tbuckley/cabot-search huggingface dataset:
Abstract 5796: Modulation of transcription factor landscape through BET family protein inhibition is dependent on specific driver mutations in pancreatic cancer
Authors: Mikele G. Weldon, Albert R. Wang, Hope A. Beyer, Shannon G. Stiles, Gopal Iyer
Journal: Cancer Research (2018)

Abstract Targeting of bromodomain and extra-terminal domain (BET) family protein activity has the potential to reduce proliferation in many cancers. However, changes in transcription factor (TF) landscape can be influenced by different mutational profiles of specific cancers. Within this mutational background, BET proteins can target these TFs and create an oncogenic phenotype. To exploit these altered TF readouts, we tested the hypothesis that inhibition of BET activity in different genetic mutations of pancreatic cancer will lead to antiproliferative effects. Towards this, we treated pancreatic cancer cell lines that had mutations in KRAS, CDKN1A, SMAD4 and TP53 with a bromodomain inhibitor. We showed that cell lines with CDKN1A deletion and wild-type SMAD4 were highly resistant to BET inhibition and had a high nanomolar IC50 concentration. Through targeted transcription factor gene expression profiling of over 400 TFs, we discovered that LMO2, GTF2B, ID1, and CREB1 were upregulated, while SALL4, TCF4, and TP63 were downregulated in these cell lines. This suggests that these TFs may be partly responsible for resistance to BET inhibition. Furthermore, we showed dramatic changes in TF landscapes in pancreatic cancer cells sensitive to BET treatment compared to the resistant cells. This indicates that for antiproliferative effects in pancreatic cancer cells, modulating BET activity may be necessary to switch on or off specific TFs. Together, these results suggest that BET inhibitors may be useful in pancreatic cancer treatment and that mutation-specific differences in TF targets of BETs may dictate the progression of pancreatic cancer. Citation Format: Mikele G. Weldon, Albert R. Wang, Hope A. Beyer, Shannon G. Stiles, Gopal Iyer. Modulation of transcription factor landscape through BET family protein inhibition is dependent on specific driver mutations in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5796.
Abstract 2751: Regorafenib attenuates IFN-γ-induced PD-L1 expression and enhances antitumor immunity
Authors: Xiao-Feng Zhu
Journal: Cancer Research (2018)

Abstract Immune checkpoint blocked therapy (ICB) targeting the PD-1/PD-L1 axis induce durable tumor regressions in a sizeable minority of cancer patients. To enhance the efficacy of existing immunotherapies, we implemented a screen of kinase inhibitors capable of increasing the activity of T cells suppressed by PD-L1. Here, we identified regorafenib, which was approved to treat patients with advanced gastrointestinal stromal tumors and metastatic colorectal cancer, as a potent agent significantly attenuating IFN-γ-induced PD-L1 expression without affecting MHC-I expression, contributing to enhanced anti-tumor effects with ICB in vitro and in vivo, due in part to inhibit JAK1/2-STAT1 signaling and the activation of ERK by suppressing the tyrosine kinase receptor RET-Src axis. Additionally, our analysis of GEO database and TCGA database revealed that RET and Src co-high expression was an independent unfavorable prognosis factor in both melanoma patients with or without ICB via inhibiting anti-tumor immune response. Further, gene set enrichment analysis (GSEA) demonstrated, compared to RET and Src co-high expression group, anti-tumor immune response related gene signatures as prominent modules in other group. Collectively, our data unveiled a new mechanism of reducing IFN-γ-induced PD-L1 expression and provided a rationale to explore a new combination of immunotherapies and regorafenib in melanoma treatment. Citation Format: Xiao-Feng Zhu. Regorafenib attenuates IFN-γ-induced PD-L1 expression and enhances antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2751.
Wt1 and Epicardial Fate Mapping
Authors: CarstenRudat, AndreasKispert
Journal: Circulation Research (2012)

Rationale:The embryonic epicardium is a crucial cell source of the cardiac fibrous skeleton as well as of the coronary system. Genetic lineage tracing systems based on Wt1 regulatory sequences provided evidence that epicardium-derived cells also adopt a myocardial fate in the mouse. Objective:To define the adequacy of Wt1-based lineage tracing systems for epicardial fate mapping. Methods and Results:Using in situ hybridization analysis and immunofluorescence on tissue sections, we detected endogenous expression of Wt1 mRNA and Wt1 protein in the proepicardium and epicardium and also in endothelial cells throughout cardiogenesis. Expression analysis of a sensitive GFP reporter showed that recombination mediated by cre recombinase in the Wt1creEGFP line occurs randomly and sporadically in all cells of the embryo. Recombination in cardiomyocytes was found in the linear heart tube before establishment of a (pro)epicardium. In contrast, the tamoxifen-inducible Wt1creERT2 mouse line mediated poor and variable r...
Agonist-Induced Activation of Matrix Metalloproteinase-7 Promotes Vasoconstriction Through the Epidermal Growth Factor–Receptor Pathway
Authors: LiHao, MinDu, AnaLopez-Campistrous, CarlosFernandez-Patron
Journal: Circulation Research (2004)

Matrix metalloproteinase (MMP)-dependent shedding of heparin-binding epidermal growth factor (HB-EGF) and subsequent activation of the EGF receptor (EGFR) in the cardiovasculature is emerging as a unique mechanism signaling growth effects of diverse G protein–coupled receptors (GPCRs). Among these GPCRs are adrenoceptors and angiotensin receptors that contribute to the pathogenesis of hypertension through their vasoconstrictive and growth effects. Focusing on α1b-adrenoceptors, we suggest here that MMP-dependent activation of the EGFR promotes vasoconstriction as well as growth. We identified MMP-7 as a major HB-EGF sheddase in rat mesenteric arteries and α1b-adrenoceptors, angiotensin receptors, and hypertension-stimulated MMP-7 activity. Adrenoceptors stimulated EGFR autophosphorylation in arteries, and this transactivation was opposed by the MMP-7 inhibitor GM6001 as well as MMP-7–specific antibodies. In isolated microperfused arteries, blockade of EGFR transactivation with inhibitors of the EGFR (AG14...
Abstract 16828: Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-based Studies From 90 Countries
Authors: Katherine T Mills, Joshua D Bundy, Tanika N Kelly, Jennifer Reed, Patricia M Kearney, Kristi Reynolds, Jing Chen, Jiang He
Journal: Circulation (2015)

Introduction: Hypertension is the leading preventable cause of premature death worldwide. We aimed to examine the global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compare secular changes in these disparities from 2000 to 2010. Methods: We searched MEDLINE from January 1995 to December 2014 and supplemented with manual searches of references from retrieved articles. A total of 135 population-based studies with 968,419 individuals aged ≥20 years from 90 countries were included. Sex-age-specific prevalences of hypertension from each country were applied to population data to calculate the number of hypertensive adults in each region and globally. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates. Results: An estimated 30.2% (95% confidence interval, 30.1-30.4%) of the world’s adult population in 2010 had hypertension; 28.6% (28.3-28.9%) in high-income countries and 30.3% (30.1-30.5%) in low- and middle-income countries. An estimated 1.35 billion (1.34-1.36 billion) people had hypertension in 2010; 349 million (339-359 million) in high-income and 1.00 billion (0.99-1.01 billion) in low- and middle-income countries. From 2000 to 2010, age-standardized prevalence of hypertension decreased by 2.3% in high-income countries but increased by 6.1% in low- and middle-income countries. During the same period, the proportions of awareness (56.6% vs 68.8%), treatment (42.9% vs 56.1%), and control (16.6% vs. 28.9%) increased substantially in high-income countries, whereas awareness (34.7% vs 35.1%), treatment (23.4% vs 26.4%), and control (7.0% vs 7.8%) increased only slightly in low- and middle-income countries. Conclusions: Global disparities in hypertension prevalence, awareness, treatment, and control are large and increasing. Collaborative efforts from national and international stakeholders are urgently needed to combat the emerging hypertension burden in low- and middle-income countries.
Coronary Microvascular Dysfunction and Cardiovascular Risk in Obese Patients
Authors: Navkaranbir S. Bajaj, Michael T. Osborne, Ankur Gupta, Ali Tavakkoli, Paco E. Bravo, Tomas Vita, Courtney F. Bibbo, Jon Hainer, Sharmila Dorbala, Ron Blankstein, Deepak L. Bhatt, Marcelo F. Di Carli, Viviany R. Taqueti
Journal: Journal of the American College of Cardiology (2018)
Soil exposure modifies the gut microbiota and supports immune tolerance in a mouse model
Authors: Noora Ottman, Lasse Ruokolainen, Alina Suomalainen, Hanna Sinkko, Piia Karisola, Jenni Lehtimäki, Maili Lehto, Ilkka Hanski, Harri Alenius, Nanna Fyhrquist
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 3600: Early detection of esophageal adenocarcinoma using near-infrared lectin-based imaging
Authors: Andre A. Neves, Massimiliano Di Pietro, Maria O'Donovan, Dale J. Waterhouse, Sarah E. Bohndiek, Kevin M. Brindle, Rebecca C. Fitzgerald
Journal: Cancer Research (2018)

Abstract Background: Long procedure times and sampling error frequently limit the efficacy of endoscopic surveillance for Barrett's esophagus (BE). Near-infrared (NIR) fluorescence imaging minimizes optical scattering and tissue autofluorescence. We assessed, in an ex vivo setting, the feasibility of using a topically applied NIR dye-labeled lectin for the detection of early neoplasia in BE. Methods: We recruited consecutive patients undergoing endoscopic mucosal resection (EMR) for BE-related early neoplasia. EMR specimens were freshly collected and sprayed at the bedside with a fluorescent lectin and then imaged ex vivo. A maximum of two punch biopsies were collected from each EMR under NIR light guidance. Fluorescence intensity from dysplastic and nondysplastic areas within EMRs were compared and from punch biopsies with different histological grades. Results: We analyzed 29 EMR specimens from 17 patients. Dysplastic regions showed significantly lower fluorescence across whole EMR specimens (P &amp;lt; 0.001). A 41% reduction in fluorescence was found for dysplastic compared to nondysplastic punch biopsies (P &amp;lt; 0.001), with a sensitivity and specificity for dysplasia detection of 80% and 82.9%, respectively. Conclusion: NIR imaging using fluorescently-labeled lectins can distinguish dysplastic from nondysplastic Barrett's mucosa ex vivo. We are currently planning a first-in-human study to validate this imaging platform. Citation Format: Andre A. Neves, Massimiliano Di Pietro, Maria O'Donovan, Dale J. Waterhouse, Sarah E. Bohndiek, Kevin M. Brindle, Rebecca C. Fitzgerald. Early detection of esophageal adenocarcinoma using near-infrared lectin-based imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3600.
Abstract 18374: Targeted Sequencing and Massively Parallel Reporter Assay Identify the Functional Variation Underlying the 4q25 Locus for Atrial Fibrillation
Authors: Nathan R Tucker, Jiangchuan Ye, Honghuang Lin, Michael A McLellan, Emelia J Benjamin, Kathryn L Lunetta, Tarjei S Mikkelsen, Steven A Lubitz, Patrick T Ellinor
Journal: Circulation (2015)

Introduction: Genome-wide association studies have identified 14 independent loci for atrial fibrillation (AF). The 4q25 locus upstream of the left-right asymmetry gene PITX2 is, by far, the strongest association signal for AF. However, as with most GWAS loci, the functional variants are noncoding, presumed to be regulatory, and remain unknown. We therefore sought to rapidly identify the functional variants at an AF locus by combining high throughput sequencing and massively parallel reporter assays. Methods and Results: We sequenced a ~750kb region encompassing the PITX2 locus in 462 individuals with early-onset AF from the MGH AF Study and 464 referents from the Framingham Heart Study. The SNP most significantly associated with AF in our sequenced sample was rs2129983, which is 140kb from PITX2 (OR=2.43, P =8.9X10 -16 ). rs2129983 is approximately 1.7kb from the most significantly associated SNP in a prior AF GWAS, rs6817105 (r 2 =0.52). From the targeted sequencing analysis, we identified 262 SNVs with a MAF &gt;0.5% within a genomic region bounded by SNPs with an r2 greater than 0.4 with the top variant. To identify functional variants, we then utilized a massively parallel reporter assay (MPRA) in order to measure enhancer activity at each SNP across the entire AF locus. In both HL-1 and C2C12 myoblasts, MPRA identified many distinct SNP regions with differential enhancer activity. Using AF-association status as a standard, we were able to identify a series of variants that have both differential activity in either cell line tested and also a high level of association (rs17042076, rs4469143). Mechanistically, these functional SNPs are predicted to alter transcription factor binding. Conclusions: We have comprehensively identified the AF-associated variation at 4q25 and determined which of these variants are functional through differential enhancer activity. Here, in addition to identifying the causative variation for AF at 4q25, we provide a generalizable pathway for translating this work to other loci, a method that could expedite the identification of causative genetic variants at other disease loci.
Letter by Lozano et al Regarding Articles, “Transcatheter Valve-in-Valve Implantation for Failed Bioprosthetic Heart Valves” and “Percutaneous Therapy for Valvular Heart Disease: A Huge Advance and a Huge Challenge to Do It Right”
Authors: IñigoLozano, DavidCalvo, JuanRondan
Journal: Circulation (2011)
Abstract 13181: Characteristics of Diurnal Change of Pulse Rate in Resistant Hypertension
Authors: HiroakiWatanabe, TomoyukiKabutoya, SatoshiHoshide, KazuoEguchi, KazuomiKario
Journal: Circulation (2014)

Introduction: Sympathetic hyperactivity is one of the most important causes of resistant hypertension. Ambulatory blood pressure monitoring (ABPM) allows measurement of blood pressure (BP) and pulse rate (PR) throughout the day, as well as measurement of diurnal variations in BP and PR, which are controlled by the autonomic nervous system. Hypothesis: We hypothesized that abnormal diurnal change of BP and PR are associated with resistant hypertension. Methods: We evaluated 1003 patients with hypertension who were enrolled in the Japan Morning Surge Home Blood Pressure Study and were using ABPM. Resistant hypertension was defined as clinic BP≧140/90 mmHg despite the use of optimal doses of 3 classes of antihypertensive drugs, including a diuretic. BP or PR dipper status was defined as (awake systolic BP (SBP) or PR-sleep SBP or PR)/awake SBP or PR ≧0.1. BP or PR nondipper status was defined as (awake SBP or PR-sleep SBP or PR)/awake SBP or PR <0.1 and ≧0. BP and PR riser status were defined as awake SBP or...
Nationwide Improvements in Survival From Out-of-Hospital Cardiac Arrest in Japan
Authors: TetsuhisaKitamura, TakuIwami, TakashiKawamura, MasahikoNitta, KenNagao, HiroshiNonogi, NaohiroYonemoto, TakeshiKimura
Journal: Circulation (2012)

Background—Little is known about the nationwide trend in the survival of out-of-hospital cardiac arrest (OHCA) in Japan and the differences in incidence and survival by age group and origin of arrest. Methods and Results—A nationwide, prospective, population-based observation covering the whole population of Japan and involving consecutive OHCA patients with resuscitation attempts was conducted from January 2005 to December 2009. The main outcome measure was 1-month survival with favorable neurological outcome. The nationwide trends in OHCA incidence and outcome by age and origin of arrest were assessed. Multiple logistic regression analysis for bystander-witnessed OHCA was used to adjust for factors that were potentially associated with favorable neurological outcome. During 5 years, 547 153 overall OHCAs and 169 360 bystander-witnessed OHCAs were enrolled. The annual incidence significantly increased among overall OHCAs and bystander-witnessed OHCAs. Neurologically favorable survival significantly incre...
Echocardiographic Speckle-Tracking Based Strain Imaging for Rapid Cardiovascular Phenotyping in Mice
Authors: MichaelBauer, SusanCheng, MohitJain, SoeunNgoy, CatherineTheodoropoulos, AnnaTrujillo, Fen-ChiungLin, RonglihLiao
Journal: Circulation Research (2011)

Rationale:High-sensitivity in vivo phenotyping of cardiac function is essential for evaluating genes of interest and novel therapies in small animal models of cardiovascular disease. Transthoracic echocardiography is the principal method currently used for assessing cardiac structure and function; however, standard echocardiographic techniques are relatively insensitive to early or subtle changes in cardiac performance, particularly in mice. Objective:To develop and validate an echocardiographic strain imaging methodology for sensitive and rapid cardiac phenotyping in small animal models. Methods and Results:Herein, we describe a modified echocardiographic technique that uses speckle-tracking based strain analysis for the noninvasive evaluation of cardiac performance in adult mice. This method is found to be rapid, reproducible, and highly sensitive in assessing both regional and global left ventricular (LV) function. Compared with conventional echocardiographic measures of LV structure and function, peak...
National Surgical, Obstetric, and Anesthesia Planning in the Context of Global Surgery
Authors: Kristin A. Sonderman, Isabelle Citron, John G. Meara
Journal: JAMA Surgery (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 Surgery 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 Surgery journal
Angiotensin-Converting Enzyme Inhibition Restores Flow-Dependent and Cold Pressor Test–Induced Dilations in Coronary Arteries of Hypertensive Patients
Authors: IsabelleAntony, GuyLerebours, AlainNitenberg
Journal: Circulation (1996)

Background Cold pressor test (CPT)–induced and flow-dependent epicardial coronary artery dilations are impaired in patients with hypertension. ACE inhibition can attenuate sympathetic coronary constriction and potentiate or restore endothelium-dependent relaxations. This study was designed to determine whether the ACE inhibitor perindoprilat can restore normal coronary dilative responses in hypertensive patients. Methods and Results Coronary vasomotor responses to CPT and to maximal increase of blood flow induced by papaverine were studied in 10 untreated patients with essential hypertension, no other risk factors, and angiographically normal coronary arteries before and after intravenous ACE inhibition by perindoprilat. Diameters of proximal and distal left anterior descending (LAD) and circumflex coronary arteries were measured by quantitative angiography. Estimates of coronary blood flow and resistance index were calculated with an intracoronary Doppler catheter in the distal LAD. Perindoprilat did not...
Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis
Authors: Guido Carpino, Vincenzo Cardinale, Trine Folseraas, Diletta Overi, Krzysztof Grzyb, Daniele Costantini, Pasquale Bartolomeo Berloco, Sabina Di Matteo, Tom Hemming Karlsen, Domenico Alvaro, Eugenio Gaudio
Journal: Hepatology (2018)

Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholangiopathy frequently complicated by cholangiocarcinoma (CCA). Massive proliferation of biliary tree stem/progenitor cells (BTSCs), expansion of peribiliary glands (PBGs), and dysplasia were observed in PSC. The aims of the present study were to evaluate the involvement of PBGs and BTSCs in CCA which emerged in PSC patients. Specimens from normal liver (n = 5), PSC (n = 20), and PSC‐associated CCA (n = 20) were included. Samples were processed for histology, immunohistochemistry, and immunofluorescence. In vitro experiments were performed on human BTSCs, human mucinous primary CCA cell cultures, and human cholangiocyte cell lines (H69). Our results indicated that all CCAs emerging in PSC patients were mucin‐producing tumors characterized by PBG involvement and a high expression of stem/progenitor cell markers. Ducts with neoplastic lesions showed higher inflammation, wall thickness, and PBG activation compared to nonneoplastic PSC‐affected ducts. CCA showed higher microvascular density and higher expression of nuclear factor kappa B, interleukin‐6, interleukin‐8, transforming growth factor β, and vascular endothelial growth factor‐1 compared to nonneoplastic ducts. CCA cells were characterized by a higher expression of epithelial‐to‐mesenchymal transition (EMT) traits and by the absence of primary cilia compared to bile ducts and PBG cells in controls and patients with PSC. Our in vitro study demonstrated that lipopolysaccharide and oxysterols (PSC‐related stressors) induced the expression of EMT traits, the nuclear factor kappa B pathway, autophagy, and the loss of primary cilia in human BTSCs. Conclusion : CCA arising in patients with PSC is characterized by extensive PBG involvement and by activation of the BTSC niche in these patients, the presence of duct lesions at different stages suggests a progressive tumorigenesis.