tbuckley/cabot-search huggingface dataset:
RhoA/Rho-Kinase in the Cardiovascular System
Authors: HiroakiShimokawa, ShinichiroSunamura, KimioSatoh
Journal: Circulation Research (2016)

Twenty years ago, Rho-kinase was identified as an important downstream effector of the small GTP-binding protein, RhoA. Thereafter, a series of studies demonstrated the important roles of Rho-kinase in the cardiovascular system. The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Furthermore, the important role of Rho-kinase has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. Cyclophilin A is secreted by vascular smooth muscle cells and inflammatory cells and activated platelets in a Rho-kinase–dependent manner, playing important roles in a wide range of cardiovascular diseases. Thus, the RhoA/Rho-kinase pathway plays crucial roles under both physiological and pathological conditions...
Abstract 2851: The evolution of tumor cells under AsiDNA treatment results in “autosensitization”
Authors: Maria Kozlac, Wael Jdey, Pierre-Marie Girard, Françoise Bono, Marie Dutreix
Journal: Cancer Research (2018)

Abstract Purpose: The Achilles' heel of all conventional and targeted anticancer treatments is intrinsic or acquired resistance. The era of precision medicine where tumors are selected for specific treatments based on their genetic alterations is revolutionary, but unfortunately prolonged responses are rarely observed due to rapid emergence of resistant clones. We recently developed a new concept of DNA repair inhibitor (Dbait) acting by activating enzymes involved in DNA damage signaling. We tested how such agonist activity would be prone to induce resistance to Dbait treatment. Experimental design: We performed repeated cycles of treatment with various targeted therapy agents (Imatinib, Olaparib, 6-thioguanine and the clinical form of Dbait, AsiDNATM). We analyzed the specific sensitivity of independent cultures after each treatment cycle. The study was performed in different tumor cell lines ((MDAMB231, MDAMB468, HCC1143, THP1, U937, KBM7) and in two non-malignant breast cell lines (MCF10A, MCF12A). Extensive transcriptome and genome studies were performed on MDAMB231 breast cancer cell lines. Results: Resistant clones appeared at a frequency of 1.45% for Olaparib, 0.62% for imatinib, and 1.66% for 6-thioguanine. Similar protocol did not select for resistance to AsiDNA. Unexpectendly, tumor cells became more sensitive to AsiDNA after each cycle of treatment. This behavior was specific of AsiDNA and was not observed with other treatments. The six tumor cell lines tested developed AsiDNA autosensitisation and no resistance. Non tumoral cells were not affected by repeated treatments. The acquired sensitivity of the treated tumor populations was conserved for months after end of treatment Transcriptional and genetic analysis of independently treated MDAMB-231 populations reveals that all evolved similarly. They display a few conserved genome modifications and a large deregulation of 1160 genes resulting in an overexpression of luminal associated genes and a decrease in mesenchymal associated genes. Conclusion: Our results indicate a phenomenon of “autosensitisation”, along treatment which has never been described for anticancer treatment and could prevent development of resistance during treatment. Citation Format: Maria Kozlac, Wael Jdey, Pierre-Marie Girard, Françoise Bono, Marie Dutreix. The evolution of tumor cells under AsiDNA treatment results in “autosensitization” [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 2851.
Phasic Coronary Flow Characteristics in Patients With Constrictive Pericarditis
Authors: TakashiAkasaka, KiyoshiYoshida, AtushiYamamuro, TakeshiHozumi, TsutomuTakagi, ShigefumiMorioka, JunichiYoshikawa
Journal: Circulation (1997)

Background Phasic coronary flow characteristics have been reported in patients with aortic valve disease and hypertrophic cardiomyopathy. The purpose of this study was to assess the differences in coronary flow characteristics between patients with constrictive pericarditis and those with restrictive cardiomyopathy. Methods and Results The study populations consisted of 7 case patients with constrictive pericarditis, 8 with restrictive cardiomyopathy, and 11 control subjects with chest pain and normal coronary arteries. Five minutes after injection of 3 mg of isosorbide dinitrate, phasic coronary flow velocity patterns were analyzed in the proximal segment of the angiographically normal left anterior descending coronary artery at rest using a 0.014-in, 15-MHz Doppler guidewire. Coronary flow reserve was obtained from the ratio of adenosine-induced (0.14 mg · kg−1 · min−1 IV) hyperemic/baseline time-averaged peak velocity. Although in case patients with constrictive pericarditis and restrictive cardiomyopa...
Abstract 3907: Birinapant co-treatments of colon cancer cell lines show consensus molecular subtype-specific synergistic effects
Authors: Michael Fichtner, Emir Bozkurt, Katherine McAllister, Christopher McCann, Daniel Longley, Jochen H. Prehn
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite recent advances, the treatment success differs strongly between colorectal cancer patients and new treatment options are urgently needed. Since most tumors avoid apoptosis by a dysregulation of Inhibitor of apoptosis proteins (IAPs), IAP inhibitors such as the SMAC mimetic birinapant are promising new drugs for the treatment of CRC. However, it is currently not possible to stratify for patients who might benefit from adjuvant therapy and those who need new treatments. In 2015, an international consortium unified six independent subtyping approaches and defined 4 distinct, so-called consensus molecular subtypes (CMS). The CMSs are the current gold standard for CRC subtyping and have some prognostic values. Nevertheless, whether the CMS classification can be used to estimate the treatment success is currently under investigation. This study aimed to evaluate the efficacy of treatments with the chemotherapeutics oxaliplatin and 5-fluoruracil (5-FU), TNFalpha, the SMAC-mimetic birinapant and a combination of these drugs. We selected 10 cell lines, representing the four CMSs, and treated them for 24h and 48h with the respective drugs. At both time points, we assessed the cell death by staining with Annexin V/PI followed by flow cytometric analysis of the cells. We were able to show that birinapant has very strong synergistic effects if used in combination with either oxaliplatin/5-FU or TNFalpha, but does not induce apoptosis alone. Importantly, the efficacy of the various co-treatments differed between the cell lines. These differences can, to some extent, be linked to the corresponding CMS of the cells. Cells belonging to the CMS1 subtype showed strong synergistic effects of birinapant and oxaliplatin/5-FU. In contrast, birinapant and TNFalpha co-treatments showed synergistic effects in CMS2 cells, but not in CMS1 cells. Cells belonging to the CMS3 subtype, however, showed a mixed but generally weak response to the co-treatments. Our results highlight birinapant as a promising drug for the treatment of CRC. Our data also suggest that CMSs not only have prognostic values but may also be used as patient stratification tools. Citation Format: Michael Fichtner, Emir Bozkurt, Katherine McAllister, Christopher McCann, Daniel Longley, Jochen H. Prehn. Birinapant co-treatments of colon cancer cell lines show consensus molecular subtype-specific synergistic effects [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 3907.
Demonstration of Tubercular “Abdominal Cocoon” (Sclerosing Encapsulating Peritonitis) in 18F-FDG PET/CT
Authors: Shelvin Kumar Vadi, Bhagwant Rai Mittal, Ashwin Singh Parihar, Rajender Kumar, Vishal Sharma, Harshal S. Mandavdhare
Journal: Clinical Nuclear Medicine (2018)

Sclerosing encapsulating peritonitis also called as abdominal cocoon is a less understood condition mostly due to idiopathic causes and sometimes secondary to tuberculosis or peritoneal dialysis. This report describes the typical features of "abdominal cocoon" on F-FDG PET/CT in a young woman, which was later diagnosed to be secondary to tuberculosis. Because the early features of this unusual entity are often nonspecific, high clinical suspicion along with understanding of the typical radiological/PET/CT features of this intriguing entity may guide the physician in ruling out the secondary treatable causes like tuberculosis, as noted in the index case.
Abstract 38: HDL Cholesterol, Inflammation and Peripheral Arterial Disease in U.S. Adults
Authors: LeiKuang
Journal: Circulation (2014)

Introduction: The protective relation of high density lipoprotein-cholesterol (HDL-C) with coronary heart disease may be weakened in the presence of inflammation; however, whether inflammation may attenuate any association of HDL-C with peripheral arterial disease (PAD) is unknown. Hypothesis: We hypothesized that inflammation measured by high-sensitivity C-reactive protein (hs-CRP) will attenuate any inverse association of HDL-C with PAD. Methods: We studied 6512 men and women aged ≥ 40 years who participated in the National Health and Nutrition Examination Survey (NHANES ) from 1999-2004 who had measures of ankle brachial index (positive for PAD defined as <0.9 or ≥1.5), lipids, high-sensitivity CRP (hs-CRP) and other risk factors. Groups were categorized by low (<40 mg/dL for men or <50 mg/dl or women), intermediate (40 or 50-59 mg/dL), and high (≥60 mg/dL) HDL-C, and low (<1 mg/L), normal (1-3), and high (3 mg/L) hs-CRP levels. We evaluated the odds ratio (ORs) for PAD by logistic regression adjusted ...
Abstract 4749: VISTA immune checkpoint deregulation in human triple-negative breast cancer
Authors: Joshua J. Gruber, Marisa M. Juntilla, Soo-Ryum Yang, Benjamin Geller, Natalie Jager, Chien-Yu Lin, Andrew M. Lipchik, Justin Chen, Ashwin Ram, Shaveta Vinayak, Melinda L. Telli, Robert B. West, James M. Ford, Michael P. Snyder
Journal: Cancer Research (2018)

Abstract Immunotherapy for breast cancer has lagged behind the advances in other tumor types, suggesting the need for novel immune targets. VISTA/PD-1H is a checkpoint receptor expressed on immune cells that is an effective anti-cancer target in mouse models and now in early human clinical trials. We utilized an in vitro system to examine epigenetic changes arising early after depletion of breast cancer tumor suppressor proteins. This demonstrates that epigenetic alterations occur in normal human mammary cell lines lacking BRCA2 and result in regulation of VISTA through an NF-kB-dependent pathway. VISTA is strongly induced by growth factor limitation, an effect that is blunted by BRCA2-induced NF-kB activation and binding to a kB site in the VISTA promoter. This suggests that repression of VISTA may be an early consequence of BRCA2 depletion in pre-neoplastic tissues leading to immune infiltration. In contrast, in primary, untreated human triple-negative breast cancers, VISTA is over-expressed on tumor cells, independent of its presence on immune cells. VISTA positive TNBCs (14%) have significantly increased tumor infiltrating lymphocytes (TILs) whereas VISTA strong positive TNBCs (6%) have significantly decreased TILs and tumor PD-L1 staining, suggesting a higher level of immunosuppression. Gene expression and tumor genomics in TNBCs suggests that transcriptional networks to regulate physiologic immunoreceptor levels are corrupted during malignant transformation. In summary, this work identifies a BRCA2-loss-of-function signaling pathway that regulates an important immune checkpoint molecule via NF-kB activation in pre-neoplastic tissues and triple-negative breast cancers with important consequences for the immune microenvironment. We expect these observations to enhance immunotherapeutics for breast cancer. Citation Format: Joshua J. Gruber, Marisa M. Juntilla, Soo-Ryum Yang, Benjamin Geller, Natalie Jager, Chien-Yu Lin, Andrew M. Lipchik, Justin Chen, Ashwin Ram, Shaveta Vinayak, Melinda L. Telli, Robert B. West, James M. Ford, Michael P. Snyder. VISTA immune checkpoint deregulation in human triple-negative breast 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 4749.
Red Wine Polyphenols Inhibit Vascular Smooth Muscle Cell Migration Through Two Distinct Signaling Pathways
Authors: KatsuyaIijima, MasaoYoshizumi, MasayoshiHashimoto, MasahiroAkishita, KoichiKozaki, JunyaAko, TokumitsuWatanabe, YumikoOhike, BokyungSon, JingYu, KoichiNakahara, YasuyoshiOuchi
Journal: Circulation (2002)

Background— Red wine polyphenols (RWPs) have been shown to have an antiatherogenic activity mainly through antioxidative effects on LDL oxidation. Although vascular smooth muscle cell (SMC) migration is critical to atherosclerosis formation, the effect of RWPs on SMC migration has not been elucidated. In this study, we investigated whether RWPs could affect the migration of cultured SMCs stimulated by growth factors. Methods and Results— RWP concentration dependently inhibited platelet-derived growth factor (PDGF)-BB–induced and serum-induced SMC migration in wounding assay and Boyden chamber assay. However, these inhibitory effects of RWPs were not seen in serum-stimulated vascular endothelial cell migration in either assay. Moreover, specific inhibitors of phosphatidylinositol-3′ kinase (PI3K) and p38 mitogen-activated protein kinase (p38MAPK), but not of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), reduced PDGF-BB–induced SMC migration. To elucidate the signaling mechanism underlyin...
Abstract 14611: Protease-Activated Receptor 4 Deficiency Impairs Resolution of Inflammation and Predisposes the Heart to Cardiac Rupture After Myocardial Infarction
Authors: Mikhail A Kolpakov, Xinji Guo, Bahman Hooshdaran, Khadija Rafiq, Yulia V Bashkirova, Liudmila Vlasenko, Tao Wang, Rachid Seqqat, Satya P Kunapuli, Steven R Houser, Abdelkarim Sabri
Journal: Circulation (2016)

Introduction: Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture is accelerated by thrombolytic therapy. However, the mechanisms by which thrombolytic therapy leads to the development of cardiac rupture remains largely unknown. Hypothesis: In this study, we tested the effect of thrombin protease activated receptor (PAR) 4 deficiency on cardiac rupture and function after MI. Methods and Results: PAR4 mRNA and protein expression were increased in human ischemic and dilated cardiomyopathy and in response to MI in mice. PAR4 gene deletion in mice protected the heart against acute MI by reducing inflammatory signals and cardiomyocyte apoptosis. However, PAR4-deficient mice showed significantly increased mortality and cardiac rupture rates (3-fold increase vs wild-type mice, P<0.05) along with impaired functional recovery after chronic MI. Pat...
Prognostic Significance of Admission Troponin T Concentrations in Patients With Myocardial Infarction
Authors: PeterStubbs, PaulCollinson, DavidMoseley, TrevorGreenwood, MarkNoble
Journal: Circulation (1996)

Background New, highly specific cardiac structural proteins can now be measured. The early presence of one of these proteins, troponin T, has been found to have important prognostic significance in patients with unstable angina pectoris. The prognostic significance of its presence on admission was assessed in patients with myocardial infarction. Methods and Results Two hundred forty patients admitted with myocardial infarction were studied and followed prospectively for a median of 3 years. The prognostic significance of an admission troponin T concentration ≥0.2 ng/mL for subsequent cardiac death and/or reinfarction was assessed and compared with other variables in a regression model. Any detectable troponin T on admission was associated with a worse prognosis on follow-up. An admission concentration of ≥0.2 ng/mL was associated with a higher risk of subsequent cardiac death (χ2, 13.3; P=.0002) and death or nonfatal reinfarction (χ2, 16; P=.00006). The excess risk was seen primarily in patients with admi...
Abstract 18086: Psychometric Testing and Shocks in Patients with Implantable Cardioverter Defibrillators
Authors: Jason George, Kecia-Ann Blissett, Melanie Panko, Lauren Brock, Julie Thornton, Scott Bea, Karen Broer, Betty Ching, Samuel Sears, Susanne Pedersen, Leopoldo Pozuelo, Mina Chung
Journal: Circulation (2012)

Background Emotional stress and anxiety have been reported to be triggers for arrhythmias causing ICD shocks. We aimed to determine whether psychometric parameters are associated with ICD shocks. M...
Abstract 1103: Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche through macrophage polarization in liver metastasis
Authors: Yingkuan Shao, Ting Chen, Xi Zheng, Shu Zheng
Journal: Cancer Research (2018)

Abstract Liver metastases develop in more than half of patients with colorectal cancer (CRC) and indicate a poor prognosis. In this study, we aim to investigate CRC-derived small extracellular vesicles (CRC-sEVs) participating in liver-specific metastasis. Fluorescence-labeled CRC-sEVs were found to accumulate in macrophages in mouse liver and prime macrophage polarization toward an interleukin-6 (IL-6)-secreting pro-inflammatory phenotype (macrophage expresses different programs in response to different microenvironmental signals called macrophage polarization). By analyzing miRNA expression profiles of the CRC-sEVs and their parental cells (SW480 and SW620), we identified miR-21-5p (miR-21) as the top ranked miRNA that was highly upregulated both in the sEVs and their parental CRC cells. The majority of macrophage-secreted inflammatory signaling pathways are activated by Toll-like receptor (TLR). Macrophages treated with miR-21 analogs exhibited enhanced expression of pro-inflammatory cytokines such as IL-6 and TNF-α. Silencing either miR-21 in CRC-sEVs, or the Toll-like receptor 7 (TLR7) in macrophages which miR-21 binds to, abolished the effect of CRC-sEVs in inducing pro-inflammatory macrophage polarization. Upon intravenous injection, CRC-sEVs promoted miR-21 expression and macrophage infiltration in the mouse liver, followed by the up-regulation of inflammatory genes. Accordingly, the multiplicity of liver metastases was increased upon transplantation of CRC cells in mice treated with CRC-sEVs. Furthermore, miR-21 expression in plasma-derived sEVs positively correlated with tumor stage and liver metastasis in CRC patients. Finally, co-expression of the miR-21 and IL-6 macrophages markers was observed in liver metastatic tissues from CRC patients. Together, our data point to a pivotal role of CRC-sEVs in inducing an inflammatory pre-metastatic niche through the miR-21-TLR7-IL6 axis. Moreover, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis. Citation Format: Yingkuan Shao, Ting Chen, Xi Zheng, Shu Zheng. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche through macrophage polarization in liver metastasis [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 1103.
The Half-Lives of Facts, Paradigm Shifts, and Reproducibility in Cancer Research
Authors: Chi Van Dang
Journal: Cancer Research (2018)

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The history of science documents how our perception of the natural world changes over time, and cancer research is no exception, having shifted profoundly as new information opened uncharted paths to empirical truths. Most illustrative of a seismic shift of our world-view is
Abstract 5275: Comparing self-reported cognitive function among Caucasian and African American breast cancer survivors
Authors: Kayla A. Lewis, Jacqueline B. Vo, Kendra J. Royston, Silvia Gisiger-Camata, Karen Meneses
Journal: Cancer Research (2018)

Abstract Approximately 35% of breast cancer survivors (BCS) report changes in cognitive function after cancer treatment. The purpose of this abstract is to compare self-reported cognitive changes between Caucasian (CAU) and African American (AA) BCS who participated in the Think Well program. Think Well is an educational program to increase awareness of cognitive function and promote healthy living. Sixteen Think Well seminars were delivered in-person to urban and rural counties throughout North Central Alabama. Following each seminar, participants completed an evaluation of demographic information and cognitive changes. Descriptive statistics and chi-squared tests were used. Data were analyzed using SPSS v23. Among BCS who completed the evaluation, 82 (54%) were CAU, and 62 (41%) were AA. Many BCS were employed (32%) or disabled/retired (51%). CAU were more likely to be married than AA BCS (p&amp;lt;0.01). More CAU self-reported “poor/below average” in domains of memory, ability to think, speed of problem solving, and ability to pay attention than AA BCS (p&amp;lt;0.01). CAU were more likely than AA BCS to report “moderately” or “very much/extremely” in changes in ability to think (p&amp;lt;0.01), speed of problem solving (p=0.02), and ability to pay attention (p=0.01) since completion of breast cancer treatment. CAU BCS self-reported poorer cognitive function and changes since cancer treatment. Differences in self-reported changes between AA and CAU may be contributed to geographic location, racial differences in perception of cognitive function, or marital status. Race-related stigmas may affect self-reporting of cognitive function. Future research is warranted to examine factors that contribute to racial differences in cognitive function and interventions aimed at improving cognitive function among both AA and CAU BCS. Acknowledgement: Think Well is supported by a grant from the North Central Alabama Affiliate of Susan G. Komen. Authors are also supported by funding: Susan G. Komen Graduate Traineeship in Disparities Research, Robert Wood Johnson Foundation Future of Nursing Scholarship, and American Cancer Society Doctoral Degree Scholarship in Cancer Nursing (DSCN-17-076-01). Citation Format: Kayla A. Lewis, Jacqueline B. Vo, Kendra J. Royston, Silvia Gisiger-Camata, Karen Meneses. Comparing self-reported cognitive function among Caucasian and African American breast cancer survivors [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 5275.