Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.

Construction and validation of prognostic model of hepatocellular carcinoma based on epigenetic factors

Objective:To explore the targeting relationship between miRNA and epigenetic factors related to the prognosis of hepatocellular carcinoma(HCC),and to identify the potential impact of miRNA targeted epigenetic factors on the prognosis of HCC.Methods:The mRNA and miRNA sequencing data of all HCC samples were downloaded from the tumor Genome Atlas(TCGA)database,and the R program was used to analyze the difference of the sequencing data.The data of survival time,survival status and differential expression of miRNA were combined,and the risk score model of miRNA was constructed by univariate and multivariate Cox regression.The miRNA target genes and all the corresponding Epigenetic factors were predicted,and the differentially expressed Epigenetic factors(DEEFs)were screened.Then,the regulatory network of miRNA targeting deefs was established,the apparent factors in the network were enriched and analyzed,and the core genes in the protein-protein interaction(PPI)network and selection network were constructed.Finally,the relationship between the apparent factors and the prognosis of patients was analyzed and verified by Kaplan Meier(K-M)method.Results:305 differentially expressed miRNAs were identified using EDGE algorithm.After Cox analysis,hsa-miR-139-5p,hsa-miR-101-3p and hsa-miR-7-5p(miR-139-5p,miR-101-3p and miR-7-5p)were finally screened as the Overall survival of HCC patients(Overall survival,OS).In addition,34 DEEFs targeted by miRNAs were identified,among which EZH2,PKM,HJURP and CHEK1 had a significant impact on the survival of hepatocellular carcinoma.Conclusion:In this study,we successfully established a prognostic model of hepatocellular carcinoma miRNA-targeted epigenetics,and screened out epigenetic factors that are significantly related to the prognosis of hepatocellular carcinoma.It provides new potential prognostic biomarkers and therapeutic targets for HCC treatment,and lays a theoretical foundation for the follow-up basic research of HCC.

Occult hepatitis B—the result of the host immune response interaction with different genomic expressions of the virus

With over 40 years of history,occult hepatitis B infection(OBI)continues to remain an important and challenging public health problem.Defined as the presence of replication-competent hepatitis B virus(HBV)DNA(i.e.,episomal HBV covalently closed circular DNA)in the liver and/or HBV DNA in the blood of people who test negative for hepatitis B surface antigen(HBsAg)in currently available assays,OBI is currently diagnosed using polymerase chain reaction(PCR)and real-time PCR assays.However,all efforts should be made to exclude a false negative HBsAg in order to completely follow the definition of OBI.In recent years,significant advances have been made in understanding the HBV lifecycle and the molecular mechanisms that lead to the persistence of the virus in the occult form.These factors are mainly related to the host immune system and,to a smaller proportion,to the virus.Both innate and adaptive immune responses are important in HBV infection management,and epigenetic changes driven by host mechanisms(acetylation,methylation,and microRNA implication)are added to such actions.Although greater genetic variability in the S gene of HBV isolated from OBIs was found compared with overt infection,the mechanisms of OBI are not mainly viral mutations.

Impairment of liver regeneration by the histone deacetylase inhibitor valproic acid in mice

Background and objective:Liver regeneration is a complex process regulated by a group of genetic and epigenetic factors.A variety of genetic factors have been reported,whereas few investigations have focused on epigenetic regulation during liver regeneration.In the present study,valproic acid(VPA),a histone deacetylase(HDAC) inhibitor,was used to investigate the effect of HDAC on liver regeneration.Methods:VPA was administered via intraperitoneal injection to 2/3 partially hepatectomized mice to detect hepatocyte proliferation during liver regeneration.The mice were sacrificed,and their liver tissues were harvested at sequential time points from 0 to 168 h after treatment.DNA synthesis was detected via a BrdU assay,and cell proliferation was tested using Ki-67.The expressions of cyclin D1,cyclin E,cyclin dependent kinase 2(CDK2),and CDK4 were detected by Western blot analysis.Chromatin immunoprecipitation(ChIP) assay was used to examine the recruitment of HDACs to the target promoter regions and the expression of the target gene was detected by Western blot.Results:Immunohistochemical analysis showed that cells positive for BrdU and Ki-67 decreased,and the peak of BrdU was delayed in the VPA-administered mice.Consistently,cyclin D1 expression was also delayed.We identified B-myc as a target gene of HDACs by complementary DNA(cDNA) microarray.The expression of B-myc increased in the VPA-administered mice after hepatectomy(PH).The ChIP assay confirmed the presence of HDACs at the B-myc promoter.Conclusions:HDAC activities are essential for liver regeneration.Inhibiting HDAC activities delays liver regeneration and induces liver cell cycle arrest,thereby causing an anti-proliferative effect on liver regeneration.

Potential Mechanisms Underlying the Therapeutic Effects of Electroconvulsive Therapy

In spite of the extensive application of electroconvulsive therapy（ECT）, how it works remains unclear.So far, researchers have made great efforts in figuring out the mechanisms underlying the effect of ECT treatment via determining the levels of neurotransmitters and cytokines and using genetic and epigenetic tools, as well as structural and functional neuroimaging. To help address this question and provide implications for future research, relevant clinical trials and animal experiments are reviewed.