tbuckley/cabot-search huggingface dataset:
HGG-14. IDENTIFICATION OF PERSONALIZED ACTIVE AGENTS IN PEDIATRIC GLIOMAS THROUGH HIGH-THROUGHPUT DRUG SCREENING IN MATCHING PAIRS OF PATIENT DERIVED ORTHOTOPIC XENOGRAFT (PDOX) NEUROSPHERE AND MONOLAYER CELLS
Authors: Lin Qi, Yuchen Du, Goeum Bae, Mari Kogiso, Frank Braun, Holly Lindsay, Huiyuan Zhang, Sarah Injac, Patricia Baxter, Jack Su, Michael Mancini, Oliver Hampton, William Parsons, Murali Chintagumpala, Clifford Stephan, Peter Davies, Xiao-Nan Li
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is one of the deadliest brain tumors both in adults and children. The efficacy of targeting mutated genes/pathways has not been systematically analyzed. Additionally, it remains unknown if neurospheres and non-stem monolayer tumor cells will respond equally to the same target therapies. Relatively long-term treatment was achieved for high-throughput drug screening and revealed time- and dose-dependent effects in most of the 4,629 compounds that were active in at least one culture at one time point. When gene mutations were druggable, not all inhibitors of the same family were active. In IC-4687GBM, high NF1 mutation (>76–99% allele) frequency was found in patient tumor, xenografts, and cultured cells, but only 3/17 MEK inhibitors were active in neurospheres and 2/17 in monolayer cells on day 7. In IC-R0315GBM that carried PI3KCA mutation (allele frequency 22–27%), 5/33 PI3K inhibitors were active in neurospheres and 8/33 in monolayer cells after 7 days. In IC-3752GBM (recurrent GBM) and ICb-1127AA, no druggable mutations were detected. The number of active drugs on day 7 was 366 in IC-4768GBM, 406 in IC-3752GBM, 284 in IC-R0315GBM, and 305 in ICb-1277AA. When the 4 matching pairs of neurospheres and monolayers were compared, the agents active in both cultures ranged from 36% to 60%, active only in neurosphere from 10.3% to 25%, and active only in monolayer cells from 14.8% to 53%. Subsequent in vivo validation using MLN8327 in IC-4687GBM and IC-R0315GBM showed that effective targeting of both neurosphere and monolayer was required for significantly-improved animal survival times. We showed that long-term treatment is feasible for high-throughput drug screening. Targeting druggable mutations can be achieved but only by a fraction of specific agents. Neurospheres and monolayer cells do not always respond equally toward the same drugs, and effective targeting of both subpopulations is needed to generate prolonged animal survival times.
Genome-Wide Analysis of a Novel Murine Model of Chronic Lymphocytic Leukemia
Authors: Lili Wang, Rutendo Gambe, Jing Sun, Sachet Shukla, Jaegil Kim, Angela N Brooks, Donna S. Neuberg, Mark D. Fleming, Benjamin L. Ebert, Ruben D. Carrasco, Catherine J Wu
Journal: Blood (2016)
TRTH-14. TARGETING CHK1 AND AKT CROSSTALK IN MUTANT P53 PEDIATRIC GLIOBLASTOMA
Authors: Chris Stamatkin, Nimita Dave, Harlan Shannon, Barbara Bailey, Jixin Ding, Reza Saadatzadeh, Mary Murray, Aaron Cohen-Gadol, Jamie Renbarger, Karen Pollok
Journal: Neuro-Oncology (2017)

Pediatric high-grade gliomas are the most common and universally deadly form of CNS malignancy. Combination therapies that exploit the DNA Damage Response (DDR) offer avenues to improve clinical outcome in patients with pediatric glioblastoma (GBM). We hypothesize that dual inhibition of the prosurvival kinases Akt and checkpoint kinase 1 (Chk1), both of which are activated during the DDR, will block DNA replication and prevent repair of DNA damage mediated by cytotoxic chemotherapy. The rationale of this therapeutic approach for mutant p53 (mtp53) GBM is that Chk1-mediated G2 arrest is not dependent on wildtype p53. Moreover, the rationale for dual inhibition of Akt and Chk1 emerges from studies demonstrating that activated Akt can directly inhibit Chk1 function. Therefore, to optimally inhibit Chk1-dependent survival and growth, Akt inhibition will be critical. To develop a clinically relevant strategy, a mouse brain uptake assay was first conducted to select small molecule inhibitors to Chk1 and Akt that exhibit blood-brain-barrier permeability. In the pediatric mtp53 GBM cell lines, SJ-GBM2 and SF188, the effects of CCNU, Chk1 inhibition (AZD7762) or AKT inhibition (GDC0068) alone, and in combination were evaluated. As a single agent, AZD7762 potently inhibited GBM cell growth presumably due a block in Chk1-dependent regulation of DNA replication forks. Pharmacodynamic studies indicated that Chk1 inhibition led to upregulation of the PI3K/AKT and MEK/ERK signaling pathways, further underscoring the critical need to develop strategic drug combinations. At therapeutically achievable concentrations, CCNU/AZD7762/GDC0068 combinations decreased GBM cell proliferation relative to single-agent treatments, demonstrating additive to synergistic effects over a wide range of drug-dose ratios. The present results indicate that a multi-pronged strategy directed at crippling the DDR will be required. In the context of DNA damaging agents and CHK1 blockade, targeting of PI3K/AKT and/or MEK/ERK effectors may overcome therapeutic resistance by knocking out feedback loops that promote survival.
Bringing Transparency to Medicine: Exploring Physicians' Views and Experiences of the Sunshine Act
Authors: Susan Chimonas, Nicholas J. DeVito, David J. Rothman
Journal: The American Journal of Bioethics (2017)

The Physician Payments Sunshine Act (PPSA) requires health care product manufacturers to report to the federal government payments more than $10 to physicians. Bringing unprecedented transparency to medicine, PPSA holds great potential for enabling medical stakeholders to manage conflicts of interest (COI) and build patient trust—crucial responsibilities of medical professionalism. The authors conducted six focus groups with 42 physicians in Chicago, IL, San Francisco, CA, and Washington, DC, to explore attitudes and experiences around PPSA. Participants valued the concept of transparency but were wary of the law's design and consequences. They downplayed PPSA's potential and felt it undermined public trust. Showing broad unawareness of COI, they dismissed the notion of industry influence and welcomed company "perks." Misapprehensions may leave physicians unprepared to advance the opportunities PPSA holds for professionalism. The authors offer recommendations for government and medicine to improve physicians' and other stakeholders' understandings and use of the data.
Pegfilgrastim (P) administration after 24, 72, or 96 hours (h) to allow dose-dense (DD) anthracycline- and taxane-based chemotherapy (CT) in breast cancer (BC) patients (pts): A single-center experience within the GIM2 randomized phase III study.
Authors: Matteo Lambertini, Matteo Clavarezza, Francesca Poggio, Simona Pastorino, Annalisa Abate, Claudia Bighin, Paolo Pronzato, Lucia Del Mastro
Journal: Journal of Clinical Oncology (2014)

9632 Background: The GIM2 study (ClinicalTrials.gov number, NCT00433420) compared two different schedules of CT (DD versus standard duration) as adjuvant treatment of 2,091 node positive BC pts. DD arms were supported by P scheduled 24 h after CT. P can induce early leukocytosis after its administration with the potential risk of capillary leak syndrome and spleen rupture. To evaluate the best timing of P administration, 3 different cohorts of pts enrolled in the GIM2 study and treated at the coordinating center received P 24 or 72 or 96 h after CT. Methods: 5 pts were planned to be enrolled in each cohort; pts in cohort A received P after 24 h, pts in cohort B after 72 h and pts in cohort C after 96 h. After the preliminary results, cohort A and B were expanded up to 9 and 21 pts. A complete blood count was obtained 24 h after P and every 2 days for each cycle thereafter. Results: Median values of white blood cell (WBC) counts for all anthracycline and taxane cycles are reported in the table. Pts in cohort A showed WBC and neutrophil (N) counts 24 h after P higher than pts in the other cohorts; pts treated with P after 96 h showed a high WBC and N counts at day 13 (i.e. the day before the following CT cycle). No differences in CT delays were observed between pts treated with P after 24 h or 72 h. On the basis of these findings, the protocol was amended and pts in the DD arms received P after 72 h. Conclusions: The best timing of P administration in DD regimens is 72 h after CT. Clinical trial information: NCT00433420. Cohort A P 24 h Cohort B P 72 h Cohort C P 96 h WBC count median x 103/uL (range) WBC count median x 103/uL (range) WBC count median x 103/uL (range) Anthracycline-based CT Day 1 9.1 (4.3 – 17.3) 9.2 (4.5 – 28.7) 12.2 (5.2 – 32.8) 24 hours after P 62.5 (23.3 – 116.4) 35.0 (14.1 – 79.8) 28.7 (14.4 – 64.4) 72 hours after P 36.8 (27.5 – 53.2) 15.9 (5.0 – 36.1) 4.7 (0.8 – 24.3) Day 13 9.9 (2.9 – 16.3) 12.7 (4.7 – 26.1) 18.7 (9.0 – 37.5) Taxane-based CT Day 1 8.4 (4.7 – 15.0) 10.5 (3.4 – 26.9) 13.8 (5.2 – 30.7) 24 hours after P 67.4 (29.5 – 92.9) 53.8 (6.6 – 81.3) 45.0 (23.7 – 61.9) 72 hours after P 46.7 (27.0 – 78.7) 36.9 (19.0 – 66.8) 34.3 (15.7 – 58.6) Day 13 15.2 (7.7 – 25.6) 20.5 (11.2 – 35.6) 24.0 (13.1 – 49.3)
Accelerated Approval and Expensive Drugs — A Challenging Combination
Authors: Walid F. Gellad, Aaron S. Kesselheim
Journal: New England Journal of Medicine (2017)

Interview with Dr. Walid Gellad on strategies for managing the cost of drugs receiving accelerated FDA approval. (09:56)Download Accelerated FDA approval can mean that private payers choose not to cover a drug because of high cost and lack of evidence of efficacy, thwarting patient access, while major government payers must cover the product, directing substantial tax dollars to unproven drugs.
Assessment of blood biomarkers of mild traumatic brain injury in professional rugby: a case control study
Authors: Fiona Wilson, Aine Kelly, Noreen Boyle, Matej Oresic, Tuulia Hyotylainen, Karl Denvir, Garreth Farrell,, Brendan O’Connell
Journal: British Journal of Sports Medicine (2017)

Objective to investigate plasma S100b concentration following competitive play and concussive episodes; to compare plasma S100b concentration in professional rugby players with age matched non-contact athletic controls; to develop an objective blood biomarker to aid in the diagnosis of concussion. Design Prospective case-control study Setting Professional rugby club, Elite rowing clubs. Participants Professional rugby players (n=44); elite rowers (age/activity matched athletic controls) (n=16). Interventions Blood samples were collected at baseline (14 days prior to training/competitive play) in both the rugby and rowing cohort. Rugby players were again assessed one hour following competitive games in the early, middle and late season (3 times). This was repeated again the following season (6 data sets). Concussed players were re-evaluated following concussion. Outcomes Plasma was prepared and assessed for S100b concentration by ELISA (Abnova). Metabolomic profiling of samples was carried out by two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Main results There was significant increase in plasma S100b following competitive play, compared to baseline (p&lt;0.001). Over 1000 metabolites were detected by GC×GC-TOFMS in a single sample run, covering a functionally wide range of small molecules. The post-match metabolic profile showed significant changes in several metabolites; these are at present being validated and analysed further. Conclusions There is a significant effect of competitive play on circulating S100b. Data on metabolomic profiles are being collected continually throughout the season and being clustered according to concussive and non-concussive episodes. It is hoped that this analysis may reveal concussion-specific changes in the metabolomic profile of players. Competing interests None.
MEDU-19. CITRON KINASE AS THERAPEUTIC TARGET FOR MEDULLOBLASTOMA
Authors: Gianmarco Pallavicini, Francesco Sgrò, Francesca Garello, Valeria Bitonto, Mattia Falcone, Juan Carlos Cutrin, Enzo Terreno, Emilia Turco, Ferdinando Di Cunto
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatments for MB is surgery followed by irradiation of the entire neuraxis together with high-dose multi-agent chemotherapy. The identification and validation of novel target molecules, which doesn’t disturb the normal postnatal physiology and development of the central nervous system and other tissues, are urgently needed. We have hypothesized Citron kinase (CIT-K) could be a potential target for MB treatment. Indeed, we know that CIT-K is fundamental for correct cytokinesis and survival of neuronal precursors and especially of those that give rise to cerebellar granules, from which MB is thought to develop. We tested this hypothesis using the MB cell lines DAOY and ONS-76. We found that in these cells CIT-K knockdown increases both cytokinesis failure and DNA-damage leading to apoptosis, reducing growth rates and inducing senescence. On this basis we have implemented a temporally controlled conditional CIT-K knockout strategy in the SmoA1 transgenic mouse, which spontaneously develop cerebellar MB at high frequency. As well as cell lines mouse MB showed increased DNA-damage after cit-k loss; p27kip1, p21Waf1/Cip1 and p16INK4a were up regulated indicating that MB of these mice arrested their growth and underwent senescence. Furthermore, CIT-K deletion increased overall survival of mice with any evident side effect. Together, these results indicate CIT- K as a potential target for MB treatment.
Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling
Authors: Toshiaki Teratani, Kengo Tomita, Takahiro Suzuki, Hirotaka Furuhashi, Rie Irie, Shigeaki Hida, Yoshikiyo Okada, Chie Kurihara, Hirotoshi Ebinuma, Nobuhiro Nakamoto, Hidetsugu Saito, Toshifumi Hibi, Soichiro Miura, Ryota Hokari, Takanori Kanai
Journal: Journal of Hepatology (2017)
Abstract #3037: Contribution of the Rad50, Mre11 and NBN genes to HBOC
Authors: Nancy Uhrhammer, Yves-Jean Bignon
Journal: Cancer Research (2009)

The Rad50-Mre11-Nbs1 complex is essential for the repair of DNA double-strand breaks. Rare genetic disorders are associated with homozygosity for mutations of the complex components; each including very high cancer risk. Heterozygotes also appear to be at higher risk of breast cancer, suggesting that they may be classified as low- or moderate-penetrance HBOC genes. To evaluate the contribution of mutations and variants in these genes to familial breast cancer in France, we analyzed their full coding sequence in a series of non-BRCA HBOC cases. Cases were seen at the Oncogenetics consultation at the Centre Jean Perrin; written informed consent was obtained for genetic analysis, and DNA purified from peripheral blood. BRCA mutations were excluded in 600 cases by full sequencing, plus MLPA analysis for BRCA1. A locally recruited control population of 600 women with no personal or family history breast or ovarian cancer was also studied. Results: To date, Rad50 was fully sequenced in 267 cases, revealing two variants (Q426R in exon 9 and Q1011R in exon 19) predicted to significantly disrupt protein structure or function. Q426R was observed in two families. Exons 9 and 19, plus exon 5, the site of a Finnish founder mutation, were analyzed in 600 controls: none of these variants were found, though one additional likely deleterious variant, N981I, was observed. Mre11 was thus far fully sequenced in 303 cases, revealing two deleterious mutations (R576X and R592X) and three variants likely to be benign (A492D, E497K and R576Q) based on splicing predictions, conservation of amino acid sequence among species, and predicted structural perturbation. Heterozygosity for A492D was observed in 1.2 % of cases and 1.4 % of controls. One probably deleterious mutation was also observed among controls: W210G has not been previously described, but concerns the same amino acid seen in a Saudi family with two ATLD patients homozygous for W210C. NBN has been fully sequenced in 140 cases, revealing no variants or deleterious mutations. Complete results for all three genes as well as segregation data for variants will be presented at the AACR annual meeting.Our results, with five deleterious or probably deleterious mutations in approximately 300 families, suggest that the R-M-N complex may contribute to breast cancer risk in a small proportion of non-BRCA HBOC families. The observation of deleterious mutations among the non-HBOC control group, however, suggests that the oncogenic penetrance of such mutations may be modest.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3037.
Allogeneic Transplants from HLA-Mismatched Unrelated Donors Using Total Lymphoid Irradiation and Antithymocyte Globulin Conditioning Retain a Low Risk of Graft-Versus-Host Disease and Non-Relapse Mortality with at Least As Potent Anti-Tumor Activity As with Matched Unrelated Donors
Authors: Michael A. Spinner, Marcelo Fernandez Vina, Linda Elder, Sally Arai, Laura Johnston, Everett Meyer, David Miklos, Lori Muffly, Robert S. Negrin, Judith Shizuru, Wen-Kai Weng, Ginna G. Laport, Samuel Strober, Robert Lowsky, Andrew R. Rezvani
Journal: Blood (2016)
Trump proposes slashing funding for Medicaid, poverty programs, and medical research
Authors: Michael McCarthy
Journal: BMJ (2017)

In a budget proposal released by the White House on 23 May, President Donald Trump plans to cut federal funding for Medicaid, the government health insurance plan for poor and disabled people, and to substantially cut funding for poverty programs and medical research.1

The $4.1 trillion (£3.16trn; €3.67trn) budget for the fiscal year 2018 is part of a long term budget plan that the Trump administration said would cut more than $1trn from social safety net programs over the next 10 years and would, with cuts to other programs, reduce federal spending by $3.6trn overall. The US government fiscal year begins on 1 October 2017 and runs through to 30 September 2018.

Mick Mulvaney, director of the White House’s Office of Management and Budget, said that the …
Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Gary T Ferguson, J Mark FitzGerald, Eugene R Bleecker, Michel Laviolette, David Bernstein, Craig LaForce, Lyndon Mansfield, Peter Barker, Yanping Wu, Maria Jison, Mitchell Goldman, Guy Chouinard, J Mark FitzGerald, Maryam Rostami, Jean Oosthuizen, Bonavuth Pek, Deepen Patel, Pierre-Alain Houle, Michel Laviolette, Sohail Khattak, Patrick Killorn, Claus Keller, Isabelle Schenkenberger, Stefan Zielen, Sabine Ballenberger, Martin Hoffmann, Joachim Kirschner, Márta Papp, Teréz Kecskés, Magdolna Póczi, Lajos Molnár, Éva Radeczky, Judit Schlezák, Ewa Springer, Violetta Balicka, Jadwiga Kaczmarek, Danuta Madra-Rogacka, Ewa Pisarczyk-Bogacka, Malgorzata Zurowska-Gebala, Maciej Marczak, Piotr Napora, Witold Pomiecko, Erika Pribulova, Svetlana Kurthova, Maria Drugdova, Denisa Kavkova, Luboslava Frajtova, Alexander Golubov, Dagmar Paulinyova, Daniela Hasicova, Miriam Michalickova, Miguel Trevino, Charles Campbell, Andrew Wachtel, Eugene Bleecker, Craig LaForce, David Bernstein, Selwyn Spangenthal, Edward Kerwin, Lyndon Mansfield, Paul Ratner, Samir Arora, Gregory Feldman, Benedict Okwara, Humberto Cruz, Lawrence Sher, Andrew Pedinoff, Clinton Corder
Journal: The Lancet Respiratory Medicine (2017)
Erratum: Autoantibodies to annexin XI-A and other autoantigens in the diagnosis of breast cancer (Cancer Research (2004) 64 (5089-5096))
Authors: F. Fernández-Madrid, N. Tang, H. Alansari, J. L. Granda, L. Tait, K. C. Amirikia, M. Moroianu, X. Wang, R. L. Karvonen
Journal: Cancer Research (2006)
A novel endoloop system for closure of colonic mucosal defects through a single-channel colonoscope
Authors: Jiankun Wang, Lili Zhao, Xiang Wang, Li Liu, Min Wang, Zhining Fan
Journal: Endoscopy (2017)

Abstract Background and study aims Successful closure of the postoperative mucosal defect is crucial for endoscopic treatment. The purse-string suture strategy via a double-channel endoscope has been recommended as being both safe and feasible for large gastrointestinal mucosal defects. However, for colonic treatment, use of a single-channel colonoscope is more popular because of its longer length and greater flexibility. A novel pre-detached endoloop system was therefore developed for endoscopic purse-string suture closure via a single-channel endoscope. This study evaluated its feasibility and efficacy, especially for right colonic mucosal defects. Patients and methods A total of 18 patients with colonic defects post-endoscopic submucosal dissection (ESD) were treated using the single-channel endoscope method. Results All mucosal defects were successfully closed using the novel closure technique. No severe complications, such as massive intraoperative bleeding, delayed bleeding, peritonitis, or perforation, were recorded. All patients recovered well after ESD and left the hospital within 7 days. Conclusions This novel pre-detached endoloop strategy via a single-channel endoscope was safe and feasible for the closure of colonic mucosal defects using an endoscopic purse-string suture.
55 the recognition of paediatric sports related concussion (5–16 year olds), initial management and advice among london based emergency medicine trainees
Authors: Catherine Hornby, Mike England, Akbar de Medici, Courtney Kipps
Journal: British Journal of Sports Medicine (2017)

Objective This study aimed to investigate knowledge of paediatric concussion amongst emergency medicine trainees, testing the hypothesis that emergency medicine trainees lack sufficient knowledge to competently assess, diagnose and manage sports-related paediatric concussion. Design cross-sectional questionnaire survey. Setting Secondary care emergency medicine departments. Participants All emergency medicine trainees in one geographical training region in the UK were invited to participate. Outcome measures occupational grade, years of experience, history of specific concussion training, awareness of head injury guidelines, perceived knowledge and confidence in concussion diagnosis and management. Main results Sixty questionnaires were returned. Across all training grades, the mean correct response score on questions of diagnosis, assessment and management of concussion was 73.4%. Nearly 70% of trainees were not aware of any concussion guidelines, and only 10% had attended a course or received training regarding concussion. There was a negative correlation between awareness of guidelines and perceived confidence (r=−0.50 p&lt;0.001), and knowledge in diagnosis and management of concussion (r=−0.51, p&lt;0.001). The majority (91.7%) of the participants would like further education on concussion management, with an online learning module being the preferred format (71.7%). Conclusions The study revealed insufficient level of knowledge and confidence in the assessment, diagnosis and management of paediatric concussion among emergency medicine trainees. None of the variables studied statistically predicted knowledge score. Additional concussion-specific education would be beneficial to optimise trainees’ knowledge of paediatric concussion. Competing interests None.
Bortezomib Consolidation Following Autologous Transplant Equalizes the Outcome for Older Patients with Less Intensive Pretreatment Compared to Younger Patients with Newly Diagnosed Multiple Myeloma
Authors: Christian Straka, Stefan Knop, Martin Vogel, Jurgen Müller, Martin Kropff, Bernd Metzner, Christian Langer, Herbert Sayer, Wolfram Jung, Heinz Dürk, Hans-Juergen Salwender, Hannes Wandt, Florian Bassermann, Martin Gramatzki, Wolf Rösler, Hans-Heinrich Wolf, Wolfram Brugger, Monika Engelhardt, Thomas Fischer, Peter Liebisch, Hermann Einsele
Journal: Blood (2016)