tbuckley/cabot-search huggingface dataset:
Abstract P175: Effectiveness Of A Community Screening Program For Metabolic Syndrome And Cardiovascular Risk Factor Identification In Young South Asians Adults
Authors: MeghaPrasad, ElenaFlowers, AshishMathur, VishaalSridhar, CesarMolina, MintuTurakhia
Journal: Circulation (2014)

Background: Metabolic syndrome has been associated with increased risk of cardiovascular disease.We aimed to determine the effectiveness of a community-based screening program in identifying cardiovascular risk factors in a healthy young South Asian population. Methods: Between 2006 and 2011, 3,314 patients of all ages were recruited as a part of a prospective cohort study investigating cardiovascular risk in South Asians. We analyzed 1537 patients between the ages of 18 and 40. Demographic and baseline characteristics including baseline laboratory markers and blood pressures were obtained at initial visit. Results: The total cohort of 1537 patients was 66.5% male, and the mean age was 35±5 years. Among participants who denied a history of hypercholesterolemia, 62% had elevated LDL-C (>100 mg/dL), and 8% had markedly elevated LDL-C (>160 mg/dL). Overall, diabetes was present in 4%, hypertension was present in 12% and hyperlipidemia was present in 46%. Low HDL-C (50% of men, 52% of women) and elevated trig...
Abstract 4289: Involvement of the miR-6883 family and the circadian rhythm gene PER1 in the DNA damage response (DDR) and chemosensitivity
Authors: Amriti R. Lulla, Avital Lev, Michael Slifker, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2018)

Abstract PER1 is a circadian clock protein known to play a role in the cell cycle by directly regulating levels of Wee1 and indirectly influencing levels of Cdc2 and Cyclin B1. PER1 interaction with CHK2 promotes apoptosis in response to DNA damaging agents and loss of PER1 promotes chemoresistance. Expression of PER1 is found to be lost in most CRC tumors and restoring it sensitizes CRC cell lines to DNA damaging chemotherapeutic agents. However, the regulation of PER1 and its mechanism of repression in CRC remains unknown. We recently discovered and characterized miR-6883-5p, which is an intronic miRNA in the PER1 gene. Since PER1 is lost in most CRC it is suggested that the expression of miR-6883-5p is also lost. We showed that restoring the expression of miR-6883-5p via mimics induces G1-arrest and subsequent cell death in CRC cell lines. Similar to the overexpression of PER1, expression of miR-6883-5p with mimics increased the sensitivity of CRC cell lines to chemotherapeutic agents such as irinotecan and 5-FU. miR-6883-5p is a direct negative regulator of CDK4 and CDK6 and the downstream G1-S transition via RB. Our ongoing studies are characterizing molecular targets of miR-6883-5p and its role in the DNA damage response (DDR). FOXM1 is a downstream effector of CDK4 that plays a role in the DDR. Downregulation of FOXM1 sensitizes cells to DNA damage and restores chemosensitivity. We are further evaluating the direct effects of miR-6883-5p on FOXM1. FOXM1 is a member of the forkhead box (FOX) transcription factor family, expressed exclusively in proliferating cells. Its upregulation in different tumor types, including CRC promotes cell proliferation, EMT and chemoresistance. Interestingly, FOXM1 is also a repressor of the clock gene CRY2. Here, we hypothesize that miR-6883-5p mediated targeting of FOXM1 is crucial for the DDR, and, further, like CRY2, FOXM1 might have a role in regulating PER1 and thus miR-6883-5p endogenous levels. We report that miR-6883-5p levels are increased following exposure of tumor cells to chemotherapeutic agents that cause DNA damage. We are further elucidating the role of FOXM1 in the induction of miR-6883-5p under the DDR, and propose that induction of miR-6883-5p may provide a novel mechanism for tumor growth arrest in chemotherapy-exposed cells. Citation Format: Amriti R. Lulla, Avital Lev, Michael Slifker, David T. Dicker, Wafik S. El-Deiry. Involvement of the miR-6883 family and the circadian rhythm gene PER1 in the DNA damage response (DDR) and chemosensitivity [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 4289.
Abstract IA26: Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies
Authors: Ross Levine
Journal: Clinical Cancer Research (2017)

Abstract Clinical, cytogenetic, and gene-based studies have been used to inform biology and improve prognostication for patients with acute myeloid leukemia (AML), myelodysplasia (MDS), and myeloroliferative neoplasms (MPN). Most recently, a series of candidate gene and whole-genome studies have identified recurrent somatic mutations in AML patients including TET2, ASXL1, DNMT3A, and cohesin complex mutations. Moreover, these mutations can be used to improve risk stratification in AML independent of established clinical parameters. Integrating mutational data with dose-intensity revealed that high-dose daunorubicin improved survival in patients with DNMT3A/NPM1 mutations or MLL translocations relative to treatment with standard-dose daunorubicin, but not in patients wild-type for these alterations. These data provide important clinical implications of genetic alterations in AML by delineating mutation combination genotypes that predict outcome in AML and improve AML risk stratification. Of biologic importance, the TET family of proteins have been shown to place a hydroxyl mark on methylated DNA and lead to DNA demethylation. We and others have found that TET2/IDH mutations lead to loss of DNA hydroxymethylation and a hypermethylation phenotype in leukemia patients. In addition, in vitro and in vivo studies show that TET2 loss or neomorphic IDH1/2 mutations lead to impaired hematopoietic differentiation, increased stem cell self-renewal, and myeloid transformation in vivo. We have also investigated the role of mutant DNMT3A in AML pathogenesis, and shown that these mutations cooperate with other disease alleles to induce leukemic transformation and to confer chemoresistance due to impaired DNA damage sensing. We will present novel data showing how these mutations coopt the epigenetic state of hematopoietic stem/progenitor cells in order to contribute to transformation and that these mutations have biologic and prognostic relevance. Citation Format: Ross Levine. Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA26.
Development of Proximal Coronary Arteries in Quail Embryonic Heart
Authors: KatsumiAndo, YujiNakajima, ToshiyukiYamagishi, SadamuYamamoto, HiroakiNakamura
Journal: Circulation Research (2004)

Studies have shown that the proximal coronary artery (PCA) develops via endothelial ingrowth from the peritruncal ring (PR) of the coronary vasculature. However, the details of PCA formation remain unclear. We examined the development of PCAs in quail embryonic hearts from 5 to 9 days of incubation (embryonic day [ED]) using double-immunostaining for QH1 (quail endothelial marker) and smooth muscle α-actin. At 6 to 7 ED, several QH1-positive endothelial strands from the PR penetrated the facing sinuses, and in some embryos, several endothelial strands penetrated the posterior (noncoronary) sinus. At 7 to 8 ED, the endothelial strands penetrating the facing sinuses seemed to fuse, forming a proximal coronary stem that was demarcated from the aortic wall by the nascent smooth muscle layer of the coronary artery. By 9 ED, two coronary stems were completely formed, and the endothelial strands previously penetrating the noncoronary sinus had disappeared. Confocal microscopy at 6 ED revealed discontinuous QH1-p...
Abstract 16459: Myocardial Replenishment of Tissue Inhibitor of Metalloproteinase (TIMP)-3 and TIMP4 Following Myocardial Infarction Result in Differential Protective Effects
Authors: Abhijit Takawale, Ratnadeep Basu, Xiuhua Wang, Zamaneh Kassiri
Journal: Circulation (2015)

Introduction: The cardiomyopathy ensuing myocardial infarction (MI) results from the ischemic loss of the myocardium, impaired left ventricular (LV) dilation, eventually leading to heart failure. This is accompanied with adverse remodeling of the extracellular matrix (ECM) and disrupted balance of its regulatory proteins, particularly TIMP3 and TIMP4 that are reduced shortly after MI induction. Hypothesis: Replenishment of TIMP3 and/or TIMP4 post-MI will hinder adverse remodeling of the ECM and may also promote beneficial cellular response to limit tissue injury and cardiac dysfunction. Methods: MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad-hTIMP3), human TIMP4 (Ad-hTIMP4) or no-TIMP control (Ad-Null) were injected in the peri-infarct zone (5 injections/heart; 5.4x107 pfu/heart). Cardiac function was assessed by Vevo2100 ultrasound imaging system. Cellular and molecular analyses (inflammation, cell viability, angiogenesis, ECM composition) were assessed at 3 and 7 days post-MI. Results: Injection of Ad-Null had minimal effects in the post-MI dysfunction and remodeling. Ad-hTIMP3 injection exerted more beneficial effects compared to Ad-hTIMP4. Ad-TIMP3 group showed significantly better cardiac function (EF=35.49±2.52%, p&lt;0.05), and to a lesser extent Ad-TIMP4 group (EF=28.79±1.79%) compared to Ad-Null group (EF=25.46±2.29%). Similarly, LV dilation was markedly attenuated in Ad-TIMP3 (LVEDV=77.08±6.05μL) but not in Ad-TIMP4 group (LVED=112.98±5.68 μL) compared to Ad-Null (LVEDV=112.98±7.0 μL). Inflammatory response (macrophage/neutrophil density) was not altered with Ad-TIMP treatment. Interestingly, the infarct size was smaller in Ad-TIMP3 group and even after 1wk post-MI, viable myocytes were detected in these hearts. Assessment of coronary density in the infarct and peri-infarct regions (intra-jugular fluoro-tagged lectin injection) revealed that Ad-TIMP3 promoted angiogenesis in the infarcted myocardium. Conclusions: This novel pro-angiogenic function of TIMP3 post-MI, in addition to its MMP inhibitory function, could provide additional beneficial effects in post-MI treatment.
Abstract 263: Effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on hepatoma cell lines and liver tumorigenesis
Authors: Yohei Shirakami, Koki Obara, Masaya Kubota, Hiroyasu Sakai, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima
Journal: Cancer Research (2018)

Abstract Obesity, diabetes mellitus, and their related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Anti-diabetic agents sodium glucose cotransporter (SGLT)-2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of the SGLT2 inhibitor tofogliflozin on the development of NAFLD-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The direct effects of tofogliflozin on human hepatoma cell lines were also evaluated. Male db/db mice were administered diethylnitrosamine-containing water for two weeks and were then treated with tofogliflozin throughout the experiment. Tofogliflozin was kindly provided by Kowa Co., Ltd. and the chemical structure will be disclosed at the time of presentation at the meeting. In mice treated with tofogliflozin, the development of hepatic pre-neoplastic lesions, foci of cellular alterations, was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the NAFLD activity score (NAS), in comparison to those in the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of SGLT2 protein-expressing hepatoma cells was not inhibited and the insulin signaling in those cells was not altered by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and NAFLD-related liver carcinogenesis by attenuating chronic inflammation and steatosis in the liver, while the agent had no significant direct effect on the proliferation of hepatoma cells. Therefore, SGLT2 inhibitors may have a chemopreventive effect on obesity-related HCC. Citation Format: Yohei Shirakami, Koki Obara, Masaya Kubota, Hiroyasu Sakai, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima. Effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on hepatoma cell lines and liver tumorigenesis [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 263.
Abstract 993: Wnt-er is coming: WNT5A promotes a slow cycling phenotype via p53 in conditions of stress
Authors: Marie R. Webster, Mitchell Fane, Amanpreet Kaur, Gretchen Alicea, Brett L. Ecker, Abibatou Ndoye, Curtis Kugel, Subhasree Basu, Alexander Valiga, Jessica L. Appleton, Maureen E. Murphy, Ashani Weeraratna
Journal: Cancer Research (2018)

Abstract Resistance to targeted therapy and chemotherapy increases with age. Previously, we found that aged skin fibroblasts secrete sFRP2, which decreases ß-catenin, MITF, and APE1 in melanoma cells, and promotes invasion. Loss of APE1, a key redox effector, increased DNA damage in melanoma cells and caused the cells to become resistant to targeted therapy. Here we show that the aging tumor microenvironment drives a slow cycling phenotype in melanoma cells via WNT5A and p53. We found WNT5A expression in melanoma cells correlates with p53 expression and a higher percent of slow cycling cells. Knocking down WNT5A decreases both p53 expression and the percent of slow cycling cells. When we isolated slow cycling cells by flow cytometry, we found that they have increased WNT5A, p53, and p21 expression. Analysis of patient tumors in the TCGA data base revealed that patients with higher than average p53 expression, also express WNT5A. To determine if WNT5A and p53 may be promoting the survival of metastatic melanoma in an aged microenvironment, we examined tumors from young and aged C57/BL6 mice generated using Yumm1.7 cells. We found that tumors in aged mice have a higher percentage of cells expressing p53 and increased WNT5A expression compared to tumors in young mice. Treatment of human melanoma cells with conditioned media from aged dermal fibroblasts decreases proliferation and increases the percent of slow cycling. Inhibition of p53 re-sensitizes human melanoma cells in conditioned media from aged fibroblasts to combination BRAFi/MEKi. These data suggest, it may be these slow cycling cells driven by WNT5A and p53, which are enriched in an aging microenvironment, that are driving resistance to targeted therapy in aged patients. Citation Format: Marie R. Webster, Mitchell Fane, Amanpreet Kaur, Gretchen Alicea, Brett L. Ecker, Abibatou Ndoye, Curtis Kugel, Subhasree Basu, Alexander Valiga, Jessica L. Appleton, Maureen E. Murphy, Ashani Weeraratna. Wnt-er is coming: WNT5A promotes a slow cycling phenotype via p53 in conditions of stress [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 993.
Abstract 3424: Genomic alterations in clonal hematopoiesis
Authors: Kuan-Lin Huang, Mingchao Xie, Yige Wu, Reyka Jayasinghe, Rajees Varghese, R. Jay Mashl, Song Cao, Matthew Wyczalkowski, Wen-wei Liang, Michael C. Wendel, Ryan Fields, Michael D. McLellan, Daniel C. Link, Feng Chen, Li Ding
Journal: Cancer Research (2018)

Abstract Cancer development is an incremental process. Mutations that initiate clonal hematopoiesis often arise in individuals many years before disease symptoms are apparent. We discovered blood somatic mutations in 8,612 germline blood samples in The Cancer Genome Atlas, drawing fundamental distinctions between these events and germline variants. In a preliminary scan of 5,949 samples, 13,345 blood-specific mutations were identified, preferentially distributed across 26 genes, including ones frequently mutated in hematologic malignancies (e.g., DNMT3A, ASXL1, TET2, JAK2, IDH2, SF3B1, MLL3, and KDM6A) and genes rarely mutated in primary hematologic tumors, including EGFR, PIK3CA, NOTCH2, and PPM1D. Further, we utilized both exome sequencing and SNP array data to conduct the first large-scale survey of blood somatic copy number variation, discovering potentially oncogenic events such as JAK2 amplification. Finally, elderly individuals and smokers have increased likelihoods of undergoing clonal expansion. Our analysis of genomic alterations reveals the origins of hematologic malignancies and can facilitate advancement in early detection and prevention. Citation Format: Kuan-Lin Huang, Mingchao Xie, Yige Wu, Reyka Jayasinghe, Rajees Varghese, R. Jay Mashl, Song Cao, Matthew Wyczalkowski, Wen-wei Liang, Michael C. Wendel, Ryan Fields, Michael D. McLellan, Daniel C. Link, Feng Chen, Li Ding. Genomic alterations in clonal hematopoiesis [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 3424.
Abstract 3331: Development of a sensitive method to detect aberrant DNA methylation in cfDNA for pancreas cancer diagnosis
Authors: Keiko Shinjo, Keisuke Katsushima, Miho Suzuki, Genta Nagae, Hiroyuki Aburatani, Kenji Yamao, Yutaka Kondo
Journal: Cancer Research (2018)

Abstract Pancreatic cancer is a highly lethal malignancy despite recent clinical advances. Since pancreatic cancer is often difficult to diagnose, there is an urgent need to develop noninvasive biomarkers for detection. Epigenetic alterations have been recognized as a common hallmark of many types of human cancers as well as pancreatic cancer. The cell-free DNA (cfDNA) in blood possesses tumor-related genetic alterations as well as epigenetic alterations. Therefore, invention of blood-based DNA methylation biomarkers and their high-sensitive detection system may be a promising diagnostic tool for pancreatic cancer. In order to establish the diagnostic biomarkers, first we performed genome-wide DNA methylation analysis of 38 endoscopic ultrasound-guided fine-needle aspiration specimens of pancreatic cancer using Illumina Infinium HumanMethylation450 BeadChip. We further analyzed the DNA methylation profiles of other types of tumors in the public database TCGA (The Cancer Genome Atlas), and identified five marker genes, which were specifically methylated in pancreatic cancers. Analysis of DNA methylation status of pancreas cancers comparing 10 normal tissues in TCGA data set revealed that 99% of tumors were methylated in at least one of the five markers (sensitivity, 98.9%; specificity, 44%). We next examined the DNA methylation status of these markers in the validation cohort (n=46) by bisulfite pyrosequencing or quantitative methylation-specific PCR and found that 42/46 (91.3%) cases were methylated in at least one marker. Finally, we analyzed methylation status in cfDNA from pancreatic cancer patients. We performed bisulfite sequencing using next-generation sequencer and detected methylation in only 5/13 (38.5%) samples in one of the markers. Since the amount of DNA from cancer tissue is very small, we need to develop more a sensitive technique to detect aberrant DNA methylation to diagnose cancer patients. Now we are developing a new sensitive method to detect DNA methylation in cfDNA. Citation Format: Keiko Shinjo, Keisuke Katsushima, Miho Suzuki, Genta Nagae, Hiroyuki Aburatani, Kenji Yamao, Yutaka Kondo. Development of a sensitive method to detect aberrant DNA methylation in cfDNA for pancreas cancer diagnosis [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 3331.
Abstract 10164: Dronedarone but Not Amiodarone Ameliorates Atrial Tachyarrhythmia-Induced Decrease of Ventricular Microperfusion
Authors: Matthias Hammwohner, Alicja Bukowska, Antje Sixdorf, Friedrich-Wilhelm Rohl, Uwe Lendeckel, Andreas Goette
Journal: Circulation (2011)

Introduction: Atrial fibrillation (AF) is associated with an increased risk for acute coronary syndromes. AF-induced myocardial ischemia seems to be related to disturbance of ventricular microcircu...
Immunosuppressive Therapy for Active Lymphocytic Myocarditis
Authors: AndreaFrustaci, CristinaChimenti, FiorellaCalabrese, MaurizioPieroni, GaetanoThiene, AttilioMaseri
Journal: Circulation (2003)

Background— The beneficial effect of immunosuppressive treatment on myocarditis is still controversial, possibly because the immunologic and virological profile of potential candidates is largely unknown. Methods and Results— Out of 652 biopsied patients, 112 had a histological diagnosis of active lymphocytic myocarditis; 41 of these 112 patients were characterized by progressive heart failure despite conventional therapy and were treated with prednisone and azathioprine for 6 months. All were resubmitted to cardiac catheterization, angiography, and endomyocardial biopsy at 1 and 6 months and followed-up for 1 year. A total of 21 patients responded with prompt improvement in left ventricular ejection fraction from 25.7±4.1% to 47.1±4.4% and showed evidence of healed myocarditis at control biopsy. Conversely, 20 patients failed to respond and showed a histological evolution toward dilated cardiomyopathy: 12 remained stationary, 3 underwent cardiac transplantation, and 5 died. We retrospectively performed a...
Elevated Troponin T Levels and Lesion Characteristics in Non–ST-Elevation Acute Coronary Syndromes
Authors: KentaroOkamatsu, MasamichiTakano, ShuntaSakai, FumiyukiIshibashi, RyotaUemura, TeruoTakano, KyoichiMizuno
Journal: Circulation (2004)

Background— Elevated troponin T levels in non–ST-elevation acute coronary syndromes (NSTE-ACS) have been shown to predict an adverse outcome. Furthermore, it has been reported that troponin T could help improve the effectiveness of such new antithrombotic drugs as platelet GPIIb/IIIa antagonists and low-molecular-weight heparins. We hypothesized that such elevated troponin T levels in NSTE-ACS indicate the presence of thrombus at culprit lesions, and this hypothesis was verified through the use of coronary angioscopy. Methods and Results— We studied 57 consecutive patients with NSTE-ACS who underwent preinterventional angioscopy. Before catheterization, we obtained blood samples to determine troponin positivity, and the patients were then classified as either troponin-positive or troponin-negative groups (diagnostic threshold, 0.1 ng/mL). Using angioscopy at the culprit lesions, we examined the presence of coronary thrombus, yellow plaque, and complex plaque. Moreover, we compared the preinterventional an...