Miracle-dz/UniFAR-FTUs huggingface dataset:
Hyperforin-Induced Activation of the Pregnane X Receptor Is Influenced by the Organic Anion-Transporting Polypeptide 2B1

The herbal remedy St. John’s wort (SJW) is used in the treatment of mild depressive symptoms and is known for its drug-drug interaction potential when enhanced expression of CYP3A4 modifies clearance of concomitantly applied substrate drugs. Hyperforin is one constituent of SJW that alters CYP3A4 expression by activation of the nuclear receptor pregnane X receptor (PXR). However, little is known about the transmembrane transport of hyperforin. One membrane protein that modulates cellular entry of drugs is the organic anion-transporting polypeptide (OATP) 2B1. It was the aim of this study to test whether hyperforin interacts with this transport protein. Transport inhibition studies and competitive counterflow experiments suggested that hyperforin is a substrate of OATP2B1. This notion was validated by showing that the presence of OATP2B1 enhanced the hyperforin-induced PXR activation in cell-based luciferase assays. Moreover, in Caco-2 cells transcellular transport of the known OATP2B1 substrate atorvastatin was changed in the presence of hyperforin, resulting in an increased efflux ratio. Eleven commercially available SJW formulations were assessed for their influence on OATP2B1-mediated transport of estrone 3-sulfate and for their impact on CYP3A4 promoter transactivation. The correlation between effect size and the hyperforin content as determined by high-performance liquid chromatography with ultraviolet detection suggested that hyperforin is the major determinant. Our results indicate an interaction between hyperforin and OATP2B1, which is not only known to contribute to hepatocellular uptake but also to intestinal absorption of its substrates. These findings extend the complexity of mechanisms that should be considered when evaluating the interaction potential of SJW preparations.
Research Priorities for Health Care Chaplaincy in The Netherlands: A Delphi Study Among Dutch Chaplains

The aim of this study was to identify research priorities for health care chaplaincy in The Netherlands according to practicing chaplains and chaplaincy leaders. To this end, a two-round Delphi study was conducted. The first round in which participants were asked to list at least three research priorities was completed by 249 respondents. Through content analysis, the resulting 811 priorities were merged into 54 research topics in 10 domains. In the second round, 179 respondents ranked these topics on a Likert scale from 1 to 5 (low priority–high priority) from the perspective of the patient/client, the organization, and the profession. Based on the mean score of each topic, five research priorities were identified: (a) to investigate the effect of chaplain care according to the patient/client; (b) to determine the patients’/clients’ need(s) for chaplaincy; (c) to investigate the effect of chaplain care on the patient/client; (d) to identify possibilities for chaplaincy practice in outpatient care; and (e) to investigate how to develop a stronger profile for chaplaincy in The Netherlands. These priorities resonate with research on this topic from other countries and indicate directions for future research efforts to improve chaplaincy care.
ZNF671 DNA methylation as a molecular predictor for the early recurrence of serous ovarian cancer

Serous ovarian cancer is the most frequent type of epithelial ovarian cancer. Despite the use of surgery and platinum‐based chemotherapy, many patients suffer from recurrence within 6 months, termed platinum resistance. Currently, the lack of relevant molecular biomarkers for the prediction of the early recurrence of serous ovarian cancers is linked to the poor prognosis. To identify an effective biomarker for early recurrence, we analyzed the genome‐wide DNA methylation status characteristic of early recurrence after treatment. The patients in The Cancer Genome Atlas (TCGA) dataset who showed a complete response after the first therapy were categorized into 2 groups: early recurrence serous ovarian cancer (ERS, recurrence ≤12 months, n = 51) and late recurrence serous ovarian cancer (LRS, recurrence >12 months, n = 158). Among the 12 differently methylated probes identified between the 2 groups, we found that ZNF671 was the most significantly methylated gene in the early recurrence group. A validation cohort of 78 serous ovarian cancers showed that patients with ZNF671 DNA methylation had a worse prognosis (P < .05). The multivariate analysis revealed that the methylation status of ZNF671 was an independent factor for predicting the recurrence of serous ovarian cancer patients both in the TCGA dataset and our cohort (P = .049 and P = .021, respectively). Functional analysis revealed that the depletion of ZNF671 expression conferred a more migratory and invasive phenotype to the ovarian cancer cells. Our data indicate that ZNF671 functions as a tumor suppressor in ovarian cancer and that the DNA methylation status of ZNF671 might be an effective biomarker for the recurrence of serous ovarian cancer after platinum‐based adjuvant chemotherapy.
Murine myeloid‐derived suppressor cells are a source of elevated levels of interleukin‐27 in early life and compromise control of bacterial infection

Microbial infections early in life remain a major cause of infant mortality worldwide. This is consistent with immune deficiencies in this population. Interleukin (IL)‐27 is suppressive toward a variety of immune cell types, and we have shown that the production of IL‐27 is elevated in humans and mice early in life. We hypothesize that elevated levels of IL‐27 oppose protective responses to infection during the neonatal period. In this study, we extended previous findings in neonatal mice to identify a population of IL‐27 producers that express Gr‐1 and were further identified as myeloid‐derived suppressor cells (MDSCs) based on the expression of surface markers and functional studies. In neonates, MDSCs are more abundant and contribute to the elevated pool of IL‐27 in this population. Although the ability of MDSCs to regulate T lymphocyte activation has been well‐studied, sparingly few studies have investigated the influence of MDSCs on innate immune function during bacterial infection. We demonstrate that macrophages are impaired in their ability to control growth of Escherichia coli when cocultured with MDSCs. This bacterium is a significant concern for neonates as a common cause of bacterial sepsis and meningitis. The suppressive effect of MDSCs on macrophage function is mediated by IL‐27; inclusion of a reagent to neutralize IL‐27 promotes improved control of bacterial growth. Taken together, these results suggest that the increased abundance of MDSCs may contribute to early life susceptibility to infection and further highlight production of IL‐27 as a novel MDSC mechanism to suppress immunity.
DNMT3A/3B overexpression might be correlated with poor patient survival, hypermethylation and low expression of ESR1/PGR in endometrioid carcinoma: an analysis of The Cancer Genome Atlas

Background: DNA methylation is involved in numerous biologic events and associates with transcriptional gene silencing, playing an important role in the pathogenesis of endometrial cancer. ESR1/PGR frequently undergoes de novo methylation and loss expression in a wide variety of tumors, including breast, colon, lung, and brain tumors. However, the mechanisms underlying estrogen and progesterone receptors (ER/PR) loss in endometrial cancer have not been studied extensively. The aims of this study were to determine the expression of DNA (cytosine-5)-methyltransferase 3A/3B (DNMT3A/3B) in endometrial cancer to investigate whether the methylation catalyzed by DNMT3A/3B contributes to low ER/PR expression. Methods: The clinicopathologic information and RNA-Seq expression data of DNMT3A/3B of 544 endometrial cancers were derived from The Cancer Genome Atlas (TCGA) uterine cancer cohort in May 2018. RNA-Seq level of DNMT3A/3B was compared between these clinicopathologic factors with t-test or one-way analysis of variance. Results: DNMT3A/3B was overexpressed in endometrioid carcinoma (EEC) and was even higher in non-endometrioid carcinoma (NEEC) (DNMT3A, EEC vs. NEEC: 37.6% vs. 69.9%, t = −7.440, P < 0.001; DNMT3B, EEC vs. NEEC: 42.4% vs. 72.8%, t = −6.897, P < 0.001). In EEC, DNMT3A overexpression was significantly correlated with the hypermethylation and low expression of the ESR1 and PGR (P < 0.05). The same trend was observed in the DNMT3B overexpression subgroup. In the ESR1/PGR low-expression subgroups, as much as 83.1% of ESR1 and 59.5% of PGR were hypermethylated, which was significantly greater than the ESR1/PGR high-expression subgroups (31.3% and 11.9%, respectively). However, the above phenomena were absent in NEEC, while DNMT3A/3B overexpression, ESR1/PGR hypermethylation, and low ER/PR expression occurred much more often. In univariate analysis, DNMT3A/3B overexpressions were significantly correlated with worse prognosis. In multivariate analysis, only DNMT3A was an independent predictor of disease-free survival (P < 0.05). Conclusions: DNMT3A/3B expression increases progressively from EEC to NEEC and is correlated with poor survival. The mechanisms underlying low ER/PR expression might be distinct in EEC vs. NEEC. In EEC, methylation related to DNMT3A/3B overexpression might play a major role in ER/PR downregulation.
Transcriptional Alterations by Ischaemic Postconditioning in a Pig Infarction Model: Impact on Microvascular Protection

Although the application of cardioprotective ischaemia/reperfusion (I/R) stimuli after myocardial infarction (MI) is a promising concept for salvaging the myocardium, translation to a clinical scenario has not fulfilled expectations. We have previously shown that in pigs, ischaemic postconditioning (IPostC) reduces myocardial oedema and microvascular obstruction (MVO), without influencing myocardial infarct size. In the present study, we analyzed the mechanisms underlying the IPostC-induced microvascular protection by transcriptomic analysis, followed by pathway analysis. Closed-chest reperfused MI was induced by 90 min percutaneous balloon occlusion of the left anterior descending coronary artery, followed by balloon deflation in anaesthetised pigs. Animals were randomised to IPostC (n = 8), MI (non-conditioned, n = 8), or Control (sham-operated, n = 4) groups. After three hours or three days follow-up, myocardial tissue samples were harvested and subjected to RNA-seq analysis. Although the transcriptome analysis revealed similar expression between IPostC and MI in transcripts involved in cardioprotective pathways, we identified gene expression changes responding to IPostC at the three days follow-up. Focal adhesion signaling, downregulated genes participating in cardiomyopathy and activation of blood cells may have critical consequences for microvascular protection. Specific analyses of the gene subsets enriched in the endothelium of the infarcted area, revealed strong deregulation of transcriptional functional clusters, DNA processing, replication and repair, cell proliferation, and focal adhesion, suggesting sustentative function in the endothelial cell layer protection and integrity. The spatial and time-dependent transcriptome analysis of porcine myocardium supports a protective effect of IPostC on coronary microvasculature post-MI.
Binomial Logistic Regression and Artificial Neural Network Methods to Classify Opioid-Dependent Subjects and Control Group Using Quantitative EEG Power Measures

Logistic regression (LR) and artificial neural networks (ANNs) are widely referred approaches in medical data classification studies. LR, a statistical fitting model, is suggested in medical problems because of its well-established methodology and coefficients contributing to the evaluation of clinical interpretations. ANNs are graphical models structured with node networks interconnected with arcs each of which is expressed in terms of weights discovered throughout the modeling process. Since ANNs have a complex structure with its layers and nodes in the layers, which provides ANNs the ability to model any data with complex relationships. Among the various models having origins in statistics and computer science, LR and ANNs have prevailed in the area of mass medical data classification. In this study, we introduce the 2 aforementioned approaches in order to generate a model dichotomizing 75 opioid-dependent patients and 59 control subjects from each other. Quantitative electroencephalography (QEEG) absolute power value of each electrode were calculated for 4 consecutive frequency bands namely delta, theta, alpha, and beta with the frequencies, 0.5 to 4, 4 to 8, 8 to 12, and 12 to 20 Hz, respectively. Significant independent variables contributing to the classification were underlined in LR while a feature selection (FS) method, genetic algorithm, is being applied to the ANN model to reveal more informative features. The performances of the classifiers were finally compared considering overall classification accuracies, area under receiver operating characteristic curve scores, and Gini coefficient. Although ANN-based classifier outperformed compared with LR, both models performed satisfactorily for absolute power measure in beta frequency band. Our results underline the potential benefit of the introduced methodology is promising and is to be treated as a clinical interface in dichotomizing substance use disorders subjects and for other medical data analysis studies.
Long noncoding RNA ABHD11-AS1 predicts the prognosis of pancreatic cancer patients and serves as a promoter by activating the PI3K-AKT pathway.

OBJECTIVE Accumulating evidence showed aberrant expressions of long non-coding RNAs (lncRNAs) strongly correlated to the development of cancers, including pancreatic cancer (PC). Whether lncRNA ABHD11-AS1 (ABHD11-AS1) is involved in PC remains to be elucidated. Thus, we aimed to evaluate the effects of ABHD11-AS1 on PC and the underlying molecular mechanism. PATIENTS AND METHODS RT-PCR was used to detect the expression level of ABHD11-AS1 in both PC tissue and cell lines. Then, the correlation of ABHD11-AS1 expression with clinicopathological features and prognosis was studied. Cell proliferation, apoptosis, migration and invasion abilities were detected by MTT, flow cytometry, and transwell assays. We further investigated the effect of abnormal ABHD11-AS1 expression through the PI3K/AKT and EMT pathway by Western blot assays in treated PC cells. RESULTS We found that the expression of ABHD11-AS1 was significantly increased in both PC tissues and cell lines. The clinical analysis revealed that a high level of ABHD11-AS1 expression was correlated with distant metastasis, TNM stage, and tumor differentiation. The Kaplan-Meier analysis showed that high ABHD11-AS1 expression levels predicted poorer survival. Moreover, univariate and multivariate analyses confirmed that the expression of ABHD11-AS1 was an independent and significant factor associated with poor overall survival rates. Loss-of-function experiments showed that the knockdown of ABHD11-AS1 suppressed PC cell proliferation, migration, invasion, and EMT in vitro. Mechanistically, the knockdown of ABHD11-AS1 decreased phospho(p) AKT and phospho(p) PI3K expression, but did not affect the AKT and PI3K expression in PC cells CONCLUSIONS: This study suggested that ABHD11-AS1 may potentially function as a valuable prognostic biomarker and a therapeutic target for PC patients.
Adiposity in middle and old age and risk of death from dementia: 40-year follow-up of 19,000 men in the Whitehall study

AIMS AND OBJECTIVES to examine the hypothesis that obesity is protective for dementia, we compared the associations of death from dementia with body weight and body mass index (BMI) in both middle and old age. DESIGN height and weight were measured in a prospective study of 19,019 middle-aged men in the Whitehall study in 1967-70 and in 6,158 surviving participants at resurvey in 1997. Cox regression was used to examine the associations of death from dementia over a 40-year period with weight or BMI measured by health professionals in middle and old age adjusting for age, smoking habits, employment grade and marital status. SETTING central government employees in London, UK. MAIN OUTCOMES MEASURE death due to dementia in 320 participants. RESULTS body weight measured in middle age was weakly inversely associated with death from dementia (hazard ratio 0.98 [95%CI: 0.97-0.99] per kg), but neither height nor BMI were related to risk of dementia. In contrast, body weight in old age was more strongly inversely related to deaths from dementia (0.96; [0.95-0.98] per kg) as was BMI (0.92 [0.86-0.97] per kg/m2). Weight loss over the 30 years between baseline and resurvey was associated with a higher risk of death from dementia, with an adjusted HR per kg/30 years of 1.04 [95%CI: 1.02-1.08] and the association with loss of BMI was even stronger (adjusted HR of 1.10 [1.03-1.19]) per kg/m2 decrease. CONCLUSIONS the stronger inverse associations of deaths from dementia with BMI in old age, compared with middle age, together with strong positive associations of loss of BMI or body weight between middle and old age casts doubt on previous suggestions that obesity protects against death from dementia.
Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study.

PURPOSE We determined the prognostic factors and utility of allogeneic hematopoietic cell transplantation among children with newly diagnosed hypodiploid acute lymphoblastic leukemia (ALL) treated in contemporary clinical trials. PATIENTS AND METHODS This retrospective study collected data on 306 patients with hypodiploid ALL who were enrolled in the protocols of 16 cooperative study groups or institutions between 1997 and 2013. The clinical and biologic characteristics, early therapeutic responses as determined by minimal residual disease (MRD) assessment, treatment with or without MRD-stratified protocols, and allogeneic transplantation were analyzed for their impact on outcome. RESULTS With a median follow-up of 6.6 years, the 5-year event-free survival rate was 55.1% (95% CI, 49.3% to 61.5%), and the 5-year overall survival rate was 61.2% (95% CI, 55.5% to 67.4%) for the 272 evaluable patients. Negative MRD at the end of remission induction, high hypodiploidy with 44 chromosomes, and treatment in MRD-stratified protocols were associated with a favorable prognosis, with a 5-year event-free survival rate of 75% (95% CI, 66.0% to 85.0%), 74% (95% CI, 61.0% to 89.0%), and 62% (95% CI, 55.0% to 69.0%), respectively. After exclusion of patients with high hypodiploidy with 44 chromosomes and adjustment for waiting time to transplantation and for covariables in a Poisson model, disease-free survival did not differ significantly ( P = .16) between the 42 patients who underwent transplantation and the 186 patients who received chemotherapy only, with an estimated 5-year survival rate of 59% (95% CI, 46.5% to 75.0%) versus 51.5% (95% CI, 44.7% to 59.4%), respectively. Transplantation produced no significant impact on outcome compared with chemotherapy alone, especially among the subgroup of patients who achieved a negative MRD status upon completion of remission induction. CONCLUSION MRD-stratified treatments improved the outcome for children with hypodiploid ALL. Allogeneic transplantation did not significantly improve outcome overall and, in particular, for patients who achieved MRD-negative status after induction.
The Potential Role of Dietary Antioxidant Capacity in Preventing Age-Related Macular Degeneration

Abstract Objectives: Age-related macular degeneration (AMD) is a progressive disorder among people aged ≥50 years. Some dietary factors associated with the susceptibility to AMD include dietary glycemic index and glycemic load, as well as intake of antioxidants and other nutrients, such as vitamins, minerals, and dietary fatty acids. Methods: This case-control study was conducted between July 2015 and February 2016 on 100 case subjects with AMD and 100 healthy controls without AMD. The participants were recruited from the Department of Ophthalmology of Hacettepe University Hospitals in Ankara, Turkey. Dietary intake was estimated from a 3-day food intake record and food frequency questionnaire, and anthropometric measurements were recorded. The relationship between nutritional factors and AMD was assessed using logistic regression. Results: Dietary total antioxidant intake of AMD group was found to be lower (p < 0.05) than that of healthy individuals. In a multivariate analysis, smoking, daily red meat intake, omega-6 intake, and higher glycemic index were identified as risk factors for AMD development. Meanwhile, daily fruit intake, daily fish intake, omega-3 intake, and zinc intake were associated with a protective effect. However, no difference was found in dietary total antioxidant capacity. Conclusions: In this study, a high dietary intake of carotenoids, vitamins C and E, zinc, and omega-3, as well as maintaining optimal waist circumference, were found to substantially reduce the risk of developing AMD in people aged >50 years. By contrast, in addition to smoking and old age, obesity, high red meat intake, and omega-6 intake might increase the risk of developing AMD. Therefore, a better understanding of nutritional risk factors is necessary for preventing AMD.
IL‐17R deletion predicts high‐grade colorectal cancer and poor clinical outcomes

The IL‐17 receptor (IL‐17R) has a perplexing role in cancer, which may be explained by its yin‐yang signaling pathways. Recently, the critical role of IL‐17R in maintaining basal levels of A20—a key negative regulator of NF‐κB and JNK‐c‐Jun pathways has been demonstrated in cancer cell lines. Cross‐cancer analyses of somatic copy number alterations in IL‐17RA, IL‐17RC and A20 genes reveal that IL‐17RA‐deletion is common in colorectal cancer (CRC) patients, representing 24, 26, 37 and 49% of stage I, II, III and IV of patients, respectively, and mutually exclusive with patients displaying microsatellite instability. Importantly, patients with IL‐17R‐deletion or concurrent deletions of A20 show significantly reduced overall survival. Analysis of multiple published microarray studies confirms that IL‐17RA expression is significantly reduced in CRC samples compared to normal counterparts, and its level is closely associated with A20 expression. Analyses of RNAseq data indicate that tumors with IL‐17R‐deletion express strong molecular markers of tumor invasion, growth and metastasis. Notably, approximately 20 genes responsible for protein synthesis and mitochondrial metabolism are inversely correlated with both IL‐17RA and A20. Immunohistochemistry staining in human colorectal tissue arrays further reveals that high‐grade tumors have significantly reduced IL‐17RA staining compared to low‐grade tumors. Thus, collective evidence strongly supports a previously unrecognized CRC‐promoting mechanism triggered by IL‐17RA‐deletion and highlights its utility as a prognostic marker in CRC.