bluuebunny/crossref_metadata_2025_split huggingface dataset:
Testing Cyclic Fatigue Resistance of Nickel Titanium Rotary Endodontic Instruments: A Validation Study for a Minimum Quality Criterion in a Standardized Environment
Authors: Peters Ove A. , Chien Philip Y.-H. , Armitt Keryl , Macorra Jose C. , Arias Ana 
Published: September 2021

Introduction: Cyclic fatigue resistance of rotary endodontic instruments has been extensively studied in the last two decades, yet with no standardization. While new low-cost instruments are now manufactured, a standard is lacking to guarantee a minimum quality. This study aimed to validate a new model for CF testing through a fixture proposed for ISO Specification 3630-1 and to establish a minimum quality standard based on testing conditions and material characteristics.Materials and methods: Size 25/0.06 instruments of ProFile Vortex (PF) and Vortex Blue (VB) were run until failure in curved metallic fixtures (5 or 7.5 mm radius) built according to a proposal for an additional test for the ISO 3630-1 standard. High resolution videos were recorded, number of cycles to failure (NCF) registered and apical fragments measured with a digital caliper. Surface strain was determined from test dimensions and fragment lengths. Mean life, β and η parameters were calculated with Weibull analysis. NCF data were compared using student's t-tests and referenced to a minimum required cycles at fracture (Cmin) based on austenite finish temperatures, testing temperature and deformation.Results: VB instruments were statistically more resistant than PF in both 7.5 mm radius curve (p = 0.001) and 5 mm radius curve (p = 0.002) simulated canals. Weibull probability plots showed higher mean life for VB than PV. NCF for both instruments were higher than Cmin.Conclusions: The NCF results in this study support the findings of previous studies where VB and PF were compared. The novel test design appears a suitable addition to ISO 3630-1.
Lower Limb Deformity and Gait Deviations Among Adolescents and Adults With X-Linked Hypophosphatemia
Authors: Mindler Gabriel T. , Kranzl Andreas , Stauffer Alexandra , Kocijan Roland , Ganger Rudolf , Radler Christof , Haeusler Gabriele , Raimann Adalbert 
Published: September 2021

BackgroundX-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by lower limb deformity, gait and joint problems, and pain. Hence, quality of life is substantially impaired. This study aimed to assess lower limb deformity, specific radiographic changes, and gait deviations among adolescents and adults with XLH.DesignData on laboratory examination and gait analysis results were analyzed retrospectively. Deformities, osteoarthritis, pseudofractures, and enthesopathies on lower limb radiographs were investigated. Gait analysis findings were compared between the XLH group and the control group comprising healthy adults.Patients and ControlsRadiographic outcomes were assessed retrospectively in 43 patients with XLH (28 female, 15 male). Gait analysis data was available in 29 patients with confirmed XLH and compared to a healthy reference cohort (n=76).ResultsPatients with XLH had a lower gait quality compared to healthy controls (Gait deviation index GDI 65.9% +/- 16.2). About 48.3% of the study population presented with a greater lateral trunk lean, commonly referred to as waddling gait. A higher BMI and mechanical axis deviation of the lower limbs were associated with lower gait scores and greater lateral trunk lean. Patients with radiologic signs of enthesopathies had a lower GDI.ConclusionsThis study showed for the first time that lower limb deformity, BMI, and typical features of XLH such as enthesopathies negatively affected gait quality among adolescents and adults with XLH.
Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases
Authors: Shen Ziwei , Huang Wei , Liu Jun , Tian Jie , Wang Shengjun , Rui Ke 
Published: September 2021

Recent years, the immunosuppressive properties of mesenchymal stem cells (MSCs) have been demonstrated in preclinical studies and trials of inflammatory and autoimmune diseases. Emerging evidence indicates that the immunomodulatory effect of MSCs is primarily attributed to the paracrine pathway. As one of the key paracrine effectors, mesenchymal stem cell-derived exosomes (MSC-EXOs) are small vesicles 30-200 nm in diameter that play an important role in cell-to-cell communication by carrying bioactive substances from parental cells. Recent studies support the finding that MSC-EXOs have an obvious inhibitory effect toward different effector cells involved in the innate and adaptive immune response. Moreover, substantial progress has been made in the treatment of autoimmune diseases, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), type-1 diabetes (T1DM), uveitis, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). MSC-EXOs are capable of reproducing MSC function and overcoming the limitations of traditional cell therapy. Therefore, using MSC-EXOs instead of MSCs to treat autoimmune diseases appears to be a promising cell-free treatment strategy. In this review, we review the current understanding of MSC-EXOs and discuss the regulatory role of MSC-EXOs on immune cells and its potential application in autoimmune diseases.
Identification of Mast Cell-Based Molecular Subtypes and a Predictive Signature in Clear Cell Renal Cell Carcinoma
Authors: Liu Hanxiang , Yang Yi 
Published: September 2021

Background: Kidney renal clear cell carcinoma (KIRC) is a common malignant tumor of the urinary system. Surgery is the preferred treatment option; however, the rate of distant metastasis is high. Mast cells in the tumor microenvironment promote or inhibit tumorigenesis depending on the cancer type; however, their role in KIRC is not well-established. Here, we used a bioinformatics approach to evaluate the roles of mast cells in KIRC.Methods: To quantify mast cell abundance based on gene sets, a single-sample gene set enrichment analysis (ssGSEA) was utilized to analyze three datasets. Weighted correlation network analysis (WGCNA) was used to identify the genes most closely related to mast cells. To identify new molecular subtypes, the nonnegative matrix factorization algorithm was used. GSEA and least absolute shrinkage and selection operator (LASSO) Cox regression were used to identify genes with high prognostic value. A multivariate Cox regression analysis was performed to establish a prognostic model based on mast cell-related genes. Promoter methylation levels of mast cell-related genes and relationships between gene expression and survival were evaluated using the UALCAN and GEPIA databases.Results: A prolonged survival in KIRC was associated with a high mast cell abundance. KIRC was divided into two molecular subtypes (cluster 1 and cluster 2) based on mast cell-related genes. Genes in Cluster 1 were enriched for various functions related to cancer development, such as the TGFβ signaling pathway, renal cell carcinoma, and mTOR signaling pathway. Based on drug sensitivity predictions, sensitivity to doxorubicin was higher for cluster 2 than for cluster 1. By a multivariate Cox analysis, we established a clinical prognostic model based on eight mast cell-related genes.Conclusion: We identified eight mast cell-related genes and constructed a clinical prognostic model. These results improve our understanding of the roles of mast cells in KIRC and may contribute to personalized medicine.
Efficacy and Safety of Tumor Treating Fields (TTFields) in Elderly Patients with Newly Diagnosed Glioblastoma: Subgroup Analysis of the Phase 3 EF-14 Clinical Trial
Authors: Ram Zvi , Kim Chae-Yong , Hottinger Andreas F. , Idbaih Ahmed , Nicholas Garth , Zhu Jay-Jiguang 
Published: September 2021

BackgroundUnderstudied elderly patients comprise a large segment of high-risk patients with glioblastoma (GBM) that are challenging to treat. Tumor Treating Fields (TTFields) is a locoregional, noninvasive, antimitotic therapy delivering low-intensity, intermediate-frequency alternating electric fields to the tumor. In the phase 3 EF-14 clinical trial, TTFields (200 kHz) improved median progression-free survival (PFS) and median overall survival (OS) in patients with newly diagnosed GBM (ndGBM) when added concomitantly to maintenance temozolomide (TMZ). This EF-14 subgroup analysis evaluated the safety and efficacy of TTFields in elderly patients.MethodsAll 134 patients who are ≥65 years of age were included (TTFields/TMZ combination, n=89; TMZ monotherapy, n=45; 2:1 ratio of randomization). PFS and OS were analyzed using Kaplan–Meier methodology (α=0.05). Health-related quality-of-life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire QLQ-C30 supplemented with the brain tumor module (QLQ-BN20). Adverse events (AEs) were evaluated using Common Terminology Criteria for AEs (CTCAE) v4.0.ResultsThe PFS was 6.5 months in patients randomized to the treatment group with TTFields/TMZ combination versus 3.9 months in patients treated with TMZ monotherapy (HR, 0.47; 95% CI, 0.30–0.74; P=0.0236). The OS was 17.4 months in patients treated with TTFields/TMZ combination versus 13.7 months in patients treated with TMZ monotherapy (HR, 0.51; 95% CI, 0.33–0.77; P=0.0204). Annual survival rates with TTFields/TMZ versus TMZ monotherapy were 39% (95% CI, 29–50%) versus 27% (95% CI, 15–41%; P=0.072) at 2 years, 19% (95% CI, 11–29%) versus 11% (95% CI, 4–23%; P=0.135) at 3 years, and 15% (95% CI, 7–25%) versus 0% at 5 years, respectively. There were no significant differences between groups in the preselected items of HRQoL assessment. Grade ≥3 systemic AEs were 46% in the TTFields/TMZ group versus 40% in the TMZ monotherapy group, without statistically significant difference between the two groups. The only TTFields-related AEs were reversible scalp skin reactions, with grades 1–2 and grade 3 skin reactions reported by 51% and 2% of patients, respectively.ConclusionsCombining TTFields with maintenance TMZ significantly improved PFS and OS in elderly patients with ndGBM in the phase 3 EF-14 clinical trial, without significant increases in systemic toxicity or negatively affecting patient HRQoL. TTFields-related skin AEs were low-grade and manageable.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT00916409, identifier: NCT00916409.
Effects of Fluoride on Submandibular Glands of Mice: Changes in Oxidative Biochemistry, Proteomic Profile, and Genotoxicity
Authors: Lima Leidiane Alencar de Oliveira , Miranda Giza Hellen Nonato , Aragão Walessa Alana Bragança , Bittencourt Leonardo Oliveira , dos Santos Sávio Monteiro , de Souza Michel Platini Caldas , Nogueira Lygia S. , de Oliveira Edivaldo Herculano Corrêa , Monteiro Marta Chagas , Dionizio Aline , Leite Aline Lima , Pessan Juliano Pelim , Buzalaf Marília Afonso Rabelo , Lima Rafael Rodrigues 
Published: September 2021

Although fluoride (F) is well-known to prevent dental caries, changes in cell processes in different tissues have been associated with its excessive exposure. Thus, this study aimed to evaluate the effects of F exposure on biochemical, proteomic, and genotoxic parameters of submandibular glands. Twenty one old rats (n = 30) were allocated into three groups: 60 days administration of drinking water containing 10 mgF/L, 50 mgF/L, or only deionized water (control). The submandibular glands were collected for oxidative biochemistry, protein expression profile, and genotoxic potential analyses. The results showed that both F concentrations increased the levels of thiobarbituric acid–reactive substances (TBARS) and reduced glutathione (GSH) and changed the proteomic profile, mainly regarding the cytoskeleton and cellular activity. Only the exposure to 50 mgF/L induced significant changes in DNA integrity. These findings reinforce the importance of continuous monitoring of F concentration in drinking water and the need for strategies to minimize F intake from other sources to obtain maximum preventive/therapeutic effects and avoid potential adverse effects.
Evaluation of a Clinically Relevant Drug–Drug Interaction Between Rosuvastatin and Clopidogrel and the Risk of Hepatotoxicity
Authors: Ning Chen , Su Shengdi , Li Jiaming , Kong Dexuan , Cai Hui , Qin Zhiying , Xing Han , Chen Xijing , He Jiake 
Published: September 2021

Purpose: The combination therapy of rosuvastatin (RSV) and the platelet inhibitor clopidogrel (CP) is widely accepted in the management of cardiovascular diseases. The objective of the present study was to identify the mechanism of RSV–CP DDI and evaluate the risk of hepatotoxicity associated with the concomitant use of CP.Methods: We first studied the effect of CP and its major circulating metabolite, carboxylic acid metabolite (CPC), on RSV transport by overexpressing cells and membrane vesicles. Second, we investigated whether a rat model could replicate this DDI and then be used to conduct mechanistic studies and assess the risk of hepatotoxicity. Then, cytotoxicity assay in hepatocytes, biochemical examination, and histopathology were performed to measure the magnitude of liver injury in the presence and absence of DDI.Results: CP inhibited OATP1B1-mediated transport of RSV with an IC50 value of 27.39 μM. CP and CPC inhibited BCRP-mediated RSV transport with IC50 values of &lt;0.001 and 5.96 μM, respectively. The CP cocktail (0.001 μM CP plus 2 μM CPC) significantly inhibited BCRP-mediated transport of RSV by 26.28%. Multiple p.o. doses of CP significantly increased intravenous RSV plasma AUC0-infinity by 76.29% and decreased intravenous RSV CL by 42.62%. Similarly, multiple p.o. doses of CP significantly increased p.o. RSV plasma AUC0-infinity by 87.48% and decreased p.o. RSV CL by 43.27%. CP had no effect on cell viability, while RSV exhibited dose-dependent cytotoxicity after 96 h incubation. Co-incubation of 100 μM CP and RSV for 96 h significantly increased intracellular concentrations and cell-to-medium concentration ratios of RSV and reduced hepatocyte viability. Histological evaluation of liver specimens showed patterns of drug-induced liver injury. Cholestasis was found in rats in the presence of DDI.Conclusion: CP is not a clinically relevant inhibitor for OATP1B1 and OATP1B3. The primary mechanism of RSV–CP DDI can be attributed to the inhibition of intestinal BCRP by CP combined with the inhibition of hepatic BCRP by CPC. The latter is likely to be more clinically relevant and be a contributing factor for increased hepatotoxicity in the presence of DDI.
Robust Reductions of Body Weight and Food Intake by an Oxytocin Analog in Rats
Authors: Elfers Clinton T. , Blevins James E. , Lawson Elizabeth A. , Pittner Richard , Silva David , Kiselyov Alex , Roth Christian L. 
Published: September 2021

Background: Oxytocin is a hypothalamic neuropeptide that participates in the network of appetite regulation. Recently the oxytocin signaling pathway has emerged as an attractive target for treating obesity. However, the short half-life limits its development as a clinical therapeutic. Here we provide results from testing a long-lasting, potent and selective oxytocin analog ASK1476 on its efficacy to reduce food intake and body weight in comparison to the native oxytocin peptide.Methods: ASK1476 features two specific amino acid substitutions in positions 7 and 8 combined with a short polyethylene glycol spacer. Short time dose escalation experiments testing increasing doses of 3 days each were performed in diet-induced overweight (DIO) male rats assessing effects on body weight as well as changes in food intake. Furthermore, DIO rats were tested for changes in body weight, food intake, temperature, and locomotor activity over 28 days of treatment (oxytocin, ASK1476, or vehicle).Results: In dose escalation experiments, significant reductions in food intake relative to baseline were detected beginning with doses of 15 nmol/kg ASK1476 (−15.2 ± 2.3 kcal/d, p = 0.0017) and 20 nmol/kg oxytocin (−11.2.9 ± 2.4 kcal/d, p = 0.0106) with corresponding significant changes in body weight (ASK1476: −5.2 ± 0.8 g, p = 0.0016; oxytocin: −2.6 ± 0.7 g, p = 0.0326). In long-term experiments, there was no difference on body weight change between 120 nmol/kg/d ASK1476 (−71.4 ± 34.2 g, p = 0.039) and 600 nmol/kg/d oxytocin (−91.8 ± 32.2 g, p = 0.035) relative to vehicle (706.9 ± 28.3 g), indicating a stronger dose response for ASK1476. Likewise, both ASK1476 and oxytocin at these doses resulted in similar reductions in 28-day cumulative food intake (ASK1476: −562.7 ± 115.0 kcal, p = 0.0001; oxytocin: −557.1 ± 101.3 kcal, p = 0.0001) relative to vehicle treatment (2716 ± 75.4 kcal), while no effects were detected on locomotor activity or body temperature.Conclusion: This study provides proof-of-concept data demonstrating an oxytocin analog with extended in vivo stability and improved potency to reduce food intake and body weight in DIO animals which could mark a new avenue in anti-obesity drug interventions.
Plasma-Derived microRNAs Are Influenced by Acute and Chronic Exercise in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Witvrouwen Isabel , Gevaert Andreas B. , Possemiers Nadine , Ectors Bert , Stoop Tibor , Goovaerts Inge , Boeren Evi , Hens Wendy , Beckers Paul J. , Vorlat Anne , Heidbuchel Hein , Van Craenenbroeck Amaryllis H. , Van Craenenbroeck Emeline M. 
Published: September 2021

Background: Exercise training improves VO2peak in heart failure with reduced ejection fraction (HFrEF), but the effect is highly variable as it is dependent on peripheral adaptations. We evaluated changes in plasma-derived miRNAs by acute and chronic exercise to investigate whether these can mechanistically be involved in the variability of exercise-induced adaptations.Methods: Twenty-five male HFrEF patients (left ventricular ejection fraction &lt; 40%, New York Heart Association class ≥ II) participated in a 15-week combined strength and aerobic training program. The effect of training on plasma miRNA levels was compared to 21 male age-matched sedentary HFrEF controls. Additionally, the effect of a single acute exercise bout on plasma miRNA levels was assessed. Levels of 5 miRNAs involved in pathways relevant for exercise adaptation (miR-23a, miR-140, miR-146a, miR-191, and miR-210) were quantified using RT-qPCR and correlated with cardiopulmonary exercise test (CPET), echocardiographic, vascular function, and muscle strength variables.Results: Expression levels of miR-146a decreased with training compared to controls. Acute exercise resulted in a decrease in miR-191 before, but not after training. Baseline miR-23a predicted change in VO2peak independent of age and left ventricular ejection fraction (LVEF). Baseline miR-140 was independently correlated with change in load at the respiratory compensation point and change in body mass index, and baseline miR-146a with change in left ventricular mass index.Conclusion: Plasma-derived miRNAs may reflect the underlying mechanisms of exercise-induced adaptation. In HFrEF patients, baseline miR-23a predicted VO2peak response to training. Several miRNAs were influenced by acute or repeated exercise. These findings warrant exploration in larger patient populations and further mechanistic in vitro studies on their molecular involvement.
Acute Kidney Injury Increase Risk of Left Ventricular Remodeling: A Cohort of 1,573 Patients
Authors: Li Qiang , Chen Weihua , Shi Shanshan , Huang Haozhang , Lai Wenguang , Liu Liwei , Ying Ming , Wang Bo , Li Huanqiang , Huang Zhidong , Chen Liling , Chen Jiyan , Chen Shiqun , Liu Jin , Liu Yong 
Published: September 2021

Background: Acute kidney injury (AKI) is a common complication after coronary angiography (CAG) and associated with heart failure (HF). Left ventricular (LV) remodeling is a vital process in the progression of HF. However, few studies investigate the relationship between AKI and LV remodeling.Methods: We included consecutive patients undergoing CAG from January 2007 to December 2018 at Guangdong Provincial People’s Hospital (NCT04407936). AKI was defined as an absolute increase in serum creatinine (Scr) of ≥ 0.3mg/dl or a ≥ 50% increase in Scr from baseline within the first 48–72 h after the procedure. LV remodeling was defined as: (1) an absolute decrease in left ventricular ejection fraction (LVEF) of ≥ 10% compared to baseline, or (2) a follow-up LVEF &lt; 40%. Univariate and multivariate logistical regressions were used to assess the association between AKI and LV remodeling.Results: Of the 1,573 patients (62.2 ± 9.7 years, female 36.7%) included in the study, 231 (14.7%) had AKI. The incidence of LV remodeling was higher in patients with AKI than in those without AKI (24.7% vs. 14.5%). After adjusting for confounding, multivariate logistic regression showed that AKI was associated with a significantly higher risk of LV remodeling [adjusted odds ratio (aOR) 1.87; 95% CI, 1.30–2.66; p &lt; 0.001]. In addition, LV remodeling patients had higher all-cause mortality compared to non-LV remodeling patients (9.7% vs. 19.1%).Conclusion: Our data suggested that AKI is present in up to 15% of patients after CAG and that nearly a quarter of AKI patients suffered LV remodeling and AKI patients have a two-fold risk of developing LV remodeling than non-AKI patients. Our findings suggest that more active measures be taken not only to prevent AKI patient developing into LV remodeling, but to prevent patients undergoing CAG from developing AKI.
An Inconsistent Canadian Provincial and Territorial Response During the Early COVID-19 Pandemic
Authors: Cyr Amelie , Mondal Prosanta , Hansen Gregory 
Published: September 2021

Objectives: According to the World Health Organization (WHO), an early and consistent international and national response is needed to control a pandemic's spread. In this analysis, we evaluate the coordination of Canada's early response to the coronavirus (COVID-19) pandemic in terms of public health interventions and policies implemented in each province and territory.Methods: Retrospective data was obtained from publicly accessible websites maintained by federal, provincial and territorial governmental agencies. Consistent with WHO's spreading of the disease pandemic action, individual and community-based public health interventions and policies were the focus. Time of intervention or policy, and COVID-19 cases per million at time of intervention was recorded for each province and territory.Results: Most public health interventions and policies demonstrated wide time ranges of implementation across individual provinces and territories. At time of implementation, there were also wide variations in the number of positive COVID-19 cases in these jurisdictions. Cases per million per implemented day were also not similar across interventions or policy, suggesting that other factors may have been preferentially considered.Conclusions: Whether an earlier and more structured national approach would have lessened the pandemic's burden is uncertain, calls for greater federal coordination and leadership should to examined.