tbuckley/cabot-search huggingface dataset:
GENE-09. PRECISION MEDICINE ANALYSIS OF 203 PEDIATRIC BRAIN TUMORS REVEALS CLINICALLY RELEVANT GENOMIC ALTERATIONS
Authors: Pratiti Bandopadhayay, Shakti Ramkissoon, Jaeho Hwang, Lori Ramkissoon, Noah Greenwald, Steven Schumacher, Ryan O’Rourke, Nathan Pinches, Patricia Ho, Hayley Malkin, Claire Sinai, Mariella Filbin, Ashley Plant, Wenya Bi, Michael Chang, Edward Yang, Karen Wright, Peter Manley, Matthew Ducar, Sanda Alexandrescu, Hart Lidov, Ivana Delalle, Liliana Goumnerova, Alanna Church, Katherine Janeway, Marian Harris, Laura MacConaill, Rebecca Folkerth, Neal Lindeman, Charles Stiles, Mark Kieran, Azra Ligon, Sandro Santagata, Adrian Dubuc, Susan Chi, Rameen Beroukhim, Keith Ligon
Journal: Neuro-Oncology (2017)

INTRODUCTION: Clinical genomics platforms identify targetable alterations for precision medicine in pediatric neuro-oncology, allowing both the genomic profiling of tumors to inform clinical care and facilitating the potential discovery of novel driver alterations. METHODS: We applied two clinical genomic platforms (OncoPanel and OncoCopy) to profile pediatric brain tumors in a clinical setting. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer causing genes, was used to assess single nucleotide variants and rearrangements/indels. OncoCopy, a high-resolution genome-wide array comparative genomic hybridization (aCGH) assay, was used to evaluate copy number alterations and refine rearrangement breakpoints. RESULTS: Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes including 117 analyzed by OncoPanel, 146 by OncoCopy, and 60 evaluated using both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. EWSRa rearrangements were observed unexpectedly in two patients; one with a Atypical Teratoid Rhabdoid Tumor with loss of INI-1 (SMARCB1), and the second in an ependymoma. Whole Genome Sequencing of the rhabdoid tumor confirmed a rearrangement involving EWSR1 and PLAGL1.CONCLUSIONS: The combined deployment of OncoPanel and OncoCopy multiplex genomic assays can identify clinically relevant genomic alterations in pediatric brain tumors and facilitate the discovery of novel driver alterations. *equal contribution
The prognostic significance of polyclonal bone marrow plasma cells in patients with relapsing multiple myeloma
Authors: Toshi Ghosh, Wilson I. Gonsalves, Dragan Jevremovic, Angela Dispenzieri, David Dingli, Michael M. Timm, William G. Morice, Prashant Kapoor, Taxiarchis V. Kourelis, Martha Q. Lacy, Suzanne R. Hayman, Francis K. Buadi, Nelson Leung, Ronald S. Go, Yi Lin, Stephen J. Russell, John A. Lust, Steven R. Zeldenrust, Rahma Warsame, Yi L. Hwa, Robert A. Kyle, Morie A. Gertz, S. Vincent Rajkumar, Shaji K. Kumar
Journal: American Journal of Hematology (2017)

Prior studies have revealed that the presence of increasing number of polyclonal plasma cells (pPCs) in the bone marrow (BM) are associated with better outcomes in newly diagnosed multiple myeloma (MM) patients. This effect has not been studied in patients with MM at the time of disease relapse. We determined the prognostic value of depletion of pPCs in the BM by 7-color multiparameter flow cytometry in a series of 174 relapsing MM patients. The time to next therapy (TTNT) in those with <5% pPCs was 9.4 months versus 13.9 months in those with ≥5% pPCs (P = .0091). The median overall survival (OS) in those with <5% pPCs was 21.4 months, while the median OS was not reached in those patients with ≥5% pPCs (P = .019). Of the 109 patients with standard risk cytogenetics, the median OS of those with <5% pPCs was 28.4 months, while the median OS was not reached in those with ≥5% pPCs (P = .033). As such, <5% pPCs in the BM appears to have prognostic utility in identifying a subset of relapsing MM patients, even with standard-risk cytogenetics, who have a particularly adverse outcome.
Phenethyl isothiocyanate, a constituent of processed cruciferous vegetables, inhibits growth of PC-3 human prostate cancer xenografts in vivo in association with induction of Bax and Bid.
Authors: Stanley W. Marynowski, Dong Xiao, Karen L. Lew, Yan Zeng, Rajiv Dhir, Hui Xiao, Shivendra V. Singh
Journal: Cancer Research (2006)

5601  Epidemiological studies continue to support the premise that dietary intake of cruciferous vegetables may be protective against the risk of various types of malignancies including cancer of the prostate. Anti-carcinogenic effect of cruciferous vegetables is attributed to organic isothiocyanates (ITCs), such as phenethyl-ITC (PEITC), that are highly effective in affording protection against chemically induced cancers in animal models. More recent studies have indicated that PEITC can cause G2/M phase cell cycle arrest and/or apoptosis induction to suppress proliferation of cancer cells in culture, but the mechanism of PEITC-induced cell death is not fully defined. The present study was undertaken to determine the role of Bcl-xL in regulation of apoptosis induction by PEITC using PC-3 human prostate cancer cells as a model, and to determine the effect of oral administration of PEITC on PC-3 xenograft growth in athymic mice. The viability of PC-3 cells was reduced significantly in the presence of PEITC in a concentration-dependent manner as revealed by sulforhodamine B assay. Structure-activity analysis indicated a marked effect of alkyl chain length on activity of PEITC against proliferation of PC-3 cells. Ectopic expression of Bcl-xL, whose protein level is reduced markedly on treatment of PC-3 cells with PEITC, conferred partial yet statistically significant protection against PEITC-induced apoptosis in PC-3 cells at higher drug concentrations (10 and 20 μM) as revealed by analysis of cytoplasmic histone associated DNA fragmentation, sub-diploid cells, and cleavage of caspase-3 and poly(ADP-ribose)polymerase. Oral administration of 12 μmol PEITC/day (Monday through Friday) significantly inhibited PC-3 xenograft growth in athymic mice. For instance, 31 days after initiation of the therapy, the average tumor volume in control mice was approximately 1.9-fold higher (P
Concussion in the emergency department; unconsciously incompetent?
Authors: Thom Phillips, Katie Guy, Rhodri Martin, Alicia Tomkinson, Dan Phillips, Nicole Sloane
Journal: British Journal of Sports Medicine (2017)

Objective Sports related concussion is an increasingly common occurrence. Outside professional sport it is typically managed within Emergency Departments. The objective was to assess the level of knowledge and understanding of UK emergency medicine doctors of concussion; it’s recognition, diagnosis and management. Design Cross-sectional observational study using self-report questionnaires. Setting Questionnaires were distributed at regional EM conferences between October 2015 and January 2016. 15 secondary and 5 tertiary care centres were represented. Participants 156 questionnaires were completed. Illegible answers, defaced or incorrectly completed questionnaires were discarded. 134 were included in the analysis. Training levels represented were: Consultant (10%), Specialist Registrar (12%), Staff Grade (5%), Core Trainee (34%), Foundation Trainee (20%), Emergency Nurse Practitioners (1.5%), Medical Students (16%). Interventions (or Assessment of Risk Factors) The questionnaire asked respondents to correctly identify signs and symptoms of concussion according to the Zurich consensus statement. It asked whether there were differences in the management of adult and paediatric concussion together with questions regarding RTP guidelines and use of potentially protective equipment. Main results Consultants obtained the highest signs and symptoms score (6.2). The least correct were Specialist Registrars (2.0). Diagnostic accuracy did not differ between secondary and tertiary centres (p=0.67). 80% of participants incorrectly identified headguards as being protective against concussion. 35.4% of respondents acknowledged a difference between adult and paediatric concussion. Conclusions This small yet representative sample highlights a lack of knowledge in concussion in health professionals working in EDs in the UK. Efforts to improve the knowledge and understanding of concussion are required given the increasing awareness of the impact and occurrence of sports concussion. Competing interests None.
Compliance with and effectiveness of return-to-activity progressions following concussion: a systematic review of the literature
Authors: Tamara C Valovich McLeod, Joy H Lewis, Kate Whelihan, Cailee E Welch Bacon
Journal: British Journal of Sports Medicine (2017)

Objective To systematically review the literature regarding healthcare provider compliance with and the effectiveness of the graded return-to-activity progression. Design Systematic Review. Search strategy An electronic search was conducted in 6 databases. Search terms included: brain concussion AND-rest; concuss*AND-sports-AND-rest, -sports-AND-return-to-play; mild traumatic brain injury AND-return-to-activity, -return-to-play; recurrent concussion-AND-sport. Hand searches were also performed. Study selection After removal of duplicates, initial screen of titles and abstracts was completed by 3 authors, followed by full text review. Articles were included if they were in English and original studies related to the clinical questions. Reviews, editorials, commentaries, and animal research were excluded. Data extraction The initial search yielded 2851 articles, with 1239 undergoing title/abstract screen, 143 undergoing full-text review, and 21 included in the review. Study design, patient/participant, instrumentation/interventions utilised, outcome measures, main results, and conclusions were extracted. Strength of recommendation (SOR) as outlined by the Oxford Centre for Evidence-Based Medicine was assigned to the body of literature. Data synthesis Articles were categorised based on their ability to answer one of the clinical questions of interest and the conclusions were summarised using a qualitative synthesis of the findings. Data were not appropriate for meta-analysis due to the observational nature of many included studies and heterogeneity of the patients, participants, interventions and outcomes. Conclusions The review identified that significant variability in the use of assessment tools and compliance with recommended return-to-activity guidelines exists (SOR=B) and there is little evidence to support the effectiveness of the graded return-to-activity progression (SOR=D). Competing interests None.
Attenuation of Follicular Helper T Cell-Dependent B Cell Hyperactivity by Abatacept Treatment in Primary Sjögren's Syndrome
Authors: Gwenny M. Verstappen, Petra M. Meiners, Odilia B. J. Corneth, Annie Visser, Suzanne Arends, Wayel H. Abdulahad, Rudi W. Hendriks, Arjan Vissink, Frans G. M. Kroese, Hendrika Bootsma
Journal: Arthritis & Rheumatology (2017)

Objective To assess the effect of abatacept (CTLA‐4Ig), which limits T cell activation, on homeostasis of CD4+ T cell subsets and T cell–dependent B cell hyperactivity in patients with primary Sjögren's syndrome (SS). Methods Fifteen patients with primary SS treated with abatacept were included. Circulating CD4+ T cell and B cell subsets were analyzed by flow cytometry at baseline, during the treatment course, and after treatment was completed. CD4+ effector T cell subsets and Treg cells were identified based on expression of CD45RA, CXCR3, CCR6, CCR4, CXCR5, programmed death 1, inducible costimulator (ICOS), and FoxP3. Serum levels of anti‐SSA/anti‐SSB and several T cell–related cytokines were measured. Expression of ICOS and interleukin‐21 (IL‐21) protein was examined in parotid gland tissue at baseline and after treatment. Changes in laboratory parameters and associations with systemic disease activity (EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI]) over time were analyzed using generalized estimating equations. Results Abatacept selectively reduced percentages and numbers of circulating follicular helper T (Tfh) cells and Treg cells. Other CD4+ effector T cell subsets were unaffected. Furthermore, expression of the activation marker ICOS by circulating CD4+ T cells and expression of ICOS protein in parotid gland tissue declined. Reduced ICOS expression on circulating Tfh cells correlated significantly with lower ESSDAI scores during treatment. Serum levels of IL‐21, CXCL13, anti‐SSA, and anti‐SSB decreased. Among circulating B cells, plasmablasts were decreased by treatment. After cessation of treatment, all parameters gradually returned to baseline. Conclusion Abatacept treatment in patients with primary SS reduces circulating Tfh cell numbers and expression of the activation marker ICOS on T cells. Lower numbers of activated circulating Tfh cells contribute to attenuated Tfh cell–dependent B cell hyperactivity and may underlie the efficacy of abatacept.
Pylorotomie endoscopique par POEM gastrique dans le traitement des gastroparésies réfractaires: résultats de la première série rétrospective européenne sur 9 cas
Authors: JM Gonzalez, V Lestelle, V Vitton, M Barthet
Journal: Endoscopy (2016)

La gastroparésie est une pathologie fonctionnelle qui atteint 4% de la population générale. Elle est d'origine diabétique (30%), postopératoire (25%) ou idiopathique. Elle affecte la qualité de vie des patients et les traitements actuels restent insatisfaisants. La pylorotomie endoscopique par tunnel gastrique (G-POEM) a été décrite en 2014 aux USA puis en Europe par notre équipe avec un résultat clinique prometteur, confirmé par une série rétrospective américaine (7 patients). Nous proposons notre expérience.
Abstract P431: The Effect of Ten Days of Reduced Physical Activity (rPA) on Markers of Vascular Function
Authors: Sarah Witkowski, Kara Tassinari, Gayatru Guhanarayan
Journal: Circulation (2014)

Flow-mediated dilation (FMD) is an early marker of cardiovascular disease. Circulating angiogenic cells (CAC) are hypothesized to support endothelial health and repair and have been related to Framingham risk score. Both FMD and CAC have been investigated as early biomarkers of vascular dysfunction and are related to physical activity. Low physical activity is a risk factor for cardiovascular disease however, the effect of a short-term reduction in physical activity on FMD and CACs is unclear. Purpose: To use a novel, objectively monitored model of rPA wherein participants maintain energy balance to evaluate changes in a physiological and cellular marker of vascular function. Hypothesis: rPA will result in lower FMD and CAC compared with baseline. Methods: Physical activity was measured via Actigraph GT3X before and during 10 days of rPA in healthy trained men (n=6). Baseline caloric intake was assessed and participants were instructed to reduce their intake to match the reduction in energy expenditure during rPA. FMD was assessed via duplex ultrasound of the brachial artery. Artery diameter and shear rate were analyzed with FMD Studio software (Quipu, Pisa). Data for baseline shear rate, baseline vessel diameter, peak shear rate, peak vessel diameter, absolute FMD, relative FMD, area under the curve (AUC), and normalized FMD were calculated for each subject. CAC colony forming units (CFU-EC) were measured before and after rPA. Paired T-tests were used to determine differences between variables before and after rPA. Results: Actigraph data revealed increased sedentary time (656 ± 42 to 758 ± 36 min/day, p=0.02) and decreased moderate to vigorous physical activity with rPA (MVPA, 87 ± 16 to 59 ± 9, p=0.03). Weight did not change with rPA. There was a 60 ± 27% increase in baseline shear rate (p=0.03) and a 22 ± 5% decrease in peak shear rate with rPA (p=0.003). We also found a 39% decrease in CAC with rPA (21 ± 5 to 14 ± 6, p=0.03). Conclusion: Our preliminary data show that short-term rPA results in significant changes in shear stress and CACs, two markers of vascular function. Future research should explore the independent influence of changes in physical activity and sedentary behavior on vascular function.
Targeting Epigenetics in Cancer
Authors: Richard L. Bennett, Jonathan D. Licht
Journal: The Annual Review of Pharmacology and Toxicology (2017)

Alterations of genes regulating epigenetic processes are frequently found as cancer drivers and may cause widespread alterations of DNA methylation, histone modification patterns, or chromatin structure that disrupt normal patterns of gene expression. Because of the inherent reversibility of epigenetic changes, inhibitors targeting these processes are promising anticancer strategies. Small molecules targeting epigenetic regulators have been developed recently, and clinical trials of these agents are under way for hematologic malignancies and solid tumors. In this review, we describe how the writers, readers, and erasers of epigenetic marks are dysregulated in cancer and summarize the development of therapies targeting these mechanisms.
Plasma cystatin C is a predictor of renal dysfunction, acute‐on‐chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis
Authors: Daniel Markwardt, Lesca Holdt, Christian Steib, Andreas Benesic, Flemming Bendtsen, Mauro Bernardi, Richard Moreau, Daniel Teupser, Julia Wendon, Frederik Nevens, Jonel Trebicka, Elisabet Garcia, Marco Pavesi, Vicente Arroyo, Alexander L. Gerbes
Journal: Hepatology (2017)

The development of acute‐on‐chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase‐associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL‐CLIF Acute‐on‐Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8‐49.7), HRS (odds ratio, 4.2; 95% CI, 1.2‐14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3‐25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90‐day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1‐4.7) and for NGAL of 1.9 (95% CI, 1.5‐2.4). Conclusion : Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short‐term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (H epatology 2017;66:1232‐1241)
Gp and emergency medicine trainee’s knowledge of appropriate diagnostic and treatment options for concussion in the west of ireland
Authors: Stephen Gilmartin, Aine Waters, Karen Harris
Journal: British Journal of Sports Medicine (2017)

Objective To Investigate GP and Emergency medicine trainee’s knowledge and application of concussion treatment and diagnostic options in the west of Ireland Design Cross Sectional Setting Sligo and Galway University Hospitals, Ireland Participants 37 GP and 8 emergency medicine trainees. The doctors were all working in an Emergency department or community GP Practice Interventions All trainees were instructed to complete a questionnaire in person without any aids or educational advice. Outcome measures We aimed to establish baseline trainee knowledge of concussion and also their appropriate use of current diagnostic and treatment guidelines. Main Results 13% of those asked had received formal concussion training. Only 35% used any formal concussion assessment tool, SCAT3 was the most common. 35.6% and 15.6% of trainees prescribe physical and cognitive rest respectively to all of their concussion patients. All of his has led to only 20% of those questioned providing a return to play plan to their patients following concussion diagnosis. One sample t-tests found all of these findings were statistically significant (P&lt;0.05). Conclusions Our results show that despite concussion’s increasing media profile worldwide, GP and emergency medicine trainee’s in the west of Ireland remain ill informed of the appropriate diagnostic and treatment protocols. It is felt that this is likely representative of trainee knowledge levels nationwide, although a larger demographic is needed to prove this. In conjunction with acquired brain injury Ireland we have created a new concussion pathway for Sligo University Hospital which includes diagnostic aids and outpatient treatment options for our locality. Competing interests None
MEDU-27. DETERMINING MECHANISMS OF METASTASIS IN MEDULLOBLASTOMA SUBGROUPS
Authors: Rachel Hartley, Timothy Phoenix
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB), the most common malignant pediatric brain tumor, comprises of four molecularly and clinically distinct subgroups (termed WNT, SHH, Group3, and Group4). Across all subgroups, metastatic dissemination is a feature of high-risk disease and very poor outcome. WNT-MB, considered low-risk, are rarely metastatic and contain activating mutations in CTNNB1; Group3-MB, commonly classified as high-risk, are frequently metastatic and contain genomic alterations resulting in elevated MYC expression. Depending on subgroup identity, recurrent MB tend to occur at primary or metastatic sites, but all subgroups commonly display MYC or MYCN amplifications and p53 loss at relapse while maintaining their primary subgroup molecular identity3,4. There is a critical need to understand mechanisms that drive differences in metastatic frequency among MB subgroups, and to develop new biomarkers and therapies that prevent metastasis. We have previously demonstrated the utility of comparing low risk WNT-MBs to other MB subgroups to identify mechanisms that contribute to MB subgroups specific pathology and their differential treatment response. During these studies we noticed marked differences in MB subgroup cell adhesion properties. Gene expression data from primary human MB revealed differences in extra cellular matrix (ECM) regulation and cell adhesion, indicating these pathways may play key roles in regulating MB subgroup metastatic capability. We are performing studies to elucidate the regulation and function of these differences, and their effects on MB subgroup migration and metastasis.
Postgraduate training will be more flexible under new standards, says GMC
Authors: Abi Rimmer
Journal: BMJ (2017)

New standards for medical curriculums will improve the flexibility of postgraduate training, the General Medical Council (GMC) has said.

The GMC published a new framework for the approval and provision of postgraduate medical education and training across the UK on 22 May.1 The new standards say that medical curriculums should support flexibility and the transferability of learning, making it easier for trainees to switch specialties or take a break.

The publication of the standards came after the GMC issued its flexible training review in March. The review called for an end to the “snakes and ladders” experience of trainees wishing to …
Languages as semiotically heterogenous systems
Authors: Adam Kendon
Journal: Behavioral and Brain Sciences (2017)

Abstract The target article is consistent with seeing languages as semiotically heterogenous, using categorial, depictive, and analogic semiotic signs. “Gesture,” used in the target article, is shown to be vague and not useful. Kendon's view, criticised in the target, is restated. His proposal for comparative semiotic analyses of how visible bodily action is used in utterance production is reexplained.