tbuckley/cabot-search huggingface dataset:
Abstract MP086: Association Between the Angiotensin-Converting Enzyme-2 Gene and Blood Pressure in a Cohort of Canadian Adolescents
Authors: Lucile Malard, Lisa Kakinami, Jennifer O’Loughlin, Marie-Hélène Roy-Gagnon, Aurélie Labbe, Louise Pilote, Pavel Hamet, Johanne Tremblay, Gilles Paradis
Journal: Circulation (2012)

Background: The Angiotensin-Converting Enzyme-2 (ACE2) gene, located on chromosome X, is believed to be implicated in blood pressure (BP) regulation. However the few studies that have assessed this association have yielded mixed results. We examined the association between BP and ACE2 single nucleotide polymorphisms (SNPs) in a population-based cohort of adolescents, thereby minimizing confounding by treatment for hypertension and other chronic diseases. Methods: Participants were 852 of 1293 adolescents from the Nicotine Dependence In Teens (NDIT) cohort study. Participants provided a blood sample for DNA, and BP was measured on the right arm at rest, in the sitting position, by trained, certified technicians using an automated oscillometric device at age 12, 15 and 17 years. Instruments were calibrated against mercury sphygmomanometer before each data collection. Systolic (SBP) and diastolic blood pressure (DBP) were measured 3 times at 1-minute intervals, and the mean was used for analysis. Four SNPs (rs2074192, rs233575 , rs2158083, rs1978124) in the ACE2 gene were genotyped. The relationship between ACE2 SNPs and each of SBP and DBP was examined using linear growth models adjusted for height and ethnicity, and stratified by sex. Results: Mean age at baseline was 12.7 years; 47.8% of participants were male (n=407 of 852). All SNPs were in Hardy-Weinberg equilibrium (p&gt;0.05), and three of the four SNPs were in linkage disequilibrium ( rs233575 and rs2158083 r2: 0.71; rs1978124 and rs233575 r2: 0.36; rs2158083 and rs1978124 r2: 0.52) with each other. SNP rs2074192 was in low linkage disequilibrium with these 3 SNPs (r2 &lt;0.3). Compared to boys carrying the G allele, SBP in boys carrying the A allele of SNP rs2074192 was 2.45 mmHg lower (CI: 0.20-4.70, p=0.0350); DBP was 1.67 mmHg lower (CI: 0.47-2.87, p=0.0067). SNPs rs233575 , rs2158083, and rs1978124 were not significantly associated with SBP or DBP in boys. None of the four SNPs were associated with SBP or DBP in girls. Conclusion: Because elevated BP tracks from childhood to adulthood, the ACE2 gene could represent a new therapeutic target in boys to prevent elevated BP. Association between this gene and BP and potential for prevention should be further investigated.
Contribution of K <sub>V</sub> 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease
Authors: Yoshinori Nishijima, Sheng Cao, Dawid S. Chabowski, Ankush Korishettar, Alyce Ge, Xiaodong Zheng, Rodney Sparapani, David D. Gutterman, David X. Zhang
Journal: Circulation Research (2016)

Hydrogen peroxide (H2O2) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating large-conductance Ca2+-activated K+ channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) when compared with those with CAD remain unknown.We hypothesize that H2O2-elicited dilation involves different K+ channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease.H2O2 induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a large-conductance Ca2+-activated K+ channel blocker, and by 4-aminopyridine, a voltage-gated K+ (KV) channel blocker. Assays of mRNA transcripts, protein expression, and subcellular localization revealed that KV1.5 is the major KV1 channel expressed in vascular smooth muscle cells and is abundantly localized on the plasma membrane. The selective KV1.5 blocker diphenylphosphine oxide-1 and the KV1.3/1.5 blocker 5-(4-phenylbutoxy)psoralen reduced H2O2-elicited dilation to a similar extent as 4-aminopyridine, but the selective KV1.3 blocker phenoxyalkoxypsoralen-1 was without effect. In arterioles from CAD subjects, H2O2-induced dilation was significantly reduced, and this dilation was inhibited by paxilline but not by 4-aminopyridine, diphenylphosphine oxide-1, or 5-(4-phenylbutoxy)psoralen. KV1.5 cell membrane localization and diphenylphosphine oxide-1-sensitive K+ currents were markedly reduced in isolated vascular smooth muscle cells from CAD arterioles, although mRNA or total cellular protein expression was largely unchanged.In human arterioles, H2O2-induced dilation is impaired in CAD, which is associated with a transition from a combined large-conductance Ca2+-activated K+- and KV (KV1.5)-mediated vasodilation toward a large-conductance Ca2+-activated K+-predominant mechanism of dilation. Loss of KV1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.
Abstract 515: Integrative analysis of LncRNA-drug interactions in cancer identified <i>EPIC1</i> as an oncogenic lncRNA that regulates breast cancer tumorigenesis and iBET resistance through regulating MYC transcriptional activity
Authors: Yue Wang, Zehua Wang, Bo Yang, Min Zhang, Da Yang
Journal: Cancer Research (2018)

Abstract Emerging evidence suggests that lncRNAs can serve as promising biomarkers and therapeutic targets in cancer. Here, by integrating multiple dimensional pharmacogenomic data of 11,950 lncRNA in 5,605 tumors and 1,005 cancer cell lines, we build lncRNA drug response models for 265 anti-cancer compounds across 27 cancer types. Our study reveals the cancer cell lines can realistically recapitulate patient tumors in IncRNA genomic and epigenetic alterations. Using Elastic Net (EN) regression model combined with bootstrap cross validation, our analysis identified 162,327 unique lncRNA-drug interactions. The robustness of lncRNA based EN-models is validated by independent cancer cell line drug response data. By applying lncRNA EN-models of 49 FDA approved drugs to TCGA pan-cancer patient samples across 21 caner types, we have shown that the cancer cell line based EN-models could readily predict chemotherapy responses in patients with breast, stomach, thyroid, and colon rectal cancer. Further lncRNA-protein coding gene co-expression analysis reveals that drug-predictive lncRNAs regulated drug-metabolism and drug-target pathways, which provide underlying mechanism for lncRNAs' regulation of drug response. This analysis has identified a novel intergenic lncRNA, EPIC1, regulates breast cancer tumorigenesis and iBET (Bromodomain Inhibitors) resistance through directly interacting with MYC and regulating MYC transcriptional activity. Knockdown of EPIC1 in breast cancer cells leads to inhibition of colony formation, cell cycle arrest, and suppression of tumor growth in vitro and in vivo. Overexpression of EPIC1 increased MYC target expression, breast tumorigenesis in vitro and in vivo, and promote iBET resistance in breast cancer. Mechanistically, EPIC1 directly interacts with MYC through EPIC1's 129-283 nt region. EPIC1 knockdown reduces the occupancy of MYC protein to the promoters of its target genes (e.g., p21, CCNA2, CDC20, and CDC45) without influencing MYC expression. The oncogenic effect of EPIC1 can be abolished by MYC knockdown. To our best knowledge, this is the first study to link noncoding genotypes with drug response phenotypes in both cancer cell lines and patient tumors. Citation Format: Yue Wang, Zehua Wang, Bo Yang, Min Zhang, Da Yang. Integrative analysis of LncRNA-drug interactions in cancer identified EPIC1 as an oncogenic lncRNA that regulates breast cancer tumorigenesis and iBET resistance through regulating MYC transcriptional activity [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 515.
Abstract 4778: Assessing efficacy of neratinib in HER2-driven lung cancer
Authors: Shuai Li, Shengwu Liu, Ting Chen, Jiehui Deng, Min Wu, Mari Kuraguchi, Cam Anh Tran, Paul T. Kirschmeier, Francesca Avogadri-Connors, Richard E. Cutler, Alshad S. Lalani, Kwok-Kin Wong
Journal: Cancer Research (2018)

Abstract HER2 mutations have been classified as oncogenic drivers that are present in 2-4% of lung adenocarcinomas. However, due to limited preclinical studies and clinical trials, there is still no available standard of care for this group of lung cancer patients. To fulfill the clinical need for targeting HER2 mutations in lung cancer patients, we performed a comprehensive preclinical study to evaluate the efficacy of neratinib, an irreversible small-molecule pan-HER tyrosine kinase inhibitor that potently binds and inhibits EGFR, HER2, and HER4. We used the previously described genetically modified mouse model (GEMM) of lung adenocarcinomas driven by the major mutant form of human HER2 exon 20 insertions (A775_G776insYVMA) for testing neratinib either as a single agent or in combination with other therapies including trastuzumab in vivo. Treatment efficacy was evaluated based on both monitoring tumor volume changes and survival. Magnetic resonance imaging (MRI) was used for quantifying tumor burden. Tolerability and the overall health of animals were evaluated based on body weight change. We found that neratinib treatment alone provided a modest yet significant response in inhibiting HER2 mutant lung tumors in this model. Pharmacodynamic studies showed that neratinib effectively abolished HER2 phosphorylation and inhibited major downstream signaling targets such as pAKT and pERK. Moreover, combination therapy with neratinib and trastuzumab showed a greater treatment effect by reducing tumor burden with significantly longer progression-free survival and overall survival compared to single agents tested. In all neratinib-based regimens, body weight of treated animals remained stable. On this basis, our study provides a strong rationale to test the combination of neratinib with trastuzumab for the treatment of HER2 mutant NSCLC patients. Citation Format: Shuai Li, Shengwu Liu, Ting Chen, Jiehui Deng, Min Wu, Mari Kuraguchi, Cam Anh Tran, Paul T. Kirschmeier, Francesca Avogadri-Connors, Richard E. Cutler, Alshad S. Lalani, Kwok-Kin Wong. Assessing efficacy of neratinib in HER2-driven lung 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 4778.
Author Correction: Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts
Authors: Daria Merkurjev, Wan-Ting Hong, Kei Iida, Ikumi Oomoto, Belinda J. Goldie, Hitoshi Yamaguti, Takayuki Ohara, Shin-ya Kawaguchi, Tomoo Hirano, Kelsey C. Martin, Matteo Pellegrini, Dan Ohtan Wang
Journal: Nature Neuroscience (2018)
Predictive Adaptive Responses to Maternal High-Fat Diet Prevent Endothelial Dysfunction but Not Hypertension in Adult Rat Offspring
Authors: ImranKhan, VasiaDekou, MarkHanson, LucillaPoston, PaulTaylor
Journal: Circulation (2004)

Background— Population-based studies suggest that fetal adaptive responses to maternal dietary imbalance confer survival benefit when the postnatal diet remains suboptimal but increase susceptibility to cardiovascular disease when postnatal nutrition is improved. We have investigated “predictive adaptive” responses in a rodent model in which adult offspring of fat-fed dams develop characteristics of the metabolic syndrome. Methods and Results— Sprague-Dawley rats were fed a fat-rich diet or normal chow throughout pregnancy and weaning. Vascular endothelial function and blood pressure were determined in 180-day-old offspring of fat-fed dams raised on standard chow (FC) or on the fat-rich diet (FF) and in offspring of chow-fed dams raised on chow (CON). Small mesenteric artery endothelium-dependent dilation to acetylcholine was impaired in male and female FC (by ANOVA, P<0.001 versus CON) but similar to CON in FF (P=NS). Blood glucose was lower in FF versus FC. Heart rate was reduced in male FC versus CON (...
Abstract 3565: Role of novel microRNA 4287 at a frequently deleted chromosome 8p region in prostate cancer
Authors: Divya Bhagirath, Thao Yang, Laura Tabatabai, Shahana Majid, Soichiro Yamamura, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini
Journal: Cancer Research (2019)

Abstract Deletion of chromosome (chr)8p21-22 region that has been traditionally associated with the loss of homeodomain protein, NKX3.1 and with tumor initiation, is frequently observed in prostate cancer (PCa). More significantly, loss of this region is associated with aggressiveness and poor prognosis of PCa, thereby emphasizing a key role of this region in advanced prostate cancer. In a paradigm shifting hypothesis, we proposed that this frequently deleted locus is associated with a cluster of miRNA genes - miR-3622a/b and miR-383- that are lost in PCa and play an important mechanistic role in PCa progression and metastasis by regulating Epithelial-mesenchymal-transition (EMT) and stemness. Extending our hypothesis, in this study we evaluated the role of miR-4287, a miRNA gene located within this region in PCa. We profiled the expression of miR-4287 in laser capture microdissected (LCM) PCa tissues and matched adjacent normal regions by real time PCR. miR-4287 expression was down regulated in ~79% of tissue samples. High miR-4287 expression was observed in 20% of cases. Analyses of miR-4287 expression in prostate cell lines showed that its expression is specifically attenuated in PCa cell lines compared to normal or immortalized prostate epithelial cells. Further, we evaluated the functional role of miR-4287 in prostate cancer by overexpressing miR-4287 precursor in PCa cell lines PC3 and LNCaP. miR-4287 overexpression in PCa cell lines led to decreased cellular viabilities as compared to control cells. Moreover, PCa cell lines overexpressing miR-4287 showed an increase in apoptosis and G0/G1 arrest. Further, we found that miR-4287 inhibits epithelial to mesenchymal transition (EMT) in PCa as its overexpression in PCa cell lines led to increased E-cadherin and decreased vimentin expression concomitant with morphological changes consistent with mesenchymal to epithelial transition (MET). We identified SRC, SFPR4 and CD44 as potential miR-4287 targets. Taken together, our data suggests that miR-4287 plays a significant role as tumor suppressor in PCa pathogenesis. Citation Format: Divya Bhagirath, Thao Yang, Laura Tabatabai, Shahana Majid, Soichiro Yamamura, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini. Role of novel microRNA 4287 at a frequently deleted chromosome 8p region in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3565.
Abstract 3511: The mechanism of antitumor effect of metformin forgemcitabine-resistant pancreatic adenocarcinoma
Authors: Keiichi Suzuki, Osamu Takeuchi, Yukio Suzuki
Journal: Cancer Research (2018)

Abstract Metformin (MET) is the first-line treatment for type 2 diabetes mellitus. Several epidemiological studies have reported anti-cancer effects of MET, including against pancreatic ductal adenocarcinoma (PDAC), which mainly acts through induction of AMP activated protein kinase (AMPK). Gemcitabine (GEM) has become the standard chemotherapy for PDAC but tolerance to GEM has become a burdensome issue. We evaluated the anti-tumor effects of MET for GEM-resistant PDAC in a xenograft mouse model. For this in vivo study, BxG30 (the cell line for GEM-resistant PDCA) was implanted into both flanks of female BALB/c nude mice. Mice were divided into four groups: (i) control (no treatment); (ii) the GEM-treated group (100 mg/kg); (iii) the MET-treated group (600 mg/kg); and (iv) the combined treatment group (G+M). Mice were fed for 4 weeks. Estimated tumor volumes and body weights were measured each week. Treatments were initiated 2 weeks after implantation. MET was administrated orally once per day. GEM was given by intraperitoneal injection once per week. Compared with the control, the final tumor volumes were decreased significantly only in the G+M group. [SCW1] The treated control ratio (T/C%) was calculated: GEM, 80.2%; MET, 54.0%; G+M, 47.2%. The anti-tumor effect of GEM for BxG30 was clearly limited[SCW2] . MET group showed satisfactory anti-tumor effects, but T/C% was &amp;lt;50% only in the G+M group. This result revealed that combination therapy had excellent anti-tumor effects even for GEM-resistant PDAC. The phosphorylation of ribosomal proteins S6 and 4E-BP, important targets of the mammalian target of rapamycin (mTOR) signaling pathway, was surveyed by western blot analysis. Western blot analysis showed inhibition of S6 and 4E-BP phosphorylation by co-incubation with MET, but not with GEM. Hypoxia-inducible factor 1 (HIF-1) is the one of the most important target of mTOR signaling pathway influencing tumor cell to progress, thus the expression level of HIF-1 was evaluated by western blot analysis as well. The results showed significant inhibition of HIF-1 expression by MET treatment, but not by GEM incubated under hypoxia (95%N2, 5%O2). Then the production of VEGF was evaluated by ELISA under hypoxia. The result showed suppression of VEGF production by MET treatment, but not by GEM. Our data showed that MET develops a different anti-tumor effect from GEM by suppression of mTOR-HIF-1 signaling. These results are of great clinical interest and reveal the potential of another anti-tumor agent for treatment of PDAC. Citation Format: Keiichi Suzuki, Osamu Takeuchi, Yukio Suzuki. The mechanism of antitumor effect of metformin forgemcitabine-resistant pancreatic adenocarcinoma [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 3511.
Soluble CD40 Ligand Impairs the Function of Peripheral Blood Angiogenic Outgrowth Cells and Increases Neointimal Formation After Arterial Injury
Authors: MihailHristov, DenisGümbel, EstherLutgens, AlmaZernecke, ChristianWeber
Journal: Circulation (2010)

Background— Recent work has revealed an essential involvement of soluble CD40 ligand (sCD40L) in inflammation and atherosclerosis. We investigated whether sCD40L functionally affects peripheral blood–derived angiogenic early outgrowth cells (EOCs) and neointimal remodeling after arterial injury. Methods and Results— Besides myeloid and endothelial markers, cultured human EOCs strongly expressed CD40 mRNA and protein. EOC adhesion to fibronectin, fibrinogen, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 under flow conditions, as well as their transmigration toward stromal cell–derived factor-1α, was dose-dependently reduced after preincubation with recombinant human sCD40L for 24 hours. Integrin expression was unaffected by sCD40L, implying that integrin adhesiveness was attenuated. Surface-immobilized CD40L supported much lower adhesion of EOCs than fibronectin. Treatment of EOCs with sCD40L increased superoxide anion production and decreased viability and proliferation. Notably...
Abstract 3735: Somatostatin receptor-based imaging and treatment of murine pancreatic neuroendocrine tumors induced by MEN1-loss
Authors: Janet W. Li, Hanwen Zhang, Sean D. Carlin, Nitya Raj, David S. Klimstra, Steven K. Libutti, Wolfgang A. Weber, Diane Reidy-Lagunes, Brian R. Untch
Journal: Cancer Research (2018)

Abstract Background: Somatostatin receptor ligands are used for the detection and treatment of neuroendocrine tumors. Mutations of MEN1 are frequently observed in human pancreatic neuroendocrine tumors (PanNETs). We utilized a previously described murine model of PanNET that harbors a floxed Men1 allele to study the feasibility of somatostatin receptor type 2 (SSTR2) imaging and therapy in mice. Methods: Mice with pancreatic-specific expression of Cre recombinase and floxed Men1 (Pdx1-cre, Men1f/f) were aged to 9-12 months to allow for the development of PanNETs. Mice were injected with either the SSTR2 agonist 68Ga-DOTA-TATE or antagonist 177Lu-DOTA-JR11 via tail vein. Imaging with 68Ga-DOTA-TATE was performed using PET/CT. Percent uptake of injected activity was calculated for visualized tumors. 177Lu-DOTA-JR11 binding was visualized with autoradiography. Immunofluorescence (IF) detected SSTR2 expression and a marker of DNA damage (γ-H2AX). Results: IF staining for SSTR2 showed membranous localization of the receptor limited to areas of neoplasia with high and low levels of SSTR2 expression variable by individual animal and tumor. Tumors were successfully detected in mice injected with 68Ga-DOTA-TATE using PET/CT. The mean maximum percent uptake of injected activity for visualized tumors was 2.8% +/- 0.34. Injection of 177Lu-DOTA-JR11 and subsequent autoradiography confirmed localization of radionuclide to areas of histology-confirmed neoplasia. Treatment effect (DNA damage) was observed with co-localization of γ-H2AX and SSTR2 staining in neoplastic areas as compared to hyperplastic islets and normal pancreatic parenchyma that were both SSTR2 and γ-H2AX negative. Conclusion: PanNETs from Pdx1-cre, Men1f/f mice can be successfully imaged and treated using somatostatin-based radionuclides. This genetically accurate model can be employed to study peptide receptor radionuclide therapy efficacy and toxicity either alone or in combination with other treatment strategies. Citation Format: Janet W. Li, Hanwen Zhang, Sean D. Carlin, Nitya Raj, David S. Klimstra, Steven K. Libutti, Wolfgang A. Weber, Diane Reidy-Lagunes, Brian R. Untch. Somatostatin receptor-based imaging and treatment of murine pancreatic neuroendocrine tumors induced by MEN1-loss [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 3735.
Outcomes After Acute Myocardial Infarction in HIV-Infected Patients
Authors: LucLorgis, JonathanCottenet, GuillaumeMolins, EricBenzenine, MarianneZeller, HervéAube, ClaudeTouzery, JoelleHamblin, AurélieGudjoncik, YvesCottin, CatherineQuantin
Journal: Circulation (2013)

Background—We aimed to assess in-hospital case fatality and 1-year prognosis in HIV-infected patients with acute myocardial infarction. Methods and Results—From the PMSI (Program de Medicalisation des Systemes d’informatique) database, data from 277 303 consecutive acute myocardial infarction patients hospitalized from January 1, 2005, to December 31, 2009, were analyzed. Surviving patients were followed up for 1 year after discharge. HIV-infected patients were compared with uninfected patients. Among the cohort, HIV-infected patients (n=608) accounted for 0.22%. All-cause hospital and 1-year mortality rates were lower in the HIV-infected group than in uninfected patients (3.1% versus 8.1% [P<0.001] and 1.4% versus 5.5% [P<0.001], respectively). From the database, we then analyzed a cohort derived from a matching procedure, with 1 HIV patient matched with 2 patients without HIV, based on age and sex (n=1824). Ischemic cardiomyopathy was more frequent in the HIV group (7.6% versus 4.2%, P=0.003). Hospitali...