tbuckley/cabot-search huggingface dataset:
Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAF<sup>V600</sup>-mutant metastatic melanoma (mel): Updated safety and clinical activity.
Authors: Ryan J. Sullivan, Rene Gonzalez, Karl D. Lewis, Omid Hamid, Jeffrey R. Infante, Manish R. Patel, F. Stephen Hodi, Jeffrey Wallin, Bethany Pitcher, Edward Cha, Louise Roberts, Marcus Ballinger, Patrick Hwu
Journal: Journal of Clinical Oncology (2017)

3063 Background: Targeted inhibition of MEK with C and BRAF with V in BRAF V600 -mutant mel can lead to both anticancer immune activation and direct tumor cell death. A, an anti–PD-L1 monoclonal antibody, inhibits PD-L1/PD-1 signaling. Combining C + V with A may enhance antitumor activity, potentially leading to improved clinical responses and durability. Preliminary data from this phase Ib study (NCT01656642) showed that A + C + V had a manageable safety profile and promising antitumor activity in patients (pts) with untreated BRAF V600 -mutant unresectable/metastatic mel, with increases in CD8-positive T-cell infiltration observed after C + V (Sullivan et al SMR 2016). We present updated safety and efficacy data. Methods: Pts received A + C + V after a 28-day run-in with C + V. A was given at 800 mg q2w, C at 60 mg qd for the first 21 days of each 28-day cycle, and V at 960 mg bid during day 1–21 of run-in and 720 mg thereafter. Safety was evaluated in pts who had ≥1 dose of A; efficacy, in pts who had ≥1 dose of A by the data cutoff date and received ≥1 dose of A, C, or V by the dosed-by date. Results: Thirty-four patients were treated and evaluated for both safety and efficacy. Median survival follow-up was 7.1 months (range 2.5–19.9). Elevated AST/ALT, diarrhea, arthralgia, fatigue, photosensitivity, pyrexia, nausea, flu-like symptoms, maculopapular rash, and pruritus were reported as A- and/or C- and/or V-related in &gt; 20% of pts at any grade (G). A/C/V-related G3–4 adverse events (AEs) were seen in 15 pts (44.1%) with the triple combination (none G5). Three serious AEs were A-related. All AEs were manageable and reversible. Elevated ALT/AST (three pts each) and rash (one pt) led to discontinuation of any drug. Unconfirmed RECIST V1.1 responses were observed in 29 pts (85.3%; six complete, 23 partial). Three pts with confirmed partial responses had resolution of target lesions. Twenty of the 29 responding patients continue to respond at the time of the data cutoff. Conclusions: Updated results confirm preliminary findings that A + C + V has a manageable safety profile and promising antitumor activity in pts with BRAF V600 -mutant metastatic mel. Continued exploration of A + C + V is warranted. Clinical trial information: NCT01656642.
Vicky Mary Osgood
Authors: Penelope Gordon, David Davies, Danny Dubois
Journal: BMJ (2017)

Vicky Mary Osgood was an obstetrician, a mentor, and an educator. She took A levels in geography, biology, and history and an O level in use of English before first MB at the Royal Free. Her love of literature was exemplified when years later she provided a reading list of non-medical works for foundation doctors.

She trained as an obstetrician in London and conducted research into the endocrinology of fertility, followed by senior registrar and senior lecturer posts in Oxford, where she worked with Chris Redman for the Silver Star Society. Her husband, Danny, was offered a consultant post in Portsmouth, and Vicky followed him as consultant obstetrician specialising in fetomaternal medicine. Clinically she loved intrapartum care and continued her sessions on the labour ward until she left the trust to become dean of the Wessex …
STUDY OF VALIDATION OF ANGIOGENESIS POLYMORPHISMS IN HCC PATIENTS TREATEDWITH SORAFENIB. INNOVATE STUDY
Authors: A.C. Gardini, L. Faloppi, B. Daniele, G.F. Foschi, S. Cascinu, G. Marisi, G. Masi, L. Chessa, F. Negri, E. Scarpi, D. Santini, J. Corbelli, N. Silvestris, E. Tamburini, V. Zagone, M. Scartozzi
Journal: Journal of Hepatology (2016)
A phase 1 study of the c-Met inhibitor tivantinib (ARQ 197, IND#112603) in children with relapsed or refractory solid tumors: A Children’s Oncology Group study.
Authors: James I. Geller, John Peter Perentesis, Charlotte H. Ahern, Rachel A. Kudgus, Elizabeth Fox, Susan Blaney, Brenda Weigel
Journal: Journal of Clinical Oncology (2014)

2627 Background: Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase (RTK), which is dysregulated in many pediatric cancers. A phase I and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with refractory solid and CNS tumors. Methods: Oral tivantib capsules were administered bid, continuously in 28-day cycles. Three dose levels (170, 200 or 240mg/m2/dose) were evaluated using a rolling 6 design (Part A). In Part B, patients received tivantinib powder sprinkled on food at the RP2D from Part A. Serial PK (day 1) and trough samples (day 28) were obtained in Cycle 1. CYP450 genotyping was performed in all participants. Results: Thirty-six patients were enrolled (24 male, median age 12.1 years (range, 3.8-21): 20 in Part A, 6 to a PK expansion cohort, and 10 to Part B. Fifteen patients had primary CNS tumors and 21 had solid tumors. Twenty-six patients were evaluable for toxicity assessment and 32 for response. In Part A there were 0/5, 0/6 and 0/5 pts with DLT at dose levels 1-3. There was 1 grade (GR) 4 intracranial hemorrhage in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2). Non dose-limiting toxicities at least possibly attributable to tivantinib included grade 3 or 4 myelosuppression [lymphopenia (3), neutropenia (2), anemia (2), and thrombocytopenia (1)]; Gr 1 or 2 toxicities occurring in > 10% of evaluable patients included fatigue (9), leukopenia (7), vomiting (5), nausea (5), anemia (12), neutropenia (5), lymphopenia (3), hypoalbuminemia (4), and thrombocytopenia (3). PK analysis showed marked inter-patient variability (20-fold) in the Cmax and AUClast across all dose levels. Sprinkling tivantinib powder over food did not appear to alter exposure. The average terminal elimination t1/2 was 2.5 hours. Conclusions: The RP2D of tivantinib given with food is 240 mg/m2/dose. PK of tivantinib in children demonstrated high variability. Clinical trial information: NCT01725191.
HIV Testing Among Transgender Women and Men — 27 States and Guam, 2014–2015
Authors: Marc A. Pitasi, Emeka Oraka, Hollie Clark, Machell Town, Elizabeth A. DiNenno
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Transgender persons are at high risk for human immunodeficiency virus (HIV) infection; in a recent analysis of the results of over nine million CDC funded HIV tests, transgender women* had the highest percentage of confirmed positive results (2.7%) of any gender category (1). Transgender men,† particularly those who have sex with cisgender§ men, are also at high risk for infection (2). HIV testing is critical for detecting and treating persons who are infected and delivering preventive services to those who are uninfected. CDC recommends that persons at high risk for HIV infection be screened for HIV at least annually, although transgender persons are not specified in the current recommendations. CDC analyzed data from the Behavioral Risk Factor Surveillance System (BRFSS) to describe HIV testing among transgender women and men and two cisgender comparison groups in 27 states and Guam. After adjusting for demographic characteristics, transgender women and men had a lower prevalence of ever testing and past year testing for HIV (35.6% and 31.6% ever, and 10.0% and 10.2% past year, respectively) compared with cisgender gay and bisexual men (61.8% ever and 21.6% past year) and instead reported testing at levels comparable to cisgender heterosexual men and women (35.2% ever, and 8.6% past year). This finding suggests that transgender women and men might not be sufficiently reached by current HIV testing measures. Tailoring HIV testing activities to overcome the unique barriers faced by transgender women and men might increase rates of testing among these populations.
Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial
Authors: Cyriel Y Ponsioen, E Joline de Groof, Emma J Eshuis, Tjibbe J Gardenbroek, Patrick M M Bossuyt, Ailsa Hart, Janindra Warusavitarne, Christianne J Buskens, Ad A van Bodegraven, Menno A Brink, Esther C J Consten, Bart A van Wagensveld, Marno C M Rijk, Rogier M P H Crolla, Casper G Noomen, Alexander P J Houdijk, Rosalie C Mallant, Maarten Boom, Willem A Marsman, Hein B Stockmann, Bregje Mol, A Jeroen de Groof, Pieter C Stokkers, Geert R D'Haens, Willem A Bemelman, Karlien Bruin, John Maring, Theo van Ditzhuijsen, Hubert Prins, Jan van den Brande, Paul Kingma, Anna van Geloven, Nanne de Boer, Donald van der Peet, Jeroen Jansen, Michael Gerhards, Janneke van der Woude, Ruud Schouten, Bas Oldenburg, Richard van Hillegersberg, Rachel West, Guido Mannaerts, Marcel Spanier, Ernst Jan Spillenaar Bilgen, Rob Lieverse, Edwin van der Zaag, Annekatrien Depla, Arnold van de Laar, Clemens Bolwerk, Hans Brouwer, Nofel Mahmmod, Eric Hazebroek, Juda Vecht, Robert Pierik, Gerard Dijkstra, Sijbrand Hofker, Tessa Uiterwaal, Quirijn Eijsbouts, Liekele Oostenbrug, Meindert Sosef, Djuna Cahen, Sjoerd van der Werff, Andreas Marinelli, Job Peters, Huib Cense, Nynke Talstra, Pritesh Morar
Journal: The Lancet. Gastroenterology & hepatology (2017)
Eliminating Creatine Kinase–Myocardial Band Testing in Suspected Acute Coronary Syndrome
Authors: Matthew D. Alvin, Allan S. Jaffe, Roy C. Ziegelstein, Jeffrey C. Trost
Journal: JAMA Internal Medicine (2017)

Cardiac biomarker testing is estimated to occur in nearly 30 million emergency department visits nationwide each year in the United States. The American College of Cardiology/European Society of Cardiology indicate that cardiac troponin is the biomarker of choice owing to its nearly absolute myocardial tissue specificity and high clinical sensitivity for myocardial injury. Multiple academic medical centers have implemented interventions to eliminate the routine ordering of creatine kinase-myocardial band tests, with published patient safety outcomes data; however, creatine kinase-myocardial band testing is still ordered in many hospitals and emergency departments. Eliminating a simple laboratory test that provides no incremental value to patient care can lead to millions of health care dollars saved without adversely affecting patient care quality, and in this case potentially improving patient care.
THU0600 Cumulative adverse childhood experiences are associated with poor outcomes in adults with systemic lupus erythematosus
Authors: K DeQuattro, L Trupin, PP Katz, C Lanata, EH Yelin, LA Criswell, CG Helmick, M Dall'Era, J Yazdany
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Adverse childhood experiences (ACE) such as abuse, neglect and household challenges are associated with poorer adult health status and onset of rheumatic diseases. There has been no research associating ACE with outcomes among adults with systemic lupus erythematosus (SLE). <h3>Objectives</h3> To characterize relationships of ACE and health outcomes of disease activity, damage, quality of life and depression in SLE patients. <h3>Methods</h3> Data were derived from the California Lupus Epidemiology Study (CLUES), a population based, multi-ethnic cohort of patients with SLE. Participants completed self-report measures of SLE activity (Systemic Lupus Activity Questionnaire; SLAQ), damage (Brief Index of Lupus Damage; BILD), quality of life (SF-36), depression (Patient Health Questionnaire; PHQ8) and sociodemographics. They completed the Adverse Childhood Experiences (ACE) survey, a validated 10-item scale covering 3 domains (abuse, neglect and household challenges prior to age 18). We compared demographics and SLE outcomes by ACE score and domains using ANOVA. <h3>Results</h3> The 166 CLUES participants were mostly women (89%) and were racially/ethnically diverse (31% non-Hispanic White, 22% Hispanic, 15% African American, 31% Asian American). Mean age was 44±14; mean age at diagnosis 28±12. The median ACE score was 1; 30 (18%) had a score of 4 or higher. ACE scores ≥4 were more common in Hispanic (27%) and African American (32%) participants (p=0.01) compared to other races/ethnic groups, and in participants with poverty level incomes (61% vs 13%, p&lt;0.001); but did not differ by education or age at study entry or diagnosis. Higher overall ACE scores were associated with greater SLE activity and damage, poorer quality of life, and higher levels of depressive symptoms. For each ACE domain, increasing scores were generally associated with worse outcomes, but did not always reach statistical significance (Table). <h3>Conclusions</h3> Adverse childhood experiences are reported frequently in individuals with SLE; accumulation of adverse experiences is associated with poor SLE outcomes. Higher scores in each domain, especially childhood neglect or abuse, were associated with poorer health measures in adulthood. Further research regarding ACE patterns and SLE outcomes is warranted. <h3>Disclosure of Interest</h3> None declared
Combining Flow Cytometry and Molecular Assessment Improves the Prognostic Value of Pre-Transplant Minimal Residual Disease in Acute Myeloid Leukemia
Authors: Fabio Guolo, Paola Minetto, Federica Galaverna, Daniela Guardo, Nicoletta Colombo, Annalisa Kunkl, Marino Clavio, Carmen Di Grazia, Anna Maria Raiola, Filippo Ballerini, Maurizio Miglino, Roberto Massimo Lemoli, Marco Gobbi, Andrea Bacigalupo
Journal: Blood (2016)
Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms
Authors: Inan Olmez, Breanna Brenneman, Aizhen Xiao, Vlad Serbulea, Mouadh Benamar, Ying Zhang, Laryssa Manigat, Tarek Abbas, Jeongwu Lee, Ichiro Nakano, Jakub Godlewski, Agnieszka Bronisz, Roger Abounader, Norbert Leitinger, Benjamin Purow
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell-cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. Experimental Design: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed. Results: We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib. Conclusions: Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial. Clin Cancer Res; 23(22); 6958–68. ©2017 AACR.
Abstract 99: Conditional Depletion of CD11c <sup>+</sup> Cells Attenuates Myocardial Ischemia-Reperfusion Injury in Mice
Authors: Jun Li, Mozow Y Zuidema, Cuihua Zhang, Michael A. Hill, Feng Gao
Journal: Circulation Research (2012)

Excessive infiltration of pro-inflammatory monocytes /macrophages early after myocardial ischemia/reperfusion (MI/R) contributes to myocardial injury and cardiac dysfunction. We tested the hypothesis that conditional depletion of pro-inflammatory macrophages and dendritic cells may dampen excessive inflammatory response in the infarct myocardium, and thus attenuate MI/R injury. To achieve this, we took advantage of CD11c-diphtheria toxin receptor (DTR) transgenic mice, which allow for selective and conditional ablation of CD11c + cells for 2-3 days after diphtheria toxin administration. CD11c-DTR mice with conditional deficiency of CD11c + cells and wild type (WT) mice were subjected to MI/R (30 min /48 h). CD11c-DTR mice showed decreased infiltration of CD11c + dendritic cells and CD11c + F4/80 + macrophages in the I/R heart, reduced infarct size, attenuated myocardium apoptosis and improved cardiac function compared with those in WT mice. Moreover, inflammatory cytokines, such as TNF-α, MCP-1 and IFN-γ in the infracted myocardium as well as myocardial nitrotyrosine level, an index of oxidative and nitrative stresses, were dramatically decreased in CD11c-DTR mice than those in WT mice. These data indicate that the decreased infiltration of pro-inflammatory macrophages /dendritic cells and subsequent ameliorated inflammation may contribute to attenuated reperfusion injury and better reserved cardiac function in CD11c-DTR mice. This may provide potential novel strategies to target pro-inflammatory cells to reduce detrimental effects while sparing the beneficial wound healing roles of the recruited macrophages.
Abstract 172: The Role of Activin A in Maternal Diabetes-Induced Cardiac Malformations
Authors: Zhiyong Zhao
Journal: Circulation Research (2012)

Diabetes mellitus in pregnancy causes heart defects, especially atrioventricular septal defects (AVSDs), in infants. Manifestation of AVSDs results from dysmorphogenesis of the endocardial cushions in the embryo, which is regulated by members of the transforming growth factor (TGF) β family. Among the TGFβs, we have previously observed that the inhibin βA gene, which encodes a protein to form homodimers as activin A, is markedly downregulated by maternal diabetes. To further determine the involvement of inhibin βA and its signaling in diabetic embryopathy, the levels of inhibin βA protein and activation of its downstream transcription factors, Smad2 and Smad3, were examined using immunohistochemical, proximity ligation, and immunoblot assays, and shown to be decreased in the embryonic hearts of diabetic mice induced via intravenous injection of streptozotocin. To investigate the role of activin A in hyperglycemia-induced cardiac malformations, mouse embryos at embryonic day 9.5 (E9.5) cultured in high glucose (22 mM) were treated with activin A (50 ng/ml) for 24 hours. The treatment rescued the development of the endocardial cushions and cell proliferation (BrdU-incorporation assay) in the myocardium, similar to those in normal glucose control (8.3 mM). The role of activin A in endocardial cell migration, an important process for cellularization of the cardiac jelly, was investigated by treating E10.5 endocardial cushion explants cultured in high glucose with activin A (50 ng/ml) in a collagen matrix-based assay system. The treatment significantly increased the number of migrating cells, compared with that in high glucose-treated group, to the level in the control group. These effects were associated with restoration of the activation of Smad2/3. The results demonstrate that the activin-Smad2/3 signaling system plays an important role in cardiac malformation in diabetic embryopathy.
Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors
Authors: Anton G. Henssen, Casie Reed, Eileen Jiang, Heathcliff Dorado Garcia, Jennifer von Stebut, Ian C. MacArthur, Patrick Hundsdoerfer, Jun Hyun Kim, Elisa de Stanchina, Yasumichi Kuwahara, Hajime Hosoi, Neil J. Ganem, Filemon Dela Cruz, Andrew L. Kung, Johannes H. Schulte, John H. Petrini, Alex Kentsis
Journal: Science Translational Medicine (2017)

PGBD5 DNA transposase confers therapeutically actionable dependency in solid tumors.
Abstract 307: Quantitative Characterization of the Contractile Architecture of Human Stem Cell Derived Cardiomyocytes
Authors: Francesco S Pasqualini, Sean P Sheehy, Ashutosh Agarwal, Kevin K Parker
Journal: Circulation Research (2015)

Human induced pluripotent stem cell derived cardiomyocytes (hiCMs) exhibit a fetal phenotype, but tools to quantify their relative immaturity are scarce. We reasoned that, during myocyte specification, cells progress through myofibrillogenesis as force-generating units, known as sarcomeres, self-assemble along the cell cytoskeleton. Therefore, we developed image processing techniques to quantitatively score myocyte structural phenotypes by the increasing degree of organization and alignment that sarcomeres acquire during myofibrillogenesis. Since this is a highly conserved process, quantifications obtained from α-actinin immunostains in rodent and hiCMs can be compared. Utilizing these metrics we quantitatively showed that hiCMs patterned on square fibronectin islands had significantly under-developed contractile architecture, in agreement with the qualitative observation that these cells retain a more migratory cytoskeleton. Furthermore, we trained thee independent machine learning algorithms on over 100 α-actin immunostains from engineered primary cardiac tissues at 6, 24 and 48 hours after seeding. These preparations were taken to represent differentiated, immature and mature structural architectures, respectively. After training,[[Unable to Display Character: &amp;#61472;]]α-actinin immunostains of hiPS-derived cardiac tissues were unbiasedly analyzed by these classifiers. The results indicated that ~30% of cells exhibited cytoskeletal architectures similar to those of mature myocytes and that treatment with commercially available small molecules influence hiCM structural maturation. In conclusion, we provided metrics to assess the organization of the contractile cytoskeleton in primary and stem cell-derived cardiomyocytes and to unbiasedly quantify their maturation.
Reply to Erfan Ayubi and Saeid Safiri's Letter to the Editor re: Sungmin Woo, Chong Hyun Suh, Sang Youn Kim, Jeong Yeon Cho, Seung Hyup Kim. Diagnostic Performance of Prostate Imaging Reporting and Data System Version 2 for Detection of Prostate Cancer: A Systematic Review and Diagnostic Meta-analysis. Eur Urol 2017;72:177–88
Authors: Sungmin Woo, Chong Hyun Suh, Sang Youn Kim
Journal: European Urology (2017)
Sharing and Healing Through Storytelling in Medicine
Authors: Emily Silverman
Journal: JAMA Internal Medicine (2017)

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