tbuckley/cabot-search huggingface dataset:
Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance
Authors: Manish Kohli, Yeung Ho, David W. Hillman, Jamie L. Van Etten, Christine Henzler, Rendong Yang, Jamie M. Sperger, Yingming Li, Elizabeth Tseng, Ting Hon, Tyson Clark, Winston Tan, Rachel E. Carlson, Liguo Wang, Hugues Sicotte, Ho Thai, Rafael Jimenez, Haojie Huang, Peter T. Vedell, Bruce W. Eckloff, Jorge F. Quevedo, Henry C. Pitot, Brian A. Costello, Jin Jen, Eric D. Wieben, Kevin A.T. Silverstein, Joshua M. Lang, Liewei Wang, Scott M. Dehm
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3′ terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31–12.2; P = 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704–15. ©2017 AACR.
Abstract 371: Down Regulation of ECM Genes Laminin and Collagen IV Lead to Preserved Cardiac Function With Age and Increased Lifespan in Drosophila
Authors: Ayla O Sessions
Journal: Circulation Research (2015)

Increased deposition of extracellular matrix (ECM) is observed in all advanced age heart failure patients, but current model systems are complex and slow to age. To investigate the effect of extracellular remodeling on mechanical function in genetically tractable, rapidly aging, and simple model organisms, we employed Drosophila melanogaster, which has a simple trilayered heart tube. We found that two common wildtype strains of Drosophila, i.e. yellow-white (yw) and white-1118 (w1118), exhibit different cytoskeletal and ECM remodeling with age. Using a recently developed nanoindentation method to measure cardiomyocyte stiffness and high speed optical imaging to assess contractility of intact Drosophila hearts, we found that yw flies had stiffer intercalated discs (ICD) and exhibited diastolic dysfunction with age. On the other hand, w1118 flies had a shorter lifespan compared to yw, did not exhibit ICD stiffening, had a less severe diastolic dysfunction, and showed an increase in ECM layer thickness between ventral muscle (VM) and cardiomyocyte (CM) layers of the heart tube. To modulate ECM and assess its effect in the aged w1118 flies, we knocked-down ECM genes LamininA and Viking (homologous to Collagen IV). Both ECM KD genotypes exhibited diastolic dilation with increased fractional shortening at adult (1wk) and aged (5wk) time points. The LamininA KD resulted in decreased cardiomyocyte stiffness correlating with increased relaxation velocities in adult flies and preservation of shortening and relaxation velocities in aged flies over controls. However, both the LamininA and Collagen IV KD flies experienced a basal increase in the decoupling of their cardiomyocytes as determined by heart period variance and % fibrillar heart-beats. These conductance issues were not enough to counteract the increased cardiac output and performance with age, and the Collagen IV KD outlived controls by 1.5 weeks median survival and the LamininA KD by 3 weeks. This suggests that the cell-ECM contacts in the basement membrane are intimately tied not only to the coupling of the cardiomyocytes of the Drosophila heart tube but also to cytoskeletal remodeling, but perhaps different ECM proteins have different mechanisms for interacting with the cardiomyocyte cytoskeleton.
Leukemia Following Chemotherapy for Ovarian Cancer
Authors: John M. Kaldor, Nicholas E. Day, Folke Pettersson, E. Aileen Clarke, Dorthe Pedersen, Wolf Mehnert, Janine Bell, Herman Høst, Patricia Prior, Sakari Karjalainen, Frank Neal, Maria Koch, Pierre Band, Won Choi, Vera Pompe Kirn, Annie Arslan, Birgitta Zarén, A.R. Belch, Hans Storm, Bernd Kittelmann, Patricia Fraser, Marilyn Stovall
Journal: New England Journal of Medicine (1990)

An international collaborative group of cancer registries and hospitals identified 114 cases of leukemia following ovarian cancer. We investigated the possible etiologic role of chemotherapy, radiotherapy, and other factors, using a case–control study design, with three controls matched to each case of leukemia.
Physician Charges and Medicare Payments
Authors: Ge Bai, Gerard F. Anderson
Journal: JAMA (2017)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
EULAR recommendations for disease management: guidance not guidelines
Authors: David S Pisetsky
Journal: Annals of the Rheumatic Diseases (2017)

The past two decades have witnessed remarkable advances in the treatment of inflammatory arthritis that have made remission in previously untreatable conditions a realistic goal for many patients. These advances derive from new insights into disease mechanisms; the advent of the biologics and other new therapies; the development of robust measures of disease activity; coherent treatment strategies to guide therapy (ie, treat to target or T2T); and a sufficient supply of rheumatologists to implement the new approaches.1 

The advances in rheumatology have been unprecedented and, arguably, the treatment of inflammatory arthritis has progressed faster and further than that of any other serious chronic disease in all of medicine. Indeed, a patient with rheumatoid arthritis (RA) today can lead an essentially normal life, whereas, a few decades ago, such a patient would have a restricted existence and be easily recognised by the appearance of grave illness, wasting and deformity.

Along with better outcomes have come challenges in the utilisation of the current armamentarium of disease modifying antirheumatic drugs or DMARDs (table 1). These challenges are, of course, welcome since they signify progress. In the face of literally hundreds to thousands of ways to treat arthritis and the continuing influx of novel agents, they also demand guidance for both providers and patients to establish a treatment plan, recognising potential risks, benefits and costs. The publication of three articles on European League Against Rheumatism (EULAR) recommendations for the treatment of early inflammatory arthritis, RA and axial spondyloarthritis (axSpA) is therefore an important event and provides a much needed perspective and framework for the delivery of best care.2–4 

View this table:

Table 1 
Disease-modifying antirheumatic drugs (DMARDs)



Each article represents a remarkable effort by panels of rheumatologists, health professionals and patient representatives to encompass an ever-expanding literature and provide overarching principles as well as specific recommendations. The work …
How Should Journals Handle the Conflict of Interest of Their Editors?
Authors: Julie D. Gottlieb, Neil M. Bressler
Journal: JAMA (2017)

Conflict of interest (COI) policies at most academic medical centers require that investigators disclose research-related financial interests to their institutions so the institution can review the potential risks of the COI. To manage COI, academic medical centers typically direct investigators to disclose their financial interests to research participants and to journal editors. If an institution follows the guidelines of the Association of American Medical Colleges,1 except for situations in which a researcher has a significant financial interest in research involving humans, investigators generally are permitted to retain their financial interests while performing related research as long as there is transparency about their financial interests via disclosure to the consumers (eg, research participants, co-investigators, and individuals who receive reports of the research, including those listening to a presentation of the research or reading an article about the research).
Pulmonary hypertension with warm hands
Authors: Liza Botros, Jurjan Aman, Harm Jan Bogaard, Anton Vonk Noordegraaf
Journal: Thorax (2017)

A 19-year-old woman of Moroccan descent presented with severe dyspnoea on exertion. She had difficulty walking stairs (New York Heart Association functional class 3) and accompanying symptoms included fatigue, palpitations and near collapse. She had no cough or wheezing, but mentioned severe and continuous menstrual bleeds since menarche without use of contraceptives. Her medical history included long-standing complaints of fainting, abdominal pains and chest pain, without a clear diagnosis. The family history included hypercholesterolaemia and venous thromboembolic disease (VTE). In fact, 1 year prior to this presentation, the patient was diagnosed with PE herself. Other than a temporary mild polycythaemia (haemoglobin concentration of 16 g/dL) no risk factors for VTE had been discovered at that time.

Physical examination showed a thin woman with a body mass index of 17 kg/m2 (height 161 cm and weight 44 kg). Her blood pressure was 82/51 mm Hg, while her extremities appeared warm. Her heart rate was 91 bpm, the respiratory rate 16/min and oxygen saturation (SpO2) 98%. Heart and lungs appeared normal, but abdominal examination revealed overt hepatosplenomegaly. There were no signs of peripheral oedema, venous thrombosis or clubbing.

Routine blood chemistry showed a haemoglobin level of 16.0 g/dL, haematocrit 57%, a mean corpuscular volume of 72, reticulocyte index 18% together with a serum iron of 6.1 μmol/L and a ferritin of 7 μg/L, suggestive for anaemia secondary to severe iron deficiency, most likely due to hypermenorrhoea. The N-terminal pro brain natriuretic peptide level was elevated to 196 pg/mL. Thrombocytes, white blood cells, kidney function, liver enzymes and thyroid stimulating hormone were all within reference values (see online supplementary table S3). No abnormalities were noted on the chest radiograph; however, a transthoracic echocardiogram showed mild right ventricular (RV) dilatation and dysfunction, a tricuspid annular plane systolic excursion of 23 mm, an estimated RV systolic pressure of 57 mm Hg and right atrial pressure of …
Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007
Authors: Rebecca Leece, Jordan Xu, Quinn T Ostrom, Yanwen Chen, Carol Kruchko, Jill S Barnholtz-Sloan
Journal: Neuro-Oncology (2017)

Previous reports have shown that overall incidence of malignant brain and other central nervous system (CNS) tumors varied significantly by country. The aim of this study was to estimate histology-specific incidence rates by global region and assess incidence variation by histology and age.Using data from the Central Brain Tumor Registry of the United States (CBTRUS) and the International Agency for Research on Cancer's (IARC) Cancer Incidence in Five Continents X (including over 300 cancer registries), we calculated the age-adjusted incidence rates (AAIR) per 100000 person-years and 95% CIs for brain and other CNS tumors overall and by age groups and histology.There were significant differences in incidence by region. Overall incidence of malignant brain tumors per 100000 person-years in the US was 5.74 (95% CI = 5.71-5.78). Incidence was lowest in Southeast Asia (AAIR = 2.55, 95% CI = 2.44-2.66), India (AAIR = 2.85, 95% CI = 2.78-2.93), and East Asia (AAIR = 3.07, 95% CI = 3.02-3.12). Incidence was highest in Northern Europe (AAIR = 6.59, 95% CI = 6.52-6.66) and Canada (AAIR = 6.53, 95% CI = 6.41-6.66). Astrocytic tumors showed the broadest variation in incidence regionally across the globe.Brain and other CNS tumors are a significant source of cancer-related morbidity and mortality worldwide. Regional differences in incidence may provide clues toward genetic or environmental causes as well as a foundation for broadening knowledge of their epidemiology. Gaining a comprehensive understanding of the epidemiology of malignant brain tumors globally is critical to researchers, public health officials, disease interest groups, and clinicians and contributes to collaborative efforts in future research.
Steroids hydroxylation catalyzed by the monooxygenase mutant 139-3 from Bacillus megaterium BM3
Authors: Xing Liu, Jian-qiang Kong
Journal: Acta Pharmaceutica Sinica B (2017)

The search of new substrates with pharmaceutical and industrial potential for biocatalysts including cytochrome P450 enzymes is always challenging. Cytochrome P450 BM3 mutant 139-3, a versatile biocatalyst, exhibited hydroxylation activities towards fatty acids and alkanes. However, there were limited reports about its hydroxylation activity towards steroids. Herein, an Escherichia coli-based whole-cell extract containing the recombinant 139-3 protein was used as the biocatalyst to screen 13 steroids. Results revealed that 139-3 was able to specifically hydroxylate androstenedione (1) at 1α-position, generating a hydroxylated steroid 1α-OH-androstenedione (1a). To investigate whether C-1α hydroxylation catalyzed by BM3 mutant 139-3 could be industrially used, an optimization of catalyzing conditions was performed. Accordingly, the BM3 mutant 139-3 enzyme was observed to display maximum activity at 37 °C, under pH 7.0 for 4 h, with 37% transformation rate. Moreover, four 139-3 variants were generated by random mutagenesis with the aim of improving its activity and expanding substrate scope. Surprisingly, these mutants, sharing a common mutated site R379S, lost their activities towards androstenedione (1). These data clearly indicated that arginine residue located at site 379 played key role in the hydroxylation activities of 139-3. Overall, these new findings broadened the substrate scope of 139-3 enzyme, thereby expanding its potential applications as a biocatalyst on steroids hydroxylation in pharmaceutical industry.
Calcium Intake and Cardiovascular Disease Risk
Authors: Aisawan Petchlorlian
Journal: Annals of Internal Medicine (2017)

Letters2 May 2017Calcium Intake and Cardiovascular Disease RiskAisawan Petchlorlian, MDAisawan Petchlorlian, MDFrom King Chulalongkorn Memorial Hospital, Bangkok, Thailand.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0132 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:In the section on results from RCTs, Chung and colleagues (1) state the following:Only 2 subgroup analyses revealed statistically significant differences between groups. One showed that use of personal calcium supplements altered the effect of calcium and vitamin D on [cardiovascular disease] … . In postmenopausal women receiving calcium supplements, the hazard ratios with calcium and vitamin D were 1.13 to 1.22 for [cardiovascular disease] end points. In contrast, among those not taking supplements, the hazard ratios were 0.83 to 1.08.This indicates an increased risk in women currently taking personal calcium supplements. However, in Bolland ...References1. Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium intake and cardiovascular disease risk: an updated systematic review and meta-analysis. Ann Intern Med. 2016;165:856-66. [PMID: 27776363]. doi:10.7326/M16-1165 LinkGoogle Scholar2. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040. [PMID: 21505219] doi:10.1136/bmj.d2040 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From King Chulalongkorn Memorial Hospital, Bangkok, Thailand.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0132. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoCalcium Intake and Cardiovascular Disease Risk Mei Chung , Alice M. Tang , Zhuxuan Fu , Ding Ding Wang , and Sydne Jennifer Newberry Calcium Intake and Cardiovascular Disease Risk Elizabeth J. Samelson Calcium Intake and Cardiovascular Disease Risk Ian R. Reid , Alison Avenell , Andrew Grey , and Mark J. Bolland Calcium Intake and Cardiovascular Disease Risk Joshua R. Lewis and Richard L. Prince Calcium Intake and Cardiovascular Disease Risk Mei Chung , Alice M. Tang , and Sydne Jennifer Newberry Metrics 2 May 2017Volume 166, Issue 9Page: 686KeywordsCalciumCardiovascular disease riskCardiovascular diseasesConflicts of interestCoronary revascularizationDisclosureHazard ratioMyocardial infarctionVitamin D ePublished: 2 May 2017 Issue Published: 2 May 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and GVL.
Authors: Alan M. Hanash, Marcel R. M. Van Den Brink, Guoqiang Hua, Richard Kolesnick, Bruce R. Blazar
Journal: Journal of Clinical Oncology (2012)

6539 Background: Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. Methods: We investigated the role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) mice as donors or recipients in allo-BMT. Results: We found that administration of an anti-IL-22 neutralizing antibody to allo-BMT recipients during the first month post-BMT led to increased GVHD mortality, indicating that IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of IL-22 KO donor T cells did not impair their ability to eliminate A20 lymphoma cells upon tumor challenge, thus indicating that IL-22 was not essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. BMT with WT donors and recipients indicated that IL-22 levels in small and large intestine were increased after BMT and after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical for protection of host epithelium during GVHD and critical for protection of ISC, and it does not contribute to donor T cell GVL responses. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases, and may be useful for clinical separation of pathologic GVH and therapeutic GVL responses.