tbuckley/cabot-search huggingface dataset:
Abstract LB-120: Systematic association analysis of immune checkpoint blockade of PD-1 by RNA-seq data in advanced melanoma patients
Authors: Shu Wang
Journal: Cancer Research (2018)

Abstract Immune checkpoint blockade with anti-programmed cell death protein-1 (PD-1) monoclonal antibodies (mAbs) provides long-term clinical benefits to 30-40% patients with advanced melanoma. In spite of this success, the majority of the melanoma patients (MPs) fail to respond to therapy. To further explore the mechanisms about how immunotherapy influences immune systems and cancers, we have developed a novel clinical trial with anti-PD-1 antibody (Pembrolizumab) and Peginterferon. In this trial, 43 melanoma patients were treated and had tumor biopsies pre- and post-treatment (week 12) that were used for transcriptomic studies using RNA-seq. Here, we report the data obtained from 21 MPs with lymph node metastases, including 10 responders and 10 non-responders. We found that lymph nodes and metastatic tumors show different gene expression pattern for response: besides immune signature which is expressed in lymph nodes also, metastatic tumors presents gene signature related to cell-ECM communication, vasculogenesis, etc. In addition, we found several pathways that favor response, such as IGF1/mTOR pathway. Our work gives a deeper insight into how anti-PD1 immunotherapy functions and how resistance against it occurs, which may predict clinical outcome in MPs treated with anti-PD-1 mAbs and Peginterferon. Citation Format: Shu Wang. Systematic association analysis of immune checkpoint blockade of PD-1 by RNA-seq data in advanced melanoma patients [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 LB-120.
Abstract IA23: How does the immune system contend with intratumoral heterogeneity in ovarian cancer?
Authors: Brad H. Nelson
Journal: Clinical Cancer Research (2018)

Abstract The presence of tumor-infiltrating T cells and B cells is associated with markedly prolonged survival in high-grade serous ovarian cancer (HGSC), yet we have only a rudimentary understanding of how the immune system contends with the continually evolving tumor genome. HGSC exhibits extensive spatial heterogeneity at diagnosis, and tumors undergo dramatic changes in response to treatment. In long-term survivors, the immune system presumably deploys mechanisms that successfully respond to these changes. With better understanding, it may be possible to exploit these mechanisms to create more effective immunotherapies. We have shown that the most prognostically favorable immune responses involve both cytolytic and antibody-based mechanisms, suggesting important cooperative interactions between the T cell and B cell branches of the immune system. By studying serial tumor samples, we have uncovered extensive temporal dynamics of the antitumor immune response. We found that neoadjuvant chemotherapy can enhance preexisting immune responses yet generally fails to initiate responses in tumors that lack immune infiltrates at baseline. Indeed, with better understanding, these immunologically inert or “cold” tumors may represent an attractive therapeutic opportunity, as they can express high levels of tumor-specific antigens with corresponding systemic T-cell and antibody responses. Currently, we are looking at the issue of spatial heterogeneity by subjecting tumor samples collected from different anatomical locations to comprehensive genomic and immunologic analyses, including mutational profiling, RNA-seq, TCR/BCR-seq, and multi-plexed immunohistochemistry. This work is providing novel insights into the relationship between the clonal architecture of tumors and antitumor immunity. Our findings to date indicate that tumor deposits with a high degree of clonal heterogeneity generally have low densities of immune infiltrates, suggesting a means by which tumor evolutionary processes are insulated from immunologic attack. Furthermore, TCR-seq experiments are providing early evidence that T-cell clones track with individual tumor clones across space, suggesting that the immune system contends with intratumoral heterogeneity by battling each tumor clone individually. The presentation will address the implications of these findings on the design of more effective immunotherapies for HGSC and related cancers. Citation Format: Brad H. Nelson. How does the immune system contend with intratumoral heterogeneity in ovarian cancer? [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA23.
Vascular Endothelial Growth Factor Induces Activation and Subcellular Translocation of Focal Adhesion Kinase (p125FAK) in Cultured Rat Cardiac Myocytes
Authors: NaoyukiTakahashi, YoshinoriSeko, EiseiNoiri, KazuyukiTobe, TakashiKadowaki, HisatakaSabe, YoshioYazaki
Journal: Circulation Research (1999)

Abstract—Vascular endothelial growth factor (VEGF) has been proposed to be among the candidate factors with the most potential to play a role in ischemia-induced collateral vessel formation. Recently, we found that VEGF activated the mitogen-activated protein kinase cascade in cultured rat cardiac myocytes. To elucidate how VEGF affects adhesive interaction of cardiac myocytes with the extracellular matrix (ECM), one of the important cell functions, we investigated the molecular mechanism of activation of focal adhesion-related proteins, especially focal adhesion kinase (p125FAK), in cultured rat cardiac myocytes. We found that the 2 VEGF receptors, KDR/Flk-1 and Flt-1, were expressed in cardiac myocytes and that KDR/Flk-1 was significantly tyrosine phosphorylated on VEGF stimulation. VEGF induced tyrosine phosphorylation and activation of p125FAK as well as tyrosine phosphorylation of paxillin; this was accompanied by subcellular translocation of p125FAK from perinuclear sites to the focal adhesions. Thi...
Amplitude Spectrum Area to Guide Defibrillation
Authors: GiuseppeRistagno, TommasoMauri, GiancarloCesana, YongqinLi, AndreaFinzi, FrancescaFumagalli, GianpieraRossi, NiccolòGrieco, MaurizioMigliori, AidaAndreassi, RobertoLatini, CarlaFornari, AntonioPesenti
Journal: Circulation (2015)

Background—This study sought to validate the ability of amplitude spectrum area (AMSA) to predict defibrillation success and long-term survival in a large population of out-of-hospital cardiac arrests. Methods and Results—ECGs recorded by automated external defibrillators from different manufacturers were obtained from patients with cardiac arrests occurring in 8 city areas. A database, including 2447 defibrillations from 1050 patients, was used as the derivation group, and an additional database, including 1381 defibrillations from 567 patients, served as validation. A 2-second ECG window before defibrillation was analyzed, and AMSA was calculated. Univariable and multivariable regression analyses and area under the receiver operating characteristic curve were used for associations between AMSA and study end points: defibrillation success, sustained return of spontaneous circulation, and long-term survival. Among the 2447 defibrillations of the derivation database, 26.2% were successful. AMSA was signifi...
Abstract 13478: Increased Changes in Calculated Plasma Volume Predict Poor Prognosis in Heart Failure
Authors: Nathaniel Chishinga, Kenneth Bilchick, LaVone Smith, Alex Parker, David Zhuo, Sula Mazimba
Journal: Circulation (2016)

Introduction: Plasma volume (PV) is contracted in stable patients with heart failure (HF) due to the effects of therapy aimed at reducing congestion, while increased PV can complicate the progression of HF. We sought to determine the prognostic implications of calculated PV in patients with HF. Hypothesis: Increased changes in PV predict mortality after hospital discharge in HF patients. Methods: We used data from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial for our analysis. The outcome in our study was all-cause mortality after hospital discharge. We used the hemoglobin and 1-hematocrit method to calculate the percentage change in PV (%ΔPV) between baseline and hospital discharge. We used Kaplan-Meier curves to compare 180-day (6-month) survival for patients that had increased %ΔPV to patients that had reduced or no %ΔPV. We used Cox proportional hazard regression analysis to adjust for age and gender, and obtained adjusted hazard ratios (AHR) and 95% confidence intervals (CI) of the association between mortality and %ΔPV. Results: There were 315 patients with complete data on PV that were included, of which 231 (73.3%) were men. The mean age was 56 years (range: 22-88 years). Of these 315 patients, 59 (18.7%) died after discharge during 4365.3 person days (PDs) of observation from baseline; mortality incidence rate was 1.4 deaths/100 PDs. Patients with reduced or no %ΔPV were more likely to survive than those with increased %ΔPV at the end of follow-up (Log rank test p=0.0042). Patients with increased %ΔPV had a statistically significant increased risk of mortality compared to patients with reduced or no %ΔPV (AHR 1.9, 95% CI: 1.1-3.2). Conclusions: Increased changes in calculated plasma volume predicted 6-month mortality in HF patients enrolled in the ESCAPE trial. Plasma volume changes during hospitalization for acute decompensated HF could guide risk stratification and prognosis in HF patients.
Hepatocyte Growth Factor Ameliorates the Progression of Experimental Autoimmune Myocarditis
Authors: HidekiFutamatsu, Jun-ichiSuzuki, ShinyaMizuno, NoritakaKoga, SusumuAdachi, HisanoriKosuge, YasuhiroMaejima, KenzoHirao, ToshikazuNakamura, MitsuakiIsobe
Journal: Circulation Research (2005)

Hepatocyte growth factor (HGF) plays a role in cell protection, antiapoptosis, antifibrosis, and angiogenesis. However, the role of HGF in the immune system is not well defined. We examined the influence of HGF on T cells and the effects of HGF therapy in acute myocarditis. Lewis rats were immunized on day 0 with cardiac myosin to establish experimental autoimmune myocarditis (EAM). Human HGF gene with hemagglutinating virus of the Japan-envelope vector was injected directly into the myocardium on day 0 or on day 14 (two groups of treated rats). Rats were killed on day 21. Expression of c-Met/HGF receptor in splenocytes and myocardial infiltrating cells was confirmed by immunohistochemical staining or FACS analysis. Myocarditis-affected areas were smaller in the treated rats than in control rats. Cardiac function in the treated rats was markedly improved. An antigen-specific T cell proliferation assay was done with CD4-positive T cells isolated from control rats stimulated with cardiac myosin. HGF suppres...
Abstract 4378: Novel CARP-1- H2AX interaction regulates apoptosis in breast cancer cells
Authors: Sreeja C. Sekhar, Vino T. Cheriyan, Arun K. Rishi
Journal: Cancer Research (2018)

Abstract CCAR1/CARP-1 is a peri-nuclear phosphoprotein that regulates apoptosis signaling by breast cancer therapeutic Doxorubicin and a novel class of CARP-1 Functional Mimetic (CFM) compounds. Prior reports have established that Doxorubicin exposure causes DNA damage in cells. Phosphorylation of histone 2AX (often referred as γH2AX) protein is involved in regulating DNA damage repair and apoptosis signaling. Although, currently it is unclear whether CFMs also induce DNA damage, we found that Doxorubicin or CFM-4.16 treatments caused elevated CARP-1 and γH2AX in HBC cells. In fact, a robust nuclear or peri-nuclear co-localization of CARP-1 and γH2AX occurred in HBC cells undergoing apoptosis. Knock-down of CARP-1 abolished increase of CARP-1 and γH2AX, their co-localization, and apoptosis in CFM-4.16 or Doxorubicin-treated HBC cells. We found that CARP-1 directly binds with H2AX, and the H2AX-interacting epitope is located within CARP-1 amino acids 600 to 652. We generated HBC cells that have stable expression of myc-tagged, wild-type CARP-1 (1-1150) or CARP-1 (1-1150; Δ600-652) mutant. Further analyses revealed that CARP-1 (1-1150), but not CARP-1 (1-1150; Δ600-652) mutant, interacted with H2AX. Moreover, HBC cells expressing CARP-1 (1-1150; Δ600-652) mutant were resistant to apoptosis by Doxorubicin or CFM-4.16, and had diminished levels of γH2AX, when compared with their counterparts expressing wild-type CARP-1. We have earlier reported involvement of the Stress-Activated Protein Kinases (SAPKs) such as p38 and JNKs in apoptosis by Doxorubicin or CFMs. Since the PI3K family of serine-threonine kinases ATM/ATR, as well as JNK SAPKs, phosphorylate serine-139 of H2AX following DNA damage, our current studies are investigating whether H2AX binding with CARP-1 serves to facilitate phosphorylation of CARP-1 and H2AX proteins for transduction of apoptosis signaling. Citation Format: Sreeja C. Sekhar, Vino T. Cheriyan, Arun K. Rishi. Novel CARP-1- H2AX interaction regulates apoptosis in breast cancer cells [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 4378.
Abstract 3257: Polygenic risk score, stage, and mode of detection in relation to breast cancer risk
Authors: Amy Trentham-Dietz, John M. Hampton, Irene M. Ong, C David Page, Michael N. Gould, Jill D. Haag, Polly A. Newcomb, James D. Shull, Elizabeth S. Burnside
Journal: Cancer Research (2018)

Abstract Identification of increasing numbers of breast cancer risk variants holds promise to improve risk prediction and identify population subgroups that could benefit from targeted prevention and early detection. We aimed to examine whether women with increased polygenic risk are more likely to be diagnosed with symptomatic breast cancer. A case-control study including data collected from interviews, DNA from saliva, and cancer registry data collected between 2001-2007 (4,315 cases, 3,919 controls) was used to construct a polygenic risk score (PRS). Single nucleotide polymorphisms (SNPs, N=98) were selected from recently published genome-wide association studies of breast cancer and breast density, and comparative rat genome studies. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) associated with the SNPs. SNPs with p-values ≤0.10 (N=24) were used to construct quintiles of the PRS by multiplying the log-odds of the SNPs by the number of risk alleles; multivariable logistic regression models evaluated all women and strata of women defined by method of detection and stage at diagnosis. Odds ratios were adjusted for age, family history of breast cancer, age at menopause/menopausal status, body mass index, parity, and age at first birth. Overall, PRS quintile categories were associated with breast cancer risk in a dose response manner (Q1: OR=1, reference; Q2 OR=1.36, 95% CI 1.16-1.58; Q3 OR=1.66, 95% CI 1.43-1.93; Q4 OR=1.83, 95% CI 1.58-2.12; Q5 OR=2.58, 95% CI 2.23-2.98). Evaluated on a continuous scale, the PRS was associated with an OR=1.38 for a 1-unit change in the standard deviation (SD), 95% CI 1.32-1.45. Odds ratios were essentially unchanged when stratified by method of detection (p-value=0.40). The odds ratio of breast cancer associated with the continuous PRS was elevated among women diagnosed with advanced breast cancer: DCIS, OR=1.36, 95% CI 1.26-1.47 per 1 SD; localized OR=1.37, 95% CI 1.30-1.45 per 1 SD; regional OR=1.38, 95% CI 1.28-1.48 per 1 SD; and distant OR=1.82, 95% CI 1.39-2.40. These results suggest that polygenic risk scores are strongly related to breast cancer risk, that the association does not vary by method of breast cancer detection, but that the association is strongest for metastatic breast cancer. Citation Format: Amy Trentham-Dietz, John M. Hampton, Irene M. Ong, C David Page, Michael N. Gould, Jill D. Haag, Polly A. Newcomb, James D. Shull, Elizabeth S. Burnside. Polygenic risk score, stage, and mode of detection in relation to breast cancer risk [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 3257.
Is 8-mm More Effective Than 4-mm Tip Electrode Catheter for Ablation of Typical Atrial Flutter?
Authors: Chin-FengTsai, Ching-TaiTai, Wen-ChungYu, Yi-JenChen, Ming-HsiungHsieh, Chern-EnChiang, Yu-AnDing, Mau-SongChang, Shih-AnnChen
Journal: Circulation (1999)

Background—The prospective, randomized study comparing 4- with 8-mm tip electrodes for radiofrequency linear ablation of typical atrial flutter is not available. Methods and Results—A total of 104 consecutive patients with typical atrial flutter were randomly assigned to undergo radiofrequency linear ablation using a 4- (Group I, n=54) or 8-mm tip electrode (Group II, n=50) catheter (temperature-control model, preset 70°C). If complete bidirectional isthmus block could not be achieved after 5 pulses, the ablation catheter was changed to the other type; the maximal radiofrequency pulse number was limited to <10 pulses. Complete or incomplete isthmus conduction block was assessed by activation sequence in a multielectrode Halo catheter during low lateral right atrial and proximal coronary sinus pacing. Before shifting to the other catheter type, the 8-mm electrode catheter achieved higher complete isthmus block rate (92% versus 67%, P<0.05) with fewer pulses (2±1 versus 3±1, P<0.05), shorter procedure time ...
Angiotensin II Increases Expression of α1C Subunit of L-Type Calcium Channel Through a Reactive Oxygen Species and cAMP Response Element–Binding Protein–Dependent Pathway in HL-1 Myocytes
Authors: Chia-TiTsai, Danny LingWang, Wen-PinChen, Juey-JenHwang, Chia-ShanHsieh, Kuan-LihHsu, Chuen-DenTseng, Ling-PingLai, Yung-ZuTseng, Fu-TienChiang, Jiunn-LeeLin
Journal: Circulation Research (2007)

Angiotensin II (Ang II) is involved in the pathogenesis of atrial fibrillation (AF). L-type calcium channel (LCC) expression is altered in AF remodeling. We investigated whether Ang II modulates LCC current through transcriptional regulation, by using murine atrial HL-1 cells, which have a spontaneous calcium transient, and an in vivo rat model. Ang II increased LCC α1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient in atrial myocytes. An ≈2-kb promoter region of LCC α1C subunit gene was cloned to the pGL3 luciferase vector. Ang II significantly increased promoter activity in a concentration- and time-dependent manner. Truncation and mutational analysis of the LCC α1C subunit gene promoter showed that cAMP response element (CRE) (−1853 to −1845) was an important cis element in Ang II-induced LCC α1C subunit gene expression. Transfection of dominant-negative CRE binding protein (CREB) (pCMV-CREBS133A) abolished the Ang II effect. Ang II (1 μmol/L, ...
Abstract 15523: Absence of Chordae Tendineae near Valve Coaptation Leads to Mitral Regurgitation in Lone Atrial Fibrillation
Authors: YujiItabashi, HirotsuguMihara, JavierBerdejo, HirotoUtsunomiya, KenMatsuoka, TakahiroShiota
Journal: Circulation (2014)

Introduction: Mitral annuloplasty is performed to treat mitral valve regurgitation (MR) in lone atrial fibrillation (AF) patients. The mechanisms of the significant MR in lone AF patients are not known well. We assessed the hypothesis that absence of chordae tendineae near the mitral valve (MV) coaptation could lead to the significant functional MR in the lone AF patients. Methods: We analyzed 64 patients with a history of AF with greater than 50 % of the left ventricular (LV) ejection fraction, and no organic abnormality of MV. Of these 31 has mild or lesser MR (AF Groups) and 33 has moderate or severe MR (AFMR Group). We also analyzed 33 sinus rhythm patients with normal echocardiographic findings (Sinus Group). Parameters concerning to MV morphology were measured with commercial software. Chordae attaching points (CAPs) nearest from the coaptation line were detected on the anterior mitral leaflet (Figure). Ratio of the length from CAP to coaptation line against that from anterior annulus to coaptation ...
Abstract 12337: Platelet-neutrophil Complex Infiltration is Regulated by Serotonin in a Mouse Model of Myocardial Reperfusion Injury
Authors: Maximilian Mauler, Thilo Witsch, Ludwig Dorner, Kelly D Blanz, Christoph Koentges, Daniela Stallmann, Heiko Bugger, Christoph Bode, Daniel Duerschmied
Journal: Circulation (2015)

Background: Myocardial reperfusion injury leads to platelet neutrophil complex (PNCs) migration into cardiac tissue, which promotes post-infarction necrosis. Local serotonin levels are elevated during ischemia and platelet serotonin promotes recruitment of inflammatory cells. Tryptophan hydroxylase-1-deficient mice (Tph1-/-) lack peripheral serotonin and show attenuated inflammatory response. We evaluated PNC infiltration after myocardial ischemia reperfusion (I/R) in the absence of peripheral serotonin. Methods: C57Bl/6 (WT) and Tph1-/- mice underwent coronary artery ligation to induce myocardial infarction. Reperfusion was allowed after 30min, heart function determined by echocardiography after 24h. Hearts were excised to evaluate infarct size. PNC content was determined by flow cytometry and histology. The function of healthy WT and Tph1-/- hearts was analyzed in an ex vivo working heart model and compared to global flow/no flow/flow. Cardiomyocytes were isolated from healthy WT and Tph1-/- mice and their survival following different in vitro challenges was assessed over 48h. Results: Infarct size was 37±9% in Tph1-/- and 53±13% area at risk in WT mice (p&lt;0.01). Fractional shortening in echocardiography was better in Tph1-/- mice (49±4% vs. 41±6%, p&lt;0.05), whereas cardiac power after no flow in the ex vivo working heart assay was similar (33±4 vs. 31±3mW/gHW). Isolated cardiomyocytes of Tph1-/- and WT mice showed similar survival after 48h (11.5% vs. 8.8%). These data indicate that contractility and cardiomyocyte function were independent of serotonin in this setting. Histology displayed a reduced number of PNCs in Tph1-/- hearts (7±3) compared to WT (16±3/350μm2, p&lt;0.01). This was confirmed by flow cytometry of homogenized heart tissue (4±2 vs. 13±1%leukocytes, p&lt;0.05) and blood samples (24±8 vs. 41±15%leukocytes; p&lt;0.05). Conclusion: Lack of peripheral, i.e. platelet serotonin did not influence the function of isolated hearts or cardiomyocytes in vitro. However, PNC formation and infiltration was reduced in the absence of serotonin, resulting in attenuated reperfusion injury in vivo. Serotonin appears to account for up to 30% of myocardial reperfusion injury by promoting PNC formation.