tbuckley/cabot-search huggingface dataset:
Regulation of Aldosterone Biosynthesis by Adrenal Renin Is Mediated Through AT1 Receptors in Renin Transgenic Rats
Authors: MassimoVolpe, SperanzaRubattu, BrunaGigante, DetlevGanten, AntonioPorcellini, RosariaRusso, MicheleRomano, IolandaEnea, Min AeLee, BrunoTrimarco
Journal: Circulation Research (1995)

Abstract The transgenic (TG) rat (mREN2)27 is characterized by overexpression of the additional mouse Ren-2d gene in the adrenal cortex with marked suppression of renal renin. We have previously shown that in salt-depleted TG rats enhanced activation of mineralocorticoid biosynthesis is associated with selective stimulation of adrenal renin. To investigate whether the local renin-angiotensin system regulates aldosterone biosynthesis in the adrenal cortex of TG rats, we studied the effects of the AT1–angiotensin subtype receptor antagonist DuP 753 on aldosterone production in 5-week-old TG rats during salt restriction. All the rats (n=56) were shifted from regular chow to a diet containing only 0.04% NaCl for 1 week. The AT1-receptor antagonist DuP 753 (10 mg/kg per day in drinking water) was administered to 27 of these rats during low-salt diet. Subgroups of rats were killed at 0, 4, and 7 days. Low-salt diet increased both adrenal renin activity (from 31±3 to 77±4 and 85±2 ng angiotensin I · h−1 · mg pro...
Abstract 4408: Development and validation of a serum miRNA biomarker panel for the detection of early stage lung cancer
Authors: Lisha Ying, Ruiyang Zou, Lingbin Du, Lei Shi, Nan Zhang, Jiaoyue Jin, Junzhou Wu, Fanrong Zhang, Kaiyan Chen, Herbert Yu, Weimin Mao, Dan Su
Journal: Cancer Research (2018)

Abstract Lung cancer is the most prevalent cancer and leading cause of cancer death worldwide. Low-dose spiral computed tomography (LDCT) scan is being recommended as a screening test for smokers in the U.S. However, the poor specificity (73% specificity at 94% sensitivity) of LDCT has raised significant concern for its high chance of false positive (96% of LDCT positives are benign nodules). This study aims to develop a blood (serum) miRNA based molecular diagnostic test for the detection of early stage lung cancer. In the discovery phase, more than 400 miRNAs were profiled with MiRXES's qPCR based high throughput assay platform through a highly defined Chinese male smoker case-control cohort (n=424) where the cases were collected from Zhejiang Cancer Hospital and the controls were collected from the LDCT screening program in Zhejiang province, China. 29 miRNA biomarkers with p-value (FDR) &amp;lt; 0.01 and more than one z-score (standardized score) difference were identified and validated in another Chinese case-control cohort (n=432) collected from similar sources and a Caucasian case-control cohort (n=218) collected from EU and US. 18 out of the 29 miRNA biomarkers were validated in both cohorts (p-value &amp;lt; 0.01 and z-score &amp;gt;0.4). With multiple time of two-fold cross-validation, 5 miRNAs were found to be minimally required to form the biomarker panel for the accurate prediction of early stage lung cancer and the panel gives 0.984 (95% CI 0.973-0.991) AUC for the discovery cohort, 0.936 (95% CI 0.912-0.957) AUC for the Chinese validation cohort and 0.970 (95% CI 0.939-0.986) AUC for the Caucasian validation cohort. The 5-miRNA biomarker panel were then further validated in three additional Asian cohorts: a Chinese cohort collected from the similar sources (0.973, 95% CI 0.950-0.986, AUC), a Chinese cohort collected from independent sources (0.916, 95% CI 0.852-0.949, AUC) and a Singaporean cohort (Chinese, Malay and Indian population) (0.911, 95% CI 0.822-0.963, AUC). Citation Format: Lisha Ying, Ruiyang Zou, Lingbin Du, Lei Shi, Nan Zhang, Jiaoyue Jin, Junzhou Wu, Fanrong Zhang, Kaiyan Chen, Herbert Yu, Weimin Mao, Dan Su. Development and validation of a serum miRNA biomarker panel for the detection of early stage lung 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 4408.
Using Benefit-Based Tailored Treatment to Improve the Use of Antihypertensive Medications
Authors: JeremySussman, SandeepVijan, RodHayward
Journal: Circulation (2013)

Background—Current guidelines for prescribing antihypertensive medications focus on reaching specific blood pressure targets. We sought to determine whether antihypertensive medications could be used more effectively by a treatment strategy based on tailored estimates of cardiovascular disease events prevented. Methods and Results—We developed a nationally representative sample of American adults aged 30 to 85 years with no history of myocardial infarction, stroke, or severe congestive heart failure using the National Health and Nutrition Examination Survey III. We then created a simulation model to estimate the effects of 5 years of treatment with treat-to-target (treatment to specific blood pressure goals) and benefit-based tailored treatment (treatment based on estimated cardiovascular disease event reduction) approaches to antihypertensive medication management. All effect size estimates were derived directly from meta-analyses of randomized trials. We found that 55% of the overall population of 176 m...
Abstract SY43-01: Coordinated gene expression mediated by RNA modifications
Authors: Reuven Agami
Journal: Cancer Research (2018)

Abstract Gene transcription and mRNA translation are two main pillars of gene expression. Due to the different timings, spots of action, and mechanisms of regulation, these processes are mainly regarded as distinct and generally uncoupled, despite serving a common purpose. We identified that the rate of transcription regulates the efficacy of translation. We show that RNA modification, in the form of N6-adenosine methylation (m6A), is co-transcriptional and depends on the dynamics of RNA transcription. Altogether, our study uncovered a general and widespread link between transcription and translation that is governed by epigenetic modification of mRNAs. We postulate that this mechanism will play a role in cancer-related processes. Citation Format: Reuven Agami. Coordinated gene expression mediated by RNA modifications [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 SY43-01.
Abstract 4331: High-throughput whole-genome sequencing of formalin fixed, paraffin-embedded tissues from colorectal cancer patients
Authors: Matthew Kubit, Christina Wood-Bouwens, Sue Grimes, John Bell, GiWon Shin, Billy Lau, Mickey Miller, Kenneth Day, Helaman Escobar, Hanlee Ji, Lincoln Nadauld, Paul Van Hummelen
Journal: Cancer Research (2018)

Abstract Formalin-fixed, paraffin-embedded (FFPE) storage is a universally-adopted, cost-effective and long-term solution for tissue storage. Given the abundance of FFPE clinical samples, they provide a good source of tissue for genome sequencing studies. However, the extraction of nucleic acids from FFPE tissues yield highly fragmented DNA of variable quality. The poor quality and low yield make it difficult to generate adequate sequencing libraries for genomic studies. For a population cancer genome study, we optimized a procedure for whole-genome sequencing on FFPE tumor and normal tissue of colorectal cancer patients. This pilot study aimed to first identify changes in DNA copy number using low-pass sequencing, with the additional goal of later adding structural variant and gene fusion detection and single nucleotide variant analysis with deeper sequencing. We processed, sequenced and analyzed 193 patients. These FFPE samples had varying storage characteristics. We optimized the initial extraction quality thresholds, DNA extraction and library preparation to generate high quality sequencing data. We identified an initial sample quality and library threshold to hold the best correlation for sequencing quality. Optimal yield and DNA size from extracted FFPE was achieved by using Promega's LEV DNA FFPE Extraction Kit. Library prep optimization involved using mechanical shearing of DNA to increase overall library size for structural variant detection as well as using unique dual index adapters to identify index swapping artifacts during sequencing. An additional cleanup was also performed post-fragmentation to increase overall library size. Overall, we successfully developed a robust protocol for conducting whole genome sequencing on FFPE tumor samples. Citation Format: Matthew Kubit, Christina Wood-Bouwens, Sue Grimes, John Bell, GiWon Shin, Billy Lau, Mickey Miller, Kenneth Day, Helaman Escobar, Hanlee Ji, Lincoln Nadauld, Paul Van Hummelen. High-throughput whole-genome sequencing of formalin fixed, paraffin-embedded tissues from colorectal cancer patients [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 4331.
Development of Atherosclerosis in Dogs with Hypercholesterolemia and Chronic Hypertension
Authors: Campbellmoses
Journal: Circulation Research (1954)

Hypercholesterolemia was induced in pure-bred dogs by cholesterol feeding and propylthiouracil or radioiodine. Hypertension induced by the injection of silica into the renal artery increased the severity of aortic atherosclerosis. Marked hypercholesterolemia increased the severity of aortic atherosclerosis even in normotensive dogs.
Abstract 1169: Novel renal medullary carcinoma cell lines, UOK353 and UOK360, provide preclinical tools to identify new therapeutics
Authors: Darmood Wei, Youfeng Yang, Christopher J. Ricketts, Cathy D. Vocke, Mark W. Ball, Carole Sourbier, Darawalee Wangsa, Danny Wangsa, Rajarshi Guha, Xiaohu Zhang, Paul Meltzer, Thomas Reid, Craig J. Thomas, Maria J. Merino, W. Marston Linehan
Journal: Cancer Research (2018)

Abstract Renal medullary carcinoma (RMC) is a rare and aggressive disease that predominantly afflicts individuals of African or Mediterranean descent with sickle cell trait. RMC comprises 1% of all renal cell carcinoma diagnoses, and the median overall survival for RMC patients is only 13 months. Patients are typically young (median age-22yo) and male (male:female ratio of 2:1). RMC was first characterized in 1995, and its hallmark SMARCB1 loss was identified in 2008. Due to the low incidence of RMC and the disease's aggressiveness, treatment decisions are often based on case reports. Thus, it is critical to develop preclinical models of RMC to both better understand the pathogenesis of this disease and identify an effective therapy. These RMC cell lines overexpress EZH2, relative to normal renal proximal tubule epithelium, thus making it an attractive druggable target. EZH2 inhibition in RMC tumor spheroids did not result in decreased viability. We have evaluated a potential clinical treatment (bortezomib) found in the literature and validate bortezomib's potency in vitro. Intriguingly, these cells lines not only lack NQO1, an antioxidant enzyme, but also the addition of N-acetyl cysteine, an antioxidant, has a protective effect against bortezomib. Together the data suggest that RMC are highly sensitive to oxidative stress. This evidence is consistent with case reports in the literature that found bortezomib treatment of RMC resulted in positive outcomes. Citation Format: Darmood Wei, Youfeng Yang, Christopher J. Ricketts, Cathy D. Vocke, Mark W. Ball, Carole Sourbier, Darawalee Wangsa, Danny Wangsa, Rajarshi Guha, Xiaohu Zhang, Paul Meltzer, Thomas Reid, Craig J. Thomas, Maria J. Merino, W. Marston Linehan. Novel renal medullary carcinoma cell lines, UOK353 and UOK360, provide preclinical tools to identify new therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1169.
Abstract 5359: Regulatory germline variants in 10,389 adult cancers
Authors: Kuan-lin Huang, Amila Weerasinghe, Yige Wu, Wen-wei Liang, R. Jay Mashl, Sheila Reynolds, Kathleen E. Houlahan, Ninad Oak, The Cancer Genome Atlas, Alexander J. Lazar, Michael C. Wendel, Ekta Khurana, Sharon Plon, Feng Chen, Mark Gerstein, Ilya Shmulevich, Li Ding
Journal: Cancer Research (2018)

Abstract Previous studies of rare germline variants in cancer has largely been limited to the coding regions of known predisposition genes. The TCGA PanCanAtlas Germline Working Group is analyzing germline predisposing variants of 10,389 cases in 33 cancer types. We deployed more than 121,000 virtual machines running for over 600,000 hours on the ISB Cancer Genome Cloud to conduct massively parallel variant calling and analyses, and the resulting data are shared with scientists across institutions worldwide. Carriers of the functional regulatory variants add on to the 8.9% of cases carrying known pathogenic variants. Burden analyses reveal enrichment of rare variants in the 3'UTR region of NHP2 and POLH. Further, we observed variants aggregating in conserved regions of selected microRNA families that are also affected by somatic mutations, including mir-17 and mir-29. We nominate regulatory variants by using GWAVA and FunSeq2 corroborated with their enrichment in cancer. The prioritized variants are then further evaluated by further co-occurrence of two-hit events and expression changes in their respective tumor samples. Finally, we examine ancestries, familial history and age at onset for carriers of these variants. Overall, we aim to discover and establish the role of regulatory germline variants in oncogenesis. Citation Format: Kuan-lin Huang, Amila Weerasinghe, Yige Wu, Wen-wei Liang, R. Jay Mashl, Sheila Reynolds, Kathleen E. Houlahan, Ninad Oak, The Cancer Genome Atlas, Alexander J. Lazar, Michael C. Wendel, Ekta Khurana, Sharon Plon, Feng Chen, Mark Gerstein, Ilya Shmulevich, Li Ding. Regulatory germline variants in 10,389 adult cancers [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 5359.
Four-Limb Acute Ischemia Induced by Ergotamine in an AIDS Patient Treated With Protease Inhibitors
Authors: LeopoldoMarine, PabloCastro, AndresEnriquez, DouglasGreig, Luis ManuelSanhueza, RenatoMertens, MichelBergoeing, AlbrechtKramer, FranciscoValdes, MichelSerri
Journal: Circulation (2011)
Abstract LB-365: Microscopic imaging for understanding gold nanorods-protein interactions in inhibiting cancer cell migration
Authors: Yue Wu, Moustafa R. Ali, Ning Fang, Mostafa A. El-Sayed
Journal: Cancer Research (2018)

Abstract Metastasis is the primary cause of cancer-related deaths. Current clinical treatments for anti-metastasis, however, are not effective. Gold nanorods (AuNRs), which are safe within biological systems, were recently discovered to inhibit cancer cell migration and prevent metastasis. However, the mechanism of how AuNRs inhibit cancer cell migration remains largely unexplored. The migration of cancer cells from one site to another requires dramatic remodeling of cytoskeleton proteins. Our recent studies have shown a great impact of AuNRs treatment on proteins that regulate the cytoskeleton. However, the interaction of AuNRs and the cytoskeletal structures are not well studied due to the lack of advanced microscopic technologies at single nanoparticle-single protein level. Herein, we used cutting-edge imaging techniques to enable the study of the direct correlation between cytoskeleton filaments (microtubule) and AuNRs . Differential interference contrast (DIC) (for imaging AuNRs) and the stochastic optical reconstruction microscopy (STORM) (for imaging proteins) were combined to resolve the interaction of how AuNRs interact with the cytoskeleton filaments, disrupt the cytoskeleton structures, including microtubule and therefore inhibit cell migration. In conclusion, we are able to visualize the interaction of AuNRs with cytoskeleton filaments at nanometer resolution with their accurate intracellular location, which is beneficial for the future studies of nanoparticle-cell interactions. Citation Format: Yue Wu, Moustafa R. Ali, Ning Fang, Mostafa A. El-Sayed. Microscopic imaging for understanding gold nanorods-protein interactions in inhibiting cancer cell migration [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-365.
Abstract 308: Chronic Aspirin Treatment Possibly Poses a Risk to Ischemic Heart via Impairment of Cardiac Proteasome Functions
Authors: ChunjiangTan, WenlieChen, YanbingWu, JiumaoLin, RuhuiLin, XueruiTan, SongmingChen
Journal: Circulation Research (2012)

Background: Impaired cardiac proteasome (CP) has been reported in ischemia and heart failure. Recent data highlighted aspirin as an inhibitor of the ubiquitin-proteasome system, however, it’s unclear whether it affects CP functions. Objective: We investigated the influence of aspirin on CP in the rat model of myocardial infarction (MI). Methods and Results: MI, sham or normal male SD rats were injected intraperitoneally with high (300mg/kg), low (5mg/kg) aspirin or saline (control) once a day for seven weeks. Parallel experiments were performed in the hypoxia/reoxygenated cell model of primary human ventricular myocytes incubated with different concentrations of aspirin. Myocardial hypertrophy, cardiac function, cell viability and the functions of 26S, 20S and 19S, including the β1, β2 and β5 subunits of 20S were determined. The activity of 26S, 20S and 19S declined by about 30%, and β5, β2 and β1 by 40%, 20% and 30%, respectively, in the MI rats compared with the non-MI rats (P<0.05). Compared with the s...
Implantation of the Right Ventricular Lead of an Implantable Cardioverter-Defibrillator Complicated by Apical Myocardial Infarction
Authors: NobuhiroNishiyama, SeijiTakatsuki, TakehiroKimura, YoshiyasuAizawa, KotaroFukumoto, YokoHagiwara, KojiroTanimoto, KeiichiFukuda
Journal: Circulation (2012)
Rapamycin Selectively Inhibits Angiotensin II–Induced Increase in Protein Synthesis in Cardiac Myocytes In Vitro
Authors: JunichiSadoshima, SeigoIzumo
Journal: Circulation Research (1995)

Abstract It has been suggested that phosphorylation of a 40S ribosomal protein, S6, regulates protein synthesis. Two distinct families of S6 kinase have been identified, the rsk-encoded 85- to 92-kD S6 kinase (RSK) and the 70- or 85-kD S6 kinase (p70S6K). We have previously shown that hypertrophic stimuli, such as angiotensin II (Ang II), rapidly activate RSK in cardiac myocytes. However, RSK and p70S6K are regulated by distinct mechanisms, and p70S6K, but not RSK, is the physiological S6 kinase in vivo in other cell types. Using cultured neonatal rat ventricular myocytes, we examined whether Ang II activates p70S6K and investigated the effect of rapamycin, a potent yet indirect inhibitor of p70S6K, on the Ang II–induced hypertrophic response. Immunoblot analyses indicate that cardiac myocytes express the 70- and 85-kD forms of p70S6K. Ang II caused a rapid and sustained activation of p70S6K through the type I Ang II receptor. Rapamycin inhibited Ang II–induced activation of p70S6K in a dose-dependent man...
Abstract 5197: Single-cell analysis of the brain metastatic microenvironment in breast cancer
Authors: Katrina Evans, Quy Nguyen, Kerrigan Blake, Devon Lawson
Journal: Cancer Research (2018)

Abstract Breast cancer brain metastasis affects 10-20% of patients, and there are no effective treatments. Activated infiltrating microglia and astrocytes are a major component of metastatic breast tumors in the brain, but it is not known whether these cells are involved in the promotion or rejection of breast cancer cells. To characterize the brain metastatic microenvironment, we used an FACS-based approach to capture pure and viable microglia and astrocytes from normal and metastatic mouse brains for single-cell mRNA sequencing analysis. Using this approach, we have captured more than 10,000 microglia and astrocytes from normal and metastatic brains. Applying our analysis pipelines to this data revealed distinct pathways and markers associated with microglia and astrocytes in metastatic brains. Future work will aim to identify spatial locations and function of specific microglia and astrocyte subpopulations in the metastatic brain. Citation Format: Katrina Evans, Quy Nguyen, Kerrigan Blake, Devon Lawson. Single-cell analysis of the brain metastatic microenvironment in 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 5197.
Abstract 3374: CRISPR/Cas9 mediated genome editing induces exon skipping by alternative splicing or exon deletion
Authors: Haiwei Mou, Jordan Smith, Lingtao Peng, Hao Yin, Jill Moore, Xiao-Ou Zhang, Chunqing Song, Ankur Sheel, Qiongqiong Wu, Deniz Ozata, Yingxiang Li, Daniel Anderson, Charles Emerson, Melissa Moore, Zhiping Weng, Wen Xue
Journal: Cancer Research (2018)

Abstract CRISPR is widely used to disrupt gene function by inducing small insertions and deletions. Here, we show that some single-guide RNAs (sgRNAs) can induce exon skipping or large genomic deletions that delete exons. For example, CRISPR-mediated editing of β-catenin exon 3, which encodes an autoinhibitory domain, induces partial skipping of the in-frame exon and nuclear accumulation of β-catenin. A single sgRNA can induce small insertions or deletions that partially alter splicing or unexpected larger deletions that remove exons. Exon skipping adds to the unexpected outcomes that must be accounted for, and perhaps taken advantage of, in CRISPR experiments. Citation Format: Haiwei Mou, Jordan Smith, Lingtao Peng, Hao Yin, Jill Moore, Xiao-Ou Zhang, Chunqing Song, Ankur Sheel, Qiongqiong Wu, Deniz Ozata, Yingxiang Li, Daniel Anderson, Charles Emerson, Melissa Moore, Zhiping Weng, Wen Xue. CRISPR/Cas9 mediated genome editing induces exon skipping by alternative splicing or exon deletion [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 3374.