tbuckley/cabot-search huggingface dataset:
Electrocardiography Screening for Atrial Fibrillation
Authors: Rod Passman, Jonathan Piccini
Journal: JAMA Cardiology (2018)

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Abstract 551: Discovering the co-drivers of mutant TP53 that promote breast cancer progression
Authors: Anasuya Pal, Jin Park, Joshua LaBaer
Journal: Cancer Research (2018)

Abstract Breast cancer is a heterogeneous disease and has different subtypes. Genetically 30% of all breast tumors and 80% of basal-like breast tumors harbor mutations in TP53 and numerous somatic mutations in other genes. This molecular heterogeneity has posed a challenge in developing effective therapeutic regimens and targeted therapies. Different TP53 missense mutations co-exist with other mutations in tumors and we hypothesize that tumor heterogeneity results from combinatorial effects of neo-morphic functions of specific TP53 driver mutations and a distinct subset of functionally important co-mutations (or ‘co-drivers'). We ectopically expressed the ten most prevalent missense TP53 mutants found in breast cancer tumors in non-transformed mammary epithelial cells and examined their phenotypes associated with the hallmarks of cancer. The results showed wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell invasion and cell polarity. As a proof of concept for the ‘co-driver', we knocked-out PTEN in a non-invasive TP53 Y234C mutant using the CRISPR system and observed increased cell invasion. A subsequent genome-wide CRISPR library-based screen on non-invasive TP53 Y234C expressing cells identified co-driver candidates that were highly enriched in the invasive population of Y234C cells. The top candidates included several known mutated genes in breast cancer patients with TP53 mutations, and were associated with signaling and cytoskeletal pathways that play crucial role in regulating cell invasion. These results demonstrate that this approach can pinpoint the key loss-of-function mutations in clinically important TP53 mutant backgrounds that can promote cancer-like behavior, and identify the combinations of ‘TP53 mutant and co-driver pathways' that can be targeted by specific inhibitors. Citation Format: Anasuya Pal, Jin Park, Joshua LaBaer. Discovering the co-drivers of mutant TP53 that promote breast 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 551.
Prediction of High-grade Prostate Cancer Following Multiparametric Magnetic Resonance Imaging: Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculators
Authors: Arnout R. Alberts, Monique J. Roobol, Jan F.M. Verbeek, Ivo G. Schoots, Peter K. Chiu, Daniël F. Osses, Jasper D. Tijsterman, Harrie P. Beerlage, Christophe K. Mannaerts, Lars Schimmöller, Peter Albers, Christian Arsov
Journal: European Urology (2018)
Role of Endothelin in Deterioration of Heart Failure Due to Cardiomyopathy in Hamsters
Authors: RikakoYamauchi-Kohno, TakashiMiyauchi, TomokoHoshino, TsutomuKobayashi, HajimeAihara, SatoshiSakai, HideoYabana, KatsutoshiGoto, YasuroSugishita, SakaeMurata
Journal: Circulation (1999)

Background—We previously reported that chronic endothelin (ET) receptor blockade ameliorated the survival rate and cardiac hemodynamics in rats with chronic heart failure (CHF) due to myocardial infarction. However, it remains unclear whether ET-1 is involved in the pathophysiology of cardiomyopathy, which is one of the major causes of CHF. Accordingly, we investigated the production of ET-1 in the heart and the effect of chronic ETA receptor blockade on survival rate and cardiac function in the Bio 14.6 hamster, which is an idiopathic model of CHF caused by cardiomyopathy. Methods and Results—We used 52-week-old Bio 14.6 cardiomyopathic hamsters and age-matched F1b normal hamsters. The expression of preproET-1 mRNA and the ET-1 level in the hearts were markedly higher in the cardiomyopathic hamsters than in the normal hamsters. The cardiomyopathic hamsters showed severe CHF, illustrated by lower left ventricular (LV) +dP/dt/Pmax and right ventricular (RV) +dP/dt/Pmax and by higher LV end-diastolic pressu...
Abstract 3865: ActivSignal platform technology for direct multiplex analysis of signaling pathway activation profiles
Authors: Ilya Alexandrov, Irina Brandina, Nader Rahimi, Michael Sherman, Julia Yaglom, Rosana Meyer, Marwa Ali, Esma Ersoy
Journal: Cancer Research (2018)

Abstract The multiplex IPAD assay technology from ActivSignal monitors activity of 26 major signaling pathways by examining phosphorylation events or expression of more than 60 most relevant human and mouse protein targets. The technology uses antibodies against established and well known targets that reflect activities of canonical pathways. We utilize paired antibodies for each protein target for high specificity, and these pairs are carefully selected and tested. Only if both antibodies in a pair bind to their specific target molecule will the detection take place during the analysis phase - avoiding false hits. The IPAD assay can be used to profile samples made from cell culture, tissues, blood, etc. The IPAD assay requires only minute amounts of sample, which can be easily taken from your precious sample where available amounts may be limited. Applications include: Direct snapshot of signaling pathway activity rather than downstream effects. Understanding the physiological effects of a drug. What pathways are regulated in response to lead candidate drug? Does the drug of interest cause biologically significant secondary and off target effects? Evaluation of signaling pathway activities in response to shRNA, CRISPR, hormones, stresses and other treatments. Elucidating the signaling proteome in a medium-throughput format (96-well format). Profiling of tissue samples from patients and animals. Signaling profiling of tumor biopsies. In one application, our collaborators used the IPAD assay to understand signaling effects of a novel protein, TMIGD1, whose expression is markedly downregulated in renal cancer. The Activsignal platform analysis showed changes in activities of several major pathways, e.g. inhibition of cell cycle and cell proliferation after reintroduction of TMIGD1. In another application of our platform our collaborators studied the mechanism of action of a small molecule inhibitor that targets Hsp70. They used ActivSignal platform technology to profile signaling pathways in response to the inhibitor. They identified several pathways whose activities were affected by the inhibitor. ActivSignal is a breakthrough, low-cost tool for the analysis of signaling pathway activation profiles. It enables researchers to rapidly and efficiently gain insight into function of their favorite drug molecules, genes etc. Citation Format: Ilya Alexandrov, Irina Brandina, Nader Rahimi, Michael Sherman, Julia Yaglom, Rosana Meyer, Marwa Ali, Esma Ersoy. ActivSignal platform technology for direct multiplex analysis of signaling pathway activation profiles [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 3865.
Association of Bullous Pemphigoid With Dipeptidyl-Peptidase 4 Inhibitors in Patients With Diabetes
Authors: Khalaf Kridin, Reuven Bergman
Journal: JAMA Dermatology (2018)

The association of bullous pemphigoid (BP) with the use of dipeptidyl-peptidase 4 (DPP-4) inhibitors among patients with diabetes has recently emerged. The risk of developing BP during treatment with new DPP-4 inhibitor agents like linagliptin is yet to be established. The clinical features and the prognostic outcomes of patients with DPP-4 inhibitor-associated BP are yet to be established.Primarily to estimate the association between DPP-4 inhibitor exposure and the development of BP, and secondarily to characterize the clinical features and history of patients with DPP-4 inhibitor-associated BP.A retrospective case-control study of the intake of different DPP-4 inhibitor agents and metformin and occurrence of BP among patients with diabetes in a tertiary care referral center for autoimmune bullous diseases in northern Israel. Included were 82 consecutive patients with diabetes and immunopathologically validated BP diagnosed between January 1, 2011, and December 31, 2017, and 328 age-, sex-, and ethnicity-matched control participants with diabetes but without BP.Patients with diabetes and BP and exposure to DPP-4 inhibitors were followed up for a median of 2.0 years and compared with other patients with diabetes and BP who were not exposed to DPP-4 inhibitors regarding clinical and immunological features, laboratory analyses, treatments, and clinical outcomes.Eighty-two patients with BP and 328 age- and sex-matched control participants were enrolled; mean (SD) age, 79.1 (9.1) years; and 44 patients were female (53.7%). Overall, DPP-4 inhibitor intake was associated with a 3-fold increased risk for BP (adjusted odds ratio [OR], 3.2; 95% CI, 1.9-5.4). The adjusted ORs for vildagliptin and linagliptin were 10.7 (95% CI, 5.1-22.4) and 6.7 (95% CI, 2.2-19.7), respectively. The association of DPP-4 inhibitor use with BP was independent of the use of metformin and was stronger among male (OR, 4.46; 95% CI, 2.11-9.40) than female (OR, 1.88; 95%, CI 0.92-3.86) patients and strongest in patients younger than 70 years (OR, 5.59; 95% CI, 1.73-18.01). Patients with DPP-4 inhibitor-associated BP presented with higher mucosal involvement (22.2% vs 6.5%; P = .04) and lower mean (SD) peripheral eosinophil counts (399.8 [508.0] vs 1117.6 [1847.6] cells/μL; P = .01) than those with BP who had not been exposed to DPP-4 inhibitor. Discontinuation of DPP-4 inhibitor treatment was followed by improved clinical outcomes.Vildagliptin and, to a lesser extent, linagliptin are associated with an increased risk of BP. This may partly explain the increasing incidence of BP in Israel. Discontinuation of DPP-4 inhibitor treatment in patients with diabetes should be considered when BP is diagnosed.
Abstract CT097: Quantitative MR measurements in glioblastoma patients: Mean diffusivity with tumor treating fields plus standard therapy versus standard treatment alone
Authors: Josef Vymazal, Radovan Zacek, Jan Sroubek, Jan Klener, Aaron M. Rulseh
Journal: Cancer Research (2018)

Abstract Introduction: Quantitative MR parameters, including those derived from diffusion imaging, may advance knowledge on the biological characteristics of gliomas in both diagnostic and treatment settings. We evaluated quantitative diffusion differences that could be detected in glioblastoma patients treated with standard therapy plus TTFields (Optune) versus standard therapy alone. Methods: Twelve patients with glioblastoma were subjected to surgical resection, radiotherapy and temozolomide. Six subjects were additionally treated with TTFields. All patients were followed by MRI every two months (range 210-1036 days) with standard imaging and diffusion tensor imaging until tumor progression. Results: Progression-free survival (PFS) was significantly longer in the subgroup treated by TTFields (mean 784 days ± 163 SD) as compared to standard therapy alone (443 days ± 249). No difference was detected between groups in the initial mean diffusivity values measured within the affected white matter near the resection cavity. However the linear regression slope describing mean diffusivity in this region over serial measurements was higher in the subgroup treated by TTFields than in the other group (5.43 ± 2.4 versus -3.77 ± 11.8). Furthermore, we detected significant positive correlation between mean diffusivity slope and PFS. Discussion: Our data demonstrate increasing mean diffusivity in the affected white matter of glioblastoma patients, which is favorable with positive correlation to PFS seen in steeper regression slopes. The patients treated with TTFields showed greater PFS in comparison to those who did not receive TTFields. There was a corresponding increase in mean diffusivity in the affected white matter of these patients. In the group that received standard therapy, the increase was not as apparent and, if present, the slope was not as steep. Changes in mean diffusivity likely reflect changes in tumor density in the white matter. Citation Format: Josef Vymazal, Radovan Zacek, Jan Sroubek, Jan Klener, Aaron M. Rulseh. Quantitative MR measurements in glioblastoma patients: Mean diffusivity with tumor treating fields plus standard therapy versus standard treatment alone [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 CT097.
Abstract 5228: Mammary gland tumors in progesterone receptor transgenic mice
Authors: Katelin A. Gibson, Merit L. Goodman, Christy R. Hagan
Journal: Cancer Research (2018)

Abstract The role of progesterone and its receptor, the progesterone receptor, in breast cancer remains controversial. Although years of clinical trial data have shown that synthetic progesterone (progestins) increases breast cancer risk, the role for native progesterone in breast cancer development is the source of much debate. PR is post-translationally modified, primarily through phosphorylation, by many mitogenic kinases, including ck2, cdk2 and MAPK. These phosphorylation events on PR dictate many aspects of PR biology, including promoter specificity and transcriptional co-factor interactions. Ck2, a mitogenic kinase shown to be upregulated in breast cancer, has been shown to phosphorylate PR and regulate transcription of a certain subset of PR target genes. In an effort to determine how this translates to murine mammary gland tumor formation, we created a bi-transgenic mouse overexpressing both PR and ck2 in the murine mammary gland. We studied long-term tumor formation in the PR/ck2 bi-transgenic mice, as compared to the single transgene controls (PR only or ck2 only), in both virgin and multiparous mice. Our preliminary data suggest a number of interesting results. First, tumor development is the highest in the PR transgenic mice, as compared to ck2 alone or PR/ck2 bi-transgenic mice. This is of particular interest as previous studies in PR transgenic mice failed to show mammary gland tumor formation, despite the presence of dysplastic mammary gland tissue. Moreover, the rate of tumor formation appears to be unaffected by parity: virgin and multiparous mice develop tumors at the same rate. This is in contrast to ck2 single-transgenic mice, where multiparty increases the rate of tumor formation (as observed by us and others). Interestingly, and most significantly to our studies, the combination of ck2 and PR appears to slow tumor formation rates as compared to either single transgenic mouse control. This phenotype is potentiated by pregnancy, as all multiparous PR/ck2 bi-transgenic animals still remain tumor free. These data, while still preliminary, suggest that ck2-dependent modification of PR may prevent mammary gland tumor formation, suggesting that PR regulation of a subset of genes (those genes regulated by ck2-phopshorylation) may drive anti-proliferative, tumor-preventing gene programs. Citation Format: Katelin A. Gibson, Merit L. Goodman, Christy R. Hagan. Mammary gland tumors in progesterone receptor transgenic mice [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 5228.
Abstract 3543: USP7 inhibitor P5091 inhibits esophageal squamous cell carcinoma growth by inducing NOXA-mediated apoptosis
Authors: Tao Hu, Jing-Yang Zhang, Bei-Bei Sha, Miao-Miao Li, Xing-Ge Liu, Yi Zhang, Zi-Ming Dong, Pei Li, Ping Chen
Journal: Cancer Research (2018)

Abstract Recently, deubiquitinase USP7/HAUSP was reported to be an attractive anti-cancer target. However, its expression and role in esophageal cancer remain elusive. Here, immunohistochemistry and western blot assay were used to detect the expression of USP7/HAUSP in esophageal squamous cell carcinoma (ESCC) tissues. Specific inhibitor P5091 was used to inhibit the activity of USP7 and explore the role and mechanism of USP7 in KYSE450, KYSE510 and KYSE30 ESCC cell lines. Result: Staining-intensity analysis by immunohistochemistry demonstrated that USP7 was expressed higher in ESCC tissues compared with their corresponding adjacent tissues (P&amp;lt;0.01), which was confirmed by western blot analysis. CCK-8 assay, colony formation assay and tumor growth assay in subcutaneous transplantation tumor model indicated that P5091 could significantly inhibit ESCC cell growth in vitro and in vivo. Moreover, P5091 induced apoptosis by triggering unfolded protein reaction, accumulating the protein of ATF4 and thus transcriptionally upregulating the expression of NOXA. Conclusion: These results showed that P5091 effectively inhibited ESCC cell growth in vitro and in vivo and supported the clinical investigation of P5091 for the treatment of ESCC. Keywords: P5091, esophageal squamous cell carcinoma, ATF4, apoptosis, NOXA * T H and J-Y Z contributed to this work equally. Citation Format: Tao Hu, Jing-Yang Zhang, Bei-Bei Sha, Miao-Miao Li, Xing-Ge Liu, Yi Zhang, Zi-Ming Dong, Pei Li, Ping Chen. USP7 inhibitor P5091 inhibits esophageal squamous cell carcinoma growth by inducing NOXA-mediated apoptosis [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 3543.
Abstract 20546: Dynamic Transcriptomics Analyses Uncover Gene Regulatory Networks for Atrial Septation and Cardiac Chamber Development
Authors: Menglan Xiang, Hokyi Lai, Jielin Liu, Damian Heine Suñer, Linglin Xie, Kurt Zhang
Journal: Circulation (2016)

Background: Cardiovascular development is regulated by a complex gene regulatory network that includes a number of cardiac transcription factors (TFs) and their downstream target genes. The genes i...
2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update)
Authors: Frederick G. Kushner, Mary Hand, Sidney C. Smith, Spencer B. King, Jeffrey L. Anderson, Elliott M. Antman, Steven R. Bailey, Eric R. Bates, James C. Blankenship, Donald E. Casey, Lee A. Green, Judith S. Hochman, Alice K. Jacobs, Harlan M. Krumholz, Douglass A. Morrison, Joseph P. Ornato, David L. Pearle, Eric D. Peterson, Michael A. Sloan, Patrick L. Whitlow, David O. Williams
Journal: Journal of the American College of Cardiology (2009)
Abstract 641: Cell free DNA in the supernatant of pleural effusion can detect driver and resistance mutations and can guide TKI treatment decisions
Authors: Karlijn Hummelink, Mirte Muller, Dorothe Linders, Vincent van der Noort, Petra Nederlof, Sjaak Burgers, Gerrit Meijer, Michel van den Heuvel, Daan van den Broek, Kim Monkhorst
Journal: Cancer Research (2018)

Abstract Introduction: Molecular profiling of tumors has become the mainstay of diagnostics for metastasized solid malignancies and guides personalized treatment, especially in non-small cell lung cancer (NSCLC). In current practice it is often challenging to obtain sufficient tumor material for reliable molecular analysis. Cell free (cf) DNA in blood or other bio-sources could present an alternative approach to obtain genetic information from the tumor. In a retrospective cohort we analyzed the added value of cfDNA analysis in pleural effusions for molecular profiling. Methods: We retrospectively analyzed both the supernatant and the cell pellet of 44 pleural effusions sampled from 39 patients with KRAS (23) or EGFR (16) positive tumors for the original driver gene mutation as well as for EGFR T790M resistance mutations. Patients were diagnosed with either NSCLC (32), colon carcinoma (4), appendiceal carcinoma (2) or adenocarcinoma of unknown primary (1). Samples collected in the context of routine clinical care were stored in the NKI-AVL biobank. We used Bio-Rad QX200 droplet digital PCR for analysis. Results: The original driver gene mutation could be detected in 37 of the 44 pleural effusions by analysis of both supernatant (35/44 positive) and cell pellet (29/44 positive). In 7 out of 20 pleural effusions from patients with EGFR mutation positive tumors, a T790M mutation was detected. All 7 supernatants were positive as were 5 of the 7 cell pellets. The EGFR T790M mutation was confirmed in all supernatants (4/4) and in 3 of the 4 cell pellets sampled from patients with T790M positive tumors (4). Conclusions: Cell free DNA in pleural effusion proved to be a valuable bio-source and can be used to detect driver gene mutations as well as resistance mechanisms like EGFR T790M in pleural effusion. Citation Format: Karlijn Hummelink, Mirte Muller, Dorothe Linders, Vincent van der Noort, Petra Nederlof, Sjaak Burgers, Gerrit Meijer, Michel van den Heuvel, Daan van den Broek, Kim Monkhorst. Cell free DNA in the supernatant of pleural effusion can detect driver and resistance mutations and can guide TKI treatment decisions [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 641.
Percutaneous Transcatheter Balloon Valvuloplasty for Bioprosthetic Tricuspid Valve Stenosis
Authors: KeiYunoki, TakahikoNaruko, AkiraItoh, JunkoOhashi, KoheiFujimoto, NaoyaShirai, KoichiShimamura, RyushiKomatsu, YujiSakanoue, KazuoHaze
Journal: Circulation (2006)