tbuckley/cabot-search huggingface dataset:
Effect of paclitaxel and carboplatin on tumor-reactive T cells and the efficacy of PD-1 blockade.
Authors: Yiyi Yan, Roxana Stefania Dronca, Xin Liu, Svetomir Markovic, Haidong Dong
Journal: Journal of Clinical Oncology (2017)

65 Background: The addition of chemotherapy to immune checkpoint inhibitors has been explored clinically in solid tumors in order to overcome one of the challenges of immunotherapy: clinical outcomes are variable, with only a subset of patients achieving durable responses. Further understanding of the immunoregulatory mechanisms of chemotherapy in the setting of immunotherapy is crucial for the development of optimal combinatorial chemo-immunotherapeutic strategies to improve clinical outcomes in patients with advanced cancer. Methods: Metastatic melanoma (MM) patients who failed anti-PD-1 single therapy were subsequently treated with paclitaxel and carboplatin in addition to PD-1 blockade. Using peripheral blood (PB) from MM patients and healthy donor, the phenotypic and functional changes in T cells induced by chemotherapy, in the setting of PD-1 blockade, were examined. Results: Paclitaxel and carboplatin, in combination with PD-1 blockade, were able to induce significant clinical responses in a subset of MM patients who were resistant to anti-PD-1 therapy alone. In patients who responded to this combination, a subset of tumor-reactive effector T cells (CD8 + CD11a + PD1 + GranzymeB + ) survived the treatment, with increased frequency after the addition of chemotherapy. This T cell population preserved its effector phenotype, although ongoing PD-1 blockade was needed to improve its anti-tumor activity. In vitro experiments, using CD8 + CD11a + PD1 + GranzymeB + isolated from healthy donor PB, also demonstrated its ability to survive chemotherapy treatment. In addition, after cultured with chemotherapy, this T cell subset demonstrated higher cytotoxic T cell functions as well as increased chemotherapy efflux. Conclusions: Chemotherapy regulates a subset of tumor-reactive effector T cells (CD8 + CD11a + PD1 + GranzymeB + ) and increases clinical efficacy of PD-1 blockade. This novel effector T cell population underlies the key cellular and molecular immunoregulatory mechanisms of chemotherapy. It serves as a meaningful marker to measure these collaborative effects and to develop the optimal chemo-immunotherapy strategy to improve clinical responses to current immune checkpoint blocking agents.
Optimizing the pretransplant regimen for autologous stem cell transplantation in acute myelogenous leukemia: Better outcomes with busulfan and melphalan compared with busulfan and cyclophosphamide in high risk patients autografted in first complete remission: A study from the acute leukemia working party of the EBMT
Authors: Norbert Claude Gorin, Myriam Labopin, Didier Blaise, Pierre‐Yves Dumas, Thomas Pabst, Silvia Maria Trisolini, William Arcese, Mohamed Houhou, Mohamad Mohty, Arnon Nagler
Journal: American Journal of Hematology (2018)

Abstract Autologous stem cell transplantation remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL. All factors differing in distribution between the 2 conditioning groups were introduced in multivariate analyzes. In a primary analysis, we found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3‐ITD mutation. During analysis of the poor risk group, 176 patients received BUCY and 62 BUMEL. BUMEL was associated with a lower RI at 5 years (53% versus 69%, HR: 0.52, P = .002), a better Leukaemia‐free survival (LFS) (42% versus 25%, HR: 0.54, P = .002) and a better OS (54% versus 36%, HR: 0.61, P = .02). During analysis of the non poor risk group, 961 patients received BUCY and 450 BUMEL. At 5 years, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60% respectively, with no significant difference. We conclude that BUMEL is the preferable conditioning regimen for the poor risk leukemic patients, while in AML patients without poor risk cytogenetics or FLT3 both conditioning regimens are valid.
Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies
Authors: Christian Chabannon, Jurgen Kuball, Attilio Bondanza, Francesco Dazzi, Paolo Pedrazzoli, Antoine Toubert, Annalisa Ruggeri, Katharina Fleischhauer, Chiara Bonini
Journal: Science Translational Medicine (2018)

Over the last 60 years, more than a million patients received hematopoietic cell transplantation. Having incorporated multiple changes in clinical practices, it remains a complex procedure facing a dual challenge: cure of the underlying disease and prevention of relapse while controlling potentially severe complications. Improved understanding of underlying biological processes resulted in the design of innovative therapies engineered from defined cell populations and testing of these therapies as addition or substitution at virtually every step of the procedure. This review provides an overview of these developments, many of them now applied outside the historical field of hematopoietic cell transplantation.
How does light-intensity physical activity associate with adult cardiometabolic health and mortality? Systematic review with meta-analysis of experimental and observational studies
Authors: Sebastien F M Chastin, Marieke De Craemer, Katrien De Cocker, Lauren Powell, Jelle Van Cauwenberg, Philippa Dall, Mark Hamer, Emmanuel Stamatakis
Journal: British Journal of Sports Medicine (2018)

Aim To assess the relationship between time spent in light physical activity and cardiometabolic health and mortality in adults. Design Systematic review and meta-analysis. Data sources Searches in Medline, Embase, PsycInfo, CINAHL and three rounds of hand searches. Eligibility criteria for selecting studies Experimental (including acute mechanistic studies and physical activity intervention programme) and observational studies (excluding case and case–control studies) conducted in adults (aged ≥18 years) published in English before February 2018 and reporting on the relationship between light physical activity (&lt;3 metabolic equivalents) and cardiometabolic health outcomes or all-cause mortality. Study appraisal and synthesis Study quality appraisal with QUALSYST tool and random effects inverse variance meta-analysis. Results Seventy-two studies were eligible including 27 experimental studies (and 45 observational studies). Mechanistic experimental studies showed that short but frequent bouts of light-intensity activity throughout the day reduced postprandial glucose (−17.5%; 95% CI −26.2 to −8.7) and insulin (−25.1%; 95% CI −31.8 to –18.3) levels compared with continuous sitting, but there was very limited evidence for it affecting other cardiometabolic markers. Three light physical activity programme intervention studies (n ranging from 12 to 58) reduced adiposity, improved blood pressure and lipidaemia; the programmes consisted of activity of &gt;150 min/week for at least 12 weeks. Six out of eight prospective observational studies that were entered in the meta-analysis reported that more time spent in daily light activity reduced risk of all-cause mortality (pooled HR 0.71; 95% CI 0.62 to 0.83). Conclusions Light-intensity physical activity could play a role in improving adult cardiometabolic health and reducing mortality risk. Frequent short bouts of light activity improve glycaemic control. Nevertheless, the modest volume of the prospective epidemiological evidence base and the moderate consistency between observational and laboratory evidence inhibits definitive conclusions.
The American College of Cardiology 2018; a Starbuckian ODYSSEY and a Black Barbershop
Authors: Matthew J Daniels
Journal: Cardiovascular Research (2018)

If you have not been to the ACC Scientific Sessions, you might not realize this meeting is a lot closer to the clinical coalface than it is to basic science.That is not a bad thing, but the reality is that cardiovascular research is slovenly in comparison to the inroads basic science has made in the other major disease of our era, cancer.We are tied down with descriptive disease entities like 'atrial fibrillation' (AF).AF is common, you have a lifetime risk of 1:4 of developing it. 1Contemporary AF classification describes how long it lasts (paroxysmal, persistent or permanent) rather than what causes it.It's like talking about cancer in terms of the amount of tumour -a Starbuckian classification of Tall, Grande and Venti which oncology abandoned decades ago.AF causes stroke, and death by promoting clot formation in the heart, 1 so there was good news on the clinical horizon that the anti-coagulants (that reduce stroke and death in patients with AF) based on factor Xa inhibition now appear to have an effective antidote 2 that translates into clinical practice based on the interim analyses presented for the Annexa-4 study (http://www.acc.
The Role of Mitochondria in Pulmonary Hypertension-Warburg Redux
Authors: Stephen Archer
Journal: Circulation (2010)

Throughout my career I have benefited from the superb mentorship of Dr. E Kenneth Weir, from an array of talented collaborators, and from the contributions of masterful technicians and staff scientists. I have also enjoyed mentoring many talented trainees who developed into independent scientists and leaders in their own right. This lecture summarizes work of these individuals over the past 25 years. We initially identified a mechanism of hypoxic pulmonary vasoconstriction (HPV) and gradually recognized that this mechanism was subverted in proliferative disorders, including pulmonary arterial hypertension (PAH). We showed that mitochondria in pulmonary artery smooth muscle cells (PASMC) act as oxygen sensors by generating reactive oxygen species (ROS) that regulate oxygen-sensitive potassium channels (e.g. Kv1.5) and thereby control vascular tone. More recently we found that acquired disorders of mitochondrial function and structure are important in the pathogenesis of PAH. We discovered that the mitochondria-ROS-HIF-1α-Kv1.5 pathway is disordered in PAH such that cells perceive themselves as hypoxic, despite adequate PO 2 . This hypoxic mitochondrial-metabolic transformation confers a survival advantage, leading to excessive cell proliferation and impaired apoptosis. Despite adequate oxygen, PAH PASMC have impaired oxidative glucose metabolism and enhanced glycolytic metabolism, due to activation of pyruvate dehydrogenase kinase (PDK) and HIF-1α. This glycolytic shift constitutes a survival mechanism for PAH PASMC and endothelial cells (thus Warburg9s hypothesis redux). We have identified several mitochondrial abnormalities that may offer therapeutic targets:  (1)  There is pathologic  PDK activation  that inhibits oxidative metabolism and favors glycolysis. Dichloroacetate, a prototypic PDK inhibitor, normalizes the  mitochondria-ROS-HIF-1α-Kv1.5 pathway  and regresses several experimental models of PAH.  (2)  There is a heritable,  epigenetic downregulation of mitochondrial superoxide dismutase (SOD2) , due to methylation of CpG islands in the SOD2 gene. Therapies that reverse epigenetic silencing of SOD2 or supplement SOD may be feasible.  (3)  Normal mitochondria are fused into a reticulum by fusogenic proteins (notably mitofusin-2). Mitofusin-2 also regulates cell proliferation. In PAH there is an increased ratio of mitochondrial fission to fusion, due in part to reduced mitofusin-2 levels. Fusogenic mitochondrial therapies are being developed.
Phase II study of nivolumab in patients with advanced non-small cell lung cancer (NSCLC) in Korea.
Authors: Keunchil Park, Eun Kyung Cho, Jin Hyoung Kang, Ji-Youn Han, Jong Seok Lee, Dong-Wan Kim, Sang-We Kim, Byoung Chul Cho, Young Joo Min, Ki Hyeong Lee, Joo-Hang Kim
Journal: Journal of Clinical Oncology (2017)

92 Background: Nivolumab (BMS-936558/ONO-4538), a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in several tumor types. Recently, two phase III studies (CheckMate-017 and -057) demonstrated that nivolumab improved overall survival (OS) than docetaxel in second-line of squamous (SQ) and non-squamous (NSQ) Non-Small Cell Lung Cancer (NSCLC), respectively. Here, we report the results of a phase II study to evaluate the efficacy and safety of nivolumab in Korean patients (pts) with previously treated advanced SQ and NSQ NSCLC. Methods: This study requires pts aged ≥ 20 years with ECOG Performance Status (PS) of 0 or 1, stage IIIB/IV or recurrent NSCLC and at least one prior chemotherapy including platinum containing regimen. Pts received nivolumab 3 mg/kg IV Q2W until progression or unacceptable toxicity. The primary endpoint in this study was the objective response rate (ORR) (RECIST v1.1). Results: Nivolumab was administered to 100 NSCLC pts (SQ: 44, NSQ: 56), male/female: 78 (SQ: 44, NSQ: 34)/22 (SQ: 0, NSQ: 22); PS 0/1: 14 (SQ: 6, NSQ: 8)/86 (SQ: 38, NSQ: 48); aged 29 to 80 [median: 66.5] years (SQ: 40 to 80 [median: 69.5], NSQ: 29 to 77 [median: 63.5]); Stage IIIB/IV/recurrence: 6 (SQ: 5, NSQ: 1)/91 (SQ: 37, NSQ: 54)/3 (SQ: 2, NSQ: 1)). In SQ and NSQ NSCLC, ORR was 15.9% (7/44) and 23.2% (13/56), respectively. Median progression-free survival was 2.6 mo and 5.3 mo, respectively. Complete Response was observed in 2.3% (1/44) and 1.8% (1/56), respectively. Median OS was 12.3 mo and 16.3 mo, respectively. Median follow-up was 8.9 mo and 12.3 mo, respectively. Most common adverse drug reaction (ADR) was decreased appetite 15.9% (7/44), followed by pyrexia 9.1% (4/44) in SQ NSCLC, and decreased appetite 12.5% (7/56), followed by pruritus 10.7% (6/56), fatigue 8.9% (5/56), pyrexia 5.4% (3/56) and nausea 5.4% (3/56) in NSQ NSCLC. Grade 3-4 ADR was observed in 6.8% (3/44) and 10.7% (6/56) of SQ and NSQ NSCLC, respectively. No interstitial lung disease and no grade 5 ADRs were observed in this study. Conclusions: Nivolumab was considered to be effective and used safely in Korean pts with SQ and NSQ NSCLC as well as in non-Korean pts with SQ and NSQ NSCLC. Clinical trial information: NCT02175017.
Redefining mouse transgenesis with CRISPR/Cas9 genome editing technology
Authors: Gaetan Burgio
Journal: Genome biology (2018)

The generation of genetically modified alleles in mice using conventional transgenesis technologies is a long and inefficient process. A new study shows that the in situ delivery of CRISPR/Cas9 reagents into pregnant mice results in a high efficiency of editing, and enables the rapid generation of both simple and complex alleles.
Chromatin Accessibility-Based Characterization of the Gene Regulatory Network Underlying Plasmodium falciparum Blood-Stage Development
Authors: Christa Geeke Toenhake, Sabine Anne-Kristin Fraschka, Mahalingam Shanmugiah Vijayabaskar, David Robert Westhead, Simon Jan van Heeringen, Richárd Bártfai
Journal: Cell Host & Microbe (2018)

Underlying the development of malaria parasites within erythrocytes and the resulting pathogenicity is a hardwired program that secures proper timing of gene transcription and production of functionally relevant proteins. How stage-specific gene expression is orchestrated in vivo remains unclear. Here, using the assay for transposase accessible chromatin sequencing (ATAC-seq), we identified ∼4,000 regulatory regions in P. falciparum intraerythrocytic stages. The vast majority of these sites are located within 2 kb upstream of transcribed genes and their chromatin accessibility pattern correlates positively with abundance of the respective mRNA transcript. Importantly, these regions are sufficient to drive stage-specific reporter gene expression and DNA motifs enriched in stage-specific sets of regulatory regions interact with members of the P. falciparum AP2 transcription factor family. Collectively, this study provides initial insights into the in vivo gene regulatory network of P. falciparum intraerythrocytic stages and should serve as a valuable resource for future studies.
Abstract 14471: Benzene Exposure Is Associated With Increased CVD Risk, Hyperlipidemia, and Decreased Circulating Angiogenic Cells in Humans and Mice
Authors: Wesley Abplanalp, Natasha DeJarnett, Daniel Riggs, Xiaoping Li, James McCracken, Ray Yeager, Andrew Defilippis, Zhengzhi Xie, David Tollerud, Daniel Conklin, Shesh Rai, Sanjay Srivastava, Aruni Bhatnagar, Timothy O’Toole
Journal: Circulation (2016)

Introduction: Benzene is present in tobacco smoke, gasoline exhaust and industrial emissions, and while benzene exposure is known to disrupt hematopoiesis, the cardiovascular effects of exposure ar...
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer
Authors: Patrick M. Forde, Jamie E. Chaft, Kellie N. Smith, Valsamo Anagnostou, Tricia R. Cottrell, Matthew D. Hellmann, Marianna Zahurak, Stephen C. Yang, David R. Jones, Stephen Broderick, Richard J. Battafarano, Moises J. Velez, Natasha Rekhtman, Zachary Olah, Jarushka Naidoo, Kristen A. Marrone, Franco Verde, Haidan Guo, Jiajia Zhang, Justina X. Caushi, Hok Yee Chan, John-William Sidhom, Robert B. Scharpf, James White, Edward Gabrielson, Hao Wang, Gary L. Rosner, Valerie Rusch, Jedd D. Wolchok, Taha Merghoub, Janis M. Taube, Victor E. Velculescu, Suzanne L. Topalian, Julie R. Brahmer, Drew M. Pardoll
Journal: New England Journal of Medicine (2018)

Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade.In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses.Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab.Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .).
Trastuzumab versus MYL-1401O (a proposed trastuzumab biosimilar) in a phase I bioequivalence study: In vivo and in vitro immunomodulation.
Authors: RÃÂ©gine Audran, Haithem Chtioui, Anne-Christine Thierry, Carole Mayor, Laure Vallotton, Kim Dao, Laura Rothuizen, Ali Maghraoui, Eduardo J. Pennella, Françoise Brunner-Ferber, Thierry Buclin, Francois Spertini
Journal: Journal of Clinical Oncology (2017)

10 Background: Trastuzumab is a humanized monoclonal antibody targeting breast cancer cells overexpressing the HER2-oncoprotein. During a Phase-I single centre, single dose, randomized, double-blind, cross-over study assessing the bioequivalence of a proposed trastuzumab biosimilar (MYL-1401O) versus the initially marketed drug (Herceptin), we investigated in addition a large panel of pharmacodynamics parameters comparing the immunomodulatory activity of both drugs. Methods: 22 healthy males were included, 19 subjects receiving randomly a single intravenous infusion of MYL-1401O and 22 of Herceptin, separated by 16 to 22 week wash-out. Blood samples drawn pre- and post- infusion were assessed for in vivo serum cytokines induction (IL-1β, IL-2, IL-6, IL-10, IL-12, TNF-α, GM-CSF and IFN-γ) whereas the impact of treatment on mononuclear cell subsets and their level of activation was tested ex vivo. Volunteers’ PBMC (peripheral blood monocnuclear cells) were stimulated in vitro with recall antigens and mitogen for cytokine production. At baseline, we performed in addition a cytokine release assay on PBMC upon stimulation with trastuzumab as a preclinical safety test. Results: Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6h, and a modulation of mononuclear cell subset profile and level of activation. Notably CD16+ cells frequency decreased at 3h and peaked at 48h. Except for CD8+ T cells, there were no significant differences between Herceptin and its proposed biosimilar ex vivo. PBMC stimulated in vitro with trastuzumab secreted IL-6, TNF-a, IL-1β, GM-CSF, IFN-γ, and IL-10, but no IL-2. There was no significant difference between the two mAbs. Conclusions: Based on these in vivo, ex vivo and in vitro experiments, there is a strong assumption that MYL-1401O is biosimilar to the reference drug Herceptin for its immunomodulation properties as already proven for its bioequivalence. Clinical trial information: 2011-001406-94.
Efficacy and safety of ixekizumab over 4 years of open-label treatment in a phase 2 study in chronic plaque psoriasis
Authors: Claus Zachariae, Kenneth Gordon, Alexandra B. Kimball, Mark Lebwohl, Andrew Blauvelt, Craig Leonardi, Daniel Braun, Missy McKean-Matthews, Russel Burge, Gregory Cameron
Journal: Journal of the American Academy of Dermatology (2018)
The effect of linkers on the self-assembling and anti-tumor efficacy of disulfide-linked doxorubicin drug-drug conjugate nanoparticles
Authors: Yaoqi Wang, Xing Wang, Feiyang Deng, Nan Zheng, Yanqin Liang, Hua Zhang, Bing He, Wenbing Dai, Xueqing Wang, Qiang Zhang
Journal: Journal of Controlled Release (2018)