Miracle-dz/UniFAR-FTUs huggingface dataset:
Methylation status of KLF4 and HS3ST2 genes as predictors of endometrial cancer and hyperplastic endometrial lesions

Endometrial carcinoma is one of the most common tumours in developed countries. In addition to the active role of genetic factors, epigenetic changes also have an important effect. The present study analysed the methylation status of kruppel like factor 4 (KLF4) and heparan sulfate-glucosamine 3-sulfotransferase 2 (HS3ST2) genes in three endometrial tissue types for carcinoma prediction. The sample comprised 91 women with histologically-confirmed endometrial carcinoma (64.16±9.64 years old), 36 women with hyperplasia (53.39±9.64 years old) and 45 with no signs or symptoms of malignancy (48.53±11.11 years old). The CpG dinucleotide methylation levels were examined by quantitative pyrosequencing, and the discrimination accuracy of the model was calculated using the Random Forest classification algorithm of the area under the ROC curve (AUC). The mean values of KLF4 and HS3ST2 methylation indices were 23.83±11.39 and 8.52±2.57 in the control samples; 30.40±8.52 and 33.76±20.66 in hyperplasia and 34.72±10.79 and 34.49±18.39 in the cancerous tissues. Multinomial logistic regression indicated that the HS3ST2 CpG1 methylation status is a predictor of hyperplasia (P<0.05) and that the KLF4 CpG2 dinucleotide can predict carcinoma formation (P<0.001). The AUC value of 0.95 indicates high discrimination accuracy of the CpG nucleotides methylation status model between the controls and the two other diagnoses. The results of the present study establish the likelihood that aberrations in KLF4 and HS3ST2 gene methylation levels are important in the development of endometrial hyperplasia and carcinoma, with hyperplasia an intermediate step between healthy and tumour tissues.
Oncogenic microRNA signature for early diagnosis of cervical intraepithelial neoplasia and cancer

Cervical cancer is one of the leading causes of cancer death in women globally, despite the widespread use of cytology/human papillomavirus (HPV) screening. In the present study, we aimed to identify the potential role of microRNA (miRNA) as a diagnostic biomarker in the detection of cervical pre‐malignant lesions and cancer. In total, we recruited 582 patients with cervical diseases and 145 control individuals. The expression levels of six miRNAs (miR‐20a, miR‐92a, miR‐141, miR‐183*, miR‐210 and miR‐944) were found to be significantly up‐regulated in cervical cancer and pre‐malignant lesions compared to normal cervical samples, indicating that they are oncogenic miRNAs. Receiver operating characteristic curve analysis showed that these six miRNAs can be used to distinguish patients with cervical pre‐malignant lesions or cancer from normal individuals and they also had a good predictive performance, particularly in cervical lesions. Combined use of these six miRNAs further enhanced the diagnostic accuracy over any single miRNA marker, with an area under the curve of 0.998, 0.996 and 0.959, a diagnostic sensitivity of 97.9%, 97.2% and 91.4%, and a specificity of 98.6%, 96.6% and 87.6% for low‐grade lesions, high‐grade lesions and cancer, respectively. This six oncogenic miRNA signature may be suitable for use as diagnostic marker for cervical pre‐malignant lesions and cancer in the near future.
Embedded Spheroids as Models of the Cancer Microenvironment

To more accurately study the complex mechanisms behind cancer invasion, progression, and response to treatment, researchers require models that replicate both the multicellular nature and 3D stromal environment present in an in vivo tumor. Multicellular aggregates (i.e., spheroids) embedded in an extracellular matrix mimic are a prevalent model. Recently, quantitative metrics that fully utilize the capability of spheroids are described along with conventional experiments, such as invasion into a matrix, to provide additional details and insights into the underlying cancer biology. The article begins with a discussion of the salient features of the tumor microenvironment, introduces the early work on non‐embedded spheroids as tumor models, and then concentrates on the successes achieved with the study of embedded spheroids. Examples of studies include cell movement, drug response, tumor cellular heterogeneity, stromal effects, and cancer progression. Additionally, new methodologies and those borrowed from other research fields (e.g., vascularization and tissue engineering) are highlighted that expand the capability of spheroids to aid future users in designing their cancer‐related experiments. The convergence of spheroid research among the various fields catalyzes new applications and leads to a natural synergy. Finally, the article concludes with a reflection and future perspectives for cancer spheroid research.
Protective effect of berberine on aconite-induced myocardial injury and the associated mechanisms

Aconitum plants, which have analgesic, diuretic and anti-inflammatory effects, have been widely used to treat various types of disease. However, the apparent toxicity of Aconitum-derived agents, particularly in the cardiovascular system, has largely limited their clinical use. Thus, the present study investigated whether berberine (Ber), an isoquinoline alkaloid, may reduce myocardial injury induced by aconitine (AC) in rats and the underlying mechanisms. Rats (n=40) were randomly divided into four groups: Control, Chuan-wu and Chuan-wu + Ber (8 and 16 mg/kg doses). Electrocardiograms (ECG) of the rats were recorded and serum biomarkers of cardiac function [lactate dehydrogenase (LDH), creatine kinase (CK) and CK-MB] were assayed. Histopathological changes were assessed using myocardial tissue sectioning and hematoxylin and eosin staining. Additionally, the effects of Ber on AC-induced arrhythmias in rats were observed. The changes in ECG following AC perfusion were observed, and the types and onset time of arrhythmias were analyzed. Furthermore, the effects of Ber and AC on papillary muscle action potentials were observed. The results suggested that Ber ameliorated myocardial injury induced by Chuan-wu, which was indicated by reduced arrhythmias and decreased LDH, CK and CK-MB levels in serum. Furthermore, histological damage, including dilation of small veins and congestion, was also markedly attenuated by Ber. In addition, the occurrence of arrhythmias was significantly delayed, and the dosage of AC required to induce arrhythmias was also increased by Ber pretreatment. Additionally, AC-induced changes in action potential amplitude, duration of 30% repolarization and duration of 90% repolarization in the papillary muscle were attenuated by Ber. All of these results indicate that Ber had a preventive effect on acute myocardial injury induced by Chuan-wu and arrhythmias caused by AC, which may be associated with the inhibition of delayed depolarization and triggered activity caused by AC. Thus, combination treatment of Ber with Aconitum plants may be a novel strategy to prevent AC-induced myocardial injury in clinical practice.
Evolution and Expression Divergence of E2 Gene Family under Multiple Abiotic and Phytohormones Stresses in Brassica rapa

To understand ubiquitination mechanism, E2s (ubiquitin conjugating enzymes) have crucial part as they play a major role in regulating many biological processes in plants. Meanwhile, Brassica rapa is an important leafy vegetable crop and therefore its characterization along with the expression pattern of E2s under various stresses is imperative. In this study, a total of 83 genes were identified in B. rapa and were classified into four different classes based on domain information. Here, we analyzed phylogenetic relationships, collinear correlation, gene duplication, interacting network, and expression patterns of E2 genes in B. rapa. Furthermore, RT-PCR analysis for 8 multiple abiotic and hormone treatments (namely, ABA, GA, JA, BR, PEG, NaCl, and heat and cold stress) illustrated striking expression pattern under one or more treatments, speculating that these might be stress-responsive genes. The cis-elements and interaction network analyses implicate valuable clues of important function of E2 genes in development and multiple stress responses in B. rapa. This study will further facilitate functional analysis of E2s for improving stress resistance mechanism in B. rapa.
Do Your Cores Play Nicely? A Portable Framework for Multi-core Interference Tuning and Analysis

Multi-core architectures can be leveraged to allow independent processes to run in parallel. However, due to resources shared across cores, such as caches, distinct processes may interfere with one another, e.g. affecting execution time. Analysing the extent of this interference is difficult due to: (1) the diversity of modern architectures, which may contain different implementations of shared resources, and (2) the complex nature of modern processors, in which interference might arise due to subtle interactions. To address this, we propose a black-box auto-tuning approach that searches for processes that are effective at causing slowdowns for a program when executed in parallel. Such slowdowns provide lower bounds on worst-case execution time; an important metric in systems with real-time constraints. Our approach considers a set of parameterised "enemy" processes and "victim" programs, each targeting a shared resource. The autotuner searches for enemy process parameters that are effective at causing slowdowns in the victim programs. The idea is that victim programs behave as a proxy for shared resource usage of arbitrary programs. We evaluate our approach on: 5 different chips; 3 resources (cache, memory bus, and main memory); and consider several search strategies and slowdown metrics. Using enemy processes tuned per chip, we evaluate the slowdowns on the autobench and coremark benchmark suites and show that our method is able to achieve slowdowns in 98% of benchmark/chip combinations and provide similar results to manually written enemy processes.
Negative Update Intervals in Deep Multi-Agent Reinforcement Learning

In Multi-Agent Reinforcement Learning (MA-RL), independent cooperative learners must overcome a number of pathologies to learn optimal joint policies. Addressing one pathology often leaves approaches vulnerable towards others. For instance, hysteretic Q-learning addresses miscoordination while leaving agents vulnerable towards misleading stochastic rewards. Other methods, such as leniency, have proven more robust when dealing with multiple pathologies simultaneously. However, leniency has predominately been studied within the context of strategic form games (bimatrix games) and fully observable Markov games consisting of a small number of probabilistic state transitions. This raises the question of whether these findings scale to more complex domains. For this purpose we implement a temporally extend version of the Climb Game, within which agents must overcome multiple pathologies simultaneously, including relative overgeneralisation, stochasticity, the alter-exploration and moving target problems, while learning from a large observation space. We find that existing lenient and hysteretic approaches fail to consistently learn near optimal joint-policies in this environment. To address these pathologies we introduce Negative Update Intervals-DDQN (NUI-DDQN), a Deep MA-RL algorithm which discards episodes yielding cumulative rewards outside the range of expanding intervals. NUI-DDQN consistently gravitates towards optimal joint-policies in our environment, overcoming the outlined pathologies.
Effect of Aspirin on All‐Cause Mortality in the Healthy Elderly

BACKGROUND In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability‐free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo. METHODS From 2010 through 2014, we enrolled community‐dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric‐coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial‐group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed. RESULTS Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow‐up. The risk of death from any cause was 12.7 events per 1000 person‐years in the aspirin group and 11.1 events per 1000 person‐years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person‐years. Cancer‐related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56). CONCLUSIONS Higher all‐cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer‐related death. In the context of previous studies, this result was unexpected and should be interpreted with caution. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583.)
Action‐selection perseveration in young children: Advances of a dynamic model

Abstract This study presents an empirical test and dynamic model of perseverative limb selection in children of 14‐, 24‐, and 36‐months old (N = 66 in total). In the experiment, children repeatedly grasped a spoon with a single hand. In two separate conditions, the spoon was presented either four times on their right side or four times on their left side. In both conditions, following this training, the spoon was presented on midline for two more trials. This setup enabled us to determine whether children's limb selection was influenced by their prior choices in the task (i.e., perseveration). Individual children's handedness was determined in a third condition consisting of nine object presentations (laterally or on midline). A dynamic model for limb selection is presented combining external input, motor memory, and preferences. The model was used to simulate the experiment and reproduced the results, including the age‐related changes.
Surface analysis of long-term hemodialysis catheters made of carbothane (poly(carbonate)urethane) before and after implantation in the patients' bodies.

PURPOSE The vascular cannulation is associated with a number of complications. The aim of this work was to study the composition and distribution of the film covering the surfaces of Mahurkar Maxid and Palindrome catheters, which were removed from the body of long-term hemodialysis patients. Moreover, the roughness and contact angle of the catheters were evaluated. METHODS Two brand new (as a reference) and thirty used catheters were the subject of the study. Their implantation period lasted from 4 months to a year and the reason for removal was the production of another vascular access or obstruction. Surfaces were analyzed by scanning electron microscope, atomic force microscope and goniometer. RESULTS The inner surfaces of the used catheters were covered with a film of various complexity which includes a plurality of protein, blood cell counts and the crystals. The closer to the distal part the film becomes more complex and multi-layered. Even the surfaces of brand new catheter were not completely smooth. The only significant difference between analyzed models was the presence of thrombus in the distal part of Mahurkar Maxid catheters, not in the Palindrome. CONCLUSIONS The distal part of the catheters is the place most exposed to obstruction and infection, which may be due to not reaching the anticoagulant agent into this part. Not only the occurrence of side holes affects the formation of thrombus, but also their quantity, geometry and distribution which effect on fluid mechanics. The surface of the catheters needs to improvement to minimize the occurrence of defects and cracks.
Dicer affects cisplatin-mediated apoptosis in epithelial ovarian cancer cells

Dicer is an essential enzyme that processes micro (mi)-RNA precursors into mature miRNAs, and serves a critical role in cancer development and progression by regulating gene expression. However, the role of Dicer in cisplatin-mediated apoptosis and chemotherapy resistance in epithelial ovarian cancer (EOC) cells is poorly understood. In the present study, Dicer was expressed at low levels in cisplatin-resistant A2780 cells when compared with parental cells. In addition, knocking down Dicer using short hairpin RNA decreased the sensitivity of A2780 and CAOV3 cells to cisplatin. Furthermore, downregulating Dicer significantly inhibited cisplatin-induced apoptosis in ovarian cancer cells, and decreased the levels of proteins involved in apoptosis signaling pathways, including P73, P63, P53, caspase-9 and caspase-3. These findings indicated that Dicer may be a promising target for overcoming drug resistance in ovarian cancer.
Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

ABSTRACT Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA. Cell free RNA was quantified by Reverse Transcriptase -PCR), and plasmatic microRNAs (miRNAs) were evaluated by targeted sequencing. Expression of PD-L1 on tumour biopsies was performed by immunohistochemistry using E13LN. High sPD-L1 at 2 months and increase of sPD-L1 concentrations were associated with poor response and absence of clinical benefit (nivolumab treatment less than 6 months). The variation of sPD-L1 concentrations were confirmed by RNA quantification. sPD-L1 concentrations were not correlated with PD-L1 expression on corresponding tumour samples. Low sGranB at nivolumab initiation was also associated with poor response. High sPD-L1 and low sGranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low sIl-2 and high sIFN-γ were associated with grade 3–4 toxicities. Finally, miRNA screening showed that patients with clinical benefit (n = 9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n = 9). In conclusion, our results highlight the interest of circulating biomarkers in patients treated with nivolumab.
Use of contraceptive depot medroxyprogesterone acetate is associated with impaired cervicovaginal mucosal integrity

BACKGROUND. Injectable depot medroxyprogesterone acetate (DMPA) is one of the most popular contraception methods in areas of high HIV seroprevalence. Evidence is accumulating that use of DMPA might be associated with an increased risk of HIV-1 acquisition by women; however, mechanisms of this association are not completely understood. The goal of this study was to gain insight into mechanisms underlying the possible link between use of DMPA and risk of HIV-1 acquisition, exploring transcription profiling of ectocervical tissues. METHODS. Healthy women received either DMPA (n = 31) or combined oral contraceptive (COC), which has not been linked to an increased risk of HIV acquisition (n = 32). We conducted a comparative microarray-based whole-genome transcriptome profiling of human ectocervical tissues before and after 6 weeks of hormonal contraception use. RESULTS. The analysis identified that expression of 235 and 76 genes was significantly altered after DMPA and COC use, respectively. The most striking effect of DMPA, but not COC, was significantly altered expression (mostly downregulation) of many genes strategically involved in the maintenance of mucosal barrier function; the alterations, as indicated by Ingenuity Pathway Analysis (IPA), were most likely due to the DMPA-induced estrogen deficiency. Furthermore, IPA predicted that transcriptome alterations related to ectocervical immune responses were in general compatible with an immunosuppressive effect of DMPA, but, in some women, also with an inflammatory-like response. CONCLUSION. Our results suggest that impairment of cervicovaginal mucosal integrity in response to DMPA administration is an important mechanism contributing to the potential increased risk of HIV-1 acquisition in DMPA users. TRIAL REGISTRATION. ClinicalTrials.gov NCT01421368. FUNDING. This study was supported by the United States Agency for International Development (USAID) under Cooperative Agreement GPO-A-00-08-00005-00.
The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis

Abstract Aims Single nucleotide polymorphisms on chromosome 4q25 have been associated with risk of atrial fibrillation (AF) but the exiguous knowledge of the mechanistic links between these risk variants and underlying electrophysiological alterations hampers their clinical utility. Here, we tested the hypothesis that 4q25 risk variants cause alterations in the intracellular calcium homoeostasis that predispose to spontaneous electrical activity. Methods and results Western blotting, confocal calcium imaging, and patch-clamp techniques were used to identify mechanisms linking the 4q25 risk variants rs2200733T and rs13143308T to defects in the calcium homoeostasis in human atrial myocytes. Our findings revealed that the rs13143308T variant was more frequent in patients with AF and that myocytes from carriers of this variant had a significantly higher density of calcium sparks (14.1 ± 4.5 vs. 3.1 ± 1.3 events/min, P = 0.02), frequency of transient inward currents (ITI) (1.33 ± 0.24 vs. 0.26 ± 0.09 events/min, P < 0.001) and incidence of spontaneous membrane depolarizations (1.22 ± 0.26 vs. 0.56 ± 0.17 events/min, P = 0.001) than myocytes from patients with the normal rs13143308G variant. These alterations were linked to higher sarcoplasmic reticulum calcium loading (10.2 ± 1.4 vs. 7.3 ± 0.5 amol/pF, P = 0.01), SERCA2 expression (1.37 ± 0.13 fold, P = 0.03), and RyR2 phosphorylation at ser2808 (0.67 ± 0.08 vs. 0.47 ± 0.03, P = 0.01) but not at ser2814 (0.28 ± 0.14 vs. 0.31 ± 0.14, P = 0.61) in patients carrying the rs13143308T risk variant. Furthermore, the presence of a risk variant or AF independently increased the ITI frequency and the increase in the ITI frequency observed in carriers of the risk variants was exacerbated in those with AF. By contrast, the presence of a risk variant did not affect the amplitude or properties of the L-type calcium current in patients with or without AF. Conclusions Here, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.