Gut Microbiota-Derived Butyrate Induces Epigenetic and Metabolic Reprogramming in Myeloid-Derived Suppressor Cells to Alleviate Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC. METHODS: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model. RESULTS: Decreased butyrate levels and defective MDSCs function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid ß-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone 3 modifications at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate. CONCLUSIONS: We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.

Associations between new obesity indices and abnormal bone density in type 2 diabetes mellitus patients.

The clinical data analysis found that, compared with the traditional obesity index, the waist-weight ratio (WWR) has more advantages in predicting abnormal bone mineral density in subjects with type 2 diabetes. WWR may serve as a new predictive indicator for osteoporosis in T2DM patients. PURPOSE: This study was designed to explore the correlation between obesity-related indices and bone mineral density (BMD) and its influencing factors in type 2 diabetes mellitus (T2DM) patients. METHODS: A total of 528 patients with type 2 diabetes were recruited. Glucose tolerance, insulin stimulation, and blood biochemical tests were conducted on all participants. All subjects underwent dual-energy X-ray bone density testing and were grouped based on the bone density results. RESULTS: Compared with those in the normal BMD group, the waist-to-body weight ratio (WWR) and weight-adjusted-waist index (WWI) in the osteopenia and osteoporosis groups were significantly greater, while body mass index (BMI) was significantly lower (P < 0.05). The logistic regression results showed that the WWR, WWI, and BMI were independently correlated with abnormal BMD in T2DM patients (P < 0.05). WWR and the WWI were negatively correlated with the T-value of bone density in various parts of the body, while BMI was positively correlated with the T-value of bone density (P < 0.05). The area under the working characteristic curve (AUC) for T2DM patients with abnormal bone mass predicted by the WWR [0.806, 95% CI = (0.770-0.843), P < 0.001] was greater than that for patients with other obesity indicators, such as the WWI and BMI. CONCLUSION: We found a positive correlation between the WWR and bone density in T2DM patients. Compared with other obesity indicators, such as BMI and WWI, the WWR has a stronger discriminative ability for T2DM patients with abnormal bone density. Therefore, more attention should be given to the WWR in T2DM patients.

Intestinal microbiota in biliary diseases.

PURPOSE OF REVIEW: Biliary diseases are a group of disease affecting biliary tract, including immune-mediated primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). With limited treatment options, PBC and PSC may lead to liver cirrhosis. RECENT FINDINGS: Emerging evidence has shown the participation of gut microbiota in the etiology of PBC and PSC. Patients with PBC and PSC exhibit alterations in gut microbiota composition. Dysfunctional gut barrier facilitates the translocation of possible pathogenic bacteria and derived metabolites. Along with molecular mimicry between host and bacterial antigen, these factors result in aberrant auto-immune activation, and subsequently lead to liver injury. Though the precise mechanism has not been fully elucidated, studies investigating the role of gut microbiota in pathogenesis of PBC and PSC have inspired novel biomarkers and therapeutic strategies. SUMMARY: In this review, recent evidence on the alteration of intestinal microbiota and possible mechanistic and therapeutic applications are discussed, predominantly focusing on PSC and PBC.

Effects of dexmedetomidine on postoperative sleep quality: a systematic review and meta-analysis of randomized controlled trials.

STUDY OBJECTIVES: To assess the effect of dexmedetomidine (DEX) on postoperative sleep quality using polysomnography (PSG) to identify possible interventions for postoperative sleep disturbances. METHODS: An electronic search of PubMed/MEDLINE, EMBASE, Cochrane Library and Web of Science was conducted from database inception to November 20, 2022. Randomized controlled trials (RCTs) on the effect of DEX administration on postoperative sleep quality using PSG or its derivatives were included. No language restrictions were applied. The sleep efficiency index (SEI), arousal index (AI), percentages of stage N1, N2 and N3 of non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were measured in our meta-analysis. RESULTS: Five studies, involving 381 participants were included. Administration of DEX significantly improved SEI, lowered AI, decreased the duration of stage N1 sleep and increased the duration of stage N2 sleep compared to placebo groups. There were no significant differences in the duration of stage N3 sleep and REM sleep. DEX administration lowered the postoperative Visual Analogue Scale (VAS) score and improved the Ramsay sedation score with no adverse effect on postoperative delirium (POD). However, high heterogeneity was observed in most of the primary and secondary outcomes. CONCLUSIONS: Our study provides support for the perioperative administration of DEX to improve postoperative sleep quality. The optimal dosage and overall effect of DEX on postoperative sleep quality require further investigation using large-scale randomized controlled trials.

Altered faecal microbiome and metabolome in IgG4-related sclerosing cholangitis and primary sclerosing cholangitis.

OBJECTIVE: Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC. DESIGN: We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling. RESULTS: Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host-microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host-microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes. CONCLUSIONS: Our data reveal that IgG4-SC and PSC possess divergent host-microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.

NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis.

BACKGROUND & AIMS: Pyruvate dehydrogenase (PDC)-E2 specific CD8+ T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8+ T cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8+ T-cell subpopulations and investigate their immunobiology in PBC. METHODS: Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103+ TRM cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of TRM cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of TRM cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model. RESULTS: Intrahepatic CD103+ TRM (CD69+CD103+CD8+) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103+ TRM cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103+ TRM cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8+ T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103+ TRM cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8+ T-cell tissue-residency via the PARP1-TGFßR axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103+ TRM cell durable survival and TGFß-Smad signaling. CONCLUSIONS: CD103+ TRM cells are the dominant population of PDC-E2-specific CD8+ T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103+ TRM cell accumulation and longevity represents a novel therapeutic target in PBC. LAY SUMMARY: Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8+ T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8+ T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.

Neutrophil-derived lipocalin-2 in adult-onset Still's disease: a novel biomarker of disease activity and liver damage.

OBJECTIVE: Liver damage is a common manifestation and can be life-threatening in adult-onset Still's disease (AOSD), an autoinflammatory disease. The hallmark of AOSD is activation of neutrophils, whose infiltration in liver is suspected to promote tissue injury. Here we aimed to identify a candidate biomarker and to validate its association with liver damage in AOSD. METHODS: Transcriptome analysis of neutrophils from treatment-naïve active AOSD patients and healthy donors was performed. Lipocalin-2 (LCN2) expression was assessed in neutrophils, plasma and liver biopsies of AOSD. The correlations of LCN2 with different variables and its ability to identify liver damage from AOSD patients were analysed. RESULTS: LCN2, a novel biomarker in hepatic inflammation, was found to be upregulated in AOSD neutrophils by RNA sequencing and confirmed at the mRNA and protein levels. Plasma levels of LCN2 were significantly higher in AOSD patients than healthy controls, RA and SLE patients. Plasma LCN2 levels were closely correlated with inflammatory markers, systemic score, HScore and cytokines. Moreover, LCN2 levels were increased in active AOSD with liver involvement and independently associated with liver dysfunction. Enhanced expression of LCN2 was detected in liver biopsies from three patients with ongoing liver injury. Furthermore, the area under the curve value of LCN2 for identifying AOSD with liver injury from other liver diseases was 0.9694. CONCLUSION: Our results reveal that neutrophils-derived LCN2 is higher in plasma and liver tissue in AOSD patients than in healthy controls, and it could serve as a potent biomarker for identifying AOSD with systemic inflammation, especially liver damage caused by hyperinflammation.

Factors influencing smoking behaviour of online ride-hailing drivers in China: a cross-sectional analysis.

BACKGROUND: Online ride-hailing is a fast-developing new travel mode. However, tobacco control policies on its drivers remain underdeveloped. This study aims to reveal the status and determine the influencing factors of ride-hailing drivers' smoking behaviour to provide a basis for the formulation of tobacco control policies. METHODS: We derived our cross-sectional data from an online survey of full-time ride-hailing drivers in China. We used a survey questionnaire to collect variables, including sociodemographic and work-related characteristics, health status, health behaviour, health literacy and smoking status. Finally, we analysed the influencing factors of current smoking by conducting chi-square test and multivariate logistic regression. RESULTS: A total of 8990 ride-hailing drivers have participated in the survey, in which 5024 were current smokers, accounting to 55.9%. Nearly one-third of smokers smoked in their cars (32.2%). The logistic regression analysis results were as follows: male drivers (OR = 0.519, 95% CI [0.416, 0.647]), central regions (OR = 1.172, 95% CI [1.049, 1.309]) and eastern regions (OR = 1.330, 95% CI [1.194, 1.480]), working at both daytime and night (OR = 1.287, 95% CI [1.164, 1.424]) and non-fixed time (OR = 0.847, 95% CI [0.718, 0.999]), ages of 35-54 years (OR = 0.585, 95% CI [0.408, 0.829]), current drinker (OR = 1.663, 95% CI [1.526, 1.813]), irregular eating habits (OR = 1.370, 95% CI [1.233, 1.523]), the number of days in a week of engaging in at least 10 min of moderate or vigorous exercise ≥3 (OR = 0.752, 95% CI [0.646, 0.875]), taking the initiative to acquire health knowledge occasionally (OR = 0.882, 95% CI [0.783, 0.992]) or frequently (OR = 0.675, 95% CI [0.591, 0.770]) and underweight (OR = 1.249, 95% CI [1.001, 1.559]) and overweight (OR = 0.846, 95% CI [0.775, 0.924]) have association with the prevalence of current smoking amongst online ride-hailing drivers. CONCLUSION: The smoking rate of ride-hailing drivers was high. Sociodemographic and work-related characteristics and health-related factors affected their smoking behaviour. Psychological and behavioural interventions can promote smoking control management and encourage drivers to quit or limit smoking. Online car-hailing companies can also establish a complaint mechanism combined with personal credit.

The wound severity of animal bite victims visiting rabies prevention clinics and the influencing factors in Central China: a cross-sectional investigation.

BACKGROUND: Animal bites are a major public health problem. The more serious the bite wound is, the higher the risk of developing rabies is. This study aimed to investigate the severity of wounds among animal bite victims and identify the influencing factors in Wuhan, China. METHODS: A cross-sectional study was conducted among 1015 animal bite victims visiting rabies prevention clinics. We performed a face-to-face interview to collect information on the exposure category of the bite wound, the type of the offending animal, exposure-to-risk situations, etc. Factors associated with exposure categories were identified by multivariate logistic regression analysis. RESULTS: Five hundred and sixty-four (55.57%) cases were category III exposures, 418 (41.18%) were category II exposures, and 33 (3.25%) were category I exposures. People who were hurt by their own domestic animals (odds ratio [OR] = 1.55, 95% confidence interval [CI]: 1.14-2.10), and those exposed to animals unvaccinated against rabies (OR = 1.45, 95% CI: 1.08-1.95) had a higher risk for category III exposures. Respondents who did not know the fatality of rabies were more likely to be injured seriously compared to those who knew that rabies is fatal, and the OR was 1.40 (95% CI, 1.05-1.86). CONCLUSIONS: This study showed that factors associated with the severity of bite wounds mainly included types of the offending animal, vaccination status of the animal, and knowledge of rabies fatality. Educational programs and awareness-raising campaigns should be provided to decrease severe animal bites, especially targeting pet owners and those with limited rabies knowledge.

A national survey of turnover intention among general practitioners in China.

Studies on turnover intention among Chinese general practitioners (GPs) at the national level are limited. This study aimed to assess intention to leave and its associated factors among a nationally representative sample of GPs. The participants were selected using a multistage stratified random sampling method. A self-administered structured questionnaire was used to collect data from 3236 GPs in China between October 2017 and February 2018. A multiple linear stepwise regression analysis was used to identify factors associated with turnover intention. Over 70.0% GPs had a moderate or high turnover intention. GPs who were male, were younger, had a higher education level, had a lower professional title, had a lower income level, and had a temporal work contract had higher turnover intention. In addition, GPs who worked night shifts, had low job satisfaction, and had few opportunities for professional development reported higher turnover intention. Substantial gender and regional differences in predictors of turnover intention among GPs were observed. The study showed that turnover intention in Chinese GPs is high, and the factors influencing turnover intention were low professional title and income level, high education level, having a temporary work contract, working night shifts, and limited opportunities for professional development.

Knowledge, attitude and associated factors towards tuberculosis in Lesotho: a population based study.

BACKGROUND: Lesotho has one of the highest rates of tuberculosis (TB) incidence and TB-HIV co-infection in the world. Our study aimed to assess the knowledge, attitude and associated factors towards TB in the general population of Lesotho. METHODS: A cross-sectional analysis from the Lesotho Demographic and Health Survey (LDHS) 2014 was carried out among 9247 respondents. We used the chi-square test as well as univariate and multivariate logistic regression analyses to assess the associations of socio-demographic variables with respondent knowledge of and attitude towards TB. RESULTS: The overall knowledge of TB in the general population of Lesotho was adequate (59.9%). There was a significant difference between female and male respondents regarding knowledge about TB (67.0% vs. 41.8%). Almost 95% of respondents had "heard of an illness called tuberculosis", and 80.5% knew that TB can be cured. Only 11.5% knew the correct cause of TB (TB is caused by Mycobacterium tuberculosis). Female respondents were relatively aware of TB, knew about the correct cause and mode for transmission of TB and knew that TB is a curable disease compared to male respondents. A higher proportion of respondents (72.8%) had a positive attitude towards TB. Multivariate logistic regression analysis showed that sex (adjusted odds ratio [AOR] = 2.45, 95% CI: 2.10-2.86; p < 0.001), age (AOR) =1.76, 95% CI: 1.29-2.41; p < 0.001), educational level (AOR = 6.26, 95% CI: 3.90-10.06; p < 0.001), formerly married or cohabitated (AOR = 1.42, 95% CI: 1.10-1.85; p = 0.008), mass media exposure (AOR = 1.33, 95% CI: 1.08-1.64; p = 0.008) and occupation (AOR = 1.20, 95% CI: 1.00-1.44; p = 0.049) were strongly associated with respondent knowledge of TB. Sex (AOR = 1.19, 95% CI: 1.01-1.41; p = 0.034), educational level (AOR = 1.661, 95% CI: 06-2.60; p = 0.028), mass media exposure (AOR = 1.31, 95% CI: 1.06-1.62; p = 0.012) and occupation (AOR = 1.26, 95% CI: 1.04-1.52; p = 0.016) were strongly associated with respondent attitude towards TB. CONCLUSION: Strategies to improve the knowledge of Lesotho's people about TB should focus on males, young residents, those who are illiterate, those who are unmarried and farmers. Special attention should be given to males, young residents, rural residents, those who are illiterate and farmers to improve their attitude towards TB in Lesotho.

Development of an Animal Model for Inducing Various Degrees of Severity of Incontinence-Associated Dermatitis.

PURPOSE: The purpose of this study was to describe the biological changes after incontinence-associated dermatitis (IAD) induction by pancreatin in the guinea pigs and to explore the potentially appropriate timing and pancreatin concentration for IAD induction with different severity. DESIGN: In vivo, experimental study. SUBJECTS AND SETTING: An experimental animal model (guinea pig) in a controlled laboratory setting was used for investigation. METHODS: We developed an IAD model in guinea pigs by occluded application of 1%, 5%, and 10% pancreatin solutions for 1, 3, and 5 days, respectively. The irritant was applied to the posterior aspect of shaved guinea pigs. We used an adapted visual scoring system to evaluate IAD and its severity. We also measured differences of the fluid absorption rate as a proxy for transepidermal water loss and enzyme-linked immunosorbent assays of interleukin 2 and interferon-γ expression as indicators of IAD-related inflammation. Analysis of variance (ANOVA) was used to examine group differences. RESULTS: Higher pancreatin concentrations led to more severe skin responses and higher mean visual scale scores, yet the statistically score differences were only observed in the 1% and 5% pancreatin groups after 3 and 5 days of exposure compared with 1 day of exposure (P < .05). The average absorbed fluid rate increased from 1 to 3 days of exposure and reached a plateau at 3 days; significant differences were observed in 3 and 5 days of exposure (P < .05) when compared with 1 day of exposure but not between 3 and 5 days of exposure. CONCLUSIONS: Exposure of a guinea pig animal model to 1%, 5%, and 10% pancreatin solutions over a 3-day period induced IAD with different levels of severity. Additional studies using this model are warranted.

Antidepressant effects of dexmedetomidine compared with ECT in patients with treatment-resistant depression.

OBJECTIVE: This pilot study was designed to investigate the antidepressant effects of dexmedetomidine (DEX), a selective α2-adrenergic receptor agonist, in patients with treatment-resistant depression (TRD). The antidepressant effects of dexmedetomidine was compared with ECT, which is widely used in clinical practice for treatment of patients with TRD. METHODS: Seventy six patients with TRD were randomly assigned to receive 10 sessions of DEX infusions or electroconvulsive therapy (ECT) treatment. The primary outcome was the changes of depression severity determined by the improvement of 24-item Hamilton Depression Rating Scale (HDRS-24). The second outcomes were the rates of therapeutic response (reduction in HDRS-24 ≥ 50 %) and remission (HDRS-24 ≤ 10 and reduction in HDRS-24 ≥ 60 %) at posttreatment and after 3 months of follow-up visits. RESULTS: We found that 10 sessions of DEX infusions or ECT treatments significantly improved HDRS-24 scores at posttreatment and after 3 months of follow-up visits compared with the baseline. In addition, there was no significant difference between DEX infusions and ECT treatments regarding HDRS-24 at these evaluating points. Furthermore, the depression severity dropped to mild after 2 sessions of DEX infusion. In contrast, at least 6 sessions of ECT treatment were needed to achieve a same level. Finally, the rates of therapeutic response and remission were comparable between the two groups. No serious adverse events were observed. CONCLUSIONS: Based on current published evidence, we conclude that DEX exhibits rapid and durable antidepressant properties similar to ECT but with fewer side effects.

Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis.

Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016-1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023-1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025-1.067; P = 8.17 × 10-6). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.

[Applying graphics processing unit in real-time signal processing and visualization of ophthalmic Fourier-domain OCT system].

This investigation introduces GPU (Graphics Processing Unit)- based CUDA (Compute Unified Device Architecture) technology into signal processing of ophthalmic FD-OCT (Fourier-Domain Optical Coherence Tomography) imaging system, can realize parallel data processing, using CUDA to optimize relevant operations and algorithms, in order to solve the technical bottlenecks that currently affect ophthalmic real-time imaging in OCT system. Laboratory results showed that with GPU as a general parallel computing processor, the speed of imaging data processing using GPU+CPU mode is more than dozens times faster than traditional CPU platform based serial computing and imaging mode when executing the same data processing, which reaches the clinical requirements for two dimensional real-time imaging.

Effects of Sepsis Serum on the Fate of Adipose Tissue-Derived Stem Cells.

BACKGROUND: Adipose tissue-derived stem cells (ADSCs), a type of mesenchymal stem cell, have been used extensively in clinical trials for the treatment of multiple conditions, including sepsis. However, increasing evidence indicates that ADSCs vanish from tissues within days of administration. Consequently, it would be desirable to establish the mechanisms underlying the fate of ADSCs following transplantation. METHODS: In this study, sepsis serum from mouse models was used to mimic microenvironmental effects. Healthy donor-derived human ADSCs were cultured in vitro in the presence of mouse serum from normal or lipopolysaccharide (LPS)-induced sepsis models for the purposes of discriminant analysis. The effects of sepsis serum on ADSC surface markers and cell differentiation were analyzed by flow cytometry, and the proliferation of ADSCs was assessed using a Cell Counting Kit-8 (CCK-8) assay. Quantitative real-time PCR (qRT-PCR) was applied to assess the degree of ADSC differentiation. The effects of sepsis serum on the cytokine release and migration of ADSCs were determined based on ELISA and Transwell assays, respectively, and ADSC senescence was assessed by ß-galactosidase staining and western blotting. Furthermore, we performed metabolic profiling to determine the rates of extracellular acidification and oxidative phosphorylation and the production of adenosine triphosphate and reactive oxygen species. RESULTS: We found that sepsis serum enhanced the cytokine and growth factor secretion and migratory capacities of ADSCs. Moreover, the metabolic pattern of these cells was reprogrammed to a more activated oxidative phosphorylation stage, leading to an increase in osteoblastic differentiation capacity and reductions in adipogenesis and chondrogenesis. CONCLUSIONS: Our findings in this study reveal that a septic microenvironment can regulate the fate of ADSCs.

Research progress on the anticancer activity of plant polysaccharides.

Tumor is a serious threat to human health, with extremely high morbidity and mortality rates. However, tumor treatment is challenging, and the development of antitumor drugs has always been a significant research focus. Plant polysaccharides are known to possess various biological activities. They have many pharmacological properties such as immunomodulation, antitumor, antiviral, antioxidative, antithrombotic, and antiradiation effects, reduction of blood pressure and blood sugar levels, and protection from liver injury. Among these effects, the antitumor effect of plant polysaccharides has been widely studied. Plant polysaccharides can inhibit tumor proliferation and growth by inhibiting tumor cell invasion and metastasis, inducing cell apoptosis, affecting the cell cycle, and regulating the tumor microenvironment. They also have the characteristics of safety, high efficiency, and low toxicity, which can alleviate, to a certain extent, the adverse reactions caused by traditional tumor treatment methods such as surgery, radiotherapy, and chemotherapy. Therefore, this paper systematically summarizes the direct antitumor effects of plant polysaccharides, their regulatory effects on the tumor microenvironment, and intervening many common high-incidence tumors in other ways. It also provides data support for the administration of plant polysaccharides in modern tumor drug therapy, enabling the identification of new targets and development of new drugs for tumor therapy.

Real-world data of pyrotinib-based therapy for patients with brain metastases of HER2-positive advanced breast cancer: a single-center retrospective analysis and molecular portraits.

Introduction: Pyrotinib is a novel irreversible pan-HER tyrosine kinase inhibitor (TKI). However, real-world data of pyrotinib-containing therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and developing brain metastases (BMs) are limited, and the genomic profile of this subpopulation is almost undefined. Methods and materials: Patients with BM of HER2-positive MBC (n = 35) treated with pyrotinib-containing therapy were enrolled in this analysis. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease progression were estimated using the Cox proportional hazards models. Targeted next-generation sequencing of 618 cancer-relevant genes was performed on plasma and primary breast tumors from patients with BM and without BM. Results: The median PFS time was 8.00 (95% CI, 5.98-10.017) months, and the median OS time was 23 (95% CI, 10.412-35.588) months. The ORR was 45.7%, and the DCR was 74.3%. In the Cox multivariate analysis, prior exposure to brain radiotherapy (HR = 3.268), received pyrotinib as third- or higher-line treatment (HR = 4.949), subtentorial brain metastasis (HR = 6.222), and both supratentorial and subtentorial brain metastases (HR = 5.863) were independently associated with increased risk of progression. The frequent grade 3-4 adverse event was increased direct bilirubin (14.3%), and two patients suffered from grade 3-4 diarrhea. In the exploratory genomic analysis, altered frequencies of FGFR3, CD276, CDC73, and EPHX1 were higher in the BM group. The consistency of mutated profiles of plasma and primary lesion in the BM group was significantly lower (30.4% vs. 65.5%; p = 0.0038). Conclusions: Pyrotinib-containing therapy shows favorable effectiveness and tolerable safety in patients with BM of HER2-positive MBC, particularly in a population that is brain radiotherapy-naïve, received pyrotinib as first- or second-line treatment, and developed supratentorial brain metastasis. In the exploratory genomic analysis, patients with BM showed distinct genomic features from patients without BM.

A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression.

Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.