tbuckley/cabot-search huggingface dataset:
Abstract 11233: Trends in Coronary Revascularization and Ischemic Heart Disease-Related Mortality in Israel
Authors: Orit Blumenfeld, Wasef Nhamnih, Ayelet Shapira-Daniels, Ziona Haklai, Chaim Lotan, Tamy Shohat, Oz M Shapira
Journal: Circulation (2016)

Introduction: This study investigated national trends in percutaneous coronary angioplasty (PCI), coronary artery bypass grafting (CABG) and ischemic heart disease (IHD)-related mortality in Israel. Methods: Using ICD-9 and 10 codes we linked 5 Israeli national databases: the Centers for Disease Control National PCI and CABG Registries, Ministry of Health Hospitalization Reports, Center of Bureau of Statistics and the Ministry of Interior Mortality Report to assess the annual PCI and CABG volume, procedural mortality, co-morbidities and IHD-related mortality between 2002 and 2014. Time trends were analyzed using linear regression, assuming a Poisson distribution. Results: A total of 341,056 revascularization procedures (PCI-298,390, CABG-42,666) were performed during the study period. The volume of PCI increased by 9% from 2002 to 2008 (378.0/100K to 423.2/100K) and then steadily decreased to 378.5/100K in 2014 (p=0.70 for the trend). CABG volume decreased by 58% (109.0/100K to 45.8/100K) from 2002 to 2012 leveling during the last 3 years to 46.3/100K (p&lt;0.0001). The PCI/CABG ratio increased from 3.6 in 2002 to 8.5 in 2012, slightly decreasing to 8.2 by 2014 (P&lt;0.0001). In-hospital procedural mortality remained stable (PCI- 1.2-1.6%, p=0.34, CABG- 3.7-4.4%, p=0.29) despite a significant change in patient characteristics. During the study period, annual IHD-related mortality decreased by 46% (84.6 to 46/100K, p&lt;0.001). Conclusions: We observed a dramatic change in coronary revascularization procedures type and volume with a parallel marked decrease in IHD-related mortality in Israel. Improvement in medical treatment, better patient selection related to data derived from large-scale clinical trials and adherence to appropriateness criteria, as well as improved procedural techniques and technology may account for these changes.
Abstract 1480: Overexpression of histone H3.1 induced cell malignant transformation and mutation of H3.1 C96/110A further induced chromatin instability
Authors: Yusha Zhu, Hong Sun, Max Costa
Journal: Cancer Research (2018)

Abstract Histones are major proteins in chromatin and are important for chromatin structure and gene expression. Canonical histones are defined as a group of replication-dependent histone proteins and are mainly synthesized during S phase of the cell cycle. Their mRNAs are devoid of poly-adenylated tails, but end up with a stem loop structure, which can be targeted by proteins such as stem-loop binding proteins (SLBP) for processing, exportation, and degradation. In our previous studies, arsenic exposure was found to be associated with reduced levels of SLBP and accumulation of poly-adenylated mRNA of canonical histone H3.1, and ultimately led to malignant transformation of cells. Histone H3.1 and H3.2 are canonical histones and they differ by only one amino acid, Ser96 on H3.2 compared with Cys96 on H3.1, and both of them have a Cys110. Histone H3 is the only histone that contains cysteine. Cysteine (C) is a unique amino acid that is rarely used by nature and it has a reactive thiol side chain that can easily form dimers containing disulfide bridge when oxidized. Here it is hypothesized that cysteine is vital for the structure and stability of chromatin. To test this hypothesis, we generated an H3.1 mutant H3.1 C96/110A, where two cysteine residues were replaced by alanine (A). The wild-type H3.1 and H3.1 C96/110A were exogenously expressed in the Beas-2B cells. Interestingly, Beas-2B cells ectopically expressing poly-adenylated H3.1 and H3.1 C96/110A showed decreased proliferation rate with cell cycle arrest at S phase, and cells also acquired cancer cell properties such as increased anchorage-independent growth along with migration and invasion ability. It was confirmed that H3.1 C96/110A could be incorporated into chromatin, resulting in increased chromatin instability and DNA damage. In addition, the RNA-seq assay revealed a total of 678 genes that were oppositely expressed between H3.1 and H3.1 C96/110A ectopically expressed cells. These findings emphasize the importance of a balance among histone variants in the cell and an essential role of cysteines in histone H3.1. Citation Format: Yusha Zhu, Hong Sun, Max Costa. Overexpression of histone H3.1 induced cell malignant transformation and mutation of H3.1 C96/110A further induced chromatin instability [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 1480.
Abstract 14672: A Pivotal Role of Synthetic Smooth Muscle Cells Activated by Hepatocyte Growth Factor in Extracellular Matrix Modulation-Related Functional Recovery Post-Cell Sheet Transplantation in a Rat Chronic Myocardial Infarction Model
Authors: Motoko Shiozaki, Shigeru Miyagawa, Satsuki Fukushima, Daisuke Yoshioka, Atsuhiro Saito, Yoshiki Sakai, Kunio Matsumoto, Yoshiki Sawa
Journal: Circulation (2016)

Background: Transplantation of autologous skeletal myoblast cell (SMB)-sheet has been shown to upregulate intramyocardial expression of various factors including hepatocyte growth factor (HGF) and ...
Abstract 3021: Plexin-B3 regulates cellular motility, invasiveness and metastasis in pancreatic cancer
Authors: Sugandha Saxena, Yuri Hayashi, Satyanarayana Rachagani, Surinder Kumar Batra, Rakesh Kumar Singh
Journal: Cancer Research (2018)

Abstract Cancer metastasis significantly worsens the survival of pancreatic cancer (PC) patients. Currently, semaphorins and their high-affinity receptors plexins are considered versatile regulators of cancer cell migration, angiogenesis, invasion and metastasis. Our group identified semaphorin-5A (SEMA5A) as a putative cell adhesion molecule involved in organ-specific homing of PC cells and playing a significant role in PC angiogenesis and metastasis. Thus, SEMA5A and its receptor plexin-B3 represents an attractive targetable axis in PC metastasis. However, for a better understanding of the SEMA5A-initiated downstream signaling events and regulation of cellular phenotypes, it is necessary to delineate the function of its receptor plexin-B3 in PC as well. Thus, understanding the pathologic expression and functional role of plexin-B3 is essential for characterization of SEMA5A/plexin-B3 axis in PC. In the present study, we analyzed plexin-B3 expression in PC disease progression model of PDX-Cre-Kras(G12D) (KC) mice and evaluated the functional role by utilizing plexin-B3 knockdown T3M-4 and CD18/HPAF cells. We observed a reduction of plexin-B3 expression with disease progression in KC mice model and also the poor survival of pancreatic adenocarcinoma stage II patients (n = 24) with lower plexin-B3 expression. Functionally, knockdown of plexin-B3 enhanced in vitro cellular migration and invasiveness of PC cells. Furthermore, plexin-B3 knockdown cells showed a significant increase in cellular size with impaired colony formation in three-dimensional culture. Cell proliferation analysis demonstrated that plexin-B3 knockdown cells showed lower proliferation in comparison with the control cells. We also observed higher metastasis with lower tumor burden in nude mice injected with CD18/HPAF-sh plexin-B3 cells than CD18/HPAF-control cells. Furthermore, the tumors formed by CD18/HPAF-plexin-B3 cells showed higher fibrosis, a higher number of vimentin-positive cells, and lower number of proliferation marker Ki-67-positive cells in comparison with the CD18/HPAF-control tumors. In addition, we observed similar phenotypic changes in PC cells with loss of SEMA5A-ligand of plexin-B3. In summary, our data demonstrate that impairment in SEMA5A/plexin-B3 axis enhances cellular motility and invasiveness of PC cells, thereby resulting in higher metastasis. Citation Format: Sugandha Saxena, Yuri Hayashi, Satyanarayana Rachagani, Surinder Kumar Batra, Rakesh Kumar Singh. Plexin-B3 regulates cellular motility, invasiveness and metastasis in pancreatic 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 3021.
Abstract 4460: <i>BRCA1</i>-associated R-loop accumulation at noncoding putative ERα enhancer area regulates expression of adjacent genes
Authors: Huai-Chin Chiang, Xiaowen Zhang, Chi Zhang, Xiayan Zhao, Jingwei Li, Yanfen Hu, Rong Li
Journal: Cancer Research (2018)

Abstract Most BRCA1-associated breast tumors are basal-like yet originate from luminal progenitor cells. BRCA1 is best known for its functions in double strand break (DSB) repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions of BRCA1 fully explains the cell lineage-specific increase in breast tumor development. By sorting and profiling lineage-specific cells from precancerous human breast tissue, I found that BRCA1 mutation carriers tend to have a luminal cell-specific accumulation of R-loop, a transcriptional byproduct of DNA-RNA hybrid structure important for transcriptional regulation and genomic instability. R-loops accumulate preferentially at enhancers and transcription start sites (TSS) of luminal fate-related genes. Using CRISPR-Cas9 system, I've deleted an ERα enhancer area with BRCA1-associated R-loops accumulation in MCF7 cells. The deletion of this non-coding putative ESR1 enhancer area reduced the gene expression level of the neighboring genes of the deleted region, including ERα, RMND1, and CCDC170. In addition, compare to the reduced expression level of ERα, RMND1, and CCDC170 in BRCA1 knockdown of the parental MCF7, knocking down BRCA1 in these deletion clones showed less reduction of these genes. On the other hand, overexpression RNASEH1, an enzyme that specifically removes R-loop, had little effect in these genes after BRCA1 knockdown. These results indicate BRCA1-associated R-loop accumulation at least partially affect gene transcription at these loci. To investigate whether BRCA1-assocaited R-loop accumulation directly contributes to luminal differentiation blockage, I overexpressed RNASEH1 in breast epithelial cells freshly isolated from BRCA1 mutation carriers, flow cytometry comparing different breast lineage reveal a luminal population shift toward more mature luminal. All in all, the results infer that BRCA1 promotes luminal epithelial differentiation by alleviating R-loop accumulation at enhancer of ERα. Aberration in luminal transcription could contribute to lineage-specific BRCA1-associated tumorigenesis. Citation Format: Huai-Chin Chiang, Xiaowen Zhang, Chi Zhang, Xiayan Zhao, Jingwei Li, Yanfen Hu, Rong Li. BRCA1-associated R-loop accumulation at noncoding putative ERα enhancer area regulates expression of adjacent genes [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 4460.
Effect of Acute and Long-term Smoking on Myocardial Blood Flow and Flow Reserve
Authors: JohannesCzernin, KarlSun, RichardBrunken, MortenBöttcher, MichaelPhelps, HeinrichSchelbert
Journal: Circulation (1995)

Background Cigarette smoking is a major preventable risk factor for coronary artery disease and sudden cardiac death. However, the effect of acute and long-term cigarette smoking on coronary vasodilatory capacity and myocardial flow reserve has not been quantified in humans. Methods and Results To examine the effect of short-term and long-term smoking, myocardial blood flow was quantified at rest and during dipyridamole-induced hyperemia (0.56 mg/kg) in 12 smokers (10 males and 2 females; mean age, 27±4 years) under baseline conditions (reflecting the effect of long-term smoking) and during short-term cigarette smoking with 13N ammonia, positron emission tomography, and a two-compartment model. Twelve sex- and age-matched nonsmokers served as control subjects. Smoking significantly increased the rate-pressure product at rest from 7525±1290 to 9160±1125 (P<.001 versus baseline), which was paralleled by a proportional increase in myocardial blood flow at rest (0.70±0.17 versus 0.88±0.17 mL · g−1 · min−1; P<...
Abstract B40: High-throughput screening of new potential targets for high-grade serous ovarian cancer treatment
Authors: Jun Dai, Erdogan Pekcan Erkan, Kaiyang Zhang, Katja Kaipio, Tarja Lamminen, Kaisa Huhtinen, Johanna Hynninen, Seija Grenman, Olli Mikael Carpen, Sampsa Hautaniemi, Anna Vähärautio
Journal: Clinical Cancer Research (2018)

Abstract High-grade serous ovarian cancer (HGSOC) is the most common cause of gynecologic-cancer-associated death. Although HGSOC is initially extremely sensitive to platinum-based chemotherapy, relapse and progression to chemotherapy resistance are frequently seen, resulting in the low 5-year survival rate of this disease. Therefore, we aim to establish a feasible methodology that combines genome editing and single-cell RNA-seq to high-throughput screen new potential targets that could be utilized alone or combined with platinum for HGSOC treatment. Firstly, we constructed several inducible Cas9-expressed HGSOC cell lines, including both platinum-sensitive and -resistant cells. Secondly, we transduced these cell lines with a pooled sgRNA lentivirus consisting of 105 non-target scrambled sgRNAs and sgRNAs against 188 genes (10 sgRNAs per gene) that are currently targets of FDA/EMA approved drugs or drugs undergoing clinical trials in ovarian cancer treatment. Our analysis of multiple HGSOC dissociated tumors by single-cell RNA-seq has revealed intertumoral heterogeneity in expression of these drug targets in vivo. The majority of these 188 genes, approximately two thirds, are expressed in low level in most epithelial ovarian cancer (EOC) cells. Only 4 genes (AKT1, IL6, C1QA, INHBA) show relatively high expression, and only in a small subset of EOC cells. Also, the remaining drug target genes that are expressed show intertumoral heterogeneity, e.g., high expression of PARP-1 in tumors that are potentially deficient in homologous recombination repair. To elucidate the functionality of these drug targets, we will next analyze the transcriptomic effects of specific gene CRISPR/Cas9 knockouts in these HGSOC cell lines by droplet-based single-cell RNA-seq. From the data, we will compare the differences between platinum-sensitive and -resistant cell lines after the gene knockouts to identify the correlations between specific genetic perturbations and platinum resistance. As a future perspective, we will continue optimizing our platform for screening other potential targets. Overall, this study provides a comprehensive and unbiased approach for potential HGSOC target screening. Note: This abstract was not presented at the conference. Citation Format: Jun Dai, Erdogan Pekcan Erkan, Kaiyang Zhang, Katja Kaipio, Tarja Lamminen, Kaisa Huhtinen, Johanna Hynninen, Seija Grenman, Olli Mikael Carpen, Sampsa Hautaniemi, Anna Vähärautio. High-throughput screening of new potential targets for high-grade serous ovarian cancer treatment. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B40.
Abstract 2062: Selective gene dependencies in <i>MYCN</i>-amplified neuroblastoma include the core transcriptional regulatory circuitry
Authors: Adam D. Durbin, Mark W. Zimmerman, Neekesh V. Dharia, Brian J. Abraham, Brian J. Abraham, Amanda Balboni-Iniguez, Nina Weichert-Leahey, Shuning He, John M. Krill-Burger, David E. Root, Francisca Vazquez, Aviad Tsherniak, William C. Hahn, Todd R. Golub, Richard A. Young, A. Thomas Look, Kimberly Stegmaier
Journal: Cancer Research (2018)

Abstract Childhood neuroblastomas with MYCN gene amplification form a particularly high-risk subset of this disease and are difficult to treat effectively. This has focused attention on tumor-specific gene dependencies that reflect important pathways in tumorigenesis, and thus could provide valuable targets for the development of novel therapeutics. Using genome-scale CRISPR-Cas9 approaches that allow unbiased detection of genes critically involved in tumor cell growth and survival, we identified 147 candidate genes associated with selective vulnerabilities in nine MYCN-amplified neuroblastoma cell lines, compared to findings in over 300 other human cancer cell lines representing multiple tumor cell types. We then used genome-wide ChIP-seq analysis to test the hypothesis that a small number of transcription factors - MYCN, HAND2, ISL1, PHOX2B, GATA3, and TBX2, all represented in the selective dependency group - are members of the transcriptional core regulatory circuitry (CRC) that underlies cell state in MYCN-amplified neuroblastoma. We show that these transcription factors bind as dense clusters at defined epicentres within the enhancers of their own genes, as well as those of the other CRC transcription factor genes, creating a positive feed-forward autoregulatory loop that establishes and maintains high levels of gene expression. To disable the CRC, we tested a combination of BRD4 and CDK7 inhibitors, which we postulated would act synergistically by targeting both transcriptional initiation and elongation required to synthesize regulatory transcription factors. MYCN-amplified neuroblastoma cells treated with both drugs were killed synergistically, in vitro and in vivo, and accompanied by rapid downregulation of CRC transcription factor gene expression. This study defines a set of critical dependency genes in MYCN-amplified neuroblastoma, a subset of which comprises the oncogenic transcriptional regulatory circuitry that underlies cell state and survival in this tumor. Citation Format: Adam D. Durbin, Mark W. Zimmerman, Neekesh V. Dharia, Brian J. Abraham, Brian J. Abraham, Amanda Balboni-Iniguez, Nina Weichert-Leahey, Shuning He, John M. Krill-Burger, David E. Root, Francisca Vazquez, Aviad Tsherniak, William C. Hahn, Todd R. Golub, Richard A. Young, A. Thomas Look, Kimberly Stegmaier. Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry [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 2062.
Dispersion of Ventricular Depolarization-Repolarization
Authors: PietroTurrini, DomenicoCorrado, CristinaBasso, AndreaNava, BarbaraBauce, GaetanoThiene
Journal: Circulation (2001)

Background—We retrospectively investigated the value of clinical and ECG findings as well as QT-QRS dispersion in predicting the risk of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods and Results—Duration and interlead variability of the QT interval and QRS complex were measured manually from standard ECGs in 20 sudden death victims with ARVC diagnosed at autopsy (group I), in 20 living ARVC patients with sustained ventricular tachycardia (group II), in 20 living ARVC patients with ≤3 consecutive premature ventricular beats (group III), and in 20 control subjects (group IV). QT and QRS dispersions were greater in group I (77.5±10.6 ms for QT and 45.7±8.1 ms for QRS) compared with group II (64.5±13.9 ms for QT [P=0.001] and 33.5±8.7 ms for QRS [P=0.0004]) and in group II compared with group III (48±8.9 ms for QT [P<0.0001] and 28±5.2 ms for QRS [P<0.0001]) and group IV (33.5±4.8 ms for QT [P<0.0001] and 18.5±3.6 ms for QRS [P<0.0001]). Negative T wave beyond V...
Effects of Menopause on Trends of Serum Cholesterol, Blood Pressure, and Body Mass Index
Authors: MasazumiAkahoshi, MidoriSoda, EijiNakashima, KatsutaroShimaoka, ShinjiSeto, KatsusukeYano
Journal: Circulation (1996)

Background To elucidate the impact of menopause on coronary risk factors, we determined the trends of serum cholesterol (mg/dL), blood pressure (BP, mm Hg), and body mass index (BMI, kg/m2) and investigated whether menopause affects these trends in women in Nagasaki, Japan. Methods and Results Trends of cholesterol, systolic BP (SBP), and BMI from 9 years before menopause through 9 years after menopause in 579 women with natural menopause (ranging in age from 40.2±3.1 to 57.9±3.1 years; age at menopause, 49.4±3.0 years) and 134 women with surgical menopause (hysterectomy with or without bilateral oophorectomy; ranging in age from 34.9±4.5 to 51.7±5.1 years; age at menopause, 42.9±5.0 years) and those in 579 and 134 age- and time-matched male subjects (ranging in age from 40.1±3.1 to 57.8±3.2 years and from 35.2±4.5 to 51.6±5.0 years, respectively) in Nagasaki were determined by rearrangement of the data from 1958 to 1989 with time of menopause as the datum line. Although cholesterol tended to increase wit...
Abstract P321: Oxidative Stress Induces DNA Double-Strand Breaks and Activates DNA Damage Responses in Vascular Smooth Muscle Cells: A Possible Mechanism for Atherosclerosis Progression
Authors: TakafumiIshida, MariIshida, SatoshiTashiro, ChiemiSakai, HitomiUchida, KiyoshiMiyagawa, MasaoYoshizumi, YasukiKihara
Journal: Circulation Research (2011)

Backgrounds: Oxidative stress is thought to be a pathogenic mediator of atherosclerosis. Oxidative stress induces DNA damage, and the unrepaired or improperly repaired DNA damage increases genomic instability, which cause cell death, senescence, or dysregulation of cellular functions. Pathogenesis of both Hutchinson-Gilford Progeria syndrome and Werner syndrome, which feature prominent atherosclerotic disease at young age, involves impaired DNA repair and the resultant genomic instability. The purpose of this study is to determine whether oxidative stress causes DNA damage in vascular smooth muscle cells (VSMC) and to elucidate the role of DNA damage responses in atherosclerosis and the fate of VSMC. Methods and Results: Immunoreactivity against gamma-H2AX, a sensitive marker for DNA double-strand breaks (DSBs), which is the most severe form of DNA damage, was increased in human atherosclerotic plaques, but not in the adjacent normal areas. gamma-H2AX staining was observed in almost same regions where 8-o...