tbuckley/cabot-search huggingface dataset:
Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk
Authors: Anastasia G. Efthymiou, Alison M. Goate
Journal: Molecular Neurodegeneration (2017)

Alzheimer's disease (AD) is a highly heritable complex disease with no current effective prevention or treatment. The majority of drugs developed for AD focus on the amyloid cascade hypothesis, which implicates Aß plaques as a causal factor in the disease. However, it is possible that other underexplored disease-associated pathways may be more fruitful targets for drug development. Findings from gene network analyses implicate immune networks as being enriched in AD; many of the genes in these networks fall within genomic regions that contain common and rare variants that are associated with increased risk of developing AD. Of these genes, several (including CR1, SPI1, the MS4As, TREM2, ABCA7, CD33, and INPP5D) are expressed by microglia, the resident immune cells of the brain. We summarize the gene network and genetics findings that implicate that these microglial genes are involved in AD, as well as several studies that have looked at the expression and function of these genes in microglia and in the context of AD. We propose that these genes are contributing to AD in a non-Aß-dependent fashion.
DIPG-27. CLEE011XUS17T (NCT 02607124): A PHASE I/II STUDY OF RIBOCICLIB (LEE011) FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)
Authors: Mariko DeWire, Christine Fuller, Trent Hummel, Lionel M.L. Chow, Ralph Salloum, Luke Pater, Rachid Drissi, Qing Lu, Charles Stevenson, Adam Lane, John Breneman, David Witte, James Leach, Maryam Fouladi
Journal: Neuro-Oncology (2017)

Genomic sequencing studies have uncovered alterations of checkpoint cell cycle regulators (CDK4/6, CDK2NA) in diffuse intrinsic pontine gliomas (DIPG) and high-grade gliomas (HGG). Ribociclib (LEE011) is an orally bioavailable, small molecule inhibitor of CDK4/CyclinD1 and CDK6/CyclinD3 complexes resulting in hypophosphorylation of RB and cell cycle arrest. In a feasibility, phase II study, patients with newly-diagnosed DIPG or HGG received radiation therapy prior to enrollment. All HGG patients and any DIPG patient who had undergone biopsy were screened for total RB protein by immunohistochemistry. Ribociclib was administered daily for 21 of 28 days at 350 mg/m2/day. Feasibilty endpoints included toxic death, Grade 3/4 toxicities possibly related to ribociclib resulting in drug discontinuation, > 2 weeks delay in the start of any course or discontinuation of the protocol therapy even after appropriate dose modification. Efficacy was measured by the overall survival distribution for DIPG and HGG. Of the 10 patients enrolled (median 6.5 years; range:4–20), 9 received treatment (8 DIPG, 1 HGG) and one developed leptomeningeal disease prior to therapy. To date, the median number of courses are 4.5 (range: 1–10). Ribociclib was well-tolerated; three patients required dose reduction for grade 4 neutropenia; no patients have come off therapy for toxicity. The most common adverse events were leukopenia, neutropenia, lymphopenia, nausea, vomiting, and fatigue. MRI evaluations in 2 patients revealed increased T2 FLAIR signal with new neurological symptoms within the first 2 cycles of therapy. These patients were responsive to steroids and remain on study. Six patients remain on active therapy at a median of 9 months post diagnosis (range: 3–12). The preliminary analysis demonstrates that ribociclib, administered post radiation therapy is well-tolerated in children and young adults with DIPG and RB+ HGG. Analyses for efficacy and correlative studies will be presented at the meeting.
EPND-06. IDENTIFICATION OF DISTINCT MOLECULAR CHARACTERISTICS IN PEDIATRIC SPINAL EPENDYMOMA
Authors: Anbarasu Lourdusamy, Li Luo, Lisa Storer, Kenneth Cohen, Linda Resar, Richard Grundy
Journal: Neuro-Oncology (2017)

Pediatric spinal ependymomas (pSP) are exceedingly rare central nervous system (CNS) tumors. Children with these tumours are likely to experience a more aggressive disease course, with a higher rate of local failure following treatment, and a higher rate of CNS metastasis, compared to adults. Because these tumours are uncommon, the molecular basis of pSP is poorly characterized. Microarray analysis of 66 pediatric ependymomas showed distinct expression patterns and detected up-regulation of several genes involved in development-related processes for spinal tumours. In addition, multiple biological processes that are less known for their involvement in pSP, oxidative phosphorylation, cellular respiration, electron transport, and cofactor metabolic process were also detected. When we compared the expression profiles of pSP to adult spinal ependymomas (aSP), we found a very low number of differentially expressed genes (12.5%) shared between pSP and aSP. Analysis of microRNA (miRNA) expression arrays on an overlapping cohort of 49 patients showed that six miRNAs (miR-196a, miR-27b, miR-23b, miR-144*, and miR-10a and 10b) were up-regulated and four (miR-26a, and miR-885-5p, miR-124, and miR-153) were down-regulated in pSP. The integrative miRNA-mRNA network and predicted miRNA target analysis revealed that the miR-23–27 cluster (miR23b/miR27b) coordinately repressed expression of cell differentiation genes (ACVR1C, CBFA2T3, GPSM1, and PKDCC), and the miR-10 family (miR10a/10b) that reside within the Hox clusters of developmental regulators, repressed expression of CAM2, HDAC4, IL1RAPL1, and MTSS1L. Furthermore, these miRNA-mRNA interactions were not detected in other cancers when we conducted the TCGA data analysis across ten different cancer types. Further investigation of gene expression and DNA methylation profiles in a larger cohort of pediatric ependymomas is on going, and will establish specific molecular characteristics of pSP. The identification of these candidate genes/miRNAs provides an evidence-based rationale for functional studies that will help to interrogate the initiation and progression of pSP.
Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis
Authors: Clément Gosset, Denis Viglietti, Marion Rabant, Jérôme Vérine, Olivier Aubert, Denis Glotz, Christophe Legendre, Jean-Luc Taupin, Jean-Paul Duong Van-Huyen, Alexandre Loupy, Carmen Lefaucheur
Journal: Kidney International (2017)
Measuring cognitive-motor integration to detect prolonged performance declines post-concussion
Authors: Lauren E Sergio, Marc Dalecki, Johanna Hurtubise, Jeffrey Brown, Diana Gorbet, Cindy Hughes, Alison Macpherson
Journal: British Journal of Sports Medicine (2017)

Objective There is a higher risk of re-injury for athletes with concussion history when returning to play, despite being asymptomatic and cleared for activity. One possible explanation is that current return to play assessments test thinking and moving separately, but sport activities often require their concurrent processing (cognitive-motor integration, CMI). The aim of this research is to characterize CMI performance across a range of ages and skill levels following concussion. We hypothesize that there will be CMI impairment, even when cognition and motor action measured separately are deemed recovered, and that impairment level is affected by age and skill level. Methods 133 participants with concussion history (mix of youth, adolescent, university, and elite athletes) and 130 no-concussion controls (age/sex/skill matched) performed two eye-hand coordination tasks. Participants displaced a cursor from a central to peripheral targets by either sliding their finger on a vertically-oriented touchscreen or with decoupled eye-hand coordination (targets/cursor viewed on vertical screen but finger slid on second horizontal touchscreen with 180° cursor feedback rotation). Results Children, young adult, and elite athletes with concussion history all had CMI performance deficits in movement planning, timing and execution, despite being asymptomatic and returned to play. Younger and less skilled athletes were more impaired relative to older/elite performers. Conclusions Cognitive-motor integration tasks are successful in detecting performance post-concussion relative to established assessment tools that test these domains separately. We propose that testing CMI performance, a skill crucial in sport, is important to comprehensively assess function post-concussion and to prevent re-injury. Competing interests None.
Molecular dynamics simulation of higher-order G-quadruplex complexes in telomeric DNA
Authors: Shozeb Haider, Stephen Neidle
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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Telomeres are specialised ends of linear chromosomes containing tandem repeats of short guanine rich sequences that can form four-stranded structures called G-quadruplexes. G-quadruplex based inhibitors chaperone the formation and stabilisation of such structures and have been shown to inhibit telomerase activity. Thus the link between oncogenesis and telomerase inhibition properties makes these DNA motifs a potential target for anti-cancer diagnosis and therapy. Structural information is available on isolated quadruplexes formed from two or four repeats, but there is no information on how they are organised along the single-stranded overhang of telomeric DNA. We have carried out five independent 10ns molecular dynamics simulations on two different lengths of telomeric DNA containing 45 and 93 nucleotides ie two and four G-quadruplexes respectively. Simulations have also been carried out on a 45mer G-quadruplex DNA in the presence of two different di-substituted small molecule compounds that had been previously tested to show anti-telomerase activity.

Analysis of all the simulations has revealed extremely stable G-quadruplex structures. We have also carried out the first ever principal components analysis on G-quadruplex structures to study the internal motion within the structures. The motions of the loops are the major contributors to the flexibility of the structure. The linker loops can be extended to form a potential small molecule binding site within the complex. The 2,6 di-substituted acridine (BSU6039) and 2,6 di-substituted acridone (BRACO31) both have shown to stabilise the complex. Essential dynamics on the ligand-quadruplex complexes have revealed the relative movement of quadruplexes and ligands within their binding sites. The structures are disrupted if there is no ligand in the binding site. Understanding the structural dynamics of G-quadruplexes will enhance our ability to rationally design small molecules that can bind and stabilise these structures to achieve therapeutic selectivity.
GENE-12. THE CHILDREN’S BRAIN TUMOR TISSUE CONSORTIUM (CBTTC) INFRASTRUCTURE FACILITATES COLLABORATIVE RESEARCH IN PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Alex Felmeister, Rishi Lulla, Angela Waanders, Pichai Raman, Mariarita Santi, Jena Lilly, Jennifer Mason, Javad Nazarian, Adam Resnick
Journal: Neuro-Oncology (2017)

INTRODUCTION: The Children’s Brain Tumor Tissue Consortium (CBTTC) is a multi-institutional, international research collaboration comprised of 13 institutions utilizing an infrastructure of web based open source tools to accelerate pediatric brain tumor research. The CBTTC mission is to provide the largest accessible, de-identified, longitudinal clinical data set linked to available biospecimens and -omic data in the world. METHODS: Clinical data collection and protection of Personal Health Information (PHI) is a major research regulatory hurdle. The CBTTC database is protected by a custom designed electronic honest broker that maintains links from a subject to multiple research records in the physical biobank and data collection tool. Currently the CBTTC utilizes three interconnected open source tools; the biorepository portal, electronic honest broker and the harvest query tool. CBTTC biospecimen and clinical records are also connected via web-protocols to the pedCBioPortal, a genomic data visualization tool, and Cavatica, a cloud based infrastructure genomic data storage and analysis. These tools work concurrently and communicate over https protocols and complement well known research tools such as an enterprise laboratory management systems (LIMS) and REDCap for data management. They are further expanded to include imaging tools, pathology slide review, genomic analysis and file repository resources. RESULTS: The CBTTC integrates phenotypic and genomic data for pediatric brain tumors and associated biospecimens. The platform facilitates open ended longitudinal data collection currently reflecting 1,900 subjects and 9,140 specimens available for research. The CBTTC has empowered 16 unique hypothesis driven collaborative research projects to date (See: www.cbttc.org). Remarkably, researchers are able to link molecular biology findings with clinical information such as overall survival through the web-based interface. DISCUSSION: The web-platform based approach facilitates real-time collaboration with researchers around the world. The CBTTC continues to grow, with additional collaborating sites and data generation added each year.
The effect of prior concussion history on dual-task gait following a concussion
Authors: David R Howell, Michael Beasley, Lisa Vopat, William P Meehan
Journal: British Journal of Sports Medicine (2017)

Objective To examine gait characteristics among patients following their first lifetime concussion, second or greater lifetime concussion, and individuals with no concussion history. Design Prospective observational study. Setting Regional sport-concussion clinic. Participants Fourteen patients presented following their first lifetime concussion (57% female; 15.6 [95% CI:=13.0, 17.2] years of age; 11.1 [8.3, 13.9] days post-concussion), 21 following their second or greater lifetime concussion (52% female; 16.9 [15.5, 18.4] years of age; 8.6 [6.2, 11.1] days post-concussion), and thirty-one controls without a concussion history (65% female; 15.0 [14.2, 15.8] years of age). Exclusion criteria included a current lower extremity injury or diagnosed learning disability. Interventions/independent variables Participants completed gait evaluations and medical history questionnaires. MANCOVAs evaluated between-group gait differences; correlations were calculated between the number of lifetime concussions and gait. Outcome measures Participants recorded their number of prior concussions. Three inertial sensors quantified single and dual-task gait; variables included average gait speed, cadence, and stride length. Main results During dual-task gait, patients reporting for their ≥ second lifetime concussion walked significantly slower (0.81 [0.75, 0.89] m/s vs. 0.92 [0.86, 0.97] m/s; p =0.009) and with smaller stride lengths (0.98 [0.92, 1.04] m vs. 1.08 [1.04, 1.13] m; p =0.02) compared to controls. A moderate correlation was detected between dual-task gait speed and the number of prior concussions (ρ= 0.44, p = 0.04). Conclusions Patients with a prior concussion history demonstrated altered dual-task gait strategies relative to controls. Dual-task gait velocity and number of prior concussions were moderately correlated, suggesting a worsening effect from multiple concussions across the lifetime. Competing interests None. Dr. Meehan receives royalties from ABC-Clio publishing for the sale of his book, Kids, Sports, and Concussion: A guide for coaches and parents , and royalties from Wolters Kluwer for working as an author for UpToDate . He is under contract with ABC-Clio publishing for a future book entitled, Concussions , and with Springer International publishing for a future book entitled, Head and Neck Injuries in Young Athletes . His research is funded, in part, by a grant from the National Football League Players Association and by philanthropic support from the National Hockey League Alumni Association through the Corey C. Griffin Pro-Am Tournament. Drs. Howell, Beasley, and Vopat have no conflicts of interest to report.
miR-146a-5p plays an essential role in the aberrant epithelial–fibroblast cross-talk in COPD
Authors: Emmanuel T. Osei, Laura Florez-Sampedro, Hataitip Tasena, Alen Faiz, Jacobien A. Noordhoek, Wim Timens, Dirkje S. Postma, Tillie L. Hackett, Irene H. Heijink, Corry-Anke Brandsma
Journal: European Respiratory Journal (2017)

We previously reported that epithelial-derived interleukin (IL)-1α drives fibroblast-derived inflammation in the lung epithelial–mesenchymal trophic unit. Since miR-146a-5p has been shown to negatively regulate IL-1 signalling, we investigated the role of miR-146a-5p in the regulation of IL-1α-driven inflammation in chronic obstructive pulmonary disease (COPD). Human bronchial epithelial (16HBE14o-) cells were co-cultured with control and COPD-derived primary human lung fibroblasts (PHLFs), and miR-146a-5p expression was assessed with and without IL-1α neutralising antibody. Genomic DNA was assessed for the presence of the single nucleotide polymorphism (SNP) rs2910164. miR-146a-5p mimics were used for overexpression studies to assess IL-1α-induced signalling and IL-8 production by PHLFs. Co-culture of PHLFs with airway epithelial cells significantly increased the expression of miR-146a-5p and this induction was dependent on epithelial-derived IL-1α. miR-146a-5p overexpression decreased IL-1α-induced IL-8 secretion in PHLFs via downregulation of IL-1 receptor-associated kinase-1. In COPD PHLFs, the induction of miR-146a-5p was significantly less compared with controls and was associated with the SNP rs2910164 (GG allele) in the miR-146a-5p gene. Our results suggest that induction of miR-146a-5p is involved in epithelial–fibroblast communication in the lungs and negatively regulates epithelial-derived IL-1α induction of IL-8 by fibroblasts. The decreased levels of miR-146a-5p in COPD fibroblasts may induce a more pro-inflammatory phenotype, contributing to chronic inflammation in COPD.
CARACTERÍSTICAS, TRATAMIENTO Y EVOLUCIÓN DE LAS PERFORACIONES POST-CPRE
Authors: L Ruiz Campos, X Andújar Múrcia, J Espinós Pérez, M Esteve Comas, C Loras Alastruey
Journal: Endoscopy (2015)

La perforación tras una colangiopancreatografía retrógada endoscópica (CPRE) aunque es poco frecuente puede llegar a ser muy grave. El tratamiento de elección ha sido el quirúrgico siendo menos reportado un manejo conservador.
What is the definition of sports-related concussion: a systematic review
Authors: Paul McCrory, Nina Feddermann-Demont, Jiří Dvořák, J David Cassidy, Andrew McIntosh, Pieter E Vos, Ruben J Echemendia, Willem Meeuwisse, Alexander A Tarnutzer
Journal: British Journal of Sports Medicine (2017)

Objectives Various definitions for concussion have been proposed, each having its strengths and weaknesses. We reviewed and compared current definitions and identified criteria necessary for an operational definition of sports-related concussion (SRC) in preparation of the 5th Concussion Consensus Conference (Berlin, Germany). We also assessed the role of biomechanical studies in informing an operational definition of SRC. Design This is a systematic literature review. Data sources Data sources include MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Clinical Trials and SPORT Discus (accessed 14 September 2016). Eligibility criteria for selecting studies Eligibility criteria were studies reporting (clinical) criteria for diagnosing SRC and studies containing SRC impact data. Results Out of 1601 articles screened, 36 studies were included (2.2%), 14 reported on criteria for SRC definitions and 22 on biomechanical aspects of concussions. Six different operational definitions focusing on clinical findings and their dynamics were identified. Biomechanical studies were obtained almost exclusively on American football players. Angular and linear head accelerations linked to clinically confirmed concussions demonstrated considerable individual variation. Summary/conclusions SRC is a traumatic brain injury that is defined as a complex pathophysiological process affecting the brain, induced by biomechanical forces with several common features that help define its nature. Limitations identified include that the current criteria for diagnosing SRC are clinically oriented and that there is no gold/standard to assess their diagnostic properties. A future, more valid definition of SRC would better identify concussed players by demonstrating high predictive positive/negative values. Currently, the use of helmet-based systems to study the biomechanics of SRC is limited to few collision sports. New approaches need to be developed to provide objective markers for SRC.
HGG-06. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Ralph Salloum, Melissa K. McConechy, Leonie G. Mikael, Hamid Nikhbakht, Nicolas De Jay, Christine Fuller, Rachid Drissi, Mariko DeWire, Daniel R Boue, Lionel Chow, Tenzin Gayden, Jason Karamchandani, Trent Hummel, Jonathan Finlay, Diana S Osorio, Charles Stevenson, Claudia Kleinman, Jacek Majewski, Nada Jabado, Maryam Fouladi
Journal: Neuro-Oncology (2017)

Pediatric high-grade gliomas (pHGG) are aggressive malignant neoplasms representing approximately 20% of all pediatric central nervous system tumors. Current therapies offer limited disease control, and patients with recurrent disease have a particularly poor prognosis. While the empiric use of targeted therapy, especially at progression, is being increasingly practiced, there is a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To better understand the genetic landscape of pHGGs at recurrence, we performed whole exome, transcriptome and methylation analyses on pHGG matched primary and recurrent tumors from 16 patients, median age of 15 years (range: 4–29). Matched normal tissue, where available, was evaluated to determine mutation somatic status. Genetic mutational results suggested that our cohort could be segregated into 3 groups. Group 1 tumor pairs (n=6) carry driver mutations in histone 3 (H3F3A, HIST1H3B) or IDH1 that were retained between the primary tumor and recurrence. In tumors with H3F3A and IDH1 mutations, their obligate partner TP53 or ATRX mutations were also conserved. Group 2 tumor pairs (n=8) were histone 3 or IDH1 wild-type, but most harbored mutations in genes that are modifiers of histone or chromatin (KMT2D, ZMYND11, EP300, BCOR). TP53 and ATRX driver mutations were present in 50% (n=4) of tumors, and 25% (n=2) had a BRAF V600E mutation. Mutations in other putative drug targets (EGFR, ERBB2, PI3-kinase mutations) were not always shared between primary and recurrent tumors, indicating evolution during tumor progression. Group 3 samples (n=2) carried germline mutations in NF1. Mutational burden, gene ontology analysis and correlation with treatment exposure are ongoing. The finding that key driver mutations, some of which are targetable (e.g. IDH1, BRAF V600E) are conserved at recurrence, while other targetable mutations are acquired, indicates that re-biopsy at recurrence may provide better guidance for effective treatment of pHGG with targeted therapy.
CircRNA: functions and properties of a novel potential biomarker for cancer
Authors: Shujuan Meng, Hecheng Zhou, Ziyang Feng, Zihao Xu, Ying Tang, Peiyao Li, Minghua Wu
Journal: Molecular Cancer (2017)

Circular RNAs, a novel class of endogenous noncoding RNAs, are characterized by their covalently closed loop structures without a 5' cap or a 3' Poly A tail. Although the mechanisms of circular RNAs' generation and function are not fully clear, recent research has shown that circular RNAs may function as potential molecular markers for disease diagnosis and treatment and play an important role in the initiation and progression of human diseases, especially in tumours. This review summarizes some information about categories, biogenesis, functions at the molecular level, properties of circular RNAs and the possibility of circular RNAs as biomarkers in cancers.