tbuckley/cabot-search huggingface dataset:
Angiotensin II Activates Collagen Type I Gene in the Renal Vasculature of Transgenic Mice During Inhibition of Nitric Oxide Synthesis
Authors: Jean-JacquesBoffa, Pierre-LouisTharaux, SandrinePlacier, RaymondArdaillou, Jean-ClaudeDussaule, ChristosChatziantoniou
Journal: Circulation (1999)

Background—Hypertension is frequently associated with renal vascular fibrosis. The purpose of this study was to investigate whether angiotensin II (Ang II) is involved in this fibrogenic process. Methods and Results—Experiments were performed on transgenic mice harboring the luciferase gene under the control of the collagen I-α2 chain promoter [procolα2(I)]. Hypertension was induced by chronic inhibition of NO synthesis (NG-nitro-l-arginine methyl ester, L-NAME). Procolα2(I) activity started to increase in the renal vasculature after 4 weeks of L-NAME treatment (P<0.01) and at 14 weeks reached 3- and 8-fold increases over control in afferent arterioles and glomeruli, respectively (P<0.001). Losartan, an AT1 receptor antagonist, given simultaneously with L-NAME prevented the increase of procolα2(I) levels and attenuated the development of renal vascular fibrosis without normalizing systolic pressure increase. Because we found previously that endothelin mediated renal vascular fibrosis in the L-NAME model, ...
Abstract 236: Identification of novel cancer target genes by combining data from the cancer genome-wide association studies (GWAS), regulatory DNA elements and The Cancer Genome Atlas (TCGA)
Authors: Diptee A. Kulkarni, Karl Guo, Junping Jing, Mugdha Khaladkar, Kijoung Song, Coco Dong, David Cooper, Benjamin Schwartz
Journal: Cancer Research (2018)

Abstract Unlike tumors that develop because of somatic genetic alterations such as frequent coding mutations or chromosomal deletions, amplifications or translocations, some tumors are addicted to expression of certain genes for their sustained proliferation and survival - for example, LIM domain only 1 (LMO1) expression in neuroblastoma (NB). Numerous genome-wide association studies (GWAS) have identified significant associations between germline single-nucleotide polymorphisms (SNPs), many in the non-coding genome, and cancer. A robust genome-wide association has been reported previously between an intronic LMO1 SNP and NB susceptibility. By further sequencing and epigenetic fine mapping of the SNP locus, it was demonstrated that the causal SNP is part of a transcription factor binding site within an enhancer element, regulates expression of LMO1 and in turn increases the tumorigenic potential. To identify additional examples of regulatory SNPs as cancer drivers, we overlaid published genome-wide significant cancer associations with active chromatin marks from Encyclopedia of DNA Elements and searched for SNPs that resided within gene regulatory elements. To map these SNPs to candidate genes and determine direction of effect, we co-localized GWAS signals with expression quantitative trait (eQTL) signals from the Genotype-Tissue Expression (GTEx) Consortium database. Lastly, we checked for gene amplification and/or overexpression of the mapped genes in the Cancer Genome Atlas (TCGA) data to identify a set of target genes that not only exhibit significant cancer association in GWAS, but also have evidence for epigenetic regulation and propensity for amplification and/or overexpression in tumors. We identified more than 25 novel cancer-target pairs with strong germline, regulatory and somatic evidence. A look up through synthetic lethality screen data available in-house suggested that several of these targets are self-lethal, further underscoring their importance for cancer cell proliferation and survival. Additional in vitro experiments are being planned to further validate the targets. Citation Format: Diptee A. Kulkarni, Karl Guo, Junping Jing, Mugdha Khaladkar, Kijoung Song, Coco Dong, David Cooper, Benjamin Schwartz. Identification of novel cancer target genes by combining data from the cancer genome-wide association studies (GWAS), regulatory DNA elements and The Cancer Genome Atlas (TCGA) [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 236.
Dynamic Responses of Single Cardiomyocytes to Graded Ischemia Studied by Oxygen Clamp in On-Chip Picochambers
Authors: VladimirGanitkevich, SibylleReil, BrigittaSchwethelm, ThomasSchroeter, KlausBenndorf
Journal: Circulation Research (2006)

Single mouse cardiomyocytes were exposed to defined ischemia. We designed chambers on glass chips with a volume of 192 pL (picochambers). After a picochamber was loaded with a single cardiomyocyte, Po2 in the picochamber was equilibrated with that in the headspace, where it was controlled in the critical range between <0.2 and 10 mm Hg. Because the extracellular fluid volume in a picochamber was restricted, these conditions are close to tissue ischemia. Responses of the sarcolemmal KATP-channel current (IKATP), the production of reactive oxygen species (ROS), and the mitochondrial membrane potential (Δψ) of single cardiomyocytes to graded ischemia and, in particular, to rapid changes of the ischemic grade by defined oxygen steps were studied. The results show that IKATP is readily activated during ischemia and that the grade of ischemia tightly controls the amplitude of IKATP. Furthermore, maximal ischemia-induced IKATP was similar when it followed either reoxygenation or reperfusion, suggesting that ther...
Ezh2 loss propagates hypermethylation at T cell differentiation–regulating genes to promote leukemic transformation
Authors: Changshan Wang, Motohiko Oshima, Daisuke Sato, Hirotaka Matsui, Sho Kubota, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Shuhei Koide, Jun Matsubayashi, Makiko Mochizuki-Kashio, Takako Nakano-Yokomizo, Jie Bai, Toshitaka Nagao, Akinori Kanai, Atsushi Iwama, Goro Sashida
Journal: Journal of Clinical Investigation (2018)

Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a new pathological entity with poor outcomes in T cell ALL (T-ALL) that is characterized by a high incidence of loss-of-function mutations in polycomb repressive complex 2 (PRC2) genes. We generated a mouse model of ETP-ALL by deleting Ezh2, one of the PRC2 genes, in p53-null hematopoietic cells. The loss of Ezh2 in p53-null hematopoietic cells impeded the differentiation of ETPs and eventually induced ETP-ALL-like disease in mice, indicating that PRC2 functions as a bona fide tumor suppressor in ETPs. A large portion of PRC2 target genes acquired DNA hypermethylation of their promoters following reductions in H3K27me3 levels upon the loss of Ezh2, which included pivotal T cell differentiation-regulating genes. The reactivation of a set of regulators by a DNA-demethylating agent, but not the transduction of single regulator genes, effectively induced the differentiation of ETP-ALL cells. Thus, PRC2 protects key T cell developmental regulators from DNA hypermethylation in order to keep them primed for activation upon subsequent differentiation phases, while its insufficiency predisposes ETPs to leukemic transformation. These results revealed a previously unrecognized epigenetic switch in response to PRC2 dysfunction and provide the basis for specific rational epigenetic therapy for ETP-ALL with PRC2 insufficiency.
Abstract 12520: Senescence Marker Protein-30 Deficiency Impairs Collateral Growth Under Ischemia in Aging
Authors: Hiroyuki Yamauchi, Shu-ichi Saitoh, Takashi Owada, Shinya Yamada, Yasuchika Takeishi
Journal: Circulation (2013)

Aging causes collateral rarefaction, however underlying mechanism is unknown. Senescence marker protein-30 (SMP30) decreases with aging. Mice with SMP30 deficiency, a model of aging, have a short l...
Abstract 5623: Development of a CD47-blocking antibody as a cancer therapy
Authors: Joshua Oaks, Ming Wang, Hui Zou
Journal: Cancer Research (2018)

Abstract Immune system avoidance by cancer cells is controlled through a variety of mechanisms such as CTLA-4 and PD-1/L1, which inhibit the T-cell mediated adaptive immune response to cancer. Similar mechanisms exist for evasion from innate immunity, for example, through CD47 overexpression. On healthy cells, CD47 serves as a “don't eat me” signal by the binding to the transmembrane SIRPα protein on phagocytic cells, and prevents the engulfment of “self” by macrophages. In several cancer types, tumor cells overexpress CD47 to elude the immune system. This property of CD47 makes it an attractive target for cancer treatment. Here we describe a humanized monoclonal antibody that is a potent disruptor of the CD47/SIRPα interaction and therefore presents itself as a potential therapeutic anti-CD47 antibody. This antibody binds robustly to recombinant extracellular domains (ECD) of human and cynomolgus CD47, and to full-length human and cynomolgus CD47 expressed on HEK293 cells. Functionally, it blocks the CD47/SIRPα interaction in an ELISA-based assay with an IC50 of single-digit nM. In a cell-based assay, effect on phagocytosis by this antibody was assessed. In addition, disruption of the TSP-1/CD47 interaction has been postulated to have positive outcomes in cancer therapy and the efficacy of this antibody on inhibiting this interaction is also investigated. Finally, the effect of the antibody on Raji human Burkitt's lymphoma xenograft growth in mice will be presented. A concern with anti-CD47 therapy is the undesired targeting of red blood cells (RBCs). This antibody does not induce marked hemagglutination, suggesting a limited impact on RBCs. Taken together, our data suggest that we have developed a novel, humanized anti-CD47 antibody that can restore immune system targeting of cancer cells without inducing significant RBC agglutination. Citation Format: Joshua Oaks, Ming Wang, Hui Zou. Development of a CD47-blocking antibody as a cancer therapy [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 5623.
Receptor-Interacting Protein Kinase 3 Contributes to Abdominal Aortic Aneurysms via Smooth Muscle Cell Necrosis and Inflammation
Authors: QiweiWang, ZhenjieLiu, JunRen, StephanieMorgan, CarmelAssa, BoLiu
Journal: Circulation Research (2015)

Rationale:Depletion of medial smooth muscle cell (SMC) is a major pathological characteristic of abdominal aortic aneurysm (AAA), although the mechanism by which these cells are eliminated remains incompletely understood. We reasoned that necroptosis, a recently described form of necrosis mediated by receptor-interacting protein kinase 3 (RIP3), may contribute to AAA pathology through the induction of SMC death and the significant production of inflammatory cytokines. Objective:To test the hypothesis that RIP3-mediated necroptosis is actively involved in aneurysm pathogenesis. Methods and Results:RIP3 and RIP1 levels were found to be elevated in human AAAs, most noticeably in SMCs. Elevations of RIP3 and SMC necrosis were also observed in the elastase-induced mouse model of AAAs. Deletion of one or both copies of Rip3 prevented AAA formation. By transplanting Rip3+/− aortae to Rip3+/+ mice, we demonstrated that reduced Rip3 expression in arterial wall was the primary cause of aneurysm resistance. In vitro...
Nuclear magnetic resonance-based metabolomics in respiratory medicine
Authors: Debora Paris, Mauro Maniscalco, Andrea Motta
Journal: European Respiratory Journal (2018)

Metabolomics investigates the chemical end products of biological processes in living systems. It combines high-throughput analytical techniques with bioinformatics to investigate and quantify, in a global (untargeted) and/or specific (targeted) manner, the metabolites present in living systems in response to any exposure (including therapeutics), lifestyle, environmental and genetic stress [1]. The unique profile obtained can provide direct information on a physiological status or on a sequence of events in an organism. Since the metabolome ( i.e. all the endogenous metabolites of molecular weight <1500 Da) is a downstream system of the proteome and transcriptome it is amplified covering several aspects of a pathology [2]. Therefore, selection of an appropriate biomatrix (exhaled breath condensate (EBC), urine, serum, plasma, bronchoalveolar lavage fluid (BALF), saliva or cell and tissue extracts) can shed light on several fields of medicine. In the near future, NMR-based metabolomics will become a valid means of support for pulmonary personalised and precision medicine <http://ow.ly/CXOT30lpGUr>
Abstract 2044: Lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) modulates VEGF-C and VEGF-D secretion in the triple negative breast cancer cell line MDA-MB-231
Authors: Sara Caceres, Andrew C. Little, Joel A. Yates, Rabia A. Gilani, Sofia D. Merajver
Journal: Cancer Research (2018)

Abstract Breast cancer commonly gives rise to lymph node metastases, and it has been suggested that tumor cell migration is facilitated by the generation of new lymphatic vessels, or lymphangiogenesis. Lymphatic endothelial cell hyaluronic acid receptor 1 (LYVE-1) is a hyaluronic acid (HA) receptor commonly used as a lymphatic vessel endothelial marker. LYVE-1 has been observed in a variety of breast cancer epithelial cells, and its lymphangiogenic function remains unclear. LYVE-1 has been casually linked to the vascular endothelial growth factors VEGF-C and VEGF-D, which are well appreciated for their roles in lymphangiogenic responses. Therefore, we hypothesize that LYVE-1 may impact lymphangiogensis via a VEGF-C/VEGF-D mediated pathway. We utilized LYVE-1-targeted RNAi in MDA-231 cells followed by HA stimulation and measured production and secretion of both VEGF-C and VEGF-D by western blot and ELISA, respectively. Surprisingly, LYVE-1 knockdown resulted in elevated levels of basal VEGF-C secretion, while LYVE-1 knockdown followed by HA stimulation decreased secreted levels of VEGF-C, with no observed changes in intracellular levels when compared to their controls. Conversely, LYVE-1 knockdown displayed no significant changes in basal VEGF-D levels, although, secreted VEGF-D levels were elevated following HA stimulation. Collectively, our preliminary findings suggest that LYVE-1 modulates VEGF-C/D secretion, potentially defining a novel function for LYVE-1 in MDA-231 triple negative breast cancer epithelial cells. Citation Format: Sara Caceres, Andrew C. Little, Joel A. Yates, Rabia A. Gilani, Sofia D. Merajver. Lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) modulates VEGF-C and VEGF-D secretion in the triple negative breast cancer cell line MDA-MB-231 [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 2044.
Abstract 19818: Coronary CT Angiography for Suspected Acute Coronary Syndrome in the Era of High-Sensitivity Troponins - A Randomized Multicenter Study
Authors: Admir Dedic, Jeroen Schaap, Evert Lamfers, Jeroen Lammers, Hans Post, Benno Rensing, Richard Braam, Hendrik Nathoe, Eric Boersma, Koen Nieman
Journal: Circulation (2015)

Introduction: It is uncertain whether a diagnostic strategy supplemented by early coronary CT angiography (CCTA) is superior to contemporary standard optimal care (SOC) encompassing high sensitivity troponins for patients suspected of acute coronary syndrome (ACS) in the emergency department. Hypothesis: To assess whether a diagnostic strategysupplemented by early CCTA improves clinical effectiveness compared to contemporary SOC. Methods: In a prospective, open-label, multicentre, randomized trial, we enrolled patients presenting with symptoms suggestive of an ACSat the emergency department (ED) of five community and two university hospitals in the Netherlands. Exclusion criteria included the need for urgent cardiac catheterization, history of ACS or coronary revascularisation. The primary endpoint was the number of patients identified with significant coronary artery disease requiring revascularization within 30 days. Results: The study population consisted of 500 patients of whom 236 (47%) were women (mean age 54±10 years). There was no difference in the primary endpoint (22 [9%] patients underwent coronary revascularizationwithin 30 days in the CCTA group and 17 [7%] in the SOC group [p= 0·40]). Discharge from ED was not more frequent after CCTA (65% versus 59%, p= 0·16) and length of stay was similar(6·3 hours in both groups, p= 0·80). Direct medical costs were lower in the CCTA group (є337 versus є511, p&lt;0·01). Less outpatient testing was seen with CCTA after index ED visit (10 [4%] versus 26 [10%], p&lt;0·01). There was no difference in incidence of undetected ACS. Conclusions: A diagnostic strategy supplemented by early CCTAis safe, less expensive and averts outpatient testing. However, in the era of high-sensitivity troponins, CCTA does not identify more patients with significant CAD requiring coronary revascularization, nor does CCTAshorten hospital stay or allow for more direct discharge from the ED.
Histologic Examination of the Origin of the Action Potential Characteristically Obtained from the Region Bordering the Atrioventricular Node
Authors: Toyomisano, Minorutasaki, Takioshimamoto
Journal: Circulation Research (1959)

In the region of the atrioventricular node a characteristic cell potential was obtained by microelectrode recording in dogs. The resting and action potentials obtained here were small and the latter had a step-like potential before the steepest rise. The site of origin was examined histologically by a special staining technic and was found to be from a cell of the atrioventricular node or a part of the special junctional tissue adjacent to it.
Genetics of Variation in HDL Cholesterol in Humans and Mice
Authors: XiaosongWang, BeverlyPaigen
Journal: Circulation Research (2005)

Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are genetically determined to a great extent, and quantitative trait locus (QTL) analysis has been used to identify chromosomal regions containing genes regulating HDL-C levels. We discuss new genes found to participate in HDL metabolism. We also summarize 37 mouse and 30 human QTLs for plasma HDL-C levels, finding that all but three of the mouse QTLs have been confirmed by a second cross or a homologous human QTL, that the mouse QTL map is almost saturated because 92% of recently reported QTLs are repeats of those already found, and that 28 of the 30 human QTLs are located in regions homologous to mouse QTLs. This high degree of concordance between mouse and human QTLs suggests that the underlying genes may be the same. Strategies to more rapidly identify genes underlying mouse and human QTLs for HDL-C include focusing on the mouse and using mouse–human homologies, combining crosses, and haplotyping to narrow the region. Sequence analysis...
Late Results of Percutaneous Mitral Commissurotomy in a Series of 1024 Patients
Authors: BernardIung, EricGarbarz, PierreMichaud, SteevenHelou, BrunoFarah, PatriciaBerdah, Pierre-LouisMichel, BertrandCormier, AlecVahanian
Journal: Circulation (1999)

Background—The optimal use of percutaneous mitral commissurotomy (PMC) in a wide range of patients requires accurate evaluation of late results and identification of their predictors. Methods and Results—Late results of PMC were assessed in 1024 patients whose mean age was 49±14 years. Echocardiography showed that 141 patients (14%) had pliable valves and mild subvalvular disease, 569 (55%) had extensive subvalvular disease, and 314 (31%) had calcified valves. A single balloon was used in 26 patients, a double balloon in 390, and the Inoue Balloon in 608. Good immediate results were defined as valve area ≥1.5 cm2 without regurgitation >2/4 (Sellers’ grade) and were obtained in 912 patients. Median duration of follow-up was 49 months. The 10-year actuarial rate of good functional results (survival with no cardiovascular death and no need for surgery or repeat dilatation and in New York Heart Association [NYHA] class I or II) was 56±4% in the entire population. Follow-up echocardiography was available in 90...
Abstract 66: The Role of the Viral Nef Protein as a Mediator of HIV-1--Induced Endothelial Dysfunction
Authors: Ting Wang
Journal: Circulation Research (2012)

With the prevalence of antiviral therapy in the developed world, many HIV-1-infected people die of diseases other than AIDS. One of the emerging major causes is cardiovascular disease, leading to the prediction that the majority of HIV-1 patients are expected to develop cardiovascular complications. Endothelial dysfunction is thought to be a key event in the development of cardiovascular diseases, particularly atherosclerosis. Assays testing the effect of HIV-1 on endothelial activation shows that direct contact with HIV-1 infected T cells enhance endothelial cell activation to a greater extent than HIV-1 alone, suggesting an intracellular HIV-1 protein is responsible for endothelial activation. The HIV-1 viral protein Nef, which is responsible for T cell activation and maintenance of high viral loads in vivo , has been shown to mediate its own transfer to bystander cells. We demonstrate here for the first time that Nef induces nanotube-like conduits connecting T cells and endothelial cells. We also show that Nef is transferred from T cells to endothelial cells via these nanotubes, and is necessary and sufficient for endothelial cell activation. Moreover, we show that SIV-infected macaques exhibit endothelial Nef expression in coronary arteries. Nef expression in endothelial cells causes endothelial apoptosis, ROS and MCP-1 production. Interestingly, a Nef SH3 binding site mutant abolishes Nef-induced apoptosis and ROS formation and reduces MCP-1 production in endothelial cells, suggesting that the Nef SH3 binding site is critical for Nef effects on endothelial cells. Nef induces apoptosis of endothelial cells through an NADPH oxidase- and ROS-dependent mechanism, while Nef-induced MCP-1 production is NF-kB dependent. Taken together, these data suggest that Nef can mediate its transfer from T cells to endothelial cells through nanotubes to enhance endothelial dysfunction.Thus, Nef is a promising new therapeutic target for reducing the risk for cardiovascular disease in the HIV-1 positive population.