tbuckley/cabot-search huggingface dataset:
Abstract 5438: XPNPEP3: A novel transcriptional target of canonical Wnt/β-catenin signalling
Authors: Raju Kumar, Ashmala Naz, Viswakalyan Kotapalli, Swarnalata Gowrishankar, Satish Rao, Jonathan R. Pollack, Murali Dharan Bashyam
Journal: Cancer Research (2018)

Abstract Canonical Wnt/β-catenin signalling plays pivotal roles during embryonic development and adult tissue regeneration. Its aberrant activation however drives expression of a panoply of genes to facilitate colorectal tumorigenesis. Hence, it is imperative to delineate the complete β-catenin transcriptome. We performed genome-wide mRNA profiling of sporadic rectal cancer samples stratified by Wnt status. Results revealed significant up-regulation of XPNPEP3 transcript levels along with that of canonical Wnt targets AXIN2 and EPHB2 in Wnt+ samples. The differential expression of XPNPEP3 was further validated by quantitative PCR (Q-PCR) in additional samples. Nuclear stabilization of β-catenin achieved through LiCl treatment in three colorectal cancer (CRC) cell lines followed by Q-PCR and promoter-luciferase assays confirmed up-regulation of XPNPEP3. XPNPEP3 encodes X-prolyl aminopeptidase 3 which functions to remove the penultimate N-terminal Proline residue from nascent proteins and appears to play a role in ciliary function. Immunohistochemistry based expression analysis using a CRC tissue microarray revealed significant correlation between XPNPEP3 levels and β-catenin nuclear localization as well as increased XPNPEP3 expression in tumor compared to matched normal samples. Survival analysis of The Cancer Genome Atlas (TCGA) breast invasive carcinoma, skin cutaneous melanoma and lung adenocarcinoma data sets revealed poor survival among patients having perturbed XPNPEP3 expression. Characterization of possible oncogenic function of XPNPEP3 in CRC cells and in mice tumor xenografts is currently underway. Altogether, our results suggest XPNPEP3 to be a novel transcriptional target of Wnt/β-catenin signalling having a possible significance in CRC tumorigenesis. Citation Format: Raju Kumar, Ashmala Naz, Viswakalyan Kotapalli, Swarnalata Gowrishankar, Satish Rao, Jonathan R. Pollack, Murali Dharan Bashyam. XPNPEP3: A novel transcriptional target of canonical Wnt/β-catenin signalling [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 5438.
Abstract 3155: Loss of YAP1 dysregulates RhoA signaling and promotes cell invasion
Authors: Natalie M. Hendrick, Marcin P. Iwanicki, Carman Man-Chung Li, Duyen Amy Bui, Laura M. Selfors, Joan S. Brugge
Journal: Cancer Research (2018)

Abstract While Hippo pathway signaling undoubtedly plays an important role in cancer, the role of its effector YAP1 as an oncogene or tumor suppressor is context dependent. The precise conditions that support the tumor-promoting or tumor-suppressing roles of YAP1 remain largely undefined. While YAP1 can drive oncogenic programs through its nuclear function as a transcriptional coactivator of TEAD and other transcription factors, previous findings from our lab and others suggest that loss of YAP1 function can also have tumor promoting consequences. One well-characterized role of YAP1 is that of a nuclear relay of signals triggered by mechanical forces that lead to activation of Rho GTPases. Our new studies using a combination of genetic, biochemical, and microscopy techniques provide evidence that YAP1 is not only activated by Rho, but can also regulate Rho activation and the actin cytoskeleton. Knockdown of YAP1 in MCF10A immortalized mammary epithelial cells resulted in increased lamellipodia formation in culture as seen by time-lapse microscopy, and increased protrusive, invasive activity in 3D Matrigel culture. YAP1 knockdown also induced a scattering phenotype, characterized by cell dissociation from the leading edge of a wounded monolayer. While E-cadherin protein levels were unaffected by YAP1 knockdown, adherens junction maturation at cell-cell junctions was compromised. These morphological alterations were associated with decreased levels of active RhoA, as well as a decrease in downstream myosin light chain phosphorylation. Our results indicate loss of YAP1 decreases active RhoA, leading to reduced cell-cell adhesion and increased protrusive cellular behavior. Our findings raise the possibility that YAP1 is not only a Rho-sensor, but also mediates a feedforward regulatory loop to maintain Rho-regulated cytoskeletal structures, and that loss of YAP1 through genetic deletion in tumor cells could promote invasive behavior. Citation Format: Natalie M. Hendrick, Marcin P. Iwanicki, Carman Man-Chung Li, Duyen Amy Bui, Laura M. Selfors, Joan S. Brugge. Loss of YAP1 dysregulates RhoA signaling and promotes cell invasion [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 3155.
Abstract 17350: Neuronal Na+ Channels Serve as a Trigger for Atrial Arrhythmias
Authors: Przemyslaw B Radwanski, Qing Lou, Megan Koleske, Roberto Ramos Mondragon, Silvia Priori, Pompeo Volpe, Héctor H Valdivia, Sandor Gyorke
Journal: Circulation (2016)

Background: Triggered arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) and often accompanying atrial fibrillation (AF) are associated with diastolic Ca2+ release. ...
Abstract P281: Comparing the Impact of Price Change and Mass Media Campaigns in Reducing Cardiovascular Disease Mortality and Disparities in the US
Authors: Jonathan Pearson-Stuttard, Piotr Bnadosz, Colin D Rehm, Ashkan Afshin, Jose Penalvo, Laurie Whitsel, Goodarz Danaei, Renata Micha, Zach Conrad, Thomas Gaziano, Helen Bromley, Ffion Lloyd-Williams, Dariush Mozaffarian, Simon Capewell, Martin O’Flaherty
Journal: Circulation (2016)

Introduction: Cardiovascular disease (CVD) mortality burdens remain large and unequal in the US, and much is attributable to poor diets. However, few data exist regarding the potential population level impact of policies aimed at improving dietary intake, such as the Supplemental Nutrition Assistance Programme (SNAP), and potential effects on disparities. Aim: To estimate reductions in CVD mortality and disparities achievable in the US population up to 2030 through food price changes and mass media campaign interventions targeting fruits and vegetables (F&amp;V) and sugar sweetened beverages (SSBs). Methods: We developed a US IMPACT Food Policy Model to compare four contrasting food policy scenarios targeting dietary intake: A) - national F&amp;V mass media campaign, B) F&amp;V price reductions of 10% universally and C) 30% to SNAP participants, D) - SSB price increase of 10% universally. Data sources included the National Vital Statistics System, SEER single year population estimates, the US Bureau 2012 National Population projections, and NHANES. We stratified the US population into SNAP participants, SNAP eligible but not participating, and SNAP ineligible. We modelled cumulative deaths prevented or postponed (DPP) and life years gained (LYG) using best-evidence effect sizes for each policy, existing mortality rates and trends, and F&amp;V and SSB mortality effects. We stratified by age, sex, and CVD subtype from 2015 to 2030. Sensitivity analyses were conducted with Monte Carlo simulation. Results: Scenario B (universal 10% price reduction) would yield the greatest national benefits, generating approximately 88,000 DPPs (95% CI: 81,000-94,000) and 1,369,000 LYGs (1,268,000-1,460-000) by 2030. This compares with between 28,000 (26,000-30,000) and 84,000 (79,000-89,000) DPPs in Scenario A, depending on duration of media campaigns; and approximately 27,000 (24,000-30,000) and 29,000 (25,000-33,000) DPPs in scenarios C and D respectively. Scenario C (30% price reduction to SNAP participants) might reduce CVD disparities by about 18% comparing SNAP participants with the ineligible population. Scenarios A, B and D would have negligible effects on mortality disparities. Conclusions: All four dietary policies would be effective in reducing mortality. Reducing fruit and vegetable (F&amp;V) price by 10% to the entire US would save most lives. Reducing F&amp;V price by 30% to SNAP participants would reduce disparities the most, particularly if SNAP program coverage and penetration were improved. These results support population fiscal strategies targeting diet to reduce cardiovascular mortality and disparities in the US.
Taurine Prevents the Decrease in Expression and Secretion of Extracellular Superoxide Dismutase Induced by Homocysteine
Authors: HidemiNonaka, TakeshiTsujino, YasuhiroWatari, NoriakiEmoto, MitsuhiroYokoyama
Journal: Circulation (2001)

Background— Hyperhomocysteinemia is an independent risk factor for atherosclerosis. Homocysteine has been shown to induce endoplasmic reticulum (ER) stress in vascular endothelial cells. ER stress is a condition in which glycoprotein trafficking is disrupted and unfolded proteins accumulate in the ER. ER molecular chaperons, such as GRP78, are induced and an ER resident kinase, PERK, is activated when cells are subjected to ER stress. Conversely, taurine is reported to have antiatherogenic effects by unknown mechanisms. To elucidate the mechanisms by which homocysteine induces atherosclerosis and taurine prevents it, we examined whether homocysteine and taurine affect the expression and secretion of extracellular superoxide dismutase (EC-SOD), a glycoprotein secreted from vascular smooth muscle cells (VSMCs) that protects the vascular wall from oxidative stress. Methods and Results— We assessed the expression of EC-SOD and GRP78 mRNA in cultured rat VSMCs by Northern blot analysis. The EC-SOD protein secr...
Insulin Resistance Associated With Compensatory Hyperinsulinemia as an Independent Risk Factor for Vasospastic Angina
Authors: KazuyaShinozaki, MasaakiSuzuki, MotoyoshiIkebuchi, HiroshiTakaki, YasushiHara, MotooTsushima, YutakaHarano
Journal: Circulation (1995)

Background It is generally believed that coronary artery spasm plays an important role in the progression of obstructive coronary artery disease. Since insulin resistance together with hyperinsulinemia plays an important role in the pathogenesis of coronary atherosclerosis, we investigated the association of hyperinsulinemia and insulin resistance with vasospastic angina (VAP). Methods and Results The study population consisted of 60 patients with VAP and 42 control subjects (62 subjects with normal glucose tolerance and 40 with impaired glucose tolerance). Insulin sensitivity was determined by the steady-state plasma glucose (SSPG) method for nondiabetic, normotensive, nonobese subjects (16 control subjects, 16 obstructive coronary artery disease patients, and 16 VAP patients). Compared with the control groups, the 2-hour insulin area (area under the plasma insulin concentration-time curve) during a 75-g oral glucose tolerance test was significantly higher in both VAP groups with normal and impaired gluc...
Homeobox oncogene activation by pan-cancer DNA hypermethylation
Authors: Jianzhong Su, Yung-Hsin Huang, Xiaodong Cui, Xinyu Wang, Xiaotian Zhang, Yong Lei, Jianfeng Xu, Xueqiu Lin, Kaifu Chen, Jie Lv, Margaret A. Goodell, Wei Li
Journal: Genome biology (2018)

Cancers have long been recognized to be not only genetically but also epigenetically distinct from their tissues of origin. Although genetic alterations underlying oncogene upregulation have been well studied, to what extent epigenetic mechanisms, such as DNA methylation, can also induce oncogene expression remains unknown.
Abstract 19755: A More Accurate Automatic Cuff Blood Pressure Measurement Method
Authors: Jiankun Liu, Hao-Min Cheng, Chen-Huan Chen, Shih-Hsien Sung, Jin-Oh Hahn, Ramakrishna Mukkamala
Journal: Circulation (2015)

Most automatic cuff blood pressure (BP) measurement devices are based on oscillometry. These devices compute BP from the envelope of the oscillometric cuff pressure waveform using fixed-ratios. The fixed-ratio values are derived from population averages. As a result, the devices are often inaccurate in patients with stiff arteries. Our hypothesis is that oscillometry can be made more accurate in this important patient population by physical modeling of the phenomenon. We studied 126 patients (ages 38-85, 97 males) referred for diagnostic cardiac catheterization at the Taipei Veterans General Hospital under IRB approval. We obtained oscillometric cuff pressure waveforms for analysis using a commercial device (Omron VP1000 or Microlife WatchBP Office) and reference BP waveforms via an invasive catheter in the opposite brachial artery. We recorded these waveforms before and after sublingual nitroglycerin in many of the patients. We divided the data into a training set comprising 57 of the patient records and a testing set consisting of the remaining 69 patient records. We used the training dataset to develop a method to compute BP from the oscillometric cuff pressure waveform based on a physical model. In contrast to existing devices, the model-based method simultaneously determines BP and the arterial stiffness of the patient. In this way, the method is patient-specific rather than population-based. We used the testing dataset to evaluate the new method against the reference BP levels as well as to compare its accuracy to the commercial device. The Table illustrates the resulting BP errors. The model-based method showed, on average, 28% lower precision errors than the commercial device (statistically significant via Pitman-Morgan test with Bonferroni correction for multiple comparisons) and 41% less absolute BP errors exceeding 10 mmHg. In conclusion, the model-based method may afford more accurate automatic cuff BP measurement in patients with stiff arteries.
Abstract 2263: The dysregulation of circadian genes across cancers
Authors: Zexian Liu, Huan Lin, Zekun Liu, Kai Yu, Qi Zhao, Xiaolong Zhang, Yan Wang, Zhixiang Zuo
Journal: Cancer Research (2018)

Abstract As the daily oscillation in physiological processes, circadian is critical for health while disruption of the circadian rhythm has been associated with cancer in humans. Generally, circadian rhythm was proposed to play important roles in tumor suppression, while there were also evidences that disruption of canonical circadian pathway have anti-cancer effects. In this study, we systematically analyzed the aberrances including mutation, somatic copy number alternation, differential DNA methylation and differential expression of circadian genes across cancers based on TCGA data. It is observed that core circadian network genes (CCNGs) such as PER1/2/3, CLOCK, CRY1/2, ARNTL were highly mutated in a number of cancers such as uterine corpus endometrial carcinoma, skin cutaneous melanoma, stomach adenocarcinoma and colon adenocarcinoma. Generally, the expression for the majority of CCNGs was down regulated in a variety of the cancers such as bladder urothelial carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, cervical and endocervical cancers, prostate adenocarcinoma, glioblastoma multiforme and stomach adenocarcinoma, while the expression of a number of CCNGs were related with overall survival in various cancers. The alternations of somatic copy number and DNA methylation were observed to be consistent with the differential expression of these CCNGs. Furthermore, the PCA based circadian gene expression signature was found to be related with the overall survivals and immunophenotypes among cancers, which indicated that circadian rhythm might play critical roles in regulation of immune signaling state in tumor environment. Taken together, our study provided comprehensive analyses of the aberrances and functional roles of circadian genes in cancer, while the results should be helpful for further investigation of the molecular mechanisms and therapy development for cancer. Citation Format: Zexian Liu, Huan Lin, Zekun Liu, Kai Yu, Qi Zhao, Xiaolong Zhang, Yan Wang, Zhixiang Zuo. The dysregulation of circadian genes across cancers [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 2263.
Abstract 845: Acute irradiation exposure induces long-term cardiac adverse effects in the spontaneously hypertensive rat
Authors: Elliot T. Rosen, Dmitry Kryndushkin, Baikuntha Aryal, Yanira Gonzalez, Leena Chehab, Jennifer Dickey, Steven Mog, V Ashutosh Rao
Journal: Cancer Research (2018)

Abstract Radiation-induced heart disease (RIHD) presents a significant challenge in the oncology setting. For instance, patients receiving acute doses of irradiation to the thoracic cavity for Hodgkin's lymphoma or breast cancer are subject to an elevated risk of RIHD. Excessive oxidative stress, at least in part, is responsible for some of the tissue damage. The ability to monitor and mitigate the long-term cardiac effects of radiation exposure in these populations by modulating oxidative stress has the potential to lead to improved health outcomes. We utilized the spontaneously hypertensive rat (SHR), which has proven a good model for drug-induced cardiotoxicity, to evaluate irradiation-induced heart damage. SHRs were exposed to low, medium, or high doses of full-body irradiation. Necropsy was performed to collect serum and tissue samples at two and four weeks post-irradiation, as well as followed for one year. Four weeks following gamma irradiation, both males and females showed decreased heart mass and decreased whole body mass after exposure to medium and high doses of radiation and these decreases were sustained in the high dose groups after one year. Serum cardiac troponin I and T analysis revealed signs of cardiomyopathy in both the medium and high dose groups at early time points and this signal was sustained in some animals up to one year later. Echocardiography revealed functional changes in cardiac performance including an increase in left ventricular volume at diastole in males and a decrease in left ventricular mass. Low red blood cell count indicated sustained anemic conditions in both males and females receiving the highest dose of irradiation, yet males appeared to be more sensitive. Levels of pro-inflammatory IL-6 were elevated at four weeks in males receiving the high dose. Finally, multiple animals receiving radiation developed spontaneous tumors after one year. We are currently investigating the oxidative stress-mediated molecular mechanisms behind the radiation-induced cardiac damage. Citation Format: Elliot T. Rosen, Dmitry Kryndushkin, Baikuntha Aryal, Yanira Gonzalez, Leena Chehab, Jennifer Dickey, Steven Mog, V Ashutosh Rao. Acute irradiation exposure induces long-term cardiac adverse effects in the spontaneously hypertensive rat [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 845.
Abstract 1699: Treatment with agonist anti-GITR antibody after chemotherapy enhances tumor immunity
Authors: Allison Betof Warner, Daniel Hirschhorn, Adam Cohen, Cailian Liu, Walter Newman, Cyndi Sirard, Jedd Wolchok, Taha Merghoub
Journal: Cancer Research (2018)

Abstract Stimulation of glucocorticoid-induced tumor necrosis factor receptor (GITR) has been shown to enhance antitumor immunity by stimulating effector CD4+ and CD8+ T cells and attenuating suppression and depleting by CD4+Foxp3+ regulatory T cells (Treg). However, GITR monotherapy does not effectively control tumor growth. We hypothesize that cyclophosphamide (CTX), a cytotoxic chemotherapeutic agent with key immunomodulatory properties, can enhance the potency of GITR engagement anti-tumor effects. Further, we hypothesize that CTX can induce neoantigen formation by increasing tumor mutation burden. In this study, we administered high-dose CTX (250 mg/kg) followed the next day by an agonist anti-GITR antibody (DTA-1) to C56BL/6 mice bearing poorly immunogenic B16 melanoma tumors. We found that the combination therapy can cause regression of established tumors whereas the single agents did not. Mechanistically, we found that CTX administration results in tumor antigen release, which enhances the antitumor T cell response after treatment with DTA-1. This effect is lost when lower doses of CTX are given or CTX is administered prior to tumor inoculation, suggesting that tumor cell death and cross-presentation of tumor antigens to T cells is necessary. Furthermore, Treg cells are an important target of combination therapy. Intratumoral Treg levels were substantially reduced in treated mice, which greatly increased the ratio of T effector/Treg in the tumor. In conclusion, CTX and agonist anti-GITR antibody slows tumor progression and can induce regression of palpable, poorly immunogenic B16 melanoma tumors, likely by enhancing cross-priming and increasing the T effector/Treg ratio in the tumor. Thus, this combination warrants further investigation as a novel immunotherapy approach and provides rational for exploring combination of GITR agonist antibodies with chemotherapeutic treatments in clinical settings. Citation Format: Allison Betof Warner, Daniel Hirschhorn, Adam Cohen, Cailian Liu, Walter Newman, Cyndi Sirard, Jedd Wolchok, Taha Merghoub. Treatment with agonist anti-GITR antibody after chemotherapy enhances tumor immunity [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 1699.
Index Matching to Improve Optical Coherence Tomography Imaging Through Blood
Authors: MarkBrezinski, KathleenSaunders, ChristineJesser, XingdeLi, JamesFujimoto
Journal: Circulation (2001)

Background—Most myocardial infarctions are caused by the rupture of small rather than large plaques in the arteries of the heart that are beyond the detection limit of current technologies. Methods and Results—Recently, optical coherence tomography (OCT) has demonstrated considerable potential as a method for high-resolution assessment of vulnerable plaque. However, intravascular OCT imaging is complicated by the need to remove blood from the imaging field because blood results in substantial signal attenuation. This work examines index matching as a method for increasing penetration. Index matching is based on the hypothesis that the predominant source of scattering in blood is the difference in refractive index between the cytoplasm of erythrocytes and serum. By increasing the refractive index of serum to a value near that of the cytoplasm, or index matching, scattering can be substantially reduced. The concept was tested with a system that pumped blood in vitro through transparent tubing. The test comp...
Mitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway
Authors: XiaomeiGuo, Kuang-HueihChen, YanhongGuo, HuaLiao, JianTang, Rui-PingXiao
Journal: Circulation Research (2007)

Previous studies have shown that mitofusin 2 (Mfn-2) (or hyperplasia suppressor gene [HSG]) inhibits vascular smooth muscle cell (VSMC) proliferation. Here, we demonstrate that Mfn-2 is a primary determinant of VSMC apoptosis. First, oxidative stress with H2O2, inhibition of protein kinase C with staurosporine, activation of protein kinase A with forskolin, and serum deprivation concurrently elevate Mfn-2 expression and induce VSMC apoptosis. Second, overexpression of Mfn-2 also triggers apoptosis of VSMCs in culture and in balloon-injured rat carotid arteries, thus contributing to Mfn-2–mediated prevention of neointima formation after angioplasty. Third, Mfn-2 silencing protects VSMCs against H2O2 or Mfn-2 overexpression–induced apoptosis, indicating that upregulation of Mfn-2 is necessary and sufficient for oxidative stress–mediated VSMC apoptosis. The Mfn-2 proapoptotic effect is independent of its role in mitochondrial fusion but mainly mediated by inhibition of Akt signaling and the resultant activat...