AIM To identify the miRNA-mRNA regulatory network in hepatitis B virus X (HBx)-expressing hepatic cells. METHODS A stable HBx-expressing human liver cell line L02 was established. The mRNA and miRNA expression profile...AIM To identify the miRNA-mRNA regulatory network in hepatitis B virus X (HBx)-expressing hepatic cells. METHODS A stable HBx-expressing human liver cell line L02 was established. The mRNA and miRNA expression profiles of L02/HBx and L02/pcDNA liver cells were identified by RNA-sequencing analysis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed to investigate the function of candidate biomarkers, and the relationship between miRNA and mRNA was studied by network analysis. RESULTS Compared with L02/pcDNA cells, 742 unregulated genes and 501 downregulated genes were determined as differentially expressed in L02/HBx cells. Gene ontology analysis suggested that the differentially expressed genes were relevant to different processes. Concurrently, 22 differential miRNAs were also determined in L02/HBx cells. Furthermore, integrated analysis of miRNA and mRNA expression profiles identified a core miRNA-mRNA regulatory network that is correlated with the carcinogenic role of HBx. CONCLUSION Collectively, the miRNA-mRNA network-based analysis could be useful to elucidate the potential role of HBx in liver cell malignant transformation and shed light on the underlying molecular mechanism and novel therapy targets for hepatocellular carcinoma.展开更多
Background: Hepatitis B virus(HBV)-associated acute-on-chronic liver failure(HBV-ACLF) is a lifethreatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the...Background: Hepatitis B virus(HBV)-associated acute-on-chronic liver failure(HBV-ACLF) is a lifethreatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum mi RNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF.Methods: Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to30 chronic asymptomatic HBV carriers as controls. The mi RNAs expressions were measured by real-time quantitative PCR(q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed mi RNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model.Results: Real-time q-PCR indicated that serum miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and mi R-122-3 p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na+-1.72 × INR-4.963 × gastrointestinal bleeding(Yes = 0; No = 1)-0.278 ×(mi R-122-3 p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve(AUROC) was 0.847.Conclusions: Expression levels of these mi RNAs(miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.展开更多
AIM： To undertake analysis of hepatitis A viral load, alanine aminotransferase （ALT）, and viral genotypes with duration of viremia, and to correlate these parameters with CD4^＋/ CD8^＋ lymphocyte populations that ...AIM： To undertake analysis of hepatitis A viral load, alanine aminotransferase （ALT）, and viral genotypes with duration of viremia, and to correlate these parameters with CD4^＋/ CD8^＋ lymphocyte populations that control cell-mediated immunity. METHODS： Cell counts were carried out using fresh whole blood collected in EDTA vials using a fluorescence activated cell sorter. Hepatitis A virus （HAV） RNA was extracted from blood serum, reverse transcribed into cDNA and quantified by Real-Time polymerase chain reaction and was genotyped. RESULTS： Among 11 patients, 10 could be analyzed completely. Of these, 3 had severe acute hepatitis （s-AH） and the remainder had a self-limited acute hepatitis A （AHA）, with one patient with fulminant disease （encephalopathy Grade IV） dying on the 4^th d. The ALT level was significantly higher both in AHA （1070.9±894.3; P = 0.0014） and s-AH （1713.9±886.3; P = 0.001） compared to normal controls （23.6±7.2）. The prothrombin time in s-AH patients （21.0 ±2.0; P=0.02） was significantly higher than in AHA （14.3±1.1;P = 0.44）. The CD4^＋/CD8^＋ ratio in AHA patients （1.17 ＋ 0.11; P = 0.22） and s-AH （0.83 ＋ 0.12; P = 0.0002） were lower than seen in normal healthy controls （1.52）. Self-limited cases had peak viral load at the beginning of analysis while in s-AH patients this occurred at the 15TM or 30^th d. In acute and severe groups, one patient each belonged to genotype IA, with the remaining 8 cases belonging to genotype IIIA. The only fulminant hepatic failure case belonged to genotype IA. HAV viral load and AIT values collected during the entire course of the selflimited infection were directly correlated but this was not the case for s-AH patients.CONCLUSION： Based on a small-scale study, the persistently higher viral load of s-AH might be due to diminished cellular immunity and hemolysis. The duration of viremia was dependent on the host, as the viral genotype had no apparent role in clinical outcome of AVH and s-AH cases.展开更多
The National Center for Biotechnology Information(NCBI)Taxonomy is widely applied in biomedical and ecological studies.Typical demands include querying taxonomy identifier(TaxIds)by taxonomy names,querying complete ta...The National Center for Biotechnology Information(NCBI)Taxonomy is widely applied in biomedical and ecological studies.Typical demands include querying taxonomy identifier(TaxIds)by taxonomy names,querying complete taxonomic lineages by TaxIds,listing descendants of given TaxIds,and others.However,existed tools are either limited in functionalities or inefficient in terms of runtime.In this work,we present TaxonKit,a command-line toolkit for comprehensive and efficient manipulation of NCBI Taxonomy data.TaxonKit comprises seven core subcommands providing functions,including TaxIds querying,listing,filtering,lineage retrieving and reformatting,lowest common ancestor computation,and TaxIds change tracking.The practical functions,competitive processing performance,scalability with different scales of datasets and good accessibility can facilitate taxonomy data manipulations.TaxonKit provides free access under the permissive MIT license on GitHub,Brewsci,and Bioconda.The documents are also available at https://bioinf.shenwei.me/taxonkit/.展开更多
Liver fibrosis is a key transformation stage and also a reversible pathological process in various types of chronic liver diseases.However,the pathogenesis of liver fibrosis still remains elusive.Here,we report that t...Liver fibrosis is a key transformation stage and also a reversible pathological process in various types of chronic liver diseases.However,the pathogenesis of liver fibrosis still remains elusive.Here,we report that the calcium binding protein A11(S100A11)is consistently upregulated in the integrated data from GSE liver fibrosis and tree shrew liver proteomics.S100A11 is also experimentally activated in liver fibrosis in mouse,rat,tree shrew,and human with liver fibrosis.While overexpression of S100A11 in vivo and in vitro exacerbates liver fibrosis,the inhibition of S100A11 improves liver fibrosis.Mechanistically,S100A11 activates hepatic stellate cells(HSCs)and the fibrogenesis process via the regulation of the deacetylation of Smad3 in the TGF-βsignaling pathway.S100A11 physically interacts with SIRT6,a deacetylase of Smad2/3,which may competitively inhibit the interaction between SIRT6 and Smad2/3.The subsequent release and activation of Smad2/3 promote the activation of HSCs and fibrogenesis.Additionally,a significant elevation of S100A11 in serum is observed in clinical patients.Our study uncovers S100A11 as a novel profibrogenic factor in liver fibrosis,which may represent both a potential biomarker and a promising therapy target for treating liver fibrosis and fibrosis-related liver diseases.展开更多
BACKGROUND Early diagnosis of hepatocellular carcinoma may help to ensure that patients have a chance for long-term survival;however,currently available biomarkers lack sensitivity and specificity.AIM To characterize ...BACKGROUND Early diagnosis of hepatocellular carcinoma may help to ensure that patients have a chance for long-term survival;however,currently available biomarkers lack sensitivity and specificity.AIM To characterize the serum metabolome of hepatocellular carcinoma in order to develop a new metabolomics diagnostic model and identifying novel biomarkers for screening hepatocellular carcinoma based on the pattern recognition method.METHODS Ultra-performance liquid chromatography-mass spectroscopy was used to characterize the serum metabolome of hepatocellular carcinoma(n=30)and cirrhosis(n=29)patients,followed by sequential feature selection combined with linear discriminant analysis to process the multivariate data.RESULTS The concentrations of most metabolites,including proline,were lower in patients with hepatocellular carcinoma,whereas the hydroxypurine levels were higher in these patients.As ordinary analysis models failed to discriminate hepatocellular carcinoma from cirrhosis,pattern recognition analysis was used to establish a pattern recognition model that included hydroxypurine and proline.The leaveone-out cross-validation accuracy and area under the receiver operating characteristic curve analysis were 95.00%and 0.90[95%Confidence Interval(CI):0.81-0.99]for the training set,respectively,and 78.95%and 0.84(95%CI:0.67-1.00)for the validation set,respectively.In contrast,forα-fetoprotein,the accuracy and area under the receiver operating characteristic curve were 65.00%and 0.69(95%CI:0.52-0.86)for the training set,respectively,and 68.42%and 0.68(95%CI:0.41-0.94)for the validation set,respectively.The Z test revealed that the area under the curve of the linear discriminant analysis model was significantly higher than the area under the curve ofα-fetoprotein(P<0.05)in both the training and validation sets.CONCLUSION Hydroxypurine and proline might be novel biomarkers for hepatocellular carcinoma,and this disease could be diagnosed by the metabolomics model based on pattern recognition.展开更多
Casein kinase 1α(CK1α) mediates the phosphorylation and degradation of interferon-α/β receptor 1(IFNAR1) in response to viral infection. However, how CK1α regulates hepatitis B virus(HBV) replication and the anti...Casein kinase 1α(CK1α) mediates the phosphorylation and degradation of interferon-α/β receptor 1(IFNAR1) in response to viral infection. However, how CK1α regulates hepatitis B virus(HBV) replication and the anti-HBV effects of IFN-α are less reported. Here we show that CK1α can interact with IFNAR1 in hepatoma carcinoma cells and increased the abundance of IFNAR1 by reducing the ubiquitination levels in the presence of HBV.Furthermore, CK1α promotes the IFN-α triggered JAK-STAT signaling pathway and consequently enhances the antiviral effects of IFN-α against HBV replication. Our results collectively provide evidence that CK1α positively regulates the anti-HBV activity of IFN-α in hepatoma carcinoma cells, which would be a promising therapeutic target to improve the effectiveness of IFN-α therapy to cure CHB.展开更多
AIM To investigate whether hepatitis viral DNA load at 24 wk of treatment predicts response at 96 wk in patients with chronic hepatitis B.METHODS A total of 172 hepatitis B envelope antigen(HBe Ag)-positive chronic he...AIM To investigate whether hepatitis viral DNA load at 24 wk of treatment predicts response at 96 wk in patients with chronic hepatitis B.METHODS A total of 172 hepatitis B envelope antigen(HBe Ag)-positive chronic hepatitis B patients who received initial treatment at 16 tertiary hospitals in Hunan Province, China were enrolled in this study. All patients received conventional doses of lamivudine and adefovir dipivoxil, telbivudine, entecavir dispersible tablets, or entecavir tablets for 96 wk. Patients who used other antiviral drugs or antitumor and immune regulation therapy were excluded. Patients were stratified into three groups according to their viral DNA load at 24 wk: < 10 IU/m L(group 1), 10-103 IU/m L(group 2), and > 103 IU/m L(group 3). Correlations of 24-wk DNA load with HBe Ag negative status and HBe Ag seroconversion at 96 wk were analyzed. Receiver operating characteristic curve analysis was used to test the predictive value of the HBV DNA load at 24 wk for long-term response.RESULTS The rates of conversion to HBe Ag negative status and HBe Ag seroconversion rates were 53.7% and 51.9%, respectively, in group 1; 35.21% and 32.39% in group 2; and 6.38% and 6.38% in group 3. The receiver operating characteristic curves for the three subgroups revealed that the lowest DNA load(< 10 IU/m L) was better correlated with response at 96 wk than a higher DNA load(10-103 IU/m L). Nested PCR was used for amplifying and sequencing viral DNA in patients with a viral DNA load > 200 IU/m L at 96 wk; resistance mutations involving different loci were present in 26 patients, and three of these patients had a viral DNA load 10-103 IU/m L at 96 wk. CONCLUSION Hepatitis B viral DNA load at 24 wk of antiviral treatment in patients with chronic hepatitis B is a predictor of the viral load and response rate at 96 wk.展开更多
Background:Cholangiocarcinoma(CCA)is highly malignant and has a poor prognosis has a high malignant degree and poor prognosis.The purpose of this study is to develop a new prognostic model based on genes related to th...Background:Cholangiocarcinoma(CCA)is highly malignant and has a poor prognosis has a high malignant degree and poor prognosis.The purpose of this study is to develop a new prognostic model based on genes related to the tumor microenvironment(TME).Methods:Derived from the discerned differentially expressed genes within The Cancer Genome Atlas(TCGA)dataset,this investigation employed the methodology of weighted gene co-expression network analysis(WGCNA)to ascertain gene co-expressed modules intricately linked to the Tumor Microenvironment(TME)among Cholangiocarcinoma(CCA)patients.The genes associated with prognosis,as identified through Cox regression analysis,were employed in the formulation of a predictive model.This model underwent validation,leading to the development of a risk score formula and nomogram.Concurrently,we validated the model’s reliability using data from CCA patients in the Gene Expression Omnibus(GEO)database(accession:GSE107943).Results:6139 DEGs were divided into 10 co-expressed gene modules using WGCNA.Among these,two modules(blue module with 832 genes and brown module with 1379 genes)showed high correlation with the TME.Five prognostic genes(BNIP3,COL4A3,SPRED3,CEBPB,PLOD2)were identified through Cox regression analysis,and a prognostic model and risk score formula were developed based on these genes.Risk score formula:Risk score=BNIP3×1.70520-COL4A3×2.39815+SPRED3×1.17936+CEBPB×0.40456+PLOD2×0.24785.Kaplan-Meier survival analysis revealed that the survival probabilities of the low-risk group were significantly higher than those of the high-risk group.Furthermore,the related evaluation indexes suggested that the model exhibited strong predictive ability.Conclusion:The prognostic model,based on five TME-related genes(BNIP3,COL4A3,SPRED3,CEBPB,PLOD2),could accurately assess the prognosis of CCA patients to aid in guiding clinical decisions.展开更多
Aims:Minimal hepatic encephalopathy(MHE)significantly affects the prognosis of patients with cirrhosis.This study was performed to determine whether there is a difference in the prevalence of MHE among patients with c...Aims:Minimal hepatic encephalopathy(MHE)significantly affects the prognosis of patients with cirrhosis.This study was performed to determine whether there is a difference in the prevalence of MHE among patients with cirrhosis of different etiologies and whether the etiology directly influences the occurrence of MHE.Methods:This multicenter,cross-sectional study enrolled 1879 patients with confirmed cirrhosis at 40 hospitals from October 25,2021,to January 10,2023(Trial registration:https://clinicaltrials.gov/[NCT05140837]).The patients'demographics,etiologies of cirrhosis,and laboratory test results were collected.The psychometric hepatic encephalopathy score(PHES)was determined in all patients to screen for MHE.Multivariate logistic analyses were performed to identify the risk factors for MHE.Results:In total,736 patients with cirrhosis were analyzed.The prevalence of MHE was 42.0%(n=309).The primary etiology among all patients was hepatitis B virus(HBV)-related cirrhosis(71.9%[529/736]).The prevalence of MHE was significantly higher in patients with alcoholic cirrhosis(57.1%[40/70])than in those with HBV-related cirrhosis(40.6%[215/529],p=0.009)or hepatitis C virus(HCV)-related cirrhosis(38.2%[26/68],p=0.026).Age(odds ratio[OR],1.042;95%confidence interval[CI],1.024-1.059;p<0.001),duration of education(OR,0.935;95%CI,0.899-0.971;p=0.001),etiology(OR,1.740;95%CI,1.028-2.945;p=0.039),and high MELD-Na scores(OR,1.038;95%CI,1.009-1.067;p=0.009)were independent risk factors for MHE.When patients with cirrhosis of different etiologies were analyzed separately,the results showed that age(OR,1.035;95%CI,1.014-1.057;p=0.001)and duration of education(OR,0.924;95%CI,0.883-0.966;p=0.001)were risk factors for MHE among patients with HBV-related cirrhosis,whereas age(OR,1.138;95%CI,1.033-1.254;p=0.009)and creatinine concentration(OR,16.487;95%CI,1.113-244.160;p=0.042)were risk factors for MHE in patients with HCV-related cirrhosis.No risk factors for MHE were found in patients with autoimmune cirrhosis.For patients with alcoholic cirrhosis,the platelet count(OR,1.014;95%CI,1.000-1.027;p=0.045)was a risk factor for MHE.The PHES subtest results were inconsistent among patients who had MHE with cirrhosis of different etiologies.Patients with HBV-related cirrhosis performed better on Number Connection Test B and the serial dotting test than those with alcoholic cirrhosis(p=0.007 and p<0.001),better on Number Connection Test B than those with HCV-related cirrhosis(p=0.020),and better on the line tracing test than those with autoimmune cirrhosis(p=0.037).Conclusion:The etiology of cirrhosis affected the prevalence of MHE and risk factors for MHE.The domains of major cognitive impairment varied among patients with cirrhosis of different etiologies.Further studies are required to verify these findings.展开更多
Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepat...Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepatocellular carcinoma (HCC) patients’response to immune checkpoint inhibitors (ICIs). We categorized HCC patients into various immune subtypes based on feature scores linked to ICI response. Single-cell sequencing technology was to investigate the cellular heterogeneity of different immune subtypes and acquiresignificant ICI response-associated cells. Candidate drugs were identified using a blend ofvarious drug databases and network approaches. HCC patients were divided into two distinct immune subtypes based on characterization scores of 151 immune-related gene sets. Patientsin both subtypes showed varying overall survival, immunity levels, biological activities, andTP53 mutation rates. Subtype 1-related natural killer cells showed a positive correlation withimmune-promoting scores but a negative correlation with immune-suppressing scores.Notably, docetaxel sensitivity in HCC patients rose as the levels of subtype 1-related naturalkiller cells increased. Our study demonstrated that immune subtypes have cellular heterogeneity in predicting response to ICIs. A combination of subtype 1-associated natural killer cellsand docetaxel may offer new hope for ICI treatment in HCC.展开更多
Chromosomal instability(CIN)drives cancer development by causing the accumulation of significant gains,losses,and rearrangements of DNA,although the degree to which this impact relies on DNA damage is uncertain in ter...Chromosomal instability(CIN)drives cancer development by causing the accumulation of significant gains,losses,and rearrangements of DNA,although the degree to which this impact relies on DNA damage is uncertain in terms of mechanisms and key molecules.Nevertheless,a structured system for evaluating various forms of CIN and their impact on hepatocellular carcinoma(HCC)is lacking.展开更多
Background:Metastasis is the leading cause of cancer-related mortality,with circulating tumor cell(CTC)clusters serving as highly efficient precursors of distant metastasis.Survival of CTC clusters in the bloodstream ...Background:Metastasis is the leading cause of cancer-related mortality,with circulating tumor cell(CTC)clusters serving as highly efficient precursors of distant metastasis.Survival of CTC clusters in the bloodstream is the primary contributor to tumor metastasis.However,the underlying mechanisms of how CTC clusters respond to the blood environment and drive metastasis remain elusive.This study aimed to elucidate the potential mechanisms that enable CTC clusters to adapt and survive in the bloodstream.Methods:CTC clusters were detected using a microfluidic system in cancer patients,as well as in patient-derived xenograft(PDX),cell line-derived xenograft,and syngeneic models.The key molecules responsible for the adaptive survival of CTC clusters were characterized using RNA-sequencing(RNAseq),gene interference,and flow cytometry.To investigate the underlying mechanisms of adaptive survival,RNA-seq,targeted metabolomics,isotope tracing experiments,chromatin immunoprecipitation(ChIP)sequencing,and immunofluorescence(IF)staining were employed.The therapeutic potential of survival pathway inhibitor combined with chemotherapy drug was evaluated in patient-derived CTCs and the PDX model.Results:CTC clusters exhibited superior survival and metastatic capacity compared to single CTCs and were associated with adverse clinical outcomes.The unfolded protein response mediator protein kinase R-like endoplasmic reticulum kinase(PERK)was activated in CTC clusters and maintained Sadenosylmethionine(SAM)availability,facilitating their adaptive survival in the bloodstream.Mechanistically,PERK mediated the upregulation of activating transcription factor 4(ATF4),which enhanced methionine adenosyltransferase 2A(MAT2A)expression,contributing to SAM synthesis.Increased SAM enhanced H3K4me3 modification of the platelet-derived growth factor B(PDGFB)promoter,leading to elevated PDGFB secretion and its accumulation in the intercellular region within CTC clusters.PDGFB functioned as a shared survival signal,triggering the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway via platelet-derived growth factor receptor beta(PDGFRβ),supporting CTC cluster survival in the bloodstream.Inhibition of PERK and PDGFRβprofoundly impaired the survival signaling and suppressed the metastatic dissemination of CTC clusters.Conclusions:Our findings revealed a PERK/MAT2A/PDGFB axis that confers adaptive survival capabilities to CTC clusters in the bloodstream.Targeting this survival signaling pathway represents a promising therapeutic strategy for metastatic cancer.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative virus of the coronavirus disease 2019(COVID-19)pandemic.To establish a safe and convenient assay system for studying entry inhibitors and neu...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative virus of the coronavirus disease 2019(COVID-19)pandemic.To establish a safe and convenient assay system for studying entry inhibitors and neutralizing antibodies against SARS-CoV-2,we constructed a codon-optimized,full-length C-terminal mutant spike(S)gene of SARS-CoV-2.We generated a luciferase(Luc)-expressing pseudovirus containing the wild-type or mutant S protein of SARS-CoV-2 in the envelope-defective HIV-1 backbone.The key parameters for this pseudovirus-based assay,including the S mutants and virus incubation time,were optimized.This pseudovirus contains a Luc reporter gene that enabled us to easily quantify virus entry into angiotensin-converting enzyme 2(ACE2)-expressing 293T cells.Cathepsin(Cat)B/L inhibitor E64d could significantly block SARS-CoV-2 pseudovirus infection in 293T-ACE2 cells.Furthermore,the SARS-CoV-2 spike pseudotyped virus could be neutralized by sera from convalescent COVID-19 patients or recombinant ACE2 with the fused Fc region of human IgG1.Thus,we developed a pseudovirus-based assay for SARS-CoV-2,which will be valuable for evaluating viral entry inhibitors and neutralizing antibodies against this highly pathogenic virus.展开更多
On 24 November,a new detected variant B.1.1.529 of SARS-CoV-2 by South Africa was reported to WHO.After only 2 days,this variant was designated as“variant of concern”(VOC)and named as Omicron.In the past few weeks,O...On 24 November,a new detected variant B.1.1.529 of SARS-CoV-2 by South Africa was reported to WHO.After only 2 days,this variant was designated as“variant of concern”(VOC)and named as Omicron.In the past few weeks,Omicron had reported from more than 80 countries.It has been reported as the dominant SARS-CoV-2 in U.S.due to the rapid spread of Omicron.A new wave of infection driven by Omicron is in progress.展开更多
The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming.One of the most important cancer hallmarks,including aerobic glycolysis(the W...The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming.One of the most important cancer hallmarks,including aerobic glycolysis(the Warburg effect),the central carbon pathway,and multiple-branch metabolic pathway remodeling,enables tumor growth,progression,and metastasis.Phosphoenolpyruvate carboxykinase1(PCK1),a key rate-limiting enzyme in gluconeogenesis,catalyzes the conversion of oxaloacetate to phosphoenolpyruvate.PCK1 expression in gluconeogenic tissues is tightly regulated during fasting.In tumor cells,PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracellular environment.Interestingly,PCK1has ananti-oncogenic role in gluconeogenic organs(the liver and kidneys),but a tumor-promoting role in cancers arising from non-gluconeogenic organs.Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways.Aberrant PCK1 expression results in the activation of oncogenic pathways,accompanied by metabolic reprogramming,to maintain tumorigenesis.In this review,we summarize the mechanisms underlying PCK1 expression and regulation,and clarify the crosstalk between aberrant PCK1 expression,metabolic rewiring,and signaling pathway activation.In addition,we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.展开更多
Many countries around the world have seen a sharp rise in COVID-19 cases since the beginning of October due to the second wave of the pandemic.A decline in the antibody response to severe acute respiratory syndrome co...Many countries around the world have seen a sharp rise in COVID-19 cases since the beginning of October due to the second wave of the pandemic.A decline in the antibody response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which was reported exclusively in the early month,increases the risk of reinfection for convalescent individuals.There is a current need to follow the maintenance of specific antibodies against SARS-CoV-2.展开更多
Natural killer(NK)cells have a vital role in killing hepatocellular carcinoma(HCC)cells;however,the mechanism underlying tumor-infiltrating NK(TINK)-cell dysfunction remains poorly understood.Using flow cytometry stai...Natural killer(NK)cells have a vital role in killing hepatocellular carcinoma(HCC)cells;however,the mechanism underlying tumor-infiltrating NK(TINK)-cell dysfunction remains poorly understood.Using flow cytometry staining,we precisely characterized the frequency,phenotype and function of NK subsets distinguished by CD27 and CD11b in 30 patients with HCC in comparison to 30 healthy controls.Interestingly,we found a substantial proportion of liver-infiltrating CD11b−CD27−(DN)NK subsets in tumor tissue from HCC patients.Remarkably,these relatively expanded DN NK subsets exhibited an inactive and immature phenotype.By detecting the expression of CD107a and interferon-gamma(IFN-γ)on NK subsets and NK cells,we demonstrated that DN NK subsets exhibited a poor cytotoxic capacity and deficient potential to produce IFN-γin comparison to the other three subsets,which contributed to the dysfunction of TINK cells in HCC patients.In addition,we found that the presence of DN NK cells was closely associated with the clinical outcomes of HCC patients,as the frequency of DN NK cells among TINK cells was positively correlated with tumor stage and size.A large percentage of DN NK cells among TINK cells was an independent prognostic factor for lower survival in the 60-month follow-up period.In conclusion,a substantial proportion of CD11b−CD27−NK subsets among TINK cells accounts for NK-cell dysfunction in patients with HCC and is associated with tumor progression.Our study may provide a novel therapeutic target for the treatment of patients with HCC.展开更多
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is an ongoing pandemic that poses a great threat to human health worldwide.As the humoral immune response plays ...Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is an ongoing pandemic that poses a great threat to human health worldwide.As the humoral immune response plays essential roles in disease occurrence and development,understanding the dynamics and characteristics of virus-specific humoral immunity in SARS-CoV-2-infected patients is of great importance for controlling this disease.In this review,we summarize the characteristics of the humoral immune response after SARS-CoV-2 infection and further emphasize the potential applications and therapeutic prospects of SARSCoV-2-specific humoral immunity and the critical role of this immunity in vaccine development.Notably,serological antibody testing based on the humoral immune response can guide public health measures and control strategies;however,it is not recommended for population surveys in areas with very low prevalence.Existing evidence suggests that asymptomatic individuals have a weaker immune response to SARS-CoV-2 infection,whereas SARS-CoV-2-infected children have a more effective humoral immune response than adults.The correlations between antibody(especially neutralizing antibody)titers and protection against SARS-CoV-2 reinfection should be further examined.In addition,the emergence of cross-reactions among different coronavirus antigens in the development of screening technology and the risk of antibody-dependent enhancement related to SARS-CoV-2 vaccination should be given further attention.展开更多
Coronaviruses are enveloped,positive-stranded RNA viruses that contain the largest known RNA genomes to date.As severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to circulate in the human population...Coronaviruses are enveloped,positive-stranded RNA viruses that contain the largest known RNA genomes to date.As severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to circulate in the human population,multiple mutations have accumulated over time,which may affect its transmission,virulence and antigenicity.展开更多
基金Supported by the National Natural Sciences Foundation of China,No.81272253,No.81502098 and No.81670538the Special National International Technology Cooperation of China,No.2015DFA31490
文摘AIM To identify the miRNA-mRNA regulatory network in hepatitis B virus X (HBx)-expressing hepatic cells. METHODS A stable HBx-expressing human liver cell line L02 was established. The mRNA and miRNA expression profiles of L02/HBx and L02/pcDNA liver cells were identified by RNA-sequencing analysis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed to investigate the function of candidate biomarkers, and the relationship between miRNA and mRNA was studied by network analysis. RESULTS Compared with L02/pcDNA cells, 742 unregulated genes and 501 downregulated genes were determined as differentially expressed in L02/HBx cells. Gene ontology analysis suggested that the differentially expressed genes were relevant to different processes. Concurrently, 22 differential miRNAs were also determined in L02/HBx cells. Furthermore, integrated analysis of miRNA and mRNA expression profiles identified a core miRNA-mRNA regulatory network that is correlated with the carcinogenic role of HBx. CONCLUSION Collectively, the miRNA-mRNA network-based analysis could be useful to elucidate the potential role of HBx in liver cell malignant transformation and shed light on the underlying molecular mechanism and novel therapy targets for hepatocellular carcinoma.
基金supported by a grant from the Clinical Research Foundation of Xiangya Hospital,Central South University(No.2016L10)
文摘Background: Hepatitis B virus(HBV)-associated acute-on-chronic liver failure(HBV-ACLF) is a lifethreatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum mi RNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF.Methods: Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to30 chronic asymptomatic HBV carriers as controls. The mi RNAs expressions were measured by real-time quantitative PCR(q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed mi RNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model.Results: Real-time q-PCR indicated that serum miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and mi R-122-3 p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na+-1.72 × INR-4.963 × gastrointestinal bleeding(Yes = 0; No = 1)-0.278 ×(mi R-122-3 p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve(AUROC) was 0.847.Conclusions: Expression levels of these mi RNAs(miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.
文摘AIM： To undertake analysis of hepatitis A viral load, alanine aminotransferase （ALT）, and viral genotypes with duration of viremia, and to correlate these parameters with CD4^＋/ CD8^＋ lymphocyte populations that control cell-mediated immunity. METHODS： Cell counts were carried out using fresh whole blood collected in EDTA vials using a fluorescence activated cell sorter. Hepatitis A virus （HAV） RNA was extracted from blood serum, reverse transcribed into cDNA and quantified by Real-Time polymerase chain reaction and was genotyped. RESULTS： Among 11 patients, 10 could be analyzed completely. Of these, 3 had severe acute hepatitis （s-AH） and the remainder had a self-limited acute hepatitis A （AHA）, with one patient with fulminant disease （encephalopathy Grade IV） dying on the 4^th d. The ALT level was significantly higher both in AHA （1070.9±894.3; P = 0.0014） and s-AH （1713.9±886.3; P = 0.001） compared to normal controls （23.6±7.2）. The prothrombin time in s-AH patients （21.0 ±2.0; P=0.02） was significantly higher than in AHA （14.3±1.1;P = 0.44）. The CD4^＋/CD8^＋ ratio in AHA patients （1.17 ＋ 0.11; P = 0.22） and s-AH （0.83 ＋ 0.12; P = 0.0002） were lower than seen in normal healthy controls （1.52）. Self-limited cases had peak viral load at the beginning of analysis while in s-AH patients this occurred at the 15TM or 30^th d. In acute and severe groups, one patient each belonged to genotype IA, with the remaining 8 cases belonging to genotype IIIA. The only fulminant hepatic failure case belonged to genotype IA. HAV viral load and AIT values collected during the entire course of the selflimited infection were directly correlated but this was not the case for s-AH patients.CONCLUSION： Based on a small-scale study, the persistently higher viral load of s-AH might be due to diminished cellular immunity and hemolysis. The duration of viremia was dependent on the host, as the viral genotype had no apparent role in clinical outcome of AVH and s-AH cases.
基金supported by grants from the National Natural Science Foundation of China(32000474)to W.Sthe National Science and Technology Major Project of China(2017ZX10202203-007-001)to H.R.
文摘The National Center for Biotechnology Information(NCBI)Taxonomy is widely applied in biomedical and ecological studies.Typical demands include querying taxonomy identifier(TaxIds)by taxonomy names,querying complete taxonomic lineages by TaxIds,listing descendants of given TaxIds,and others.However,existed tools are either limited in functionalities or inefficient in terms of runtime.In this work,we present TaxonKit,a command-line toolkit for comprehensive and efficient manipulation of NCBI Taxonomy data.TaxonKit comprises seven core subcommands providing functions,including TaxIds querying,listing,filtering,lineage retrieving and reformatting,lowest common ancestor computation,and TaxIds change tracking.The practical functions,competitive processing performance,scalability with different scales of datasets and good accessibility can facilitate taxonomy data manipulations.TaxonKit provides free access under the permissive MIT license on GitHub,Brewsci,and Bioconda.The documents are also available at https://bioinf.shenwei.me/taxonkit/.
基金supported by the National Natural Science Foundation of China (U1702288, 81700520, U1702287, 31671230, 91857113, 31860323, 32000818)the Yunnan Applied Basic Research Projects (2019FY003021, 2017FA007, 2018FB117, 202101AT070009)+1 种基金the Ministry of Science and Technology of the People’s Republic of China (2018YFA0800700)the Yunnan Province Innovation Team of Intestinal Microecology-Related Disease Research and Technological Transformation (202005AE160010)
文摘Liver fibrosis is a key transformation stage and also a reversible pathological process in various types of chronic liver diseases.However,the pathogenesis of liver fibrosis still remains elusive.Here,we report that the calcium binding protein A11(S100A11)is consistently upregulated in the integrated data from GSE liver fibrosis and tree shrew liver proteomics.S100A11 is also experimentally activated in liver fibrosis in mouse,rat,tree shrew,and human with liver fibrosis.While overexpression of S100A11 in vivo and in vitro exacerbates liver fibrosis,the inhibition of S100A11 improves liver fibrosis.Mechanistically,S100A11 activates hepatic stellate cells(HSCs)and the fibrogenesis process via the regulation of the deacetylation of Smad3 in the TGF-βsignaling pathway.S100A11 physically interacts with SIRT6,a deacetylase of Smad2/3,which may competitively inhibit the interaction between SIRT6 and Smad2/3.The subsequent release and activation of Smad2/3 promote the activation of HSCs and fibrogenesis.Additionally,a significant elevation of S100A11 in serum is observed in clinical patients.Our study uncovers S100A11 as a novel profibrogenic factor in liver fibrosis,which may represent both a potential biomarker and a promising therapy target for treating liver fibrosis and fibrosis-related liver diseases.
基金Supported by National Natural Science Foundation of China,No.81800472 and No.81670538the Science Foundation of Hunan Health Commission,No.B2019184.
文摘BACKGROUND Early diagnosis of hepatocellular carcinoma may help to ensure that patients have a chance for long-term survival;however,currently available biomarkers lack sensitivity and specificity.AIM To characterize the serum metabolome of hepatocellular carcinoma in order to develop a new metabolomics diagnostic model and identifying novel biomarkers for screening hepatocellular carcinoma based on the pattern recognition method.METHODS Ultra-performance liquid chromatography-mass spectroscopy was used to characterize the serum metabolome of hepatocellular carcinoma(n=30)and cirrhosis(n=29)patients,followed by sequential feature selection combined with linear discriminant analysis to process the multivariate data.RESULTS The concentrations of most metabolites,including proline,were lower in patients with hepatocellular carcinoma,whereas the hydroxypurine levels were higher in these patients.As ordinary analysis models failed to discriminate hepatocellular carcinoma from cirrhosis,pattern recognition analysis was used to establish a pattern recognition model that included hydroxypurine and proline.The leaveone-out cross-validation accuracy and area under the receiver operating characteristic curve analysis were 95.00%and 0.90[95%Confidence Interval(CI):0.81-0.99]for the training set,respectively,and 78.95%and 0.84(95%CI:0.67-1.00)for the validation set,respectively.In contrast,forα-fetoprotein,the accuracy and area under the receiver operating characteristic curve were 65.00%and 0.69(95%CI:0.52-0.86)for the training set,respectively,and 68.42%and 0.68(95%CI:0.41-0.94)for the validation set,respectively.The Z test revealed that the area under the curve of the linear discriminant analysis model was significantly higher than the area under the curve ofα-fetoprotein(P<0.05)in both the training and validation sets.CONCLUSION Hydroxypurine and proline might be novel biomarkers for hepatocellular carcinoma,and this disease could be diagnosed by the metabolomics model based on pattern recognition.
基金supported by the National Key Research and Development Program of China(2018YFE0107500)the Natural Science Foundation Project of Science and Technology Agency of Chongqing YuZhong District(20200122)to Hu Yuana Natural Science Foundation Project of CQ CSTC(cstc2021jcyj-msxmX0276)to Chen YanMeng
文摘Casein kinase 1α(CK1α) mediates the phosphorylation and degradation of interferon-α/β receptor 1(IFNAR1) in response to viral infection. However, how CK1α regulates hepatitis B virus(HBV) replication and the anti-HBV effects of IFN-α are less reported. Here we show that CK1α can interact with IFNAR1 in hepatoma carcinoma cells and increased the abundance of IFNAR1 by reducing the ubiquitination levels in the presence of HBV.Furthermore, CK1α promotes the IFN-α triggered JAK-STAT signaling pathway and consequently enhances the antiviral effects of IFN-α against HBV replication. Our results collectively provide evidence that CK1α positively regulates the anti-HBV activity of IFN-α in hepatoma carcinoma cells, which would be a promising therapeutic target to improve the effectiveness of IFN-α therapy to cure CHB.
基金Supported by the National High Technology Research and Development Program(863 Program)No.2012AA022605
文摘AIM To investigate whether hepatitis viral DNA load at 24 wk of treatment predicts response at 96 wk in patients with chronic hepatitis B.METHODS A total of 172 hepatitis B envelope antigen(HBe Ag)-positive chronic hepatitis B patients who received initial treatment at 16 tertiary hospitals in Hunan Province, China were enrolled in this study. All patients received conventional doses of lamivudine and adefovir dipivoxil, telbivudine, entecavir dispersible tablets, or entecavir tablets for 96 wk. Patients who used other antiviral drugs or antitumor and immune regulation therapy were excluded. Patients were stratified into three groups according to their viral DNA load at 24 wk: < 10 IU/m L(group 1), 10-103 IU/m L(group 2), and > 103 IU/m L(group 3). Correlations of 24-wk DNA load with HBe Ag negative status and HBe Ag seroconversion at 96 wk were analyzed. Receiver operating characteristic curve analysis was used to test the predictive value of the HBV DNA load at 24 wk for long-term response.RESULTS The rates of conversion to HBe Ag negative status and HBe Ag seroconversion rates were 53.7% and 51.9%, respectively, in group 1; 35.21% and 32.39% in group 2; and 6.38% and 6.38% in group 3. The receiver operating characteristic curves for the three subgroups revealed that the lowest DNA load(< 10 IU/m L) was better correlated with response at 96 wk than a higher DNA load(10-103 IU/m L). Nested PCR was used for amplifying and sequencing viral DNA in patients with a viral DNA load > 200 IU/m L at 96 wk; resistance mutations involving different loci were present in 26 patients, and three of these patients had a viral DNA load 10-103 IU/m L at 96 wk. CONCLUSION Hepatitis B viral DNA load at 24 wk of antiviral treatment in patients with chronic hepatitis B is a predictor of the viral load and response rate at 96 wk.
基金supported by Medical Scientific Research Foundation of Chongqing of China(2022MSXM048).
文摘Background:Cholangiocarcinoma(CCA)is highly malignant and has a poor prognosis has a high malignant degree and poor prognosis.The purpose of this study is to develop a new prognostic model based on genes related to the tumor microenvironment(TME).Methods:Derived from the discerned differentially expressed genes within The Cancer Genome Atlas(TCGA)dataset,this investigation employed the methodology of weighted gene co-expression network analysis(WGCNA)to ascertain gene co-expressed modules intricately linked to the Tumor Microenvironment(TME)among Cholangiocarcinoma(CCA)patients.The genes associated with prognosis,as identified through Cox regression analysis,were employed in the formulation of a predictive model.This model underwent validation,leading to the development of a risk score formula and nomogram.Concurrently,we validated the model’s reliability using data from CCA patients in the Gene Expression Omnibus(GEO)database(accession:GSE107943).Results:6139 DEGs were divided into 10 co-expressed gene modules using WGCNA.Among these,two modules(blue module with 832 genes and brown module with 1379 genes)showed high correlation with the TME.Five prognostic genes(BNIP3,COL4A3,SPRED3,CEBPB,PLOD2)were identified through Cox regression analysis,and a prognostic model and risk score formula were developed based on these genes.Risk score formula:Risk score=BNIP3×1.70520-COL4A3×2.39815+SPRED3×1.17936+CEBPB×0.40456+PLOD2×0.24785.Kaplan-Meier survival analysis revealed that the survival probabilities of the low-risk group were significantly higher than those of the high-risk group.Furthermore,the related evaluation indexes suggested that the model exhibited strong predictive ability.Conclusion:The prognostic model,based on five TME-related genes(BNIP3,COL4A3,SPRED3,CEBPB,PLOD2),could accurately assess the prognosis of CCA patients to aid in guiding clinical decisions.
基金The Innovation Groups of the National Natural Science Foundation of China,Grant/Award Number:81721002Capital Clinical Diagnosis and Treatment Technology Research and Transformation Application Project,Grant/Award Number:Z201100005520046+1 种基金Tianjin Key Medical Specialty Construction Project,Grant/Award Number:TJYXZDXK-034ATianjin Health Science and Technology Project,Grant/Award Number:TJWJ2022XK029。
文摘Aims:Minimal hepatic encephalopathy(MHE)significantly affects the prognosis of patients with cirrhosis.This study was performed to determine whether there is a difference in the prevalence of MHE among patients with cirrhosis of different etiologies and whether the etiology directly influences the occurrence of MHE.Methods:This multicenter,cross-sectional study enrolled 1879 patients with confirmed cirrhosis at 40 hospitals from October 25,2021,to January 10,2023(Trial registration:https://clinicaltrials.gov/[NCT05140837]).The patients'demographics,etiologies of cirrhosis,and laboratory test results were collected.The psychometric hepatic encephalopathy score(PHES)was determined in all patients to screen for MHE.Multivariate logistic analyses were performed to identify the risk factors for MHE.Results:In total,736 patients with cirrhosis were analyzed.The prevalence of MHE was 42.0%(n=309).The primary etiology among all patients was hepatitis B virus(HBV)-related cirrhosis(71.9%[529/736]).The prevalence of MHE was significantly higher in patients with alcoholic cirrhosis(57.1%[40/70])than in those with HBV-related cirrhosis(40.6%[215/529],p=0.009)or hepatitis C virus(HCV)-related cirrhosis(38.2%[26/68],p=0.026).Age(odds ratio[OR],1.042;95%confidence interval[CI],1.024-1.059;p<0.001),duration of education(OR,0.935;95%CI,0.899-0.971;p=0.001),etiology(OR,1.740;95%CI,1.028-2.945;p=0.039),and high MELD-Na scores(OR,1.038;95%CI,1.009-1.067;p=0.009)were independent risk factors for MHE.When patients with cirrhosis of different etiologies were analyzed separately,the results showed that age(OR,1.035;95%CI,1.014-1.057;p=0.001)and duration of education(OR,0.924;95%CI,0.883-0.966;p=0.001)were risk factors for MHE among patients with HBV-related cirrhosis,whereas age(OR,1.138;95%CI,1.033-1.254;p=0.009)and creatinine concentration(OR,16.487;95%CI,1.113-244.160;p=0.042)were risk factors for MHE in patients with HCV-related cirrhosis.No risk factors for MHE were found in patients with autoimmune cirrhosis.For patients with alcoholic cirrhosis,the platelet count(OR,1.014;95%CI,1.000-1.027;p=0.045)was a risk factor for MHE.The PHES subtest results were inconsistent among patients who had MHE with cirrhosis of different etiologies.Patients with HBV-related cirrhosis performed better on Number Connection Test B and the serial dotting test than those with alcoholic cirrhosis(p=0.007 and p<0.001),better on Number Connection Test B than those with HCV-related cirrhosis(p=0.020),and better on the line tracing test than those with autoimmune cirrhosis(p=0.037).Conclusion:The etiology of cirrhosis affected the prevalence of MHE and risk factors for MHE.The domains of major cognitive impairment varied among patients with cirrhosis of different etiologies.Further studies are required to verify these findings.
基金supported by the Science and Technology Research Programme Project of Chongqing Municipal Education Commission of China(No.KJQN202300423)the National Youth Science Foundation Project(China)(No.82204159)+2 种基金the Science and Technology Project of Sichuan Provincial Administration of Traditional Chinese Medicine(China)(No.2023MS047)the Program for Youth Innovation in Future Medicine,Chongqing Medical University(No.W0150)the Intelligent Medicine Research Project of Chongqing Medical University(No.ZHYX202223).
文摘Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepatocellular carcinoma (HCC) patients’response to immune checkpoint inhibitors (ICIs). We categorized HCC patients into various immune subtypes based on feature scores linked to ICI response. Single-cell sequencing technology was to investigate the cellular heterogeneity of different immune subtypes and acquiresignificant ICI response-associated cells. Candidate drugs were identified using a blend ofvarious drug databases and network approaches. HCC patients were divided into two distinct immune subtypes based on characterization scores of 151 immune-related gene sets. Patientsin both subtypes showed varying overall survival, immunity levels, biological activities, andTP53 mutation rates. Subtype 1-related natural killer cells showed a positive correlation withimmune-promoting scores but a negative correlation with immune-suppressing scores.Notably, docetaxel sensitivity in HCC patients rose as the levels of subtype 1-related naturalkiller cells increased. Our study demonstrated that immune subtypes have cellular heterogeneity in predicting response to ICIs. A combination of subtype 1-associated natural killer cellsand docetaxel may offer new hope for ICI treatment in HCC.
基金supported by grants from the National Natural Science Foundation of China(No.82403106,82100217)Chongqing Postdoctoral Science Foundation of China(No.cstc2021jcyj-bshX0118)+3 种基金Natural Science Foundation of Chongqing,China(No.cstc2021jcyj-msxmX0292,CSTB2024NSCQ-MSX0179)Scientific and Technological Research Program of Chongqing Municipal Education Commission(China)(No.KJQN202300451)Chongqing Medical University Future Medical Youth Innovation Team Support Program(China)(No.W0008)Program for Nursing Collaborative Innovation,Chongqing Medical University,Chongqing,China(No.20240203,20240211).
文摘Chromosomal instability(CIN)drives cancer development by causing the accumulation of significant gains,losses,and rearrangements of DNA,although the degree to which this impact relies on DNA damage is uncertain in terms of mechanisms and key molecules.Nevertheless,a structured system for evaluating various forms of CIN and their impact on hepatocellular carcinoma(HCC)is lacking.
基金National Natural Science Foundation of China,Grant/Award Numbers:NSFC 82072938,NSFC82173155,NSFC82372823the Senior Medical Talents Program of Chongqing Medical University for Young and Middle-aged Scientist,Grant/Award Number:2021-W0068+1 种基金the Outstanding Professorship Program of Chongqing Medical University,Grant/Award Number:R10005the Outstanding Postgraduate Fund of Chongqing Medical University,Grant/Award Number:BJRC202313。
文摘Background:Metastasis is the leading cause of cancer-related mortality,with circulating tumor cell(CTC)clusters serving as highly efficient precursors of distant metastasis.Survival of CTC clusters in the bloodstream is the primary contributor to tumor metastasis.However,the underlying mechanisms of how CTC clusters respond to the blood environment and drive metastasis remain elusive.This study aimed to elucidate the potential mechanisms that enable CTC clusters to adapt and survive in the bloodstream.Methods:CTC clusters were detected using a microfluidic system in cancer patients,as well as in patient-derived xenograft(PDX),cell line-derived xenograft,and syngeneic models.The key molecules responsible for the adaptive survival of CTC clusters were characterized using RNA-sequencing(RNAseq),gene interference,and flow cytometry.To investigate the underlying mechanisms of adaptive survival,RNA-seq,targeted metabolomics,isotope tracing experiments,chromatin immunoprecipitation(ChIP)sequencing,and immunofluorescence(IF)staining were employed.The therapeutic potential of survival pathway inhibitor combined with chemotherapy drug was evaluated in patient-derived CTCs and the PDX model.Results:CTC clusters exhibited superior survival and metastatic capacity compared to single CTCs and were associated with adverse clinical outcomes.The unfolded protein response mediator protein kinase R-like endoplasmic reticulum kinase(PERK)was activated in CTC clusters and maintained Sadenosylmethionine(SAM)availability,facilitating their adaptive survival in the bloodstream.Mechanistically,PERK mediated the upregulation of activating transcription factor 4(ATF4),which enhanced methionine adenosyltransferase 2A(MAT2A)expression,contributing to SAM synthesis.Increased SAM enhanced H3K4me3 modification of the platelet-derived growth factor B(PDGFB)promoter,leading to elevated PDGFB secretion and its accumulation in the intercellular region within CTC clusters.PDGFB functioned as a shared survival signal,triggering the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway via platelet-derived growth factor receptor beta(PDGFRβ),supporting CTC cluster survival in the bloodstream.Inhibition of PERK and PDGFRβprofoundly impaired the survival signaling and suppressed the metastatic dissemination of CTC clusters.Conclusions:Our findings revealed a PERK/MAT2A/PDGFB axis that confers adaptive survival capabilities to CTC clusters in the bloodstream.Targeting this survival signaling pathway represents a promising therapeutic strategy for metastatic cancer.
基金This work was supported by the Emergency Project from the Science&Technology Commission of Chongqing(cstc2020jscx-fyzx0053)a Major National Science&Technology Program grant(2017ZX10202203)from the Science&Technology Commission of China,the Leading Talent Program of CQ CSTC(CSTCCXLJRC201719)+1 种基金the Scientific Research Innovation Project for Postgraduate in Chongqing(CYB19168)the Emergency Project for Novel Coronavirus Pneumonia from the Chongqing Medical University(CQMUNCP0302).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative virus of the coronavirus disease 2019(COVID-19)pandemic.To establish a safe and convenient assay system for studying entry inhibitors and neutralizing antibodies against SARS-CoV-2,we constructed a codon-optimized,full-length C-terminal mutant spike(S)gene of SARS-CoV-2.We generated a luciferase(Luc)-expressing pseudovirus containing the wild-type or mutant S protein of SARS-CoV-2 in the envelope-defective HIV-1 backbone.The key parameters for this pseudovirus-based assay,including the S mutants and virus incubation time,were optimized.This pseudovirus contains a Luc reporter gene that enabled us to easily quantify virus entry into angiotensin-converting enzyme 2(ACE2)-expressing 293T cells.Cathepsin(Cat)B/L inhibitor E64d could significantly block SARS-CoV-2 pseudovirus infection in 293T-ACE2 cells.Furthermore,the SARS-CoV-2 spike pseudotyped virus could be neutralized by sera from convalescent COVID-19 patients or recombinant ACE2 with the fused Fc region of human IgG1.Thus,we developed a pseudovirus-based assay for SARS-CoV-2,which will be valuable for evaluating viral entry inhibitors and neutralizing antibodies against this highly pathogenic virus.
基金funding support from the China National Natural Science Foundation(grant no.U20A20392)the 111 Project(No.D20028),the Research Fund Program of the Key Laboratory of Molecular Biology for Infectious Diseases,CQMU(No.202105,202102)+6 种基金the Emergency Project from the Science&Technology Commission of Chongqing(cstc2020jscx-fyzx0053)the Emergency Project for Novel Coronavirus Pneumonia from the Chongqing Medical University(CQMUNCP0302)the Leading Talent Program of CQ CSTC(CSTCCXLJRC201719)a Major National Science&Technology Program grant(2017ZX10202203)the Science&Technology Commission of China,National Natural Science Foundation of China(Grant No.82102361)China Postdoctoral Science Foundation(2021M693924),Natural Science Foundation of Chongqing,China(cstc2021jcyj-bshX0115)Chongqing Postdoctoral Science Special Foundation(2010010005216630).
文摘On 24 November,a new detected variant B.1.1.529 of SARS-CoV-2 by South Africa was reported to WHO.After only 2 days,this variant was designated as“variant of concern”(VOC)and named as Omicron.In the past few weeks,Omicron had reported from more than 80 countries.It has been reported as the dominant SARS-CoV-2 in U.S.due to the rapid spread of Omicron.A new wave of infection driven by Omicron is in progress.
基金This work was supported by The China National Natural Science Foundation,China(No.82073251,82072286,81872270)The Natural Science Foundation Project of Chongqing,China(No.cstc2019jscx-dxwtBX0019,cstc2019jcyj-msxmX0587)+2 种基金The Kuanren Talents Program of The Second Affiliated Hospital of Chongqing Medical University,ChinaThe Future Medical Youth Innovation Team of Chongqing Medical University,China(No.W0036,W0101)The Science and Technology Research Program of Chongqing Municipal Education Commission,China(No.HZ2021006,KJZD-M202000401,KJQN201900429).
文摘The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming.One of the most important cancer hallmarks,including aerobic glycolysis(the Warburg effect),the central carbon pathway,and multiple-branch metabolic pathway remodeling,enables tumor growth,progression,and metastasis.Phosphoenolpyruvate carboxykinase1(PCK1),a key rate-limiting enzyme in gluconeogenesis,catalyzes the conversion of oxaloacetate to phosphoenolpyruvate.PCK1 expression in gluconeogenic tissues is tightly regulated during fasting.In tumor cells,PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracellular environment.Interestingly,PCK1has ananti-oncogenic role in gluconeogenic organs(the liver and kidneys),but a tumor-promoting role in cancers arising from non-gluconeogenic organs.Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways.Aberrant PCK1 expression results in the activation of oncogenic pathways,accompanied by metabolic reprogramming,to maintain tumorigenesis.In this review,we summarize the mechanisms underlying PCK1 expression and regulation,and clarify the crosstalk between aberrant PCK1 expression,metabolic rewiring,and signaling pathway activation.In addition,we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.
基金We acknowledge funding support from the Key Laboratory of Infectious Diseases(CQMU,202005)the Emergency Project from the Science&Technology Commission of Chongqing(cstc2020jscx-fyzx0053)+2 种基金the Emergency Project for Novel Coronavirus Pneumonia from Chongqing Medical University(CQMUNCP0302)the Leading Talent Program of CQ CSTC(CSTCCXLJRC201719)and a Major National Science&Technology Program grant(2017ZX10202203)from the Science&Technology Commission of China.
文摘Many countries around the world have seen a sharp rise in COVID-19 cases since the beginning of October due to the second wave of the pandemic.A decline in the antibody response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which was reported exclusively in the early month,increases the risk of reinfection for convalescent individuals.There is a current need to follow the maintenance of specific antibodies against SARS-CoV-2.
基金the National Natural Science Foundation of China(81171560,30930082,81171561 and 30972584)the National Science and Technology Major Project of China(2008ZX10002-006,2012ZX1002007001,2011ZX09302005,2012ZX09303001-001 and 2012ZX10002003)+3 种基金the National High Technology Research and Development Program of China(2011AA020111)the Key Project of the Chongqing Science and Technology Commission(cstc2012ggyyjsB10007)the Chongqing Natural Science Foundation(cstc2011jjA10025)the Medical Research Fund of the Chongqing Municipal Health Bureau(2009-1-71).
文摘Natural killer(NK)cells have a vital role in killing hepatocellular carcinoma(HCC)cells;however,the mechanism underlying tumor-infiltrating NK(TINK)-cell dysfunction remains poorly understood.Using flow cytometry staining,we precisely characterized the frequency,phenotype and function of NK subsets distinguished by CD27 and CD11b in 30 patients with HCC in comparison to 30 healthy controls.Interestingly,we found a substantial proportion of liver-infiltrating CD11b−CD27−(DN)NK subsets in tumor tissue from HCC patients.Remarkably,these relatively expanded DN NK subsets exhibited an inactive and immature phenotype.By detecting the expression of CD107a and interferon-gamma(IFN-γ)on NK subsets and NK cells,we demonstrated that DN NK subsets exhibited a poor cytotoxic capacity and deficient potential to produce IFN-γin comparison to the other three subsets,which contributed to the dysfunction of TINK cells in HCC patients.In addition,we found that the presence of DN NK cells was closely associated with the clinical outcomes of HCC patients,as the frequency of DN NK cells among TINK cells was positively correlated with tumor stage and size.A large percentage of DN NK cells among TINK cells was an independent prognostic factor for lower survival in the 60-month follow-up period.In conclusion,a substantial proportion of CD11b−CD27−NK subsets among TINK cells accounts for NK-cell dysfunction in patients with HCC and is associated with tumor progression.Our study may provide a novel therapeutic target for the treatment of patients with HCC.
基金supported by the Major National S&T Program Grant(2017ZX10202203 and 2017ZX10302201 to AH)the Science&Technology Commission of China,the Emergency Project(cstc2020jscx-fyzx0053 to AH)+3 种基金the Science&Technology Commission of Chongqing,the National Natural Science Foundation of China(82002131 to YL)the Natural Science Foundation Project of CQ CSTC(cstc2020jcyjmsxmX0081 to YL)the foundation(KJCXZD2020018 to YL,CYS21244 to JZ)the Chongqing Municipal Education Commission,and the COVID-19 Emergency Project(CQMUNCP0207 to YL)from Chongqing Medical University。
文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is an ongoing pandemic that poses a great threat to human health worldwide.As the humoral immune response plays essential roles in disease occurrence and development,understanding the dynamics and characteristics of virus-specific humoral immunity in SARS-CoV-2-infected patients is of great importance for controlling this disease.In this review,we summarize the characteristics of the humoral immune response after SARS-CoV-2 infection and further emphasize the potential applications and therapeutic prospects of SARSCoV-2-specific humoral immunity and the critical role of this immunity in vaccine development.Notably,serological antibody testing based on the humoral immune response can guide public health measures and control strategies;however,it is not recommended for population surveys in areas with very low prevalence.Existing evidence suggests that asymptomatic individuals have a weaker immune response to SARS-CoV-2 infection,whereas SARS-CoV-2-infected children have a more effective humoral immune response than adults.The correlations between antibody(especially neutralizing antibody)titers and protection against SARS-CoV-2 reinfection should be further examined.In addition,the emergence of cross-reactions among different coronavirus antigens in the development of screening technology and the risk of antibody-dependent enhancement related to SARS-CoV-2 vaccination should be given further attention.
基金funding support from the Emergency Project from the Science&Technology Commission of Cho ngqing(cstc2020jscx-dxwtB0050,cstc2020jscx-fyzx0053)the Emergency Project for Novel Coronavirus Pneumonia from Chongqing Medical University(CQMUNCP0302)+2 种基金the Key Laboratory of Infectious Diseases(CQMU,202005)the Leading Talent Program of CQ CSTC(CSTCCXURC201719)a Major National Science&Technology Program grant(2017ZX10202203)from the Science&Technology Commission of China.
文摘Coronaviruses are enveloped,positive-stranded RNA viruses that contain the largest known RNA genomes to date.As severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to circulate in the human population,multiple mutations have accumulated over time,which may affect its transmission,virulence and antigenicity.
