tbuckley/cabot-search huggingface dataset:
Activation of gp130 Transduces Hypertrophic Signal Through Interaction of Scaffolding/Docking Protein Gab1 With Tyrosine Phosphatase SHP2 in Cardiomyocytes
Authors: YoshikazuNakaoka, KeigoNishida, YasushiFujio, MasahiroIzumi, KazuoTerai, YuichiOshima, ShokoSugiyama, SatoshiMatsuda, ShigeoKoyasu, KeikoYamauchi-Takihara, ToshioHirano, IchiroKawase, HisaoHirota
Journal: Circulation Research (2003)

Grb2-associated binder-1 (Gab1) is a scaffolding/docking protein and contains a Pleckstrin homology domain and potential binding sites for Src homology (SH) 2 and SH3 domains. Gab1 is tyrosine phosphorylated and associates with protein tyrosine phosphatase SHP2 and p85 phosphatidylinositol 3-kinase on stimulation with various cytokines and growth factors, including interleukin-6. We previously demonstrated that interleukin-6–related cytokine, leukemia inhibitory factor (LIF), induced cardiac hypertrophy through gp130. In this study, we report the role of Gab1 in gp130-mediated cardiac hypertrophy. Stimulation with LIF induced tyrosine phosphorylation of Gab1, and phosphorylated Gab1 interacted with SHP2 and p85 in cultured cardiomyocytes. We constructed three kinds of adenovirus vectors, those carrying wild-type Gab1 (AdGab1WT), mutated Gab1 lacking SHP2 binding site (AdGab1F627/659), and β-galactosidase (Adβ-gal). Compared with cardiomyocytes infected with Adβ-gal, longitudinal elongation of cardiomyocyt...
Abstract 16374: Low Density Granulocytes Associate With Non-Calcified Coronary Plaque in Psoriasis
Authors: Heather L Teague, Amit K Dey, Joanna I Silverman, Charlotte L Harrington, Pradeep K Dagur, Aditya A Joshi, Elena Stansky, Monica M Purmalek, Yvonne Baumer, Tarek Z Aridi, Carmelo Carmona-Rivera, Abhishek Chaturvedi, Gregory E Sanda, Alexander V Sorokin, P. John McCoy, Joel M Gelfand, Martin P Playford, Mariana J Kaplan, Marcus Y Chen, Nehal N Mehta
Journal: Circulation (2017)

Introduction: Atherogenesis in now recognized as an immune-driven, inflammatory process, however the mechanisms driving inflammatory atherogenesis remain to be elucidated. Psoriasis is a chronic in...
Abstract LB-223: Examination of intra-assay variability in a commercial ctDNA NGS assay with triplicate clinical plasma and pooled normal samples
Authors: Daniel Stetson, Brian Dougherty, Ambar Ahmed, Barrett Nuttall, Tristan J. Lubinski, Fakhera Afshar, Amelia Raymond, Carl Barrett
Journal: Cancer Research (2018)

Abstract The increased reliance on liquid biopsy next generation sequencing assays for oncology clinical decisions has highlighted the importance of understanding the factors that impact the analytical validation and clinical utility of these tests. Although recent studies have been published examining the concordance between tumor and plasma sequencing data from the same patient, there has been a lack of insight into the intra-assay variability within these tests. We have previously performed a replicate study across multiple ctDNA sequencing vendors and found a high degree of variability among assays particularly at low allele fractions (AF&amp;lt;1%). To further extend our analysis, we examined the variability of ctDNA sequencing results from replicate patient plasma samples with the same vendor assay. The cohort consisted of 25 total samples: seven cancer patient plasma samples, representing triplicate 2 ml baseline plasma samples, plus four healthy normal samples, representing two different pools of six subjects in duplicate. The plasma names were blinded and shipped to Guardant Health for Guardant360 panel testing and both the raw data and reported variant calls were returned to AstraZeneca for comparative analysis. A total of 17 unique variants were called in this study, of which four variants were concordant for all three replicate plasmas and 13 variants were reported in only one or two replicates. Examining the raw data for all samples, the majority of the discordant variants were able to be identified at low levels. Plasmas had low amounts of ctDNA, and two patients had low unique molecule counts, with allele fractions ranging from 0.10-1.13%. Interestingly, the reported yield of the extracted DNA did not correlate with the ability to detect low frequency somatic variants. Data will be presented showing the unblinded comparisons between the replicate samples for both the cancer patient plasma data and the pooled normal plasmas. This study highlights the importance of reproducibility studies for ctDNA samples with variants at low allele fractions to discern between false negative and false positive finding. Citation Format: Daniel Stetson, Brian Dougherty, Ambar Ahmed, Barrett Nuttall, Tristan J. Lubinski, Fakhera Afshar, Amelia Raymond, Carl Barrett. Examination of intra-assay variability in a commercial ctDNA NGS assay with triplicate clinical plasma and pooled normal samples [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 LB-223.
Abstract 2018: Rescue of ΔNp63α inhibits urothelial cell invasion by attenuating epithelial-to-mesenchymal transition (EMT)
Authors: Kirtiman Srivastava, Victoria Smith, Eric A. Fernandez, Conor Breen, Karen D. McCloskey
Journal: Cancer Research (2018)

Abstract Background: Loss of the transcription factor, p63 is associated with poor prognosis in muscle-invasive bladder cancers. The current study aimed to investigate the tumor-suppressive role of p63 in urothelial cancers. Methods: A 3-dimensional (3D) organotypic raft model of urothelial cancer was established by culturing human urothelial cancer cell lines (HT1376, T24) on human bladder fibroblast-embedded collagen-I. Control rafts contained normal primary human urothelial cells (HUC). Cells were also cultured as monolayers on collagen-I coated dishes before harvesting total RNA and protein for qPCR and Western blot analyses respectively. Results: Non-invasive HUC and HT1376 had an epithelial phenotype, characterized by compact and cuboidal morphology whereas invasive T24 cells were elongated with a spindle morphology, typical of mesenchymal cells and indicative of epithelial-to-mesenchymal transition (EMT), which is necessary for invasion. The number of invasive incidents in 3D rafts established with T24 cells was higher compared to those with HUC or HT1376 cells (N=3, p&amp;lt;0.05). Consistent with this, the invasive cell line had reduced mRNA and protein expression of total p63 (N=3), a differentiation marker, and the epithelial marker E-cadherin (N=3), in addition to upregulated expression of the mesenchymal markers N-cadherin (N=3) and fibronectin (N=3) and pERK-Y204 (N=2) compared to the non-invasive cells. Treatment of invasive T24 cells with histone deacetylase (HDAC) inhibitors (vorinostat (pan) or entinostat (HDAC1,3)) attenuated the number of invasive incidents (N=3, p&amp;lt;0.05), and restored protein expression of total p63 (N=3) and E-cadherin (N=2) while normalizing pERK-Y204 (N=2 for T24). The tumor-suppressive properties of the ΔNp63α isoform were studied by adenoviral-mediated overexpression of ΔNp63α in T24 cells, which mimicked the effects of HDAC inhibitors and diminished EMT by rescuing E-cadherin expression while depleting fibronectin (N=2). Overexpression of ΔNp63α also reduced the number of invasive incidents in 3D models established with T24 cells (N=2). Conclusion: Invasive T24 cells exhibited an EMT phenotype, which coincided with depleted p63 expression. Rescue of ΔNp63α expression by treatment with HDAC inhibitors or through experimental overexpression attenuated the EMT phenotype and cell invasion. Citation Format: Kirtiman Srivastava, Victoria Smith, Eric A. Fernandez, Conor Breen, Karen D. McCloskey. Rescue of ΔNp63α inhibits urothelial cell invasion by attenuating epithelial-to-mesenchymal transition (EMT) [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 2018.
Relation of Phasic Coronary Flow Velocity Characteristics With TIMI Perfusion Grade and Myocardial Recovery After Primary Percutaneous Transluminal Coronary Angioplasty and Rescue Stenting
Authors: TakashiAkasaka, KiyoshiYoshida, TakahiroKawamoto, ShuichiroKaji, YoshiakiUeda, AtsushiYamamuro, TsutomuTakagi, TakeshiHozumi
Journal: Circulation (2000)

Background—A residual stenosis and/or microvascular damage have been proposed as mechanisms of TIMI 2 flow for acute myocardial infarction. Coronary flow dynamics were assessed in patients with TIMI 2 flow to predict whether additional intervention would improve TIMI grade. Methods and Results—In 35 patients who had a successfully recanalized anterior acute myocardial infarction using angioplasty or rescue stenting, coronary flow patterns were compared with corresponding TIMI grade and regional left ventricular wall motion (LVWM) 1 month after the intervention. After angioplasty, the time-averaged peak velocity (APV) was lower in patients with TIMI 2 flow (n=22) than in those with TIMI 3 flow (n=13; 7.9±3.9 versus 20.6±5.1 cm/s; P<0.001). Two different flow patterns were recorded in patients with TIMI 2 flow (versus TIMI 3, P<0.001); patients with type 1 TIMI 2 flow (n=15) had a reduced diastolic APV (8.3±4.8 versus 24.2±7.4 cm/s), prolonged diastolic deceleration time (1176±455 versus 728±205 ms), and a ...
Abstract 16326: Safety and Efficacy of Novel Oral Anticoagulants in Subjects With Atrial Fibrillation in Relation to Renal Function: Meta-analysis of Randomized Clinical Trials
Authors: Freddy Del Carpio, Shahyar M Gharacholou, Andrea M Branson, Dawn M Paletta, Pamela K Brose, Samuel J Asirvatham
Journal: Circulation (2015)

Introduction: The efficacy and safety of novel oral anticoagulants (NOACs) has not been assessed in subjects with renal impairment. Methods: We performed a meta-analysis of RCTs comparing NOACs with warfarin in patients with atrial fibrillation (AF), in relation to renal function estimated by glomerular filtration rate (GFR): normal (GFR&gt;80 ml/min/1.73m2), mild (50-80 mL/min/1.73m2), and moderate (&lt;50 mL/min/1.73m2) impairment. MEDLINE, Embase, Web of Science and the Cochrane Library were searched to identify articles published up to the third week of January 2015. Data were supplemented with FDA data. Data on stroke or systemic embolism (S/SE) and major bleeding according to renal function were collected and extracted. We estimated the pooled relative risk (RR) of S/SE and major bleeding, for NOACs compared to warfarin. Results: We retrieved four randomized clinical trials (each randomizing dabigatran, rivaroxaban, apixaban, or endoxaban versus warfarin) enrolling a total of 58338 subjects, 29123 randomized to NOACs and 29123 randomized to warfarin; 21132 had normal renal function, 13126 had mild and 11027 had moderate renal impairment. In subjects with moderate renal impairment, compared to warfarin, NOACs reduced the risk of S/SE (RR 0.8; 95% CI 0.68-0.94) and major bleeding (RR 0.80; 95% CI 0.71-0.91). In subjects with mild renal impairment NOACs were associated with a reduced risk of S/SE (RR 0.75; 95% CI 0.66-0.85) and major bleeding (RR 0.87; 95% CI 0.79-0.95). In subjects with normal renal function no difference in the risk of S/SE was observed, while the risk of major bleeding was slightly less for subjects taking NOACs (RR 0.87; 95% CI 0.76-0.99). The test for interaction among groups of renal function was borderline significant for S/SE, but not for major bleeding. Conclusions: The use of NOACs was associated with a reduced risk of S/SE in subjects with mild or moderate renal impairment; while the risk of bleeding was reduced by NOACs compared to warfarin.
Polymorphism in Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Impairment of Nitric Oxide–Mediated Coronary Vasomotor Function
Authors: Shin-ichiNakamura, SeigoSugiyama, DaisukeFujioka, Ken-ichiKawabata, HisaoOgawa, KiyotakaKugiyama
Journal: Circulation (2003)

Background— The minor −588T allele of polymorphism −588C/T of a modifier subunit gene in glutamate-cysteine ligase (GCLM), a rate-limiting enzyme for glutathione (GSH) synthesis, was associated with lower plasma GSH levels and was a risk factor for myocardial infarction. Methods and Results— We examined effects of the −588C/T polymorphism on coronary arterial diameter and blood flow responses to intracoronary infusion of acetylcholine in 157 consecutive subjects who had normal coronary angiograms. In multivariate linear regression analysis with covariates including traditional risk factors, the minor −588T allele had an independent association with impaired dilation or enhanced constriction of epicardial coronary arteries in response to acetylcholine, and it was independently associated with blunted increase in coronary flow response to acetylcholine. In a subgroup of 59 consecutive subjects, constrictor responses of epicardial coronary diameter to intracoronary infusion of NG-monomethyl-l-arginine, refle...
Abstract 1180: Quantifying melanoma drug resistance and tumor heterogeneity by live cell interferometry
Authors: Kevin A. Leslie, Dian Huang, Graeme Murray, Daniel Guest, Irena J. Roy, Marco Piva, Gatien Moriceau, Roger S. Lo, Michael A. Teitell, Jason C. Reed
Journal: Cancer Research (2018)

Abstract Melanoma is the most aggressive type of skin cancer. Tumor heterogeneity and drug resistance are significant obstacles to survival benefits from mutation-targeted therapy. Over 50% of metastatic melanomas harbor V600BRAF mutations. Targeting of MUTBRAF melanoma with BRAF inhibitor monotherapy or the combination of BRAF and MEK inhibitors leads to a high rate of initial responses, but adaptive and acquired resistance frequently leads to clinical relapse. Although the presence of V600BRAF mutations guides the selection of therapy with MAPK inhibitors, methods to track preexisting and adaptive resistance and thereby predict response patterns, or to use this new information to modify therapy, are still lacking. Here, we aimed to develop a rapid, massively parallel tumor cell profiling method, based on Live Cell Interferometry (LCI), to quantify heterogeneous single tumor cell responses and emergent drug resistance. LCI is an ex vivo imaging approach that quantifies changes in total cell biomass, biomass motion, or cell stiffness over time. We report a novel high-throughput screening version of the LCI platform, HSLCI, which rapidly profiles changes in biomass in BRAF inhibitor (BRAFi)-sensitive, parental melanoma cell lines and their isogenic, BRAFi-resistant sub-lines. We show reproducible results from two different HSLCI platforms at two institutions and generate biomass kinetic signatures capable of discriminating between BRAFi-sensitive and -resistant melanoma cells within 24 hours. Our measurements require no fluorescence or dye labeling and are faster than field-standard growth inhibition assays. The accuracy and speed of HSLCI in profiling tumor cell heterogeneity and therapy resistance are promising features of potential tools to guide patient therapeutic selections. Citation Format: Kevin A. Leslie, Dian Huang, Graeme Murray, Daniel Guest, Irena J. Roy, Marco Piva, Gatien Moriceau, Roger S. Lo, Michael A. Teitell, Jason C. Reed. Quantifying melanoma drug resistance and tumor heterogeneity by live cell interferometry [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 1180.
Development of diagnostic prediction tools for bacteraemia caused by third-generation cephalosporin-resistant enterobacteria in suspected bacterial infections: a nested case–control study
Authors: W.C. Rottier, C.H. van Werkhoven, Y.R.P. Bamberg, J.W. Dorigo-Zetsma, E.M. van de Garde, B.C. van Hees, J.A.J.W. Kluytmans, E.M. Kuck, P.D. van der Linden, J.M. Prins, S.F.T. Thijsen, A. Verbon, B.J.M. Vlaminckx, H.S.M. Ammerlaan, M.J.M. Bonten
Journal: Clinical Microbiology and Infection (2018)

Current guidelines for the empirical antibiotic treatment predict the presence of third-generation cephalosporin-resistant enterobacterial bacteraemia (3GCR-E-Bac) in case of infection only poorly, thereby increasing unnecessary carbapenem use. We aimed to develop diagnostic scoring systems which can better predict the presence of 3GCR-E-Bac.A retrospective nested case-control study was performed that included patients ≥18 years of age from eight Dutch hospitals in whom blood cultures were obtained and intravenous antibiotics were initiated. Each patient with 3GCR-E-Bac was matched to four control infection episodes within the same hospital, based on blood-culture date and onset location (community or hospital). Starting from 32 commonly described clinical risk factors at infection onset, selection strategies were used to derive scoring systems for the probability of community- and hospital-onset 3GCR-E-Bac.3GCR-E-Bac occurred in 90 of 22 506 (0.4%) community-onset infections and in 82 of 8110 (1.0%) hospital-onset infections, and these cases were matched to 360 community-onset and 328 hospital-onset control episodes. The derived community-onset and hospital-onset scoring systems consisted of six and nine predictors, respectively. With selected score cut-offs, the models identified 3GCR-E-Bac with sensitivity equal to existing guidelines (community-onset: 54.3%; hospital-onset: 81.5%). However, they reduced the proportion of patients classified as at risk for 3GCR-E-Bac (i.e. eligible for empirical carbapenem therapy) with 40% (95%CI 21-56%) and 49% (95%CI 39-58%) in, respectively, community-onset and hospital-onset infections.These prediction scores for 3GCR-E-Bac, specifically geared towards the initiation of empirical antibiotic treatment, may improve the balance between inappropriate antibiotics and carbapenem overuse.
Abstract 2502: Role of TMEM97/σ2 receptor in breast cancer cell proliferation and responses to chemotherapy
Authors: Yuanqin Zhang, Jiuhui Wang, Daotai Nie
Journal: Cancer Research (2018)

Abstract Introduction: Breast cancer is the most prevalent cancer for women both in the developed and the developing countries. In 2017, about 40,610 women are expected to die from breast cancer in the U.S. The sigma receptors (σRs) are transmembrane receptors with two subtypes, termed sigma-1 receptor and sigma-2 receptor. Sigma-2 receptor has been found overexpressed in numerous human cancer tissues, and compound targeting it are now in clinical trials for breast cancer diagnosis. But it's biological role in breast cancer is unknown because the encoded gene has not been clearly identified. Recently, it has been demonstrated that TMEM97, not progesterone Receptor Membrane Component 1 (PGRMC1), is a bona fide sigma-2 receptor. The identification of sigma-2 (σ2) receptor will make it possible to define its biological functions in breast cancer and develop modulator of σ2 receptor as potential cancer therapeutics. Methods: The expression of TMEM97/σ2 receptor in multiple cancer cells was evaluated by RT-qPCR. Regulation of P53 on TMEM97/σ2 receptor was determined by Western Blot after 48 hours Doxorubicin treatment of MCF7 cell and HCT116 wild type and P53-/- cells. PB28, an agonist of σ2 receptor and an antagonist of σ1 receptor, was used (0, 1μM, 10μM and 20μM for 4 days) to test its effects on MCF7 cell growth and colony formation. TMEM97/σ2 receptor was cloned and sequenced. We overexpressed TMEM97/σ2 receptor in MCF7 cells to characterize its role in cell proliferation, survival, and colony formation, with or without treatment of its agonist PB28. Results and conclusion: TMEM97/σ2 receptor is expressed in various cancer cell lines including lung, breast and prostate cancer, albeit at different levels. TMEM97 expression was reduced in MCF7 cells when p53 expression was stimulated by doxorubicin. PB28 reduced the number of viable cells and also reduced colony formation of MCF7 cells in a dose dependent manner. Meanwhile overexpression of TMEM97/σ2 receptor retarded cell growth in MCF7 cells and sensitized them to PB28 as evidenced by reduced IC50 when compared with control cells. The data suggest that TMEM97/σ2 receptor is expressed in breast cancer cells, with its expression suppressed by p53, and activation of this receptor led to reduced tumor cell proliferation. Citation Format: Yuanqin Zhang, Jiuhui Wang, Daotai Nie. Role of TMEM97/σ2 receptor in breast cancer cell proliferation and responses to chemotherapy [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 2502.
Corrigan’s Pulse and Quincke’s Pulse
Authors: Hector I Michelena, Maurice Enriquez-Sarano
Journal: New England Journal of Medicine (2018)

A 58-year-old man with a bioprosthetic aortic valve presented with exertional dyspnea. Videos show rapidly declining pulsation of the right carotid artery and capillary pulsation of the index finger, thumb, and nail bed, findings suggestive of severe aortic regurgitation.
Racial Disparities in Nephrology Consultation and Disease Progression among Veterans with CKD: An Observational Cohort Study
Authors: Jonathan Suarez, Jordana B. Cohen, Vishnu Potluri, Wei Yang, David E. Kaplan, Marina Serper, Siddharth P. Shah, Peter Philip Reese
Journal: Journal of the American Society of Nephrology (2018)

Background Incident rates of ESRD are much higher among black and Hispanic patients than white patients. Access to nephrology care before progression to ESRD is associated with better clinical outcomes among patients with CKD. However, it is unknown whether black or Hispanic patients with CKD experience lower pre-ESRD nephrology consultation rates compared with their white counterparts, or whether such a disparity contributes to worse outcomes among minorities. Methods We assembled a retrospective cohort of patients with CKD who received care through the Veterans Health Administration from 2003 to 2015, focusing on individuals with incident CKD stage 4 who had an initial eGFR≥60 ml/min per 1.73 m 2 followed by two consecutive eGFRs&lt;30 ml/min per 1.73 m 2 . We repeated analyses among individuals with incident CKD stage 3. Outcomes included nephrology provider referral, nephrology provider visit, progression to CKD stage 5, and mortality. Results We identified 56,767 veterans with CKD stage 4 and 640,704 with CKD stage 3. In both cohorts, rates of nephrology referral and visits were significantly higher among black and Hispanic veterans than among non-Hispanic white veterans. Despite this, both black and Hispanic patients experienced faster progression to CKD stage 5 compared with white patients. Black patients with CKD stage 4 experienced slightly lower mortality than white patients, whereas black patients with CKD stage 3 had a small increased risk of death. Conclusions Black or Hispanic veterans with CKD are more likely than white patients to see a nephrologist, yet are also more likely to suffer disease progression. Biologic and environmental factors may play a bigger role than nephrology consultation in driving racial disparities in CKD progression.