tbuckley/cabot-search huggingface dataset:
03.15 Identification of novel micrornas in monocytes from rheumatoid arthritis and systemic sclerosis patients using next generation sequencing
Authors: Marzena Ciechomska, Krzysztof Bonek, Anna Plaza, Piotr Gluszko, Monika Swacha, Marzena Olesinska, Bettina Haase, Vladimir Benes, Bartosz Wojtas, Bozena Kaminska, Wlodzimierz Maslinski
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Monocytes play an important role in autoimmune disease including rheumatoid arthritis (RA) or systemic sclerosis (SSc). Monocytes are the first immune cells which migrate from blood to the site of inflammation leading to tissue destruction due to enhanced proinflammatory cytokines secretion. It has been shown that abnormalities in microRNA (miRNA) expression are related to inflammatory cytokines production by T and B cells in several rheumatic diseases, however miRNAs have never been fully analysed in monocytes population. The aim of this study was to evaluate a global miRNAs profiling of monocytes from RA and SSc patients which are predicted to target proinflammatory genes. <h3>Materials and methods</h3> Total RNAs from CD14+ monocytes of 12 RA, 10 SSc patients and 10 HC were isolated. Thirty-two samples were barcoded using Small-RNA-Library-Set, pooled and sequenced on Illumina HiSeq 2000 platform. Expression of circulating miRNA-5196 was also measured in sera of 12 RA patients before and after 6 month TNF-α therapy and correlated (Spearman analysis) with disease activity score (DAS) 28. <h3>Results</h3> Based on next generation sequencing (NGS) we received 10 million reads from each sample. Following computational analysis we selected 14 specific miRNA candidates which are predicted to target inflammatory mediators out of 188 and 171 significantly changed miRNAs in monocytes of RA and SSc patients, respectively. Interestingly, miRNA-10–5p (targeting IRAK4) was 3.1-fold increased in SSc compared to RA (p&lt;0.001) and 7.8-fold (p&lt;0.001) upregulated compared to HC monocytes. Additional validation of miRNA candidates using qPCR and correlation with clinical data will be performed. Furthermore, the level of circulating miRNA-5196 was significantly elevated (p&lt;0.001, 4.7-fold) in RA compared to HC sera. There was a positive correlation between delta DAS28 following 6 months therapy and delta miRNA-5196 expression (p=0.03). <h3>Conclusions</h3> Our results identify new miRNA candidates which are predicated to regulate inflammatory genes in RA and SSc monocytes whereas miRNA-10–5p could be used as a biomarker exclusively characterising SSc. Also circulating miRNA-5196 can be used as a good predictor of anti-TNF-α treatment in RA patients. Supported by 2015/16/S/NZ6/00041 from National Science Centre, Poland and EMBO ST Fellowship.
Red flags or red herrings? Redefining the role of red flags in low back pain to reduce overimaging
Authors: Gilat L Grunau, Ben Darlow, Timothy Flynn, Kieran O’Sullivan, Peter B O’Sullivan, Bruce B Forster
Journal: British Journal of Sports Medicine (2017)

Low back pain is the leading cause of years lived with disability and the second most common reason for a physician visit.1 Although its prevalence has not changed, imaging for low back pain and the cost of its management have continued to increase. For example, in a US study 9.6% of all patients with low back pain had a CT or MRI in 2006 compared with 3.2% in 2002.1 

Lumbar imaging is of low yield in the general population presenting with low back pain, as the majority of cases are self-limited and benign. In a previous editorial,2 we discussed the negative effects of inappropriate imaging such as subsequent additional downstream testing, additional imaging, invasive diagnostic procedures and unwarranted patient fear and anxiety leading to poorer outcomes, with concomitant cost and radiation exposure.

Lumbar imaging is indicated when serious pathology is suspected and red flags are an accepted method for identifying when such pathology …
Hepatitis C virus seroprevalence and prevalence of chronic infection in the adult population in Ireland: a study of residual sera, April 2014 to February 2016
Authors: Patricia Garvey, Brian O'Grady, Geraldine Franzoni, Maeve Bolger, Katie Irwin Crosby, Jeff Connell, Deirdre Burke, Cillian De Gascun, Lelia Thornton
Journal: Eurosurveillance (2017)

Robust data on hepatitis C virus (HCV) population prevalence are essential to inform national HCV services. In 2016, we undertook a survey to estimate HCV prevalence among the adult population in Ireland. We used anonymised residual sera available at the National Virus Reference Laboratory. We selected a random sample comprising persons ≥ 18 years with probability proportional to the general population age-sex distribution. Anti-HCV and HCV Ag were determined using the Architect anti-HCV and HCV Ag assays. Fifty-three of 3,795 specimens were seropositive (age-sex-area weighted seroprevalence 0.98% (95% confidence interval (CI): 0.73–1.3%)). Thirty-three specimens were HCV-antigen and antibody-positive (age-sex-area weighted prevalence of chronic infection 0.57% (95% CI: 0.40–0.81%)). The prevalence of chronic infection was higher in men (0.91%; 95% CI: 0.61–1.4%), in specimens from the east of the country (1.4%; 95%CI: 0.99–2.0%), and among persons aged 30–39 years and 40–49 years (1.1% (95% CI: 0.59–2.0%) and 1.1% (95% CI: 0.64–1.9%) respectively). Ireland ranks at the lower end of the spectrum of prevalence of chronic HCV infection internationally. Men born between 1965 and 1984 from the east of the country have the highest rate of chronic HCV infection.
Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab.
Authors: Margaret K. Callahan, Christine E. Horak, Michael A. Curran, Travis Hollman, David A. Schaer, Jianda Yuan, Alexander M. Lesokhin, Shigehisa Kitano, Quan Hong, Charlotte Eielson Ariyan, Klaus J. Busam, William Feely, Maria Jure-Kunkel, Joseph Grosso, Jason S. Simon, Alan J. Korman, Jon M. Wigginton, Ashok Kumar Gupta, Mario Sznol, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2013)

3003^ Background: Nivolumab and ipilimumab are fully human monoclonal antibodies that block the immune checkpoint receptors PD-1 and CTLA-4, respectively. In a multi-cohort, phase I study of nivolumab/ipilimumab combination therapy in melanoma patients (pts), objective response rates up to 47% were observed (NCT01024231). Putative predictive biomarkers from peripheral blood (PB) or tumor, including tumor PD-L1 expression, absolute lymphocyte count (ALC) and PB myeloid derived suppressor cells (MDSC) were evaluated. Pharmacodynamic changes in activated and effector T cells were also assessed. Methods: Tumor PD-L1 membrane expression was assessed in archival FFPE specimens by immunohistochemistry (28-8 PD-L1 antibody). ALC was measured in serial PB samples; changes in the percentage, number and phenotype of activated CD4 + and CD8 + T cells and MDSC were characterized by flow cytometry. Results: PD-L1 expression was seen in 37% (10/27) of pts, using a cut-off of 5% tumor cell membrane staining. Objective responses (OR) were seen in pts with both PD-L1 negative (8/17) and PD-L1 positive (4/10) tumors. Relative to baseline, a rise in ALC was not detected, but phenotypic changes in PB T-cell subsets, including increases in the percentage of CD4 and CD8 expressing HLA-DR, ICOS and/or Ki67 were seen with combination therapy. Low ALC (&lt;1.0 at wk 6-7) did not preclude OR as 3 of 12 pts with low ALC responded. Of pts evaluated, OR with ≥80% reduction in tumor burden at 12 wk were seen in pts with a low frequency of pretreatment PB MDSC (3/7) but no OR were seen in pts with high MDSC (0/6). Conclusions: In this small subset of pts,OR were seen independent of PD-L1 or ALC status in contrast to prior observations with nivolumab or ipilimumab, respectively. Thus, the immune response generated by combination therapy may have unique features compared to either monotherapy. The relationship between frequency of PB MDSC and reduction in tumor burden will be further explored. Further efforts in this study and in future phase III randomized studies will investigate these and other phenotypic changes in immune cell populations and their relationship to patterns of clinical activity. Clinical trial information: NCT01024231.
AODTH-002 Full thickness endoscopic colonic resection?– data from the uk ftrd registry
Authors: A Castro Silva, P Boger, I Rahman, P Bhandari, S Green, J Martin, S Pugh, N Suzuki, S Ishaq, P Patel
Journal: Endoscopy (2017)

<h3>Introduction</h3> Attempts to endoscopically resect non-lifting adenomas, subepithelial tumours, and T1 cancers are very challenging and are traditionally in the realm of surgery. Here we report the first multi-centre UK experience of colonic resections of these lesions using a novel endoscopic full thickness resection device (FTRD) <h3>Method</h3> Data on consecutive patients who underwent endoscopic full thickness resection (eFTR) at 6 UK institutions from April 2015 – February 2017 were prospectively analysed. The procedure was undertaken using the, over-the-scope FTRD. Main outcome measures were technical success, total procedure times, histological confirmation of full thickness, R0 resection, technical failures and adverse events. <h3>Results</h3> A total of 29 patients underwent eFTR, of which 14 were non-lifting adenomas, 8 T1 polyps and 7 subepithelial tumours. Procedure was technically successful in 89.7% (26/29) cases. The mean age was 68.7 years (39–93 years), median procedure time 38 min (10–80 mins), and median specimen size of 22 mm (13–30 mm). Histology confirmed full thickness resection in 96.2% (25/26) cases, with an R0 resection in 73.1% (19/26) cases. The institution with the greatest number of FTRD cases had a R0 resection of 81.3% (13/16). Technical difficulties occurred in 38.5% (10/26) cases; 5 due to snare failure (R0 still achieved in 4/5 by use of further snare after deployment of device clip), 2 lesions could not be introduced into the FTRD cap, 2 lesions slipped from forceps during clip deployment, and 1 lesion could not be reached with FRTD device, due to sigmoid diverticular segment. There were no cases of immediate or delayed bleeding or perforation. <h3>Conclusion</h3> eFTR using the FTRD system is a promising technique allowing full thickness resection of difficult polyps that would otherwise require surgery. Our data demonstrates that it is a safe and effective technique requiring a short but significant learning curve before outcomes similar to European case series are achieved. <h3>Reference</h3> . Arthur Schmidt, et al. Endoscopic full-thickness resection in the colorectum with a novel over-the-scope device: first experience. Endoscopy2015; 47(08): 719–725 <h3>Disclosure of Interest</h3> None Declared
Abstract 10: MicroRNA 17 in Angiogenesis: Lessons Learned From Immobilized Vascular Endothelial Growth Factor
Authors: Sezin Aday, Marie Besnier, Janet Zoldan, Jaimy Saif, Tiago Santos, Laura Carreto, Liliana Bernardino, Robert Langer, Costanza Emanueli, Lino Ferreira
Journal: Circulation Research (2015)

Several pre-clinical and clinical studies are exploring the therapeutic effect of cell-based therapies in ischemic diseases, including Peripheral Artery Disease (PAD). Unfortunately, most of the cells (more than 80%) die few days after delivery. We postulate that better understanding of VEGF Biology might be important for the design of more effective pro-survival strategies. Release of VEGF from ECM activates a carcinogenic program since it triggers vasculogenesis, tumor growth and metastasis. Contrarily, immobilized VEGF might have all the properties of soluble VEGF without inducing a carcinogenic program. Thus, identification of downstream players such as miRNAs mediating this process might be important. Herein, we evaluated therapeutic effect of miR-17 downregulation, which mediates the effect of immobilized VEGF both in vitro and in vivo. We recently showed that conjugated VEGF modulates cell activity by decreasing the expression miR-17 both in vitro and in vivo. In the present study, cell survival and angiogenesis were evaluated firstly in vitro using endothelial cells (ECs) transfected with antagomiR-17 to mimic the down-regulation of miR-17 by conjugated VEGF. AntagomiR-17 increased EC survival at least 1.5 times (n=6) compared to pro-angiogenic miRNAs reported in the literature (e.g. miR-424 and miR-132) and sprout formation on Matrigel at least 2 times (n=5) compared to all groups. The effect of antagomiR-17 was more pronounced under hypoxia conditions. In vivo, antagomiR-17 accelerated hemodynamic recovery of the whole limb (n=12) in unilateral limb ischemia obtained by occlusion of the left femoral artery. Blood flow recovery evaluated by Laser Doppler analysis was significantly higher 21 days after surgery in antagomiR-17 group compared to all other groups. Immunohistochemical analyses showed an increase in the capillary density of skeletal muscle in antagomiR-17 condition. In order to determine the gene target and potential pathway involved in the biological effect of antagomiR-17, next generation mRNA sequencing was performed. In conclusion, here we show the potential and underlying molecular mechanism of antagomiR-17 treatment in endothelial cell survival and angiogenesis both in vitro and in vivo.
05.10 Comparison of cd4+ and b lymphocyte expression quantitative trait associations at ra risk loci in untreated early arthritis patients
Authors: Nishanthi Thalayasingam, Jonathan Massey, Amy E Anderson, Nisha Nair, Alex Clark, Andrew Skelton, Dennis W Lendrem, Julie Diboll, Louise N Reynard, Heather J Cordell, Stephen Eyre, Anne Barton, John D Isaacs, Arthur G Pratt
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. Genome-wide association scans (GWAS) have shown common variants at approximately 100 genetic loci to be associated with RA. Single nucleotide polymorphisms (SNPs) are typically intergenic and causative disease genes remain ill-defined. Examining how RA-associated SNPs influence gene expression in relevant biological contexts will begin to address this. <h3>Methods</h3> Patients naïve to immunomodulatory therapy attending the Newcastle Early Arthritis Clinic donated RNA and DNA, extracted from purified peripheral blood CD4<sup>+</sup> T- and B-lymphocytes within 4 hours of blood draw. Detailed baseline and longitudinal clinical data were recorded for all participants, each followed up for &gt;1 year. Genotyping and global gene expression measurement was carried out using the Illumina Human CoreExome array, and either HT12v4 or WG6v3 BeadChip arrays, respectively, and expression data was batch-corrected and normalised using standard algorithms. Data from both cell types were analysed using the R package. Variants in linkage disequilibrium (LD) with 100 confirmed RA- SNPs (r<sup>2</sup> &gt;0.8) were included in analyses, seeking evidence of cis- and trans- eQTLs according to whether associated probes were or were not within 4 MB of these LD blocks. <h3>Results</h3> Cell-type specific gene expression data from 351 genotyped white Caucasian early arthritis patients were available for analysis (including paired CD4+/B lymphocyte data for 160 of these). Genes subject to <i>cis</i> eQTL effects common to both CD4+ and B-lymphocytes at RA risk loci included <i>FADS1</i>, <i>FCRL3</i>, <i>PIPL3, ORMDL</i>3 and <i>GSDMB. Cis</i> eQTLs acting on <i>BLK</i>, <i>IKZF3</i> and <i>PADI4</i> were, by contrast, unique to CD4+ lymphocytes in this population, and equivalent B-lymphocyte-specific effects were seen for <i>IRF5</i> and <i>FAM167.</i> Evidence emerged that the 12q13 RA risk variant regulates <i>STX1B</i> gene expression on chromosome 7 of B-lymphocytes, but no <i>trans</i> eQTLs achieved experiment-wide significance thresholds in CD4+ lymphocytes. Linear modelling could not identify a significant influence of biological co-variates (diagnosis, systemic inflammation, age) upon eQTL effect sizes. <h3>Conclusions</h3> We present the first detailed eQTL analysis in the pathophysiologically relevant setting of early arthritis lymphocytes, free of confounding immunomodulatory treatment. The findings should help refine understanding of candidate causal genes in RA pathogenesis.
Recommendations for HIV Screening of Gay, Bisexual, and Other Men Who Have Sex with Men — United States, 2017
Authors: Elizabeth A. DiNenno, Joseph Prejean, Kathleen Irwin, Kevin P. Delaney, Kristina Bowles, Tricia Martin, Amrita Tailor, Gema Dumitru, Mary M. Mullins, Angela B. Hutchinson, Amy Lansky
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

CDC's 2006 recommendations for human immunodeficiency virus (HIV) testing state that all persons aged 13-64 years should be screened for HIV at least once, and that persons at higher risk for HIV infection, including sexually active gay, bisexual, and other men who have sex with men (MSM), should be rescreened at least annually (1). Authors of reports published since 2006, including CDC (2), suggested that MSM, a group that is at highest risk for HIV infection, might benefit from being screened more frequently than once each year. In 2013, the U.S. Preventive Services Task Force (USPSTF) found insufficient evidence to specify an HIV rescreening interval but recommended annual screening for MSM as a reasonable approach (3). However, some HIV providers have begun to offer more frequent screening, such as once every 3 or 6 months, to some MSM. A CDC work group conducted a systematic literature review and held four expert consultations to review programmatic experience to determine whether there was sufficient evidence to change the 2006 CDC recommendation (i.e., at least annual HIV screening of MSM in clinical settings). The CDC work group concluded that the evidence remains insufficient to recommend screening more frequently than at least once each year. CDC continues to recommend that clinicians screen asymptomatic sexually active MSM at least annually. Each clinician can consider the benefits of offering more frequent screening (e.g., once every 3 or 6 months) to individual MSM at increased risk for acquiring HIV infection, weighing their patients' individual risk factors, local HIV epidemiology, and local testing policies.
Setting the Record Straight on FDA Approvals in Oncology—Reply
Authors: Scott R. Bauer, Rita F. Redberg
Journal: JAMA Internal Medicine (2017)

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Two-by-Two Factorial Cancer Treatment Trials: Is Sufficient Attention Being Paid to Possible Interactions?
Authors: Boris Freidlin, Edward L. Korn
Journal: JNCI Journal of the National Cancer Institute (2017)

Factorial 2 × 2 designs can be used to combine evaluation of two treatments in a single study. The standard analysis approach is based on a factorial analysis that evaluates each treatment by pooling data over the other treatment. This approach relies on the assumption that the effect of each treatment is not substantially affected by the other treatment. In many oncology settings, this no-interaction assumption cannot be adequately supported at the time the trial is designed. In this Commentary, we consider current practices for the design and analysis of factorial trials by performing a survey of factorial treatment trials published in the Journal of the National Cancer Institute, Journal of Clinical Oncology, and the New England Journal of Medicine (2007–2016). The protocol-specified sample size was derived based on the factorial (pooled) analysis in 96.7% of the 30 identified trials, and the factorial analysis was specified as the primary analysis in 90.0% of these identified trials. An interaction complicating study interpretation was reported in 16.7% of the trials. We provide recommendations for matching the trial analysis and design to the study goals to account for possible interaction and illustrate the recommendations on the data from several published trials.
Detecting and Attributing Health Burdens to Climate Change
Authors: Kristie L. Ebi, Nicholas H. Ogden, Jan C. Semenza, Alistair Woodward
Journal: Environmental Health Perspectives (2017)

Detection and attribution of health impacts caused by climate change uses formal methods to determine a) whether the occurrence of adverse health outcomes has changed, and b) the extent to which that change could be attributed to climate change. There have been limited efforts to undertake detection and attribution analyses in health.Our goal was to show a range of approaches for conducting detection and attribution analyses.Case studies for heatwaves, Lyme disease in Canada, and Vibrio emergence in northern Europe highlight evidence that climate change is adversely affecting human health. Changes in rates and geographic distribution of adverse health outcomes were detected, and, in each instance, a proportion of the observed changes could, in our judgment, be attributed to changes in weather patterns associated with climate change.The results of detection and attribution studies can inform evidence-based risk management to reduce current, and plan for future, changes in health risks associated with climate change. Gaining a better understanding of the size, timing, and distribution of the climate change burden of disease and injury requires reliable long-term data sets, more knowledge about the factors that confound and modify the effects of climate on health, and refinement of analytic techniques for detection and attribution. At the same time, significant advances are possible in the absence of complete data and statistical certainty: there is a place for well-informed judgments, based on understanding of underlying processes and matching of patterns of health, climate, and other determinants of human well-being. https://doi.org/10.1289/EHP1509.
Variable MIBG Activity in the Same Renal Cyst
Authors: Xiaofei Zhao, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2017)

Abstract A series of 123 I-MIBG scanning was performed in a 33-year-old woman with a history of ganglioneuroblastoma and a known left renal cyst. The initial studies did not reveal any MIBG activity in the renal cyst. However, increased MIBG activity was noted in the same renal cyst in the subsequent follow-up scans.