tbuckley/cabot-search huggingface dataset:
Instantaneous Pressure-Volume Relationships and Their Ratio in the Excised, Supported Canine Left Ventricle
Authors: Hiroyukisuga, Kiichisagawa
Journal: Circulation Research (1974)

We have previously shown in the normally ejecting canine left ventricle that E(t), the time-varying ratio of instantaneous pressure, P(t), to instantaneous volume, V(t), is little affected by end-diastolic volume or aortic pressure. The present study on an excised, supported canine heart preparation indicates that the thesis on E(t) is also valid for either totally isovolumic or auxobaric beats. Intraventricular volume was measured more accurately than it was in the previous study by a new volumetric system. Regression analysis of the data showed that the instantaneous pressure-volume relationship could be approximated by the equation P(t) = E(t).[V(t) - Vd], where Vd is an empirical constant, over a wide range of intraventricular volume. Similar E(t) curves were obtained from both isovolumic and auxobaric beats for a given contractile state. When the contractile state of the preparation was enhanced by a constant-rate infusion (0.2 µg/min) of norepinephrine or isoproterenol into the coronary artery, the ...
Prognostic Values of Clockwise and Counterclockwise Rotation for Cardiovascular Mortality in Japanese Subjects
Authors: YasuyukiNakamura, TomonoriOkamura, AyaHigashiyama, MakotoWatanabe, AyaKadota, TakayoshiOhkubo, KatsuyukiMiura, FumiyoshiKasagi, KazunoriKodama, AkiraOkayama, HirotsuguUeshima
Journal: Circulation (2012)

Background—Although clockwise rotation and counterclockwise rotation are distinct findings of the ECG, their prognostic significance is rarely studied. Methods and Results—We studied prognostic values of clockwise and counterclockwise rotation on total, cardiovascular disease (CVD), and subtype mortality using the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980–2004 (NIPPON DATA80) database with a 24-year follow-up. At baseline in 1980, data were collected on study participants aged ≥30 years from randomly selected areas in Japan. We followed 9067 participants (44% men; mean age, 51 years). During the 24-year follow-up, mortality was as follows: 2581 total, 887 CVD, 179 coronary heart disease, 173 heart failure, and 411 stroke. The multivariate-adjusted hazard ratio (HR) with the use of the Cox model including biochemical and other ECG variables revealed that clockwise rotation was significantly positively associated with heart failure in...
Abstract 19848: Impact of Lower Cardiac Index on the Hyperemic Efficacy of Intravenous Adenosione in Patients With Intermediate Coronary Stenosis
Authors: Ho Jun Jang, Ji-Bak Kim
Journal: Circulation (2017)

Introduction: Maximal hyperemia is a key element of invasive physiological studies and intravenous (IV) infusion of adenosine is the most commonly used method. However, hyperemic efficacy of IV ade...
Abstract 4048: Comprehensive analysis of the suppressed tumor immune microenvironment of CIN gastro-esophageal adenocarcinomas
Authors: Sarah Derks, Xinsen Xu, Leonie de Klerk, Tania Fleitas, Kevin Liu, Yang Liu, Claire A. Margolis, Felix Dietlein, Anna Maria Chiaravalli, Annacarolina da Silva, Gordon Freeman, Scott J. Rodig, Eliezer M. Van Allen, Bo Li, Jingxin Fu, Jin Wang, Shirley X. Liu, Adam J. Bass
Journal: Cancer Research (2018)

Abstract Background and aims: Gastro-esophageal adenocarcinoma (GEA) is a common and lethal disease where immune checkpoint inhibitors have demonstrated efficacy within a minority of patients. Prior studies have identified distinct molecular classes of GEA, characterized by specific features that would be predicted to influence responses to checkpoint therapy. We here perform a comprehensive analysis of tumor immune associations in GEAs to further define the tumor immune microenvironment in distinct classes of GEA and to identify additional candidate mediators of immune evasion that may impact response to immunotherapy efficacy. Methods: Tumor immune interactions in GEAs were studied first using computational analyses to infer immune cell subsets from RNAseq data generated from The Cancer Genome Atlas (TCGA). These data were complemented by additional focused studies spanning immunohistochemistry, gene expression profiling and flow cytometry on archival tissue samples and from freshly resected GEA tumor samples. Results: Our results confirmed substantial heterogeneity in the composition of the tumor immune microenvironment between distinct GEA subtypes. As shown earlier, tumors with microsatellite instability (MSI) or Epstein-Barr virus (EBV) harbored larger T cell infiltrates in contrast to those with chromosomal instability (CIN), the most common class of GEA. We then focused greater attention on the CIN cohort, finding a spectrum of phenotypes including tumors with ‘immune hot' and ‘immune cold' states. The ‘hot' cases were more often from Western patients and had greater degrees of DNA methylation. Notably, these tumors often showed co-expression of secondary immune checkpoint proteins, as confirmed by flow cytometry. There was no association between number of infiltrating T cells and mutational or neoantigen load within the CIN GEA subgroup. Immunological cold CIN GEAs were characterized by a higher level of chromosomal instability, enrichment of cell cycle pathways, specifically amplification of cyclin E1, CCNE1, and enrichment of an unfolded protein response. Citation Format: Sarah Derks, Xinsen Xu, Leonie de Klerk, Tania Fleitas, Kevin Liu, Yang Liu, Claire A. Margolis, Felix Dietlein, Anna Maria Chiaravalli, Annacarolina da Silva, Gordon Freeman, Scott J. Rodig, Eliezer M. Van Allen, Bo Li, Jingxin Fu, Jin Wang, Shirley X. Liu, Adam J. Bass. Comprehensive analysis of the suppressed tumor immune microenvironment of CIN gastro-esophageal adenocarcinomas [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 4048.
Abstract 11001: Growth Factor Midkine Deteriorates Cadiac Hypertrophy via Epidermal Growth Factor Receptor Signaling: A Novel Mediator of Cardio-Renal Interaction
Authors: YukiHonda, TetsuroShishido, ShunsukeNetsu, YoichiroOtaki, DaisukeKinoshita, MiyukiYokoyama, ShinpeiKadowaki, TaroNarumi, AkiraFunayama, SatoshiNishiyama, HirokiTakahashi, TakanoriArimoto, TakuyaMiyamoto, TetsuWatanabe, IsaoKubota
Journal: Circulation (2014)

Background: Midkine (MK), a 13-kDa heparin-binding growth factor, has shown to be up-regulated in injured renal tubule, and released into circulation. We recently reported that cardiac-specific overexpression of MK exacerbates cardiac hypertrophy in mice. However, it remains unknown by which mechanisms MK affects on heart. Although receptors for MK are thought to be receptor-type tyrosine kinase, specific receptor for MK has not been determined. Here we show that MK acts by activating the epidermal growth factor receptor (EGFR) and its downstream signaling and leads to cardiac hypertrophy. Methods and Results: MK phosphorylated EGFR (Tyr1068) on neonatal rat cardiomyocytes. MK also promoted phosphorylation of ERK1/2 and Akt, induced fetal cardiac gene expression, and led to cardiomyocyte hypertrophy. Pre-treatment with EGFR inhibitors attenuated MK-induced ERK1/2 and Akt phosphorylation, and induction of fetal cardiac gene, as well as cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. EGFR silencin...
Abstract 12438: Efficacy and Safety Evaluation of a Platelet Glycoprotein Ib Inhibitor for Patients With Non-ST Segment Elevation Myocardial Infarction
Authors: Bo Zheng, Jianping Li, Jie Jiang, Dingcheng Xiang, Yundai Chen, Junbo Ge, Zaixin Yu, Xiangrong Dai, Benjamin Li, Yong Huo
Journal: Circulation (2015)

Introduction: Platelet receptor glycoprotein Ib (GPIb) plays a crucial role in the first step of platelet adhesion. Hypothesis: We hypothesized that GPIb inhibitor would attenuate platelet aggregation without increasing bleeding risk. Methods: This was a prospective, multicenter, double-blind, placebo controlled, randomized trial in 90 Chinese patients with non-ST segment elevation myocardial infarction (NSTEMI) undergoing percutaneous coronary intervention (PCI). GPIb inhibitor was initially administered via intravenous bolus injections at three dosing levels (low dose of 2IU/60kg, moderate dose of 3IU/60kg, and high dose of 5IU/60kg), followed by continuous intravenous infusion at 0.002IU/kg/h for up to 48 hours. Primary endpoint was the inhibition of platelet aggregation measured at baseline, 5 minutes, 24 hours and 48 hours from the beginning of infusion as well as 4 hours after withdrawal. Safety endpoint was in-hospital major bleeding. Results: Ninety patients were randomly assigned to low dose group (n=20), moderate dose group (n=20), high dose group (n=20), and placebo group (n=30). Overall, the median age was 57.7 and 14.4% were female. There was no significant difference among the 4 groups for demographic, clinical and procedural characteristics. Higher inhibition of platelet aggregation occurred in each GPIb inhibitor dosing group, compared with placebo at each time point, with strongest antiplatelet effect found in high-dose group (Figure 1). The TIMI flow and myocardial blush grade did not differ significantly among the 4 groups. The 30-day mortality (0% vs 3.3%, p=0.33), non-fatal MI (0% vs 3.3%, p=0.33) and major bleeding (1.7% vs 3.3%, p=1.00) were rare and comparable between the patients receiving GPIb inhibitor and placebo. Conclusions: The current study demonstrated that intravenous platelet receptor GPIb inhibitor could be feasible and safe with significant antiplatelet effect among patients with NSTEMI undergoing PCI.
Endoplasmic Reticulum Chaperone GRP78 Protects Heart From Ischemia/Reperfusion Injury Through Akt Activation
Authors: Xukun Bi, Guangyu Zhang, Xiaoding Wang, Chau Nguyen, Herman I. May, Xiaoting Li, Ali A. Al-Hashimi, Richard C. Austin, Thomas G. Gillette, Guosheng Fu, Zhao V. Wang, Joseph A. Hill
Journal: Circulation Research (2018)

Rationale: Restoration of coronary artery blood flow is the most effective means of ameliorating myocardial damage triggered by ischemic heart disease. However, coronary reperfusion elicits an increment of additional injury to the myocardium. Accumulating evidence indicates that the unfolded protein response (UPR) in cardiomyocytes is activated by ischemia/reperfusion (I/R) injury. Xbp1s (spliced X-box binding protein 1), the most highly conserved branch of the unfolded protein response, is protective in response to cardiac I/R injury. GRP78 (78 kDa glucose-regulated protein), a master regulator of the UPR and an Xbp1s target, is upregulated after I/R. However, its role in the protective response of Xbp1s during I/R remains largely undefined. Objective: To elucidate the role of GRP78 in the cardiomyocyte response to I/R using both in vitro and in vivo approaches. Methods and Results: Simulated I/R injury to cultured neonatal rat ventricular myocytes induced apoptotic cell death and strong activation of the UPR and GRP78. Overexpression of GRP78 in neonatal rat ventricular myocytes significantly protected myocytes from I/R-induced cell death. Furthermore, cardiomyocyte-specific overexpression of GRP78 ameliorated I/R damage to the heart in vivo. Exploration of underlying mechanisms revealed that GRP78 mitigates cellular damage by suppressing the accumulation of reactive oxygen species. We go on to show that the GRP78-mediated cytoprotective response involves plasma membrane translocation of GRP78 and interaction with PI3 kinase, culminating in stimulation of Akt. This response is required as inhibition of the Akt pathway significantly blunted the antioxidant activity and cardioprotective effects of GRP78. Conclusions: I/R induction of GRP78 in cardiomyocytes stimulates Akt signaling and protects against oxidative stress, which together protect cells from I/R damage.
Randomized Evaluation of Anticoagulation Versus Antiplatelet Therapy After Coronary Stent Implantation in High-Risk Patients
Authors: PhilipUrban, CarlosMacaya, Hans-JürgenRupprecht, FerdinandKiemeneij, HakanEmanuelsson, AlessandroFontanelli, MichaelPieper, TheaWesseling, LucSagnard
Journal: Circulation (1998)

Background—Although the association of ticlopidine and aspirin has been shown to be superior to anti–vitamin K agents and aspirin after coronary stent implantation in low-risk patients, the latter combination has remained an unproven reference regimen for high-risk patients until recently. Methods and Results—We randomized 350 high-risk patients within 6 hours after stent implantation to receive during 30 days either aspirin 250 mg and ticlopidine 500 mg/d (A+T group) or aspirin 250 mg/d and oral anticoagulation (A+OAC group) targeted at an international normalized ratio of 2.5 to 3. The primary composite end point was defined as the occurrence of cardiovascular death, myocardial infarction, or repeated revascularization at 30 days. Patients were eligible if (1) the stent(s) were implanted to treat abrupt closure after PTCA; (2) the angiographic result after implantation was suboptimal; (3) a long segment was stented (>45 mm and/or ≥3 stents); or (4) the largest balloon inflated in the stent had a nominal...
Retinoids and Amyotrophic Lateral Sclerosis—Reply
Authors: Gabriele Nagel, Dietrich Rothenbacher, Albert C. Ludolph
Journal: JAMA Neurology (2018)

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Abstract 4095: Active Kras induced metaplasia progression toward gastric neoplasia is suppressed by MEK inhibition during gastric carcinogenesis
Authors: Eunyoung Choi, Amy C. Engevik, James R. Goldenring
Journal: Cancer Research (2018)

Abstract Intestinal type gastric cancer develops within metaplastic mucosal fields and development of gastric neoplasia represents the most prominent example of gastric cancer developing within the morphologic changes of metaplasia. Recent investigations have noted activation of Ras activity in up to 40% of human gastric cancers and suggest. Our recent study has suggested that chief cells might be an origin of gastric cancer using a mouse model, Mist1-CreERT2;LSL-KRas(G12D) mouse (Mist1-Kras). The Mist1-Kras mice rapidly developed SPEM and IM within 3 months and invasive metaplasia within 4 months following induction of constitutively-active Kras(G12D) expression in the chief cells in the mouse stomach. We also observed regression of metaplasia by targeting downstream mediators of Kras signaling using a MEK inhibitor, Selumetinib. We therefore have now investigated how the progression and proliferation of metaplasia can be controlled. In this study, we have established metaplastic organoid lines (Meta3 and Meta4) from Mist1-Kras mouse stomach mucosa at 3 or 4 months after tamoxifen induction. We examined these organoids to understand the mechanisms of metaplasia progression through MEK inhibition. Both Meta3 and Meta4 organoids have formed distinguishable glandular structures in 3D cultures and maintained a stable phenotype observed in metaplastic glands in the Mist1-Kras mouse stomachs. The MEK inhibition with Selumetinib in the metaplastic organoids inhibited growth, but promoted differentiation of metaplastic cells toward intestinal absorptive cells with elaboration of an apical brush border. Single cell RNA sequencing data revealed that Meta-4 have distinct characteristics that differ from Meta3. In 3D culture, Meta4 organoids developed more aggressive phenotypes than Meta3 and expressed Cortactin, which has critical roles in cancer cell migration and metastasis. Cortactin localized at the lamellipodia in monolayer culture of Meta4. Meta4 organoids treated with Selumetinib produced significantly fewer colonies in soft agar and resulted in loss of lamellipodia localization of Cortactin. Our results indicate that gastric carcinogenesis can be controlled by a MEK inhibitor, Selumetinib, and support the concept that growth of pre-neoplastic metaplasia and early stage gastric cancer in humans might be controlled with administration of Selumetinib. Citation Format: Eunyoung Choi, Amy C. Engevik, James R. Goldenring. Active Kras induced metaplasia progression toward gastric neoplasia is suppressed by MEK inhibition during gastric carcinogenesis [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 4095.
Sixty seconds on . . . the Hippocratic oath
Authors: Susan Mayor
Journal: BMJ (2018)

Exeter Medical, which has just seen its first cohort of medical students graduate, has put a new spin on the Ancient Greek oath. They promised to “work towards a fairer distribution of health resources,” as well as the usual Hippocratic stuff such as “never intentionally cause harm to patients.” The graduands also promised to oppose policies that breach human …
Abstract 2326: Time-resolved studies of necroptosis reveal distinct regulatory functions for NFκB
Authors: Marie Oliver Metzig, Simon Mitchell, Brooks Taylor, Alexander Hoffmann
Journal: Cancer Research (2018)

Abstract Resistance to regulated cell death (RCD) is an important hallmark of cancer and reason why chemotherapy fails. Efficient reprogramming of cancer cells requires a molecular and dynamic understanding of regulatory circuits. Research has uncovered several resistance mechanisms for apoptosis with nuclear factor κB (NFκB) as a key inhibitory transcription factor. Targeted induction of necroptosis, which was recently discovered as an alternative form of RCD, could be a promising strategy to overcome apoptosis resistance. However, whether NFκB has a regulatory role in necroptosis is less clear. Here, we develop a molecular and time-resolved understanding of how NFκB regulates necroptosis. We present a real-time experimental system to quantify necroptosis in single cancer cells to study the cytotoxic effect of substances while avoiding the bias of proliferation in endpoint protocols. Using live-cell microscopy, computational cell tracking and automated image analysis we quantitate necroptotic death rates in L929 cells, a murine fibrosarcoma cell line, treated with tumor necrosis factor (TNF). While it is known that L929 cells predominantly respond with necroptosis despite rapid activation of NFκB, our experiments reveal an unsuspected temporal phasing of necroptosis over a time course of 24 hours. By perturbing NFκB activation dynamics using targeted CRISPR/Cas9 of IκB and/or Rel proteins, we find that NFκB has at least two distinct roles regulating early and late phases of TNF-induced necroptosis. Further, we will present our molecular analysis that identified NFκB-responsive candidate genes and mapped them into a functional temporo-spatial context within the NFκB-necroptosis signaling network. Our combined approach may inform novel personalized anticancer strategies to exploit targeted necroptosis while avoiding NFκB-induced drug resistance. Citation Format: Marie Oliver Metzig, Simon Mitchell, Brooks Taylor, Alexander Hoffmann. Time-resolved studies of necroptosis reveal distinct regulatory functions for NFκB [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 2326.
Abstract 5431: BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis
Authors: Xingchen Dong
Journal: Cancer Research (2018)

Abstract Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3'-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anti-cancer drugs. Citation Format: Xingchen Dong. BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis [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 5431.
Laminin 511 is a target antigen in autoimmune pancreatitis
Authors: Masahiro Shiokawa, Yuzo Kodama, Kiyotoshi Sekiguchi, Takeshi Kuwada, Teruko Tomono, Katsutoshi Kuriyama, Hajime Yamazaki, Toshihiro Morita, Saiko Marui, Yuko Sogabe, Nobuyuki Kakiuchi, Tomoaki Matsumori, Atsushi Mima, Yoshihiro Nishikawa, Tatsuki Ueda, Motoyuki Tsuda, Yuki Yamauchi, Yojiro Sakuma, Takahisa Maruno, Norimitsu Uza, Tatsuaki Tsuruyama, Tsuneyo Mimori, Hiroshi Seno, Tsutomu Chiba
Journal: Science Translational Medicine (2018)

The extracellular matrix protein laminin 511 is an autoantigen involved in the pathophysiology of autoimmune pancreatitis.