tbuckley/cabot-search huggingface dataset:
αvβ3 Integrin Induces Tyrosine Phosphorylation–Dependent Ca2+ Influx in Pulmonary Endothelial Cells
Authors: SunitaBhattacharya, XiaoyouYing, ChenzhongFu, RashmiPatel, WolfgangKuebler, StevenGreenberg, JaharBhattacharya
Journal: Circulation Research (2000)

Abstract—The endothelial αvβ3 integrin occurs luminally, where its ligation by soluble agents may induce inflammatory signaling. We tested this hypothesis in bovine pulmonary artery endothelial cell monolayers with the use of vitronectin and cross-linking antibodies to ligate and aggregate the integrin. We quantified the endothelial cytosolic Ca2+ concentration ([Ca2+]i) according to the Fura 2 ratio imaging method in single cells of confluent monolayers. At baseline, endothelial [Ca2+]i levels remained steady at 86 nmol/L for >20 minutes. Cross-linking of the αvβ3 integrin through the sequential exposure of monolayers to anti-αvβ3 monoclonal antibody LM609 and secondary IgG resulted in a [Ca2+]i increase of 100% above baseline. This increase commenced in <0.5 minute, peaked in <2 minutes, and decayed to baseline in ≈5 minutes. Similar responses occurred after the addition of vitronectin (400 μg/mL). In contrast, external Ca2+ depletion blunted the cross-linking–induced [Ca2+]i increase by 60%, a response...
Abstract P015: Associations of Activated Coagulation Factor VII-Antithrombin Complex (FVIIa-AT), a Novel Coagulation Biomarker, with Genetic Variants in the F7/F10 Locus and Risk of Cardiovascular Disease Mortality: The Cardiovascular Health Study
Authors: Nels C Olson, Leslie A Lange, W.T. Longstreth, Alex P Reiner, Russell P Tracy
Journal: Circulation (2016)

Introduction: Circulating activated factor VII (FVIIa; ~ 1-2% of total FVII) needs to bind tissue factor (TF) to initiate coagulation. This is a rare event in a healthy person, with the FVIIa-TF complex almost immediately inactivated by antithrombin (AT). Therefore, the FVIIa-AT complex reflects the amount of recent TF-FVIIa formation and may be a biomarker of thrombotic risk. We hypothesized that FVIIa-AT would be associated with single nucleotide polymorphisms (SNPs) in genes involved in the activation and regulation of coagulation and with incident cardiovascular disease (CVD) events. Methods: FVIIa-AT, FVIIa (ELISA and truncated TF-based clot rate assay, both Diagnostica Stago, Inc.), and FVII clotting activity (FVIIc) (in-house clot rate assay) were measured in citrated plasma samples from ~3,500 older adults from the Cardiovascular Health Study (CHS) during the Year 5 CHS exam. Associations of FVIIa-AT with ~50K SNPs in CVD-related genes were evaluated using the IBCv2 genotyping array. Cox proportional hazards models were used to evaluate associations of FVIIa-AT with incident coronary heart disease (CHD), ischemic stroke, and CVD event-related mortality over a median 14.5 years of follow-up. Results: FVIIa-AT was moderately correlated with FVIIa (Pearson r 2 =0.48) and FVIIc ( r 2 =0.28; both p-values &lt;0.0001). Mean FVIIa-AT was higher in women (152 pM, standard deviation (SD)= 54 pM) than men (128 pM, SD= 49 pM) and higher in European-Americans (EAs) (142 pM, SD= 53 pM) than African-Americans (124 pM, SD= 57 pM) (both p-values &lt;0.0001). Among EAs, 11 SNPs in the F7 / F10 locus and 5 SNPs in the PROCR locus, which encodes the gene for endothelial protein C receptor (EPCR), were significantly associated with FVIIa-AT. The most significant association was rs488703 located in an intron of the F7 gene (p=3.7x10 -85 ); each copy of the minor allele was associated with 24.6 pM lower FVIIa-AT. The most significant SNP in the PROCR locus was rs867186 (3.3x10 -10 ) associated with 9.0 pM higher FVIIa-AT per minor allele. After adjustment for CVD-risk factors, the hazard ratio for CVD-related mortality among participants in the highest FVIIa-AT quintile was 1.24 (95% confidence interval=1.01, 1.54; p=0.04) compared with those in the lowest quintile. FVIIa-AT was not significantly associated with risk of incident CHD or ischemic stroke independently of traditional CVD risk factors. Conclusions: These results are consistent with a role of common F7 / F10 and PROCR genetic variants on the extent of FVII activation and support a role for recent TF-FVIIa formation in CVD-related mortality among older adults.
Abstract 3500: A pipeline to identify driver mutations
Authors: Deepankar Chakroborty, Kari Kurppa, Ilkka Paatero, Laura Elo, Klaus Elenius
Journal: Cancer Research (2018)

Abstract Introduction: Cancer tissues harbor thousands of mutations while the current list of clinically validated actionable variants contains only about a dozen genetic markers. Most of the somatic mutations in cancer are expected to be inconsequential passenger mutations that reflect the general instability of the tumors. The discovery of most of the currently known driver mutations has been facilitated by their accumulation in mutation hot-spots within their respective genes. However, a great majority of mutations in cancer tissues are rare and no information is currently available about their functional significance. Several lines of in vitro and in vivo clinical evidence also indicate that there is a significant number of, as yet unidentified, activating driver mutations that could serve as predictive markers for oncology. Method: To identify functional driver mutations, we have established a functional genetics screen based on expression of random gene variants and the ability of driver mutations to promote a growth-advantage in vitro, as compared to passenger mutations. The screen was set up using a randomly mutated expression library encoding thousands of variants of epidermal growth factor receptor (EGFR), a well-known oncogene, as a model. The library was retrovirally introduced into murine lymphoid Ba/F3 cells, that normally require interleukin-3 (IL-3) for survival but can exploit ectopic expression of activated variants of oncogenic kinases to compensate for the deficiency of exogenous IL-3. While expression of wild-type EGFR did not promote IL3-independent survival of the Ba/F3 cells, as expected, transduction of the mutant EGFR library did, indicating that the surviving Ba/F3 pool included EGFR mutations with ligand-independent activity. To identify and quantify the frequency of these mutations, targeted next-generation sequencing of the EGFR inserts was carried out. Results: Using the method we were able to identify approximately 20 candidate activating mutations out of the 7000 random EGFR mutations in the original library. The 20 candidates included the well-known activating EGFR mutation, L858R, validating the pipeline. A previously unidentified activating mutation was also found, and the growth promoted by the mutant was susceptible to inhibition by clinically available EGFR inhibitors. Citation Format: Deepankar Chakroborty, Kari Kurppa, Ilkka Paatero, Laura Elo, Klaus Elenius. A pipeline to identify driver mutations [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 3500.
Abstract 5330: DNA hypomethylation promotes carcinogenesis by inducing cryptic transcription
Authors: Dan Lou, Yanqiang Li, Suzanne M. Martos, Yan Zhu, Dana Freeman, Zhibin Wang
Journal: Cancer Research (2018)

Abstract DNA methylation, regulate genomic processes and serve at the interface between genes and the environment, has long been recognized as the key event involved in cancer initiation and development. However, how exactly the role of DNA methylation and their epigenomic consequences underlying carcinogenesis remains to be elucidated. We previously reported that a division of labor between DNA methyltransferase (DNMT) (DNMT1 and DNMT3a/3b) to suppress distinct types of genome components. Additionally, allelic and biomodal methylation patterns have been revealed by using two bioinformatics methods. To determine how the DNA methylation affects the integrity of gene transcription, we applied the appropriate PRO-cap technique that detects 5'-capped RNA transcripts in wildtype (WT) mESCs and three mutant mESCs with altered DNMT: loss of DNMT1 (DNMT1-/- ; 1KO), loss of DNMT3a/3b (DNMT3a-/-/DNMT3b-/-; DKO) and loss of DNMT1 and DNMT3a/3b (DNMT1-/-/ DNMT3a-/-/DNMT3b-/-; TKO). With high quality of sequencing reads at high fold coverage and 150 millions of mapped reads for WT and mutant cells, our analyses revealed significant RNA transcripts alterations. By mapping global transcription start site (TSS) and chromatin dynamics, cryptic transcription of thousands of DNMT loss-induced non-annotated TSSs were observed. Some of the non-annotated TSSs were further confirmed in arsenic-treated malignant transformated cell line. Our results indicated that the alteration (completely loss or partially loss) of DNA methylation may promote the carcinogenesis by sabotaging the fidelity of gene transcription initiation. Citation Format: Dan Lou, Yanqiang Li, Suzanne M. Martos, Yan Zhu, Dana Freeman, Zhibin Wang. DNA hypomethylation promotes carcinogenesis by inducing cryptic transcription [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 5330.
Evolution of the Volume-Outcome Relation for Hospitals Performing Coronary Angioplasty
Authors: VivianHo
Journal: Circulation (2000)

Background—Hospitals performing more surgical procedures tend to yield better outcomes. This study examines the evolution of this volume-outcome relation over time. Methods and Results—The relation between the number of percutaneous transluminal coronary angioplasty (PTCA) procedures performed at hospitals (volume) and in-hospital bypass surgery and death for 353 488 patients treated in California between 1984 and 1996 was examined. Descriptive statistics and logistic regression were used to compare outcomes for 3 periods: 1984 to 1987, 1988 to 1992, and 1993 to 1996. The in-hospital mortality rate was 2.5% for hospitals performing  400 procedures per year in 1984 to 1987. By 1993 to 1996, mortality rates in these 2 volume categories narrowed to 1.7% and 1.3%, respectively. Bypass surgery rates also narrowed and fell in low-volume ( 400 procedures) hospitals from 12.4% versus 6.9% in 1984 to 1987 to 4...
Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London
Authors: Sean M Cavany, Emilia Vynnycky, Charlotte S Anderson, Helen Maguire, Frank Sandmann, H Lucy Thomas, Richard G White, Tom Sumner
Journal: Thorax (2018)

Background In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. Methods We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). Results Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. Conclusions Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines.
Abstract 914: COX-2 expression is associated with chemoresistance through cancer stemness property in head and neck squamous cell carcinoma
Authors: Shin Saito, Hiroyuki Ozawa, Yorihisa Imanishi, Mariko Sekimizu, Yoshihiro Watanabe, Fumihiro Ito, Yuichi Ikari, Nana Nakahara, Kaori Kameyama, Kaoru Ogawa
Journal: Cancer Research (2018)

Abstract Introduction: COX-2 is one of the two isoforms of cyclooxygenase, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 is considered to be associated with progression in various cancers, and its expression has been reported to have an impact on poor prognosis in head and neck squamous cell carcinomas (HNSCCs). Furthermore, COX-2 expression has been shown to be associated with resistance to anticancer drugs. However, the precise mechanism of COX-2 for chemoresistance in HNSCC is not fully elucidated. The aim of the present study was to investigate the impact of COX-2 on cancer stem cell property, and to reveal its effect on chemoresistance by in vitro and clinicopathological assays. Methods: We examined the chemoresistance to docetaxel with or without COX-2 inhibitor (celecoxib) in HNSCC cell lines (FaDu, Detroit512) by MTS assays. To evaluate the association of COX-2 expression with stemness property, we assessed alteration of expression levels of the genes related to cancer stem cell (CSC) property after exposure to celecoxib by quantitative real-time PCR. We also performed a sphere formation assay using ultra low attachment dishes and microscopic imaging. Moreover, we analyzed immunohistochemical expressions of COX-2 and clinicopathological factors by using matched samples of pre-treatment biopsy and surgical specimens from hypopharyngeal carcinoma patients who had undergone trans-oral tumor resection with preoperative induction chemotherapy including docetaxel. Results: Cell survival rate under exposure to docetaxel was decreased by addition of celecoxib. COX-2 inhibitor downregulated the expression of Oct3/4 and Nanog. Sphere formation was inhibited by co-culture with COX-2 inhibitor, especially in FaDu cells. Immunohistochemical study in biopsy specimens revealed a negative correlation between COX-2 expression in biopsy specimens and pathological effect of induction chemotherapy in surgical specimens. Conclusion: The present study suggests that COX-2 expression is associated with cancer stemness property, and inhibition of COX-2 has a possibility to enhance chemosensitivity in HNSCCs. Furthermore, initial COX-2 expression in biopsy specimens may predict the effect of chemotherapy in HNSCCs. These results indicate that COX-2 can be an attractive target for the treatment of HNSCC. Citation Format: Shin Saito, Hiroyuki Ozawa, Yorihisa Imanishi, Mariko Sekimizu, Yoshihiro Watanabe, Fumihiro Ito, Yuichi Ikari, Nana Nakahara, Kaori Kameyama, Kaoru Ogawa. COX-2 expression is associated with chemoresistance through cancer stemness property in head and neck squamous cell carcinoma [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 914.
A new Luminex‐based peptide assay to identify reactivity to baked, fermented, and whole milk
Authors: Cansin Sackesen, Mayte Suárez‐Fariñas, Ronaldo Silva, Jing Lin, Stephanie Schmidt, Robert Getts, Gustavo Gimenez, Ebru A. Yilmaz, Ozlem Cavkaytar, Betul Buyuktiryaki, Ozge Soyer, Galina Grishina, Hugh A. Sampson
Journal: Allergy (2018)

The majority of children with cow's milk allergy (CMA) tolerate baked milk. However, reactivity to fermented milk products such as yogurt/cheese has not been previously evaluated. We sought to determine whether children with CMA could tolerate yogurt/cheese and whether a patient's IgE and IgG4-binding pattern to milk protein epitopes could distinguish clinical reactivity.Four groups of reactivity were identified by Oral food challenge: baked milk reactive, fermented milk reactive, whole milk reactive, and outgrown. sIgE and sIgG4 binding to milk protein epitopes were assessed with a novel Luminex-based peptide assay (LPA). Using machine learning techniques, a model was developed to predict different degrees of CMA.The baked milk reactive patients demonstrated the highest degree of IgE epitope binding, which was followed sequentially by fermented milk reactive, whole milk reactive, and outgrown. Data were randomly divided into two groups with 75% of the data utilized for model development (n = 68) and 25% for testing (n = 21). All 68 children used for training were correctly classified with models using IgE and IgG4 epitopes. The average cross-validation accuracy was much higher for models using IgE plus IgG4 epitopes by LPA (84.8%), twice the performance of the serum component proteins assayed by UniCAP (41.9%). The performance of the model on "unseen data" was tested using the 21 withheld patients, and the accuracy of IgE was 86% (AUC = 0.89) while of IgE+IgG4 model was 81% (AUC = 0.94).Using a novel high-throughput LPA, we were able to distinguish the diversity of IgE/IgG4 binding to epitopes in the varying CMA phenotypes. LPA is a promising tool to predict correctly different degrees of CMA.
Abstract 4088: Metabolic disease drivers of liver cancer, a new disease paradigm
Authors: Michael R. Briggs, Dipti Deshpande, Nikole Siegmund
Journal: Cancer Research (2018)

Abstract Much of the global burden of HCC until recently has been caused by alcohol abuse and hepatitis viruses (HepB &amp; HepC). With a vaccine for HepB being widely used in Asian countries and multidrug cocktails to effectively cure much HepC, these drivers of HCC will be reduced in the future. Ironically, HCC continues to be one of the few cancers growing in incidence. It is postulated that the global obesity epidemic is fueling a new etiology of HCC, through fatty liver disease, nonalcoholic steatohepatitis (NASH) and cirrhosis. Liver and pancreatic cancers are projected to continue to increase in incidence for the foreseeable future, and distressingly, for the first time, children are being diagnosed with NASH. We have undertaken the development of a mouse model of NASH leading to HCC and performed a longitudinal analysis of liver samples through the phenotypes of obesity and hyperglycemia, inflammation and fibrosis leading to hyperproliferative disease and HCC to begin to map out the pathways and biomarkers of this metabolically driven liver cancer for comparison to human clinical data and biomarkers of disease progression to HCC. Citation Format: Michael R. Briggs, Dipti Deshpande, Nikole Siegmund. Metabolic disease drivers of liver cancer, a new disease paradigm [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 4088.
Abstract 12044: East Meets West in the Assessment of Cardiac Risk: A Multicenter Comparative Study of the Influence of Racial, Ethnic and Cultural Risk Factors on Cardiac Surgical Risk Model Performance
Authors: Paul Kurlansky, Onur Baser, Samantha Nemeth, Judy Tingley, Michael Argenziano, Craig Smith
Journal: Circulation (2016)

Introduction: Numerous risk models have been applied to coronary artery bypass (CABG) patients. Their applicability across racial, ethnic and cultural backgrounds has not been well-described. We therefore compared the performance of the SinoSCORE, derived from 43 Chinese medical centers (c-statistic=0.80), with the Society of Thoracic Surgeons (STS) CABG mortality risk model in a population of CABG patients from a diverse multicenter American registry. Hypothesis: Racial, ethnic and cultural differences will impact the performance of surgical risk models. Methods: Perioperative data on all patients undergoing CABG between May 2006 and December 2015 from each of 8 centers was entered into the STS database. SinoSCORE and STS predicted risk of mortality was calculated for each patient. Logistic regression was used to develop a risk model based on SinoSCORE variables and performance was compared to STS risk model. Results: 7918 patients underwent CABG of whom 1.36% % were Asian. Sino-SCORE successfully categorized surgical mortality into low (0.12%), medium (0.36%) and high (2.42%) risk of mortality. However, the discrimination and calibration was better for STS than for the derived SinoSCORE (c-statistic 0.8087 vs. 0.767; p=0.0007; Figure; Hosemer-Lemeshow χ 2 52.64 vs. 40.05). Moreover, several of the factors which were predictors of mortality in the original SinoSCORE (age 65-70, BMI&lt;18, chronic renal insufficiency, extracardiac arteriopathy, COPD, atrial fibrillation, urgent status) were not predictors in the derived model when applied to this multicenter Western patient population Conclusions: A CABG risk model derived from a from a broad sampling of Chinese patients did not perform as well in a diverse multicenter American population as it did in the population of origin, or as did the STS risk model. Considerable caution should be exercised, even for common operations, in applying surgical risk models across racial, ethnic and cultural divisions.
Estrogen Signaling and Cardiovascular Disease
Authors: ElizabethMurphy
Journal: Circulation Research (2011)

Estrogen has pleiotropic effects on the cardiovascular system. The mechanisms by which estrogen confers these pleiotropic effects are undergoing active investigation. Until a decade ago, all estrogen signaling was thought to occur by estrogen binding to nuclear estrogen receptors (estrogen receptor-α and estrogen receptor-β), which bind to DNA and function as ligand-activated transcription factors. Estrogen binding to the receptor alters gene expression, thereby altering cell function. Estrogen also binds to nuclear estrogen receptors that are tethered to the plasma membrane, resulting in acute activation of signaling kinases such as PI3K. An orphan G-protein-coupled receptor, G-protein-coupled receptor 30, can also bind estrogen and activate acute signaling pathways. Thus, estrogen can alter cell function by binding to different estrogen receptors. This article reviews the different estrogen receptors and their signaling mechanisms, discusses mechanisms that regulate estrogen receptor levels and location...
Endothelial PAS Domain Protein 1 Gene Promotes Angiogenesis Through the Transactivation of Both Vascular Endothelial Growth Factor and Its Receptor, Flt-1
Authors: NorihikoTakeda, KojiMaemura, YasushiImai, TomohiroHarada, DaijiKawanami, TakefumiNojiri, IchiroManabe, RyozoNagai
Journal: Circulation Research (2004)

Endothelial PAS domain protein 1 (EPAS1) is a basic-helix-loop-helix/PAS domain transcription factor that is expressed preferentially in vascular endothelial cells. EPAS1 shares high homology with hypoxia-inducible factor-1α (HIF-1α) and is reported to transactivate vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1), and Tie2 promoters. In this study, we analyzed the role of EPAS1 in the process of angiogenesis. Using microarray technology, we looked for target genes regulated by EPAS1 in vascular endothelial cells. A total of 130 genes were upregulated by EPAS1, including fms-like tyrosine kinase-1 (Flt-1). Reporter analysis using human Flt-1 promoter and gel mobility shift assays showed that the heterodimer of EPAS1 and aryl hydrocarbon receptor nuclear translocator binds directly to HIF-1-binding site upstream of Flt-1 promoter and transactivates it. Small interfering RNA targeted to EPAS1 but not HIF-1α attenuated desferrioxamine-induced Flt-1 mRNA expression, thus EPAS1 is though...