bluuebunny/crossref_metadata_2025_split huggingface dataset:
The relationships between IFNL4 genotype, intrahepatic interferon‐stimulated gene expression and interferon treatment response differs in HCV‐1 compared with HCV‐3
Authors: Holmes J. A. , Congiu M. , Bonanzinga S. , Sandhu M. K. , Kia Y. H. , Bell S. J. , Nguyen T. , Iser D. M. , Visvanathan K. , Sievert W. , Bowden D. S. , Desmond P. V. , Thompson A. J. 
Published: June 2015

SummaryBackgroundThe biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV‐1 is thought to involve differential intrahepatic interferon‐stimulated gene expression. HCV‐3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon‐stimulated gene expression in HCV‐3.AimWe evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon‐stimulated gene expression, according to HCV genotype.MethodsHCV‐1 and HCV‐3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt‐PCR.ResultsTwo hundred and fifty‐nine patients were identified: 55% HCV‐1, 45% HCV‐3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r2 = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV‐3 vs. HCV‐1 (HCV‐3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV‐1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV‐1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV‐3 vs. HCV‐1 (P‐value for interaction = 0.046), with levels of interferon‐stimulated gene expression being highest in HCV‐1 patients who carried a poor‐response IFNL4 genotype.ConclusionsThe relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon‐stimulated gene expression differs between HCV‐1 and HCV‐3. These data suggest fundamental differences in host–virus interactions according to HCV genotype.
Undetectable anti‐TNF drug levels in patients with long‐term remission predict successful drug withdrawal
Authors: Ben‐Horin S. , Chowers Y. , Ungar B. , Kopylov U. , Loebstein R. , Weiss B. , Eliakim R. , Del Tedesco E. , Paul S. , Roblin X. 
Published: June 2015

SummaryBackgroundLow drug levels are associated with emerging loss of response to anti‐TNF. However, this may not be the case in patients with long‐term remission.AimTo investigate the outcome of anti‐TNF discontinuation in patients with long‐term remission and incidental undetectable drug levels.MethodsA retrospective cohort study examining the duration of relapse‐free survival in IBD patients in remission who discontinued infliximab or adalimumab having undetectable drug levels.ResultsForty eight patients who discontinued anti‐TNF while in remission and had available drug levels were identified in two centres in France and Israel (infliximab‐treated 35, adalimumab‐13, Crohn's disease 30, ulcerative colitis 18, mean treatment duration of 22.7 ± 12.4 months). Endoscopy/MRE before stopping showed absence of active inflammation in 40/42 (95%) of evaluated patients, while inflammatory biomarkers (CRP and/or Calprotectin) were completely normal in only 31/48 (65%) of patients. During 12 months median follow‐up, relapse occurred in 16/20 (80%) of patients who stopped anti‐TNF while having measurable drug levels compared with 9/28 (32%) of patients who had undetectable drug levels (OR: 8.4, 95% CI: 2.2–32, P = 0.002). Relapse‐free survival after anti‐TNF cessation was significantly longer in patients with absent drug compared to those with detectable drug (P < 0.001, log rank test). On multivariate analysis, a patient's decision to stop therapy was weakly associated and abnormal inflammatory biomarkers and detectable drug levels were both strongly and independently associated with a higher risk of relapse after drug discontinuation.ConclusionIncidental finding of undetectable anti‐TNF drug levels in patients with stable long‐term deep remission may identify a subset of patients whose clinical remission is no longer dependent on anti‐TNF treatment.
Social presence in the 21st century: An adjustment to the Community of Inquiry framework
Authors: Armellini Alejandro , De Stefani Magdalena 
Published: June 2015

AbstractThe Community of Inquiry framework, originally proposed by Garrison, Anderson and Archer, identifies teaching, social and cognitive presences as central to a successful online educational experience. This paper presents the findings of a study conducted in Uruguay between 2007 and 2010. The research aimed to establish the role of cognitive, social and teaching presences in the professional development of 40 English language teachers on continuous professional development programmes delivered in blended learning settings. The findings suggest that teaching presence and cognitive presence have themselves “become social.” The research points to social presence as a major lever for engagement, sense‐making and peer support. Based on the patterns identified in the study, this paper puts forward an adjustment to the Community of Inquiry framework, which shows social presence as more prominent within the teaching and cognitive constructs than the original version of the framework suggests.
Immunocytochemical detection of ERG expression in exfoliated urinary cells identifies with high specificity patients with prostate cancer
Authors: Pal Raj P. , Kockelbergh Roger C. , Pringle John Howard , Cresswell Lara , Hew Roger , Dormer John P. , Cooper Colin , Mellon John Kilian , Barwell Julian G. , Hollox Edward J. 
Published: June 2015

ObjectivesTo evaluate the immunocytochemical detection of ERG protein in exfoliated cells as a means of identifying patients with prostate cancer (PCa) before prostate biopsy.Materials and MethodsUrine samples (30 mL) were collected after digital rectal examination (DRE) from 159 patients with an elevated age‐specific prostate‐specific antigen (PSA) and/or an abnormal DRE who underwent prostate biopsy. In all cases, exfoliated urinary cells from half of the urine sample underwent immunocytochemical assessment for ERG protein expression. Exfoliated cells in the remaining half underwent assessment of TMPRSS2:ERG status using either nested reverse‐transcriptase (RT)‐PCR (151 cases) or fluorescence in situ hybridization (FISH; eight cases). Corresponding tissue samples were evaluated using FISH to determine chromosomal gene fusion tissue status and immunohistochemistry (IHC) to determine ERG protein expression. Results were correlated with clinicopathological variables.ResultsThe sensitivity and specificity of urinary ERG immunocytochemistry (ICC) for PCa were 22.7 and 100%, respectively. ERG ICC results correlated with advanced tumour grade, stage and higher serum PSA. In comparison, urine TMPRSS2:ERG transcript analysis had 27% sensitivity and 98% specificity for PCa detection. On tissue IHC, ERG staining was highly specific for PCa. In all, 52% of cancers harboured foci of ERG staining; however, only 46% of cancers that were found to have ERG overexpression were positive on urine ICC. The ERG ICC results showed strong concordance with urinary RT‐PCR and FISH, and tissue IHC and FISH.ConclusionThis is the first study to show that cytological gene fusion detection using ICC is feasible and identifies patients with adverse disease markers. ERG ICC was highly specific, but this technique was less sensitive than RT‐PCR.
Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases
Authors: Kalra Sarathi , Atkinson Bradley J. , Matrana Marc Ryan , Matin Surena F. , Wood Christopher G. , Karam Jose A. , Tamboli Pheroze , Sircar Kanishka , Rao Priya , Corn Paul G. , Tannir Nizar M. , Jonasch Eric 
Published: June 2015

ObjectivesTo identify the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) treated with either pazopanib or sunitinib and assess whether PM is an independent prognostic variable in the current therapeutic environment.Patients and MethodsA retrospective review of patients with mRCC in an outpatient clinic was carried out for the period January 2006 to November 2011. Patient characteristics, including demographics, laboratory data and outcomes, were analysed. Baseline characteristics were compared using chi‐squared and t‐tests and overall survival (OS) and cancer‐specific survival (CSS) rates were estimated using Kaplan–Meier methods. Predictors of OS were analysed using Cox regression.ResultsA total of 228 patients were reviewed, of whom 44 (19.3%) had PM and 184 (81.7%) had metastases to sites other than the pancreas. The distribution of baseline characteristics was equal in both groups, with the exception of a higher incidence of previous nephrectomy, diabetes and number of metastatic sites in the PM group. Four patients had isolated PM, but the majority of patients (68%) with PM had at least three different organ sites of metastases, as compared with 29% in patients without PM (P < 0.01). The distribution of organ sites of metastases was similar, excluding the pancreas, in those with and those without PM (P > 0.05). The median OS was 39 months (95% confidence interval [CI] 24–57, hazard ratio 0.66, 95% CI 0.42–0.94; P = 0.02) for patients with PM, compared with 26 months (95% CI 21–31) for patients without PM (P < 0.01). CSS was 42 months (95% CI 30–57) in the PM group and 27 months (95% CI 22–33) in the control group (P = 0.05).ConclusionsDespite a higher number of affected organ sites in the PM cohort, mRCC behaviour in this cohort appears to be more indolent, as demonstrated by a higher median OS. These findings suggest that host or tumour features associated with PM may represent a less aggressive tumour phenotype.
Novel fluorescence in situ hybridization‐based definition of bacille Calmette‐Guérin (BCG) failure for use in enhancing recruitment into clinical trials of intravesical therapies
Authors: Kamat Ashish M. , Willis Daniel L. , Dickstein Rian J. , Anderson Rooselvelt , Nogueras‐González Graciela , Katz Ruth L. , Wu Xifeng , Barton Grossman H. , Dinney Colin P. 
Published: June 2015

ObjectivesTo present a molecular definition of bacille Calmette‐Guérin (BCG) failure that incorporates fluorescence in situ hybridization (FISH) testing to predict BCG failure before it becomes clinically evident, which can be used to enhance trial designs for patients with non‐muscle‐invasive bladder cancer.Patients and MethodsWe used data from 143 patients who were followed prospectively for 2 years during intravesical BCG therapy, during which time FISH assays were collected and correlated to clinical outcomes.ResultsOf the 95 patients with no evidence of tumour at 3‐month cystoscopy, 23 developed tumour recurrence and 17 developed disease progression by 2 years. Patients with a positive FISH test at both 6 weeks and 3 months were more likely to develop tumour recurrence (17/37 patients [46%] and 16/28 patients [57%], respectively) than patients with a negative FISH test (6/58 patients [10%] and 3/39 patients [8%], respectively; both P < 0.001). Using hazard ratios for recurrence with positive 6‐week and 3‐month FISH results, we constructed clinical trial scenarios whereby patients with a negative 3‐month cystoscopy and positive FISH result could be considered to have ‘molecular BCG failure’ and could be enrolled in prospective, randomized clinical trials comparing BCG therapy (control) with an experimental intravesical therapy.ConclusionsPatients with positive early FISH and negative 3‐month cystoscopy results can be considered to have molecular BCG failure based on their high rates of recurrence and progression. This definition is intended for use in designing clinical trials, thus potentially allowing continued use of BCG as an ethical comparator arm.
Variability of inter‐observer agreement on feasibility of partial nephrectomy before and after neoadjuvant axitinib for locally advanced renal cell carcinoma (RCC): independent analysis from a phase II trial
Authors: Karam Jose A. , Devine Catherine E. , Fellman Bryan M. , Urbauer Diana L. , Abel E. Jason , Allaf Mohamad E. , Bex Axel , Lane Brian R. , Thompson R. Houston , Wood Christopher G. 
Published: June 2015

ObjectiveTo evaluate how many patients could have undergone partial nephrectomy (PN) rather than radical nephrectomy (RN) before and after neoadjuvant axitinib therapy, as assessed by five independent urological oncologists, and to study the variability of inter‐observer agreement.Patients and MethodsPre‐ and post‐systemic treatment computed tomography scans from 22 patients with clear cell renal cell carcinoma in a phase II neoadjuvant axitinib trial were reviewed by five independent urological oncologists. R.E.N.A.L. nephrometry score and κ statistics were calculated.ResultsThe median R.E.N.A.L. nephrometry score changed from 11 before treatment to 10 after treatment (P = 0.002). Five tumours with moderate complexity before axitinib treatment remained moderate complexity after treatment. Of 17 tumours with high complexity before axitinib treatment, three became moderate complexity after treatment. The overall κ statistic was 0.611. Moderate‐complexity κ was 0.611 vs a high‐complexity κ of 0.428. Before axitinib treatment the κ was 0.550 vs 0.609 after treatment. After treatment with axitinib, all five reviewers agreed that only five patients required RN (instead of eight before treatment) and that 10 patients could now undergo PN (instead of three before treatment). The odds of PN feasibility were 22.8‐times higher after treatment with axitinib.ConclusionsThere is considerable variability in inter‐observer agreement on the feasibility of PN in patients treated with neoadjuvant targeted therapy. Although more patients were candidates for PN after neoadjuvant axitinib therapy, it remains difficult to identify these patients a priori.
Clearance of primary necrotic cells by non‐professional phagocytes
Authors: Schwegler Manuela , Wirsing Anna M. , Dollinger Alena J. , Abendroth Benjamin , Putz Florian , Fietkau Rainer , Distel Luitpold V. 
Published: June 2015

Background informationHomotypic internalisation of tumour cells has frequently been observed in tumour tissue sections. Events of non‐professional phagocytosis, however, may also occur in normal tissue if the number of dying cells exceeds the phagocytic capacity of professional phagocytes such as macrophages and dendritic cells. The aim of this study was to investigate the molecular background of non‐professional phagocytosis of primary necrotic cells by neighbouring tumour cells and normal skin fibroblasts.ResultsWe demonstrate that homotypic and heterotypic uptake of necrotic cells is a feature common to various cell types. Investigating critical stimuli of necrotic cell clearance we found that non‐professional phagocytes require cytoskeleton rearrangement, recognition of phosphatidylserine and GTPase activity of dynamin II, which is normally engaged in endocytosis. Additionally, we have observed an accumulation of adhesion molecule E‐cadherin, phosphorylated actin‐linker protein ezrin, lysosomal‐associated membrane protein 1 and microtubule‐associated protein 1 light chain 3 at the site of engulfment. Loss of membrane integrity and an increase in the intracellular level of heat‐shock protein 70 in the necrotic cells have also been observed.ConclusionsOur results shed light on the mechanism of necrotic cell removal by tumour cells and normal skin fibroblasts in vitro. It is reasonable to assume that this process has a physiological relevance in inflammation and autoimmune disease in normal tissue as well as in tumours regarding immune cell infiltration. We conclude that necrotic cell clearance by non‐professional phagocytes contributes to the phagocytic activity by macrophages and that this process may prevent release of proinflammatory damage‐associated molecular pattern molecules.
Possible role of cortactin phosphorylation by protein kinase Cα in actin‐bundle formation at growth cone
Authors: Yamada Hiroshi , Kikuchi Tatsuya , Masumoto Toshio , Wei Fan‐Yan , Abe Tadashi , Takeda Tetsuya , Nishiki Teiichi , Tomizawa Kazuhito , Watanabe Masami , Matsui Hideki , Takei Kohji 
Published: June 2015

Background InformationCortactin contributes to growth cone morphogenesis by forming with dynamin, ring‐shaped complexes that mechanically bundle and stabilise F‐actin. However, the regulatory mechanism of cortactin action is poorly understood.ResultsImmunofluorescence microscopy revealed that protein kinase C (PKC) α colocalises with cortactin at growth cone filopodia in SH‐SY5Y neuroblastoma cells. PKC activation by phorbol 12‐myristate 13‐acetate causes cortactin phosphorylation, filopodial retraction and F‐actin‐bundle loss. Moreover, PKCα directly phosphorylates cortactin in vitro at S135/T145/S172, mitigating both cortactin's actin‐binding and actin‐crosslinking activity, whereas cellular expression of a phosphorylation‐mimetic cortactin mutant hinders filopodial formation with a significant decrease of actin bundles.ConclusionsOur results indicate that PKC‐mediated cortactin phosphorylation might be implicated in the maintenance of growth cone.
hMOF (human males absent on the first), an oncogenic protein of human oral tongue squamous cell carcinoma, targeting EZH2 (enhancer of zeste homolog 2)
Authors: Li Qihong , Sun Haiyan , Shu Yao , Zou Xuan , Zhao Yantao , Ge Cheng 
Published: June 2015

AbstractObjectivesMOF (males absent on the first) is a histone acetyltransferase belonging to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. In mammals, MOF plays critical roles in transcription activation by acetylating histone H4 at K16. Human MOF (hMOF) essentially participates in behaviour of several human cancers. However, its role in human oral tongue squamous cell carcinoma (OTSCC) remains elusive, but we propose that hMOF regulates OTSCC cell population growth.Materials and methodsReal time PCR and western blot analysis were applied, and it was found that hMOF level was up‐regulated in human OTSCC. High hMOF expression predicted poor overall and disease‐free survival. hMOF knockdown attenuated OTSCC cell growth and transformation.ResultsEZH2 (enhancer of zeste homolog 2) was up‐regulated in human OTSCC tissues and its level positively correlated with level of hMOF. hMOF knockdown inhibited EZH2 expression by reducing its promoter activity. Moreover, we have demonstrated that EZH2 was critically essential for function of hMOF in human OTSCC.ConclusionsHuman males absent on the first regulated OSTCC growth through EZH2, thus EZH2 may serve as a candidate for anti‐OTSCC therapy.
Prescribing practices and clinical predictors of glucose‐lowering therapy within the first year in people with newly diagnosed Type 2 diabetes
Authors: Mor A. , Berencsi K. , Svensson E. , Rungby J. , Nielsen J. S. , Friborg S. , Brandslund I. , Christiansen J. S. , Vaag A. , Beck‐Nielsen H. , Sørensen H. T. , Thomsen R. W. 
Published: June 2015

AbstractAimTo examine prescribing practices and predictors of glucose‐lowering therapy within the first year following diagnosis of Type 2 diabetes mellitus in a clinical care setting.MethodsWe followed people enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort from outpatient hospital clinics and general practices throughout Denmark in 2010–2013. We used Poisson regression to compute age‐ and gender‐adjusted risk ratios (RRs).ResultsAmong 1158 new Type 2 diabetes mellitus patients, 302 (26%) did not receive glucose‐lowering therapy within the first year, 723 (62%) received monotherapy [685 (95%) with metformin], and 133 (12%) received more than one drug. Predictors of receiving any vs. no therapy and combination vs. monotherapy were: age < 40 years [RR: 1.29 (95% CI: 1.16–1.44) and 3.60 (95% CI: 2.36–5.50)]; high Charlson Comorbidity Index [RRs: 1.20 (95% CI: 1.05–1.38) and 2.08 (95% CI: 1.16–3.72)]; central obesity [RRs: 1.23 (95% CI: 1.04–1.44) and 1.93 (95% CI: 0.76–4.94)]; fasting blood glucose of ≥ 7.5 mmol/l [RRs: 1.25 (95% CI: 1.10–1.42) and 1.94 (95% CI: 1.02–3.71)]; and HbA1c ≥ 59 mmol/mol (≥ 7.5%) [RR: 1.26 (95% CI: 1.20–1.32) and 2.86 (95% CI: 1.97–4.14)]. Weight gain ≥ 30 kg since age 20, lack of physical exercise and C–peptide of < 300 pmol/l also predicted therapy.ConclusionsComorbidity, young age, central obesity and poor baseline glycaemic control are important predictors of therapy one year after Type 2 diabetes mellitus debut.
Clinical profile of diabetic ketoacidosis in tertiary hospitals in China: a multicentre, clinic‐based study
Authors: Xu Y. , Bai J. , Wang G. , Zhong S. , Su X. , Huang Z. , Chen G. , Zhang J. , Hou X. , Yu X. , Lu B. , Wang Y. , Li X. , Hu H. , Zhang C. , Liang Y. , Shaw J. , Wu X. 
Published: June 2015

AbstractAimsTo evaluate the clinical profile of patients with diabetic ketoacidosis in tertiary hospitals in China.MethodsA retrospective study of patients hospitalized with diabetic ketoacidosis between 2010 and 2012 was carried out in 15 tertiary hospitals around China. Clinical and laboratory data were collected. Patients were classified based on clinical diagnosis and treatment history. Groups were compared for differences in vital statistics and biochemical profiles at presentation.ResultsThe study comprised 643 patients with diabetic ketoacidosis: 308 patients (47.9%) with Type 1 diabetes, 294 patients (45.7%) with Type 2 diabetes and 41 patients (6.4%) with atypical diabetes. Three hundred and eighty‐eight diabetic ketoacidosis episodes (60.3%) were in patients with known diabetes. The most common precipitating factor was infection (40.1%), followed by unknown causes (36.9%) and non‐compliance with anti‐diabetes treatment (16.8%). At presentation, gastrointestinal symptoms and dehydration were more common in the Type 1 diabetes group. For new‐onset diabetes, only 74.4% and 55.9% of patients were evaluated for β–cell function and autoantibodies for classification. Only 67% of patients with diabetic ketoacidosis received appropriate fluid therapy and 56% patients with severe acidosis received bicarbonate therapy. The length of hospital stay was 10.0 (7.0–14.0) days. The mortality rate was 1.7%, and was much higher in Type 2 diabetes than that in Type 1 diabetes (3.2% vs. 0.4%, P < 0.01).ConclusionsType 2 and Type 1 diabetes contribute to a similar proportion of cases presenting with diabetic ketoacidosis in China. Admissions with diabetic ketoacidosis are still associated with significant mortality and prolonged hospitalization. The efficiency of diabetic ketoacidosis management needs to be improved by implementing the updated guidelines.