tbuckley/cabot-search huggingface dataset:
Abstract 12488: Spontaneous Beating of Cardiac Pacemaker Cells is Regulated by Basal Activation of Epidermal Growth Factor Receptor
Authors: Tatiana M Vinogradova, Kirill V Tarasov, Edward G Lakatta
Journal: Circulation (2015)

Spontaneous firing of sinoatrial node cells (SANC) is controlled by sarcoplasmic reticulum (SR) generated local subsarcolemmal Ca 2+ releases (LCRs), which appear during diastolic depolarization (DD) and activate an inward Na + -Ca 2+ exchange current to regulate DD rate and spontaneous SANC beating rate. Therapy directed against the epidermal growth factor receptor (EGFR) pathway had improved outcomes for patients with different types of cancer. It was noted, however, that inhibition of EGFR might lead to sinus bradycardia and sick sinus syndrome. Until now neither expression nor possible role of EGFR for spontaneous beating of cardiac pacemaker was examined. Here we studied expression of EGFR in rabbit SANC; effects of EGFR inhibition on spontaneous SANC firing and possible mechanisms of EGFR-dependent regulation of cardiac pacemaker function. We discovered that expression of EGFR (RNA-sequencing) in rabbit SANC exceeded that in ventricular myocytes by six-fold. Specific EGFR inhibitors erlotinib and AG1478 markedly decreased spontaneous SANC beating rate (perforated patch-clamp technique) and this effect was largely reversible upon drug washout. Both erlotinib and AG1478 suppressed SR Ca 2+ cycling (confocal microscopy, Ca 2+ indicator Fluo-3) in SANC, i.e. decreased LCR size and number per each spontaneous cycle and prolonged the LCR period (the interval between AP-induced Ca 2+ transient and subsequent LCR), which predicted the concomitant increase in the spontaneous cycle length. These data indicate basal activation of EGFR, which could activate other kinase cascades in rabbit SANC e.g. PKC-dependent phosphorylation through activation of PLC. Inhibition of either PLC activity by U-73122 or PKC activation by GF109203X or calphostin C suppressed LCRs and stopped spontaneous firing of rabbit SANC. We conclude that basal activation of EGFR regulates cardiac pacemaker function through PLC-PKC-dependent modulation of LCR characteristics. This might represent a novel pathway to control normal automaticity of SANC, which could be affected by cancer treatment therapy.
Adult IDH wild-type lower-grade gliomas should be further stratified
Authors: Abudumijit Aibaidula, Aden Ka-Yin Chan, Zhifeng Shi, Yanxi Li, Ruiqi Zhang, Rui Yang, Kay Ka-Wai Li, Nellie Yuk-Fei Chung, Yu Yao, Liangfu Zhou, Jinsong Wu, Hong Chen, Ho-Keung Ng
Journal: Neuro-Oncology (2017)

Astrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically.Seven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty-six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined.EGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification.Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups.
Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis
Authors: Joseph Michael Northey, Nicolas Cherbuin, Kate Louise Pumpa, Disa Jane Smee, Ben Rattray
Journal: British Journal of Sports Medicine (2017)

Physical exercise is seen as a promising intervention to prevent or delay cognitive decline in individuals aged 50 years and older, yet the evidence from reviews is not conclusive.To determine if physical exercise is effective in improving cognitive function in this population.Systematic review with multilevel meta-analysis.Electronic databases Medline (PubMed), EMBASE (Scopus), PsychINFO and CENTRAL (Cochrane) from inception to November 2016.Randomised controlled trials of physical exercise interventions in community-dwelling adults older than 50 years, with an outcome measure of cognitive function.The search returned 12 820 records, of which 39 studies were included in the systematic review. Analysis of 333 dependent effect sizes from 36 studies showed that physical exercise improved cognitive function (0.29; 95% CI 0.17 to 0.41; p<0.01). Interventions of aerobic exercise, resistance training, multicomponent training and tai chi, all had significant point estimates. When exercise prescription was examined, a duration of 45-60 min per session and at least moderate intensity, were associated with benefits to cognition. The results of the meta-analysis were consistent and independent of the cognitive domain tested or the cognitive status of the participants.Physical exercise improved cognitive function in the over 50s, regardless of the cognitive status of participants. To improve cognitive function, this meta-analysis provides clinicians with evidence to recommend that patients obtain both aerobic and resistance exercise of at least moderate intensity on as many days of the week as feasible, in line with current exercise guidelines.
P01.23 Genetic analysis of malignant transformation in glioma with 1p19q LOH
Authors: H. Nakamura, K. Makino
Journal: Neuro-Oncology (2017)

Purpose: Glioma is a CNS tumor resulting from accumulation of genetic alterations. In the process of malignant change in low grade gliomas another genetic alterations are supposed to be accumulated. In this study we analyzed the accumulation of genetic alterations in grade 2 or 3 oligodendroglioma with 1p19q LOH. Patients and Methods: We examined genomic alterations of whole chromosome using an Snip-microarray in grade 2 & 3 gliomas and found 66 cases with 1p19q LOH tumor. We focused on several genetic alterations such as loss of heterozygosity (LOH) and amplification in all chromosomes. IDH1 mutation was also examined by direct sequencing method. Furthermore we analyzed the mutation of 48 cancer-related genes. We compared the genetic alterations in between the primary tumors and the recurrent tumors with malignant transformation. Results: There were 5 patients with oligodendroglioma with 1p19q LOH demonstrating the malignant change at their recurrence. In 3 of 5 patients we could compare the genetic alterations between the primary tumors and the recurrent tumors. We found LOH in chromosome 18 and a mutation in PIK3CA gene as the additional common genetic change. IDH1 mutation was also found at both primary and recurrent tumors in all 3 cases. Conclusion: Although there are various genetic alterations at recurrence, PIK3CA and a gene in chromosome 18 may play a key role in malignant transformation.
Workload pressure no defence against clinical negligence, barrister warns
Authors: Abi Rimmer
Journal: BMJ (2017)

Judges considering prosecutions against doctors for gross negligence manslaughter would not view a lack of NHS resources as a defence against clinical negligence, a barrister who specialises in medical law and clinical negligence has said.

At a conference on litigation against doctors at the Royal Society of Medicine, James Badenoch QC said that he was often asked whether judges would take into account “the impossible conditions in which some doctors work.”

“The answer, to be relatively frank with you, is no,” he said. “We’ve often had discussions about whether financial constraints might …
P08.11 NMDA receptor activation differentially expresses NMDA and AMPA subtypes of glutamate receptors and mediate migration and invasion of glioma
Authors: N. Dalavaikodihalli Nanjaiah, P. Ramaswamy
Journal: Neuro-Oncology (2017)

Introduction: The most common and fatal intracranial brain tumor in adults is glioblastoma. It secretes a significant amount of glutamate and expresses glutamate receptor subunits. These tumors remain incurable because of high proliferative rate and an extremely invasive phenotype and patients have a mean survival of less than 15 months despite early diagnosis and combined modality therapy including surgical resection of tumour, chemotherapy and radiotherapy. Glutamate excitotoxicity, invasion and recurrence are major hallmarks for GBM. Glutamate activates NMDA and non-NMDA receptors to mediate its effects. Materials and Methods: Glioblastoma primary culture cells, U87MG and U251MG cells were maintained in DMEM. NMDA receptor (NMDAR) subtypes were activated by agonist NMDA and AMPA receptor (AMPAR) subtypes were activated by agonist AMPA. Migration, invasion and expression of glutamate receptors were determined by wound scratch assay, in-vitro Matrigel invasion assay and RT-qPCR respectively, in U251MG glioma cells and primary glioblastoma cultures. Results: At basal level U251MG cells expressed NR2A-D, NR3A, and U87MG cells expressed NR2A, NR2B and NR3A. On stimulation with 100 µM NMDA along with 10 µM of glycine for 24 h, U251MG and U87MG cells, significantly increased the expression of NR2B, NR2C, NR2D, and NR3B subunits of NMDAR in U252MG cells, while there was no change in expression of any of the NMDAR subunits in U87MG glioma cells. In addition, activation of NMDAR promoted the expression of calcium-permeable AMPA receptor subunit GluR1 in U251MG cells and decreased GluR3 subunit in U87MG cells. On activation of NMDAR the migration and invasion were significantly increased in U251MG cells, while in U87MG cells there was no effect on migration or invasion. Further, to confirm this elevated invasion and migration of U251MG cells were through NMDAR, we blocked NMDAR by MK-801, which significantly reversed cell invasion and migration whereas, inhibitor alone was not having any effect on invasion and migration compared to control. Blocking NMDAR activation by MK-801 decreased the invasion of U87MG glioma cells. Further these experiments carried out in primary glioma cells. We found that activation of NMDAR increased the invasion under excitotoxic milieu and these effects were reversed by MK-801. However, the effect of NMDAR in excitotoxic milieu on primary glioma cells varied between the primary cultures used in this study. CONCLUSION: We conclude that on activation of NMDAR, glioma cells differentially overexpressed NR2D, NR3B and GluR1 in U251MG cells compared to U87MG cells. Probably NR2D and calcium permeable GluR1 play crucial role in the migration and invasion mediated by NMDAR in U251MG cells and subset of primary glioma cells.
A-to-I RNA Editing in the Earliest-Diverging Eumetazoan Phyla
Authors: Hagit T. Porath, Amos A. Schaffer, Paulina Kaniewska, Shahar Alon, Eli Eisenberg, Joshua Rosenthal, Erez Y. Levanon, Oren Levy
Journal: Molecular Biology and Evolution (2017)

The highly conserved ADAR enzymes, found in all multicellular metazoans, catalyze the editing of mRNA transcripts by the deamination of adenosines to inosines. This type of editing has two general outcomes: site specific editing, which frequently leads to recoding, and clustered editing, which is usually found in transcribed genomic repeats. Here, for the first time, we looked for both editing of isolated sites and clustered, non-specific sites in a basal metazoan, the coral Acropora millepora during spawning event, in order to reveal its editing pattern. We found that the coral editome resembles the mammalian one: it contains more than 500,000 sites, virtually all of which are clustered in non-coding regions that are enriched for predicted dsRNA structures. RNA editing levels were increased during spawning and increased further still in newly released gametes. This may suggest that editing plays a role in introducing variability in coral gametes.
Abstract 212: Cd4+ T-cell Activation By T-cell Receptor Engagement Contributes To Myocardial Ischemia-reperfusion Injury
Authors: Ulrich Hofmann, Denise Mathes, Johannes Weirather, Niklas Beyersdorf, Thomas Kerkau, Stefan Frantz
Journal: Circulation Research (2013)

Background: We have recently shown that CD4 + but not CD8 + T-cells contribute to ischemia-reperfusion injury of the myocardium. We therefore hypothesized that CD4 + T-cells become activated by autoantigen recognition via their T-cell receptor during reperfusion. Methods and Results: Infarct size as percent of the area-at-risk was determined by combined Evans` blue and triphenyltetrazolium (TTC) staining after 30 minutes of in vivo ischemia followed by 24 hours reperfusion in mice. After 24 hours of reperfusion there was a significantly increased population of CD4 + T-cells which expressed the surface protein CD40L in comparison to sham operated mice [n≥7; p&lt;0.05; WT 10.8 ± 0.2% vs. sham 6.4 ± 0.5%]. CD40L is typically expressed in T-cells activated by T-cell receptor engagement. OT-II mice carry a transgenic T-cell receptor with specificity for an ovalbumin-derived peptide. These mice have a limited T-cell receptor repertoire, dominated by specificity for the irrelevant antigen ovalbumin. After 30 minutes of ischemia and 24 hours of reperfusion OT-II mice showed significantly reduction in infarct size [n≥4; p= 0.02; infarct/area at risk: OTII mice 38.9 ± 2.4% vs. WT mice 63.7 ± 6.6 % ]. Administration of a CD40L blocking antibody to wildtype mice also reduced infarct size when compared to administration of isotype-matched antibodies [n≥6; p = 0.03; infarct/ area at risk: anti-CD154 treatment 60.4 ± 3.4% vs. control 75.3 ± 4.1%]. CD4 + CD25 + Foxp3 + T-cells (natural T-regulatory cells) have a low activation threshold and constitute a T-cell subset with reactivity against autoantigens. Depletion of these cells by diphtheria-toxin application in a mouse model expressing the diphtheria-toxin receptor under the Foxp3 promotor also resulted in a significant reduction of infarct size when compared to diphtheria-toxin treated wildtype mice [n≥4; p=0.03; infarct/ area at risk: T reg -depleted DEREG mice 51.9± 3% vs. WT littermates 72.3± 2%]. Conclusion: Our results indicate that CD4 + T-cells that have been activated by an MHC class II/ T-cell receptor dependent mechanism, presumably by autoantigen recognition, contribute to myocardial ischemia-reperfusion injury.
Authors’ reply to Mjøen and Holdaas
Authors: Pippa Bailey
Journal: BMJ (2017)

We thank Mjoen and Holdaas for their comments.12 However, we did not say that there was no increased mortality after kidney donation.

We refer to the paper of 62 nephrectomies as a small case-control study of long term risks in US army personnel 45 years after undergoing unilateral nephrectomy owing to trauma. We include it as one of the …
Impact of Current Versus Previous Cardiac Resynchronization Therapy Guidelines on the Proportion of Patients With Heart Failure Eligible for Therapy
Authors: Kristin J. Lyons, Justin A. Ezekowitz, Li Liang, Paul A. Heidenreich, Clyde W. Yancy, Adam D. DeVore, Adrian F. Hernandez, Gregg C. Fonarow
Journal: JACC Heart Failure (2017)
Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of <i>BRCA2</i> Reversion Mutations Associated with Resistance to PARP Inhibitors
Authors: David Quigley, Joshi J. Alumkal, Alexander W. Wyatt, Vishal Kothari, Adam Foye, Paul Lloyd, Rahul Aggarwal, Won Kim, Eric Lu, Jacob Schwartzman, Kevin Beja, Matti Annala, Rajdeep Das, Morgan Diolaiti, Colin Pritchard, George Thomas, Scott Tomlins, Karen Knudsen, Christopher J. Lord, Charles Ryan, Jack Youngren, Tomasz M. Beer, Alan Ashworth, Eric J. Small, Felix Y. Feng
Journal: Cancer Discovery (2017)

Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as
P08.63 Hypoxia and endothelial cells sequentially, but not synergistically, affected glioma stem cell phenotypes implying an in vivo cell migration from necrotic to vascularized areas with Wnt pathway involved
Authors: R. Xie, Y. Liu
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma is resistant to adjuvant therapies due to the existence of a small fraction of tumor cells endowed with stem cell characteristics, namely, the glioma stem cells. Glioma stem cells reside in niches supporting their stemness maintenance, among which hypoxia and endothelial cells constitute the major components. Although there are evidences suggesting an interaction between hypoxia and endothelial cells, it is not clear how the two microenviromental factors are orchestrated to affect glioma stem cell phenotypes, especially given the findings that the necrosis and newly-formed vasculature in glioblastoma represent separate zones in situ. We used an in vitro model based on transwell system to cipher the co-effect of hypoxia and endothelial cells on glioma stem cell phenotypes. Materials and Methods: Transwell plates with 0.4 μm and 8 μm pore polycarbonate membrane inserts were utilized for co-culture and migration system. Human glioma stem cells and endothelial cells were seeded into the upper and lower chambers separately and kept under 1.5% O2 (hypoxia) or 20% O2 (normoxia) for 4-7 days. Temozolomide, CD133 staining and limiting dilution assay were used for determination of the stemness phenotypes. Wnt antibody and inhibitor Dkk were used to detect Wnt expression and block its function. Human glioblastoma sections stained with Nestin antibody showed the spatial distribution of glioma stem cells across the necrotic and vascular areas in situ. Results: Co-culture of glioma stem cells and endothelial cells under hypoxia showed no synergistic effect on stemness characteristics, while sequential treatment with hypoxia followed by normoxic co-culture with endothelial cells resulted in notably enhanced glioma stem cell phenotypes. Human glioblastoma tissue sections manifested a prominent aggregation of Nestin-positive cells around newly formed arterioles away from necrosis, implying cell migration from necrotic to vascularized areas. The transwell assay demonstrated a remarkable migration of hypoxic glioma stem cells towards endothelial cells compared to the control. Similar result has not yet been observed with glioma stem cells under normoxia condition. Surprisingly, the migrated cells which had direct contact with the endothelial cells showed decreased CD133 expression and spheroid formation ability compared with the cells non-migrated. Furthermore, Wnt level in glioma stem cells was elevated after hypoxia treatment and Wnt inhibitor Dkk could block the cell migration. Conclusions: Our study suggested migration of glioma stem cells from necrosis to endothelial cells upon hypoxic stimuli with Wnt pathway involved, and the sequential process from hypoxic condition to endothelial contacting modified glioma stem cell phenotypes. In vivo animal model and the role of the sequential niche conditioning in tumor progression are warranted for further study.
Adalimumab in the Treatment of Uveitis in Juvenile Idiopathic Arthritis
Authors: Jennifer E Thorne
Journal: New England Journal of Medicine (2017)

Uveitis encompasses a collection of ocular diseases that are characterized by intraocular inflammation and categorized according to the anatomical location of the inflammation in the eye. In the United States, uveitis is estimated to be the fifth or sixth leading cause of blindness and affects a broad range of age groups, including children. As such, there is the potential for more years lost because of visual disability than from age-related ocular diseases that affect people much later in life.1,2 Juvenile idiopathic arthritis (JIA)–associated uveitis is typically a chronic bilateral anterior uveitis and is among the most common forms of . . .
A Multi-Institutional Outcomes Analysis of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated with Ibrutinib
Authors: Allison Marie Winter, Daniel J. Landsburg, Francisco J. Hernandez-Ilizaliturri, Nishitha Reddy, Stephen Smith, Mazyar Shadman, Paolo Caimi, Deepa Jagadeesh, Mitchell R. Smith, Brian T. Hill
Journal: Blood (2016)
Cardiometabolic Disease Staging Predicts Effectiveness of Weight-Loss Therapy to Prevent Type 2 Diabetes: Pooled Results From Phase III Clinical Trials Assessing Phentermine/Topiramate Extended Release
Authors: Fangjian Guo, W. Timothy Garvey
Journal: Diabetes Care (2017)

To assess the ability of medication-assisted weight loss to prevent diabetes as a function of the baseline weighted Cardiometabolic Disease Staging (CMDS) score.We pooled data from 3,040 overweight and obese participants in three randomized controlled trials-CONQUER, EQUIP, and SEQUEL-assessing efficacy and safety of phentermine/topiramate extended release (ER) for weight loss. In these double-blind phase III trials, overweight/obese adult patients were treated with a lifestyle intervention and randomly assigned to placebo versus once-daily oral phentermine/topiramate ER. The weighted CMDS score was calculated using baseline quantitative clinical data including waist circumference, blood glucose, blood pressure, and blood lipids. Incident diabetes was defined based on serial measures of fasting glucose, 2-h oral glucose tolerance test glucose, and/or HbA1c.The absolute decrease in 1-year diabetes incidence rates in subjects treated with medication versus placebo was greatest in those with high-risk CMDS scores at baseline (10.43-6.29%), intermediate in those with moderate CMDS risk (4.67-2.37%), and small in the low-risk category (1.51-0.67%). The number of participants needed to treat to prevent one new case of diabetes over a 56-week period was 24, 43, and 120 in those with baseline CMDS scores of ≥60, 30-59, and 0-29, respectively.Numbers needed to treat to prevent one case of type 2 diabetes are markedly lower in patients with high-risk scores. CMDS can be used to quantify risk of diabetes in overweight/obese individuals and predict the effectiveness of weight-loss therapy to prevent diabetes.