores and higher Hunt and Hess and Fisher grades had statistically significantly higher levels of CRP in serum and CSF. Patients with angiographic vasospasm had higher CRP measurements in serum and CSF, in a statistically significant fashion (p < 0.0001). Additionally, patients with higher CRP levels in serum and CSF had less favorable outcome in this cohort. CONCLUSIONS: Patients with aSAH who had high Hunt and Hess and Fisher grades and low GCS scores showed elevated CRP levels in their CSF and serum. Furthermore, patients developing angiographically proven vasospasm demonstrated significantly elevated CRP levels in serum and CSF, and increased CRP measurements were strongly associated with poor clinical outcome in this cohort. | Is there an association between c-reactive protein concentrations and outcomes of subarachnoid hemorrhage patients? | 514cbbf9d24251bc05000065_007 | yes |
Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress. Exendin-4 (ex-4) is a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist which exerts beneficial effects on glycemic control and promotes cell viability. In the present study, we investigated the anti-apoptotic effects of ex-4, as well as the potential mechanisms responsible for these effects in rat bone marrow-derived mesenchymal stem cells (BM-MSCs) under conditions of oxygen, glucose and serum deprivation (OGD). The apoptosis of the MSCs was induced by subjecting the cells to OGD conditions for 4 h and was detected by Annexin V/PI and Hoechst 33258 staining. The MSCs were pre-conditioned with ex-4 for 12 h prior to being subjected to OGD conditions, and the expression levels of an apoptotic marker (cleaved caspase-3), endoplasmic reticulum (ER) stress markers [phosphorylated (p-)protein kinase RNA-like endoplasmic reticulum kinase (PERK), PERK, binding immunoglobulin protein (BIP), activating transcription factor 4 (ATF-4) and C/EBP homologous protein (CHOP)], as well as those of a survival marker (Bcl-2) were measured by western blot analysis. Furthermore, the mRNA levels of ATF-4 and CHOP were determined by RT-qPCR. ELISA was used to examine the activity of intracellular cAMP. Moreover, the GLP-1R antagonist, exendin9-39 (ex9-39), the protein kinase A (PKA) inhibitor, H89, and small interfering RNA (siRNA) targeting rat ATF-4 and CHOP were co-incubated with the MSCs. The apoptotic rate was markedly diminished following pre-conditioning with ex-4 in a dose - dependent manner (P<0.05). The ER stress markers, p-PERK, BIP, ATF-4 and CHOP, were upregulated in the cells subjected to OGD conditions. Ex-4 pre-conditioning significantly decreased the mRNA and protein levels of ATF-4 and CHOP (P<0.05), and increased the activity of intracellular cAMP (P<0.05). Furthermore, the anti-apoptotic effects of ex-4 were almost reversed by treatment with either H89 or ex9-39 (P<0.05); transfection with siRNA-CHOP significantly reduced the apoptotic rate of the MSCs and did not impair the cytoprotective effects of ex-4. Taken together, these findings suggest that ex-4 protects rat BM-MSCs from OGD-induced apoptosis through the activation of the PKA/cAMP pathway and the attenuation of the ER stress signaling pathway. Ex-4 may thus prove to be a therapeutic agent with the potential to improve the viability of MSCs in the ischemic milieu, and consequently, to optimize the therapeutic effects of MSC therapy in acute myocardial infarction. | Is Annexin V an apoptotic marker? | 5894597e7d9090f353000004_007 | yes |
A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Enzastaurin, a potent inhibitor of protein kinase C-beta, inhibits angiogenesis and has direct cytotoxic activity against glioma cells in preclinical studies. Patients with recurrent high-grade gliomas were stratified by histology and use of enzyme-inducing antiepileptic drugs (EIAEDs). Patients on EIAED were treated on the phase I dose-escalation portion of the trial with evaluation of serum pharmacokinetics as the primary endpoint. Patients not on EIAED were treated on the phase II portion of the trial with radiographic response and progression-free survival (PFS) as primary objectives. Patients in phase I received enzastaurin 525-900 mg/d. Phase II patients received 500 or 525 mg/d. One hundred and eighteen patients were accrued to this trial. Therapy was well tolerated with thrombosis, thrombocytopenia, hemorrhage, and elevated alanine aminotransferase as the most commonly observed drug-associated grade 3 or higher toxicities. Patients on EIAED had serum enzastaurin exposure levels approximately 80% lower than those not on EIAED. Dose escalations up to 900 mg/d did not substantially increase serum exposure levels and a maximally tolerated dose was never reached. Twenty-one of 84 evaluable patients (25%) experienced an objective radiographic response. The 6-month PFS was 7% for patients with glioblastoma and 16% for patients with anaplastic glioma. Phosphorylation of glycogen synthase kinase-3 in peripheral blood mononuclear cells was identified as a potential biomarker of drug activity. Enzastaurin has anti-glioma activity in patients with recurrent high-grade glioma, but does not appear to have enough single-agent activity to be useful as monotherapy. | Is enzastaurin effective treatment of glioblastoma? | 5a7612b483b0d9ea6600001d_007 | no |
Prospective study of methods of renal function evaluation in patients with neurogenic bladder dysfunction. OBJECTIVE: To evaluate the precision of methods used to assess renal function in patients with neurogenic voiding dysfunction. MATERIALS AND METHODS: This multicenter prospective study, which was set in Toulouse and Lyon, France, included 60 patients (mean age, 48.9 ± 15.2 years) with neurogenic bladder and sphincter dysfunction. The correlation and the concordance with the inulin clearance of each method of renal function evaluation were assessed. RESULTS: The correlation of serum creatinine with inulin clearance was low when using serum creatinine-based equations such as the Modification of Diet in Renal Disease (simplified and complete) and Cockcroft-Gault equations. The r and r(2) coefficients were higher for creatinine-based methods, such as 24-hour (r = 0.72) and 3-hour creatinine clearance (r = 0.78). The strongest correlation was found for serum cystatin C-based equations: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine/cystatin C combined equation (r = 0.78) and the CKD-EPI cystatin C equation (r = 0.80). Mean bias of serum creatinine-based equations estimating glomerular filtration rate, the Cockcroft-Gault, and the simplified and complete Modification of Diet in Renal Disease equations, was 27.5 ± 28.6, 17.48 ± 29.40, and 21.98 ± 30.40 mL/min, respectively. Mean bias of creatinine clearance was 19.89 ± 15.30 mL/min at 3 hours and 19.00 ± 31.08 mL/min at 24 hours. Mean bias of the CKD-EPI cystatin C and the CKD-EPI creatinine/cystatin C combined equations was 11.98 ± 17.68 mL/min and 18.62 ± 17.85 mL/min, respectively. Limitations are the numerous types of neurologic diseases. CONCLUSION: The CKD-EPI equation using cystatin C was the most precise method of renal function evaluation in patients with neurogenic bladder. | Is cystatin C or cystatin 3 used as a biomarker of kidney function? | 550bf315c2af5d5b7000000e_016 | yes |
Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment. | Is Wnt16b secreted in response to chemotherapy? | 56e6f027a12c1fc13b000001_002 | yes |
Phase I clinical trial assessing temozolomide and tamoxifen with concomitant radiotherapy for treatment of high-grade glioma. PURPOSE: The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas. METHODS AND MATERIALS: A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were given tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status > 60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m(2) divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m(2) increments until the MTD was reached. When > 2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m(2). A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered. RESULTS: A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m(2). One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m(2). CONCLUSIONS: The MTD of tamoxifen was 100 mg/m(2) when given concurrently with temozolomide 75 mg/m(2) and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy. | Was tamoxifen tested for treatment of glioma patients? | 56c0968def6e394741000026_005 | yes |
In vitro binding evaluation of 177Lu-AMBA, a novel 177Lu-labeled GRP-R agonist for systemic radiotherapy in human tissues. Members of the gastrin-releasing peptide (GRP) family and its analogs bombesin (BBN) have been implicated in the biology of several human cancers including prostate, breast, colon and lung. To date, three mammalian GRP/BBN receptor subtypes have been cloned and characterized: the neuromedin B receptor (NMBR), the GRP receptor (GRPR) and the BBN-receptor subtype 3 (BB(3)). The fourth BBN receptor subtype, BB(4), has only been identified in amphibian and at present no mammalian equivalent of this receptor has been described. GRPR analogs have been used as carriers to deliver drugs, radionuclides and cytotoxins to target various cancer types that are GRPR positive. We investigated the in vitro binding properties of (177)Lu-AMBA, a novel radiolabelled BBN analog currently undergoing clinical trial as systemic radiotherapy for hormone refractory prostate cancer (HRPC) patients. Pharmacological analyses of the (177)Lu-AMBA was determined using in vitro binding studies using membrane target system containing specific receptor subtypes. We investigated the distribution of binding sites for (177)Lu-AMBA by receptor autoradiography on human neoplastic and non-neoplastic tissues. Pharmacological characterizations of (177)Lu-AMBA shows, high affinity towards NMB and GRP receptors, while little or no affinity towards BB(3) receptor. Among the 40 different types of non-neoplastic tissues tested seven of them showed limited but specific binding of (177)Lu-AMBA. Fourteen of 17 primary prostate cancers, six of 13 primary breast cancers expressed binding sites for (177)Lu-AMBA. Furthermore, no apparent differences in (177)Lu-AMBA-binding sites expression were observed between matched pairs (primary vs. secondary) of prostate and breast cancer tissues. These data represent the molecular basis for clinical applications of (177)Lu-AMBA for diagnosis and treatment of GRP-R and NMB-R positive tumors. | Are the human bombesin receptors, GRPR and NMBR, frequently overexpressed G-protein-coupled-receptors by lung-cancers? | 5a8dc57ffcd1d6a10c000025_001 | yes |
Genome-wide DNA methylation variability in adolescent monozygotic twins followed since birth. DNA methylation patterns are characterized by highly conserved developmental programs, but allow for divergent gene expression resulting from stochastic epigenetic drift or divergent environments. Genome-wide methylation studies in monozygotic (MZ) twins are providing insight into the extent of epigenetic variation that occurs, irrespective of genotype. However, little is known about the variability of DNA methylation patterns in adolescence, a period involving significant and rapid physical, emotional, social, and neurodevelopmental change. Here, we assessed genome-wide DNA methylation using the 450 K Illumina BeadChip in a sample of 37 MZ twin pairs followed longitudinally since birth to investigate: 1) the extent of variation in DNA methylation in identical genetic backgrounds in adolescence and; 2) whether these variations are randomly distributed or enriched in particular functional pathways. We also assessed stability of DNA methylation over 3-6 months to distinguish stable trait-like and variable state-like genes. A pathway analysis found high within-pair variability in genes associated with development, cellular mechanisms, tissue and cell morphology, and various disorders. Test-retest analyses performed in a sub-sample of 8 twin pairs demonstrated enrichment in gene pathways involved in organismal development, cellular growth and proliferation, cell signaling, and particular disorders. The variability found in functional gene pathways may plausibly underlie phenotypic differences in this adolescent MZ twin sample. Furthermore, we assessed stability of methylation over 3-6 months and found that some genes were stable while others were unstable, suggesting that the methylome remains dynamic in adolescence and that dynamic sites tend to be organized in certain gene pathways. | Is DNA methylation an epigenetic modification of chromatin related to gene expression? | 54d9f7894b1fd0d33c00000a_009 | yes |
Efficacy and safety of ferric carboxymaltose in correcting iron-deficiency anemia: a review of randomized controlled trials across different indications. Ferric carboxymaltose (FCM, Ferinject) was effective and well tolerated in the treatment of iron-deficiency anemia (IDA) in nine, Phase III, randomized, controlled, multicenter trials in a diverse range of indications, including patients with inflammatory bowel disease (IBD), post-partum anemia (PPA) or abnormal uterine bleeding (AUB), chronic heart failure (CHF), non-dialysis-dependent chronic kidney disease (CKD) and those undergoing hemodialysis (HD). In most trials, patients received either FCM doses of < or = 1000 mg, administered intravenously (i.v.) over < or = 15 min. or oral ferrous sulfate (FeSulf) 325 mg (65 mg iron), three times daily (t.i.d.), or 304 mg (100 mg iron), twice daily (b.i.d.). In one trial, patients on HD received 200 mg i.v. of either FCM or iron sucrose (ISC), two-to-three times weekly. In a pilot study in patients with CHF and CKD, patients received 200 mg of FCM by push injection compared with 200 mg of ISC slow injection. FCM was usually administered until the patient's calculated total iron replacement dose was achieved. Treatment with FCM improved indices of anemia (hemoglobin [Hb], ferritin and transferrin saturation [TSAT] values). In patients on HD with IDA secondary to CKD, FCM demonstrated comparable efficacy to ISC in achieving an increase in Hb. In patients with IBD or PPA, improvements in Hb levels were more rapid with FCM than with FeSulf. Patients with PPA receiving FCM compared with those receiving oral iron achieved an Hb rise > or = 2.0 g/dl earlier (7 days compared with 14 days; p < 0.001), were more likely to achieve an Hb rise > or = 3.0 g/dl at any time beginning at day 14 (86.3% compared with 60.4%; p < 0.001), and achieve an Hb > 12.0 g/dl at the end of the study (Day 42; 90.5% compared with 68.6%, p < 0.01). Serum ferritin increased in the i.v. FCM treatment group, but not in the oral iron group. Differences between groups were significant at each study interval. TSAT increased significantly at every interval in both groups; however, FCM-treated patients showed higher TSAT at each interval after the first week. FCM improved patient quality of life to an equivalent extent to oral FeSulf in patients with IBD or PPA, and to a greater extent than oral FeSulf in women with AUB. FCM also improved quality of life as well as functional symptoms and exercise capacity in patients with CHF. Safety data from more than 3000 patients showed that FCM was well tolerated. No safety concerns have been identified in breastfed infants of mothers receiving FCM. FCM is, therefore, an effective and well-tolerated option in the treatment of IDA. | Can ferric carboxymaltose be used to treat anemia in inflammatory bowel disease patients? | 530cf4fe960c95ad0c00000d_000 | yes |
miR-146a inhibits cell growth, cell migration and induces apoptosis in non-small cell lung cancer cells. Aberrant expression of microRNA-146a (miR-146a) has been reported to be involved in the development and progression of various types of cancers. However, its role in non-small cell lung cancer (NSCLC) has not been elucidated. The aim of this study was to investigate the contribution of miR-146a to various aspects of the malignant phenotype of human NSCLCs. In functional experiments, miR-146a suppressed cell growth, induced cellular apoptosis and inhibited EGFR downstream signaling in five NSCLC cell lines (H358, H1650, H1975, HCC827 and H292). miR-146a also inhibited the migratory capacity of these NSCLC cells. On the other hand, miR-146a enhanced the inhibition of cell proliferation by drugs targeting EGFR, including both TKIs (gefitinib, erlotinib, and afatinib) and a monoclonal antibody (cetuximab). These effects were independent of the EGFR mutation status (wild type, sensitizing mutation or resistance mutation), but were less potent compared to the effects of siRNA targeting of EGFR. Our results suggest that these effects of miR-146a are due to its targeting of EGFR and NF-κB signaling. We also found, in clinical formalin fixed paraffin embedded (FFPE) lung cancer samples, that low expression of miR-146a was correlated with advanced clinical TNM stages and distant metastasis in NSCLC (P<0.05). The patients with high miR-146a expression in their tumors showed longer progression-free survival (25.6 weeks in miR-146a high patients vs. 4.8 weeks in miR-146a low patients, P<0.05). miR-146a is therefore a strong candidate prognostic biomarker in NSCLC. Thus inducing miR-146a might be a therapeutic strategy for NSCLC. | Can siRNA affect response to afatinib treatment? | 54297ed2289fd6cb07000001_000 | yes |
Autoantibodies to posttranslational modifications in rheumatoid arthritis. Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases (AIDs). Rheumatoid factor (RF) is known since the late 1930s to be associated with rheumatoid arthritis (RA). The discovery of anticitrullinated protein antibodies in the last century has changed this and other posttranslational modifications (PTM) relevant to RA have since been described. Such PTM introduce neoepitopes in proteins that can generate novel autoantibody specificities. The recent recognition of these novel specificities in RA provides a unique opportunity to understand human B-cell development in vivo. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. With the advancement of research methodologies it should be expected that other autoantibodies against PTM proteins could be discovered in patients with autoimmune diseases. Many of such autoantibodies may provide significant biomarker potential. | Has protein citrullination been implicated in rheumatoid arthritis? | 54d796f93706e8952800001e_005 | yes |
Blood sugar lowering potentiality of selected Cucurbitaceae plants of Indian origin. Using five experimental models, the blood sugar lowering efficacy of eight plants of Cucurbitaceae family has been assessed. The ethanolic extract of Cucumis sativus Linn, Cucumis melo utilissimum Roxb, Cucumis melo Linn, Benincasa hispida Thunb Cogn and Tricosanthes anguina Nees, when administered in 250 mg/kg dose, orally to rats failed to lower blood sugar or to depress the peak value, after glucose load. However, ethanolic extract of Momordica charantia Linn plant and Coccinia indica Whit and Arn root significantly lowered blood sugar in fasted model and depressed the peak value in glucose loaded model. Ethanolic extract of Tricosanthes dioica Roxb plant caused a significant lowering of blood sugar in fasted rats and depressed the peak value in glucose loaded single and longterm fed groups of rats. The ethanolic extract of the aerial part of T. dioica also induced significant depression in the peak values in the glucose loaded models. | Does cucumber lower blood sugar in diabetics? | 516c220e298dcd4e51000071_000 | yes |
Dopamine receptor mediation of the exploratory/hyperactivity effects of modafinil. Modafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical stimulant and is a putative cognition enhancer for schizophrenia, but the precise mechanisms of action remain unclear. Receptor knockout (KO) mice offer an opportunity to identify receptors that contribute to a drug-induced effect. Here we examined the effects of modafinil on exploration in C57BL/6J mice, in dopamine drd1, drd2, drd3, and drd4 wild-type (WT), heterozygous (HT), and KO mice, and in 129/SJ mice pretreated with the drd1 antagonist SCH23390 using a cross-species test paradigm based on the behavioral pattern monitor. Modafinil increased activity, specific exploration (rearing), and the smoothness of locomotor paths (reduced spatial d) in C57BL/6J and 129/SJ mice (increased holepoking was also observed in these mice). These behavioral profiles are similar to that produced by the dopamine transporter inhibitor GBR12909. Modafinil was ineffective at increasing activity in male drd1 KOs, rearing in female drd1 KOs, or reducing spatial d in all drd1 KOs, but produced similar effects in drd1 WT and HT mice as in C57BL/6J mice. Neither dopamine drd2 nor drd3 mutants attenuated modafinil-induced effects. Drd4 mutants exhibited a genotype dose-dependent attenuation of modafinil-induced increases in specific exploration. Furthermore, the drd1 KO effects were largely supported by the SCH23390 study. Thus, the dopamine drd1 receptor appears to exert a primary role in modafinil-induced effects on spontaneous exploration, whereas the dopamine drd4 receptor appears to be important for specific exploration. The modafinil-induced alterations in exploratory behavior may reflect increased synaptic dopamine and secondary actions mediated by dopamine drd1 and drd4 receptors. | Was modafinil tested for schizophrenia treatment? | 54fc845e6ea36a810c000005_000 | yes |
3D brown adipogenesis to create "Brown-Fat-in-Microstrands". The ability of brown adipocytes (fat cells) to dissipate energy as heat shows great promise for the treatment of obesity and other metabolic disorders. Employing pluripotent stem cells, with an emphasis on directed differentiation, may overcome many issues currently associated with primary fat cell cultures. In addition, three-dimensional (3D) cell culture systems are needed to better understand the role of brown adipocytes in energy balance and treating obesity. To address this need, we created 3D "Brown-Fat-in-Microstrands" by microfluidic synthesis of alginate hydrogel microstrands that encapsulated cells and directly induced cell differentiation into brown adipocytes, using mouse embryonic stem cells (ESCs) as a model of pluripotent stem cells, and brown preadipocytes as a positive control. Brown adipocyte differentiation within microstrands was confirmed by immunocytochemistry and qPCR analysis of the expression of the brown adipocyte-defining marker uncoupling protein 1 (UCP1), as well as other general adipocyte markers. Cells within microstrands were responsive to a β-adrenergic agonist with an increase in gene expression of thermogenic UCP1, indicating that these "Brown-Fat-in-Microstrands" are functional. The ability to create "Brown-Fat-in-Microstrands" from pluripotent stem cells opens up a new arena to understanding brown adipogenesis and its implications in obesity and metabolic disorders. | Do brown fat cells produce heat? | 58ca906a02b8c6095300002e_009 | yes |
Calpain activation by ROS mediates human ether-a-go-go-related gene protein degradation by intermittent hypoxia. Human ether-a-go-go-related gene (hERG) channels conduct delayed rectifier K(+) current. However, little information is available on physiological situations affecting hERG channel protein and function. In the present study we examined the effects of intermittent hypoxia (IH), which is a hallmark manifestation of sleep apnea, on hERG channel protein and function. Experiments were performed on SH-SY5Y neuroblastoma cells, which express hERG protein. Cells were exposed to IH consisting of alternating cycles of 30 s of hypoxia (1.5% O2) and 5 min of 20% O2. IH decreased hERG protein expression in a stimulus-dependent manner. A similar reduction in hERG protein was also seen in adrenal medullary chromaffin cells from IH-exposed neonatal rats. The decreased hERG protein was associated with attenuated hERG K(+) current. IH-evoked hERG protein degradation was not due to reduced transcription or increased proteosome/lysomal degradation. Rather it was mediated by calcium-activated calpain proteases. Both COOH- and NH2-terminal sequences of the hERG protein were the targets of calpain-dependent degradation. IH increased reactive oxygen species (ROS) levels, intracellular Ca(2+) concentration ([Ca(2+)]i), calpain enzyme activity, and hERG protein degradation, and all these effects were prevented by manganese-(111)-tetrakis-(1-methyl-4-pyridyl)-porphyrin pentachloride, a membrane-permeable ROS scavenger. These results demonstrate that activation of calpains by ROS-dependent elevation of [Ca(2+)]i mediates hERG protein degradation by IH. | Does the hERG gene code for a protein which is part of a sodium channel? | 58bdc76102b8c60953000013_014 | no |
Development and characterization of a preclinical ovarian carcinoma model to investigate the mechanism of acquired resistance to trastuzumab. Trastuzumab (Herceptin®) is a humanized monoclonal antibody designed to bind and inhibit the function of the human epidermal growth factor receptor 2 (HER2)/erbB2 receptor. Trastuzumab has demonstrated clinical activity in several types of HER2-overexpressing epithelial tumors, such as breast and metastatic gastric or gastroesophageal junction cancer. Relapse and therapeutic resistance, however, still occur in a subset of patients treated with regimens including trastuzumab, despite significant improvements in response rates, survival and quality of life. To investigate the potential mechanisms of acquired therapeutic resistance to trastuzumab, we developed a preclinical model of human ovarian cancer cells, SKOV-3 Herceptin-resistant (HR), and examined the corresponding changes in gene expression profiles. SKOV-3 HR cells were developed by in vivo serial passaging of parental trastuzumab-sensitive SKOV-3 cells. Following four rounds of serial transplantation of 'break-through' xenograft tumors under trastuzumab treatment, significant and reproducible differences in the effects of trastuzumab treatment between SKOV-3 HR and SKOV-3 cells in vivo and in vitro were revealed. SKOV-3 HR cells retained HER2 protein expression but were unaffected by the antiproliferative effects of trastuzumab. The trastuzumab binding affinity for SKOV-3 HR cells was diminished, despite these cells having more binding sites for trastuzumab. Microarray expression profiling (MEP) was performed to determine the genes involved in the resistance mechanism. Functional analysis revealed the differential expression of genes potentially involved in angiogenesis, metastasis, differentiation and proliferation, such as mucin1 (MUC1). Immunohistochemical staining of SKOV-3 HR cells demonstrated a marked overexpression of MUC1. Based on these data, we hypothesize that the overexpression of MUC1 may hinder trastuzumab binding to HER2 receptors, abrogating the antitumor effects of trastuzumab and thus could contribute to resistance to therapy. Moreover, the resultant MEP preclinical gene signature in this preclinical model system may provide the basis for further investigation of potential clinical mechanisms of resistance to trastuzumab. | Does HER2 under-expression lead to favorable response to trastuzumab? | 51542eacd24251bc05000084_002 | no |
Period 2 mutation accelerates ApcMin/+ tumorigenesis. Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and beta-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on beta-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone Apc(Min/+) mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases beta-catenin, cyclin D, and cell proliferation. Down-regulation of beta-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2(m/m) mice develop colonic polyps and show an increase in small intestinal mucosa beta-catenin and cyclin D protein levels compared with wild-type mice. Apc(Min/+)Per2(m/m) mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with Apc(Min/+) mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of beta-catenin and beta-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control. | Is c-myc subject to regulation by the circadian clock? | 531616bdb166e2b806000003_003 | yes |
A randomized, double-blind trial of 2.5 mg and 5 mg vortioxetine (Lu AA21004) versus placebo for 8 weeks in adults with major depressive disorder. OBJECTIVE: Vortioxetine (Lu AA21004) is an investigational antidepressant. In vitro studies indicate that vortioxetine is a 5-HT(3), 5-HT(7), and 5-HT(1D) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and inhibitor of the 5-HT transporter. This trial assessed the efficacy and tolerability of 2.5 and 5 mg vortioxetine for the treatment of MDD. RESEARCH DESIGN AND METHODS: Adults (N = 611) with MDD were randomized to 8 weeks of double-blind treatment with placebo, vortioxetine (2.5 or 5 mg) or active reference (duloxetine 60 mg). The primary measure was change from baseline in the 24-item Hamilton Depression Scale (HAM-D24). Secondary endpoints included responder rate, Clinical Global Impression Scale-Global Improvement scale (CGI-I), and remission rate. Participants were monitored for adverse events (AEs), and treatment-emergent sexual dysfunction using the Arizona Sexual Experiences (ASEX) scale. RESULTS: Both doses of vortioxetine were associated with declines in HAM-D24 total scores compared to placebo but were not statistically significant. At 8 weeks, changes from baseline were [mean (SE)]: -10.50 (0.76) placebo, -12.04 (0.74) 2.5 mg vortioxetine, and -11.08 (0.74) 5 mg vortioxetine. Secondary outcome measures in the vortioxetine groups, including responder rate, CGI-I, and remission rate, were also not significantly different from placebo. Duloxetine treatment was associated with declines in HAM-D24 total score [-13.47(0.75); p = 0.005] as well as significant improvements in secondary outcome measures versus placebo (p < 0.05). The most common AEs for vortioxetine were nausea, dry mouth, and headache. Rates of sexual dysfunction (ASEX) were 51.0%, 37.5%, 46.9%, and 33.3% in the vortioxetine 2.5 mg, vortioxetine 5 mg, duloxetine, and placebo groups, respectively. CONCLUSIONS: In this study of adults with MDD treated for 8 weeks with vortioxetine 2.5 mg or 5 mg per day, reductions in depression symptoms were not statistically significant compared with placebo. Study limitations are discussed, including patient characteristics, MDD severity, drug dosing, and aspects of trial design. Both doses of vortioxetine were well tolerated. This trial has been registered at clinicaltrials.gov #NCT00672620. | Is Vortioxetine effective for treatment of depression? | 53359338d6d3ac6a3400004f_000 | yes |
Cytotoxicity of paraquat in microglial cells: Involvement of PKCdelta- and ERK1/2-dependent NADPH oxidase. Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP+), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67phox cytosolic subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKCdelta) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKCdelta inhibitor, also inhibited paraquat-induced translocation of p67phox. Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKCdelta- and ERK-dependent pathways. | Can NADPH oxidase be inhibited by apocynin and diphenylene iodonium? | 58a5924060087bc10a000020_001 | yes |
Statins and their increased risk of inducing diabetes. INTRODUCTION: Statins are evidence-based drugs to prevent cardiovascular (CV) disease. However, their benefits have been disputed by a statin-related increased risk of new onset diabetes (NOD) in randomized controlled trials and meta-analyses. AREAS COVERED: This review provides an update based on recent outstanding evidence on the statin effect on the risk of diabetes. It also describes mechanisms potentially explaining adverse effects of statins on glucose homeostasis. PubMed was searched for original articles and reviews published from January 2010 (inclusive) to May 2015 (inclusive), which include the Search terms statins, diabetes, glucose, and insulin. NOD risk seems to be more relevant with high-intensity rather than with low-intensity statin treatment. Also, this risk is particularly increased in patients at risk for the development of diabetes. It appears that statins adversely affect glucose homeostasis in parallel with their 3-hydroxy-3-methylglutaryl-coenzyme A inhibition capacity. It was suggested that lipophilic statins are more diabetogenic than the hydrophilic ones. Mechanisms explaining statin diabetogeneicity include impaired insulin secretion by pancreatic β cells together with increased insulin resistance of various tissues. EXPERT OPINION: The CV outcome benefits from statin use outweigh the diabetes menace. However, patients at risk for the development of diabetes should be prescribed statins with caution. | Do statins cause diabetes? | 58a341eb60087bc10a000018_012 | yes |
Are low concentrations of serum triiodothyronine a good marker for long-term mortality in hemodialysis patients? INTRODUCTION: Low serum free triiodothyronine (FT3) concentrations have been reported in a high percentage of chronic renal failure patients and have been considered as an independent predictor of mortality in dialysis patients. OBJECTIVE: Our aim has been to evaluate the prognostic value of FT3 levels for long-term mortality in stable hemodialysis patients surviving at least 12 months. PATIENTS AND MEASUREMENTS: We retrospectively analyzed 89 stable hemodialysis patients (50 males; mean age 67.9 +/- 11.8 years). All patients had a baseline clinical and analytical evaluation. We analyzed the relationship between baseline FT3 and mortality by means of survival analysis (Kaplan-Meier) and Cox regression analysis. RESULTS: Mean values of thyroid function test were: thyrotropin (TSH) 2.02 +/- 1.5 microU/ml, free thyroxine (FT4) 1.26 +/- 0.23 ng/dl, and FT3 2.7 +/- 0.4 pg/ml. During a median follow-up time of 33.6 +/- 14.9 (12 - 62) months, 41 patients died. FT3 was similar in patients who died or survived (2.6 +/- 0.5 vs. 2.7 +/- 0.4 pg/ml ns). Kaplan-Meier analysis did not show significant differences in mean survival according to tertiles of FT3. In multivariate Cox regression analysis, FT3 was not a predictor of mortality (RR 0,001; 95% CI; 0.000 to 1.73). CONCLUSIONS: These data suggest that low FT3 levels are not predictive for mortality in a subgroup of stable HD patients who could survive more than 12 months. | Is low T3 syndrome a prognostic marker in patients with renal insufficiency? | 5325de7d9b2d7acc7e000029_008 | yes |
Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates. We report evidence for a mechanism for the maintenance of long-range conserved synteny across vertebrate genomes. We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated "bystander" genes. Bystander genes are not specifically under the control of the regulatory elements that drive the target genes and are expressed in patterns that are different from those of the target genes. 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). After whole genome duplication in teleosts, GRBs, including HCNEs and target genes, were often maintained in both copies, while bystander genes were typically lost from one GRB, strongly suggesting that evolutionary pressure acts to keep the single-copy GRBs of higher vertebrates intact. We show that loss of bystander genes and other mutational events suffered by duplicated GRBs in teleost genomes permits target gene identification and HCNE/target gene assignment. These findings explain the absence of evolutionary breakpoints from large vertebrate chromosomal segments and will aid in the recognition of position effect mutations within human GRBs. | Are there conserved noncoding elements identified between genomes of human and teleosts? | 5544bcde5beec11c10000003_000 | yes |
Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Epigenetic modifications such as histone methylation play an important role in human cancer metastasis. Enhancer of zeste homolog 2 (EZH2), which encodes the histone methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed widely in breast and prostate cancers and epigenetically silences tumor suppressor genes. Expression levels of the novel tumor and metastasis suppressor Raf-1 kinase inhibitor protein (RKIP) have been shown to correlate negatively with those of EZH2 in breast and prostate cell lines as well as in clinical cancer tissues. Here, we show that the RKIP/EZH2 ratio significantly decreases with the severity of disease and is negatively associated with relapse-free survival in breast cancer. Using a combination of loss- and gain-of-function approaches, we found that EZH2 negatively regulated RKIP transcription through repression-associated histone modifications. Direct recruitment of EZH2 and suppressor of zeste 12 (Suz12) to the proximal E-boxes of the RKIP promoter was accompanied by H3-K27-me3 and H3-K9-me3 modifications. The repressing activity of EZH2 on RKIP expression was dependent on histone deacetylase promoter recruitment and was negatively regulated upstream by miR-101. Together, our findings indicate that EZH2 accelerates cancer cell invasion, in part, via RKIP inhibition. These data also implicate EZH2 in the regulation of RKIP transcription, suggesting a potential mechanism by which EZH2 promotes tumor progression and metastasis. | Is EZH2 associated with prostate cancer? | 570908e3cf1c325851000012_022 | yes |
Mobility, microtubule nucleation and structure of microtubule-organizing centers in multinucleated hyphae of Ashbya gossypii. We investigated the migration of multiple nuclei in hyphae of the filamentous fungus Ashbya gossypii. Three types of cytoplasmic microtubule (cMT)-dependent nuclear movements were characterized using live cell imaging: short-range oscillations (up to 4.5 microm/min), rotations (up to 180 degrees in 30 s), and long-range nuclear bypassing (up to 9 microm/min). These movements were superimposed on a cMT-independent mode of nuclear migration, cotransport with the cytoplasmic stream. This latter mode is sufficient to support wild-type-like hyphal growth speeds. cMT-dependent nuclear movements were led by a nuclear-associated microtubule-organizing center, the spindle pole body (SPB), which is the sole site of microtubule nucleation in A. gossypii. Analysis of A. gossypii SPBs by electron microscopy revealed an overall laminar structure similar to the budding yeast SPB but with distinct differences at the cytoplasmic side. Up to six perpendicular and tangential cMTs emanated from a more spherical outer plaque. The perpendicular and tangential cMTs most likely correspond to short, often cortex-associated cMTs and to long, hyphal growth-axis-oriented cMTs, respectively, seen by in vivo imaging. Each SPB nucleates its own array of cMTs, and the lack of overlapping cMT arrays between neighboring nuclei explains the autonomous nuclear oscillations and bypassing observed in A. gossypii hyphae. | Has the fungus Ashbya gossypii got many nuclei that share cytoplasm? | 550e6688a103b7801600000d_012 | yes |
Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomized, controlled thromboVIT trial. BACKGROUND: Secondary thrombocytosis is a common clinical feature. In patients with cancer, it is a risk factor for venous thromboembolic events. In inflammatory bowel disease (IBD), thrombocytosis is so far considered a marker of active disease and may contribute to the increased thromboembolic risk in this population. Observed effects of iron therapy on normalization of platelet counts led us to hypothesize that iron itself may regulate megakaryopoiesis. Here, we want to test the effect of iron replacement on platelet count and activity in IBD-associated thrombocytosis. METHODS: We performed a randomized, single-blinded placebo-controlled trial testing the effect of ferric carboxymaltose (FCM) in patients with IBD with secondary thrombocytosis (platelets > 450 G/L). Changes in platelet counts, hemoglobin, iron parameters, disease activity, megakaryopoietic growth factors, erythropoietin, and platelet activity were assessed. Patients received placebo or up to 1500 mg iron as FCM. Endpoints were evaluated at week 6. RESULTS: A total of 26 patients were included in the study, 15 patients were available for the per protocol analysis. A drop in platelets >25% (primary endpoint) was observed in 4 of 8 (50%, iron group) and 1 of 7 patients (14%, placebo group, P = 0.143). Mean platelet counts dropped on FCM but not on placebo (536 G/L to 411 G/L versus 580 G/L to 559 G/L; P = 0.002). Disease activity and megakaryopoietic growth factors remained unchanged and hemoglobin and iron parameters increased on FCM. The normalization of platelet counts was associated with a decrease in platelet aggregation and P-selectin expression. CONCLUSION: FCM lowers platelet counts and platelet activation in patients with IBD-associated secondary thrombocytosis. | Can ferric carboxymaltose be used to treat anemia in inflammatory bowel disease patients? | 530cf4fe960c95ad0c00000d_004 | yes |
Effects of splice sites on the intron retention in histamine H3 receptors from rats and mice. In the alternative splicing, intron retention, of histamine H(3) receptors in rats and mice, the short transcript isoforms that are excised alternatively spliced introns are easily detected in a very low level in rats and are undetectable in mice using the regular PCR protocol. The retained introns have common 5' splice site and different 3' splice sites. The detailed mechanism for the special alternative splicing remains largely unclear. In this study, we developed a minigene splicing system to recapitulate natural alternative splicing of the receptors and investigated the effects of 5' and 3' splice sites on intron retention in HeLa cells. Mutating weak 5' and 3' splice sites of the alternatively spliced introns toward the canonical consensus sequences promoted the splicing of the corresponding introns in rat and mouse minigenes. The effect of splice site strength was context-dependent and much more significant for the 3' splice site of the longer alternative intron than for the 3' splice site of the shorter alternative intron and the common 5' splice sites; it was also more significant in the rat minigene than in the mouse minigene. Mutating the 3' splice site of the longer alternative intron resulted in almost complete splicing of the intron and made the corresponding isoform to become the nearly exclusive transcript in the rat minigene. | Is recursive splicing more common in short introns? | 5abc974bfcf456587200001f_005 | no |
Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events. BACKGROUND: RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In the present study, we have performed a comprehensive study of our HSCR series evaluating the involvement of both RET rare variants (RVs) and common variants (CVs) in the context of the disease. METHODS: RET mutational screening was performed by dHPLC and direct sequencing for the identification of RVs. In addition Taqman technology was applied for the genotyping of 3 RET CVs previously associated to HSCR, including a variant lying in an enhancer domain within RET intron 1 (rs2435357). Statistical analyses were performed using the SPSS v.17.0 to analyze the distribution of the variants. RESULTS: Our results confirm the strongest association to HSCR for the "enhancer" variant, and demonstrate a significantly higher impact of it in male versus female patients. Integration of the RET RVs and CVs analysis showed that in 91.66% of cases with both kinds of mutational events, the enhancer allele is in trans with the allele bearing the RET RV. CONCLUSIONS: A gender effect exists on both the transmission and distribution of rare coding and common HSCR causing mutations. In addition, these RET CVs and RVs seem to act in a synergistic way leading to HSCR phenotype. | Is RET the major gene involved in Hirschsprung disease? | 5503121de9bde69634000019_010 | yes |