USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency

The homeobox transcription factor Nanog has a vital role in maintaining pluripotency and self-renewal of embryonic stem cells (ESCs). Stabilization of Nanog proteins is essential for ESCs. The ubiquitin–proteasome pathway mediated by E3 ubiquitin ligases and deubiquitylases is one of the key ways to regulate protein levels and functions. Although ubiquitylation of Nanog catalyzed by the ligase FBXW8 has been demonstrated, the deubiquitylase that maintains the protein levels of Nanog in ESCs yet to be defined. In this study, we identify the ubiquitin-specific peptidase 21 (USP21) as a deubiquitylase for Nanog, but not for Oct4 or Sox2. USP21 interacts with Nanog protein in ESCs in vivo and in vitro. The C-terminal USP domain of USP21 and the C-domain of Nanog are responsible for this interaction. USP21 deubiquitylates the K48-type linkage of the ubiquitin chain of Nanog, stabilizing Nanog. USP21-mediated Nanog stabilization is enhanced in mouse ESCs and this stabilization is required to maintain the pluripotential state of the ESCs. Depletion of USP21 in mouse ESCs leads to Nanog degradation and ESC differentiation. Overall, our results demonstrate that USP21 maintains the stemness of mouse ESCs through deubiquitylating and stabilizing Nanog

The double-edged role of hydrogen sulfide in the pathomechanism of multiple liver diseases

In mammalian systems, hydrogen sulfide (H2S)—one of the three known gaseous signaling molecules in mammals—has been found to have a variety of physiological functions. Existing studies have demonstrated that endogenous H2S is produced through enzymatic and non-enzymatic pathways. The liver is the body’s largest solid organ and is essential for H2S synthesis and elimination. Mounting evidence suggests H2S has essential roles in various aspects of liver physiological processes and pathological conditions, such as hepatic lipid metabolism, liver fibrosis, liver ischemia‒reperfusion injury, hepatocellular carcinoma, hepatotoxicity, and acute liver failure. In this review, we discuss the functions and underlying molecular mechanisms of H2S in multiple liver pathophysiological conditions

Road map of the diagnosis and treatment of intractable ascites based on guidelines for the diagnosis and treatment of cirrhotic ascites and related complications

Guidelines for the diagnosis and treatment of cirrhotic ascites and related complications put forward the new criteria for the diagnosis and treatment of intractable cirrhotic ascites, and spontaneous bacterial peritonitis is a common cause of intractable cirrhotic ascites. About 50%-89% of patients with intractable cirrhotic ascites have a significant response to terlipressin (2-8 mg/d), midodrine hydrochloride (22.5 mg/d), and tolvaptan (7.5-15 mg/d). Intravenous albumin supplementation (8 g/1000 ml ascites) has a similar therapeutic effect as terlipressin (3 mg) in preventing posterior circulation dysfunction after large-volume paracentesis. Patients with a poor response to medication or those who need frequent large-volume paracentesis (more than three times per week) or frequent hospitalization (more than three times per month) should be evaluated for liver transplantation or transjugular intrahepatic portosystemic shunt. α-Crystal rifaximin may become a new strategy for preventing complications of liver cirrhosis by regulating the intestine-microbe-liver axis. Therefore, it is of great significance to explore the “road map” of the diagnosis and treatment of intractable cirrhotic ascites that is suitable for the clinical practice in China

Stratified screening of hepatocellular carcinoma in high-risk populations

The worldwide prevalence of hepatocellular carcinoma (HCC) is substantially increasing. Approximately 50% of all cases occur in China. However, more than 85% of cases are diagnosed at an advanced disease stage, thus missing the effective treatment window. Currently, the 5-year survival rate for HCC patients is less than 15%. Despite the use of new therapeutic strategies for HCC in clinical practice. The metabolic syndromes and human immunodeficiency virus (HIV) infections are to be considered as new HCC high-risk-population. Furthermore, liver cirrhosis patients with HBV mutations or with cirrhotic nodules are regarded as HCC extremely high-risk populations. This mini-review provides an overview of HCC new high-risk populations and of stratified screening strategies that are based on the latest clinical studies

Shortening liver cancer screening interval may improve the prognosis of patients with hepatitis B cirrhosis-related hepatocellular carcinoma

ObjectiveTo investigate the influence of shortening liver cancer screening interval on the detection of early-stage hepatocellular carcinoma (HCC) in patients with hepatitis B cirrhosis and their prognosis, as well as proper screening schemes for such patients at a high risk of HCC. MethodsA total of 310 patients with hepatitis B cirrhosis who were diagnosed and treated in Department of Gastroenterology and Hepatology, Beijing YouAn Hospital, from January 2007 to January 2008 were enrolled, and according to the screening interval, they were divided into 3-month screening group (group A) with 78 patients and 6-month screening group (group B) with 232 patients. The screening items included serum alpha-fetoprotein and ultrasound and the patients were followed up for 5 years. The patients with HCC screened out were followed up to the endpoint (death or December 31, 2016). The detection of HCC and prognosis were compared between the two groups. The t-test was used for comparison of continuous data between groups, the chi-square test or Fisher′s exact test was used for comparison of categorical data between groups, and the Kaplan-Meier method was used for survival analysis. ResultsAt the end of the 5-year follow-up, 73 patients were diagnosed with HCC, with 21 in group A and 52 in group B. Group A had a significantly higher proportion of patients with early-stage HCC (Barcelona Clinic Liver Cancer stage A) than group B ［66.7% (14/21) vs 15.4% (8/52), χ2=18.685, P＜0.001］. Group A also had a significantly higher proportion of patients who underwent radical surgery than group B (762% vs 36.5%, χ2=9.424, P=0.002). The patients with HCC were followed up to the endpoint, and compared with group B, group A had a significantly longer cumulative survival time (66.4±8.0 months vs 38.1±4.5 months, t=4.295, P=0.038) and a significantly higher cumulative survival rate ［71.4% (15/21) vs 46.2% (24/52), χ2=3.840, P=0.043］. ConclusionFor patients with hepatitis B cirrhosis, a 3-month screening interval can increase the early detection rate of HCC, bring the opportunity of radical treatment for these patients, and prolong their survival time

Progression on the Roles and Mechanisms of Tumor-Infiltrating T Lymphocytes in Patients With Hepatocellular Carcinoma

Primary liver cancer (PLC) is one of the most common malignancies in China, where it ranks second in mortality and fifth in morbidity. Currently, liver transplantation, hepatic tumor resection, radiofrequency ablation, and molecular-targeted agents are the major treatments for hepatocellular carcinoma (HCC). Overall, HCC has a poor survival rate and a high recurrence rate. Tumor-infiltrating lymphocytes (TILs) have been discovered to play essential roles in the development, prognosis, and immunotherapy treatment of HCC. As the major component cells of TILs, T cells are also proved to show antitumor and protumor effects in HCC. Foxp3+, CD8+, CD3+, and CD4+ T lymphocytes are the broadly studied subgroups of TILs. This article reviews the roles and mechanisms of different tumor-infiltrating T lymphocyte subtypes in HCC.ISSN:1664-322

MCMCINLA Estimation of Missing Data and Its Application to Public Health Development in China in the Post-Epidemic Era

Medical data are often missing during epidemiological surveys and clinical trials. In this paper, we propose the MCMCINLA estimation method to account for missing data. We introduce a new latent class into the spatial lag model (SLM) and use a conditional autoregressive specification (CAR) spatial model-based approach to impute missing values, making the model fit into the integrated nested Laplace approximation (INLA) framework. Combining the advantages of both the Markov chain Monte Carlo (MCMC) and INLA frameworks, the MCMCINLA algorithm is used to implement imputation of the missing data and fit the model to derive estimates of the parameters from the posterior margins. Finally, the economic data and the hemorrhagic fever with renal syndrome (HFRS) disease data of mainland China from 2016–2018 are used as examples to explore the development of public health in China in the post-epidemic era. The results show that compared with expectation maximization (EM) and full information maximum likelihood estimation (FIML), the predicted values of the missing data obtained using our method are closer to the true values, and the spatial distribution of HFRS in China can be inferred from the imputation results with a southern-heavy and northern-light distribution. It can provide some references for the development of public health in China in the post-epidemic era

The Histopathological Features and CT/MRI Imaging Performances in Hepatic Angiomyolipoma Patients

Aim: To evaluate the diagnostic value of dynamic contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) in the differential diagnosis of hepatic angiomyolipoma (HAML) and hepatocellular carcinoma (HCC) and to clarify the relationship between histopathological features and CT or MRI imaging performances in HAML. Material and methods: Six HAML and 33 non-cirrhotic HCC patients confirmed by histopathology were retrospectively analyzed. The serum biomarkers, CT and MRI examinations were conventionally performed before the confirmatory histological diagnosis. The clinical data from their medical records was also analyzed. Results: Six HAML patients were annotated as two types according to CT and MRI imaging characteristics, including hypovascular type (n = 1) and hypervascular type (n = 5). The imaging performances of the 33 HCC patients were hypervas-cular type. Moreover, all the 5 hypervascular type HAML patients were misdiagnosed as HCC by CT or MRI. We also found that the hypervascular type of HAML patients contained more vessels and less fatty tissues in histopathology than hypovascular type of HAML patients. However, the clinical features included HCC high risk factors (hepatitis B or C), non-specific symptoms, male and increased serum alpha fetoprotein (AFP) were more common in HCC patients than HAML patients (P < 0.05, respectively). Conclusions: The CT or MRI imaging performances of HAML patients containing more vessels and less fatty tissues in histopathology resemble the imaging performance of HCC patients. These clinical features may be of great help in the differential diagnosis in the current clinical practices