tbuckley/cabot-search huggingface dataset:
CSTF2-Induced Shortening of the <i>RAC1</i> 3′UTR Promotes the Pathogenesis of Urothelial Carcinoma of the Bladder
Authors: Xin Chen, Jia-Xing Zhang, Jun-Hang Luo, Song Wu, Gang-Jun Yuan, Ning-Fang Ma, Yong Feng, Mu-Yan Cai, Ri-Xin Chen, Jun Lu, Li-Juan Jiang, Jie-Wei Chen, Xiao-Han Jin, Hai-Liang Liu, Wei Chen, Xin-Yuan Guan, Tie-Bang Kang, Fang-Jian Zhou, Dan Xie
Journal: Cancer Research (2018)

Shortening of the 3' untranslated regions (3'UTR) of mRNA is an important mechanism for oncogene activation. However, 3'UTR alteration events, their pathologic functions, and underlying mechanisms in human urothelial carcinoma of the bladder (UCB) are not clear. Here, we combine RNA sequencing, bioinformatics, and clinical studies in two independent cohorts of patients with UCB to identify a novel RAC1 shorter 3'UTR isoform that is frequently expressed in UCB and is critical in the tumorigenesis and acquisition of a poor prognostic phenotype in patients. Short 3'UTR isoform of RAC1 substantially upregulated RAC1 expression by escaping from miRNA-targeted repression and played an essential oncogenic role in UCB pathogenesis. An important cleavage/polyadenylation factor, cleavage stimulation factor 2 (CSTF2), induced 3'UTR shortening of RAC1 in UCB by mediating slow transcriptional elongation at RAC1 Cotranscriptional recruitment of CSTF2 on the GUAAU motif at proximal polyadenylation site of RAC1 attenuated the recruitment of two transcription factors AFF1 and AFF4, causing the defects in elongation. CSTF2 regulated the tumorigenic functions of the shorter RAC1 isoform in UCB cells, enhancing cell proliferation, migration, and invasion. The combination of high expression of CSTF2 and high usage of RAC1 short-3'UTR isoform may be used as a powerful biomarker to predict poor prognosis in UCB. Our findings also suggest a CSTF2-regulated RAC1-3'UTR shortening program as an exploitable therapeutic strategy for patients with UCB.Significance: These findings demonstrate that the short isoform of RAC1 is critical in UCB tumorigenesis and may have implications for developing new therapeutic strategies to treat this disease. Cancer Res; 78(20); 5848-62. ©2018 AACR.
Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC
Authors: Massimo Moro, Elisa Caiola, Monica Ganzinelli, Elisabetta Zulato, Eliana Rulli, Mirko Marabese, Giovanni Centonze, Adele Busico, Ugo Pastorino, Filippo G. de Braud, Claudio Vernieri, Michele Simbolo, Emilio Bria, Aldo Scarpa, Stefano Indraccolo, Massimo Broggini, Gabriella Sozzi, Marina Chiara Garassino
Journal: Journal of Thoracic Oncology (2018)
Quantitative high-resolution computed tomography fibrosis score: performance characteristics in idiopathic pulmonary fibrosis
Authors: Stephen M. Humphries, Jeffrey J. Swigris, Kevin K. Brown, Matthew Strand, Qi Gong, John S. Sundy, Ganesh Raghu, Marvin I. Schwarz, Kevin R. Flaherty, Rohit Sood, Thomas G. O'Riordan, David A. Lynch
Journal: European Respiratory Journal (2018)

We evaluated performance characteristics and estimated the minimal clinically important difference (MCID) of data-driven texture analysis (DTA), a high-resolution computed tomography (HRCT)-derived measurement of lung fibrosis, in subjects with idiopathic pulmonary fibrosis (IPF). The study population included 141 subjects with IPF from two interventional clinical trials who had both baseline and nominal 54- or 60-week follow-up HRCT. DTA scores were computed and compared with forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide, distance covered during a 6-min walk test and St George's Respiratory Questionnaire scores to assess the method's reliability, validity and responsiveness. Anchor- and distribution-based methods were used to estimate its MCID. DTA had acceptable reliability in subjects appearing stable according to anchor variables at follow-up. Correlations between the DTA score and other clinical measurements at baseline were moderate to weak and in the hypothesised directions. Acceptable responsiveness was demonstrated by moderate to weak correlations (in the directions hypothesised) between changes in the DTA score and changes in other parameters. Using FVC as an anchor, MCID was estimated to be 3.4%. Quantification of lung fibrosis extent on HRCT using DTA is reliable, valid and responsive, and an increase of ∼3.4% represents a clinically important change.
Abstract P043: Erythrocyte Long-Chain Omega-3 Fatty Acid Levels Are Inversely Associated With Mortality and With and Incident Cardiovascular Disease: The Framingham Heart Study
Authors: William S Harris, Nathan Tintle, Mark R Etherton, Ramachandran S Vasan
Journal: Circulation (2018)

Background: The extent to which omega-3 fatty acid (FA) status is related to risk for death from any cause and for incident cardiovascular disease (CVD) remains controversial. Objective: To examine this association in the Framingham Heart Study (FHS). Design: Prospective and observational. Setting: FHS Offspring cohort. Measurements: The primary exposure marker was red blood cell (RBC) levels of eicosapentaenoic and docosahexaenoic acids (EPA and DHA; the Omega-3 Index) which was measured at baseline. Secondary markers included RBC EPA, DHA, alpha-linolenic and docosapentaenoic (n-3) acids. Outcomes included mortality (total, CVD, cancer, and other) and total CVD events. Median follow-up was 7.3 years. Cox proportional hazards models were adjusted for 18 demographic characteristics, clinical status, therapies and other CVD risk factors including C-reactive protein levels. Results: Among the 2500 participants (mean age 66 years, 54% women; all free of CVD at baseline) there were 350 deaths (58 from CVD, 146 from cancer, 128 from other known causes, and 18 from unknown causes). There were 245 CVD events. In multivariable-adjusted analyses, a higher Omega-3 Index was associated with significantly lower risks (p-values for trends across quintiles) for total mortality (p=0.02) and non-CVD, non-cancer mortality (p = 0.009; Figure), and for total CVD events (p=0.008). Those in the highest versus the lowest Omega-3 Index quintiles (i.e., &gt;6.8% vs. &lt;4.2%) had a 34% lower risk for death from any cause and a 39% lower risk for incident CVD. Associations were generally stronger for DHA than for EPA. When total cholesterol was compared with the Omega-3 Index in the same models, the latter was significantly related with these outcomes, but the former was not. Substituting the omega-6:omega-3 ratio for the Omega-3 Index did not alter the outcomes. Limitations: Relatively short follow-up time and a single exposure assessment. Conclusions: A higher Omega-3 Index was associated with reduced risk of both CVD and all-cause mortality.
Abstract 19829: Get With the Guidelines Heart Failure Risk Score and Post-Discharge Events in Hospitalized Heart Failure Patients: A Community-Based Study
Authors: Sithu Win, Imad Hussain, Virginia B Hebl, Shannon M Dunlay, Margaret M Redfield
Journal: Circulation (2016)

Background: The Get with the Guidelines (GWTG) heart failure (HF) Risk Score was developed in the GWTG inpatient HF registry to predict inpatient mortality but has not been validated in the communi...
Antibiotics and Acid-Suppressing Medications in Early Life and Allergic Disorders—Reply
Authors: Edward Mitre, Apryl Susi, Cade M. Nylund
Journal: JAMA Pediatrics (2018)

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 Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast 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 Pediatrics journal
Effect of Alcohol Consumption on Survival in Nonalcoholic Fatty Liver Disease: A National Prospective Cohort Study
Authors: Kaveh Hajifathalian, Babak Torabi Sagvand, Arthur J. McCullough
Journal: Hepatology (2018)

Nonalcoholic fatty liver disease (NAFLD) comprises more than two thirds of patients with chronic liver disease in the United States. The effect of alcohol consumption on survival in patients with NAFLD is not clear. We gathered data on National Health and Nutrition Examination Survey participants from 1988 to 2010, and linked them to the National Death Index for follow‐up of their survival. We diagnosed NAFLD based on a previously validated biochemical model (Hepatic Steatosis Index). We built multivariate Cox proportional hazards models to evaluate the effect of alcohol consumption on survival of patients with NAFLD. After excluding participants with significant alcohol use, viral hepatitis, or increased transferrin saturation, 4,568 participants with NAFLD were included in the analysis. In a Cox model adjusted for age, sex, and smoking history, drinking 0.5‐1.5 drinks per day decreased the risk of overall mortality by 41% (hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.40‐0.85, P = 0.005) compared with not drinking. Drinking ≥1.5 drinks per day showed a trend toward harm (HR = 1.16, 95% CI 0.99‐1.36, P = 0.119). After further adjustment for race, physical activity, education level, diabetes, and fiber and polyunsaturated fatty acid intake, drinking 0.5‐1.5 drinks per day continued to show a significant protective effect (HR = 0.64, 95% CI 0.42‐0.97, P = 0.035), and drinking ≥1.5 drinks per day showed a significant harmful effect on mortality (HR = 1.45, 95% CI 1.01‐2.10, P = 0.047). Among patients with NAFLD, modest alcohol consumption is associated with a significant decrease in all‐cause mortality, whereas drinking ≥1.5 drinks per day is associated with an increase in mortality. These results help to inform the discussion of potential risks and benefits of alcohol use in patients with NAFLD.
Abstract 18253: Exploiting Natural Genetic Variation to Understand Transcriptional Programs of Inflammation
Authors: Hyun B Chun, Verena Link, Christopher Glass
Journal: Circulation (2016)

Introduction: Individuals have varied responses to the same stimulus in the context of pharmacology and disease. Enhancers are important regulators of transcription. However, the exact regulation of these responses remains largely unknown. To explore the underlying molecular mechanisms, we utilized 5 different mouse strains to mimic the variation between individuals and investigated how natural genetic variation affects transcription in the context of inflammation. Hypothesis: Strain-specific loss of transcription factor binding to a specific enhancer at which there is no mutation in the binding site for that factor is due to a mutation in a nearby binding site for an essential collaborating factor. Methods: For each strain, we harvested macrophages and treated them with KLA, an inflammatory stimulus. Then, we performed RNA and GRO-seq to analyze the transcriptome and nascent transcripts. Furthermore, we performed ChIP-seq for key transcription factors and histone marks, and ATAC-Seq to analyze global tra...
Effects of Endotoxin on Type 3 Inositol 1,4,5‐Trisphosphate Receptor in Human Cholangiocytes
Authors: Andressa Franca, Antonio Carlos Melo Lima Filho, Mateus T. Guerra, Jittima Weerachayaphorn, Marcone Loiola dos Santos, Basile Njei, Marie Robert, Cristiano Xavier Lima, Paula Vieira Teixeira Vidigal, Jesus M. Banales, Meenakshisundaram Ananthanarayanan, M. Fatima Leite, Michael H. Nathanson
Journal: Hepatology (2018)

Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca 2+ release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor, Toll‐like receptor 4 (TLR4), which links to activation of nuclear factor‐κB (NF‐κB). Analysis of the human ITPR3 promoter revealed five putative response elements to NF‐κB, and promoter activity was inhibited by p65/p50. Nested 0.5‐ and 1.0‐kilobase (kb) deletion fragments of the ITPR3 promoter were inhibited by NF‐κB subunits. Chromatin immunoprecipitation (ChIP) assay showed that NF‐κB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from those with severe AH. Conclusion: Stimulation of TLR4 by LPS activates NF‐κB to down‐regulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or AH.
Rhinovirus Species–Specific Antibodies Differentially Reflect Clinical Outcomes in Health and Asthma
Authors: Spyridon Megremis, Katarzyna Niespodziana, Clarissa Cabauatan, Paraskevi Xepapadaki, Marek L. Kowalski, Tuomas Jartti, Claus Bachert, Susetta Finotto, Peter West, Sofia Stamataki, Anna Lewandowska-Polak, Heikki Lukkarinen, Nan Zhang, Theodor Zimmermann, Frank Stolz, Angela Neubauer, Mübeccel Akdis, Evangelos Andreakos, Rudolf Valenta, Nikolaos G. Papadopoulos
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Rhinoviruses (RVs) are major triggers of common cold and acute asthma exacerbations. RV species A, B, and C may have distinct clinical impact; however, little is known regarding RV species-specific antibody responses in health and asthma.Objectives: To describe and compare total and RV species-specific antibody levels in healthy children and children with asthma, away from an acute event.Methods: Serum samples from 163 preschool children with mild to moderate asthma and 72 healthy control subjects from the multinational Predicta cohort were analyzed using the recently developed PreDicta RV antibody chip.Measurements and Main Results: RV antibody levels varied, with RV-C and RV-A being higher than RV-B in both groups. Compared with control subjects, asthma was characterized by significantly higher levels of antibodies to RV-A and RV-C, but not RV-B. RV antibody levels positively correlated with the number of common colds over the previous year in healthy children, and wheeze episodes in children with asthma. Antibody levels also positively correlated with asthma severity but not with current asthma control.Conclusions: The variable humoral response to RV species in both groups suggests a differential infectivity pattern between RV species. In healthy preschoolers, RV antibodies accumulate with colds. In asthma, RV-A and RV-C antibodies are much higher and further increase with disease severity and wheeze episodes. Higher antibody levels in asthma may be caused by a compromised innate immune response, leading to increased exposure of the adaptive immune response to the virus. Importantly, there is no apparent protection with increasing levels of antibodies.
Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology
Authors: Shuji Ogino, Jonathan A. Nowak, Tsuyoshi Hamada, Danny A. Milner, Reiko Nishihara
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

Evidence indicates that diet, nutrition, lifestyle, the environment, the microbiome, and other exogenous factors have pathogenic roles and also influence the genome, epigenome, transcriptome, proteome, and metabolome of tumor and nonneoplastic cells, including immune cells. With the need for big-data research, pathology must transform to integrate data science fields, including epidemiology, biostatistics, and bioinformatics. The research framework of molecular pathological epidemiology (MPE) demonstrates the strengths of such an interdisciplinary integration, having been used to study breast, lung, prostate, and colorectal cancers. The MPE research paradigm not only can provide novel insights into interactions among environment, tumor, and host but also opens new research frontiers. New developments-such as computational digital pathology, systems biology, artificial intelligence, and in vivo pathology technologies-will further transform pathology and MPE. Although it is necessary to address the rarity of transdisciplinary education and training programs, MPE provides an exemplary model of integrative scientific approaches and contributes to advancements in precision medicine, therapy, and prevention.
Abstract 19489: Pharmacological Factors Associated With Congestive Heart Failure Hospital Readmission: A Case-Study Using 15,768 Heart Failure Patients From Two Health Systems
Authors: Kipp W Johnson, Khader Shameer, Alexandre Yahi, Riccardo Miotto, Doran Ricks, Jebakumar Jebakaran, Patricia Kovatch, Partho Sengupta, David L Reich, Andrew Kasarskis, Sean Pinney, Nicholas Tatonetti, Joel T Dudley
Journal: Circulation (2016)

Introduction: Reduction of congestive heart failure patient hospital readmissions remains challenging despite much effort. Pharmacotherapy is known to be associated with readmission, but past work ...
Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation
Authors: Jean-François Obadia, David Messika-Zeitoun, Guillaume Leurent, Bernard Iung, Guillaume Bonnet, Nicolas Piriou, Thierry Lefèvre, Christophe Piot, Frédéric Rouleau, Didier Carrié, Mohammed Nejjari, Patrick Ohlmann, Florence Leclercq, Christophe Saint Etienne, Emmanuel Teiger, Lionel Leroux, Nicole Karam, Nicolas Michel, Martine Gilard, Erwan Donal, Jean-Noël Trochu, Bertrand Cormier, Xavier Armoiry, Florent Boutitie, Delphine Maucort-Boulch, Cécile Barnel, Géraldine Samson, Patrice Guerin, Alec Vahanian, Nathan Mewton
Journal: New England Journal of Medicine (2018)

In patients who have chronic heart failure with reduced left ventricular ejection fraction, severe secondary mitral-valve regurgitation is associated with a poor prognosis. Whether percutaneous mitral-valve repair improves clinical outcomes in this patient population is unknown.We randomly assigned patients who had severe secondary mitral regurgitation (defined as an effective regurgitant orifice area of >20 mm2 or a regurgitant volume of >30 ml per beat), a left ventricular ejection fraction between 15 and 40%, and symptomatic heart failure, in a 1:1 ratio, to undergo percutaneous mitral-valve repair in addition to receiving medical therapy (intervention group; 152 patients) or to receive medical therapy alone (control group; 152 patients). The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for heart failure at 12 months.At 12 months, the rate of the primary outcome was 54.6% (83 of 152 patients) in the intervention group and 51.3% (78 of 152 patients) in the control group (odds ratio, 1.16; 95% confidence interval [CI], 0.73 to 1.84; P=0.53). The rate of death from any cause was 24.3% (37 of 152 patients) in the intervention group and 22.4% (34 of 152 patients) in the control group (hazard ratio, 1.11; 95% CI, 0.69 to 1.77). The rate of unplanned hospitalization for heart failure was 48.7% (74 of 152 patients) in the intervention group and 47.4% (72 of 152 patients) in the control group (hazard ratio, 1.13; 95% CI, 0.81 to 1.56).Among patients with severe secondary mitral regurgitation, the rate of death or unplanned hospitalization for heart failure at 1 year did not differ significantly between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone. (Funded by the French Ministry of Health and Research National Program and Abbott Vascular; MITRA-FR ClinicalTrials.gov number, NCT01920698 .).
Occupational Patterns in Unintentional and Undetermined Drug-Involved and Opioid-Involved Overdose Deaths — United States, 2007–2012
Authors: Laurel Harduar Morano, Andrea L. Steege, Sara E. Luckhaupt
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

The opioid epidemic affects multiple segments of the U.S. population (1). Occupational patterns might be critical to understanding the epidemic. Opioids are often prescribed for specific types of work-related injuries, which vary by occupation* (2). CDC used mortality data from the National Occupational Mortality Surveillance (NOMS) system to examine unintentional or undetermined drug overdose mortality within 26 occupation groups. This study included data from the 21 U.S. states participating in NOMS during 2007-2012.† Drug overdose mortality was compared with total mortality using proportional mortality ratios (PMRs) indirectly standardized for age, sex, race, year, and state. Mortality patterns specific to opioid-related overdose deaths were also assessed. Construction occupations had the highest PMRs for drug overdose deaths and for both heroin-related and prescription opioid-related overdose deaths. The occupation groups with the highest PMRs from methadone, natural and semisynthetic opioids, and synthetic opioids other than methadone were construction, extraction (e.g., mining, oil and gas extraction), and health care practitioners. The workplace is an integral part of life for the majority of the adult U.S. population; incorporating workplace research and interventions likely will benefit the opioid epidemic response.
Schwann Cells Augment Cell Spreading and Metastasis of Lung Cancer
Authors: Yan Zhou, Galina V. Shurin, Hua Zhong, Yuri L. Bunimovich, Baohui Han, Michael R. Shurin
Journal: Cancer Research (2018)

Although lungs are densely innervated by the peripheral nervous system (PNS), the role of the PNS in the progression of lung cancer is unknown. In this study, we report that mouse adult Schwann cells (SC), the principal glial cells of the PNS, can regulate the motility of lung cancer cells in vitro and the formation of metastases in vivo SCs promoted epithelial-to-mesenchymal transition (EMT) and the motility of two lung cancer cell lines by increasing expression of Snail and Twist in tumor cells; blocking of Snail and Twist expression abolished SC-induced motility of tumor cells. SC-derived CXCL5 was responsible for EMT in lung cancer cells, as the inhibition of CXCL5 or its receptor CXCR2 reduced SC-induced expression of Snail and Twist and reduced motility in tumor cells. CXCL5/CXCR2 binding activated the PI3K/AKT/GSK-3β/Snail-Twist signaling pathway in lung cancer cells, and the PI3K inhibitor blocked CXCL5-dependent phosphorylation of AKT and GSK-3β, reduced expression of Snail/Twist, and limited tumor cell invasiveness. SC conditioning of tumor cells prior to their injection into mice significantly increased the formation of metastases in the regional lymph nodes. In summary, SCs can regulate the CXCL5/CXCR2/PI3K/AKT/GSK-3β/Snail-Twist pathway to promote EMT, invasiveness, and metastatic potential of lung cancer cells. Our results reveal a new role of the PNS in the functional organization of the tumor microenvironment and tumor progression.Significance: This study increases our understanding of how nerves and, in particular, specific glial cells, Schwann cells, in the peripheral nervous system, may help promote tumor growth and metastasis. Cancer Res; 78(20); 5927-39. ©2018 AACR.