tbuckley/cabot-search huggingface dataset:
Sino-MONICA Project
Authors: ZhaosuWu, ChonghuaYao, DongZhao, GuixianWu, WeiWang, JingLiu, ZhechunZeng, YingkaiWu
Journal: Circulation (2001)

Background—The Sino-MONICA project is a 7-year study monitoring trends and determinants of cardiovascular disease (CVD) in geographically defined populations in different parts of China. Methods and Results—The study is a community-based prospective disease surveillance that uses the methodology and criteria of the World Health Organization’s Monitoring Trends and Determinants in Cardiovascular Disease (WHO MONICA) project, with slight modifications for local use. After a pilot study of 2 years (1985 through 1986), data collection started formally on January 1, 1987, and ended on December 31, 1993. The main results were as follows. By international standards, both the incidence and mortality rate of coronary heart disease in Chinese populations were low. The highest incidence was 108.7 of 100 000 (1987 to 1989), and the lowest was 3.3 of 100 000 for men 35 to 64 years of age, a 33-fold difference. Both the incidence and mortality rate of cerebrovascular disease were high. The highest incidence was 553.3 o...
Abstract 5573: Highly multiplexed diagnostic test for the detection of extended EGFR del19 variants in patients with NSCLC
Authors: Hestia S. Mellert, Leisa Jackson, Kristin Alexander, Amanda Weaver, Dianna Maar, Dawne Shelton, Gary Pestano
Journal: Cancer Research (2018)

Abstract The detection of nucleic acids in circulation has become an increasingly important part of the clinical workup and testing for cancer patients, particularly those with non-small cell lung cancer (NSCLC). The utilization of blood-based PCR platforms for detection of somatic variant mutations addresses several limitations of previously established molecular testing approaches such as an inability to access tissue, insufficient tissue quantity or quality, and slow turnaround time for results. However, the number of variants detected may be limited by use of some rapid PCR technologies. We have focused in this study on the analytic and clinical development of a highly multiplexed assay for the detection of EGFR del19 while maintaining a rapid turn-around time. The test system includes the prospective collection of whole blood into a cfDNA BCT and the reproducible detection of del19 variants out of plasma using ddPCR-based technology. Analytic specificity and sensitivity was examined using in vitro DNA designed to mimic the EGFR del19 variants in the assay. Analytic sensitivity was performed and demonstrates that the theoretical limit of detection of the test was below 0.02% minor variant frequency when using high concentrations of synthetic standards. Precision studies were conducted with both analytic and clinical samples at high, medium and low mutation frequencies, over three consecutive days, three runs in one day and with two operators. All test parameters were successfully met. Normal healthy donor (n = 11) and reference ddPCR positive and negative NSCLC donor (n = 80) samples were tested. EGFR del19 variants were not identified in the plasma from the normal healthy donors or the EGFR del19 reference negative NSCLC donors. All reference positive cases were accurately detected above our required threshold of 2 variant copies with detection ranging from 14 to 1584. For all donor specimens the wild-type copies were well above the predefined clinical QC threshold of 300, ranging from 380 to 760 copies. Of note, no negative reference samples contained more than two mutant copies. We conclude that the developed test is highly suited for the sensitive and reproducible detection of multiple EGFR del19 variants from blood specimens in the clinical laboratory. Citation Format: Hestia S. Mellert, Leisa Jackson, Kristin Alexander, Amanda Weaver, Dianna Maar, Dawne Shelton, Gary Pestano. Highly multiplexed diagnostic test for the detection of extended EGFR del19 variants in patients with NSCLC [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 5573.
Abstract 5881: Novel inhibitors of the epigenetic reader protein MBD2
Authors: Hugh Giovinazzo, Zachary R. Reichert, Andries Bergman, Xiaohui Lin, Nicolas Wyhs, David Esopi, Ajay Vaghasia, Jianyong Liu, Yash Jain, Akshay Bhamidipati, Ruchama Steinberg, Traci Speed, Matthew Vaughn, Yonggang Zhang, Nate Brennen, Theodore Deweese, Srinivasan Yegnasubramanian, William G. Nelson
Journal: Cancer Research (2018)

Abstract DNA hypermethylation can trigger silencing of tumor suppressor genes during cancer development and progression, partly through binding by methylated-DNA binding proteins (MBD), such as MBD2, that function as “epigenetic readers” and recruit co-repressor complexes to promote gene repression. Inhibiting MBD2-mediated repression represents an attractive cancer therapeutic strategy. Here, we used a cell-based screen to identify small molecules capable of reactivating hypermethylated promoter sequences. We used biochemical, molecular biologic, and pharmacologic approaches to characterize mechanism of action of identified MBD2 inhibitors. A subset of these compounds represent a new class of inhibitors capable of selectively antagonizing interactions between MBD2 and methylated DNA, leading to reactivation of the hypermethylated gene GSTP1 and the epigenetically silenced retinoic acid signaling pathway. Combinations of one of the newly identified MBD2 inhibitors, KCC-08, with the retinoic acid receptor agonist, isotretinoin, significantly reduced cancer cell growth/survival in vitro and in vivo. These novel MBD2 inhibitors are thus positioned for further pharmacologic lead development for use as probes to interrogate epigenetic gene silencing mechanisms and as cancer therapeutics. Citation Format: Hugh Giovinazzo, Zachary R. Reichert, Andries Bergman, Xiaohui Lin, Nicolas Wyhs, David Esopi, Ajay Vaghasia, Jianyong Liu, Yash Jain, Akshay Bhamidipati, Ruchama Steinberg, Traci Speed, Matthew Vaughn, Yonggang Zhang, Nate Brennen, Theodore Deweese, Srinivasan Yegnasubramanian, William G. Nelson. Novel inhibitors of the epigenetic reader protein MBD2 [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 5881.
Retinal Vasculometry Associations with Cardiometabolic Risk Factors in the European Prospective Investigation of Cancer—Norfolk Study
Authors: Christopher G. Owen, Alicja R. Rudnicka, Roshan A. Welikala, M. Moazam Fraz, Sarah A. Barman, Robert Luben, Shabina A. Hayat, Kay-Tee Khaw, David P. Strachan, Peter H. Whincup, Paul J. Foster
Journal: Ophthalmology (2018)

To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women.Retinal imaging examination as part of the European Prospective Investigation into Cancer-Norfolk Eye Study.Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry.Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width.Retinal arteriolar and venular tortuosity and width.In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%-3.3% per 5 kg/m2), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%-3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%-10.4%); wider venules were associated with older age (2.6 μm; 95% CI, 2.2-2.9 μm per decade), higher triglyceride levels (0.6 μm; 95% CI, 0.3-0.9 μm per 1 mmol/l), BMI (0.7 μm; 95% CI, 0.4-1.0 per 5 kg/m2), HbA1c level (0.4 μm; 95% CI, -0.1 to 0.9 per 1%), and being a current smoker (3.0 μm; 95% CI, 1.7-4.3 μm); smoking also was associated with wider arterioles (2.1 μm; 95% CI, 1.3-2.9 μm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 μm; 95% CI, 0.7-2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%-7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%-1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%-6.4%), and in those with prevalent stroke (8.3%; 95% CI, -0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 μm; 95% CI, 0.6-1.0 μm per decade), higher systolic blood pressure (0.5 μm; 95% CI, 0.4-0.6 μm per 10 mmHg), total cholesterol level (0.2 μm; 95% CI, 0.0-0.3 μm per 1 mmol/l), and HDL (1.2 μm; 95% CI, 0.7-1.6 μm per 1 mmol/l).Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.
Abstract P094: Gender Difference of Left Ventricular Geometry and Prolonged QRS Duration on Electrocardiogram: MESA (Multi-Ethnic Study of Atherosclerosis)
Authors: YukoInoue, HiroshiAshikaga, YoshiakiOhyama, GustavoVolpe, BharathAmbale-Venkatesh, JoãoLima
Journal: Circulation (2015)

Backgrounds: Prolonged QRS duration (QRSd) on electrocardiogram (ECG) is commonly found in otherwise healthy individuals. However, geometrical factors of the ventricles that determine QRSd are poorly defined. T1 time by cardiovascular magnetic resonance (CMR) is good parameter to estimate extracellular expansion (ECE). Our objective was to evaluate the relationship between QRSd and CMR measures of tissue composition in a large community-based multiethnic population. Methods: A total of 1,615 participants (52% women; age range 44 to 84 years) of the MESA cohort were evaluated with T1 mapping by using 1.5-T CMR scanners. We excluded the participants with focal scar on delayed enhancement CMR and bundle branch block. Midventricular short-axis T1 maps were acquired before and at 12- and 25-min after administration of gadolinium contrast using Modified Look-Locker Inversion Recovery sequence. Results: Longer QRSd was associated with greater LV end diastolic volume (LVEDV) index (p <0.001), LV mass index (p <0....
Abstract 15295: Molecular Mechanism of Chronic Sildenafil-Caused Regression of Heart Failure: Effects on the Express of Cardiac SR Ca2+-ATPase, Subtype of β-Adrenergic Receptors and Nitric Oxide Synthase Isoforms
Authors: Heng-JieCheng, TiankaiLi, Che PingCheng
Journal: Circulation (2014)

Background: Sildenafil (SIL), a selective inhibitor of PDE5 has been shown to exert profound beneficial effects in heart failure (HF). Recently we further found that SIL caused regression of cardiac dysfunction in a rat model with isoproterenol (ISO)-induced progressive HF. However, the molecular basis is unclear. We hypothesized that reversal of HF-induced detrimental alterations on the expressions of cardiac SR Ca2+-ATPase (SERCA2a), β-adrenergic receptors (AR) and nitric oxide synthase (NOS) isoforms by SIL may play a key role for its salutary role in HF. Methods: Left ventricular (LV) and myocyte function and the protein levels of myocyte β1- and β3- AR, SERCA2a, phospholamban (PLB) and three NOS were simultaneously evaluated in 3 groups of male rats (6/group): HF, 3 months (M) after receiving ISO (170 mg/kg sq for 2 days); HF/SIL, 2 M after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and Controls (C). Results: Compared with controls, ISO-treated rats progressed...
Abstract 5006: Kit-dependent tissue resident macrophage progenitors drive cancer progression
Authors: Paulina Pathria, Hideyuki Takahashi, Megan Kaneda, Judith A. Varner
Journal: Cancer Research (2018)

Abstract Macrophages play a key role in promoting tumor growth and resistance to therapy. Here we show that tissue-resident as well as bone marrow-derived macrophages play critical roles in promoting tumor growth. Tissue-resident macrophages were recently shown to originate in the yolk sac or fetal liver during embryogenesis; these cells self-maintain in post-natal tissues independent of hematopoietic stem cells. Tissue-resident macrophages and bone marrow-derived macrophages rapidly accumulate in tumors where they play independent roles in promoting tumor growth. Tissue-resident macrophages are CD11b+Gr1-F4/80hiCX3CR1hiCCR2-Ki67+ cells that accumulate in tumors independently of trafficking receptors. In contrast, bone marrow-derived CD11b+Gr1+F4/80loCX3CR1loCCR2+ macrophages accumulate in tumors in an integrin α4β1/αLβ2 and CCR2 or CXCR4-dependent manner. Gene expression studies show that tumor-associated tissue-resident macrophages are highly proliferative, immune-suppressive myeloid cells that are less proangiogenic than bone marrow-derived macrophages. Our studies show that tumor cells induce the expansion of tissue-resident macrophage progenitor cells by secreting stem cell factor and mCSF. Here we identify a Kit/KitL-dependent tissue-resident macrophage progenitor that is abundant in tumors but not in normal tissues. Notably, tumor growth and colony-forming activity are significantly inhibited in mice treated with SCF and Kit inhibitors. Tumors adoptively transferred with tissue-resident macrophage progenitor cells exhibited a significant growth advantage over control tumors. Furthermore, Kit inhibitors synergize with other immune therapy regimens to suppress tumor growth. Our studies show that tissue-resident macrophage progenitors promote aggressive tumor growth that can be targeted by Kit/SCF inhibition. Citation Format: Paulina Pathria, Hideyuki Takahashi, Megan Kaneda, Judith A. Varner. Kit-dependent tissue resident macrophage progenitors drive cancer progression [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 5006.
Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis
Authors: Cristina Pamfil, Zuzanna Makowska, Aurélie De Groof, Gaëlle Tilman, Sepideh Babaei, Christine Galant, Pauline Montigny, Nathalie Demoulin, Michel Jadoul, Selda Aydin, Ralf Lesche, Fiona McDonald, Frédéric A Houssiau, Bernard R Lauwerys
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Chronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN. Methods We performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples. Results A group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups. Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement. Conclusion Interstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.
Abstract 309: High Incidences of Postshock Asystole in VF with Low AMSA Values
Authors: YongqinLi, BihuaChen, MiHe, WeilunQuan, UlrichHerken
Journal: Circulation (2014)

Purpose: Early defibrillation is critical to survival from cardiac arrest. However, defibrillation is often followed by asystole or pulseless electrical activity (PEA) in the pre-hospital setting. These non-perfusing post-shock rhythms have been demonstrated to have a worse prognosis than primary asystole or PEA. In the present study, we used registry data of out-of-hospital cardiac arrests (OHCA) to investigate the relationship between pre-shock amplitude spectrum area (AMSA) value and incidence of post-shock asystole. Materials and Methods: A total of 543 patients treated by emergency providers following OHCA with VF as presenting rhythm were included in this study. All defibrillation shocks were attempted with ZOLL automated external defibrillators that employ rectilinear biphasic waveform. The sampling rate of the ECG was 250 Hz and only the initial shocks (120J) were analyzed. AMSA were calculated from a waveform episode of 2.05 seconds ending at 0.5 seconds before each shock attempt. Post-shock rhyt...
Abstract 5177: Metastasis: Leveraging transcriptomics to identify potential therapeutics
Authors: Matthew Ung, Jason M. Funt, Andrew C. Lysaght, Jenny Zhang, Renan Escalante-Chong, Gregory Koytiger, Sarah Kolitz, Rebecca Kusko, Benjamin Zeskind, Kevin D. Fowler
Journal: Cancer Research (2018)

Abstract Five-year survival rates for patients whose cancer has metastasized are dramatically lower than for those with localized disease. However, few therapeutic development efforts specifically focus on inhibiting the process of metastasis. Here we perform a systematic pan-cancer analysis of RNA-seq data from The Cancer Genome Atlas to identify targetable gene expression changes in primary tumors that confer metastatic potential. In 4,844 patients comprising 13 different cancer types, we construct a gene expression signature that captures consistent pan-cancer alterations that differ between primary tumors associated with node-negative disease with no recorded distant metastasis (N0 not M1) and primary tumors from patients with node-positive disease (N1, N2, or N3). In order to identify potential therapeutic targets, we query this metastasis signature against drug-induced transcriptomic signatures from CMAP and LINCS. Among the top candidates is Chembl410456, which modulates the TGFβ and Wnt/β-catenin signaling pathways, among others. Genes upregulated in metastatic primary tumors and downregulated by Chembl410456 include SERPINE1 and TWIST1. We observe that low SERPINE1 and TWIST1 expression also associate with improved prognosis in multiple cancers, including colon adenocarcinoma (p=0.007 and p=0.014, respectively). Other top-ranked drugs also target the TGFβ signaling pathway. To summarize, we leverage public RNA-seq data to identify a pan-cancer metastatic signature that can be interrogated to systematically identify potential therapeutics that target metastasis. Building on this, we pinpoint antimetastasis drug candidates including several with mechanisms of action involving modulation of TGFβ and/or Wnt/β-catenin pathways. Citation Format: Matthew Ung, Jason M. Funt, Andrew C. Lysaght, Jenny Zhang, Renan Escalante-Chong, Gregory Koytiger, Sarah Kolitz, Rebecca Kusko, Benjamin Zeskind, Kevin D. Fowler. Metastasis: Leveraging transcriptomics to identify potential therapeutics [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 5177.
Vasopressin V2-Receptor Blockade With Tolvaptan in Patients With Chronic Heart Failure
Authors: MihaiGheorghiade, ImranNiazi, JohnOuyang, FrankCzerwiec, Jun-ichiKambayashi, ManuelaZampino, CesareOrlandi
Journal: Circulation (2003)

Background— In this study, we evaluated the effects of tolvaptan (OPC-41061), a novel, oral, nonpeptide vasopressin V2-receptor antagonist in patients with chronic heart failure (CHF). Methods and Results— This was a double-blind study investigating the effects of three doses of tolvaptan and placebo in patients with CHF. After a run-in period, 254 patients were randomly assigned to placebo (n=63) or tolvaptan [30 mg (n=64), 45 mg (n=64), or 60 mg (n=63)] once daily for 25 days. Patients were not fluid-restricted and were maintained on stable doses of furosemide. At day 1, when compared with baseline, a decrease in body weight of −0.79±0.99, −0.96±0.93, and −0.84±0.02 kg was observed in the 30-, 45-, and 60-mg tolvaptan groups, respectively, and a body weight increase of +0.32±0.46 kg in the placebo group (P<0.001 for all treatment groups versus placebo). Although the initial decrease in body weight was maintained during the study, no further reduction was observed beyond the first day. An increase in uri...