tbuckley/cabot-search huggingface dataset:
ADRB2 expression in progressive metastatic castration-resistant prostate cancer.
Authors: Daniel Kwon, Li Zhang, Adam Foye, William S. Chen, Felix Y Feng, Adina Bailey, Jiaoti Huang, David A. Quigley, Josh Stuart, Verena Friedl, Alana Weinstein, Tomasz M. Beer, Joshi J. Alumkal, Matthew Rettig, Martin Gleave, Primo Lara, Patricia Li, Austin Lui, Eric Jay Small, Rahul Raj Aggarwal
Journal: Journal of Clinical Oncology (2020)

145 Background: The net oncogenic effect of the G protein-coupled receptor β 2 adrenergic receptor ADRB2, which may induce neuroendocrine differentiation via cyclic AMP and protein kinase A and whose expression is epigenetically regulated by EZH2, is controversial. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: This was a retrospective analysis of a cohort of men with mCRPC who were prospectively enrolled in the multi-center SU2C/PCF/AACR West Coast Prostate Cancer Dream Team study, in which biopsies of a metastatic site were obtained at disease progression. Specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and transcriptional cluster based on prior unsupervised hierarchical transcriptome clustering, and correlated with EZH2 expression. ADRB2 expression (lowest quartile) was correlated with OS from time of biopsy by log rank test and a multivariable Cox proportional hazard model. Results: One-hundred and twenty-seven men with progressive mCRPC underwent metastatic biopsies and had sufficient tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P&lt;0.001), and correlated inversely with EZH2 expression (r=-0.28, P&lt;0.01). Men with low ADRB2 expression had a shorter median OS than those with high (9.5 vs 18.9 mo, P=0.02). In multivariable analysis adjusting for small cell histology, performance status, LDH, and visceral metastases, high ADRB2 expression was associated with a trend towards longer OS (HR=0.65, 95% CI 0.41-1.02, P=0.06). Conclusions: Low ADRB2 expression is associated with worse OS in men with progressive mCRPC, and may be a means by which EZH2 confers resistance to antiandrogen therapy. Indirect ADRB2 stimulation with EZH2 inhibitors may improve outcomes. Validation in independent cohorts is necessary.
Financial hardship among Medicare beneficiaries prescribed oral targeted therapies for advanced prostate cancer.
Authors: Megan Veresh Caram, Mary Oerline, Stacie Dusetzina, Parth K. Modi, Lindsey A. Herrel, Ted A. Skolarus, Brent K. Hollenbeck, Vahakn B. Shahinian
Journal: Journal of Clinical Oncology (2020)

68 Background: Abiraterone and enzalutamide are increasingly being used to treat advanced prostate cancer. Understanding barriers to adhering to treatment is of paramount importance in ensuring continued access to these important therapies. Patients with limited resources or insufficient access to mechanisms that lower their out-of-pocket cost are likely to suffer from significant financial toxicity and may engage in coping mechanisms such as rationing or abandoning their medication. Methods: To address the variability in measures of financial hardship, we performed a retrospective cohort study on a 20% sample of patients eligible for Medicare Part D who received their first fill of abiraterone or enzalutamide between July 2013 and June 2015. Patients were assigned to a provider based on their first prescription, and a hospital referral region (HRR) based on their ZIP code. The primary outcomes were to determine the proportion of days covered (PDC), overall prescription adherence, and average monthly out-of-pocket cost to patients prescribed abiraterone or enzalutamide, all within the first six months of treatment. Results: From mid-2013 to mid-2015, 4529 patients filled abiraterone or enzalutamide through Medicare Part D, within 305 HRRs. There was substantial variability in PDC, adherence, and out-of-pocket cost to patients among HRRs. The mean PDC was 84% with mean adherence of 73%, which included the 393 (8.7%) of patients who abandoned oral therapy after 1-2 fills. The median standard monthly out-of-pocket cost was $707, ranging between $0 and $3505. Among patients with low-income subsidies, median out-of-pocket cost by HRR ranged from $0 to $2815. We observed that PDC tracked closely with socioeconomic status – HRRs that included a higher proportion of patients eligible for Medicaid had lower PDCs and adherence, but lower standard out-of-pocket cost. Conclusions: This investigation demonstrated significant variation in PDC, adherence, and out-of-pocket cost among different HRRs for patients prescribed abiraterone and enzalutamide and that much of the variability in financial hardship measures among HRRs may be due to socioeconomic variables and regional variability.
Error in USPSTF Report on Statin Use
Authors: Roger Chou
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 13105: Active Commuting and Cardiovascular Diseases in Chinese
Authors: Mengyu Fan, Jun Lv, Canqing Yu, Yu Guo, Zheng Bian, Songchun Yang, Ling Yang, Yiping Chen, Yuelong Huang, Biyun Chen, Lei Fan, Junshi Chen, Zhengming Chen, Lu Qi, Liming Li
Journal: Circulation (2018)

Introduction: Active commuting is related to higher level of physical activity but more exposure to ambient air pollutants. Little is known about the relations of long-term active commuting with ca...
Measuring multimorbidity beyond counting diseases: systematic review of community and population studies and guide to index choice
Authors: Lucy E Stirland, Laura González-Saavedra, Donncha S Mullin, Craig W Ritchie, Graciela Muniz-Terrera, Tom C Russ
Journal: BMJ (2020)

Abstract Objectives To identify and summarise existing indices for measuring multimorbidity beyond disease counts, to establish which indices include mental health comorbidities or outcomes, and to develop recommendations based on applicability, performance, and usage. Design Systematic review. Data sources Seven medical research databases (Medline, Web of Science Core Collection, Cochrane Library, Embase, PsycINFO, Scopus, and CINAHL Plus) from inception to October 2018 and bibliographies and citations of relevant papers. Searches were limited to English language publications. Eligibility criteria for study selection Original articles describing a new multimorbidity index including more information than disease counts and not focusing on comorbidity associated with one specific disease. Studies were of adults based in the community or at population level. Results Among 7128 search results, 5560 unique titles were identified. After screening against eligibility criteria the review finally included 35 papers. As index components, 25 indices used conditions (weighted or in combination with other parameters), five used diagnostic categories, four used drug use, and one used physiological measures. Predicted outcomes included mortality (18 indices), healthcare use or costs (13), hospital admission (13), and health related quality of life (7). 29 indices considered some aspect of mental health, with most including it as a comorbidity. 12 indices are recommended for use. Conclusions 35 multimorbidity indices are available, with differing components and outcomes. Researchers and clinicians should examine existing indices for suitability before creating new ones. Systematic review registration PROSPERO CRD42017074211.
Abstract 17102: Why Don’t Heart Failure Patients Respond to Early Symptoms? Determinants of Symptom Perception
Authors: Solim Lee, Marguerite Daus, Debra Moser, Jennifer Miller, Kristen Sethares, Barbara Riegel
Journal: Circulation (2017)

Heart failure (HF) patients need to perceive symptoms quickly, label them correctly, and manage them well if they want to avoid hospitalization. Little is known about why some are better at this th...
PAQR4 promotes chemoresistance in non-small cell lung cancer through inhibiting Nrf2 protein degradation
Authors: Peifang Xu, Liping Jiang, Yang Yang, Mengge Wu, Baiyang Liu, Yulin Shi, Qiushuo Shen, Xiulin Jiang, Yaomei He, Dating Cheng, Qiuxia Xiong, Zuozhang Yang, Lincan Duan, Jie Lin, Song Zhao, Peng Shi, Cuiping Yang, Yongbin Chen
Journal: Theranostics (2020)

Purpose: Lung cancer is the leading cause of cancer related deaths worldwide.We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method.Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC).Methods: The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells.Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4.Results: We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues.We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis.Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1.Conclusion: Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both in vitro and xenograft tumor formation in vivo, by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.
Clinical quantitative cardiac imaging for the assessment of myocardial ischaemia
Authors: Marc Dewey, Maria Siebes, Marc Kachelrieß, Klaus F. Kofoed, Pál Maurovich-Horvat, Konstantin Nikolaou, Wenjia Bai, Andreas Kofler, Robert Manka, Sebastian Kozerke, Amedeo Chiribiri, Tobias Schaeffter, Florian Michallek, Frank Bengel, Stephan Nekolla, Paul Knaapen, Mark Lubberink, Roxy Senior, Meng-Xing Tang, Jan J. Piek, Tim van de Hoef, Johannes Martens, Laura Schreiber
Journal: Nature Reviews Cardiology (2020)

Cardiac imaging has a pivotal role in the prevention, diagnosis and treatment of ischaemic heart disease. SPECT is most commonly used for clinical myocardial perfusion imaging, whereas PET is the clinical reference standard for the quantification of myocardial perfusion. MRI does not involve exposure to ionizing radiation, similar to echocardiography, which can be performed at the bedside. CT perfusion imaging is not frequently used but CT offers coronary angiography data, and invasive catheter-based methods can measure coronary flow and pressure. Technical improvements to the quantification of pathophysiological parameters of myocardial ischaemia can be achieved. Clinical consensus recommendations on the appropriateness of each technique were derived following a European quantitative cardiac imaging meeting and using a real-time Delphi process. SPECT using new detectors allows the quantification of myocardial blood flow and is now also suited to patients with a high BMI. PET is well suited to patients with multivessel disease to confirm or exclude balanced ischaemia. MRI allows the evaluation of patients with complex disease who would benefit from imaging of function and fibrosis in addition to perfusion. Echocardiography remains the preferred technique for assessing ischaemia in bedside situations, whereas CT has the greatest value for combined quantification of stenosis and characterization of atherosclerosis in relation to myocardial ischaemia. In patients with a high probability of needing invasive treatment, invasive coronary flow and pressure measurement is well suited to guide treatment decisions. In this Consensus Statement, we summarize the strengths and weaknesses as well as the future technological potential of each imaging modality.
Molecular characterization of advanced muscle invasive bladder cancer (MIBC): Comparison of low-input targeted RNA sequencing (RNAseq) strategies.
Authors: Yoichiro Shibata, Joshua M. Uronis, Jeffrey M. Conroy, Sean Glenn, John Guo, Gregory Mayhew, Joel Robert Eisner, Michael Vance Milburn
Journal: Journal of Clinical Oncology (2020)

564 Background: 5-year survival for advanced MIBC is poor (~5%), but newer targeted agents (e.g., PD-1/PD-L1 or FGFR) have improved survival over traditional chemotherapy. To better select patients suited for targeted therapies, molecular characterization is more important than ever. The following study compares RNAseq using two low-RNA-input methods (SureSelect hybridization-capture and AmpliSeq PCR amplification, using 200 ng and 10 ng extracted RNA, respectively), as part of a retrospective study of advanced MIBC patients treated with anti-PD-1/PD-L1 therapy (Mayhew et al, 2019 ASCO). RNAseq results, including correlation between methods and molecular subtype agreement are presented herein. Methods: RNA extracts from 24 representative FFPE MIBC tumor samples were analyzed using SureSelect XT RNA (Agilent) and AmpliSeq transcriptome (Illumina) by NovaSeq6000 paired end sequencing. Samples were split between 4 molecular subtypes using the GeneCentric 60-gene MIBC nearest centroid subtyper (n = 6/subtype; luminal, luminal infiltrated, basal, basal infiltrated) (Mayhew et al, 2019 ASCO). Pearson correlation analysis was performed for all genes, as well as the 60 suptyper genes. Expression subtype calls were compared using RNAseq data obtained from both sequencing methods. Results: Of 58,000 genes queried (GrCH38.v22), 27,671 (55%) were found using both methods and 13,992 (28%) were not found using either method. 15,575 unique genes were found using SureSelect and 1,149 unique genes were found using AmpliSeq. The two methods were well correlated: median of 0.87 (0.73-0.89) overall and 0.80 (0.54-0.86) for the 60 subtyper genes. 22 of the 24 samples (92%) had congruent subtype calls using the 60-gene MIBC subtyper; one luminal-infiltrated called basal and one basal called basal-infiltrated. Conclusions: This study demonstrated comparable RNAseq analysis using two low-input FFPE-compatible methods. Using AmpliSeq, MIBC tumors were able to be molecularly characterized, including subtype analysis, with only 1/20th of the extracted RNA needed for SureSelect. Further validation of AmpliSeq methodology in MIBC and other tumor types is warranted.
Nonalcoholic Fatty Liver Disease Pandemic Fuels the Upsurge in Cardiovascular Diseases
Authors: Jingjing Cai, Xiao-Jing Zhang, Yan-Xiao Ji, Peng Zhang, Zhi-Gang She, Hongliang Li
Journal: Circulation Research (2020)

Cardiovascular diseases (CVDs) remain a leading cause of death worldwide. Among the major risk factors for CVD, obesity and diabetes mellitus have received considerable attention in terms of public policy and awareness. However, the emerging prevalence of nonalcoholic fatty liver disease (NAFLD), as the most common liver and metabolic disease and a cause of CVD, has been largely overlooked. Currently, the number of individuals with NAFLD is greater than the total number of individuals with diabetes mellitus and obesity. Epidemiological studies have established a strong correlation between NAFLD and an increased risk of CVD and CVD-associated events. Although debate continues over the causal relationship between NAFLD and CVD, many mechanistic and longitudinal studies have indicated that NAFLD is one of the major driving forces for CVD and should be recognized as an independent risk factor for CVD apart from other metabolic disorders. In this review, we summarize the clinical evidence that supports NAFLD as a risk factor for CVD epidemics and discuss major mechanistic insights regarding the acceleration of CVD in the setting of NAFLD. Finally, we address the potential treatments for NAFLD and their potential impact on CVD.
‘Pathogenesis and management of fracture-related infection’ – Author's reply
Authors: M. Depypere, M. Morgenstern, R. Kuehl, E. Senneville, T.F. Moriarty, W.T. Obremskey, W. Zimmerli, A. Trampuz, K. Lagrou, W-J. Metsemakers
Journal: Clinical Microbiology and Infection (2020)
Endoscopic Ultrasonography in High-Risk Population for Pancreatic Cancer
Authors: C. Guillen-Ponce, E. Mocci, A. Amendolara, E. Vazquez-Sequeiros, C. Gonzalez Gordaliza, M. Muñoz Beltran, A. Sanjuanbenito, C. Gonzalez Garcia, A. Custodio, A. Carrato
Journal: Annals of Oncology (2012)
Tumor extravasation and infiltration as barriers of nanomedicine for high efficacy: The current status and transcytosis strategy
Authors: Quan Zhou, Chengyuan Dong, Wufa Fan, Haiping Jiang, Jiajia Xiang, Nasha Qiu, Ying Piao, Tao Xie, Yingwu Luo, Zichen Li, Fusheng Liu, Youqing Shen
Journal: Biomaterials (2020)
Clinical outcomes of abiraterone acetate + prednisone (AA) + bone resorption inhibitors (BRI) versus AA alone as first-line therapy for castration-resistant prostate cancer (CRPC) with bone metastases (BM) in an international multicenter database.
Authors: Edoardo Francini, Francesco Montagnani, Pier Vitale Nuzzo, Miguel Gonzalez-Velez, Nimira S. Alimohamed, Antonio Cigliola, Irene Moreno, Jaime Rubio, Francesca Crivelli, Grace Shaw, Roberto Petrioli, Carmelo Bengala, Guido Francini, Jesus Garcia Foncillas, Christopher Sweeney, Celestia S. Higano, Alan Haruo Bryce, Lauren Christine Harshman, Richard Lee-Ying, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2020)

30 Background: BM in patients (pts) with CRPC are associated with shorter overall survival (OS) and higher costs. BRI zoledronic acid and denosumab are frequently used to prevent skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line therapy for men with metastatic CRPC. We aimed to assess the impact of BRI on OS and time to first SRE (ttSRE) of pts receiving 1st line treatment AA for CRPC with BM. Methods: A retrospective cohort of pts starting AA as 1st line therapy for CRPC with BM between 2013-2016 was identified through 8 hospitals’ IRB approved registries. Pts were classified by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. Kaplan-Meier method and Cox models were used to assess OS and ttSRE with hazard ratio (HR) estimates (95% CI). Results: Of the 745 pts included (543 deaths), 529 (71.0%) had AA alone and 216 (29.0%) AA+BRI. Median follow-up was 23.5 months. Pts receiving concomitant BRI showed a significantly longer OS and a 35% reduced risk of death compared to AA alone (HR=0.65; 95% CI, 0.54-0.79; P&lt;.0001). The OS benefit with BRI was greater for the subgroup with high volume disease (HV) (HR=0.51; 95% CI, 0.38-0.68; P&lt;.0001). The cohort with AA+BRI had a significantly shorter ttSRE (HR=1.27; 95% CI; 1.0-1.60; P=.0439) and, notably, the risk of first SRE was more than doubled for the subgroup with LV (HR=2.29; 95% CI, 1.57-3.35; P&lt;.0001). On MVA, BRI vs. no BRI, prior local therapy (PLT) vs. no PLT, LV vs. HV, baseline VAS pain ≤3 vs. &gt;5, PS 0 vs. ≥1, and PSA are independently associated with longer OS. Conclusions: The addition of BRI to 1st line AA for CRPC men with BM was associated with improved OS, particularly in HV, and worsened ttSRE, more evident in LV. These data suggest a potentially different impact of concomitant BRI on HV vs. LV, which could affect clinical decision making.[Table: see text]
A pilot study of tazemetostat and MK-3475 (pembrolizumab) in advanced urothelial carcinoma (ETCTN 10183).
Authors: Joshua J. Meeks, Ali Shilatifard, Stephen D. Miller, Alicia K. Morgans, David James VanderWeele, Masha Kocherginsky, Maha H. A. Hussain
Journal: Journal of Clinical Oncology (2020)

TPS607 Background: Few patients with metastatic urothelial carcinoma (UC) achieve a durable response despite early stabilization with chemotherapy or immunotherapy. Mutations in the COMPASS-related proteins KMT2D, KMT2C, and KDM6A are found in 66% of patients with UC, suggesting disruption of histone regulation may be an acquired mechanism of tumor viability. Using a carcinogen-derived mouse model of UC in which 80% of animals have alterations in Kmt2d, Kmt2d or both, we found regression of tumors when treated an enzymatic inhibitor of EZH2 (Tazemetostat). In vivo administration of Tazemetostat enhanced the immune response with more necrosis when combined with an anti-PD1 antibody. Therefore, we hypothesized that treatment of UC with an Tazemetostat may further improve the activity of immunotherapy as only 21% of cisplatin refractory (KN45) and 24% of cisplatin ineligible (KN52) patients achieve an objective response. We hypothesized that restoration of the epigenetic imbalance, combined with immunotherapy may improve survival in patients with metastatic UC. Methods: ETCTN10183 (NCT03854474) is a Phase I/II trial evaluating the efficacy of Tazemetostat at 800 mg BID + Pembrolizumab 200 mg IV every 3 weeks in patients with either cisplatin-refractory (Cohort A) or cisplatin-ineligible (Cohort B) metastatic UC. The safety lead-in portion of the trial will follow a “3+3” design with one dose de-escalation level (800mg or 600mg BID Tazemetostat) and will enroll 6-12 patients to establish the recommended phase II dose (RP2D) of Tazemetostat. All DLTs will be reviewed and if tolerated, two dose expansion cohorts will be initiated and will include 24 patients with 12 in each cohort (cisplatin refractory and ineligible). The primary objectives are to identify the RP2D of Tazemetostat in combination with Pembrolizumab, and secondary objectives are to determine the objective disease response in patients with either cisplatin-refractory or unresponsive UC per RECIST criteria, safety, tolerability and progression-free survival. Translational objectives include evaluation of tumor mutations in COMPASS genes, total mutation burden, T cell infiltration, TCR clonality, tumor subtyping and PD-L1 expression. Clinical trial information: NCT03854474.