tbuckley/cabot-search huggingface dataset:
Abstract 1899: Targeting interferon induced transmembrane protein-1 (IFITM1) attenuates the aggressive phenotype of inflammatory breast cancer
Authors: Olivia Provance, Eric Geanes, Joshua Ogony, Asona Lui, Eric Young, Sumedha Gunewardena, Joan Lewis-Wambi
Journal: Cancer Research (2018)

Abstract Inflammatory breast cancer (IBC) is the most aggressive and lethal subtype of breast cancer, with triple-negative IBC being the most difficult to treat IBC subgroup. Improved understanding of mechanisms that lead to aggressiveness of triple-negative IBC could provide a basis for therapeutic targets. Our laboratory has identified a novel interferon (IFN)-α signaling target called interferon induced transmembrane protein-1 (IFITM1), which we hypothesize to promote the aggressive phenotype of triple-negative IBC. CRISPR/CAS9 was utilized to silence IFITM1 in SUM149 TN-IBC cells. In vitro, we found that knockout of IFITM1 increased in colony and mammosphere formation, inhibited migration as observed by the wound healing assay, and enhanced sensitivity to mainstay chemotherapeutic agents (taxol and doxorubicin) analyzed by flow cytometry, MTT and Tunel staining. Western blot analysis shows a decrease in c-Src and p-Src, vimentin, and CD44v expression, which are important regulators of migration and invasion. RNA sequencing analysis further indicates that knocking down IFITM1 promotes overall downregulation of pathways including breast cancer invasion, supporting our in vitro findings. In vivo, IFITM1-CRISPR/KD SUM149 cells were injected into the mammary fat pads of immunosuppressed female NSG mice to assess tumor growth. We found that mice injected with IFITM1-CRISPR/KD SUM149 cells showed significantly reduced tumor growth compared to mice injected with CRISPR/control SUM149 cells, which was observed at all time points examined. We used the mammary intraductal (MIND) method to assess tumor invasion in vivo. IFITM1-CRISPR/KD SUM149 cells showed decreased invasion outside of the mammary duct and decreased vimentin expression, further corroborating our in vitro data. Lastly, through tail vein injections to model metastasis, 33% of mice injected with SUM149 wildtype cells developed liver metastasis while 0% of mice injected with IFITM1-CRISPR/KD SUM149 mice developed liver metastasis. We have ongoing studies to further understand the mechanism by which IFITM1 regulates cellular migration, as well as invasion and angiogenesis in triple-negative IBC, which are all shown to be downregulated through RNA sequencing analysis. Overall, these findings indicate that IFITM1 may be driving the aggressiveness of triple-negative IBC and they suggest that IFITM1 may serve as a potential therapeutic target. Citation Format: Olivia Provance, Eric Geanes, Joshua Ogony, Asona Lui, Eric Young, Sumedha Gunewardena, Joan Lewis-Wambi. Targeting interferon induced transmembrane protein-1 (IFITM1) attenuates the aggressive phenotype of inflammatory breast 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 1899.
Abstract 5300: smCounter2, a highly accurate UMI-aware variant caller and its applications in detecting 0.5-1% somatic mutations using targeted panel sequencing
Authors: Chang Xu, Xiujing Gu, Zhong Wu, John DiCarlo, Yexun Wang
Journal: Cancer Research (2018)

Abstract We introduce smCounter2, our new version of low-frequency variant caller for targeted panel sequencing data. Upgraded from the previous version of smCounter (Xu et al, BMC Genomics, 2017), smCounter2 has a higher accuracy of detecting 0.5-1% variants and a more solid and scalable theoretical foundation. For 1% SNVs, smCounter2 achieved above 98% sensitivity and fewer than 10 false positives per megabase on a 680kb custom panel using a mixture of Genome in a Bottle reference samples. For 0.5% SNVs (including multi-allelic variants), smCounter2 achieved 87.5% sensitivity (7 out of 8) using a mixture of Horizon Tru-Q samples. We have also tested smCounter2 on other datasets with 5% and germline variants. On all these datasets except the germline variants, smCounter2 has demonstrated superior performance compared with other state-of-the-art UMI-aware variant calling algorithms. Currently, we are generating data on another custom panel (~900kb) to demonstrate the sensitivity and specificity of calling 0.5% variants. smCounter2 models DNA polymerase errors for each substitution type, therefore more accurately distinguishes real variants from the first-cycle PCR errors, which cannot be corrected by UMIs. smCounter2 is equipped with model-based filters that can reduce false calls in repetitive regions such as homopolymers and micro-satellite sequences, where error rate is generally higher and UMIs tend to be less effective. These features, to some extent, overcome the intrinsic limitations of UMI-based variant calling and are essential to smCounter2's improved performance. Citation Format: Chang Xu, Xiujing Gu, Zhong Wu, John DiCarlo, Yexun Wang. smCounter2, a highly accurate UMI-aware variant caller and its applications in detecting 0.5-1% somatic mutations using targeted panel sequencing [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 5300.
Coronary Artery Responses to Physiological Stimuli Are Improved by Deferoxamine but not by l-Arginine in Non–Insulin-Dependent Diabetic Patients With Angiographically Normal Coronary Arteries and No Other Risk Factors
Authors: AlainNitenberg, FrédéricPaycha, SéverineLedoux, RégisSachs, Jean-RaymondAttali, PaulValensi
Journal: Circulation (1998)

Background—Acetylcholine produces coronary artery (CA) constriction in diabetic patients, suggesting an impairment of endothelium-dependent dilation. In diabetes, multiple metabolic abnormalities may inactivate nitric oxide through oxygen free radical production. Methods and Results—To examine the mechanism of this abnormal response, two physiological tests (ie, a cold pressor test [CPT] and coronary flow increase induced by an injection of 10 mg papaverine [PAP] in the distal left anterior descending CA) were performed before and after either intravenous l-arginine (625 mg/min×10 minutes) or intravenous deferoxamine (50 mg/min×10 minutes) in 22 normotensive nonsmoking diabetic patients with angiographically normal CAs and normal cholesterol. Coronary surface areas were measured with quantitative angiography. Before the administration of l-arginine or deferoxamine, CPT induced CA constriction in both groups (−14±10% and −15±11%, respectively; each P<.001), and PAP injection in distal LAD did not modify si...
Alterations in Intracellular Calcium Handling Associated With the Inverse Force-Frequency Relation in Human Dilated Cardiomyopathy
Authors: BurkertPieske, BodoKretschmann, MarkusMeyer, ChristianHolubarsch, JörgWeirich, HerbertPosival, KazatomoMinami, HanjörgJust, GerdHasenfuss
Journal: Circulation (1995)

Background The present study was performed to test the hypothesis that the altered force-frequency relation in human failing dilated cardiomyopathy may be attributed to alterations in intracellular calcium handling. Methods and Results The force-frequency relation was investigated in isometrically contracting ventricular muscle strip preparations from 5 nonfailing human hearts and 7 hearts with end-stage failing dilated cardiomyopathy. Intracellular calcium cycling was measured simultaneously by use of the bioluminescent photoprotein aequorin. Stimulation frequency was increased stepwise from 15 to 180 beats per minute (37°C). In nonfailing myocardium, twitch tension and aequorin light emission rose with increasing rates of stimulation. Maximum average twitch tension was reached at 150 min−1 and was increased to 212±34% (P<.05) of the value at 15 min−1. Aequorin light emission was lowest at 15 min−1 and was maximally increased at 180 min−1 to 218±39% (P<.01). In the failing myocardium, average isometric t...
Abstract MP82: The Effect of Nicotinic Acetylcholine Receptor Genes CHRNA3/5 on Thoracic Aortic Calcium is Mediated by Smoking
Authors: Sharon M Lutz, Michael Cho, Greg Kinney, Kendra Young, Katherine Pratte, Lindsey Duca, Marilyn Foreman, Terri Beaty, Ed Silverman, Matthew Budoff, John Hokanson
Journal: Circulation (2016)

Introduction: Coronary artery calcium (CAC) and thoracic aortic calcium (TAC), markers of subclinical atherosclerosis, have been shown to strongly correlate with the amount of atheromatous plaque and subsequently predict future coronary disease events and mortality. CAC and TAC are complex heritable traits with both genetic and environmental risk factors such as cigarette smoking. We investigated the role of smoking, a key environmental risk factor, as a mediator of the genetic risk of subclinical atherosclerosis in the COPDGene study. Hypothesis: We hypothesized that smoking will mediate a portion of the genome-wide significant SNPs with subclinical atherosclerosis as measured by TAC and CAC. Methods: We performed genome wide genotyping of common and rare variants in COPDGene, a study of 10,192 current and former smokers with at least 10 pack-years of smoking history. CAC and TAC were measured using high dose, inspiration chest CT scans, following an established protocol in 8,739 individuals (6,150 non-Hispanic Whites and 2,589 African Americans). Mediation analysis, using the significant SNPs from the GWA of common and rare variants, was performed using R software adjusting for genetic ancestry using principal components as well as recognized risk factors (age, gender, BMI, diabetes, high blood pressure, steroid use, high cholesterol, and presence of a coronary stent). We used the log transformation of CAC plus 1 and the log transformation of TAC plus 1 as the quantitative phenotypes. Results: There were 3 SNPs on chromosome 15q25 [CHRNA5/3] achieving genome-wide significance with TAC in non-Hispanic Whites, with the most significant result being rs951266 (p= 3.074e-8). We previously replicated 9 SNPs on chromosome 9 [CDKN2B-AS1] reaching genome-wide significance with CAC in non-Hispanic Whites. In African Americans, no genome-wide significant associations were identified. Given these findings, we tested for mediation of these genetic signals by pack-years of smoking among non-Hispanic Whites in the COPDGene study. Pack-years of smoking history was a significant mediator of CHRNA5/3 [rs951266] on TAC (p &lt;0.001, 13% indirect effect), while smoking was not a significant mediator of CDKN2B-AS13 on CAC (p =0.58). Conclusions: The nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/3) were significantly associated with thoracic aortic calcium in this cohort of heavy smokers. Cigarette smoking mediates this genetic risk for subclinical atherosclerosis and may offer an avenue for intervening on the genetic susceptibility to coronary artery disease.
Abstract P098: The Association Between Obesity Status and Long-Term Adherence to Mediterranean Diet in the PREDIMED Trial
Authors: Jessica Cohen, Eric B Rimm, Miguel A Martínez-González, Jordi Salas-Salvadó, María I Covas, Dolores Corella, Rosa M Lamuela-Raventós, Ramón Estruch
Journal: Circulation (2013)

Background: The aim of this study was to determine if long-term adherence to a prescribed diet, in the context of the PREDIMED trial, a multi-year, randomized, controlled trial, was different among obese and non-obese participants after an average follow-up of three years. Previous studies only examined short term compliance or were not sufficiently powered to compare obese with nonobese participants. Methods: This randomized clinical trial included 6,463 subjects. All subjects were asymptomatic; females aged 55-80 years and males 55-80 years and were at high-risk for cardiovascular disease at baseline. Participants’ characteristics were measured at baseline and every 12 months. Obesity was defined as having a BMI of 30kg/m2 or more. The main outcome measure was achieving an average score of 10 points or more on a validated 14-point Mediterranean diet adherence scale over follow-up. Results: In all three dietary intervention groups, obesity status was significantly inversely associated with adherence to the Mediterranean diet; In the olive oil group, the odds ratio of obtaining a score of 10 or more was 23.4% (95% CI: 6.3, 37.5%) lower for obese subjects than for non-obese subjects after an average follow-up of three years. A similar pattern was also seen in the nuts group; the odds of obtaining a score of 10 or more was 24.3% (95% CI: 5.1,39.6%) lower for obese subjects than for non-obese subjects. In the low fat group, subjects who were obese at baseline had 25.7% (95% CI:5.7, 40.8%) lower odds of obtaining a score of 10 or more on the adherence score. All models were adjusted for relevant covariates. Conclusion: In this long-term trial of the Mediterranean Diet, adherence was high across all intervention groups. However, adherence was appreciably lower among obese participants after three years. Additional intervention efforts may be necessary to achieve the same adherence among high-risk obese individuals.
Tracking of Blood Pressure From Childhood to Adulthood
Authors: XiaoliChen, YoufaWang
Journal: Circulation (2008)

Background— A large number of studies have examined the tracking of blood pressure (BP) from childhood to adulthood, but the reported findings are inconsistent and few systematic analyses have been conducted. Methods and Results— We conducted a systematic search of PubMed for studies that examined the tracking of BP from childhood to adulthood published between January 1970 and July 2006. From 301 retrieved papers, 50 cohort studies met our inclusion criteria and provided 617 data points (Pearson/Spearman correlation coefficients) for systolic BP (SBP) and 547 data points for diastolic BP (DBP) for our meta-analysis. Information on sample characteristics and BP measurement protocols was extracted. Fisher z transformation and random-effects meta–regression analysis were conducted. The reported BP tracking correlation coefficients varied from −0.12 to 0.80 for SBP and from −0.16 to 0.70 for DBP, with an average of 0.38 for SBP and 0.28 for DBP. BP tracking varied significantly by baseline age and length of ...
Cardiomyocytes of Noncardiac Origin in Myocardial Biopsies of Human Transplanted Hearts
Authors: PatrickMüller, PeterPfeiffer, JörgKoglin, Hans-JoachimSchäfers, UteSeeland, IngridJanzen, SteffiUrbschat, MichaelBöhm
Journal: Circulation (2002)

Background— Cell replacement therapy with stem cells able to differentiate into cardiomyocytes has been discussed as a method for remodeling damaged myocardium. A physiological or pathophysiological situation in which this phenomenon might be relevant is not known. We studied the origin of cardiomyocytes in myocardial biopsies of male patients that had undergone sex-mismatched cardiac transplantation to determine whether cells containing a Y chromosome (and therefore being of recipient origin) are able to differentiate into cardiomyocytes. Methods and Results— Myocardial biopsies (n=21) were obtained from the right ventricles of male patients (n=13) who had undergone sex-mismatched heart transplantation. Tissue from 1 nontransplanted male and myocardial biopsies from sex-matched heart–transplanted patients served as controls. Cells from donor and recipient origins were identified by fluorescence in situ hybridization with the use of specific probes for X and Y chromosomes on paraffin sections of the biops...
Abstract 4468: Repression of CD44 expression by p53 in a breast cancer progression model
Authors: Fang Liu, Zhengxue Liu, Guannan Wang, Tanima Roy-Kundu, Isao Matsuura
Journal: Cancer Research (2018)

Abstract CD44 is an important molecule in breast cancer. Although CD44 lacks its own signaling domain, it can associate with and co-stimulate signaling by a number of growth factor receptors, such as Her2 and EGF receptor 1. Knockdown of CD44 significantly reduces mammary tumor-initiating frequency and tumor weight. Disruption of tumor cell surface CD44 function induces apoptosis in metastatic mammary carcinoma cells in vivo. Some studies showed that the breast cancer stem cells are enriched in the CD44highCD24low population. The tumor suppressor p53 is mutated or functionally inactivated in over 70% of cancer. In breast cancer, p53 is mutated in ~35% cases, and ~50% breast cancers contain MDM2 or MDMX overexpression. A previous study showed that p53 repressed the expression of CD44 and that this activity was essential for the tumor-suppressor function of p53. We find that p53 potently represses the expression of CD44 in normal human breast epithelial cells. Mutation of the p53 binding site on the CD44 promoter greatly reduces the ability of p53 to repress CD44 expression. We show that p53 repression of CD44 expression is progressively reduced in a breast cancer progression model. Our ongoing studies are elucidating the underlying mechanisms. Our findings will help for better understanding and treatment of breast cancer. Citation Format: Fang Liu, Zhengxue Liu, Guannan Wang, Tanima Roy-Kundu, Isao Matsuura. Repression of CD44 expression by p53 in a breast cancer progression model [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 4468.
Abstract 17072: A Novel Algorithm for Quantification of Mitral Valve Regurgitation Based on Pixel Density Analysis of Continuous Wave Doppler Imaging
Authors: Milad El Haddad, Tine De Backer, Marc De Buyzere, Abigail Swillens, Patrick Segers, Frank Timmermans
Journal: Circulation (2015)

Introduction: Echocardiography is important for the assessment of mitral valve regurgitation (MR) and to guide clinical decision making. Echocardiographic methods are being used to quantify MR severity but their applicability, accuracy, and reproducibility have been debated. Hypothesis: To test the feasibility and in vitro validation of a novel custom-made transthoracic echocardiographic method for the assessment of MR severity based on pixel density analysis (PDA) of the continuous wave (CW) envelope in digital images. Methods: MR was prospectively assessed in 290 patients on a VIVID E9 echo machine (GE) with fixed settings. MR severity was evaluated according to international guidelines using color doppler, vena contracta (VC) width, proximal iso-velocity surface area (PISA) method, and PDA. The applicability, inter-observer, and intra-observer variability of all methods were compared. For validation of the PDA algorithm, a pulsatile in vitro cardiac phantom was used with prosthetic mitral valves with different regurgitant orifices (13.2, 27.2, 54.7, and 86.5 mm2). Regurgitant volume (RV) was calculated by multiplying the regurgitant orifice with the time velocity integral. Results: The PDA method showed a linear correlation with color doppler (r=0.82), VC width (r=0.67), PISA-effective regurgitant orifice area (EROA, r=0.72), and PISA-RV (r=0.67); p&lt;0.001 for all. The PDA was significantly more applicable than VC width (n= 275/290, 95% vs. 218/290, 75% p&lt;0.001) and PISA-based methods (n=191/290, 65% p&lt;0.001). Additionally, PDA showed a stronger intra- and inter-observer agreement compared to the VC, PISA-EROA, and PISA-RV (intra-observer ICC = 0.96 vs. 0.79, 0.87, and 0.82 respectively; inter-observer ICC = 0.96 vs. 0.46, 0.89, and 0.85 respectively). In the in vitro validation, PDA showed a strong linear correlation with regurgitant volumes (r=0.92, p&lt;0.001). Conclusions: We showed the clinical feasibility and in vitro validation of a novel digital quantitative echocardiographic method to assess MR severity. This method is more applicable and has less inter- and intra-observer variability compared to current quantitative methods. Patient follow-up is ongoing to validate the novel methods against clinical endpoints in MR.
Abstract 12686: Cariporide, a Selective Na+-H+ Exchange Inhibitor, Improves Cardiac Basal and β-Adrenergic Stimulated Functional Performance in Experimental Hypothyroidism
Authors: Tiankai Li, Xiaowei Zhang, Heng-Jie Cheng, Qun Shao, Wei-Min Li, Che Ping Cheng
Journal: Circulation (2015)

Background: Upregulation of Na + -H + exchanger 1 (NHE1) occurs during pathological insult and contributes to the deleterious consequence on the myocardium. Cariporide (CAR), a NHE1 selective inhibitor, exerts protective actions in various forms of heart disease, including heart failure (HF). Hypothyroidism (Hypo) causes cardiac injury. Recent studies link Hypo to the pathology of cardiomyopathy and HF. However the direct cardiac effects of CAR in Hypo are unknown. We tested the hypothesis that Hypo produces direct depressions in LV and myocyte basal function and β-adrenergic reserve. CAR would improve cardiac [Ca 2+ ] i regulation and enhance myocyte basal and β-adrenergic stimulated contraction and relaxation. Methods: We simultaneously evaluated LV functional performance and compared myocyte contractile and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses to isoproterenol (ISO) in 12 control (C) and 14 rats with Hypo induced by methimazole (30 mg/kg/day for 8 weeks in the drinking water) in the absence and presence of CAR. Results: Versus controls, Hypo caused LV dysfunction with significantly increased the time constant of LV relaxation (t) and decreased LV contractility (E ES ) accompanied by concomitant significant depressed myocyte contraction (dL/dt max ) (Hypo: 65.6 vs C: 135.9 μm/s), relaxation (dR/dt max ) (52.8 vs 107.4 μm/s), and [Ca 2+ ] iT (0.16 vs 0.25). Versus normal myocytes, in Hypo myocytes, ISO (10 -8 M) caused significantly less increases in dL/dt max (36% vs 65%), dR/dt max (26% vs 52%), and [Ca 2+ ] iT (16% vs 31%). In Hypo, versus Hypo baselines, after CAR (0.5 mg/kg, ip), t (18.0 ms vs 22.8 ms) significantly decreased and the peak rate of mitral flow (4732 vs 3263 μl/s) and E ES (0.86 vs 0.60 mmHg/μl) were significantly augmented. Consistently, in Hypo myocytes, superfusion of CAR (10 -5 M) produced significant increases in dL/dt max (38%, 90.5 vs 65.6 μm/s), dR/dt max (27%, 67.1 vs 53.8 μm/s) and [Ca 2+ ] iT (23%, 0.20 vs 0.16). Importantly, compared with Hypo baselines, with CAR superfusion, ISO also caused significantly greater increases in dL/dt max (57%), dR/dt max (46%), and [Ca 2+ ] iT (29%). Conclusions: In hypothyroidism, clinically relevant dose of cariporide improves LV myocyte contraction, relaxation, [Ca 2+ ] iT and β-adrenergic responsiveness.