tbuckley/cabot-search huggingface dataset:
Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study
Authors: Lisa K Stamp, Peter T Chapman, Murray Barclay, Anne Horne, Christopher Frampton, Paul Tan, Jill Drake, Nicola Dalbeth
Journal: Annals of the Rheumatic Diseases (2017)

Objectives To determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout. Methods People, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24. Results The mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p&lt;0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups. Conclusions The majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment. Trial registration number ACTRN12611000845932
OC-166 Predictive factors of disease relapse following thiopurine withdrawal for sustained clinical remission of IBD: Abstract OC-166 Figure 1
Authors: N A Kennedy, C J Gambles, R M Musy, G R Jones, I D Arnott, J Satsangi, C W Lees
Journal: Gut (2012)

<h3>Introduction</h3> Thiopurine therapy is effective in maintaining clinical remission in IBD. However, long-term therapy is associated with an increased risk of lymphoma; therefore in clinical practice we aim to withdraw therapy after 4–5 years. Nevertheless, many patients will experience disease relapse within 12 months of drug withdrawal.<sup>1</sup> <h3>Methods</h3> The aim of the present study was to retrospectively determine the relapse rate in ulcerative colitis (UC) and Crohn9s disease (CD) following azathioprine (AZA) or mercaptopurine (MP) withdrawal and to determine factors predictive of relapse. Patients were identified by electronic case note review of an IBD research database in Edinburgh. Major inclusion criteria were AZA and/or MP therapy for a minimum of 3 years, AZA/MP withdrawn due to sustained clinical remission no steroid therapy for 6 months prior to drug withdrawal, and minimum 12 months follow-up. The primary outcome was disease relapse requiring AZA reinitiation, steroids or colectomy within 12 months of AZA/MP withdrawal, with secondary outcome assessed at 24 months. Clinical/laboratory predictors of relapse were sought. 1826 electronic records were reviewed (865 CD and 961 UC). 634 were treated with a thiopurine (348 CD and 286 UC). 74 met the strict study inclusion criteria (45 CD and 29 UC). <h3>Results</h3> CD was associated with a significantly higher risk of relapse than UC on Kaplan–Meier analysis (Abstract OC-166 figure 1, p=0.026). The moderate-severe relapse rate for 12 months was 44% for CD and 14% for UC. For 24 months, relapse rates were 60% for CD and 48% for UC. Elevated platelet count (p=0.03) and elevated white cell count (p=0.03) were predictive of relapse for UC, while no predictive factors were identified for CD. Median (range) duration of thiopurine use was 6.2 (3.4–18.7) years for CD and 6.0 (3.1–18.0) years for UC. Median duration of follow-up was 32 months for CD and 45 months for UC. Retreatment with a thiopurine after relapse was successful in 7/7 cases for UC and 18/24 for CD. <h3>Conclusion</h3> Relapse rates after withdrawal of a thiopurine are high, particularly for CD, and predicting this remains difficult. To help increase the power of this study, we are now expanding it across the UK. <h3>Competing interests</h3> None declared. <h3>Reference</h3> 1. <b>Treton</b>. <i>Clin Gastroenterol Hepatol</i> 2009;<b>7</b>:80.
Parkinson’s disease is associated with DNA methylation levels in human blood and saliva
Authors: Yu-Hsuan Chuang, Kimberly C. Paul, Jeff M. Bronstein, Yvette Bordelon, Steve Horvath, Beate Ritz
Journal: Genome Medicine (2017)

Several articles suggest that DNA methylation levels in blood relate to Parkinson's disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers ("CpGs") and clusters of CpGs (co-methylation modules) in terms of biological pathways. In a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA). Our cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 × 10–11 and cg04772575 in ABCB9 p = 4.3 × 10–10). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling. This study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships.
Pathophysiology and Treatment Considerations for Erosive Pustular Dermatosis
Authors: Omer Ibrahim, Kenneth A. Arndt, Jeffrey S. Dover
Journal: JAMA Dermatology (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 Dermatology 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 Dermatology journal
Mediastinal lymph node examination and survival in resected early-stage non-small cell lung cancer in the Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Raymond U Osarogiagbon, Xinhua Yu
Journal: Journal of Clinical Oncology (2012)

7069 Background: Pathologic nodal stage is a key prognostic factor in resectable non-small cell lung cancer (NSCLC). Mediastinal lymph node (MLN) metastasis connotes a poor prognosis. Yet, some NSCLC resections in the US do not include MLN examination. Methods: We analyzed SEER data from 1998 to 2002 to quantify the long-term survival impact of failure to examine MLN in resected NSCLC. We used Kaplan-Meier methods to compare the unadjusted survival difference between patients with, and without, MLN examination. We used Cox proportional hazards and competing risk models to serially adjust for the impact of risk factors on survival differences. Results: Sixty-two percent of patients with pathologic N0 or N1 NSCLC had no MLN examined. Men, African-Americans, patients with more advanced stage, and those who had less than pneumonectomy were less likely to have MLN examination. Five-year all-cause mortality (46.9% v 51.7%, p&lt;.001), and lung cancer-specific mortality (31.5% v 36%, p&lt;.001), rates were higher in those without MLN examination. After adjustment for potential confounders, MLN examination was associated with a 6% reduction in all-cause mortality (HR, 0.94; CI, 0.89-0.99; p=.014), and 10% reduction in lung cancer-specific mortality (HR, 0.90; 95% CI, 0.84-0.96; p=.002) rates. The excess risk in 1 year’s cohort of U.S. lung resections was 2,700 lives over 5 years. Conclusions: Failure to examine MLN was a common practice in "MLN-negative" NSCLC resections, which significantly impaired long-term survival. Efforts to understand the etiology of this quality gap, and measures to eliminate it, are warranted.
Bortezomib is a novel inducer of latent Epstein Barr virus (EBV) in EBV+ lymphoma cell lines
Authors: Vesna Kaluza, Helen J. Brown, Jeffrey Calimlim, Ren Sun, Sven De Vos
Journal: Cancer Research (2006)

1983   Epstein-Barr Virus (EBV)+ lymphomas are an important subgroup of aggressive malignant lymphomas which include lymphomas in the post-transplantation setting, Burkitt’s lymphomas (BL), AIDS-related lymphomas (ARL), and some forms of Hodgkin, T-cell, and natural killer (NK) cell lymphomas. EBV is a member of the herpes virus family, characterized by their ability to support two different life cycles: the productive “lytic” cycle leading to the production and release of new virions and the non-productive “latent” cycle. Most lymphoma cells are infected with latent EBV, and only few viral genes are expressed at low levels. Several groups of broad-acting chemical agents are able to reactivate EBV and induce herpes thymidine kinase (TK) expression in vitro and in vivo. NF-kB has been described to play a critical role in regulating the balance between latency and lytic replication of EBV. We hypothesized that the proteasome inhibitor bortezomib can be used to initiate EBV lytic antigen expression in EBV-related malignancies enabling the antiviral drug ganciclovir to kill EBV+ lymphoma cells. The human cell line P3HR-1, derived from a Burkitt’s lymphoma and latently infected with EBV, was cultured in the presence of 10 nM bortezomib for 24 hrs. The immediate early lytic phase EBV antigens ZEBRA and RTA were induced and expressed as measured by flow cytometry. The EBV-VCA and EBV-R antigens were not expressed in untreated controls but were induced as demonstrated by western blot analysis, indicating the switch to the lytic life-cycle of EBV. Histone deacetylase inhibitors are a well known group of broad-acting chemical agents able to reactivate EBV. In combination experiments, we found that bortezomib plus sodium butyrate or valproic acid act at least additive in inducing the lytic phase. An EBV transformed lymphoblastoid B-cell line (VC-1) is closer related to clinical EBV+ lymphomas in the immuno-compromised setting than HR-1. The combination treatment with 10 mM Bortezomib and 1 mM sodium butyrate for 24 hrs resulted again in enhanced EBV induction. Experiments to induce lytic phase EBV in murine xenograft models and to combine EBV induction with the nucleoside analogue ganciclovir are in progress. Reactivating EBV with proteasome inhibitors alone or in combinations with low concentrations of histone deacetylase inhibitors may be a less toxic therapeutic strategy for EBV-associated lymphomas.
Altered chromatin compaction and histone methylation drive non-additive gene expression in an interspecific Arabidopsis hybrid
Authors: Wangsheng Zhu, Bo Hu, Claude Becker, Ezgi Süheyla Doğan, Kenneth Wayne Berendzen, Detlef Weigel, Chang Liu
Journal: Genome biology (2017)

The merging of two diverged genomes can result in hybrid offspring that phenotypically differ greatly from both parents. In plants, interspecific hybridization plays important roles in evolution and speciation. In addition, many agricultural and horticultural species are derived from interspecific hybridization. However, the detailed mechanisms responsible for non-additive phenotypic novelty in hybrids remain elusive.In an interspecific hybrid between Arabidopsis thaliana and A. lyrata, the vast majority of genes that become upregulated or downregulated relative to the parents originate from A. thaliana. Among all differentially expressed A. thaliana genes, the majority is downregulated in the hybrid. To understand why parental origin affects gene expression in this system, we compare chromatin packing patterns and epigenomic landscapes in the hybrid and parents. We find that the chromatin of A. thaliana, but not that of A. lyrata, becomes more compact in the hybrid. Parental patterns of DNA methylation and H3K27me3 deposition are mostly unaltered in the hybrid, with the exception of higher CHH DNA methylation in transposon-rich regions. However, A. thaliana genes enriched for the H3K27me3 mark are particularly likely to differ in expression between the hybrid and parent.It has long been suspected that genome-scale properties cause the differential responses of genes from one or the other parent to hybridization. Our work links global chromatin compactness and H3K27me3 histone modification to global differences in gene expression in an interspecific Arabidopsis hybrid.
AB0007 Shared genetic predisposition in rheumatoid arthritis–interstitial lung disease and familial pulmonary fibrosis
Authors: PA Juge, R Borie, C Kannengiesser, S Gazal, P Revy, L Wemeau-Stervinou, MP Debray, S Ottaviani, S Marchand-Adam, N Nathan, G Thabut, C Richez, H Nunes, I Callebaut, A Justet, P Richette, H Lioté, Y Allanore, O Sand, C Dromer, RM Flipo, A Clément, J Sibilia, B Coustet, V Cottin, MC Boissier, B Wallaert, T Schaeverbeke, DLM Florence, A Frazier, C Ménard, M Soubrier, N Saidenberg, D Valeyre, S Amselem, C Boileau, B Crestani, P Dieudé
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Despite its high prevalence and mortality, little is known about the pathogenesis of RA–associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA–ILD frequently share the usual interstitial pneumonia pattern and common environmental risk factors, we hypothesized that the two diseases may share additional risk factors including FPF-linked genes. <h3>Objectives</h3> Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD. <h3>Methods</h3> We used whole-exome sequencing (WES) followed by restricted analysis of a discrete number of FPF-linked genes and performed a Burden test to assess the excess number of mutations in RA–ILD patients compared to controls. <h3>Results</h3> Among the 101 RA–ILD patients included, 12 (11.9%) had 13 WESidentified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA–ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations for RA–ILD patients (p=9.45'10-4, odds ratio [OR] 3.17 95% CI 1.53 – 6.12). Telomeres were shorter for RA-ILD patients with a TERT, RTEL1 or PARN mutation than controls (p=2.87x10-2). <h3>Conclusions</h3> Our results support the contribution of FPF-linked genes to RA–ILD susceptibility. <h3>Disclosure of Interest</h3> None declared
T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation
Authors: Brandon Kwong, Rejane Rua, Yuanyuan Gao, John Flickinger, Yan Wang, Michael J Kruhlak, Jinfang Zhu, Eric Vivier, Dorian B McGavern, Vanja Lazarevic
Journal: Nature Immunology (2017)
Screening for Colorectal Cancer
Authors: Kevin Schulman
Journal: Annals of Internal Medicine (1990)

Letters and Corrections15 August 1990Screening for Colorectal CancerKevin Schulman, MDKevin Schulman, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-113-4-333_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editors: Understanding the sensitivity and specificity of Hemoccult cards is instrumental in developing recommendations for the screening of patients for detection of colon cancer. The recent study by Allison and colleagues (1) addresses these issues, but has several serious flaws.The investigators relied on a "work-up" of Hemoccult-positive cases to determine true-positive and false-positive cases. The "work-up," however, consisted of sending physicians caring for these patients a letter recommending "a complete gastrointestinal evaluation." The letter recommended several different test modalities alone or in combination. The investigators do not report how many patients actually received a "complete evaluation," nor...References1. AllisonFeldmanTekawa JRI. Hemoccult screening in detecting colorectal neoplasm: sensitivity, specificity, and predictive value: long-term follow-up in a large group practice setting. Ann Intern Med. 1990;112:328-33. LinkGoogle Scholar2. BarryMulleyRichter MAJ. Effect of work-up strategy on the cost-effectiveness of fecal occult blood screening for colorectal cancer. Gastroenterology. 1987;93:301-10. CrossrefMedlineGoogle Scholar1. AllisonFeldmanTekawa JRI. Hemoccult screening in detecting colorectal neoplasm: sensitivity, specificity, and predictive value: long-term follow-up in a large group practice setting. Ann Intern Med. 1990;112:328-33. LinkGoogle Scholar2. BarryMulleyRichter MAJ. Effect of work-up strategy on the cost-effectiveness of fecal occult blood screening for colorectal cancer. Gastroenterology. 1987;93:301-10. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Hospital of the University of Pennsylvania Philadelphia, PA 19104 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 August 1990Volume 113, Issue 4Page: 333-333KeywordsCancer screeningColorectal cancerSpecificity Issue Published: 15 August 1990 PDF DownloadLoading ...
Abstract 122: Hyperinsulinmia Promotes Cardiac Dysfunction via Upregulation of Phosphodiesterase in Heart
Authors: Yang K Xiang
Journal: Circulation Research (2015)

Accumulating evidence suggests that hyperinsulinemia contributes to heart dysfunction. Here we show that insulin signaling is responsible for high fat diet (HFD) feeding-induced expression of phosphodiesterase 4D (PDE4D) in the myocardium of mice. The increased expression of PDE4D, in concert with reduced phosphorylation of phospholamban (PLB), promotes systolic and diastolic heart dysfunction. We revealed that insulin-mediated induction of PDE4D was dependent on β2AR-mediaed β-arrestin2-ERK pathway, which is transactivated in a GRK2-dependent fashion. Deletion of β2AR gene significantly attenuated insulin-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, as well as the upregulation of PDE4D expression, which prevented the heart dysfunction. β-arrestin2 KO mice did not display increased PDE4D expression and did not develop systolic or diastolic dysfunction following HFD. In brief, these data indicate that chronic hyperinsulinimia leads to heart dysfunction by increasing PDE4D expression via β2AR-GRK2-β-arrestin2 -ERK pathway, which suggests that β2AR signaling could be an attractive therapeutic target for preserving or improving cardiac function in subjects with insulin resistance.
GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates
Authors: Shannon E Mullican, Xiefan Lin-Schmidt, Chen-Ni Chin, Jose A Chavez, Jennifer L Furman, Anthony A Armstrong, Stephen C Beck, Victoria J South, Thai Q Dinh, Tanesha D Cash-Mason, Cassandre R Cavanaugh, Serena Nelson, Chichi Huang, Michael J Hunter, Shamina M Rangwala
Journal: Nature Medicine (2017)
Cyclosporiasis in travellers returning to the United Kingdom from Mexico in summer 2017: lessons from the recent past to inform the future
Authors: Diogo F P Marques, Claire L Alexander, Rachel M Chalmers, Peter Chiodini, Richard Elson, Joanne Freedman, Gauri Godbole, Gillian Hawkins, Janice Lo, Guy Robinson, Katherine Russell, Alison Smith-Palmer, Hilary Kirkbride
Journal: Eurosurveillance (2017)

During the summers of 2015 and 2016, the United Kingdom experienced large outbreaks of cyclosporiasis in travellers returning from Mexico. As the source of the outbreaks was not identified, there is the potential for a similar outbreak to occur in 2017; indeed 78 cases had already been reported as at 27 July 2017. Early communication and international collaboration is essential to provide a better understanding of the source and extent of this recurring situation.
ACC/AHA Guideline Update for the Management of Patients With Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction—2002: Summary Article
Authors: Eugene Braunwald, Elliott M. Antman, John W. Beasley, Robert M. Califf, Melvin D. Cheitlin, Judith S. Hochman, Robert H. Jones, Dean Kereiakes, Joel Kupersmith, Thomas N. Levin, Carl J. Pepine, John W. Schaeffer, Earl E. Smith, David E. Steward, Pierre Theroux, Raymond J. Gibbons, Elliott M. Antman, Joseph S. Alpert, David P. Faxon, Valentin Fuster, Gabriel Gregoratos, Loren F. Hiratzka, Alice K. Jacobs, Sidney C. Smith
Journal: Circulation (2002)
Particle Targeting in Complex Biological Media
Authors: Qiong Dai, Nadja Bertleff‐Zieschang, Julia A. Braunger, Mattias Björnmalm, Christina Cortez‐Jugo, Frank Caruso
Journal: Advanced Healthcare Materials (2017)

Abstract Over the past few decades, nanoengineered particles have gained increasing interest for applications in the biomedical realm, including diagnosis, imaging, and therapy. When functionalized with targeting ligands, these particles have the potential to interact with specific cells and tissues, and accumulate at desired target sites, reducing side effects and improve overall efficacy in applications such as vaccination and drug delivery. However, when targeted particles enter a complex biological environment, the adsorption of biomolecules and the formation of a surface coating (e.g., a protein corona) changes the properties of the carriers and can render their behavior unpredictable. For this reason, it is of importance to consider the potential challenges imposed by the biological environment at the early stages of particle design. This review describes parameters that affect the targeting ability of particulate drug carriers, with an emphasis on the effect of the protein corona. We highlight strategies for exploiting the protein corona to improve the targeting ability of particles. Finally, we provide suggestions for complementing current in vitro assays used for the evaluation of targeting and carrier efficacy with new and emerging techniques (e.g., 3D models and flow‐based technologies) to advance fundamental understanding in bio‐nano science and to accelerate the development of targeted particles for biomedical applications.