Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer.

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

Major changes in prevalence and genotypes of rotavirus diarrhea in Beijing, China after RV5 rotavirus vaccine introduction.

To analyze the epidemiological characteristics of group A rotavirus (RVA) diarrhea in Beijing between 2019 and 2022 and evaluate the effectiveness of the RV5 vaccine. Stool specimens were collected from patients with acute diarrhea, and RVA was detected and genotyped. The whole genome of RVA was sequenced by fragment amplification and Sanger sequencing. Phylogenetic trees were constructed using Bayesian and maximum likelihood methods. Descriptive epidemiological methods were used to analyze the characteristics of RVA diarrhea. Test-negative design was used to evaluate the vaccine effectiveness (VE) of the RV5. Compared with 2011-2018, RVA-positive rates in patients with acute diarrhea under 5 years of age and adults decreased significantly between 2019 and 2022, to 9.45% (249/634) and 3.66% (220/6016), respectively. The predominant genotype of RVA had changed from G9-VIP[8]-III between 2019 and 2021 to G8-VP[8]-III in 2022, and P[8] sequences from G8-VP[8]-III strains formed a new branch called P[8]-IIIb. The complete genotype of G8-VP[8]-III was G8-P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2. The VE of 3 doses of RV5 was 90.4% (95% CI: 28.8%-98.7%) against RVA diarrhea. The prevalence of RVA decreased in Beijing between 2019 and 2022, and the predominant genotype changed to G8P[8], which may be related to RV5 vaccination. Continuous surveillance is necessary to evaluate vaccine effectiveness and improve vaccine design.

Ethanol exposure exacerbates 4-nitroquinoline-1-oxide induced esophageal carcinogenesis and induces invasive carcinoma with muscularis propria infiltration in a mouse model.

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal cancers worldwide. Most ESCC patients are diagnosed at an advanced stage; however, current research on in vivo animal models accurately reflecting their clinical presentation is lacking. Alcohol consumption is a major risk factor for ESCC and has been used in several disease models for disease induction. In this study, we used 4-nitroquinoline-1-oxide in combination with ethanol to induce an in vivo ESCC mouse model. Esophageal tissues were stained with hematoxylin and eosin for histopathological examination and lesion scoring. In cellular experiments, cell adhesion and migration invasion ability were observed using phalloidin staining, cell scratch and transwell assays, respectively, and the expression of epithelial-mesenchymal transition-related markers was detected using quantitative reverse transcription polymerase chain reaction and western blotting. The results showed that ethanol-exposed mice lost more weight and had an increased number of esophageal nodules. Histological examination revealed that the lesion scores of the ethanol-exposed esophageal samples were significantly higher than those of the unexposed esophageal samples. Furthermore, ethanol-exposed esophageal cancer samples had more severe lesions with infiltration of tumor cells into the muscularis propria. In vitro cellular experiments showed that ethanol exposure induced cytoskeletal microfilament formation, promoted cell migration invasion elevated the expression of N-cadherin and Snail, and decreased the expression of E-cadherin. In conclusion, ethanol exposure exacerbates ESCC, promotes tumor cell infiltration into the muscularis propria, and could be an effective agent for establishing innovative models of invasive carcinoma.

Mesenchymal Stem Cells Promote Polarization of M2 Macrophages in Mice with Acute-On-Chronic Liver Failure via Mertk/JAK1/STAT6 Signaling.

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.

Activation of Ventral Tegmental Area Dopaminergic Neurons Projecting to the Parabrachial Nucleus Promotes Emergence from Propofol Anesthesia in Male Rats.

Since the clinical introduction of general anesthesia, its underlying mechanisms have not been fully elucidated. The ventral tegmental area (VTA) and parabrachial nucleus (PBN) play pivotal roles in the mechanisms underlying general anesthesia. However, whether dopaminergic (DA) projections from the VTA to the PBN play a role in mediating the effects of general anesthesia is unclear. We microinjected 6-hydroxydopamine into the PBN to damage tyrosine hydroxylase positive (TH+) neurons and found a prolonged recovery time from propofol anesthesia. We used calcium fiber photometry recording to explore the activity of TH + neurons in the PBN. Then, we used chemogenetic and optogenetic approaches either activate the VTADA-PBN pathway, shortening the propofol anesthesia emergence time, or inhibit this pathway, prolonging the emergence time. These data indicate the crucial involvement of TH + neurons in the PBN in regulating emergence from propofol anesthesia, while the activation of the VTADA-PBN pathway facilitates the emergence of propofol anesthesia.

Antigen specific VNAR screening in whitespotted bamboo shark (Chiloscyllium plagiosum) with next generation sequencing.

IgNAR exhibits significant promise in the fields of cancer and anti-virus biotherapies. Notably, the variable regions of IgNAR (VNAR) possess comparable antigen binding affinity with much smaller molecular weight (∼12 kDa) compared to IgNAR. Antigen specific VNAR screening is a changeling work, which limits its application in medicine and therapy fields. Though phage display is a powerful tool for VNAR screening, it has a lot of drawbacks, such as small library coverage, low expression levels, unstable target protein, complicating and time-consuming procedures. Here we report VANR screening with next generation sequencing (NGS) could effectively overcome the limitations of phage display, and we successfully identified approximately 3000 BAFF-specific VNARs in Chiloscyllium plagiosum vaccinated with the BAFF antigen. The results of modelling and molecular dynamics simulation and ELISA assay demonstrated that one out of the top five abundant specific VNARs exhibited higher binding affinity to the BAFF antigen than those obtained through phage display screening. Our data indicates NGS would be an alternative way for VNAR screening with plenty of advantages.

The comprehensive incidence and risk factors of fracture in kidney transplant recipients: A meta-analysis.

AIM: Kidney transplant recipients are at high risk of fracture due to many factors such as nutritional status, hyperparathyroidism, acidosis and steroid administration. The current meta-analysis aimed to comprehensively analyse the incidence and risk factors of fracture in kidney transplant recipients. METHODS: A systematic search on Embase, Web of Science, PubMed and Cochrane Library until November 2023 was performed. RStudio software was used to analyse data. RESULTS: Twenty-eight eligible studies containing 310 530 kidney transplant recipients were included in the analysis. The pooled incidence of fracture was 10% (95% confidence interval [CI]: 7%-13%) generally. When divided by regions, it was further observed that the pooled incidence of fracture was 13% (95% CI: 9%-17%) in Europe, 11% (95% CI: 6%-16%) in North America, 7% (95% CI: 3%-11%) in Asia. Regarding the risk factors, pooled analysis revealed that age of recipient (hazard ratio [HR] = 1.50, 95% CI: 1.17-1.91), female sex (HR = 1.45, 95% CI: 1.36-1.53), pretransplantation diabetes (HR = 1.76, 95% CI: 1.58-1.97), pretransplantation fracture history (HR = 2.28, 95% CI: 1.86-2.78), dialysis duration (HR = 1.09, 95% CI: 1.01-1.17) and deceased donor (HR = 1.21, 95% CI: 1.05-1.39) related to higher risk of fracture. The general quality of included studies was acceptable, and no publication bias existed except for the analysis between age of recipient and fracture incidence; further trim and fill method indicated age of recipient showed a correlation trend with the fracture incidence without the statistical significance. CONCLUSION: The pooled incidence of fracture reaches 10% in kidney transplant recipients, which relates to age of recipient, female sex, pretransplantation diabetes or fracture history, dialysis duration and decease donor.

Portable luminescent fiber- and glove-based nanosensor for multicolor visual detection of tetracycline in food samples.

An intelligent fluorescent nanoprobe (lignite-CDs-Eu) was constructed by an effective and facile method based on lignite-derived carbon dots (CDs) and lanthanide europium ions (Eu3+), which exhibited high sensitivity, low detection limit (13.35 nM) and visual color variation (from blue to red) under ultraviolet light towards tetracycline (TC) detection. Significantly, portable and economical sensors were developed using lignite-CDs-Eu immobilized fiber material of filter paper and wearable glove with the aid of color extracting and image processing application (APP) in the smartphone. Facile, fast and real-time visual detection of TC in food samples was realized. Moreover, logic gate circuit was also designed to achieve intelligent and semi-quantitative inspection of TC. To some extent, this study extended the cross-application of intelligent computer software in food analytical science, and provided a certain reference for the development of small portable detection sensors which were suitable for convenience and non-professional use in daily life.

Mesenchymal stem cell-regulated miRNA-mRNA landscape in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a major challenge in the field of hepatology. While mesenchymal stem cell (MSC) therapy can improve the prognosis of patients with ACLF, the molecular mechanisms through which MSCs attenuate ACLF remain poorly understood. We performed global miRNA and mRNA expression profiling via next-generation sequencing of liver tissues from MSC-treated ACLF mice to identify important signaling pathways and major factors implicated in ACLF alleviation by MSCs. METHODS: Carbon tetrachloride-induced ACLF mice were treated with saline or mouse bone marrow-derived MSCs. Mouse livers were subjected to miRNA and mRNA sequencing. Related signal transduction pathways were obtained through Gene Set Enrichment Analysis. Functional enrichment, protein-protein interaction, and immune infiltration analyses were performed for the differentially expressed miRNA target genes (DETs). Hub miRNA and mRNA associated with liver injury were analyzed using LASSO regression. The expression levels of hub genes were subjected to Pearson's correlation analysis and verified using RT-qPCR. The biological functions of hub genes were verified in vitro. RESULTS: The tricarboxylic acid cycle and peroxisome proliferator-activated receptor pathways were activated in the MSC-treated groups. The proportions of liver-infiltrating NK resting cells, M2 macrophages, follicular helper T cells, and other immune cells were altered after MSC treatment. The expression levels of six miRNAs and 10 transcripts correlated with the degree of liver injury. miR-27a-5p was downregulated in the mouse liver after MSC treatment, while its target gene E2f2 was upregulated. miR-27a-5p inhibited E2F2 expression, suppressed G1/S phase transition and proliferation of hepatocytes, in addition to promoting their apoptosis. CONCLUSIONS: This is the first comprehensive analysis of miRNA and mRNA expression in the liver tissue of ACLF mice after MSC treatment. The results revealed global changes in hepatic pathways and immune subpopulations. The miR-27a-5p/E2F2 axis emerged as a central regulator of the MSC-induced attenuation of ACLF. The current findings improve our understanding of the molecular mechanisms through which MSCs alleviate ACLF.

Compliance with oral nutritional supplements and its influencing factors in postoperative patients with digestive tract tumors: a cross-sectional study.

BACKGROUND: Oral nutritional supplements are one of the preferred methods of nutritional support for postoperative patients. This study aims to investigate the current status of oral nutritional supplements compliance in postoperative patients with digestive tract tumors and its influencing factors. METHODS: Convenience sampling was employed to select 242 patients who underwent surgery for digestive tract tumors at a tertiary hospital in Shanghai from October 2022 to July 2023 as the study subjects. Data following a normal distribution were analyzed using independent sample t-tests, ANOVA single-factor analysis, Pearson correlation analysis, and multiple linear regression analysis to determine the factors influencing compliance with oral nutritional supplements. RESULTS: A total of 252 questionnaires were distributed, with 10 invalid questionnaires excluded, resulting in an effective questionnaire rate of 96.03%. The compliance score for oral nutritional supplements in postoperative patients with digestive tract tumors was (2.40 ± 1.45), General Self-efficacy Scale (GSES) score was (24.72 ± 4.86), Multidimensional Scale of Perceived Social Support Scale (MSPSS) score was (58.67 ± 11.09), and Belief about Medicines Questionnaire Scale (BMQ) score was (0.17 ± 2.78). Multiple linear regression analysis revealed that age, adverse reactions, educational level, self-efficacy, medication beliefs, and social support were factors influencing compliance with oral nutritional supplements in postoperative patients with digestive tract tumors (P < 0.05). CONCLUSION: Our study revealed that the compliance to oral nutritional supplements among postoperative patients with digestive tract tumors was at a moderate level and was closely associated with age, educational level, adverse reactions to oral nutritional supplements, medication beliefs, social support, and self-efficacy. Nursing staff should conduct nursing assessments based on the specific circumstances of patients and their families, provide personalized health education management plans based on the patients' educational level, enhance patients' nutrition knowledge, improve patient self-efficacy, and enhance social support for patients, while further improving patient nutrition management.

[Relationship of triglyceride-glucose index and its derivatives with blood pressure abnormalities in adolescents: an analysis based on a restricted cubic spline model]. / åŸºäºŽé™åˆ¶æ€§ç«‹æ–¹æ ·æ¡æ¨¡åž‹åˆ†æžé’å°‘å¹´ä¸‰é °ç”˜æ²¹-è‘¡è„ç³–æŒ‡æ•°åŠå ¶è¡ç”ŸæŒ‡æ•°ä¸Žè¡€åŽ‹å¼‚å¸¸çš„å ³ç³».

OBJECTIVES: To explore the relationship of triglyceride-glucose index (TyG), triglyceride-glucose-body mass index (TyG-BMI), and triglyceride-glucose-waist circumference index (TyG-WC) with blood pressure abnormalities in adolescents, providing theoretical basis for the prevention and control of hypertension in adolescents. METHODS: A stratified cluster sampling method was used to select 1 572 adolescents aged 12 to 18 years in Yinchuan City for questionnaire surveys, physical measurements, and laboratory tests. Logistic regression analysis and restricted cubic spline analysis were employed to examine the relationship of TyG, TyG-BMI, and TyG-WC with blood pressure abnormalities in adolescents. RESULTS: Multivariable logistic regression analysis revealed that after adjusting for confounding factors, the groups with the highest quartile of TyG, TyG-BMI, and TyG-WC had 1.48 times (95%CI: 1.07-2.04), 3.71 times (95%CI: 2.67-5.15), and 4.07 times (95%CI: 2.89-5.73) higher risks of blood pressure abnormalities compared to the groups with the lowest quartile, respectively. Moreover, as the levels of TyG, TyG-BMI, and TyG-WC increased, the risk of blood pressure abnormalities gradually increased (P<0.05). A non-linear dose-response relationship was observed between TyG-BMI and the risk of blood pressure abnormalities (P overall trend<0.001, P non-linearity=0.002). Linear dose-response relationships were found between TyG and the risk of blood pressure abnormalities (P overall trend<0.001, P non-linearit =0.232), and between TyG-WC and the risk of blood pressure abnormalities (P overall trend<0.001, P non-linearity=0.224). CONCLUSIONS: Higher levels of TyG and its derivatives are associated with an increased risk of blood pressure abnormalities in adolescents, with linear or non-linear dose-response relationships.

The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells.

Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and antibody-based therapies, particularly for solid tumors. With the development of next-generation sequencing and bioinformatics technology, the rapid identification and prediction of tumor-specific antigens (TSAs) has become possible. Compared with tumor-associated antigens (TAAs), highly immunogenic TSAs provide new targets for personalized tumor immunotherapy and can be used as prospective indicators for predicting tumor patient survival, prognosis, and immune checkpoint blockade response. Here, the identification and characterization of neoantigens and the clinical application of neoantigen-based TCR-T immunotherapy strategies are summarized, and the current status, inherent challenges, and clinical translational potential of these strategies are discussed.

Increased prevalence and stable clustering rate of HIV-1 transmitted drug resistance strains after 'treat-all' in a megacity of China.

OBJECTIVES: The 'treat-all' strategy was implemented in Shenzhen, China in 2016. The effect of this extensive treatment on transmitted drug resistance (TDR) of HIV is unclear. METHODS: TDR analysis was performed, based on the partial HIV-1 pol gene obtained from the newly reported HIV-1 positive cases from 2011 to 2019 in Shenzhen, China. The HIV-1 molecular transmission networks were inferred to analyse the spread of TDR. Logistic regression was used to identify the potential risk factors with TDR mutations (TDRMs) to cluster. RESULTS: A total of 12 320 partial pol sequences were included in this study. The prevalence of TDR was 2.95% (363/12 320), which increased from 2.57% to 3.52% after 'treat-all'. The TDR prevalence was increased in populations with the characteristics of CRF07_BC, being single, educated to junior college level and above, MSM and male. The sensitivities of viruses to six antiretroviral drugs were decreased. The clustering rate of TDRMs remained stable, and the sequences in the three drug resistance transmission clusters (DRTCs) were mainly found during 2011-16. CRF07_BC and CRF55_01B were the factors associated with TDRMs clustering in the networks. CONCLUSIONS: The 'treat-all' strategy might have contributed to a small increase in TDR, while most of the TDRMs were distributed sporadically, which implies that the 'treat-all' strategy is helpful for the control of TDR in high-risk populations.

Excess acute diarrhoea cases attributed to norovirus variants in Beijing, China between 2011 and 2018.

New norovirus (NoV) variants emerge often leading to increased acute gastroenteritis outbreaks and outpatient visits. However, these increases are rarely quantified. Between September 2011 and August 2018, we included a total of 133 131 acute diarrhoea cases in 11 enteric disease outpatient clinics which were open all year round in Beijing. Over the same period, the etiology surveillance for acute diarrhoea was conducted, a total of 13 139 specimens were collected and tested, and 16.84% (2213/13 139) of all specimens were NoV-positive. The partial VP1 genes were successfully sequenced in 965 NoV strains. GII.4 Sydney, GII.17, and GII.2 predominated in 2012-2013, 2014-2015, and 2016-2017, respectively. We estimated the excess NoV-associated acute diarrhoea cases using the adjusted Serfling regression model, and three excess periods were found, corresponding to the predominance periods of GII.4 Sydney, GII.17 and GII.2, respectively, represented increases of 180.5% (95% confidence interval [CI]: 115.0%-246.0%), 114.7% (95% CI: 66.4%-163.1%) and 152.6% (95% CI: 100.2%-205.0%), compared with the baseline level. New NoV variants often caused an excess in their first year of predominance, and the excess periods of NoV-associated acute diarrhoea cases coincided with the predominance periods of NoV variants.

Phylogenetics and phylogeographic characteristics of coxsackievirus A16 in hand foot and mouth disease and herpangina cases collected in Beijing, China from 2019 to 2021.

Coxsackievirus A16 (CV-A16) is a significant pathogen responsible for causing hand foot and mouth disease (HFMD) and herpangina (HA). This study aimed to investigate the recent evolution and spread of CV-A16 by monitoring HFMD and HA cases in 29 hospitals across 16 districts in Beijing from 2019 to 2021. The first five cases of HFMD and the first five cases of HA each month in each hospital were included in the study. Real-time reverse transcription polymerase chain reaction was used to identify CV-A16, CV-A6, and EV-A71. From each district, two to four CV-A16 positive samples with a relatively long sampling time interval every month were selected for sequencing. A total of 3344 HFMD cases and 2704 HA cases were enrolled in this study, with 76.0% (2541/3344) of HFMD and 45.4% (1227/2704) of HA cases confirmed to be infected by enterovirus. Among the EV-positive samples, CV-A16 virus was detected in 33.61% (854/2541) of HFMD cases and 13.4% (165/1227) of HA cases, with the predominant cluster being B1a. Both B1a and B1b had a co-circulation of local and imported strains, with different origin time (1993 vs. 1995), different global distribution (14 countries vs. 10 countries), and different transmission centers but mainly distributed in the southern and eastern regions of Beijing. Strengthening surveillance of HFMD in southern and eastern regions will improve the prevention and control efficiency of enterovirus infections.

Transmissibility quantification of norovirus outbreaks in 2016-2021 in Beijing, China.

The transmissibility is a crucial feature for norovirus, yet its quantitative estimation has been limited. Our objective was to estimate the basic reproduction number (R0 ) of norovirus and investigate its variation characteristics. Norovirus outbreaks reported from September 2016 to August 2021 in Beijing were analyzed. The susceptible-infected-removed compartment model was established to estimate R0 . Linear regression models and logistic regression models were used to explore the factors affecting the transmissibility of norovirus. The overall median R0 of norovirus was estimated as 2.1 (interquartile range [IQR] 1.8-2.5), with 650 norovirus outbreaks. The transmissibility of norovirus varied by year, outbreak setting and genotype. The R0 of norovirus during September 2019 to August 2020 (median 2.1, IQR 1.8-2.4) and September 2020 to August 2021 (median 2.0, IQR 1.7-2.3) was lower than that of September 2016 to August 2017 (median 2.3, IQR 1.8-2.7) (ß = 0.94, p = 0.05; ß = 0.93, p = 0.008). The R0 of norovirus for all other settings was lower than that for kindergarten (median 2.4, IQR 2.0-2.9) (primary school: median 2.0, IQR 1.7-2.4, ß = 0.94, p = 0.001; secondary school: median 1.7, IQR 1.5-2.0, ß = 0.87, p < 0.001; college: median 1.7, IQR 1.5-1.8, ß = 0.89, p = 0.03; other closed settings: median 1.8, IQR 1.5-2.0, ß = 0.90, p = 0.004). GⅡ.2[P16] outbreaks had a median R0 of 2.2 (IQR 1.8-2.7), which was higher than that for GⅡ.6[P7] outbreaks (median 1.8, IQR: 1.8-2.0, odds ratio = 0.19, p = 0.03; GⅡ.2[P16] as reference) and mixed-genotype outbreaks (median 1.7, IQR: 1.5-1.8, ß = 0.92, p = 0.02; mixed-genotype as reference). In kindergartens and primary schools, norovirus shows increased transmissibility, emphasizing the vulnerable population and high-risk settings. Furthermore, the transmissibility of norovirus may change over time and with virus evolution, necessitating additional research to uncover the underlying mechanisms.

HbA1c-based rather than fasting plasma glucose-based definitions of prediabetes identifies high-risk patients with angiographic coronary intermediate lesions: a prospective cohort study.

BACKGROUND: Prediabetes is common and associated with poor prognosis in patients with acute coronary syndrome and those undergoing revascularization. However, the impact of prediabetes on prognosis in patients with coronary intermediate lesions remains unclear. The objective of the current study is to explore the impact of prediabetes and compare the prognostic value of the different definitions of prediabetes in patients with coronary intermediate lesions. METHODS: A total of 1532 patients attending Fuwai hospital (Beijing, China), with intermediate angiographic coronary lesions, not undergoing revascularization, were followed-up from 2013 to 2021. Patients were classified as normal glucose tolerance (NGT), prediabetes and diabetes according to various definitions based on HbA1c or admission fasting plasma glucose (FPG). The primary endpoint was defined as major adverse cardiovascular events (MACE), the composite endpoint of all-cause death, non-fatal myocardial infarction and repeated revascularization therapy. Multivariate cox regression model was used to explore the association between categories of abnormal glucose category and MACE risk. RESULTS: The proportion of patients defined as prediabetes ranged from 3.92% to 47.06% depending on the definition used. A total of 197 MACE occurred during a median follow-up time of 6.1 years. Multivariate cox analysis showed that prediabetes according to the International Expert Committee (IEC) guideline (6.0 ≤ HbA1c < 6.5%) was associated with increased risk of MACE compared with NGT (hazard ratio [HR]: 1.705, 95% confidence interval [CI] 1.143-2.543) and after confounding adjustment (HR: 1.513, 95%CI 1.005-2.277). Consistently, the best cut-off point of glycated haemoglobin (HbA1c) identified based on the Youden's index was also 6%. Restricted cubic spline analysis delineated a linear positive relationship between baseline HbA1c and MACE risk. Globally, FPG or FPG-based definition of prediabetes was not associated with patients' outcome. CONCLUSIONS: In this cohort of patients with intermediate coronary lesions not undergoing revascularization therapy, prediabetes based on the IEC-HbA1c definition was associated with increased MACE risk compared with NGT, and may assist in identifying high-risk patients who can benefit from early lifestyle intervention.

Bioinformatics and network pharmacology identify promotional effects and potential mechanisms of ethanol on esophageal squamous cell carcinoma and experimental validation.

Ethanol is an important risk factor for esophageal squamous cell carcinoma (ESCC); however, the molecular mechanisms behind how ethanol promotes ESCC development remain poorly understood. In this study, ethanol-ESCC-associated target genes were constructed and screened using network pharmacology and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) and bioinformatics analysis. A mouse ethanol-exposed esophageal cancer model was constructed with 4-nitroquinoline-1-oxide (4-NQO) to assess its survival and tumor lesion status, and the mechanism of ethanol-promoted ESCC lesions was verified by qRT-PCR and Western blotting. The results showed that 126 ethanol-ESCC crossover genes were obtained, which were significantly enriched in the PI3K/AKT signaling pathway. Bioinformatics results showed that the target genes TNF, IL6, IL1ß and JUN were highly expressed in esophageal tumor samples and positively correlated with tumor proliferation and apoptosis genes, and the genetic information of these genes was mutated to different degrees. Animal model experiments showed that ethanol decreased the survival rate and aggravated the occurrence of esophageal cancer in mice. qRT-PCR showed that ethanol promoted the expression of TNF, IL6, IL1ß and JUN mRNA in mouse esophageal tumor tissues, and Western blotting showed that ethanol promoted p-PI3K and p-AKT protein expression in mouse esophageal tumor tissues. In conclusion, ethanol promotes esophageal carcinogenesis by increasing the expression of TNF, IL6, IL1ß and JUN and activating the PI3K/AKT signaling pathway.

Identification of immunotherapy-related lncRNA signature for predicting prognosis, immunotherapy responses and drug candidates in bladder cancer.

BACKGROUND: Bladder cancer (BC) is one of the most common malignant diseases and the most common causes of cancer death worldwide. Immunotherapy has opened new avenues for precision treatment of bladder tumours, and immune checkpoint inhibitors (ICIs) have revolutionized the clinical treatment strategy of bladder tumours. In addition, long non-coding RNA (lncRNA) plays an important role in regulating tumour development and immunotherapy efficacy. METHODS: We obtained genes with significant differences between anti-PD-L1 response and non-response from the Imvogor210 data set and combined with the bladder cancer expression data in the TCGA cohort to obtain immunotherapy-related lncRNA. Based on these lncRNAs, the prognostic risk model of bladder cancer was constructed and verified by GEO external data set. The characterization of immune cell infiltration and immunotherapy effects between high-risk and low-risk groups were then analysed. We predicted the ceRNA network and performed molecular docking of key target proteins. The functional experiments verified the function of SBF2-AS1. RESULTS: Three immunotherapy-related lncRNAs were identified as independent prognostic biomarkers for bladder cancer and a prognostic model of immunotherapy-related prognosis was constructed. Prognosis, immune cell infiltration, and immunotherapy efficacy were significantly different between high- and low-risk groups based on risk scores. Additionally, we established a ceRNA network of lncRNA(SBF2-AS1)-miRNA(has-miR-582-5p)-mRNA (HNRNPA2B1). Targeting the protein HNRNPA2B1 identified the top eight small molecule drugs with the highest affinity. CONCLUSION: We developed a prognostic risk score model based on immune-therapy-related lncRNA, which was subsequently determined to be significantly associated with immune cell infiltration and immunotherapy response. This study not only helps to promote our understanding of immunotherapy-related lncRNA in the prognosis of BC, but also provides new ideas for clinical immunotherapy and the development of novel therapeutic drugs for patients.

Molecular epidemiology and phylodynamic analysis of enterovirus 71 in Beijing, China, 2009-2019.

BACKGROUND: Enterovirus 71(EV71)-associated hand, foot and mouth disease (HFMD) decreased dramatically in Beijing from 2009 to 2019. This study was to investigate the epidemiological characteristics, evolutionary dynamics, geographic diffusion pathway, and other features of EV71 in Beijing, China. METHODS: We conducted a retrospective study of EV71-associated HFMD and its causative agent in Beijing, China, from 2009 to 2019. Phylogenetic and phylogeographic methods based on the EV71 genome were used to determine the evolution features, origin, and spatiotemporal dynamics. Positive selection sites in the VP1 gene were identified and exhibited in the tertiary structure. Bayesian birth-death skyline model was used to estimate the effective reproductive number (Re). RESULTS: EV71-associated HFMD decreased greatly in Beijing. From 2009 to 2019, EV71 strains prevalent in Beijing shared high homology in each gene segment and evolved with a rate of 4.99*10- 3 substitutions per site per year. The genetic diversity of EV71 first increased and peaked in 2012 and then decreased with fluctuations. The time to the most recent common ancestor (TMRCA) of EV71 in Beijing was estimated around 2003 when the EV71 strains were transmitted to Beijing from east China. Beijing played a crucial role in seeding EV71 to central China as well. Two residues (E145Q/G, A293S) under positive selection were detected from both the VP1 dataset and the P1 dataset. They were embedded within the loop of the VP1 capsid and were exposed externally. Mean Re estimate of EV71 in Beijing was about 1.007. CONCLUSION: In recent years, EV71 was not the primary causative agent of HFMD in Beijing. The low Re estimate of EV71 in Beijing implied that strategies for preventing and controlling HFMD were performed effectively. Beijing and east China played a crucial role in disseminating EV71 to other regions in China.