tbuckley/cabot-search huggingface dataset:
Abstract P316: The Mediation of Racial Differences in Hypertension by Sleep Characteristics: Chicago Area Sleep Study
Authors: Laura Rasmussen-Torvik, Peter de Chavez, Kiarri Kershaw, Kristen Knutson, Kwang-Youn Kim, Phyllis Zee, Mercedes Carnethon
Journal: Circulation (2016)

Introduction: There are disparities in hypertension prevalence by race/ethnicity in the United States. Given differences in sleep by race and the association between sleep characteristics and hypertension, we examined whether racial differences in hypertension were partially mediated by differences in sleep. Methods: The Chicago Area Sleep Study (CASS) is a cross-sectional study of 155 black, 129 white, 103 Hispanic and 109 Asian men and women ages 35-64 who had an apnea/hypopnea index&lt;15 determined during 1 night of screening (ApneaLinkTM). Participants wore wrist actigraphs for 7 days (ActiwatchTM) to determine sleep characteristics. The total sleep interval was determined using the Actiwatch event marker or sleep log and sleep % was calculated as duration (determined by actigraphy) /total sleep interval. Blood pressure was measured 3 times after 5 minutes rest; hypertension was determined according to JNC-VII 2010 criteria. To examine mediation, we used the approach and SAS macro developed by Valeri and VanderWeele and fitted two models; a Poisson regression model for hypertension and a linear regression model for sleep characteristic. From these combined models, we estimated the prevalence ratios for natural direct effects (PRNDE) of race on hypertension, natural indirect effects (PRNIE) (mediated by sleep characteristics), and total effect (PRTE). We also calculated the proportion of the total effects that were mediated by sleep characteristics. Results: Participants’ mean age was 47.8 years. Sleep duration was longest in whites 445 min (SD=53min), followed by Asians 413 min (SD=51 min), Hispanics 417 min (SD=79 min) and Blacks 409 min (SD=67 min). Average sleep percentage was 92% (SD=4%) in whites, 88% (SD=5%) in Blacks, 91% (SD=5%) in Asians, and 90% (SD=4%) in Hispanics. In models adjusted for age, race, sex, education, smoking status, alcohol intake, physical activity, depressive symptoms and work schedule the direct effect (prevalence ratio) of race on hypertension was 4.6 for Blacks vs. whites, 1.5 for Asians vs. whites and 2.2 for Hispanics vs. whites. The indirect effects (mediated by sleep percentage) for the three groups were 1.19, 1.06, and 1.05 respectively, suggesting that sleep percentage mediated 10 % of the difference in prevalence for hypertension between Blacks and whites, 10% of the difference between Asians and whites and 7 % of the difference between Hispanics and whites. In contrast, there was no evidence that sleep duration mediated the race differences in hypertension. Conclusions: While sleep duration did not contribute to race differences in hypertension prevalence, sleep percentage, which may reflect quality of sleep, may contribute to racial differences in rates of hypertension.
Abstract 11480: Obesity and Long Term Outcomes After ST-elevation Myocardial Infarction in the Elderly: Does the Paradox Extend to Extreme Obesity? : Results From the National Cardiovascular Data Registry
Authors: Ian J Neeland, DaJuanicia N Simon, Tracy Y Wang, Deborah B Diercks, Matthew T Roe, Karen P Alexander, Sandeep R Das, James A de Lemos
Journal: Circulation (2016)

Introduction: An obesity paradox exists in non-STEMI in which patients with mild obesity have lower mortality than normal weight patients. It is not known if this paradox exists among older patients with STEMI and among individuals with extreme obesity over the long term. Methods: Patients ≥65 years of age with STEMI from the NCDR ACTION Registry-GWTG who survived to hospital discharge were linked to Medicare claims data. Patients were stratified by body mass index (BMI, kg/m 2 ) into normal weight (18.5-24.9), overweight (25-29.9), class I obese (30-34.9), class II obese (35-39.9), and class III (extreme) obese categories (≥40). Multivariable Cox proportional hazards models were used to evaluate the association between BMI category and all-cause mortality for 3 years after hospital discharge. Models were adjusted for clinical and socioeconomic (SES) characteristics and in-hospital outcomes. Differences in number of days alive and out of hospital (DAOH) were also assessed. Results: Of 19,499 patients included in the analysis, 70% were overweight or obese. Normal weight patients (30%) were more likely to be older and smoke and extremely obese patients (3%) more likely to be younger, female, and black, with lower SES and more comorbidity (P≤0.001). After multivariable adjustment, a U-shaped association was observed between BMI and long term mortality. Patients with mild (class I) obesity were at lowest risk, while normal weight or extremely obese patients had higher all-cause mortality ( Figure ). Normal weight and extremely obese individuals also had lower DAOH at 3 years compared with mildly obese (median 894 vs. 950 days, respectively, P&lt;0.05). Conclusions: The obesity paradox persists in older STEMI patients over long term with regards to death and readmission but is not seen with extreme obesity. Normal weight and extreme obesity are associated with consistently worse outcomes highlighting a need for aggressive treatment paradigms for these populations after STEMI.
Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver
Authors: Itziar Otano, David Escors, Anna Schurich, Harsimran Singh, Francis Robertson, Brian R. Davidson, Giuseppe Fusai, Frederick A. Vargas, Zhi M.D. Tan, Jia Y.J. Aw, Navjyot Hansi, Patrick T.F. Kennedy, Shao-An Xue, Hans J. Stauss, Antonio Bertoletti, Andrea Pavesi, Mala K. Maini
Journal: Molecular Therapy (2018)

Checkpoint inhibitors and adoptive cell therapy provide promising options for treating solid cancers such as HBV-related HCC, but they have limitations. We tested the potential to combine advantages of each approach, genetically reprogramming T cells specific for viral tumor antigens to overcome exhaustion by down-modulating the co-inhibitory receptor PD-1. We developed a novel lentiviral transduction protocol to achieve preferential targeting of endogenous or TCR-redirected, antigen-specific CD8 T cells for shRNA knockdown of PD-1 and tested functional consequences for antitumor immunity. Antigen-specific and intrahepatic CD8 T cells transduced with lentiviral (LV)-shPD-1 consistently had a marked reduction in PD-1 compared to those transduced with a control lentiviral vector. PD-1 knockdown of human T cells rescued antitumor effector function and promoted killing of hepatoma cells in a 3D microdevice recapitulating the pro-inflammatory PD-L1hi liver microenvironment. However, upon repetitive stimulation, PD-1 knockdown drove T cell senescence and induction of other co-inhibitory pathways. We provide the proof of principle that T cells with endogenous or genetically engineered specificity for HBV-associated HCC viral antigens can be targeted for functional genetic editing. We show that PD-1 knockdown enhances immediate tumor killing but is limited by compensatory engagement of alternative co-inhibitory and senescence program upon repetitive stimulation.Graphical abstract
Abstract B38: Synergistic effects of SHP2 and PI3K inhibitors in GAB2-overexpressing ovarian cancer
Authors: Hiu Wing Cheung
Journal: Clinical Cancer Research (2018)

Abstract We previously found that the scaffold/adaptor growth factor receptor bound 2 (GRB2)-associated binding protein 2 (GAB2) is frequently amplified and overexpressed in primary high-grade serous ovarian cancers (HGSOCs) and cell lines. Ovarian cancer cell lines overexpressing GAB2 are dependent on GAB2 for activation of ERK1/2 and AKT signaling, consistent with its role in regulating the protein tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) and the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K). In this study, we investigated whether ovarian cancer cell lines overexpressing GAB2 are sensitive to combinatorial SHP2 and PI3K inhibition. Analysis of gene expression profiles reveals that primary HGSOCs overexpressing GAB2 are associated with increased ERBB, RAS, and MAPK activity signatures. Inhibition of SHP2 by an allosteric inhibitor SHP099 selectively inhibits ERK1/2 activity, proliferation, and survival of ovarian cancer cell lines with GAB2 amplification/overexpression. Treatment with SHP099 has a synergistic effect with multiple PI3K pathway inhibitors such as BKM120, a pan-class I PI3K inhibitor, at suppressing proliferation and survival of ovarian cancer cells overexpressing GAB2 in part through induction of apoptosis. Combinatorial SHP2 and PI3K inhibition more effectively activates both pro-apoptotic proteins BIM and BAD and inhibits expression of transcription factor c-MYC, a master regulator of cancer stem cells, compared with individual inhibitor, and sensitized cancer cells to chemotherapeutic drugs paclitaxel and cisplatin. Combinatorial SHP2 and PI3K inhibition also suppresses spheroid formation of ALDH-positive ovarian cancer stem cells. Together, our findings identify a previously unrecognized role of SHP2 in promoting proliferation and survival of ovarian cancer cells in which GAB2 is amplified and/or overexpressed, and suggest that combinatorial SHP2 and PI3K inhibition may be a promising therapeutic approach for HGSOCs with GAB2 amplification/overexpression. Citation Format: Hiu Wing Cheung. Synergistic effects of SHP2 and PI3K inhibitors in GAB2-overexpressing 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 B38.
Abstract 2989: BET inhibitors induce Rac1-dependent MNK and eIF4E phosphorylation in cancer cells
Authors: Thao Pham, Brian T. Decant, Krishan Kumar, Meng Shang, Maria Matsangou, Kazumi Ebine, Hidayatullah G. Munshi
Journal: Cancer Research (2018)

Abstract Patients with recurrent differentiated thyroid cancers (DTCs) have poor prognosis and suffer from multiple complications from progressive symptomatic disease. Here we show that eukaryotic translation initiation factor 4E (eIF4E), an oncogene that is overexpressed in aggressive thyroid cancers, is required for growth of DTC cells in collagen microenvironment. We show that inhibitors targeting bromodomain and extra-terminal domain (BET) family of proteins also decrease growth of DTC cells in the collagen microenvironment. Unexpectedly, we have found that BET inhibitors induce MNK and eIF4E phosphorylation in cancer cells. Mechanistically, BET inhibitors induce Rac1-mediated cytoskeletal changes and targeting Rac1 blocks these changes as well as MNK and eIF4E phosphorylation. Functionally, we show that MNK inhibitors potentiate the effects of BET inhibitors at suppressing cancer cell proliferation and limiting sphere-forming ability. Together, these results demonstrate crosstalk between BET proteins and the MNK-eIF4E pathway, suggesting that combination therapy with BET and MNK inhibitors has the potential for synergistic inhibition of cancer cells. Citation Format: Thao Pham, Brian T. Decant, Krishan Kumar, Meng Shang, Maria Matsangou, Kazumi Ebine, Hidayatullah G. Munshi. BET inhibitors induce Rac1-dependent MNK and eIF4E phosphorylation in 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 2989.
Exercise Training Reduces Neointimal Growth and Stabilizes Vascular Lesions Developing After Injury in Apolipoprotein E–Deficient Mice
Authors: MariannePynn, KatrinSchäfer, StavrosKonstantinides, MartinHalle
Journal: Circulation (2004)

Background— Population-based studies have shown that exercise reduces cardiovascular morbidity and mortality. However, it is unknown whether these effects are solely a result of risk factor modification or whether exercise directly affects the homeostasis of the vessel wall. Methods and Results— We subjected 19-week-old apolipoprotein E (apoE)–knockout mice (apoE−/−; n=25) to a 6-week training program on a motorized treadmill. The control group consisted of 17 sedentary mice. After 3 weeks in the program, training and sedentary mice underwent carotid artery injury with ferric chloride. Training was then resumed for another 3 weeks. Exercise did not change body weight or lipid levels in apoE−/− mice but resulted in upregulated expression of nitric oxide synthase in the endothelium. Physical training did not significantly affect the thrombotic response to injury. However, morphometric analysis of vessels harvested 3 weeks after injury showed that neointima formation was reduced in the exercising group. This...
Suppression of Coronary Artery Spasm by the Rho-Kinase Inhibitor Fasudil in Patients With Vasospastic Angina
Authors: AkihiroMasumoto, MasahiroMohri, HiroakiShimokawa, LemmyUrakami, MakotoUsui, AkiraTakeshita
Journal: Circulation (2002)

Background— Increased activity of Rho-kinase causes hypercontraction of vascular smooth muscle and has been implicated as playing a pathogenetic role in divergent cardiovascular diseases such as coronary artery spasm. We examined whether an intracoronary infusion of fasudil, a selective Rho-kinase inhibitor, would attenuate coronary vasoconstrictor responses to acetylcholine (ACh) in patients with vasospastic angina. Methods and Results— We studied 20 consecutive patients in whom coronary artery spasm was provoked by intracoronary ACh. The patients underwent a second ACh challenge after pretreatment with intracoronary saline (n=5) or fasudil (n=15; 300 μg/min for 15 minutes). Angina and coronary vasospasm were reproducibly induced by the second testing in patients who received saline. In contrast, fasudil markedly attenuated the coronary constriction induced by ACh (P<0.001) and prevented the occurrence of chest pain and ischemic ECG changes in all treated patients (both P<0.01 versus saline). Fasudil, at...
Abstract B47: Rgnef (p190RhoGEF/Arhgef28) loss impairs ovarian tumor metastatic growth
Authors: Elizabeth G. Kleinschmidt, Isabelle Tancioni, Kristin Taylor, Carlos Osterman-Diaz, Nichol L. G. Miller, Shulin Jiang, David D. Schlaepfer
Journal: Clinical Cancer Research (2018)

Abstract Increased activation of FAK and Rho GTPase regulatory pathways is associated with shorter survival in patients with high-grade serous ovarian carcinoma (HGSOC). However, the key mediators of these signaling events in HGSOC remain unknown. We have previously shown that the Rho guanine nucleotide exchange factor Rgnef (also named p190RhoGEF or Arhgef28) activates FAK as well as RhoA GTPase in mouse fibroblasts. Here we find that Rgnef protein expression is elevated in Stage 3-4 HGSOC and that Rgnef knockout prevents ovarian tumor spheroid growth in vitro and in vivo. We isolated ascites-associated murine ID8 cells to generate a more aggressive cell line, termed ID8-IP. ID8-IP cells exhibit higher Rgnef and FAK expression than parental ID8 cells. CRISPR/Cas9-induced knockout of Rgnef in ID8-IP cells does not alter 2D growth as compared to Rgnef-KO cells re-expressing GFP-Rgnef. However, Rgnef loss significantly decreased growth as spheroids in a 3D Matrigel-on-Top assay. At five weeks following intraperitoneal injection into syngeneic C57Bl/6 mice, ID8-IP Rgnef-KO cells form significantly fewer ascites-associated cells, as well as fewer metastatic lesions on the peritoneal wall. Notably, ID8-IP Rgnef-KO cells display lower FAK and ERK1/2 phosphorylation. These studies demonstrate that Rgnef loss impedes metastatic growth in the peritoneal cavity, and suggest that an integrin-mediated Rgnef-FAK linkage facilitates ovarian tumor metastasis. Citation Format: Elizabeth G. Kleinschmidt, Isabelle Tancioni, Kristin Taylor, Carlos Osterman-Diaz, Nichol L. G. Miller, Shulin Jiang, David D. Schlaepfer. Rgnef (p190RhoGEF/Arhgef28) loss impairs ovarian tumor metastatic growth. [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 B47.
Abstract 3313: Epigenetic biomarkers of prognosis in stage IIA colon cancer
Authors: Sara Pagotto, Elisa Porcellini, Maria G. Bacalini, Diletta Sarti, Ingrid Garajova, Elisabetta Broseghini, Noemi Laprovitera, Francesco Vasuri, Paolo Garagnani, Renato Mariani-Costantini, Michele Basso, Rosa Visone, Luigi M. Larocca, Manuela Ferracin, Angelo Veronese
Journal: Cancer Research (2018)

Abstract Adjuvant therapy is a systemic treatment administered after primary tumor resection to reduce the risk of relapse and death in colorectal cancer (CRC) patients. Generally, adjuvant treatment is recommended for stage III and ‘high-risk' stage II CRC (NCCN guidelines). Nonetheless, adjuvant treatment is still debated for stage IIA (T3N0) patients, whose estimated recurrence rate is 15-20% in the absence of any further therapy after resection of the primary tumor. With the aim to find additional prognostic biomarkers that could improve current patient selection, we analyzed the global methylation profile of a discovery group of 10 relapsing/non-relapsing stage IIA colon cancer samples, without any other known risk factor (low-risk), by Illumina Epic 850K array. We identified a panel of 25 Illumina probes that were able to predict recurrence in chemotherapy-naïve patients. Then, we assessed the methylation of the most predictive Cytosine-Guanine (CpG) dinucleotides in 107 stage IIA colon cancer patients from two different cohorts, by EpiTYPER technology. We validated several CpGs as differentially methylated in relapsing vs. non-relapsing CRCs (p&amp;lt;0.05). For these CpG sites, we analyzed the methylation level also in the matching normal mucosa surrounding the tumor, to identify potential premalignant epigenetic lesions. In addition, we examined the association between the methylation level at specific CpG sites and prognostic clinical characteristics, overall survival and time-to-relapse. We concluded that the analysis of epigenetic alterations in archival colon cancer tissues could increase the panel of risk factors predictive for recurrence, and thus improve the selection of patients who could benefit from adjuvant therapy. Citation Format: Sara Pagotto, Elisa Porcellini, Maria G. Bacalini, Diletta Sarti, Ingrid Garajova, Elisabetta Broseghini, Noemi Laprovitera, Francesco Vasuri, Paolo Garagnani, Renato Mariani-Costantini, Michele Basso, Rosa Visone, Luigi M. Larocca, Manuela Ferracin, Angelo Veronese. Epigenetic biomarkers of prognosis in stage IIA colon 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 3313.
Endothelin-1 Is Involved in Stretch-Induced Early Activation of B-Type Natriuretic Peptide Gene Expression in Atrial but Not in Ventricular Myocytes
Authors: JarkkoMagga, OlliVuolteenaho, MinnaMarttila, HeikkiRuskoaho
Journal: Circulation (1997)

Background The precise role of paracrine and autocrine factors in mechanical load–induced activation of cardiac gene expression is unknown. Here we report the effects of endothelin-1 (ET-1) and angiotensin II (Ang II) receptor antagonism on acute pressure overload–induced activation of cardiac B-type natriuretic peptide (BNP) gene expression in spontaneously hypertensive rats (SHRs) in vivo and on mechanical stretch–induced increase in atrial BNP gene expression in vitro. Methods and Results Acute pressure overload produced in conscious SHRs by infusion of arginine8-vasopressin (0.05 μg · kg−1 · min−1) for 2 hours resulted in an increase in BNP mRNA levels in the left ventricle as well as in the atrium. Bolus injections of bosentan (mixed ETA/ETB receptor antagonist, 10 mg/kg IV) but not losartan (AT1 receptor antagonist, 10 mg/kg IV) blocked the increase of the BNP mRNA levels produced by pressure overload in the left atria, whereas the elevation of BNP mRNA levels was similar (a 1.9-fold increase) in th...
Abstract 4912: Targeting cyclin-dependent kinase 7 in gastric cancer
Authors: Jia-Rong Huang, Wen-Ji Zhang, Qi-Wei Jiang, Yang Yang, Meng-Ning Wei, Zhi Shi
Journal: Cancer Research (2018)

Abstract CDK7 is a member of the cyclin-dependent kinase family, which forms the CDK activating kinase (CAK) complex with Cyclin H and RING finger protein Mat1 to control cell cycle progression and transcription by phosphorylating other CDKs and RNA polymerase II. Upregulation of CDK7 frequently occurs in human gastric cancer (GC). In this study, we demonstrated that inhibition of CDK7 was able to induce cell growth inhibition, cell cycle arrest at G2/M phase and apoptosis with the increasing intracellular reactive oxidative species (ROS) levels. Pretreatment with ROS scavenger N-acety-L-cysteine partly reversed GC cell apoptosis induced by CDK7 inhibition. In the nude mice, inhibition of CDK7 also suppressed the growth of xenograft tumors of GC. Overall, our data showed that inhibition of CDK7 in GC presented outstanding anticancer effect in vitro and in vivo, suggesting that CDK7 is a potential therapeutic target for GC patients. Citation Format: Jia-Rong Huang, Wen-Ji Zhang, Qi-Wei Jiang, Yang Yang, Meng-Ning Wei, Zhi Shi. Targeting cyclin-dependent kinase 7 in gastric 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 4912.
Adverse events (AEs) with maintenance olaparib tablets in patients (pts) with <i>BRCA</i>-mutated (<i>BRCA</i>m) platinum-sensitive relapsed serous ovarian cancer (PSR SOC): Phase III SOLO2 trial.
Authors: Jonathan A. Ledermann, Alain Lortholary, Richard T. Penson, Emma Gibbs, Diane M. Provencher, Ilan Bruchim, Tomas Huzarski, Maria Pilar Barretina-Ginesta, Roberto Sabbatini, Linda R. Mileshkin, Nicoletta Colombo, Tjoung-Won Park-Simon, Koji Matsumoto, Gabe S. Sonke, Olga N. Mikheeva, Jae-Weon Kim, Gustavo Colagiovanni Girotto, Hannelore Denys, Elizabeth S. Lowe, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2017)

5518 Background: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance therapy with the PARP inhibitor olaparib significantly improved PFS vs placebo (PBO) in BRCAm PSR SOC pts (HR 0.30, 95% CI 0.22–0.41, P&lt;0.0001; median 19.1 vs 5.5 months) and was well tolerated (Pujade-Lauraine et al, SGO 2017). We analyzed AEs in SOLO2, the first study in PSR SOC to use the olaparib tablet formulation. Methods: Pts with BRCAm PSR SOC, who were in response to platinum chemotherapy, were treated with olaparib (300 mg bid; tablets; n=195) or PBO (n=99) until progression. AEs were graded by CTCAE v4.0. Results: The most common AEs with olaparib – nausea, fatigue/asthenia, anemia, and vomiting – were largely grade 1–2, though anemia was the most common grade ≥3 AE. AEs of fatigue/asthenia, vomiting and nausea generally improved as treatment continued, though fatigue/asthenia and anemia could last for several months (table). Most AEs were manageable by supportive treatment, dose interruptions (olaparib, 45%; PBO, 18%) and dose reductions (olaparib, 25%; PBO, 3%). Discontinuation of olaparib due to AEs was minimal (11%); anemia and neutropenia were the only AEs leading to discontinuation of olaparib in &gt;one pt. Conclusions: Most AEs experienced by pts receiving olaparib tablets in SOLO2 were low grade and manageable. Initial nausea, vomiting and fatigue generally improved with ongoing treatment. The majority of AEs first occurred within the first three months of treatment. AEs causing treatment discontinuation were rare and mainly hematological. Clinical trial information: NCT01874353. [Table: see text]