tbuckley/cabot-search huggingface dataset:
Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer
Authors: Lydia Meder, Philipp Schuldt, Martin Thelen, Anna Schmitt, Felix Dietlein, Sebastian Klein, Sven Borchmann, Kerstin Wennhold, Ignacija Vlasic, Sebastian Oberbeck, Richard Riedel, Alexandra Florin, Kristina Golfmann, Hans A. Schlößer, Margarete Odenthal, Reinhard Buettner, Juergen Wolf, Michael Hallek, Marco Herling, Michael von Bergwelt-Baildon, H. Christian Reinhardt, Roland T. Ullrich
Journal: Cancer Research (2018)

Abstract Small cell lung cancer (SCLC) represents the most aggressive pulmonary neoplasm and is often diagnosed at late stage with limited survival, despite combined chemotherapies. We show in an autochthonous mouse model of SCLC that combined anti-VEGF/anti-PD-L1–targeted therapy synergistically improves treatment outcome compared with anti–PD-L1 and anti-VEGF monotherapy. Mice treated with anti–PD-L1 alone relapsed after 3 weeks and were associated with a tumor-associated PD-1/TIM-3 double-positive exhausted T-cell phenotype. This exhausted T-cell phenotype upon PD-L1 blockade was abrogated by the addition of anti-VEGF–targeted treatment. We confirmed a similar TIM-3–positive T-cell phenotype in peripheral blood mononuclear cells of patients with SCLC with adaptive resistance to anti–PD-1 treatment. Mechanistically, we show that VEGFA enhances coexpression of the inhibitory receptor TIM-3 on T cells, indicating an immunosuppressive function of VEGF in patients with SCLC during anti–PD-1-targeted treatment. Our data strongly suggest that a combination of anti-VEGF and anti–PD-L1 therapies can be an effective treatment strategy in patients with SCLC. Significance: Combining VEGF and PD-L1 blockade could be of therapeutic benefit to patients with small cell lung cancer. Cancer Res; 78(15); 4270–81. ©2018 AACR.
Eroded Versus Ruptured Plaques at the Culprit Site of STEMI
Authors: Francesco Saia, Kenichi Komukai, Davide Capodanno, Vasile Sirbu, Giuseppe Musumeci, Giacomo Boccuzzi, Giuseppe Tarantini, Massimo Fineschi, Gabriele Tumminello, Chiara Bernelli, Giampaolo Niccoli, Micol Coccato, Barbara Bordoni, Hiram Bezerra, Giuseppe Biondi-Zoccai, Renu Virmani, Giulio Guagliumi
Journal: JACC. Cardiovascular imaging (2015)
Atezolizumab after Nivolumab-Induced Inflammatory Polyarthritis: Can Anti–PD-L1 Immunotherapy Be Administered after Anti–PD-1–Related Immune Toxicities?
Authors: Umang Swami, Petar Lenert, Muhammad Furqan, Taher Abu Hejleh, Gerald Clamon, Jun Zhang
Journal: Journal of Thoracic Oncology (2018)
Abstract A05: Investigating mechanisms of obesity-mediated pancreatic cancer progression
Authors: Mandar Deepak Muzumdar, Kimberly Judith Dorans, Katherine Minjee Chung, Arjun Bhutkar, Charles Fuchs, Tyler Jacks
Journal: Cancer Research (2018)

Abstract Genetically engineered mouse models (GEMMs) that faithfully recapitulate the genetics and histology of human tumors are an underutilized tool to understand how modifiable risk factors influence tumor development. Prospective cohort studies have shown that obesity is associated with an increased risk of developing pancreatic cancer, more advanced disease at diagnosis, and worse survival, though the precise mechanisms behind which obesity contributes to cancer progression remain elusive. We crossed mice harboring loss-of-function mutations in the leptin gene (ob/ob) with Pdx1-Cre; LSL-KrasG12D (KC) mice predisposed to initiate pancreatic cancers. KC; ob/ob mice are obese and exhibit markedly shortened survival (~4 months vs. ~1 year), increased primary tumor burden, and enhanced progression to adenocarcinoma compared to nonobese KC mice. Interestingly, early correction of leptin deficiency using an adeno-associated virus (AAV)-based approach induces rapid normalization of body weight and hyperglycemia and completely prevents the emergence of enhanced tumor burden. In contrast, late leptin restoration following tumor progression does not impact survival. These data suggest a causal and reversible role for obesity in early pancreatic cancer progression. Furthermore, by evaluating the degree by which alternative interventions phenocopy the effects of leptin restoration, we have developed a model to rapidly interrogate mechanisms of obesity-mediated tumor progression. As a proof of principle, we have tested the ability of immunomodulatory (aspirin) and antidiabetic (metformin) agents, observed to impact pancreatic cancer risk and survival in human cohorts, to intercept cancer progression in this model. Finally, combined molecular and biochemical analyses of tumors reveal increased immune cell activation and fibrosis in KC; ob/ob mice compared to nonobese KC and KC; p53 mutant mice and provide specific molecular targets to evaluate for pancreatic cancer therapy and prevention. Citation Format: Mandar Deepak Muzumdar, Kimberly Judith Dorans, Katherine Minjee Chung, Arjun Bhutkar, Charles Fuchs, Tyler Jacks. Investigating mechanisms of obesity-mediated pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A05.
Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)–LRR oligomerization interface
Authors: Fiona Moghaddas, Ping Zeng, Yuxia Zhang, Heike Schützle, Sebastian Brenner, Sigrun R. Hofmann, Reinhard Berner, Yuanbo Zhao, Bingtai Lu, Xiaoyun Chen, Li Zhang, Suyun Cheng, Stefan Winkler, Kai Lehmberg, Scott W. Canna, Peter E. Czabotar, Ian P. Wicks, Dominic De Nardo, Christian M. Hedrich, Huasong Zeng, Seth L. Masters
Journal: Journal of Allergy and Clinical Immunology (2018)

BackgroundMonogenic autoinflammatory disorders are characterized by dysregulation of the innate immune system, for example by gain-of-function mutations in inflammasome-forming proteins, such as NOD-like receptor family CARD-containing 4 protein (NLRC4).ObjectiveHere we investigate the mechanism by which a novel mutation in the leucine-rich repeat (LRR) domain of NLRC4 (c.G1965C, p.W655C) contributes to autoinflammatory disease. Methods: We studied 2 unrelated patients with early-onset macrophage activation syndrome harboring the same de novo mutation in NLRC4. In vitro inflammasome complex formation was quantified by using flow cytometric analysis of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 techniques and lentiviral transduction were used to generate THP-1 cells with either wild-type or mutant NLRC4 cDNA. Cell death and release of IL-1β/IL-18 were quantified by using flow cytometry and ELISA, respectively.ResultsThe p.W655C NLRC4 mutation caused increased ASC speck formation, caspase-1–dependent cell death, and IL-1β/IL-18 production. ASC contributed to p.W655C NLRC4–mediated cytokine release but not cell death. Mutation of p.W655 activated the NLRC4 inflammasome complex by engaging with 2 interfaces on the opposing LRR domain of the oligomer. One key set of residues (p.D1010, p.D1011, p.L1012, and p.I1015) participated in LRR-LRR oligomerization when triggered by mutant NLRC4 or type 3 secretion system effector (PrgI) stimulation of the NLRC4 inflammasome complex.ConclusionThis is the first report of a mutation in the LRR domain of NLRC4 causing autoinflammatory disease. c.G1965C/p.W655C NLRC4 increased inflammasome activation in vitro. Data generated from various NLRC4 mutations provides evidence that the LRR-LRR interface has an important and previously unrecognized role in oligomerization of the NLRC4 inflammasome complex.Graphical abstract
TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy
Authors: Christopher B. Rodell, Sean P. Arlauckas, Michael F. Cuccarese, Christopher S. Garris, Ran Li, Maaz S. Ahmed, Rainer H. Kohler, Mikael J. Pittet, Ralph Weissleder
Journal: Nature Biomedical Engineering (2018)
Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts
Authors: Ye He, Pei-Suen Tsou, Dinesh Khanna, Amr H Sawalha
Journal: Annals of the Rheumatic Diseases (2018)

Emerging evidence supports a role for epigenetic regulation in the pathogenesis of scleroderma (SSc). We aimed to assess the role of methyl-CpG-binding protein 2 (MeCP2), a key epigenetic regulator, in fibroblast activation and fibrosis in SSc.Dermal fibroblasts were isolated from patients with diffuse cutaneous SSc (dcSSc) and from healthy controls. MeCP2 expression was measured by qPCR and western blot. Myofibroblast differentiation was evaluated by gel contraction assay in vitro. Fibroblast proliferation was analysed by ki67 immunofluorescence staining. A wound healing assay in vitro was used to determine fibroblast migration rates. RNA-seq was performed with and without MeCP2 knockdown in dcSSc to identify MeCP2-regulated genes. The expression of MeCP2 and its targets were modulated by siRNA or plasmid. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) using anti-MeCP2 antibody was performed to assess MeCP2 binding sites within MeCP2-regulated genes.Elevated expression of MeCP2 was detected in dcSSc fibroblasts compared with normal fibroblasts. Overexpressing MeCP2 in normal fibroblasts suppressed myofibroblast differentiation, fibroblast proliferation and fibroblast migration. RNA-seq in MeCP2-deficient dcSSc fibroblasts identified MeCP2-regulated genes involved in fibrosis, including PLAU, NID2 and ADA. Plasminogen activator urokinase (PLAU) overexpression in dcSSc fibroblasts reduced myofibroblast differentiation and fibroblast migration, while nidogen-2 (NID2) knockdown promoted myofibroblast differentiation and fibroblast migration. Adenosine deaminase (ADA) depletion in dcSSc fibroblasts inhibited cell migration rates. Taken together, antifibrotic effects of MeCP2 were mediated, at least partly, through modulating PLAU, NID2 and ADA. ChIP-seq further showed that MeCP2 directly binds regulatory sequences in NID2 and PLAU gene loci.This study demonstrates a novel role for MeCP2 in skin fibrosis and identifies MeCP2-regulated genes associated with fibroblast migration, myofibroblast differentiation and extracellular matrix degradation, which can be potentially targeted for therapy in SSc.
Abstract 20016: Genetic Anticipation in Familial Hypertrophic Cardiomyopathy
Authors: Liwen Liu, Lei Zuo, Chao Sun, Bo Wang, Ruiqi Guo, Fan Yang, Bowen Yu, Menglong Dong, Yanmin Zhang, Yongyong Xu, Lifeng Wang
Journal: Circulation (2015)

Introduction: To identify HCM at the earliest time possible, estimating the onset of disease based on diagnostic criteria is vital in timing the initiation of screening and interventions. Hypothesis: Clinic observations indicate an early diagnose of HCM in second generation of most affected families. From the pedigrees with or without mutations in beta-myosin heavy chain gene (MYH7) affected in two or more generations with hypertrophic cardiomyopathy (HCM), ages and maximal wall thickness (MWT) of left ventricles at diagnosis were evaluated to investigate the potential genetic anticipation in patients with familiar HCM (FHCM). Methods: 56 individuals from 25 families were analyzed. Linear mixed effects models were adopted to prevent misinterpretation resulting from the cohort effect. Published data containing 9 sarcomere mutations (181 individuals in 52 families) also were extracted. Results: MYH7 mutations were detected in 9 of the 25 probands, The median age of HCM diagnosis was 24 in the younger generation and 55 in the older (p &lt; 0.001). In the parametric model, the estimated change in the expected age at diagnosis for the entire cohort was 25.8 years (p &lt;0.001). Statistically significant earlier ages at diagnoses were also observed within subgroups of MYH7+ and MYH7- mutations, and probands older and younger than 30 years old. Although the estimated change in MWT at diagnosis for the entire cohort was only 2.161 mm (p =0.212), the subgroup of probands in the younger generation aged less than 30 years had 10.393 mm (p=0.018) thicker MWT and showed a significant reverse correlation with age. Analysis of published data also supports these findings. Conclusions: Genetic anticipation was observed in patients with FHCM. FHCM is prone to be diagnosed at an earlier age in younger generations. Patients who are younger with relatives affected by HCM, especially those who are diagnosed before 30 years of age, should continue to be tracked to offer appropriate screening modalities as earlier as possible.
The Eyes Have it
Authors: James T. Rosenbaum, Andrew D. Dick
Journal: Arthritis & Rheumatology (2018)

Uveitis is defined as intraocular inflammation. It is an extraarticular manifestation of many forms of joint disease, which include spondyloarthritis, juvenile idiopathic arthritis, and Behçet's disease. Rheumatologists may be asked to consult on the ophthalmologic care of patients with uveitis in order to identify an associated systemic illness. Diagnoses such as spondyloarthritis, sarcoidosis, and interstitial nephritis with uveitis are frequently overlooked by referring ophthalmologists. Alternatively, rheumatologists may be asked to help manage the patient's immunosuppression, including biologic therapy, which can be required to treat a subset of patients with uveitis. This review is intended to provide rheumatologists with the necessary information to facilitate collaboration in the comanagement of patients with uveitis.
Blood Pressure Control—Much Has Been Achieved, Much Remains to Be Done
Authors: Lawrence J. Fine, David C. Goff, George A. Mensah
Journal: JAMA Cardiology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization
Authors: Sujin Kang, Yoshimitsu Nakanishi, Yoshiyuki Kioi, Daisuke Okuzaki, Tetsuya Kimura, Hyota Takamatsu, Shohei Koyama, Satoshi Nojima, Masayuki Nishide, Yoshitomo Hayama, Yuhei Kinehara, Yasuhiro Kato, Takeshi Nakatani, Tomomi Shimogori, Junichi Takagi, Toshihiko Toyofuku, Atsushi Kumanogoh
Journal: Nature Immunology (2018)
Use of Conservative Management for Low-Risk Prostate Cancer in the Veterans Affairs Integrated Health Care System From 2005-2015
Authors: Stacy Loeb, Nataliya Byrne, Danil V. Makarov, Herbert Lepor, Dawn Walter
Journal: JAMA (2018)

This study uses US Department of Veterans Affairs (VA) data to characterize trends in the use of watchful waiting and active surveillance as strategies for managing low-risk prostate cancer in US veterans from 2005 through 2015.
Abstract 18470: The Human Pancreas Contains a Compartment of Insulin-Producing Stem Cells
Authors: Alex Matsuda, Barbara Ogórek, Laura Graciotti, Ewa Wybieralska, Mark A Perrella, Junghyun Kim, Toru Hosoda, Marco Moccetti, Tiziano Moccetti, Marcello Rota, Thomas E Clancy, Xiaoli Liu, Annarosa Leri, Piero Anversa
Journal: Circulation (2016)

Diabetes is a major cause of human heart failure, and despite of the progress made in the control of this illness, a cure able to reverse the process and interfere with its systemic consequences is...
Clinical applications of gut microbiota in cancer biology
Authors: Sunny H. Wong, Thomas N.Y. Kwong, Chun-Ying Wu, Jun Yu
Journal: Seminars in Cancer Biology (2018)

The involvement of microorganisms in cancer has been increasing recognized. Collectively, microorganisms have been estimated to account for ∼20% of all cancers worldwide. Recent advances in metagenomics and bioinformatics have provided new insights on the microbial ecology in different tumors, pinpointing the roles of microorganisms in cancer formation, development and response to treatments. Furthermore, studies have emphasized the importance of host-microbial and inter-microbial interactions in the cancer microbiota. These studies have not only revolutionized our understanding of cancer biology, but also opened up new opportunities for cancer prevention, diagnosis, prognostication and treatment. This review article aims to summarize the microbiota in various cancers and their treatments, and explore clinical applications for such relevance.
Genetic variants in methylation and demethylation pathways to predict clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI/Bev: Data from TRIBE and FIRE-3 trials.
Authors: Alberto Puccini, Fotios Loupakis, Sebastian Stintzing, Martin D. Berger, Ryuma Tokunaga, Madiha Naseem, FRANCESCA BATTAGLIN, Shu Cao, Joshua Millstein, Shivani Soni, Michelle McSkane, Wu Zhang, Volker Heinemann, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

646 Background: DNA hypermethylation in CpG islands (CIMP) has been shown to promote CRC by silencing the expression of tumor suppressor genes. However, global DNA hypomethylation is now considered a common characteristic of CRC. A new family of genes (TET) has been shown to play a crucial role in actively demethylating the DNA. We explored whether genetic polymorphisms in the genes which promote DNA methylation and demethylation are associated with outcome in pts enrolled in TRIBE and FIRE-3 trials. Methods: Genomic DNA from blood samples was genotyped through the OncoArray, a custom array by Illumina including 530K SNP markers. 17 functional SNPs within 11 genes related to methylation (DNMT1/3A/3B, MDM2) and demethylation pathways (TET1/2/3, IDH1/2, MBD4, TDG) were analyzed. Results: A total of 451 pts were included. FOLFIRI/bevacizumab (bev) arms from TRIBE (N = 215, median PFS/OS: 9.7/26.3 months (mts)) and FIRE3 (N = 107, median PFS/OS: 11.6/31.5 mts) served as discovery and validation cohorts respectively. FIRE-3 FOLFIRI/cetuximab arm (N = 129, median OFS/OS: 12.8/49.8 mts) served as control. In the discovery cohort, overall pts carrying TET1 rs3814177 C/C variant showed lower response rate (RR) (42.1% vs 61.8%, p = 0.026) and shorter median PFS (9.5 vs 10.3 mts; HR = 1.54, 95%CI = 1.04-2.27; p = 0.024, univariate analysis) compare to those with any T allele. The effect was more significant among KRAS mutant pts in RR (21.4% vs 60.8%, p = 0.007) and median PFS (8.6 vs 9.5 mts) both in univariate (HR = 2.00, 95%CI = 1.07-3.73; p = 0.020) and multivariable analysis (HR = 2.01, 95%CI = 1.03-3.92 p = 0.041). These findings were validated in overall pts in FIRE-3 cohort in median OS both in univariate (23.7 vs 41.9 mts; HR = 2.08, 95%CI = 1.07-4.05; p = 0.023), and multivariable analysis (HR = 2.36, 95%CI = 1.15-4.81; p = 0.019). No significant association was observed in the control arm. Conclusions: Our results provide the first evidence that TET1 polymorphism may be used as a predictive biomarker in mCRC pts treated with FOLFIRI/bev. Therefore, TET enzymes could serve as promising new treatment targets for mCRC pts.
Association of Low-Fat Dietary Pattern With Breast Cancer Overall Survival
Authors: Rowan T. Chlebowski, Aaron K. Aragaki, Garnet L. Anderson, Michael S. Simon, JoAnn E. Manson, Marian L. Neuhouser, Kathy Pan, Marcia L. Stefanick, Thomas E. Rohan, Dorothy Lane, Lihong Qi, Linda Snetselaar, Ross L. Prentice
Journal: JAMA Oncology (2018)

<h3>Importance</h3> In a randomized clinical trial, a low-fat eating pattern was associated with lower risk of death after breast cancer. However, the extent to which results were driven by dietary influence on survival after breast cancer diagnosis was unknown. <h3>Objective</h3> To determine the association of a low-fat dietary pattern with breast cancer overall survival (breast cancer followed by death from any cause measured from cancer diagnosis). <h3>Design, Setting, and Participants</h3> This is a secondary analysis of the Women's Health Initiative randomized clinical trial that was conducted at 40 US clinical centers enrolling participants from 1993 through 1998. Participants were 48 835 postmenopausal women with no previous breast cancer and dietary fat intake of greater than 32% by food frequency questionnaire. <h3>Interventions</h3> Participants were randomized to a dietary intervention group (40%; n = 19 541) with goals to reduce fat intake to 20% of energy and increase fruit, vegetable, and grain intake or a usual-diet comparison group (60%; n = 29 294). Dietary group participants with incident breast cancers continued to participate in subsequent dietary intervention activities. <h3>Main Outcomes and Measures</h3> Breast cancer overall survival for incident breast cancers diagnosed during the 8.5-year (median) dietary intervention, examined in post hoc analyses after 11.5 years (median) postdiagnosis follow-up. <h3>Results</h3> Of 1764 women diagnosed with breast cancer during the dietary intervention period, mean (SD) age at screening was 62.7 (6.7) years and age at diagnosis was 67.6 (6.9) years. With 516 total deaths, breast cancer overall survival was significantly greater for women in the dietary intervention group than in the usual-diet comparison group (10-year survival of 82% and 78%, respectively; hazard ratio [HR], 0.78; 95% CI, 0.65-0.94;<i>P</i> = .01). In the dietary group there were fewer deaths from breast cancer (68 vs 120; HR, 0.86; 95% CI, 0.64-1.17), other cancers (36 vs 65; HR, 0.76; 95% CI, 0.50-1.17), and cardiovascular disease (27 vs 64; HR, 0.62; 95% CI, 0.39-0.99). <h3>Conclusions and Relevance</h3> In women who received a diagnosis of breast cancer during the dietary intervention period, those in the dietary group had increased overall survival. The increase is due, in part, to better survival from several causes of death. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT00000611