Urolithin A exerts anti-tumor effects on gastric cancer via activating autophagy-Hippo axis and modulating the gut microbiota.

Gastric cancer (GC) treatment regimens are still unsatisfactory. Recently, Urolithin A (UroA) has gained tremendous momentum due to its anti-tumor properties. However, the therapeutic effect and underlying mechanisms of UroA in GC are unclear. We explored the effects and related mechanisms of UroA on GC both in vivo and in vitro. A Cell Counting Kit-8 was used to determine the influence of UroA on the proliferation of GC cell lines. The Autophagy inhibitor 3-methyladenine (3MA) was employed to clarify the role of autophagy in the anti-tumor effect of UroA. Simultaneously, we detected the core-component proteins involved in autophagy and its downstream pathways. Subsequently, the in vivo anti-tumor effect of UroA was determined using a xenograft mouse model. Western blotting was used to detect the core protein components of the anti-tumor pathways, and 16S rDNA sequencing was used to detect the effect of UroA on the gut microbiota. We found that UroA suppressed tumor progression. The use of 3MA undermined the majority of the inhibitory effect of UroA on tumor cell proliferation, further confirming the importance of autophagy in the anti-tumor effect of UroA. Invigorating of autophagy activated the downstream Hippo pathway, thereby inhibiting the Warburg effect and promoting cell apoptosis. In addition, UroA modulated the composition of the gut microbiota, as indicated by the increase of probiotics and the decrease of pathogenic bacteria. Our research revealed new anti-tumor mechanisms of UroA, which may be a promising candidate for GC treatment.

Endoplasmic reticulum stress regulators exhibit different prognostic, therapeutic and immune landscapes in pancreatic adenocarcinoma.

Endoplasmic reticulum stress (ERS) and unfolded protein response are the critical processes of tumour biology. However, the roles of ERS regulatory genes in pancreatic adenocarcinoma (PAAD) remain elusive. A novel ERS-related risk signature was constructed using the Lasso regression analysis. Its prognostic value, immune effect, metabolic influence, mutational feature and therapeutic correlation were comprehensively analysed through multiple bioinformatic approaches. The biofunctions of KDELR3 and YWHAZ in pancreatic cancer (PC) cells were also investigated through colony formation, Transwell assays, flow cytometric detection and a xenograft model. The upstream miRNA regulatory mechanism of KDELR3 was predicted and validated. ERS risk score was identified as an independent prognostic factor and could improve traditional prognostic model. Meanwhile, it was closely associated with metabolic reprogramming and tumour immune. High ERS risk enhanced glycolysis process and nucleotide metabolism, but was unfavourable for anti-tumour immune response. Moreover, ERS risk score could act as a potential biomarker for predicting the efficacy of ICBs. Overexpression of KDELR3 and YWHAZ stimulated the proliferation, migration and invasion of SW1990 and BxPC-3 cells. Silencing KDELR3 suppressed tumour growth in a xenograft model. miR-137 could weaken the malignant potentials of PC cells through inhibiting KDELR3 (5'-AGCAAUAA-3'). ERS risk score greatly contributed to PAAD clinical assessment. KDELR3 and YWHAZ possessed cancer-promoting capacities, showing promise as a novel treatment target.

C/EBPα alleviates hepatic ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress via HDAC1-mediated deacetylation of ATF4.

Hepatic ischemia-reperfusion (IR) injury is a complex systemic process causing a series clinical problem. C/EBPα is a key transcription factor for hepatocyte function, but its role and mechanism in regulating hepatic IR injury are largely unknown. Occluding portal vein and hepatic artery was used to establish a mouse model of hepatic IR injury. C/EBPα expression was decreased in IR-injured liver compared with the sham, accompanied by increased contents of serum alanine transaminase (ALT), aspartate transaminase (AST), high mobility group box-1, and proportion of hepatic cells. Oxygen and glucose deprivation/recovery (OGD/R) was used to establish a cellular hepatic IR model in WRL-68 hepatocytes in vitro, and C/EBPα was overexpressed in the hepatocytes to evaluate its effect on hepatic IR injury. OGD/R promoted oxidative stress, cell apoptosis and endoplasmic reticulum (ER) stress in hepatocytes, which was reversed by C/EBPα overexpression. Then, we found that C/EBPα promoted histone deacetylase 1 (HDAC1) transcription through binding to HDAC1 promoter. Moreover, HDAC1 deacetylated the activating transcription factor 4 (ATF4), a key positive regulator of ER stress. Trichostatin-A (an HDAC inhibitor) or ATF4 overexpression reversed the improvement of C/EBPα on OGD/R-induced ER stress and hepatocyte dysfunction. 4-Phenylbutyric acid (an endoplasmic reticulum stress inhibitor) also reversed the hepatic IR injury induced by ATF4 overexpression. Finally, lentivirus-mediated C/EBPα overexpression vector was applied to administrate hepatic IR mice, and the results showed that C/EBPα overexpression ameliorated IR-induced hepatic injury, manifesting with reduced ALT/AST, oxidative stress and ER stress. Altogether, our findings suggested that C/EBPα ameliorated hepatic IR injury by inhibiting ER stress via HDAC1-mediated deacetylation of ATF4 promoter.

Prevalence of and associated factors for sarcopenia in patients with liver cirrhosis: A systematic review and meta-analysis.

BACKGROUND: Sarcopenia is associated with poor outcomes in patients with cirrhosis. However, the prevalence of and associated factors for developing sarcopenia in this population remain to be determined. OBJECTIVES: This study aimed to summarize the prevalence, characteristics, and associated factors of sarcopenia in patients with cirrhosis. METHODS: Electronic searches were performed from inception to June 9, 2022 to identify the eligible studies. We meta-analyzed the prevalence of sarcopenia in overall patients with cirrhosis and subgroups. Both crude and adjusted odds ratios (ORs) were pooled using the random effects model. RESULTS: A total of 55 studies involving 13,158 patients from 17 countries were included. The overall prevalence of sarcopenia was 40.1 % (95 % CI 35.4%-44.9 %) in patients with cirrhosis. The pooled prevalence was higher in males, Child-Pugh class C cirrhosis, decompensated stage, ascites, subjective global assessment class C cirrhosis, and when sarcopenia was defined by L3-SMI (third lumbar-skeletal muscle index) at a higher cutoff. In multivariate analysis, older age (adjusted OR 1.04, 95 % CI 1.00-1.07), male (adjusted OR 4.75, 95 % CI 2.72-8.28), lower body mass index (BMI) (adjusted OR 0.78, 95 % CI 0.73-0.83), alcoholic liver disease (ALD) (adjusted OR 1.43, 95 % CI 1.19-1.72), but not ascites and hepatic encephalopathy, were significantly associated with an increased risk of sarcopenia in patients with cirrhosis. CONCLUSION: Sarcopenia is a prevalent complication, and older age, male patients, lower BMI, and patients with ALD are associated with an increased risk of sarcopenia in patients with cirrhosis.

Letter to editor 'Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness'.

This letter to the editor relates to the study entitled "Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness". Acute bleeding caused by esophageal varices is a life-threatening complication in patients with liver cirrhosis. Due to the discomfort, contraindications, and associated complications of upper gastrointestinal endoscopy screening, it is crucial to identify an imaging-based non-invasive model for predicting high-risk esophageal varices in patients with cirrhosis.

Population attributable fractions of fatty liver disease for type 2 diabetes Mellitus.

PURPOSE: To determine the population attributable fraction (PAF) of fatty liver disease (FLD) for type 2 diabetes mellitus (T2DM) and compare it to the PAFs of other metabolic abnormalities. METHODS: We conducted a 10-year retrospective cohort study of 33,346 individuals in Karamay Central Hospital of Xinjiang. Individuals were followed up for T2DM occurrence based on FBS. The PAFs of FLD were calculated generally and respectively in different sex and age groups. A comparison of the PAF of FLD and that of other metabolic abnormalities, as well as the PAFs of FLD in different groups classified based on age and sex, was performed using Cox regression. RESULTS: During an average follow-up period of 3.71 years, 1486 T2DM were diagnosed. The incidence density of T2DM was 1.2/100 person-years, and cumulative incidence rate was 4456.31/100,000 person-years. Partial PAF (PAFp) of FLD in the entire population was 23.11%. In the male population, PAFp was higher at 30-40 years old. In the female population, it was higher when age ≥ 60 years old. In multivariable Cox regression model, FLD, male sex, age ≥ 45 years old, overweight, hypertriglyceridaemia, and systolic hypertension were independent risk factors for T2DM, with corresponding PAFp of 25.00%, 24.99%, 36.47%, 24.96%, 5.71%, and 6.76%, respectively. Age ≥ 45 years old showed the highest PAFp and adjusted hazard ratio, followed by FLD. CONCLUSIONS: FLD contributes more to T2DM incidence than other metabolic disorders. Particular attention should be given to male populations of 30-40 and female populations above 60 for FLD prevention and treatment.

Prevalence and Risk Factors of Metabolic Dysfunction-Associated Fatty Liver Disease with Renal Insufficiency in Overweight/Obese Adults.

INTRODUCTION: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) with renal insufficiency in recent years and the association between MAFLD and renal insufficiency are not entirely clear, especially in overweight/obesity. The aim of this study was to analyze the prevalence and risk factors of MAFLD with renal insufficiency in overweight/obese adults. METHODS: Individuals who attended checkup at the Second Affiliated Hospital of Xi'an Jiaotong University from 2016 to 2021 were included. The prevalence of MAFLD with renal insufficiency (estimated glomerular filtration rate ≤90 mL/min/1.73 m2) in overweight/obesity was estimated. Propensity score-matched analysis, univariate and multivariate analyses were used to determine the risk factors for MAFLD with renal insufficiency. RESULTS: From 2016 to 2021, the prevalence of MAFLD in overweight/obesity reached its highest of 44.7% in 2017 and its lowest of 36.9% in 2018; and 33.9% in 2021 and 21.8% in 2019 is the highest and lowest prevalence of MAFLD with renal insufficiency, respectively. MAFLD was more common in men, old individuals, and persons with a higher body mass index (BMI) and was characterized by significant renal insufficiency. MAFLD with renal insufficiency was more common in women, old individuals, and persons with a higher BMI and was characterized by significant metabolic dysfunction and liver fibrosis. Multivariable analysis showed that BMI, uric acid, and fibrosis (evaluated with noninvasive liver fibrosis score [fibrosis-4]) were independent risk factors for MAFLD with renal insufficiency. CONCLUSION: The prevalence of MAFLD with renal insufficiency in overweight/obese adults is quite high in the last 5 years. BMI, uric acid, and fibrosis are independent risk factors for MAFLD with renal insufficiency.

Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness.

BACKGROUND: Acute bleeding due to esophageal varices (EVs) is a life-threatening complication in patients with cirrhosis. The diagnosis of EVs is mainly through upper gastrointestinal endoscopy, but the discomfort, contraindications and complications of gastrointestinal endoscopic screening reduce patient compliance. According to the bleeding risk of EVs, the Baveno VI consensus divides varices into high bleeding risk EVs (HEVs) and low bleeding risk EVs (LEVs). We sought to identify a non-invasive prediction model based on spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) as an alternative to EVs screening. AIM: To develop a safe, simple and non-invasive model to predict HEVs in patients with viral cirrhosis and identify patients who can be exempted from upper gastrointestinal endoscopy. METHODS: Data from 200 patients with viral cirrhosis were included in this study, with 140 patients as the modelling group and 60 patients as the external validation group, and the EVs types of patients were determined by upper gastrointestinal endoscopy and the Baveno VI consensus. Those patients were divided into the HEVs group (66 patients) and the LEVs group (74 patients). The effect of each parameter on HEVs was analyzed by univariate and multivariate analyses, and a non-invasive prediction model was established. Finally, the discrimination ability, calibration ability and clinical efficacy of the new model were verified in the modelling group and the external validation group. RESULTS: Univariate and multivariate analyses showed that SSM and LSM were associated with the occurrence of HEVs in patients with viral cirrhosis. On this basis, logistic regression analysis was used to construct a prediction model: Ln [P/(1-P)] = -8.184 -0.228 × SSM + 0.642 × LSM. The area under the curve of the new model was 0.965. When the cut-off value was 0.27, the sensitivity, specificity, positive predictive value and negative predictive value of the model for predicting HEVs were 100.00%, 82.43%, 83.52%, and 100%, respectively. Compared with the four prediction models of liver stiffness-spleen diameter to platelet ratio score, variceal risk index, aspartate aminotransferase to alanine aminotransferase ratio, and Baveno VI, the established model can better predict HEVs in patients with viral cirrhosis. CONCLUSION: Based on the SSM and LSM measured by transient elastography, we established a non-invasive prediction model for HEVs. The new model is reliable in predicting HEVs and can be used as an alternative to routine upper gastrointestinal endoscopy screening, which is helpful for clinical decision making.

Urolithin C reveals anti-NAFLD potential via AMPK-ferroptosis axis and modulating gut microbiota.

The pharmacology of urolithin C (UroC) on non-alcoholic fatty liver disease (NAFLD) is largely undetermined. We sought to investigate the potential for NAFLD improvement by administration of UroC and the underlying mechanisms. We verified the therapeutic effect of UroC on choline-deficient amino acid-defined high fat diet (CDAHFD) induced NAFLD mice via evaluating NAFLD activity score (NAS), AST, ALT, hepatic phosphorylated AMPK, and 4-hydroxynonenal. Oleic acid-induced AML12 cell was appraised by oil red staining and western blotting to explore the effect and mechanism of UroC in vitro. Transcriptional regulation of UroC was explored by liver RNA sequencing, gut microbiota composition was explored by 16SrRNA sequencing, and colorectal tight junctional proteins were detected by western blotting and immunohistochemistry. The detrimental effects of CDAHFD included the increased liver index, AST, ALT, hepatic 4-hydroxynonenal, impaired intestinal mucosal barrier, and most importantly, pathological damage in liver. Oral administration of UroC largely protected against these harmful alterations. Remarkably, both RNA sequencing and western blotting results indicated an activation in hepatic AMPK signaling pathway which was thought to inhibit ferroptosis response to UroC in vivo, while no change were found in AMPK-ferroptosis axis response to UroC in oleic acid-induced AML12 cells, hinted an indispensable linkage between UroC and hepatic AMPK, presumably the gut-liver axis. Furthermore, UroC could neither alleviate lipid deposition nor inhibit ferroptosis in vitro. The 16SrRNA showed UroC partially counteracted the dysbiosis induced by CDAHFD. Specifically, UroC reversed the elevated proportion of Firmicutes/Bacteroidota and enhanced the level of Parabacteroides goldsteinii and Lactobacillus vaginalis, which played a beneficial role in metabolic disorders. Oral administration of Urolithin C protected against the detrimental impact of CDAHFD via regulating AMPK-ferroptosis axis, maintaining intestinal mucosal barrier and counteracting gut dysbiosis.

Case Report: Unusual Cause of Fever in Ulcerative Colitis Treated with Infliximab.

Introduction: Patients with inflammatory bowel disease are at high risk for opportunistic infections, and fungal infections are relatively uncommon among various infections. Case: This case is the first reported ulcerative colitis accompanied with Cryptococcus neoformans infection after infliximab treatment. In the course of the disease, the patients had a variety of opportunistic infections, including viruses, fungi and bacteria. Conclusion: This case highlights the importance of paying continued attention to opportunistic infections for patients with inflammatory bowel disease.

Cuproptosis regulatory genes greatly contribute to clinical assessments of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common abdominal cancer with dissatisfactory therapeutic effects. The discovery of cuproptosis lights on new approach for cancer treatment and assessment. So far, there is extremely limited research investigating the roles of cuproptosis-related (CR) genes in cancers. METHODS: A novel CR risk signature was constructed using the Lasso regression analysis. Its prognostic value was assessed via a series of survival analyses and validated in three GEO cohorts. The effects of CR risk signature on tumor immune microenvironment (TIM) were explored through CIBERSORT, ESTIMATE, and ssGSEA algorithms. Using GESA, we investigated its impacts on various metabolism process. The somatic mutation features of CR signature genes were also explored via cBioPortal database. Using tumor mutation burden, expressions of immune checkpoints, TIDE score, IMvigor 210 cohort, and GSE109211 dataset, we explored the potential associations of CR risk score with the efficacy of immune checkpoint inhibitors (ICIs) and sorafenib. Finally, the biofunctions of DLAT in HCC cells were ascertained through qPCR, immunohistochemistry, colony formation, and Transwell assays. RESULTS: FDX1, DLAT, CDKN2A and GLS constituted the CR risk signature. CR risk signature possessed high prognostic value and was also applicable to three validation cohorts. Meanwhile, it could improve the accuracy and clinical making-decision benefit of traditional prognostic model. Moreover, high CR risk was indicative of unfavorable anti-tumor immune response and active metabolisms of glycolysis and nucleotide. As for therapeutic correlation, CR risk score was a potential biomarker for predicting the efficacy of ICIs and sorafenib. Through qPCR and immunohistochemistry detection in clinical samples, we reconfirmed DLAT was significantly upregulated in HCC samples. Overexpression of DLAT could promote the proliferation, migration, and invasion of HepG2 and HuH-7 cells. CONCLUSIONS: The novel CR risk signature greatly contributed to the clinical assessment of HCC. Cuproptosis regulatory gene DLAT possessed cancer-promoting capacities and was expected to be a promising therapeutic target for HCC.

Zinc finger protein 671 has a cancer-inhibiting function in colorectal carcinoma via the deactivation of Notch signaling.

Zinc finger protein 671 (ZNF671) has been described as a vital cancer inhibitor in multiple neoplasms, yet the functional roles of ZNF671 in colorectal carcinoma (CRC) remain unresolved. This project examined the possible link between ZNF671 and CRC. Lower levels of ZNF671 were observed in CRC tissue compared with noncancerous tissue, which were related to a worse survival rate in CRC patients. High methylation levels at the ZNF671 gene promoter region were shown in CRC tissue, which were inversely correlated with ZNF671 expression. Treatment with demethylation agents restored ZNF671 levels in CRC cell lines. Up-regulation of ZNF671 resulted in suppressive effects on the proliferative ability and metastatic potency of CRC cells. Moreover, the up-regulation of ZNF671 reinforced the chemosensitivity of CRC cells. A mechanism study determined ZNF671 to be a vital mediator of Notch signaling. The up-regulation of ZNF671 decreased the expression of Notch1 and lowered the levels of NICD, HES1, and HEY1. The overexpression of NICD1 diminished ZNF671-mediated antitumor effects. ZNF671 depletion reinforced Notch signaling, and Notch suppression reversed ZNF671-depletion-elicited protumor effects. Moreover, the overexpression of ZNF671 weakened the tumorigenicity of CRC cells in a xenograft model in vivo. In summary, ZNF671 exerts a cancer-inhibiting function in CRC via the deactivation of Notch signaling. Low ZNF671 levels caused by gene promoter hypermethylation contribute to the malignant transformation of CRC. This work underlines the interest of ZNF671 as a target candidate for exploiting novel anti-CRC therapies.

Non-invasive model for predicting esophageal varices based on liver and spleen volume.

BACKGROUND: Upper endoscopy is the gold standard for predicting esophageal varices in China. Guidelines and consensus suggest that patients with liver cirrhosis should undergo periodic upper endoscopy, most patients undergo their first upper endoscopy when esophageal variceal bleeds. Therefore, it is important to develop a non-invasive model to early diagnose esophageal varices. AIM: To develop a non-invasive predictive model for esophageal varices based on liver and spleen volume in viral cirrhosis patients. METHODS: We conducted a cross-sectional study based on viral cirrhosis crowd in the Second Affiliated Hospital of Xi'an Jiaotong University. By collecting the basic information and clinical data of the participants, we derived the independent risk factors and established the prediction model of esophageal varices. The established model was compared with other models. Area under the receiver operating characteristic curve, calibration plot and decision curve analysis were used to test the discriminating ability, calibration ability and clinical practicability in both the internal and external validation. RESULTS: The portal vein diameter, the liver and spleen volume, and volume change rate were the independent risk factors of esophageal varices. We successfully used the factors to establish the predictive model [area under the curve (AUC) 0.87, 95%CI: 0.80-0.95], which showed better predictive value than other models. The model showed good discriminating ability, calibration ability and the clinical practicability in both modelling group and external validation group. CONCLUSION: The developed non-invasive predictive model can be used as an effective tool for predicting esophageal varices in viral cirrhosis patients.

LOXL3-promoted hepatocellular carcinoma progression via promotion of Snail1/USP4-mediated epithelial-mesenchymal transition.

Lysyl-oxidase-like 3 (LOXL3) was reported to be essential in epithelial-mesenchymal transition (EMT) of cancers. However, the role of LOXL3 in hepatocellular carcinoma (HCC) remained unclear. In this study, we explored clinical significance, biological functions, and regulatory mechanisms of LOXL3 in HCC. Our study found that LOXL3 expression was markedly associated with the tumor size and clinical stage of HCC, and it was highly expressed in tumor tissues of metastatic HCC patients. High expression of LOXL3 predicted a poor prognosis of HCC. TGF-ß1 treatment elevated LOXL3 protein expression and cell invasion, and reduced cell apoptosis in HCC cell lines (SMMC-7721 and Huh-7), while downregulation of LOXL3 reversed the promotive effects of TGF-ß1 treatment on LOXL3 protein expression and cell invasion, and the inhibitory effect on cell apoptosis. Mechanistically, LOXL3 interacted with snail family transcriptional repressor 1 (Snail1) through STRING database and RIP assay, and Snail1 bound to ubiquitin-specific peptidase 4 (USP4) promoter by JASPAR database, luciferase reporter gene and Co-IP assays. Overexpression of USP4 reversed the inhibitory effect of LOXL3 silence on EMT in HCC cells through deubiquitinating and stabilizing the expression of Snail1. Moreover, LOXL3-promoted HCC EMT through Wnt/ß-catenin/Snail1 signaling pathway. In vivo study revealed that silence of LOXL3-inhibited HCC tumor growth. In conclusion, LOXL3 silence inhibited HCC invasion and EMT through Snail1/USP4-mediated circulation loop and Wnt/ß-catenin signaling pathway.

Prediction model using readily available clinical data for colorectal cancer in a chinese population.

BACKGROUND: In China, health screening has become common, although colonoscopy is not always available or acceptable. We sought to develop a prediction model of colorectal cancer (CRC) for health screening population based on readily available clinical data to reduce labor and economic costs. METHODS: We conducted a cross-sectional study based on a health screening population in Karamay Central Hospital. By collecting clinical data and basic information from participants, we identified independent risk factors and established a prediction model of CRC. Internal and external validation, calibration plot, and decision curve analysis were employed to test discriminating ability, calibration ability, and clinical practicability. RESULTS: Independent risk factors of CRC, which were readily available in primary public health institutions, included high-density lipoprotein cholesterol, male sex, total cholesterol, advanced age, and hemoglobin. These factors were successfully incorporated into the prediction model (AUC 0.740, 95% CI 0.713-0.767). The model demonstrated a high degree of discrimination and calibration, in addition to a high degree of clinical practicability in high-risk people. CONCLUSIONS: The prediction model exhibits good discrimination and calibration and is pragmatic for CRC screening in rural areas and primary public health institutions.

Effect of sarcopenia on survival in patients with cirrhosis: A meta-analysis.

BACKGROUND & AIMS: The association between sarcopenia and prognosis in patients with cirrhosis remains to be determined. In this study, we aimed to quantify the association between sarcopenia and the risk of mortality in patients with cirrhosis, stratified by sex, underlying liver disease etiology, and severity of hepatic dysfunction. METHODS: PubMed, Web of Science, EMBASE, and major scientific conference sessions were searched without language restriction through 13 January 2021 with an additional manual search of bibliographies of relevant articles. Cohort studies of ≥100 patients with cirrhosis and ≥12 months of follow-up that evaluated the association between sarcopenia, muscle mass and the risk of mortality were included. RESULTS: Twenty-two studies involving 6,965 patients with cirrhosis were included. The pooled prevalence of sarcopenia in patients with cirrhosis was 37.5% overall (95% CI 32.4%-42.8%), and was higher in male patients, those with alcohol-associated liver disease, those with Child-Pugh grade C cirrhosis, and when sarcopenia was defined by L3-SMI (third lumbar-skeletal muscle index). Sarcopenia was associated with an increased risk of mortality in patients with cirrhosis (adjusted hazard ratio [aHR] 2.30, 95% CI 2.01-2.63), with similar findings in a sensitivity analysis of patients with cirrhosis without hepatocellular carcinoma (aHR 2.35, 95% CI 1.95-2.83) and in subgroups stratified by sex, liver disease etiology, and severity of hepatic dysfunction. The association between quantitative muscle mass index and mortality further supports the association between sarcopenia and poor prognosis (aHR 0.95, 95% CI 0.93-0.98). There was no significant heterogeneity in any of our analyses. CONCLUSIONS: Sarcopenia was highly and independently associated with higher risk of mortality in patients with cirrhosis. LAY SUMMARY: The prevalence of sarcopenia and its association with death in patients with cirrhosis remain unclear. This meta-analysis indicated that sarcopenia affected about one-third of patients with cirrhosis and up to 50% of patients with alcohol-related liver disease or Child-Pugh class C cirrhosis. Sarcopenia was independently associated with an ∼2-fold higher risk of mortality in patients with cirrhosis. The mortality rate increased with greater severity or longer durations of sarcopenia. Increasing awareness about the importance of sarcopenia in patients with cirrhosis among stakeholders must be prioritized.

Appropriate body mass index cutoffs for type 2 diabetes in Xinjiang population: defining the influence of liver aminotransferase.

BACKGROUND/PURPOSE: Recent study suggested that type 2 diabetes (T2DM) attributed to body mass index (BMI) could be influenced by liver aminotransferase. We aim to ascertain the cut-off point of BMI associated with T2DM and the influence of both elevated aminotransferase (AST) and alanine aminotransferase (ALT). MATERIALS AND METHODS: In our retrospective cohort study, T2DM was diagnosed when FBS ≥ 7.0 mmol/L, BMI of participants with baseline fasting (FBS) < 7.0 mmol/L was divided by percentiles and by aminotransferanse (ALT and AST ≥ 20 U/L, ALT or AST < 20 U/L). Hazard ratios and the turning point of BMI of high T2DM risk was estimated in totality and different aminotransferanse groups. RESULTS: During an average follow-up time of 3.71 years of 33346 participants, 1486 developed T2DM, and the average baseline BMI of participants who developed T2DM was 26.22 kg/m2. Cumulative incidence of T2DM was more than 5% when ALT and AST ≥ 20U/L, age over 44, male sex or BMI over 25.39 kg/m2; The risk of T2DM incidence increased as the BMI grow. The turning point of BMI at high risk of T2DM was 25.0 kg/m2 in totality, 25.1 kg/m2 when ALT or AST < 20 U/L and 26.1 kg/m2 when ALT and AST ≥ 20U/L. CONCLUSIONS: BMI of 25.0 kg/m2 was the cutoff point for T2DM development, and there is greater association between BMI and T2DM when ALT or AST < 20 U/L.

Non-invasive prediction model for high-risk esophageal varices in the Chinese population.

BACKGROUND: There are two types of esophageal varices (EVs): high-risk EVs (HEVs) and low-risk EVs, and HEVs pose a greater threat to patient life than low-risk EVs. The diagnosis of EVs is mainly conducted by gastroscopy, which can cause discomfort to patients, or by non-invasive prediction models. A number of non-invasive models for predicting EVs have been reported; however, those that are based on the formula for calculation of liver and spleen volume in HEVs have not been reported. AIM: To establish a non-invasive prediction model based on the formula for liver and spleen volume for predicting HEVs in patients with viral cirrhosis. METHODS: Data from 86 EV patients with viral cirrhosis were collected. Actual liver and spleen volumes of the patients were determined by computed tomography, and their calculated liver and spleen volumes were calculated by standard formulas. Other imaging and biochemical data were determined. The impact of each parameter on HEVs was analyzed by univariate and multivariate analyses, the data from which were employed to establish a non-invasive prediction model. Then the established prediction model was compared with other previous prediction models. Finally, the discriminating ability, calibration ability, and clinical efficacy of the new model was verified in both the modeling group and the external validation group. RESULTS: Data from univariate and multivariate analyses indicated that the liver-spleen volume ratio, spleen volume change rate, and aspartate aminotransferase were correlated with HEVs. These indexes were successfully used to establish the non-invasive prediction model. The comparison of the models showed that the established model could better predict HEVs compared with previous models. The discriminating ability, calibration ability, and clinical efficacy of the new model were affirmed. CONCLUSION: The non-invasive prediction model for predicting HEVs in patients with viral cirrhosis was successfully established. The new model is reliable for predicting HEVs and has clinical applicability.

Prognostic value of risk scoring systems for cirrhotic patients with variceal bleeding.

BACKGROUND: Acute variceal bleeding is one of the deadliest complications of cirrhosis, with a high risk of in-hospital rebleeding and mortality. Some risk scoring systems to predict clinical outcomes in patients with upper gastrointestinal bleeding have been developed. However, for cirrhotic patients with variceal bleeding, data regarding the predictive value of these prognostic scores in predicting in-hospital outcomes are limited and controversial. AIM: To validate and compare the overall performance of selected prognostic scoring systems for predicting in-hospital outcomes in cirrhotic patients with variceal bleeding. METHODS: From March 2017 to June 2019, cirrhotic patients with acute variceal bleeding were retrospectively enrolled at the Second Affiliated Hospital of Xi'an Jiaotong University. The clinical Rockall score (CRS), AIMS65 score (AIMS65), Glasgow-Blatchford score (GBS), modified GBS (mGBS), Canada-United Kingdom-Australia score (CANUKA), Child-Turcotte-Pugh score (CTP), model for end-stage liver disease (MELD) and MELD-Na were calculated. The overall performance of these prognostic scoring systems was evaluated. RESULTS: A total of 330 cirrhotic patients with variceal bleeding were enrolled; the rates of in-hospital rebleeding and mortality were 20.3% and 10.6%, respectively. For in-hospital rebleeding, the discriminative ability of the CTP and CRS were clinically acceptable, with area under the receiver operating characteristic curves (AUROCs) of 0.717 (0.648-0.787) and 0.716 (0.638-0.793), respectively. The other tested scoring systems had poor discriminative ability (AUROCs < 0.7). For in-hospital mortality, the CRS, CTP, AIMS65, MELD-Na and MELD showed excellent discriminative ability (AUROCs > 0.8). The AUROCs of the mGBS, CANUKA and GBS were relatively small, but clinically acceptable (AUROCs > 0.7). Furthermore, the calibration of all scoring systems was good for either in-hospital rebleeding or death. CONCLUSION: For cirrhotic patients with variceal bleeding, in-hospital rebleeding and mortality rates remain high. The CTP and CRS can be used clinically to predict in-hospital rebleeding. The performances of the CRS, CTP, AIMS65, MELD-Na and MELD are excellent at predicting in-hospital mortality.

Silencing of lemur tyrosine kinase 2 restricts the proliferation and invasion of hepatocellular carcinoma through modulation of GSK-3ß/Wnt/ß-catenin signaling.

Lemur tyrosine kinase 2 (LMTK2) was recently identified as a novel cancer-related gene in several human cancers. However, little is known of its function in hepatocellular carcinoma (HCC). Here we aim to investigate the expression pattern, biological function, and regulatory mechanism of LMTK2 in HCC. We found that LMTK2 was highly expressed in HCC tissues, and patients with high expression of LMTK2 in tumor tissues had shorter survival times. LMTK2 expression was also elevated in HCC cell lines, and LMTK2 silencing markedly repressed the proliferation and invasion of HCC cells. By contrast, LMTK2 overexpression exerted promotion effects on HCC cell proliferation and invasion. Our results demonstrate that LMTK2 silencing decreases the phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) and the expression of an active ß-catenin protein, leading to inhibition of Wnt/ß-catenin signaling. Notably, GSK-3ß inhibition significantly reversed the LMTK2 silencing-mediated antitumor effect on proliferation, invasion, and Wnt/ß-catenin signaling in HCC cells. LMTK2 silencing retarded the tumor growth of HCC cells in an in vivo xenograft tumor model, associated with downregulation of Wnt/ß-catenin signaling. In conclusion, our findings suggest that silencing of LMTK2 suppresses the proliferation and invasion of HCC cells through the inhibition of Wnt/ß-catenin signaling, via GSK-3ß, highlighting the importance of LMTK2/GSK-3ß/Wnt/ß-catenin signaling in HCC progression.