tbuckley/cabot-search huggingface dataset:
ATRT-06. BET INHIBITORS AND HDAC INHIBITORS WORK SYNERGISTICALLY IN TREATING MULTIPLE SUBTYPES OF ATYPICAL TERATOID/RHABDOID TUMOR
Authors: Fang Liu, Meng Li, Lei Zhang, Yi Sui, Wenyan Jiang, Wei Meng, Jiajia Wang, Jie Ma, Yujie Tang
Journal: Neuro-Oncology (2017)

Atypical Teratoid/Rhabdoid Tumor (AT/RT) is one of the most common aggressive brain tumors in infants with very poor prognosis. Although epigenetic dysregulation caused by loss of functional SMARCB1 has been known to serve as its tumor hallmark, oncogenic driver as well as diagnostic biomarker, effective targeted therapeutic strategies against AT/RT are still needed. Our recent epigenetic drug screening identified that BET inhibitor (BETi) and HDAC inhibitor (HDACi) could dramatically inhibit cell viability of multiple AT/RT primary cell lines, which belong to different epigenetic subtypes. They exert their therapeutic effects through inhibiting proliferation and inducing apoptosis based on our data from EdU incorporation assay and Annexin V staining assay. Moreover, these two types of epigenetic drugs exhibited synergistic inhibitory effects against AT/RT when working together in vitro. Compared to single drug treatment, combination treatment resulted in significantly stronger inhibition of cell viability, proliferation and survival. Gene expression analyses of drug-treated AT/RT cell lines found that BETi+HDACi combinatory treatment cause more profound down-regulation of crucial oncogenic driver/marker genes of each AT/RT subtype. In summary, our study has begun to illustrate BETi+HDACi as a novel combinatory therapeutic strategy against multiple subtypes of AT/RT. Next, in vivo therapeutic effects against multiple subtypes of AT/RT patient-derived xenograft (PDX) models with these two types of epigenetic drugs individually or in combination, as well as the underlying molecular mechanism of their synergy for each subtype, will be further investigated to provide a solid rational for initiating BETi+HDACi trial of AT/RT in near future.
Concussion management plan compliance: a study of ncaa power five conference schools
Authors: Melissa DiFabio, Christine Baugh, Thomas Buckley
Journal: British Journal of Sports Medicine (2017)

Objective To examine the concussions management protocols (CMPs) from the 65 institutions within the NCAA Power 5 conferences for compliance with the NCAA 2015 concussion guidelines. Design Descriptive Study. Setting N/A. Participants 65 universities of NCAA conferences: Atlantic Coast, Southeastern, Big Ten, Big 12, and Pacific-12 Interventions The 65 publicly-available CMPs were evaluated for compliance with the 47 NCAA rules and guidelines (combined N=3,055). Each CMP was reviewed and graded “yes” or “no” for each recommended or required item and compliance was reported descriptively. Outcome measures Overall compliance rate, mean, item-level, category-level, and institution-level compliance with the 47 items. Each institution’s athletic training staff size, academic performance, and athletic performance were examined as independent predictors with quasi-binomial regression. Main results CMPs varied substantially in length (range: 4-66 pages) and level of detail. The overall compliance rate for all components across all institutions was 94.3% (2,880/3,055). Twelve components achieved 100% institutional (65/65) compliance, and the lowest levels of compliance were clustered in “Return-to-Learn” (RTL). There were 22 institutions that achieved a 100% compliance rate; the lowest institutional compliance was 59.6%. There were no significant associations between the independent predictors and institutional compliance. Conclusions Overall compliance with NCAA concussion management requirements was high, but there remains room for improvement. There was low compliance with RTL as well as limited details provided in the reducing head trauma component. Items with lower compliance (reducing head trauma, return-to-learn) tended to be outside the core competencies of the medical staff, indicating an area for improvement. Competing interests None.
Tens of millions of people would lose insurance under Trump’s bill, report finds
Authors: Michael McCarthy
Journal: BMJ (2017)

The number of US people without health insurance would be 23 million higher by 2026 if the bill to repeal and replace major portions of the Affordable Care Act is enacted, a new report concludes. The analysis by the non-partisan Congressional Budget Office (CBO) has calculated that the bill, approved by the House of Representatives earlier this month, would increase the number of uninsured people to 51 million in that year, whereas the number would be 28 million if Barack Obama’s act remained intact.1

The findings underscore the difficulties the Republicans face in their effort to repeal the 2010 health care reform law, often called Obamacare, something they have promised to do since it was passed.

An earlier version of the Republicans’ bill, called the American Health Care Act, was not brought before the House after party leaders decided that it would not get enough votes. A CBO analysis of that version of the bill found that it …
Differences in symptom severity and gait balance deficit in concussed adolescents with and without concussion history
Authors: Li-Shan Chou, Quinn Peterson, Louis Osternig
Journal: British Journal of Sports Medicine (2017)

Objective There is conflicting evidence on whether a prior concussion is associated with a prolonged recovery course. This study was aimed to examine the effect of concussion history on recovery of symptoms and gait balance control in adolescents. Design A prospective, repeated-measures design was employed. Subject were assessed within 72 hours of sustaining a concussion and at 2, 4, and 8 weeks post-injury. Settings University research laboratory Participants High school student athletes with concussion injury Outcome measures Symptoms resulting from the injury were assessed using a 22 symptom inventory adapted from the Standardised Concussion Assessment Tool. Dual-task gait testing was employed to examine how divided attention affects balance control following concussion. Comparisons between subjects with and without concussion history were made for dependent variables of symptom scores and medial-lateral motion of the center-of-mass. Main Results A total of 31 concussed adolescents were tested, 9 of them had 1 or 2 diagnosed concussions more than 12 months prior to the current injury. Four subjects without concussion history and 4 subjects with concussion history were not permitted to resume normal physical activities within our 2-month study period. Subjects with concussion history displayed significantly elevated symptom scores during the first two weeks of recovery and displayed greater gait instability during the first month of recovery when compared to subjects without concussion history. Conclusions These preliminary findings indicate that previous concussion, more than one year prior to the current injury, could affect deficit severity and length of recovery. Competing interests The authors have no conflicts of interest to declare.
Clinical characteristics, referral patterns and time to recovery in youth and adults following a sport-related concussion (src)
Authors: Katie MacGregor, Christine Atkins, Tracy Blake, Micah Ziel, Kathryn Schneider
Journal: British Journal of Sports Medicine (2017)

Objective To describe the clinical characteristics, referral patterns and time to recovery in an acute sport-related concussion (SRC) clinic population. Design Prospective Case Series Setting Acute Sport Concussion Clinic (ASCC) Participants Patients aged 13-60 years seen within 4 weeks of SRC at the ASCC from September 2015–April 2016. Outcome measures Frequency, proportions, medians and interquartile ranges (IQR) were used to describe sex, age group, time from injury to assessment, referral sources, time to recovery (days), referrals to additional services, and attrition. Results ASCC assessments were requested by 111 patients a median of 9 days (IQR:4-17) post-concussion [33% female; 60 children [median age 15 years (IQR:14-16)], 51 adults [median age 31 years (IQR:21-42)]; attrition rate=10%]. Referral sources included: self-referral [n=94 (85%)], emergency department [n=9 (8%)], primary care physician [n=7 (5%)], and athletic therapist (n=1). Initial assessment occurred a median of 7 days (IQR:2-9) following the evaluation request. Patients underwent a standardised assessment including symptom scores, neurological, cervical spine and vestibulo-ocular screening a median of 17 days (IQR:9-25) post-concussion. There were 94 (85%) patients with clinical findings of cervical spine and/or vestibulo-ocular dysfunction. Treatment was received by 71/94 (76%) of patients with observed dysfunction. Medical clearance to return to play occurred a median of 30 days (IQR:21-107) post-concussion (n=51) . Conclusions A novel direct-access clinic specific to SRC assists in early triage, leading to expedited assessment, management and treatment in the early post-concussion period. Focused assessment assists in management and recovery with accelerated referral to appropriate services. Competing interests None.
Brexit threatens status of over 2000 GPs, royal college warns
Authors: Ingrid Torjesen
Journal: BMJ (2017)

More than 2000 GPs providing care to nearly 3.5 million patients could be lost to the NHS if their status were not protected during Brexit negotiations, the Royal College of General Practitioners has warned.

An analysis by the college estimates that 2137 GPs across the UK hold their primary medical qualification from an institution located in another country in the European Economic Area, which includes EU countries together with Switzerland, Norway, and Iceland. These GPs provide care to 3 456 481 patients, who are therefore at risk of being left without a GP …
DIPG-03. PRE-CLINICAL EVALUATION OF ANDROGEN RECEPTOR AND AROMATASE AS THERAPEUTIC TARGETS IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Christopher Marnell, Uday B. Maachani, Dennis Lee, Umberto Tosi, Raymond Chang, Melanie Schweitzer, Iulia Voronina, Mark M. Souweidane
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric CNS malignancy with no effective therapies. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Though appealing agents have been identified by previous studies, these candidates have been few and a broader chemical screen targeting an expanded array of therapeutic targets could potentially identify molecules with previously uncharacterized roles in DIPG. In this study, we performed a high-throughput in vitro screen of 114 FDA approved oncology drugs against patient-derived DIPG cell lines. From this screen, we identified a group of compounds commonly used in the treatment of estrogen and androgen-receptor driven breast and prostate cancers showing significant inhibition of DIPG proliferation in vitro. These included the aromatase inhibitor anastrazole and the androgen receptor inhibitor enzalutamide. Sensitivity to these drugs correlated with increased expression of aromatase (CYP19A1) and AR in DIPG cells compared to normal astrocytes. Further, analyzing retrospective DIPG patient gene expression data (n=51), we identified subsets of DIPG tumor samples with high expression of CYP19A1 and AR relative to normal brain tissue. Kaplan-Meier plots stratified by AR expression revealed shorter survival times for the group with high AR expression (p=0.02821). Androgen and estrogen have long established neurosteroid effects on the developing brain, but their role in pediatric brain malignancies is not well understood. We hypothesize that AR and CYP19A1 have important roles in DIPG tumorigenesis and progression, similar to other malignancies, and that existing therapies targeting these pathways, which have well-established safety and toxicity profiles, could function as effective treatments for DIPG.
Theatre: One Flew Over the Cuckoo's Nest
Authors: J. O'N. Roach
Journal: BMJ (2000)

Steppenwolf Theatre Company production Barbican Centre, London, 27 July to 5 August Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> The book radically challenged the public's perception of mental health and its treatment. The film managed to capture the dark imagery of Ken Kesey's tale. Now a new play, by the renowned acting ensemble Steppenwolf, has revived the story. This version is set in a state … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
Longitudinal Outcomes of Patients With Single Ventricle After the Fontan Procedure
Authors: Andrew M. Atz, Victor Zak, Lynn Mahony, Karen Uzark, Nicholas D’agincourt, David J. Goldberg, Richard V. Williams, Roger E. Breitbart, Steven D. Colan, Kristin M. Burns, Renee Margossian, Heather T. Henderson, Rosalind Korsin, Bradley S. Marino, Kaitlyn Daniels, Brian W. McCrindle
Journal: Journal of the American College of Cardiology (2017)
08.18 Anti-citrullinated protein antibodies: a marker of cardiovascular disease and mortality in patients without rheumatoid arthritis
Authors: Maaike PJ Hermans, Mikhail Volkov, Daniel van der Velden, José M Montero Cabezas, Tom WJ Huizinga, Johan Kuiper, Rene EM Toes, Martin J Schalij, J Wouter Jukema, Diane van der Woude
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) have a high risk of cardiovascular mortality, which is further increased in presence of anti–citrullinated protein antibodies (ACPA). Recently, ACPA were unexpectedly detected in a cohort of patients with coronary artery disease (CAD) in the absence of RA. However, it is unknown if ACPA are consistently present in different cohorts of CAD patients, and if ACPA presence affects the course of cardiovascular disease in these patients. The purpose of this study was to assess the relationship between ACPA and long-term outcomes (including mortality) in patients with ST-elevation myocardial infarction (STEMI) in the absence of RA. <h3>Materials and methods</h3> Patients with from the MISSION! Intervention Study were included (n=275). The cohort consists of patients with STEMI, who subsequently underwent a percutaneous coronary intervention. Patients with RA were excluded. ACPA positivity was determined using a commercially available ELISA system (Quanta Lite CCP3.1 IgG/IgA). The association between ACPA (anti-CCP3) status at baseline and outcomes, such as re-infarction and death, was investigated during a 10 year follow-up. <h3>Results</h3> In total, 29 (11%) of 275 included patients were ACPA-positive, substantiating the previous description of ACPA in CAD patients. Increased cumulative cardiac mortality was observed in ACPA-positive patients in comparison with ACPA-negative patients. Moreover, after correction for additional associated factors (such as age, gender, body mass index, presence of diabetes, etc.), ACPA-positivity was still associated with increased long-term mortality (HR 3.1 [CI 1.4–7.1] p=0.01] and the long-term combined endpoint of re-infarction and death (HR 2.4 [1.2–4.6] p=0.01). <h3>Conclusions</h3> Among STEMI patients without RA, the presence of ACPA is independently associated with increased long-term mortality and the combined endpoint of re-infarction and death. We suggest that ACPA, previously solely linked to RA development and severity, may also play a role as an additional risk factor in cardiovascular disease. The hypothesis that ACPA might act as an independent pro-atherogenic factor in patients with and without RA, has to be investigated in subsequent studies.
Housing Conditions and Respiratory Disease: Morbidity in a Poor-Class Quarter and in a Rehousing Area in Glasgow
Journal: JAMA (1934)

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Psychophysiological stress in athletes across concussion recovery milestones
Authors: Lynda Mainwaring, Arrani Senthinathan, Michael Hutchison, Scott Thomas, Doug Richards, Nathan Churchill
Journal: British Journal of Sports Medicine (2017)

Background Psychophysiological stress markers across concussion recovery milestones have not been examined in an integrated study. Objective To examine physiological (heart rate variability [HRV] and salivary cortisol) and psychological (mood, perceived stress, symptoms, and sleep quality) factors of stress in concussed athletes across clinical recovery milestones. Design A prospective case control repeated measures study was conducted over three clinical recovery milestones: Symptomatic (acute), Asymptomatic, and 1-week Post Return-to-Play (RTP). Setting Single university athlete program monitored by the university’s sport medicine clinic, Ontario, Canada. Participants Male and female varsity athletes (n=26; M=16, F=10) with medically diagnosed concussion and their matched controls (n=26; M=16, F=10). Outcome measures Physiological: HRV and salivary cortisol; psychological: mood, perceived stress, sleep quality and symptoms. Main results Univariate analyses identified a group by sex interaction for specific HRV measures (RR intervals p=0.0084, Low frequency Power p=0.0084, Mean Heart Rate p=.0049, and Low/High Frequency Ratio p=0.0084). Multivariate analyses of HRV identified main effects for sex and group, and a significant interaction with reduced HF HRV for female concussed athletes through to 1-week post RTP (FDR=.05). HRV suppression was related to mood disturbance in males (FDR.05). Psychological measures were significantly worse for concussed athletes relative to controls at the Symptomatic Phase, but significantly better at 1-week post RTP (paired Wilcoxon at FDR=.05). Funding disclosure This study was supported by a grant from the Canadian Institute of Health Research (CIHR) −2012-ABI-CAT1-971 to L. Mainwaring. Conclusions For both males and females, mood disturbance, symptoms, and sleep quality perturbations were resolved by 1-week post RTP whereas autonomic nervous system disruption persisted beyond RTP in females. Psychophysiological non-invasive markers show promise for concussion monitoring. Competing interests None.
Cardiovascular Reactivity Among Surgeons: Not Music to Everyone's Ears
Authors: Matthew B. Weinger
Journal: JAMA (1995)

<h3>To the Editor.</h3> —Drs Allen and Blascovich<sup>1</sup>are to be congratulated for pursuing an important avenue of research— the potential effect of a performance-shaping factor,<sup>2</sup>listening to music, on clinical task performance. In their well-controlled laboratory study, surgeons performed a cognitively demanding task (serial subtraction) with greater speed and accuracy but less stress (less autonomic reactivity) when preferred music was being played compared with nonpreferred or no music. Unfortunately, the authors' concluding statement, which implies an essential role for music in the operating room, is not substantiated by their data. First, the results of their study may not be generalizable to the surgeon performing in the operating room. Second, they neglect to consider the potential impact of playing a surgeon's preferred music on other members of the operating room team. Several methodological aspects of the authors' study may limit the applicability of their results to the real-life environment.
DIPG-07. INDUCING DNA LETHALITY THROUGH POLO-LIKE KINASE 1 INHIBITION: A NOVEL THERAPEUTIC APPROACH IN DIPG
Authors: Laura Franshaw, Cecilia Chang, Swapna Joshi, Anahid Ehteda, Maria Tsoli, David Ziegler
Journal: Neuro-Oncology (2017)

Diffuse Intrinsic Pontine Glioma (DIPG) is the most aggressive form of malignant glioma to affect children. DIPG tumours cannot be surgically removed, do not respond to chemotherapy and are highly resistant to radiotherapy. Almost all children present with a short history of symptoms, fast neurological decline and rapid tumour progression. With almost all children with DIPG dying within only one year of diagnosis, new and innovative treatment strategies are urgently needed to counter these devastating tumours. We have found multiple regulators of the cell cycle are overexpressed in DIPG. Polo-like Kinase 1 (PLK1) represents the most promising target within the cell cycle apparatus. PLK1 controls cell cycle progression, cellular response to DNA damage and regulates cell cycle re-entry following arrest. We examined the therapeutic potential of 3 blood brain barrier permeable PLK1 inhibitors readily amenable for rapid clinical translation (BI2536/GSK461364/BI6727). Each exhibited unprecedented anti-proliferative effects against our panel of DIPG cultures at exceptionally low nanomolar potency, decreasing clonogenic abilities and increasing arrest at the G2 checkpoint. We found PLK1 inhibition influences one of the major oncogenic pathways in DIPG, the Phosphoinositide 3-kinase (PI3K) pathway. Interestingly, several key tumour promoting aberrations in this pathway were corrected upon PLK1 inhibition. We therefore examined whether the efficacy of PLK1 inhibitors can be further enhanced through combination with agents that target this pathway. We found cytotoxic activity of PLK1 inhibitors are synergistically enhanced upon addition of the PI3K inhibitor BKM120. We also identified a novel highly potent therapeutic approach for DIPG combining PLK1 inhibitors with temsirolimus (an mTOR inhibitor). In our highly aggressive orthotopic model of paediatric supratentorial High Grade Glioma, PLK1 inhibition significantly and potently enhanced animal survival. We are currently testing PLK1 inhibitors in combination with irradiation in our patient-derived in vivo model of DIPG with preliminary results indicating prolonged animal survival.
Oncologic Outcomes for Patients with Residual Cancer at Cystectomy Following Neoadjuvant Chemotherapy: A Pathologic Stage-matched Analysis
Authors: Bimal Bhindi, Igor Frank, Ross J. Mason, Robert F. Tarrell, Prabin Thapa, John C. Cheville, Brian A. Costello, Lance C. Pagliaro, R. Jeffrey Karnes, R. Houston Thompson, Matthew K. Tollefson, Stephen A. Boorjian
Journal: European Urology (2017)