tbuckley/cabot-search huggingface dataset:
Neural Mechanisms Underlying the Disruption of Male Courtship Behavior by Adult Exposure to Di(2-ethylhexyl) Phthalate in Mice
Authors: Carlos Dombret, Daphné Capela, Kevin Poissenot, Caroline Parmentier, Emma Bergsten, Cédric Pionneau, Solenne Chardonnet, Hélène Hardin-Pouzet, Valérie Grange-Messent, Matthieu Keller, Isabelle Franceschini, Sakina Mhaouty-Kodja
Journal: Environmental Health Perspectives (2017)

Background: Courtship behavior plays a critical role in attracting females and reproduction success. However, the effects of exposure to a ubiquitous contaminant di(2-ethylhexyl) phthalate (DEHP) on these behaviors and, in particular, on courtship vocalizations have not been examined. Objective: The effects of adult exposure to DEHP on courtship and mating behaviors and gonadotropic axis and neural mechanisms involved in DEHP-induced effects were analyzed in male mice. Methods: Adult C57BL/6J males were orally exposed to DEHP (0, 0.5, 5, and 50μg/kg/d) for 4 wk. Olfactory preference, ultrasonic vocalizations (USVs), partner preference and mating, as well as locomotor activity and motor coordination, were measured. The kisspeptin system and testosterone levels were analyzed. Proteomic and molecular studies were conducted on the hypothalamic preoptic nucleus, the key region involved in sexual motivation to vocalize and mate. Results: DEHP at 50μg/kg/d reduced the emission of USVs, whereas lower doses changed the ratio of syllable categories. This was associated with diminished sexual interest of female partners toward males exposed to 5 or 50μg/kg/d and increased latency to mate, despite normal olfactory preference. The kisspeptin system and circulating testosterone levels were unaffected. In DEHP-exposed males, proteomic analysis of the preoptic nucleus identified differentially expressed proteins connected to the androgen receptor (AR). Indeed, exposure to 5 or 50μg/kg/d of DEHP induced selective AR downregulation in this nucleus and upstream chemosensory regions. The involvement of AR changes in the observed alterations was further supported by the reduced emission of courtship vocalizations in males with disrupted neural AR expression. Conclusions: These data demonstrate the critical role of neural AR in courtship vocalizations and raises the possibility that the vulnerability of this signaling pathway to exposure to endocrine disrupters may be detrimental for courtship communication and mating in several species. https://doi.org/10.1289/EHP1443
First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: Updated results.
Authors: Jesus G. Berdeja, Yi Lin, Noopur S. Raje, David Samuel DiCapua Siegel, Nikhil C. Munshi, Michaela Liedtke, Sundar Jagannath, Marcela Valderrama Maus, Ashley Turka, Lyh Ping Lam, Kristen Hege, Richard Morgan, M. Travis Quigley, James Kochenderfer
Journal: Journal of Clinical Oncology (2017)

3010 Background: To test the safety and efficacy of the CAR T cell modality in relapsed/refractory multiple myeloma (MM), we have designed a second-generation CAR construct targeting B cell maturation antigen (BCMA) to redirect T cells to MM. bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain. We will report updated safety and efficacy following initial results (Berdeja et al, ENA 2016). Methods: CRB-401 (NCT02658929) is a multi-center phase 1 dose escalation trial of bb2121 in patients with relapsed and/or refractory MM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥ 50% BCMA expression on plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis. Patients undergo lymphodepletion with Flu (30 mg/m 2 ) / Cy (300 mg/m 2 ) daily for 3 days then receive 1 infusion of bb2121. The study follows a standard 3+3 design with planned dose levels of 5, 15, 45, 80 and 120 x 10 7 CAR+ T cells. Results: As of November 18, 2016, 11 patients had been infused with bb2121 in the first 4 dose cohorts, and 9 patients had reached at least 1 month of follow-up. As of data cut-off, no dose-limiting toxicities and no &gt; Grade 2 neurotoxicities or cytokine release syndrome (CRS) had been observed. Grade 1-2 CRS had been reported in 8/11 (73%) treated patients. All patients treated with doses of 15.0 x 10 7 or higher remained on study and the overall response rate (ORR) in the 6 evaluable patients at these doses was 100%, including 2 sCRs and 2 MRD-negative responses (1 sC, 1 VGPR). CAR+ T cell expansion has been demonstrated consistently. An additional 6 months of follow up on previously reported results and initial data from an additional ~10 patients will be presented. Conclusions: bb2121 shows promising efficacy at dose levels above 5 x 10 7 CAR+ T cells, including 2 sCRs and ongoing clinical responses at 6 months, with mild and manageable CRS to date. These initial data support the potential of CAR T therapy with bb2121 as a new treatment paradigm in MM. Study sponsored by bluebird bio. Clinical trial information: NCT02658929.
Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial
Authors: Houssam Halawi, Disha Khemani, Deborah Eckert, Jessica O'Neill, Hoda Kadouh, Karen Grothe, Matthew M Clark, Duane D Burton, Adrian Vella, Andres Acosta, Alan R Zinsmeister, Michael Camilleri
Journal: The Lancet. Gastroenterology & hepatology (2017)
Off-the-Shelf Natural Killer Cell Immunotherapy for Enhanced Antibody Directed Cellular Cytotoxicity
Authors: Ryan Bjordahl, Raedun Clarke, Svetlana Gaidarova, Brian Groff, Paul Rogers, Stacey Moreno, Ramzey Abujarour, Greg Bonello, Tom Tong Lee, Weijie Lan, Michelle Burrascano, Matthieu Bauer, Megan Robinson, Jeff Sasaki, William Kim, David Robbins, Betsy Rezner, Stewart E. Abbot, Scott Wolchko, Daniel Shoemaker, Bahram Valamehr
Journal: Blood (2016)
Abstract 318: Dynamic Mass Redistribution Analysis Of Endogenous β-adrenergic Receptor Signaling In Cardiac Cells
Authors: Douglas G Tilley, Marlene A Jacobson, Rhonda L Carter, Justine Yu, Laurel A Gristanti
Journal: Circulation Research (2013)

β-adenergic receptors (βAR) are important regulators of normal and pathologic cardiac function, and are expressed in cardiomyocytes as well as cardiac fibroblasts, where relatively fewer studies have explored the biological responses to βAR stimulation. We used label-free dynamic mass redistribution (DMR) to elucidate the biological response to stimulation of endogenous βAR in primary rat neonatal cardiac fibroblasts, and to begin to explore the pathways responsible for these effects. Isoproterenol (ISO, non-selective for β1/β2), salbutamol (Sal, β2-selective) and dobutamine (Dob, β1-selective) concentration-dependently induced increases in DMR response, with the Dob-induced response significantly less than either ISO- or Sal-induced DMR, consistent with the reduced expression of β1AR vs β2AR in cardiac fibroblasts. Addition of propranolol (Prop) competitively blocked the DMR effect induced by all 3 agonists, while the addition of cholera toxin (CTX) non-competitively blocked the effects of each agonist. Overall, the CTX-sensitive DMR effect accounted for approximately 75% of the response, while 25% of the biological response was CTX-insensitive. To confirm that the CTX-sensitive DMR response was mediated by downstream Gαs protein-dependent signaling, cAMP generation was assessed via FRET where ISO produced a similar concentration-effect curve and EC50 value as attained with DMR. All of the cAMP generation response was ablated by both Prop and CTX, indicating that the CTX-sensitive acute DMR effect to βAR stimulation is directly related to cAMP generation. Since ~25% of the DMR effect was not CTX-sensitive, other Gαs protein-independent signaling pathways are presumably activated in response to βAR stimulation in cardiac fibroblasts. To assess this possibility, EGFR internalization was quantitated as an indicator of βAR-mediated EGFR transactivation. EGFR internalization increased in response to ISO stimulation in a concentration-dependent manner, with a similar EC50 value as attained in the DMR assay. Defining the relative contributions of different βAR pathways in cardiac fibroblasts will help establish the importance of these pathways as potential therapeutic targets in the heart.
Specific Inhibition of AKT with ARQ 092, an Orally-Available Selective AKT Inhibitor, Attenuates Acute Vaso-Occlusive Events in Sickle Cell Disease
Authors: Jing Li, Kyungho Kim, Alan Tseng, Andrew Barazia, Seock-Won Youn, Giovanni Abbadessa, Yi Yu, Brian Schwartz, Robert K Andrews, Victor R. Gordeuk, Jaehyung Cho
Journal: Blood (2016)
BOLERO-4: Multicenter, open-label, phase II study of everolimus plus letrozole as first-line therapy in ER<sup>+</sup>, HER2<sup>-</sup> metastatic breast cancer.
Authors: William John Gradishar, Thomas Denis Bachelot, Stephen Saletan, Anne Marie Graham, Pedro Emanuel Rubini Liedke, Sergio Jobim Azevedo, Virote Sriuranpong, Fatima Cardoso
Journal: Journal of Clinical Oncology (2013)

TPS661 Background: Endocrine therapy (ET) is the standard of care for postmenopausal women with hormone receptor positive (HR + ; typically, estrogen receptor [ER] positive) advanced breast cancer (ABC). However, women with HR + ABC can progress while on ET. Crosstalk between ER signaling and the mammalian target of rapamycin (mTOR) pathway enhances tumor progression. Co-targeting these signaling pathways with the combination of everolimus (EVE), an orally bioavailable mTOR inhibitor, and ET (letrozole [LET] or tamoxifen) has been shown to significantly improve clinical outcomes in the neoadjuvant setting and in patients with HR + ABC progressing on/after nonsteroidal aromatase inhibitors. In a pivotal phase 3 trial in women with HR + ABC progressing on ET, EVE + exemestane (EXE) prolonged progression-free survival (PFS; local/central assessment: 7.8/11.0 mo [P &lt; .0001]) compared with EXE alone (3.2/4.1 mo [P &lt; .0001]). This study (BOLERO-4) will extend previous investigations to evaluate the safety and effectiveness of EVE+LET as first-line therapy in ER + HER2 – metastatic BC (mBC), and the potential benefits of continuing EVE+ET beyond initial progression. Methods: In this multicenter, open-label, international, single-arm, phase 2 study, 200 postmenopausal women age ≥18 y with ER + HER2 – mBC or locally ABC without prior therapy for advanced disease will receive EVE (10 mg/d) + LET (2.5 mg/d) until first disease progression. Upon disease progression, patients continuing in the trial will receive EVE+EXE (25 mg/d) until further disease progression. Patients who discontinue therapy in the first-line metastatic setting because of unacceptable toxicity will not be offered second-line therapy. The primary endpoint is PFS with EVE+LET in the first-line setting. Secondary endpoints include PFS in the second-line setting, overall survival, objective response rate, clinical benefit rate, safety, and the efficacy of oral dexamethasone solution to reduce the severity and/or duration of stomatitis using Oral Stomatitis Daily Questionnaire (OSDQ). Accrual across Europe, Asia, and the Americas begins Q1 2013. Estimated study completion is Q4 2015. Clinical trial information: NCT01698918.
Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults
Authors: D. James Cooper, Zoe K. McQuilten, Alistair Nichol, Bridget Ady, Cécile Aubron, Michael Bailey, Rinaldo Bellomo, Dashiell Gantner, David O. Irving, Kirsi-Maija Kaukonen, Colin McArthur, Lynne Murray, Ville Pettilä, Craig French
Journal: New England Journal of Medicine (2017)

It is uncertain whether the duration of red-cell storage affects mortality after transfusion among critically ill adults.In an international, multicenter, randomized, double-blind trial, we assigned critically ill adults to receive either the freshest available, compatible, allogeneic red cells (short-term storage group) or standard-issue (oldest available), compatible, allogeneic red cells (long-term storage group). The primary outcome was 90-day mortality.From November 2012 through December 2016, at 59 centers in five countries, 4994 patients underwent randomization and 4919 (98.5%) were included in the primary analysis. Among the 2457 patients in the short-term storage group, the mean storage duration was 11.8 days. Among the 2462 patients in the long-term storage group, the mean storage duration was 22.4 days. At 90 days, there were 610 deaths (24.8%) in the short-term storage group and 594 (24.1%) in the long-term storage group (absolute risk difference, 0.7 percentage points; 95% confidence interval [CI], -1.7 to 3.1; P=0.57). At 180 days, the absolute risk difference was 0.4 percentage points (95% CI, -2.1 to 3.0; P=0.75). Most of the prespecified secondary measures showed no significant between-group differences in outcome.The age of transfused red cells did not affect 90-day mortality among critically ill adults. (Funded by the Australian National Health and Medical Research Council and others; TRANSFUSE Australian and New Zealand Clinical Trials Registry number, ACTRN12612000453886 ; ClinicalTrials.gov number, NCT01638416 .).
Ipilimumab and gemcitabine for advanced pancreas cancer: A phase Ib study .
Authors: Aparna Kalyan, Sheetal Mehta Kircher, Nisha Anjali Mohindra, Halla Sayed Nimeiri, Victoria Maurer, Alfred Rademaker, Al Bowen Benson, Mary Frances Mulcahy
Journal: Journal of Clinical Oncology (2016)

e15747 Background: Resistance of pancreatic adenocarcinoma (PDA) to therapy remains a challenge. One factor of the barrier is the T-lymphocyte driven inflammatory response seen in PDA. The CTLA-4 T-cell receptor provides inhibitory signals to the T cells that serve to dampen antitumor immune responses. Abrogating CTLA-4 represents a novel strategy to induce tumor regression, stabilize disease, and prolong survival by manipulating the immune system. Blocking CTLA-4 may sustain activation and proliferation of tumor specific T-cells, or alter the phenotype of tumor specific Treg . Ipilimumab (IPI), a monoclonal antibody to the CTLA-4 receptor, downregulates T-cell responses. Objective: Determine MTD of IPI combined with gemcitabine (GEM) for PDA. Methods: Single institution study with dose escalation performed in a 3+3 fashion. Dose expansion was performed at the MTD. Therapy consisted of 12 weeks of induction with DLT determined after week 12. Maintenance therapy to continue indefinitely if clinical benefit is seen. Eligibility: No prior GEM for advanced disease was allowed. Results: 16 patients enrolled (13 in dose escalation + 3 at MTD). Of the 16, 63% females, 38% male. 31% had a PS of 0 and 69% with a PS 1. 13 out of 16 patients had adenocarcinoma, 1 adenosquamous & 2 patients with mucinous features. Cohort 1 (GEM 750mg/m2+IPI 3mg/kg) enrolled 19% of patients with no DLT. Cohort 2 (GEM 1000mg/m2+IPI 3mg/kg) enrolled 25% of patients with no DLTs. Cohort 3 (GEM 1000mg/m2 + IPI 6mg/kg): enrolled 38% of patients and had 2 DLTs (elevated AST and diarrhea). MTD established at cohort 2 dosing. 63% of patients received 10 cycles of treatment with only 6% not tolerating more than 1 cycle. 12 /16 patients came off study for PD with 2 patients still remaining on study. Response (PR+SD) by waterfall plot was seen in 43% of patients. 2 out of 16 with PR & 5 of 16 had SD. 38% had PD. Median PFS was 2.5 mths (95%CI 0.8-4.8mths) & Median OS 8.5mths (95%CI 2.2-10.3mths). Exploratory Immune Correlatives: CD8 cells universally decreased in the immune inhibitory molecule LAG3 after treatment with IPI. Post IPI treatment increase in FrI Treg & decrease in FrII Treg is seen. Conclusions: GEM/IPI is tolerable and viable treatment option warranting further evaluation. (NCT01473940) Clinical trial information: NCT01473940.
A Phase I, Dose Escalation Study of Oral ASP8273 in Patients with Non–small Cell Lung Cancers with Epidermal Growth Factor Receptor Mutations
Authors: Helena A. Yu, Alexander Spira, Leora Horn, Jared Weiss, Howard West, Giuseppe Giaccone, Tracey Evans, Ronan J. Kelly, Bhardwaj Desai, Andrew Krivoshik, Diarmuid Moran, Srinivasu Poondru, Fei Jie, Kouji Aoyama, Anne Keating, Geoffrey R. Oxnard
Journal: Clinical Cancer Research (2017)

Purpose: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M.Experimental Design: In this multicohort, phase I study (NCT02113813), escalating doses of ASP8273 (25-500 mg) were administered once daily to non-small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint.Results: A total of 110 patients were treated with ASP8273 across dose escalation (n = 36), response-expansion (n = 36), RP2D (300 mg; n = 19) and food-effect (n = 19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n = 27/88; 95% CI, 19.5%-44.5%), and median progression-free survival was 6.8 months (95% CI, 5.5-10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression.Conclusions: ASP8273 was well tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy. Clin Cancer Res; 23(24); 7467-73. ©2017 AACR.
NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways
Authors: D Benedetti, E Tissino, F Pozzo, T Bittolo, C Caldana, C Perini, D Martorelli, V Bravin, T D’Agaro, F M Rossi, R Bomben, E Santinelli, F Zaja, G Pozzato, A Chiarenza, F Di Raimondo, G Del Poeta, D Rossi, G Gaidano, M Dal Bo, V Gattei, A Zucchetto
Journal: Leukemia (2017)
Multiparametric prognostic scores in chronic heart failure with reduced ejection fraction: a long‐term comparison
Authors: Piergiuseppe Agostoni, Stefania Paolillo, Massimo Mapelli, Piero Gentile, Elisabetta Salvioni, Fabrizio Veglia, Alice Bonomi, Ugo Corrà, Rocco Lagioia, Giuseppe Limongelli, Gianfranco Sinagra, Gaia Cattadori, Angela B. Scardovi, Marco Metra, Valentina Carubelli, Domenico Scrutinio, Rosa Raimondo, Michele Emdin, Massimo Piepoli, Damiano Magrì, Gianfranco Parati, Sergio Caravita, Federica Re, Mariantonietta Cicoira, Chiara Minà, Michele Correale, Maria Frigerio, Maurizio Bussotti, Fabrizio Oliva, Elisa Battaia, Romualdo Belardinelli, Alessandro Mezzani, Luigi Pastormerlo, Marco Guazzi, Roberto Badagliacca, Andrea Di Lenarda, Claudio Passino, Susanna Sciomer, Elena Zambon, Giuseppe Pacileo, Roberto Ricci, Anna Apostolo, Pietro Palermo, Mauro Contini, Francesco Clemenza, Giovanni Marchese, Paola Gargiulo, Simone Binno, Carlo Lombardi, Andrea Passantino, Pasquale Perrone Filardi
Journal: European Journal of Heart Failure (2017)
IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages
Authors: Meng Wang, Guannan Shen, Liangguo Xu, Xiaodong Liu, Jared M. Brown, Dechun Feng, Ruth Ann Ross, Bin Gao, Suthat Liangpunsakul, Cynthia Ju
Journal: Journal of Hepatology (2017)
Letter by Jin-shan and Xue-bin Regarding Article, “Effect of Aggressive Blood Pressure Control on the Recurrence of Atrial Fibrillation After Catheter Ablation: A Randomized, Open-Label Clinical Trial (SMAC-AF [Substrate Modification With Aggressive Blood Pressure Control])”
Authors: He Jin-shan, Li Xue-bin
Journal: Circulation (2017)

We read with great interest the article by Parkash et al 1 about the effect of aggressive blood pressure control on the recurrence of atrial fibrillation after catheter ablation, which shows that aggressive control of blood pressure for a median duration of 3.5 months before catheter ablation and after has no effect on subsequent arrhythmia outcome at the expense of treatment-related hypotension.Does aggressive blood control have a neutral effect on the recurrence of atrial fibrillation after catheter ablation?We have several disagreements.First, before aggressive blood pressure control for these patients, we do not know how long they had been diagnosed as hypertensive.What is the extent of the influence that hypertension has had on the atria?Is there a lot of fibrosis?All these things determine whether aggressive blood pressure control can reverse the effect it has generated.If we can control blood pressure well at the beginning or if the time of aggressive blood pressure control is long enough to change the structure and function of the atria, a positive effect toward a reduction of recurrence of atrial fibrillation may be indicated.Second, the result presented in this article is different from that of the ARREST-AF Cohort (Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation) 2 and LEGACY (Long-Term Effect of Goal Directed Weight Management in an Atrial Fibrillation Cohort) 3 studies.In these studies, in addition to blood pressure treatment, risk factor management included weight management, moderate-intensity exercise, screening for and treating obstructive sleep apnea, lipid and glycemia management, smoking cessation, and alcohol abstinence.This comprehensive risk factor modification strategy demonstrates significant improvement in arrhythmiafree survival over a mean follow-up duration of 42 months.So, blood pressure does have an effect on the recurrence of atrial fibrillation after ablation, but its effect is limited and only partly responsible for the change.Instead of focusing on blood pressure alone, we should try systemic management of all the risk factors.This helps more in reducing the recurrence of atrial fibrillation after catheter ablation.Last, now we all try to control the risk factors when atrial fibrillation has developed.Even in some of the patients who have progressed to persistent atrial fibrillation, if we can really initiate the upstream therapy and manage the risk factors when it is new-onset atrial fibrillation or even before atrial fibrillation occurs, we could reduce not only the recurrence of atrial fibrillation after catheter ablation but also the number of patients who need catheter ablation.The earlier the therapy, the better the outcome.
Co‐Delivery of Drugs and Genes Using Polymeric Nanoparticles for Synergistic Cancer Therapeutic Effects
Authors: Yi Li, Thavasyappan Thambi, Doo Sung Lee
Journal: Advanced Healthcare Materials (2017)

Drug and gene delivery systems based on nanoparticles, microparticles and hydrogels have been widely studied for cancer treatment in the past decade. To achieve an efficient and safe delivery, selection of drug and gene delivery carrier is critical. Biocompatible polymeric nanoparticles are considerably promising carrier candidates in delivery of drugs and genes because of their unique chemical and physical properties. However, delivery of a drug or gene sometimes cannot achieve a satisfactory treatment effect. Therefore, co-delivery of dual drugs or co-delivery of a drug and a gene in a polymeric nanoparticle has attracted attention. Such co-delivery systems can overcome multi-drug resistance of chemical drugs and achieve a synergistic therapeutic effect. In this progress report, we summarize recent progress in the preparation and application of polymeric drug and gene co-delivery nanosystems. The remaining challenges and future trends in this field are also included.