tbuckley/cabot-search huggingface dataset:
Exploration of a Novel Intermediate Response Endpoint in Immunotherapy Clinical Studies
Authors: Xin Gao, Lijun Zhang, Rajeshwari Sridhara
Journal: Clinical Cancer Research (2017)

Purpose: Both objective response rate (ORR) and progression-free survival as defined by RECIST are weakly associated with overall survival (OS) in trials evaluating immunotherapy drug products. We proposed a novel intermediate response endpoint (IME) for evaluating immunotherapies.Experimental Design: We defined IME response as having no nontarget lesion progression, no new lesion appearance, and reaching a target lesion response determined by baseline tumor burden, tumor reduction depth, and tumor change dynamics within one year after randomization. Database used consisted of data from randomized active-controlled immunotherapy trials. Criterion for IME was developed on the basis of patient-level data from a training dataset, and further evaluated using an independent testing dataset. A patient-level responder analysis comparing OS between patients with and without an IME response was conducted using combined data. Association between trial-level OS hazard ratio (HR) and IME odds ratio (OR) was analyzed using a weighted linear regression model.Results: A total of 5,806 patients from 9 randomized studies were included in the database. At patient level, patients with IME response had improved OS compared with nonresponders (HR = 0.09). At trial level, association between OS and IME was moderate (R2 = 0.68).Conclusions: The IME was moderately associated with OS, and the association appeared to be stronger than the association observed between RECIST-defined ORR and OS. However, the analyses conducted in this research are exploratory and further evaluation is needed before using this endpoint in future studies. Clin Cancer Res; 24(10); 2262-7. ©2017 AACR.
Radiological abnormalities following bronchial thermoplasty: is the pathophysiology understood?
Authors: Marie-Pierre Debray, Marie-Christine Dombret, Marina Pretolani, Gabriel Thabut, Loubna Alavoine, Pierre-Yves Brillet, Camille Taillé, Antoine Khalil, Pascal Chanez, Michel Aubier
Journal: European Respiratory Journal (2017)

More than one mechanism may cause early and transient opacities in non-BT-treated lung zones <http://ow.ly/3nfB30gzEpS> We read with great interest the correspondence by J.N.S. d'Hooghe and colleagues focusing on the pathophysiology of early transient radiological abnormalities following bronchial thermoplasty (BT). In line with our previous report [1], they have reported transient radiological opacities in all treated lobes of 12 BT-treated patients and in an adjacent untreated lobe in 31% of cases [2].
Abstract 12206: Altered Cardiomyocyte Inotropic Response to Chymase/Ang-(1-12) Pathway Activation in Heart Failure
Authors: Tiankai Li, Xiaowei Zhang, Sarfaraz Ahmad, Jasmina Varagic, Heng-Jie Cheng, Zhi Zhang, Leanne Groban, Carlos M Ferrario, Che Ping Cheng
Journal: Circulation (2016)

Background: Angiotensin-(1-12) [Ang-(1-12)], a new member of the renin-angiotensin system (RAS) has been identified as a chymase-dependent source for Angiotensin II (Ang II) inotropic activity. Recent observations suggest that activation of this non-canonical chymase/Ang-(1-12) pathway may modulate cardiac function bypassing the inhibitory effects of RAS blockade with ACEI and ARBs in heart failure (HF). However, the direct cardiac effects of Ang-(1-12) and Ang II are unclear. Moreover, whether and how HF alters Ang-(1-12) and Ang II cardiac responses are undefined. We assessed the hypothesis that HF is associated with a reduced action of Ang-(1-12) on myocyte contractility and [Ca 2+ ] i regulation. Methods: We compared LV myocyte contractile and calcium transient ([Ca 2+ ] iT ) responses to angiotensin peptides in 12 SD rats with isoproterenol induced HF (2 months after isoproterenol 170 mg/kg sq for 2 days) and 16 age-matched controls. Results: In normal myocytes, versus baseline, Ang II (10 -6 M) superfusion significantly increased myocyte contraction (dL/dt max ) (40%, 184.6 vs 132.1 μm/s), relaxation (dR/dt max ) (34%, 141.3 vs 107.0 μm/s) and [Ca 2+ ] iT (29%, 0.31 vs 0.24). Superfusion of Ang-(1-12) (4x10 -6 M) caused similar increases in dL/dt max (34%) dR/dt max (25%) and [Ca 2+ ] iT (25%). Compared with the changes in normal myocytes, in HF myocytes, Ang II and Ang-(1-12) caused similar but significantly attenuated positive inotropic actions with about 42% to 50% less increases in dL/dt max , dR/dt max and [Ca 2+ ] iT . The Ang-(1-12)-mediated effects were abolished by prior exposure of myocytes to chymostatin in both normal and HF. The Ang II-induced inotropic effects were completely prevented in the presence of an inhibitory cAMP analog, Rp-cAMPS (10 –4 M 2 h) in both normal and HF myocytes, but were further augmented only in HF after the incubation of myocytes with the G i inhibitor, pertussis toxin (PTX, 2 μg/ml, 36°C, 5h). Conclusions: Ang-(1-12) stimulates LV myocyte contractile function and [Ca 2+ ] iT in both normal and HF rats through a chymase mediated action. Altered inotropic responses to Ang-(1-12) and Ang II in HF myocytes is mediated through a cAMP-dependent mechanism that is coupled to both stimulatory G and inhibitory PTX-sensitive G proteins.
Publisher Correction: An interactive framework for whole-brain maps at cellular resolution
Authors: Daniel Fürth, Thomas Vaissière, Ourania Tzortzi, Yang Xuan, Antje Märtin, Iakovos Lazaridis, Giada Spigolon, Gilberto Fisone, Raju Tomer, Karl Deisseroth, Marie Carlén, Courtney A. Miller, Gavin Rumbaugh, Konstantinos Meletis
Journal: Nature Neuroscience (2017)
Letters regarding article by Coronel et al, "Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: A combined electrophysiological, genetic, histopathologic, and computational study" - Response
Authors: R. Coronel, S. Casini, T. T. Koopmann, A. O. Verkerk, J. R. de Groot, C. R. Bezzina, M. W. Veldkamp, A. C. Linnenbank, H. L. Tan, A. A. M. Wilde, J. M. T. de Bakker, F. J. G. Wilms-Schopman, Z. Bhuiyan, A. C. van der Wal, P. Brugada
Journal: Circulation (2006)
Abstract 16415: Optimal Blood Pressure Target in Patients With Acute Myocardial Infarction
Authors: Ki Hong Lee, Hyung Wook Park, Nam Sik Yoon, Jeong Gwan Cho, Ji Eun Kim, Youngkeun Ahn, Myung Ho Jeong, Jong Chun Park
Journal: Circulation (2016)

Introduction: Current guidelines for blood pressure (BP) control have not been well standardized in patients with acute myocardial infarction (AMI). They do not suggest BP goal in patients with AMI...
A phase I and pharmacologic study of MM-111, a bispecific HER2/HER3 antibody fusion protein, in combination with multiple treatment regimens in patients with advanced HER2-positive solid tumors.
Authors: Donald A. Richards, Fadi S. Braiteh, Stephen Patrick Anthony, Jeff Edenfield, Beth A. Hellerstedt, Robert N. Raju, Paul Conkling, David A. Smith, Carlos Becerra, Allen Lee Cohn, Crystal Shereen Denlinger, Lawrence E. Garbo, Hillary H. Wu, Agustin Garcia, Charlotte McDonagh, Sasha Frye, Samuel V. Agresta, Victor M. Moyo
Journal: Journal of Clinical Oncology (2012)

TPS3111 Background: The HER2/HER3 oncogenic heterodimer is a potent HER receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel bispecific antibody fusion protein that inhibits ligand activated HER3 signaling through abrogation of ligand binding specifically in HER2 overexpressing tumors. In preclinical models of HER2+ solid tumors, MM-111 inhibits ligand-induced HER3 phosphorylation, cell cycle progression, and tumor growth. HER2 is a well-established target of anticancer agents such as trastuzumab and lapatinib, specifically in breast and gastric tumors. Preclinical data demonstrate that MM-111 potentiates the antitumor activity of both trastuzumab and lapatinib and this phase I study seeks to determine if MM-111 can be safely used in combination with various standard of care HER2 targeting regimens, namely; (1) trastuzumab, cisplatin and, capecitabine, (2) trastuzumab and lapatinib, and (3) trastuzumab and paclitaxel. Methods: This is a multi-arm phase I, open label, multicenter, dose-escalation study of MM-111 in an add-on design that evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of MM-111 in combination. Each arm is designed to run as a separate phase I study to address safety and tolerability of each combination. For eligibility, patients are required to have documented advanced HER2-positive cancer, with adequate bone marrow, hepato-renal and cardiac function. The dose escalation for each arm utilizes a standard “3 + 3” design with MM-111 dosed initially at a moderate dose of 10 mg/kg and escalated up to 20 mg/kg to identify a phase II dose in combination with each regimen. Once the maximum tolerated dose or phase II dose is identified, expansion cohorts will accrue to further evaluate these combinations. The flexibility of the design allows additional combinations arms to be added. Key exploratory analyses will include an evaluation of safety, PK, and efficacy as evidenced by best overall response and duration of response.
Commentary: Increasing the Connectivity Between Implementation Science and Public Health: Advancing Methodology, Evidence Integration, and Sustainability
Authors: David A. Chambers
Journal: Annual Review of Public Health (2017)

Gaps remain between the outcomes of biomedical research and their application within clinical and community settings. The field of implementation science, also referred to as dissemination and implementation research, is intended to improve the adoption, uptake, and sustainability of evidence-based health interventions. The articles in this volume's symposium on implementation science and public health identify important directions in the effort to maximize the impact of research on public and population health. Leading researchers present reviews of the use of quasi-experimental designs in implementation science, the movement toward enhancing evidence-based public health, and intervention sustainability. Each article presents lessons learned from prior research and recommendations for the next generation of studies. Collectively, the symposium offers a road map for future implementation science that seeks to optimize public health.
Sarcoid-like granulomatosis in a patient receiving anti-TNFα for psoriasis
Authors: Vasiliki Leventaki, Jamie Flerlage
Journal: American Journal of Hematology (2017)

A 17-year-old man presented with fatigue, weight loss, and abdominal pain. The clinical history was significant for psoriasis diagnosed at the age of 3 and treated with years of topical steroids. The patient also received etanercept for 2 years, followed by adalimumab for the past year prior his presentation. An abdominal computed tomography (CT) scan was performed for his abdominal pain and revealed lymphadenopathy. Positron emission tomography (PET)/CT scan showed hypermetabolic diffuse lymphadenopathy involving neck, chest, retroperitoneal, and mesenteric lymph nodes (Image 1, panel A). Due to clinical concern for lymphoma, an axillary lymph node biopsy was performed that showed numerous, epithelioid, and non-ceseating coalescing granulomas with multinucleated giant-cells (Image 1, panel B-D). Gomori's methenamine silver stain (GMS) and acid-fast bacillus (AFB) tissue stains were negative for stainable fungal and acid-fast organisms. Infectious work-up was negative for toxoplasmosis, histoplasmosis, cytomegalovirus (CMV), epstein-barr virus (EBV), Hepatitis B, varicella-zoster virus (VZV), herpes simplex virus (HSV), and tuberculosis. Treatment with adalimumab was discontinued and patient has been doing well since last follow-up. Imaging studies and histologic findings of the lymph node biopsy. A, PET-CT showing hypermetabolic lymphadenopathy involving neck, chest, retroperitoneal, and mesenteric lymph nodes. B, Histologic sections of the lymph node core biopsies show many noncaseating granulomas that are closely packed and well-demarcated (H&E, original magnification 100×). C,D, The granulomas are composed of predominantly epithelioid cells with a central multinucleated giant cell (H&E, original magnification 4000×) This case illustrates the rare, paradoxical adverse effect of sarcoid-like granulomatosis in patients treated with anti-TNFα for chronic inflammatory diseases.1, 2 The development of sarcoid-like lesions can affect nodal and extranodal sites following variable duration of anti-TNF therapy, while discontinuation results in resolution of the symptoms.3, 4 It is important to be aware and consider sarcoid-like granulomatous reactions, after excluding other causes of granulomas (including mycobacterial infections), in patients presenting with clinical symptoms while using anti-TNFα agents.5 Nothing to report. VL and JF collected that data and wrote the manuscript. All authors have reviewed and approved the manuscript.
The Renal Challenge With Left Ventricular Assist Device Therapy—When Enough Is Enough
Authors: Sunu S. Thomas, Emily K. Zern, David A. D’Alessandro
Journal: JAMA Internal Medicine (2017)

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Effectiveness of Pharmaceutical Smoking Cessation Aids in a Nationally Representative Cohort of American Smokers
Authors: Eric C Leas, John P Pierce, Tarik Benmarhnia, Martha M White, Madison L Noble, Dennis R Trinidad, David R Strong
Journal: JNCI Journal of the National Cancer Institute (2017)

Despite strong efficacy in randomized trials, the population effectiveness of pharmaceutical aids in long-term smoking cessation is lacking, possibly because of confounding (factors that are associated with both pharmaceutical aid use and difficulty quitting). Matching techniques in longitudinal studies can remove this confounding bias.
Diabetes Is Associated With Reduced Stress Hyperlactatemia in Cardiac Surgery
Authors: Giampaolo Greco, Katherine A. Kirkwood, Annetine C. Gelijns, Alan J. Moskowitz, David W. Lam
Journal: Diabetes Care (2017)

OBJECTIVE Hyperglycemia and hyperlactatemia are associated with increased morbidity and mortality in critical illness. We evaluated the relationship among hyperlactatemia, glycemic control, and diabetes mellitus (DM) after cardiac surgery. RESEARCH DESIGN AND METHODS This was a retrospective cohort study of 4,098 cardiac surgery patients treated between 2011 and 2015. Patients were stratified by DM and glucose-lowering medication history. Hyperglycemia (glucose &amp;gt;180 mg/dL), hypoglycemia (&amp;lt;70 mg/dL), and the hyperglycemic index were assessed postoperatively (48 h). The relationship between lactate and glucose levels was modeled using generalized linear regression. Mortality was analyzed using an extended Cox regression model. RESULTS Hyperglycemia occurred in 26.0% of patients without DM (NODM), 46.5% with DM without prior drug treatment (DMNT), 62.8% on oral medication (DMOM), and 73.8% on insulin therapy (DMIT) (P &amp;lt; 0.0001). Hypoglycemia occurred in 6.3%, 9.1%, 8.8%, and 10.8% of NODM, DMNT, DMOM, and DMIT, respectively (P = 0.0012). The lactate levels of all patients were temporarily increased with surgery. This increase was greater in patients who also had hyperglycemia or hypoglycemia and was markedly attenuated in patients with DM. Peak lactate was 5.8 mmol/L (95% CI 5.6, 6.0) in NODM with hyperglycemia vs. 3.3 (95% CI 3.2, 3.4) without hyperglycemia; in DMNT: 4.8 (95% CI 4.4, 5.2) vs. 3.4 (95% CI 3.1, 3.6); in DMOM: 3.8 (95% CI 3.5, 4.1) vs. 2.9 (95% CI 2.7, 3.1); and in DMIT: 3.3 (95% CI 3.0, 3.5) vs. 2.7 (95% CI 2.3, 3.0). Increasing lactate levels were associated with increasing mortality; increasing glucose reduced this effect in DM but not in NODM (P = 0.0069 for three-way interaction). CONCLUSIONS Stress hyperlactatemia is markedly attenuated in patients with DM. There is a three-way interaction among DM, stress hyperlactatemia, and stress hyperglycemia associated with mortality after cardiac surgery.
Phase I study combining the aurora kinase A (AURKA) inhibitor alisertib (Ali) with mFOLFOX in gastrointestinal (GI) cancer.
Authors: Laura Williams Goff, Nilofer Saba Azad, Stacey Stein, Jennifer Whisenant, Ulka N. Vaishampayan, Howard S. Hochster, Roisin M. Connolly, Amy M. Weise, Patricia LoRusso, Wael El-Rifai, Jordan Berlin
Journal: Journal of Clinical Oncology (2017)

2593 Background: Overexpression and cellular mis-localization of AURKA in GI cancers results in chromosomal instability, activation of several oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 causing cell death. Our preclinical data showed synergy of Ali and platinum agents in GI cells and xenografts, and suggested an optimal timing window of the combination. The purpose of this study was to assess safety of Ali + mFOLFOX, as this is a standard platinum-based therapy for GI cancers. Methods: This CTEP-sponsored, investigator-initiated, study (NCT02319018) used standard 3+3 dose escalation to determine the maximum tolerated dose (MTD) of Ali + mFOLFOX. Eligible patients (pts) had metastatic or unresectable GI cancer where standard therapies did not exist or were no longer effective, or for whom FOLFOX was appropriate. Pts received escalating doses of Ali starting at 10 mg twice daily (D1-3), with leucovorin + oxaliplatin (85 mg/m 2 ) on D2 followed by continuous 5FU (2400 mg/m 2 ) infusion on D2-4 in 14-day cycles. Dose-limiting toxicity (DLT) was any treatment-related non-hematologic ≥Gr3 toxicity (except diarrhea or nausea, vomiting, controllable with meds) or ≥Gr4 hematologic toxicity observed during the first 28 days. Results: 13 pts were enrolled and 2 dose levels explored; 2 pts were not evaluable for DLT and replaced. Zero DLTs observed in first 3 pts. Ali was escalated to 20 mg where 2/6 had a DLT [Gr3 fatigue (n = 2); Gr3 nausea, vomiting, dehydration with hospitalization (n = 1)]. Ali was de-escalated and 2 of 3 pts have been enrolled; 0 DLTs observed thus far. Most frequent toxicities (%) were nausea (54), fatigue (46), neuropathy (46), anorexia (38), and anemia (38), most ≤Gr2. One of 10 evaluable pts had a partial response, and 6 had stable disease for a 70% disease control rate. Conclusions: The MTD will be 10 mg Ali (D1-3) + oxaliplatin (D2, 85 mg/m 2 ) + continuous 5FU (D2-4, 2400 mg/m 2 ). The combination was tolerable, and preliminary clinical activity was seen in a majority of pts. Correlative biomarker studies to evaluate AURKA target inhibition are ongoing and will be reported. Clinical trial information: NCT02319018.
Abstract 15194: Antioxidant-1, Proinflammatory Cu-Dependent Transcription Factor, Mediates Disturbed Flow-Induced Endothelial Cell Inflammation and Atherosclerosis
Authors: Sudhahar Varadarajan, Archita Das, Asahi Kato, Ken Shibata Lizama, Anuja Waghulkar, Bayasgalan Surenkhuu, Hanjoong Jo, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2016)

Introduction: Disturbed flow (d-flow) including oscillatory shear (OS) causes endothelial dysfunction, leading to atherosclerosis. SUMOylation alters localization and transcriptional activity of pr...
Atrioventricular junction ablation in patients with atrial fibrillation treated with cardiac resynchronization therapy: positive impact on ventricular arrhythmias, implantable cardioverter‐defibrillator therapies and hospitalizations
Authors: Maurizio Gasparini, Axel Kloppe, Maurizio Lunati, Frédéric Anselme, Maurizio Landolina, Jose Bautista Martinez‐Ferrer, Alessandro Proclemer, Giovanni Morani, Mauro Biffi, Renato Ricci, Roberto Rordorf, Lorenza Mangoni, Laura Manotta, Andrea Grammatico, Francisco Leyva, Giuseppe Boriani
Journal: European Journal of Heart Failure (2017)
Recent Progress in Developing Injectable Matrices for Enhancing Cell Delivery and Tissue Regeneration
Authors: Xinming Tong, Fan Yang
Journal: Advanced Healthcare Materials (2017)

Abstract Biomaterials are key factors in regenerative medicine. Matrices used for cell delivery are especially important, as they provide support to transplanted cells that is essential for promoting cell survival, retention, and desirable phenotypes. Injectable matrices have become promising and attractive due to their minimum invasiveness and ease of use. Conventional injectable matrices mostly use hydrogel precursor solutions that form solid, cell‐laden hydrogel scaffolds in situ. However, these materials are associated with challenges in biocompatibility, shear‐induced cell death, lack of control over cellular phenotype, lack of macroporosity and remodeling, and relatively weak mechanical strength. This Progress Report provides a brief overview of recent progress in developing injectable matrices to overcome the limitations of conventional in situ hydrogels. Biocompatible chemistry and shear‐thinning hydrogels have been introduced to promote cell survival and retention. Emerging investigations of the effects of matrix properties on cellular function in 3D provide important guidelines for promoting desirable cellular phenotypes. Moreover, several novel approaches are combining injectability with macroporosity to achieve macroporous, injectable matrices for cell delivery.