Miracle-dz/UniFAR-FTUs huggingface dataset:
Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice

Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug‐induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long‐term use. The present study aimed to investigate the role of FXR in OA‐induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR−/−) mice. The results showed that a significant alleviation in OA‐induced cholestatic liver injury was observed in FXR−/− mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC‐MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR−/− mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR−/− mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR−/− mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA‐induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes.
Identifying and managing adverse drug reactions: Qualitative analysis of patient reports to the UK yellow card scheme

Adverse drug reactions (ADRs) can have significant negative impact on peoples' daily lives, with physical, economic, social and/or psychological effects. Patient reporting of ADRs has been facilitated by pharmacovigilance systems across Europe. However, capturing data on patients' experiences of ADRs has proved challenging. Existing patient reports to the UK Yellow Card Scheme contain free‐text comments which could be useful sources of information.
SIMULATION OF ORGANIC RANKINE CYCLE THROUGH FLUEGAS TO LARGE SCALE ELECTRICITY GENERATION PURPOSE

A simulation model of Organic Rankine Cycle (ORC) was developed with HYSYS software driven by R245fa, with NOVEC7000 and R141b as working fluids and Fluegas of boilers as a heat source of shell and tube Heat Exchanger to generate large scale electricity. The initial working condition was in subcooled liquid and steady state condition. R141b was found to generate the highest electricity power increment in specific mass flow rates and inlet pressures of Expander because of approaching its critical temperature to inlet Fluegas temperature. Howeever, in terms of economic considerations and cost of shell and tube Heat Exchanger that related to total heat transfer capacity, NOVEC7000 is the optimum selection. Furthermore, R245fa has the highest total effiiciency of ORC compared with other working fluids in this study.
Molecular insights into the primary nucleation of polymorphic amyloid β dimers in DOPC lipid bilayer membrane

Alzheimer's disease (AD) pathology is characterized by loss of memory cognitive and behavioral deterioration. One of the hallmarks of AD is amyloid β (Aβ) plaques in the brain that consists of Aβ oligomers and fibrils. It is accepted that oligomers, particularly dimers, are toxic species that are produced extracellularly and intracellularly in membranes. It is believed that the disruption of membranes by polymorphic Aβ oligomers is the key for the pathology of AD. This is a first study that investigate the effect of polymorphic “α‐helix/random coil” and “fibril‐like” Aβ dimers on 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine (DOPC) membrane. It has been found that the DOPC membrane promotes Aβ1–42 “fibril‐like” dimers and impedes Aβ1–42 “α‐helix/random coil” dimers. The N‐termini domains within Aβ1–42 dimers play a role in Aβ aggregation in membrane milieus. In addition, the aromatic π–π interactions (involving residues F19 and F20 in Aβ1–42) are the driving forces for the hydrophobic interactions that initiate the primary nucleation of polymorphic Aβ1–42 dimers within DOPC membrane. Finally, the DOPC bilayer membrane thickness is locally decreased, and it is disrupted by an embedded distinct Aβ1–42 dimer, due to relatively large contacts between Aβ1–42 monomers and the DOPC membrane. This study reveals insights into the molecular mechanisms by which polymorphic early‐stage Aβ1–42 dimers have distinct impacts on DOPC membrane.
Clinicopathologic Evaluation and Molecular Profiling of Recurrent Stage IA Endometrial Endometrioid Carcinoma: A Case-control Study

Most low-grade, early-stage endometrial endometrioid carcinomas (EEC) have an excellent prognosis; however, recurrences occur in a small subset with several studies reporting an increase in CTNNB1 exon 3 mutations in this population. Herein we evaluated 10 recurrent low-grade (FIGO 1 or 2), early-stage (FIGO IA) EECs matched to 10 nonrecurrent EECs to further characterize their clinicopathologic features and molecular phenotype. Cases were matched to controls based on size, grade, and depth of invasion. All tumors were evaluated for specific clinicopathologic parameters followed by next-generation sequencing using a 1213 gene panel. Recurrent EECs demonstrated no significant clinicopathologic differences when compared with nonrecurrent EECs, in terms of age, body mass index, pattern of invasion, presence of endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia, associated metaplastic changes, peritumoral lymphocytes, mitoses, and tumor-infiltrating lymphocytes. Both cohorts also showed a similar number of pathogenic mutations, including CTNNB1 exon 3 mutations, as well as tumor mutational burden and microsatellite profiles. Although in this particular study, the lack of correlation between CTNNB1 exon 3 mutation and recurrence might be secondary to a small sample size, it also suggests the presence of other contributing factors. Thus, it helps set the foundation for larger series incorporating whole genome, transcriptome, proteome, and epigenome analyses to answer this clinically important question.
Differences in hospitalisation between peritoneal dialysis and haemodialysis patients

Dialysis is associated with frequent hospitalisations. Studies comparing hospitalisations between peritoneal dialysis (PD) and haemodialysis (HD) report conflicting results and mostly analyse data of patients that remain on their initial dialysis modality. This cohort study compares hospitalisations between PD and HD patients taking into account transitions between modalities.
Loot box engagement: relationships with educational attainment, employment status and earnings in a cohort of 16 000 United Kingdom gamers

Abstract Background and Aims Loot boxes are purchasable randomised rewards in video games that share structural and psychological similarities with gambling. Systematic review evidence has established reproducible associations between loot box purchasing and both problem gambling and problem video gaming. We aimed to measure the association between loot box engagement and socioeconomic correlates. Design The study was a cross‐sectional online survey using the recruitment platform, Prolific. Setting United Kingdom (UK). Participants A cohort of 16 196 UK adults (18 + years) self‐reporting as video gamers. Measurements Respondents were asked about their game‐related purchasing behaviour (including loot boxes), recent monthly spend on loot boxes and gambling engagement (gambling in any form; gambling online; playing ‘social casino’ games). A range of demographic variables were simultaneously captured, including age, sex, ethnicity, earnings, employment and educational attainment. Findings Overall, 17.16% of gamers in our cohort purchased loot boxes, with a mean self‐reported monthly spend of £29.12. These loot box purchasers are more likely to gamble (45.97% gamble) than people who make other types of game‐related purchases (on aggregate, 28.13% of non‐loot box purchasers gamble), and even greater still than those who do not make any game related purchases (24.38% gamble P < 0.001). Loot box engagement (as binary yes/no or as monthly spend normalised to earnings) was significantly associated with younger age (P < 0.001 and P < 0.001; respectively, for binary yes/no and monthly spend, adjusted for false discovery rate correction), male sex (P < 0.001 and P = 0.025), non‐university educational attainment (P < 0.001 and P < 0.001) and unemployment (P = 0.003 and P = < 0.001). Lower earners spent a higher proportion of monthly earnings on loot boxes (P < 0.001). Conclusions The demographic associations of video game loot box engagement (younger age, male sex, non‐university educational attainment and unemployment) mirror those of other addictive and problematic behaviours, including disordered gambling, drug and alcohol misuse.
Antibody profiles in COVID‐19 convalescent plasma prepared with amotosalen/UVA pathogen reduction treatment

COVID‐19 convalescent plasma (CCP), from donors recovered from severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection, is one of the limited therapeutic options currently available for the treatment of critically ill patients with COVID‐19. There is growing evidence that CCP may reduce viral loads and disease severity; and reduce mortality. However, concerns about the risk of transfusion‐transmitted infections (TTI) and other complications associated with transfusion of plasma, remain. Amotosalen/UVA pathogen reduction treatment (A/UVA‐PRT) of plasma offers a mitigation of TTI risk, and when combined with pooling has the potential to increase the diversity of the polyclonal SARS‐CoV‐2 neutralizing antibodies.
Electrophilic warheads in covalent drug discovery: an overview

ABSTRACT Introduction Covalent drugs have been used for more than hundred years, but gathered larger interest in the last two decades. There are currently over a 100 different electrophilic warheads used in covalent ligands, and there are several considerations tailoring their reactivity against the target of interest, which is still a challenging task. Areas covered This review aims to give an overview of electrophilic warheads used for protein labeling in chemical biology and medicinal chemistry. The warheads are discussed by targeted residues, mechanism and selectivity, and analyzed through three different datasets including our collection of warheads, the CovPDB database, and the FDA approved covalent drugs. Moreover, the authors summarize general practices that facilitate the selection of the appropriate warhead for the target of interest. Expert opinion In spite of the numerous electrophilic warheads, only a fraction of them is used in current drug discovery projects. Recent studies identified new tractable residues by applying a wider array of warhead chemistries. However, versatile, selective warheads are not available for all targetable amino acids, hence discovery of new warheads for these residues is needed. Broadening the toolbox of the warheads could result in novel inhibitors even for challenging targets developing with significant therapeutic potential.
Role of innate immune receptors TLR4 and TLR2 polymorphisms in systemic lupus erythematosus susceptibility

Through their recognition of various bacterial cell wall components, TLR2 and TLR4 participate in the innate response and modulate the activation of adaptive immunity. Therefore, the genetic background of these receptors might play a crucial role in autoimmune diseases such as systemic lupus erythematosus (SLE). In this study, we investigated the possible association between polymorphisms within TLR2 and TLR4 genes with SLE susceptibility.
The Role of Palliative Surgery in Stage IV Gastric Cancer: A Retrospective Study

Background: Palliative chemotherapy is the mainstay of treatment for metastatic gastric adenocarcinoma but in some patients, surgically correctable factors such as obstruction lead to intolerance of further systemic treatment. The aim of this study was to evaluate the role of selective palliative surgery in incurable gastric cancer. Methods: All patients with stage IV and locally advanced unresectable gastric adenocarcinoma treated at a single centre from March 2006 to January 2019 were included. Data were retrieved from a prospectively maintained database. Patients were categorized into palliative surgery (PS) and no surgery (NS). Results: Of 666 patients with gastric cancer treated over the study period, 146 patients had stage IV gastric adenocarcinoma and 121 patients met inclusion criteria. Sites of metastases were peritoneum (55; 46%), non-regional lymph nodes (10; 8%), solid organ (17, 14%), adjacent organ invasion (4, 3.3%) and a combination of factors (32, 26%). Forty-six (38%) patients underwent palliative surgery which included anatomical gastrectomy (total, subtotal, distal or proximal, 78%) gastro-jejunal bypass and feeding jejunostomy (12%). Thirty-day post-operative complications occurred in 24 patients (52%) with one mortality (2.1%). Following surgery, 52% received systemic chemotherapy. For the PS and NS groups respectively, median overall survival was 9.1 versus 9.4 months (p = 0.6) and median progression-free survival was 7.1 versus 6.7 months (p = 0.2) after a follow up period of 7.3 (4.7-13.1) versus 7.8 (2.6-13.4) months (p = 0.46). Conclusion: Targeted surgical intervention for incurable gastric cancer can be used to palliate symptoms and facilitate continuation of systemic therapy with acceptable risks and post-operative outcomes.
Longitudinal Patterns of Alcohol Use Following Traumatic Brain Injury in an Active Duty and Young Veteran Military Sample: A VA TBI Model Systems Study

Objective: To describe alcohol use among younger military active duty service members and veterans (SMVs) in the first 5 years after traumatic brain injury (TBI) and examine whether differential alcohol use patterns emerge as a function of brain injury severity and active duty service at time of injury. Setting: Veterans Affairs (VA) Polytrauma Rehabilitation Centers (PRCs). Participants: In total, 265 SMVs enrolled in the VA Traumatic Brain Injury Model Systems (TBIMS) PRC national database. Participants sustained a TBI of any severity level; received inpatient care at a PRC within 1 year of injury; were younger than 40 years; and completed survey interviews or questionnaires regarding their pre- and postinjury alcohol use for at least 3 of 4 time points (preinjury, postinjury years 1, 2, and 5). Main Measures: Self-reported alcohol use, defined as amount of weekly consumption and endorsement of binge drinking. Participant information related to demographics, injury, TBI severity, active duty status, mental health treatment, and FIM (Functional Independence Measure) total scores was also obtained to examine impact of these as covariates in the analyses. Results: Alcohol use generally increased following an initial period of reduced consumption for SVMs with moderate-to-severe TBI. Individuals with mild TBI showed an opposite trend, with an initial period of increased use, followed by a decline and return to baseline levels in the long term. However, alcohol use did not significantly differ over time within this subsample after adjusting for covariates. Conclusions: The current study identified longitudinal alcohol use among a young, military/veteran cohort with a history of TBI, an at-risk population for problematic alcohol use. Patterns of self-reported alcohol consumption suggest the time frame of 2 to 5 years postinjury may be a critical window of opportunity for further intervention to maintain lowered levels of alcohol use, particularly among SVMs with moderate-to-severe TBI.
Design, synthesis, and in vitro antiplatelet aggregation activities of taiwanin C

Abstract Total synthesis of taiwanin C was realised efficiently in a global yield of 52%. Taiwanin C in aggregation assays inhibited platelet aggregation in a concentration-dependent manner with an IC50 of 0.46 μM after exposure of human platelet to AA. Similarly, to AA, taiwanin C inhibited significantly TRAP-6-induced platelet aggregation with IC50 of 0.56 μM. Molecular docking studies were carried out using the molecular target the COX-1, COX-2 and PAR-1 proteins. These studies suggest that taiwanin inhibits COX-1 more strongly than COX-2. Taiwanin C showed better antiplatelet action in the presence of TRAP-6 than indomethacin and molecular docking studies suggest different mechanisms of action for the two compounds on PAR-1. These results demonstrate that taiwanin C acts very efficiently in two different signaling pathways of platelet aggregation. Although preliminary, these results indicate that taiwanin C has potential for further studies on its use for the development of new antiplatelet. Graphical Abstract
Implementation strategies for high‐performance health care simulation centres: A multicentre exploratory case study in China

The number of health care simulation centres (HSCs) in mainland China has increased exponentially recently. However, the performance of these centres varies significantly between hospitals. The aim of this study is to address two research questions: (i) what are the critical factors for implementing high‐performance HSCs and (ii) how are these critical factors used in the development of implementation strategies to achieve satisfactory performance?
Vedolizumab for perianal fistulizing Crohn’s disease: systematic review and meta-analysis

Background/Aims Perianal fistulas are a debilitating manifestation of Crohn’s disease (CD). Despite the advent of anti-tumor necrosis factor (anti-TNF) therapy, the medical management of fistulizing CD continues to be challenged by unmet needs. We conducted a systematic review and meta-analysis of the effectiveness of vedolizumab for the management of perianal fistulizing CD. Methods A search of PubMed, EMBASE and the Cochrane Library was performed from inception to June 2020 for studies reporting rates of perianal fistula healing in CD patients treated with vedolizumab. The primary outcome of interest was complete healing of perianal fistulas and the secondary outcome was partial healing. The pooled fistula healing rates with 95% confidence intervals (CI) were calculated utilizing a random effects model. Results A total of 74 studies were initially identified, 4 of which met the inclusion criteria. A total of 198 patients with active perianal fistulas were included, 87% of whom had failed previous anti-TNF therapy. The pooled complete healing rate was 27.6% (95% CI, 18.9%–37.3%) with moderate heterogeneity (I2=49.4%) and the pooled partial healing rate was 34.9% (95% CI, 23.2%–47.7%) with high heterogeneity (I2=67.1%). Conclusions In a meta-analysis of 4 studies that included 198 patients with perianal fistulizing CD, the majority of whom had failed previous anti-TNF therapy, vedolizumab treatment led to healing of perianal fistulas in nearly one-third of the patients. The lack of high-quality data and significant study heterogeneity underscores the need for future prospective studies of fistula healing in patients receiving anti-integrin therapy.
The continuous laryngoscopy exercise test in severe or in difficult-to-treat asthma in adults: a systematic review

Abstract Objective A systematic review was performed to determine if the continuous laryngoscopy exercise test (CLE) has been used in the diagnostics of exercise dyspnea in adults with asthma, and whether inducible laryngeal obstruction (ILO) is found in those with asthma or with severe or difficult-to-treat asthma. Data Sources We used Scopus and PubMed databases. The articles published up to 13 August 2019 were considered. Study Selections We excluded manuscripts that did not contain information about adult patients with asthma. We included six studies from 59 search results in Scopus and none from the 17 search results in PubMed. Results The articles included 455 study individuals. Of these, 229 (50.3%) had diagnosed asthma or were treated with asthma medication. Altogether 31/229 (13.5%) subjects with diagnosis of asthma or previous asthma treatment had exercise-induced laryngeal obstruction (EILO) as comorbidity. The CLE test was performed on 229 patients with asthma. The method was used only for differential diagnosis of exercise-induced dyspnea to confirm EILO. At least 10/455 (2.2%) out of the 455 subjects experienced adverse events. Conclusions This systematic review revealed that only a small proportion of patients with asthma had undergone the CLE test to assess exercise-induced dyspnea. None of the selected manuscripts reported severity of asthma. Whether CLE provides a valuable diagnostic tool for patients with severe or difficult-to-treat asthma cannot be determined according to this review.
IGF2BP2 maybe a novel prognostic biomarker in oral squamous cell carcinoma

Abstract Aim: The main of the present study was to investigate the role of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in oral squamous cell carcinoma (OSCC) with the overarching of providing new biomarkers or potential therapeutic targets for OSCC. Methods: We combined datasets downloaded from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and samples collected from the clinic to evaluate the expression of IGF2BP2 in OSCC. IGF2BP2 survival analysis was respectively performed based on TCGA, GEO, and clinical samples. Correlations between IGF2BP2 expression and clinicopathological parameters were then analyzed, and signaling pathways associated with IGF2BP2 expression were identified using gene set enrichment analysis (GSEA 4.1.0). Moreover, an IGF2BP2 co-expressed gene network was constructed, followed by gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on IGF2BP2 co-expressed genes. Finally, TIMER and CIBERSORT were used to analyze the correlations among IGF2BP2, IGF2BP2-coexpressed genes, and tumor-infiltrating immune cells (TICs). Results: IGF2BP2 was highly expressed in OSCC and significantly correlated with overall survival of OSCC patients (P<0.01). High IGF2BP2 expression correlated with poor overall survival. The GSEA results showed that cell apoptosis-, tumor-, and immune-related pathways were significantly enriched in samples with high IGF2BP2 expression. Furthermore, GO and KEGG enrichment analyses results of IGF2BP2 co-expressed genes indicated that these genes are mainly associated with immunity/inflammation and tumorigenesis. In addition, IGF2BP2 and its co-expressed genes are associated with TICs (P<0.01). Conclusion: IGF2BP2 may be a potential prognostic biomarker in OSCC and correlates with immune infiltrates.