tbuckley/cabot-search huggingface dataset:
Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC).
Authors: Scott Joseph Antonia, Jose A. Lopez-Martin, Johanna C. Bendell, Patrick Alexander Ott, Matthew H. Taylor, Joseph Paul Eder, Dirk Jäger, Dung T. Le, Filippo G. De Braud, Michael Morse, Paolo Antonio Ascierto, Leora Horn, Asim Amin, Rathi Narayana Pillai, T.R. Jeffry Evans, Christopher T. Harbison, Chen-Sheng Lin, Marina Tschaika, Emiliano Calvo
Journal: Journal of Clinical Oncology (2016)

100 Background: Patients (pts) with advanced (adv) SCLC after first-line platinum-based chemotherapy have limited options. Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, is approved for previously treated metastatic NSCLC in the US and for squamous NSCLC in the EU. Nivolumab + ipilimumab, a cytotoxic T-lymphocyte antigen-4 immune checkpoint inhibitor, has shown durable responses in multiple tumor types. CheckMate 032 was designed to evaluate nivolumab +/- ipilimumab in adv tumors including SCLC. Methods: AdvSCLC pts with progressive disease (PD) after ≥1 platinum-based chemotherapy, regardless of platinum sensitivity or tumor PD-1 ligand 1 (PD-L1) expression, were eligible. Pts received nivolumab ([mg/kg] N3 Q2W) or nivolumab + ipilimumab combination (N1 + I3 or N3 + I1 Q3W for 4 cycles then N3 Q2W). Primary endpoint was objective response rate (ORR). Additional endpoints were safety, overall survival (OS), progression-free survival (PFS), and biomarkers. Results: 180 pts were enrolled (n=80, N3; n=47, N1 + I3; n=53, N3 + I1). Among 127 pts in the N3 and N1 + I3 cohorts, 56% received ≥2 prior regimens and 30% were platinum resistant. Efficacy data are shown (Table). Responses were observed independent of platinum sensitivity and PD-L1 expression. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 11% of pts in N3 and 32% of pts in N1 + I3; 5% and 13% discontinued due to TRAEs, respectively. One TR death due to myasthenia gravis occurred (N1 + I3 arm). Conclusions: Nivolumab and nivolumab + ipilimumab showed durable objective responses and manageable safety profiles, with possibly higher toxicities observed with the combination, in previously treated SCLC pts. Updated efficacy including OS by prior lines of therapy, safety, and biomarkers will be presented for the N3 and N1 + I3 cohorts. Efficacy and safety for the N3 + I1 cohort will be presented. Clinical trial information: NCT01928394. N3a n=80 N1 + I3b n=47 ORR, % (n/N)c 13 (7/55) 31 (14/45) Median DOR, mo Not reached 6.90 Median OS, mo 3.55 7.75 Median PFS, mo 1.38 3.35 1yr OS rate, % 27 48 a15 pts had <6 weeks minimum follow-up bMinimumfollow-up = 120 days c25 pts in N3 and 2 pts in N1 + I3 were non-evaluable for tumor response DOR = duration of response
Risk factors for diabetes in men
Authors: V. Connolly, W. Kelly
Journal: BMJ (1995)

Number of cases of tuberculosis and annual incidence by ethnic origin and area of residence, Newcastle upon Tyne, 1990-4 White population Ethnic minorities All cases Annual Annual Annual No of cases incidence/100 000 No of cases incidence/100000 No of cases incidence/100000 Innercity
Traitement endoscopique du RGO: réactualisation des résultats de l'étude multicentrique française avec la suture Endocinch Bard
Authors: E Lepoutre, J Boyer, JC Grimaud, JC Letard, J Escourrou, F Prat, P Ducrotte, JM Canard, JF Rey, T Ponchon
Journal: Endoscopy (2005)

La suture endoscopique pour reflux gastro-oesophagien reste un traitement très discuté, ne faisant l'objet ni d'un remboursement ni d'une inscription à la nomenclature. En autres, l'efficacité à long terme est et sera un élément déterminant en faveur ou non de ce type de traitement. A partir de l'étude prospective menée en France par la SFED sur la suture Endocinch, les résultats à un an ont été revus.
Temporal Changes in Subsequent Malignancies Among Childhood Cancer Survivors
Authors: Tetsuya Tanimoto, Kenji Tsuda, Jinichi Mori
Journal: JAMA (2017)

To the Editor Dr Turcotte and colleagues1 found that cumulative incidence rates of subsequent malignancies at 15 years after initial childhood cancer diagnosis were lower among survivors treated in more recent treatment eras and that lower risk was associated with reduced therapeutic radiation dose.
Randomized phase 2 study of trebananib (AMG 386) with or without continued anti-vascular endothelial growth factor (VEGF) therapy in patients (pts) with renal cell carcinoma (RCC) who have progressed on bevacizumab, pazopanib, sorafenib, or sunitinib.
Authors: Thomas John Semrad, Susan G. Groshen, Sumanta K. Pal, Ulka N. Vaishampayan, Monika Joshi, David I. Quinn, Philip C. Mack, David R. Gandara, Primo Lara
Journal: Journal of Clinical Oncology (2016)

e16121 Background: In RCC, Angiopoietin (Ang) 2 is elevated at the time of progression on anti-VEGF therapy and may contribute to resistance. We tested trebananib, an Ang 1 and 2 neutralizing peptibody in pts with RCC progressing on anti-VEGF treatment. Methods: Pts with measurable RCC progressing despite an anti-VEGF agent within 12 weeks, any number of prior treatments, good PS and adequate organ function, were randomized to trebananib 15 mg/kg IV weekly without (arm A) or with (arm B) continuation of the prior anti-VEGF agent. After randomization, pts underwent a pre-treatment tumor biopsy. The primary endpoint for each arm was tumor response (RECIST 1.1), evaluated every 12 weeks. Each arm was a Simon Optimum design planned for 39 pts, interim analysis after 17 pts, with alpha = 0.10 and beta = 0.10. Secondary endpoints included progression free survival (PFS) and adverse events (AEs). Results: Of 40 enrolled pts, 35 started treatment (17 arm A, 18 arm B) with median age 61 (39-77) and 3 prior treatments (1-8). Four died prior to documented progression and 24 progressed as their 1st event. At interim analysis, 1 response (in Arm B, trebananib + pazopanib) was observed. Median PFS of 2.7 (95% C.I. 2.3-4.7) months in arm A and 3.4 (95% C.I. 2.7-8.3) months in arm B did not support continued study. Common AEs, mostly grade 1-2, included fatigue, hypertension, and edema, and were numerically higher in arm B. In arm A, 6/17 treated pts (35%) experienced a Grade 3+ AE attributed to trebananib. In Arm B 8/15 pts (53%) with follow up experienced a Grade 3+ AE attributed to combo treatment. The most common grade 3+ AEs were hypertension and dyspnea. A possibly related unwitnessed cardiac arrest occurred on arm B. Conclusions: While tolerable, trebananib either without or with continued anti-VEGF therapy did not show promising activity in RCC pts who recently progressed on anti-VEGF therapy alone. Analysis of pre-treatment research tumor biopsies from this study will provide insights into anti-VEGF therapy resistance, including the role of Ang signaling and the lack of efficacy of these regimens. Clinical trial information: NCT01664182.
Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies.
Authors: Brent O'Carrigan, Maria Jose de Miguel Luken, Dionysios Papadatos-Pastos, Jessica Brown, Nina Tunariu, Raquel Perez Lopez, Mahesha Ganegoda, Ruth Riisnaes, Ines Figueiredo, Suzanne Carreira, Brian Hare, Fang Yang, Katherine McDermott, Marina S. Penney, John Pollard, Juanita Suzanne Lopez, Udai Banerji, Johann S. De Bono, Scott Z. Fields, Timothy Anthony Yap
Journal: Journal of Clinical Oncology (2016)

2504 Background: ATR is a regulator of cellular responses to replication stress, where it signals DNA damage repair by homologous recombination. Many cells depend on ATR to survive DNA damage. VX-970 is a potent, selective ATR inhibitor with marked preclinical antitumor activity in combo with chemotherapy. Methods: Patients (pts) with advanced cancers were enrolled in 2 parts. Part A: N=1 pt cohorts received VX-970 QW; 3 + 3 cohorts were commenced if ³ G2 drug-related toxicities occurred. Part B: 3 + 3 pt cohorts received CP on d1 + VX-970 on d2 and 9 in 21-day cycles. Timed pre- and post-VX-970 tumor biopsies were assessed for pS345 CHK1 levels by IHC in part B. Hematologic toxicities were modeled for pts in part B. Results: 26 pts were treated; M/F 10/16, ECOG PS 0/1: 9/17. Median age: 66 yrs (range 49-76 years). VX-970 was generally well tolerated as mono or CP combo with mainly G1-2 toxicities. CP dose delays and reductions occurred in 3/3 pts (B1); 2/2 pts (B2); 0/3 pts (B3); 1/6 pts (B4) due to neutropenia and/or thrombocytopenia. Clinical data were consistent with toxicity modeling that predicted probabilities of ≤5% G4 neutropenia and <1% thrombocytopenia at B4. Recommended phase 2 doses (RP2D) were DL A3 (mono) and B4 (CP combo). VX-970 PK was dose proportional with no CP interaction. VX-970 PK exposures at combo RP2D led to tumor regression in mouse models. Tumor biopsy studies showed decreased pCHK1 by 73-90% after VX-970. In part A, a pt with ATM loss colorectal cancer had RECIST complete response (19 mths+) and 4 pts had RECIST stable disease (SD). In part B: a pt with germline BRCA1 mutant and platinum-refractory, PARP inhibitor-resistant ovarian cancer with a somatic Y220C TP53 mutation had RECIST partial response for 6 mths and 8 pts had RECIST SD. Conclusions: VX-970 is generally well tolerated as mono and in CP combo with early evidence of PD and antitumor activity. VX-970 is now being tested in phase 2 combo trials and as mono in pts with DNA repair defects. Clinical trial information: 2013. Clinical trial information: #8209;005100. Clinical trial information: #8209;34.Dose Level (DL) VX-970 dose (mg/m2) CP dose (AUC) # pts Dose limiting toxicities A1 60 - 1 - A2 120 - 2 - A3 240 - 1 - A4 480 - 7 - B1 240 5 3 Febrile neutropenia B2 120 5 3 Hypersensitivity B3 120 4 3 - B4 90 5 6 Febrile neutropenia
Directional Matrix Nanotopography with Varied Sizes for Engineering Wound Healing
Authors: Jangho Kim, Won‐Gyu Bae, Yeon Ju Kim, Hoon Seonwoo, Han‐Wool Choung, Kyoung‐Je Jang, Sunho Park, Bog Hee Kim, Hong‐Nam Kim, Kyoung Soon Choi, Myung‐Sun Kim, Pill‐Hoon Choung, Yun‐Hoon Choung, Jong Hoon Chung
Journal: Advanced Healthcare Materials (2017)

Abstract Topographic features play a crucial role in the regulation of physiologically relevant cell and tissue functions. Here, an analysis of feature‐size‐dependent cell–nanoarchitecture interactions is reported using an array of scaffolds in the form of uniformly spaced ridge/groove structures for engineering wound healing. The ridge and groove widths of nanopatterns are varied from 300 to 800 nm and the nanotopography features are classified into three size ranges: dense (300–400 nm), intermediate (500–600 nm), and sparse (700–800 nm). On these matrices, fibroblasts demonstrate a biphasic trend of cell body and nucleus elongation showing the maximum at intermediate feature density, whereas maximum migration speed is observed at the dense case with monotonic decrease upon increasing feature size. The directional organization of cell‐synthesized fibronectin fibers can be regulated differently via the nanotopographical features. In an in vitro wound healing model, the covering rate of cell‐free regions is maximized on the dense nanotopography and decreased with increasing feature size, showing direct correlation with the trend of migration speed. It is demonstrated that the properties of repaired tissue matrices in the process of wound healing may be controlled via the feature‐size‐dependent cell–nanoarchitecture interactions, which can be an important consideration for designing tissue engineering scaffolds.
Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis
Authors: Kellie R. Machlus, Stephen K. Wu, Prakrith Vijey, Thomas S. Soussou, Zhi-Jian Liu, Eran Shacham, T. J. Unger, Trinayan Kashyap, Boris Klebanov, Martha Sola-Visner, Marsha Crochiere, Joseph E. Italiano, Yosef Landesman
Journal: Blood (2017)
Extracellular Vesicle Transfer from Mesenchymal Stromal Cells Modulates Macrophage Function in Acute Lung Injury. Basic Science and Clinical Implications
Authors: Michael A. Matthay
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

the simple review of the morphology of the spirometry curves could lead to the distinction of new subgroups-another example of the pathology's heterogeneity.In both health and disease, exercise is a model of integrative physiology and provides a great opportunity to study the combined cardiopulmonary insufficiency.Rocha and colleagues have used this model to start understanding the determinants of exercise limitation resulting from a complex interaction between HF and COPD (4).Further research could bring new insights into these patients' behavior.Moreover, measurement of additional variables could provide newer information but simultaneously reveal new subgroups of patients not imagined today.
Depletion of regulatory T cells increases the in vivo CEA specific T cell response
Authors: Amy C. Hobeika, Takuya Osada, Teresa Brehm, Xiao Yi Yang, H. Kim Lyerly, Michael Morse, Timothy Clay
Journal: Cancer Research (2006)

4773  Depletion of regulatory T cells (Treg) has been shown to enhance anti-tumor responses presumably by breaking tolerance. The immunotoxin denileukin diftitox (ONTAK) consists of human interleukin-2 (IL-2) fused with diphtheria toxin that selectively targets lymphocytes expressing the IL-2 receptor and provides a potential mechanism for Treg depletion due to the high CD25 (IL-2R) expression on Treg cells. We used a CEA-transgenic (CEA-Tg) mouse model to determine whether pretreatment with ONTAK could enhance an immune response to a weak tumor antigen following vaccination with either adenovirus-CEA (Ad-CEA) or alpha virus-CEA (Alpha-CEA). In vitro we found a dose dependent increase in anti-CD3 proliferation of splenocytes as a result of overnight ONTAK treatment (48% and 60% reduction at 5 nM and 10 nM ONTAK, respectively). In vivo results showed a significant decrease in CD4+CD25+ cells 4 and 6 days following a single administration of ONTAK, similar to PC61 (anti-CD25) control. CEA-Tg mice were also vaccinated 4 days post ONTAK therapy with Ad-CEA or Alpha-CEA. Immune analysis by ELISpot was performed 2 weeks post vaccination and showed a 75% increase in the number of IFNγ producing cells when compared to untreated mice with Ad-CEA vaccination. A 35% increase by ELISpot was also seen with Alpha-CEA vaccination. These results indicate a potential role for the depletion of CD4+CD25+ Tregs by ONTAK for enhancing in vivo tumor antigen specific immunity in response to immunotherapy.
Macrophage Heterogeneity Complicates Reversal of Calcification in Cardiovascular Tissues
Authors: Maximillian A. Rogers, Masanori Aikawa, Elena Aikawa
Journal: Circulation Research (2017)

M acrophages are highly heterogeneous cells exhibiting a wide range of protein markers, tissue locations, and functions.Often thought of as host defense cells with phagocytic, innate/adaptive immune system, and proinflammatory roles, macrophages contribute to a variety of tissue functions, including adipose thermogenesis, tissue repair, splenic and hepatic iron recycling, neural synaptic pruning, and cardiac electric conduction.In the current issue of Circulation Research, Chinetti-Gbaguidi et al 1 enhance our understanding of the diverse roles of macrophages in vascular disease by reporting that macrophages near calcified regions of human atherosclerotic lesions display low mineral resorption potential.This study ties macrophage osteoclastogenesis to vascular calcification and identifies disrupted signaling pathways that may help to develop anticalcification therapies.
MAPK Signaling and Inflammation Link Melanoma Phenotype Switching to Induction of CD73 during Immunotherapy
Authors: Julia Reinhardt, Jennifer Landsberg, Jonathan L. Schmid-Burgk, Bartomeu Bibiloni Ramis, Tobias Bald, Nicole Glodde, Dorys Lopez-Ramos, Arabella Young, Shin Foong Ngiow, Daniel Nettersheim, Hubert Schorle, Thomas Quast, Waldemar Kolanus, Dirk Schadendorf, Georgina V. Long, Jason Madore, Richard A. Scolyer, Antoni Ribas, Mark J. Smyth, Paul C. Tumeh, Thomas Tüting, Michael Hölzel
Journal: Cancer Research (2017)

Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNFα cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. In a mouse model of T-cell immunotherapy, CD73 was induced in relapse melanomas, which acquired a mesenchymal-like phenotype. We also detected CD73 upregulation in melanoma patients progressing under adoptive T-cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism. Our work substantiates CD73 as a target to combine with current immunotherapies, but its dynamic regulation suggests limited value of CD73 pretreatment expression as a biomarker to stratify melanoma patients. Cancer Res; 77(17); 4697-709. ©2017 AACR.
Physical Activity and Prognosis in the TOPCAT Trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist)
Authors: Sheila M. Hegde, Brian Claggett, Amil M. Shah, Eldrin F. Lewis, Inder Anand, Sanjiv J. Shah, Nancy K. Sweitzer, James C. Fang, Bertram Pitt, Marc A. Pfeffer, Scott D. Solomon
Journal: Circulation (2017)

Background: Physical activity (PA) is inversely associated with adverse cardiovascular outcomes in healthy populations, but the impact of physical activity in patients with heart failure (HF) with preserved ejection fraction is less well characterized. Methods: The baseline self-reported PA of 1751 subjects enrolled in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) was categorized as poor, intermediate, or ideal PA with American Heart Association criteria. PA was related to the primary composite outcome (HF hospitalization, cardiovascular mortality, or aborted cardiac arrest), its components, and all-cause mortality with the use of multivariable Cox models. Results: The mean age at enrollment was 68.6±9.6 years. Few patients met American Heart Association criteria for ideal activity (11% ideal, 14% intermediate, 75% poor). Over a median follow-up of 2.4 years, the primary composite outcome occurred in 519 patients (397 HF hospitalizations, 222 cardiovascular deaths, and 6 aborted cardiac arrests). Compared with those with ideal baseline PA, poor and intermediate baseline PA was associated with a greater risk of the primary outcome (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.28–3.28; HR, 1.95; 95% CI, 1.15–3.33, respectively), HF hospitalization (HR, 1.93; 95% CI, 1.16–3.22; HR, 1.84; 95% CI, 1.02–3.31), cardiovascular mortality (HR, 4.36; 95% CI, 1.37–13.83; HR, 4.05; 95% CI, 1.17–14.04), and all-cause mortality (HR, 2.95; 95% CI, 1.44–6.02; HR, 2.05; 95% CI, 0.90–4.67) after multivariable adjustment for potential confounders. Conclusions: In patients with HF with preserved ejection fraction, both poor and intermediate self-reported PA were associated with higher risk of HF hospitalization and mortality. Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT00094302.
Abstract 263: Reduction in Chest Compression Fraction During Transition From Pre-Hospital to in-Hospital Care
Authors: Paul Dommer, Kyle McCarty, Tyler Vadeboncoeur, Pete Walka, Scott Crawford, Gary Smith, Annemarie Silver, Bentley Bobrow
Journal: Circulation (2010)

Introduction: CPR quality has a strong impact on survival from out-of-hospital cardiac arrest. The purpose of this investigation was to compare CPR quality during the early minutes at the emergency...
Association of MiR-26b mediated doxorubicin resistance signature with poor prognosis in epithelial ovarian cancer (EOC).
Authors: Ilya Korsunsky, Janaki Parameswaran, Iuliana Shapira, Michaela Oswald, John L. Lovecchio, Andrew Menzin, Jill Suzanne Whyte, Lisa A. Dos Santos, Sharon Liang, Tawfiqul Alam Bhuiya, Mary Keogh, Cathleen Mason, Houman Khalili, Meagan Fastuca, Cassandra Pond, Anthony Liew, Peter Gregersen, Annette Lee
Journal: Journal of Clinical Oncology (2016)

e17070 Background: MicroRNAs (miRNA) have been established as key regulators of tumor gene expression as well as prime biomarker candidates for clinical phenotypes. We analyzed the regulatory structure of miRNAs and their colocalized gene targets in EOC tissue to construct a regulatory signature for clinical prognosis. Methods: FFPE blocks of primary EOC tumor tissue with > 80% tumor cells were selected for 20 patients (stage ≥ IIc) for whom follow up data was available. Expression levels of mRNA and miRNA were assayed separately. An integrated analysis was performed to identify miRNA/mRNA regulatory clusters. Gene set enrichment analysis (GSEA) was carried out on the coexpression of putative miRNA target genes, from the miRTarBase database, with their respective miRNAs, to identify enriched categories for each miRNA. MiRNAs with at least one significantly enriched category from the MSigDB C2 dataset at a false discovery rate of 0.05 were chosen. For each enriched category of each miRNA, a regulon was defined by the set of genes that contributed most to the corresponding enrichment score. We tested the efficacy of each regulon as a prognostic signature using K-means clustering, the log-rank test and Benjamini-Hochberg multiple testing correction. Results: The integrated analysis resulted in 5 miRNAs associated with 8 enriched regulons. Only one regulon, consisting of FOXM1, KIAA0101, KIF4A, LMNB1, NCAPG2, TK1 and ZWINTand regulated by miR-26b, was significantly associated with prognosis, with adjusted p-values 0.015 for the regulon and 0.0009 for miR-26b. Clustering revealed two groups, one with short survival ( < 3yrs) and one with long survival (> 3yrs). Upregulation of the regulon, previously associated with doxorubicin resistance (Kang et al 2004), and downregulation of miR-26b were both observed in < 3yrs survival patients. We validated our signature on two clinically matched independent datasets from the curatedOvarianData dataset (Ganzfried et al 2013). In both datasets, the regulon was prognostic and significantly upregulated in the clusters with poor prognosis. Conclusions: Our data suggests that miR-26b mediated drug resistance may contribute to poor prognosis in EOC.