tbuckley/cabot-search huggingface dataset:
Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas
Authors: Lenha Mobuchon, Anne-Céline Derrien, Alexandre Houy, Thibault Verrier, Gaëlle Pierron, Nathalie Cassoux, Maud Milder, Jean-François Deleuze, Anne Boland, Ghislaine Scelo, Géraldine Cancel-Tassin, Olivier Cussenot, Manuel Rodrigues, Josselin Noirel, Mitchell J Machiela, Marc-Henri Stern
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1142 European UM patients and 882 healthy controls . Methods We combined 2 independent datasets (Global Screening Array) with the dataset described in a previously published GWAS in UM (Omni5 array), which were imputed separately and subsequently merged. Patients were stratified according to their chromosome 3 status, and identified UM risk loci were tested for differential association with M3 or D3 subgroups. All statistical tests were 2-sided. Results We recapitulated the previously identified risk locus on chromosome 5 on CLPTM1L (rs421284: odds ratio [OR] =1.58, 95% confidence interval [CI] = 1.35 to 1.86; P = 1.98 × 10-8) and identified 2 additional risk loci involved in eye pigmentation: IRF4 locus on chromosome 6 (rs12203592: OR = 1.76, 95% CI = 1.44 to 2.16; P = 3.55 × 10-8) and HERC2 locus on chromosome 15 (rs12913832: OR= 0.57, 95% CI = 0.48 to 0.67; P = 1.88 × 10-11). The IRF4 rs12203592 single-nucleotide polymorphism was found to be exclusively associated with risk for the D3 UM subtype (ORD3 = 2.73, 95% CI = 1.87 to 3.97; P = 1.78 × 10-7), and the HERC2 rs12913832 single-nucleotide polymorphism was exclusively associated with risk for the M3 UM subtype (ORM3 = 2.43, 95% CI = 1.79 to 3.29; P = 1.13 × 10-8). However, the CLPTM1L risk locus was equally statistically significant in both subgroups. Conclusions This work identified 2 additional UM risk loci known for their role in pigmentation. Importantly, we demonstrate that UM tumor biology and metastatic potential are influenced by patients’ genetic backgrounds.
Association of Atrial Fibrillation Burden With Health-Related Quality of Life After Atrial Fibrillation Ablation
Authors: Michelle Samuel, Paul Khairy, Jean Champagne, Marc W. Deyell, Laurent Macle, Peter Leong-Sit, Paul Novak, Mariano Badra-Verdu, John Sapp, Jean-Claude Tardif, Jason G. Andrade
Journal: JAMA Cardiology (2021)

Patients with atrial fibrillation (AF) have impaired health-related quality of life primarily owing to symptoms related to AF episodes; however, quality of life can be influenced by AF therapies, AF complications, the frequency of follow-up visits and hospitalizations, illness perceptions, and patient factors, such as anxiety or depression.To determine the association between change in AF burden and quality of life in the year following ablation.The current study is a secondary analysis of a prospective, parallel-group, multicenter, single-masked randomized clinical trial (Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double Short vs Standard Exposure Duration [CIRCA-DOSE] study), which took place at 8 Canadian centers. Between September 2014 and July 2017, 346 patients older than 18 years with symptomatic, primarily low-burden AF refractory to antiarrhythmic therapy referred for first catheter ablation were enrolled. All patients received an implantable cardiac monitor at least 30 days before ablation and were followed up with up to December 2018. Data were analyzed from April 2020 to June 2021.Patients were randomized 1:1:1 to contact force-guided radiofrequency ablation, 4-minute cryoballoon ablation, or 2-minute cryoballoon ablation. The exposure in the present analysis is the absolute difference in AF burden prior to ablation and 12 months following ablation, as evaluated by the Atrial Fibrillation Effect on Quality of Life (AFEQT) Score.Absolute difference in quality of life from baseline to 12 months postablation.Of 346 included patients, 231 (66.7%) were male, and the median (interquartile range) age was 60 (52-66) years. A total of 328 patients (94.8%) had paroxysmal AF. The median (interquartile range) preablation AF burden was 2.0% (0.1-11.9), and the AF burden decreased to 0% at 12 months postablation. At 12 months, a 1-point improvement in AFEQT score was observed for every absolute reduction in daily AF burden of 15.8 minutes (95% CI, 7.2-24.4; P < .001), or every 0.63% (95% CI, 0.30-0.95; P < .001) reduction in relative AF burden from baseline.In patients with primarily low-burden paroxysmal AF, the reduction in AF burden following ablation may be associated with a clinically meaningful improvement in quality of life.ClinicalTrials.gov Identifier: NCT01913522.
A conventional immune regulator mitochondrial antiviral signaling protein blocks hepatic steatosis by maintaining mitochondrial homeostasis
Authors: Jiajun Fu, Fengjiao Hu, Tengfei Ma, Wen‐Jie Zhao, Han Tian, Yan Zhang, Manli Hu, Junjie Zhou, Yanfang Zhang, Chongshu Jian, Yan‐Xiao Ji, Xiao‐Jing Zhang, Jingwei Jiang, Zhi‐Gang She, Xu Cheng, Peng Zhang, Lan Bai, Juan Yang, Hongliang Li
Journal: Hepatology (2021)

Background and Aims Although the prevalence of NAFLD has risen dramatically to 25% of the adult population worldwide, there are as yet no approved pharmacological interventions for the disease because of uncertainty about the underlying molecular mechanisms. It is known that mitochondrial dysfunction is an important factor in the development of NAFLD. Mitochondrial antiviral signaling protein (MAVS) is a critical signaling adaptor for host defenses against viral infection. However, the role of MAVS in mitochondrial metabolism during NAFLD progression remains largely unknown. Approach and Results Based on expression analysis, we identified a marked down‐regulation of MAVS in hepatocytes during NAFLD progression. By using MAVS global knockout and hepatocyte‐specific MAVS knockout mice, we found that MAVS is protective against diet‐induced NAFLD. MAVS deficiency induces extensive mitochondrial dysfunction during NAFLD pathogenesis, which was confirmed as impaired mitochondrial respiratory capacity and membrane potential. Metabolomics data also showed the extensive metabolic disorders after MAVS deletion. Mechanistically, MAVS interacts with the N‐terminal stretch of voltage‐dependent anion channel 2 (VDAC2), which is required for the ability of MAVS to influence mitochondrial function and hepatic steatosis. Conclusions In hepatocytes, MAVS plays an important role in protecting against NAFLD by helping to regulate healthy mitochondrial function. These findings provide insights regarding the metabolic importance of conventional immune regulators and support the possibility that targeting MAVS may represent an avenue for treating NAFLD.
Diagnostic Accuracy of Two-Dimensional Shear Wave Elastography for Liver Fibrosis: A Multicenter Prospective Study
Authors: Tatsuya Kakegawa, Katsutoshi Sugimoto, Hidekatsu Kuroda, Yasuaki Suzuki, Kento Imajo, Hidenori Toyoda, Nobuharu Tamaki, Satoshi Yasuda, Yutaka Yasui, Masayuki Kurosaki, Namiki Izumi, Atsushi Nakajima, Takashi Kumada
Journal: Clinical Gastroenterology and Hepatology (2021)
Genome-Derived Classification Signature for Ampullary Adenocarcinoma to Improve Clinical Cancer Care
Authors: Saptarshi Chakraborty, Brett L. Ecker, Ken Seier, Victoria G. Aveson, Vinod P. Balachandran, Jeffrey A. Drebin, Michael I. D'Angelica, T. Peter Kingham, Carlie S. Sigel, Kevin C. Soares, Efsevia Vakiani, Alice C. Wei, Rohit Chandwani, Mithat Gonen, Ronglai Shen, William R. Jarnagin
Journal: Clinical Cancer Research (2021)

The clinical behavior of ampullary adenocarcinoma varies widely. Targeted tumor sequencing may better define biologically distinct subtypes to improve diagnosis and management.The hidden-genome algorithm, a multilevel meta-feature regression model, was trained on a prospectively sequenced cohort of 3,411 patients (1,001 pancreatic adenocarcinoma, 165 distal bile-duct adenocarcinoma, 2,245 colorectal adenocarcinoma) and subsequently applied to targeted panel DNA-sequencing data from ampullary adenocarcinomas. Genomic classification (i.e., colorectal vs. pancreatic) was correlated with standard histologic classification [i.e., intestinal (INT) vs. pancreatobiliary (PB)] and clinical outcome.Colorectal genomic subtype prediction was primarily influenced by mutations in APC and PIK3CA, tumor mutational burden, and DNA mismatch repair (MMR)-deficiency signature. Pancreatic genomic-subtype prediction was dictated by KRAS gene alterations, particularly KRAS G12D, KRAS G12R, and KRAS G12V. Distal bile-duct adenocarcinoma genomic subtype was most influenced by copy-number gains in the MDM2 gene. Despite high (73%) concordance between immunomorphologic subtype and genomic category, there was significant genomic heterogeneity within both histologic subtypes. Genomic scores with higher colorectal probability were associated with greater survival compared with those with a higher pancreatic probability.The genomic classifier provides insight into the heterogeneity of ampullary adenocarcinoma and improves stratification, which is dictated by the proportion of colorectal and pancreatic genomic alterations. This approach is reproducible with available molecular testing and obviates subjective histologic interpretation.
Diagnostic Value of Flow Cytometry Technique By European Leukemianet for Idiopathic Cytopenia of Undetermined Significance
Authors: Shumpei Uchida, Osamu Imataki, Hiroyuki Kubo, Shigeyuki Yokokura, Makiko Uemura, Naoshi Sugimoto, Norimitsu Kadowaki
Journal: Blood (2017)
Erratum: The prevalence of cutaneous manifestations in IDDM patients and their association with diabetes risk factors and microvascular complications (Diabetes Care (1998) 21 (506-509))
Authors: G. Yosipovitch, E. Hodak, P. Vardi, I. Shraga, M. Karp, M. David, E. Sprecher
Journal: Diabetes Care (1998)
28169 Psoriasis in routine clinical care: Complete skin clearance rates with guselkumab increase through week 52—Results from the real-life PERSIST study
Authors: Matthias Hoffmann, Michael Sticherling, Bernhard Korge, Dariusch Mortazawi, Yvonne Personke, Mario Gomez, Sven Wegner, Sascha Gerdes
Journal: Journal of the American Academy of Dermatology (2021)
Donor HLA Class 1 Evolutionary Divergence Is a Major Predictor of Liver Allograft Rejection
Authors: Cyrille Féray, Jean-Luc Taupin, Mylène Sebagh, Vincent Allain, Zeynep Demir, Marc-Antoine Allard, Christophe Desterke, Audrey Coilly, Faouzi Saliba, Eric Vibert, Daniel Azoulay, Catherine Guettier, Arthur Chatton, Dominique Debray, Sophie Caillat-Zucman, Didier Samuel
Journal: Annals of Internal Medicine (2021)

Background: The HLA evolutionary divergence (HED), a continuous metric quantifying the peptidic differences between 2 homologous HLA alleles, reflects the breadth of the immunopeptidome presented to T lymphocytes. Objective: To assess the potential effect of donor or recipient HED on liver transplant rejection. Design: Retrospective cohort study. Setting: Liver transplant units. Patients: 1154 adults and 113 children who had a liver transplant between 2004 and 2018. Measurements: Liver biopsies were done 1, 2, 5, and 10 years after the transplant and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSAs) were measured in children at the time of biopsy. The HED was calculated using the physicochemical Grantham distance for class I (HLA-A or HLA-B) and class II (HLA-DRB1 or HLA-DQB1) alleles. The influence of HED on the incidence of liver lesions was analyzed through the inverse probability weighting approach based on covariate balancing, generalized propensity scores. Results: In adults, class I HED of the donor was associated with acute rejection (hazard ratio [HR], 1.09 [95% CI, 1.03 to 1.16]), chronic rejection (HR, 1.20 [CI, 1.10 to 1.31]), and ductopenia of 50% or more (HR, 1.33 [CI, 1.09 to 1.62]) but not with other histologic lesions. In children, class I HED of the donor was also associated with acute rejection (HR, 1.16 [CI, 1.03 to 1.30]) independent of the presence of DSAs. There was no effect of either donor class II HED or recipient class I or class II HED on the incidence of liver lesions in adults and children. Limitation: The DSAs were measured only in children. Conclusion: Class I HED of the donor predicts acute or chronic rejection of liver transplant. This novel and accessible prognostic marker could orientate donor selection and guide immunosuppression. Primary Funding Source: Institut National de la Santé et de la Recherche Médicale.
27383 Bimekizumab response maintenance up to 1 year in patients with moderate to severe plaque psoriasis: Pooled results from three phase 3 trials
Authors: Andrew Blauvelt, Yayoi Tada, Lars Iversen, Ulrich Mrowietz, Mark Lebwohl, Maggie Wang, Veerle Vanvoorden, Eva Cullen, Fabienne Staelens, Kim A. Papp
Journal: Journal of the American Academy of Dermatology (2021)
Endoscopic evaluation after surgery in inflammatory bowel disease – Authors' reply
Authors: Bo Shen, Martin Bortlik, David H Bruining, Nayantara Coelho-Prabhu, Sandra El-Hachem, Francis A Farraye, Marietta Iacucci, Taku Kobayashi, Gursimran S Kochhar, Paulo Gustavo Kotze, Yago González Lama, Alexander N Levy, Xiuli Liu, Ren Mao, Udayakumar Navaneethan, David A Schwartz, Amandeep Shergill, Ajit Sood, Begoña Gonzalez Suárez
Journal: The Lancet. Gastroenterology & hepatology (2021)
Association of <scp>COVID</scp>‐19 with impaired endothelial glycocalyx, vascular function and myocardial deformation 4 months after infection
Authors: Vaia Lambadiari, Asimina Mitrakou, Aikaterini Kountouri, John Thymis, Konstantinos Katogiannis, Emmanouil Korakas, Charalampos Varlamos, Ioanna Andreadou, Maria Tsoumani, Helen Triantafyllidi, Aristotelis Bamias, Konstantinos Thomas, Pinelopi Kazakou, Sotiria Grigoropoulou, Dimitra Kavatha, Anastasia Antoniadou, Meletios‐Athanasios Dimopoulos, Ignatios Ikonomidis
Journal: European Journal of Heart Failure (2021)
PD05: Skin safety and efficacy of filtered far ultraviolet C for SARS‐CoV‐2 inactivation
Authors: E Eadie, R Hickerson, M Conneely, R Hammond, S Tsutsumi, C Cabrera, A Wood, A Longbottom, A Parker, S Ibbotson, K Wood
Journal: British Journal of Dermatology (2021)
Quality and Safety in Healthcare, Part XC
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2021)

The A3 form is a structured way of solving problems using a detailed step-by-step methodology using the principles of the Plan-Do-Check-Act cycle. The A3 form supports efforts to organize the thinking of workers about new ways to improve. The form is used as a guide for many project teams to find answers, and then the team arrives at decisions through consensus. Sometimes process mapping, driver diagrams, and gap analysis are included in A3 problem solving. The A3 form is just one of numerous healthcare applications for the Toyota Production System and Lean.
A recombinant bovine adenoviral mucosal vaccine expressing mycobacterial antigen-85B generates robust protection against tuberculosis in mice
Authors: Arshad Khan, Ekramy E. Sayedahmed, Vipul K. Singh, Abhishek Mishra, Stephanie Dorta-Estremera, Sita Nookala, David H. Canaday, Min Chen, Jin Wang, K. Jagannadha Sastry, Suresh K. Mittal, Chinnaswamy Jagannath
Journal: Cell Reports Medicine (2021)

Although the BCG vaccine offers partial protection, tuberculosis remains a leading cause of infectious disease death, killing ∼1.5 million people annually. We developed mucosal vaccines expressing the autophagy-inducing peptide C5 and mycobacterial Ag85B-p25 epitope using replication-defective human adenovirus (HAdv85C5) and bovine adenovirus (BAdv85C5) vectors. BAdv85C5-infected dendritic cells (DCs) expressed a robust transcriptome of genes regulating antigen processing compared to HAdv85C5-infected DCs. BAdv85C5-infected DCs showed enhanced galectin-3/8 and autophagy-dependent in vitro Ag85B-p25 epitope presentation to CD4 T cells. BCG-vaccinated mice were intranasally boosted using HAdv85C5 or BAdv85C5 followed by infection using aerosolized Mycobacterium tuberculosis (Mtb). BAdv85C5 protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log10 reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log10 reduction). Protection was associated with robust CD4 and CD8 effector (TEM), central memory (TCM), and CD103+/CD69+ lung-resident memory (TRM) T cell expansion, revealing BAdv85C5 as a promising mucosal vaccine for tuberculosis.
Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis
Authors: Yamina Hamel, François-Xavier Mauvais, Marine Madrange, Perrine Renard, Corinne Lebreton, Ivan Nemazanyy, Olivier Pellé, Nicolas Goudin, Xiaoyun Tang, Mathieu P. Rodero, Caroline Tuchmann-Durand, Patrick Nusbaum, David N. Brindley, Peter van Endert, Pascale de Lonlay
Journal: Cell Reports Medicine (2021)

LPIN1 mutations are responsible for inherited recurrent rhabdomyolysis, a life-threatening condition with no efficient therapeutic intervention. Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency. We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their positioning and function. Oxidized mitochondrial DNA accumulates in late endosomes, where it activates Toll-like receptor 9 (TLR9) and triggers inflammatory signaling and caspase-dependent myolysis. Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and may attenuate flares of rhabdomyolysis in 6 patients treated. We suggest a critical role for defective clearance of oxidized mitochondrial DNA that activates TLR9-restricted inflammation in lipin1-related rhabdomyolysis. Interventions blocking TLR9 activation or inflammation can improve patient care in vivo.
Caution in Interpreting Facial Paralysis Data to Understand COVID-19 Vaccination Risks—Reply
Authors: Charles Khouri, Matthieu Roustit, Jean-Luc Cracowski
Journal: JAMA Internal Medicine (2021)

Lucie Renoud; Charles Khouri, PharmD, PhD; Bruno Revol, PharmD, PhD; Marion Lepelley, PharmD; Justine Perez, PharmD; Matthieu Roustit, PharmD, PhD; Jean-Luc Cracowski, MD, PhD
Abstract 10978: Effect of Exercise-based Cardiac Rehabilitation After Acute Myocardial Infarction on HDL Function: A Randomized Clinical Trial
Authors: Talia F Dalcoquio, Fatima Freitas, Flávia B Arantes, Larissa Ferreira-Santos, Leandro Alves, Mayara Santos, Maria Urbana P Rondon, Maria-janieire N Alves, Remo H Furtado, Carlos E Negrao, Raul C Maranhão, José C Nicolau
Journal: Circulation (2019)

Introduction: Exercise training increases high-density lipoprotein cholesterol (HDL-C) levels. However, HDL-C levels only partially reflect the protective functions of HDL, including cholesterol es...
P-35 HGCSG1901: A retrospective cohort study evaluating the safety and efficacy of S-1 and irinotecan plus bevacizumab in patients with metastatic colorectal cancer: Analysis of first-line treatment
Authors: K. Ito, S. Yuki, S. Nakano, M. Yagisawa, K. Sawada, A. Ishiguro, O. Muto, K. Hatanaka, H. Okuda, A. Sato, Y. Sasaki, M. Nakamura, T. Sasaki, T. Kobayashi, M. Dazai, H. Nakatsumi, A. Ueda, M. Tateyama, S. Sogabe, R. Matsumoto, Y. Sakata, Y. Komatsu
Journal: Annals of Oncology (2021)
A RAS effector, RASSF2 is a novel tumor suppressor gene in human colorectal cancer
Authors: Kimishige Akino, Minoru Toyota, Hiromu Suzuki, Masanobu Kusano, Hiroyuki Mita, Yasushi Sasaki, Mutsumi Ohe-Toyota, Yuji Hinoda, Jean-Pierre J. Issa, Kohzoh Imai, Takashi Tokino
Journal: Cancer Research (2005)

919   Background and Aims: Activation of RAS signaling is a hallmark of colorectal cancer, but the role of negative regulators of RAS is not fully understood. We attempted to clarify this by surveying genetic and epigenetic alterations of Ras-Ras effector genes in colorectal cancer. Methods: Expression and methylation status of six members of RASSF family genes were examined by RT-PCR and bisulfite-PCR. Tumor suppressor activity of RASSF1 and RASSF2 was examined by colony formation assay and flow cytometry. Immunofluorescence analysis was performed to determine the role of RASSF2 in cell morphology. Mutations of K-ras, BRAF and p53 were determined by single strand conformation analysis and direct sequencing. Results: Aberrant methylation and histone deacetylation of one of the RASSF family genes, RASSF2, is associated with gene silencing in colorectal cancer. RASSF2 shows distinct biological features compared to RASSF1, ability to induce apoptosis, induction of morphological change, and role in preventing cells from transformation, indicating that RASSF2 is a tumor suppressor in colorectal cancer. Colorectal cancer with K-ras / BRAF mutations showed frequent RASSF2 methylation (p=0.0009), and inactivation of RASSF2 enhanced oncogenic transformation effect by K-Ras. RASSF2 methylation was frequently found in colorectal adenomas as well. Conclusions: Taken together, our results provide evidences that RASSF2 is a novel tumor suppressor in the RAS signaling pathway, which plays a critical role in the early step of colorectal tumorigenesis.
Not all hematopoietic growth factors are created equal: should we gain information for their use with immunotherapy?
Authors: Paolo Bossi, Cristina Gurizzan, Luigi Lorini, Pierluigi di Mauro, Chiara Sardini, Marco Merlano
Journal: Journal for ImmunoTherapy of Cancer (2021)

Myeloid growth factors, either granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, are widely used to reduce the incidence and severity of chemotherapy-induced neutropenia by prophylactic or therapeutic administration. However, their activity in the novel therapeutic regimens, which often rely on the association between immunotherapy and chemotherapy, has not been thoroughly characterized yet. This paper presents some of the preclinical and clinical research regarding the putative interplay between myeloid growth factors and the immune system, advocating further studies to elucidate their potential positive or negative consequences on the outcomes when administered with immunotherapeutic agents.
Entinostat induces antitumor immune responses through immune editing of tumor neoantigens
Authors: Andrew S. Truong, Mi Zhou, Bhavani Krishnan, Takanobu Utsumi, Ujjawal Manocha, Kyle G. Stewart, Wolfgang Beck, Tracy L. Rose, Matthew I. Milowsky, Xiaping He, Christof C. Smith, Lisa M. Bixby, Charles M. Perou, Sara E. Wobker, Sean T. Bailey, Benjamin G. Vincent, William Y. Kim
Journal: Journal of Clinical Investigation (2021)

Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti-PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell-autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.