Role of relevant immune-modulators and cytokines in hepatocellular carcinoma and premalignant hepatic lesions

AIM To assess the levels of different immune modulators in patients with hepatocellular carcinoma(HCC),in relation to other hepatic diseases.METHODS Eighty-eight patients were included in the current study and represented patients with HCC(20),liver cirrhosis(28) and chronic hepatitis(CH;25),and normal controls(NC;15).Peripheral blood was isolated for immunophenotyping of active myeloid dendritic cells(m DCs;CD1 c and CD40),mature inactive myeloid cells(CD1 c and HLA),active plasmacytoid cells(p DCs;CD303 and CD40),mature inactive p DCs(CD30 and HLA),active natural killer(NK) cells(CD56 and CD161),active NK cells(CD56 and CD314) and inactive NK cells(CD56 and CD158) was done by flow cytometry.Serum levels of interleukin(IL)-2,IL-10,IL-12,IL-1β,interferon(IFN)-α,IFN-γ and tumor necrosis factor(TNF)-αR2 were assessed by ELISA.RESULTS Active m DCs(CD1 C+/CD40+) and inactive m DCs(CD1 c+/HLA+) were significantly decreased in HCC patients in relation to NC(P < 0.001).CD40+ expression on active p DCs was decreased in HCC patients(P < 0.001),and its level was not significantly changed among other groups.Inactive p DCs(CD303+/HLA+),inactive NKs(CD56+/CD158+) and active NKs(CD56+/CD161+) were not statistically changed among the four groups studied;however,the latter was increased in CH(P < 0.05).NKG2 D was statistically decreased in HCC,CH and cirrhosis(P < 0.001),and it was not expressed in 63%(12/20) of HCC patients.There was significant decrease of IL-2,IFN-α and IFN-γ(P < 0.001),and a significant increase in IL-10,IL-1β,and TNF-αR2(P <0.01,P < 0.001 and P < 0.001;respectively) in HCC patients.There was inverted correlation between IL-12 and IL-1β in HCC(r =-0.565,P < 0.01),with a strong correlation between p DCs(CD303+/CD40+) and NKs(CD56+/CD161+;r = 0.512,P < 0.05) as well as inactive m DCs(CD1 c+/HLA+) and inactive NK cells(CD56+/CD158+;r = 0.945,P < 0.001).CONCLUSION NKG2 D,CD40,IL-2 and IL-10 are important modulators in the development and progression of HCC.

Early detection of hepatocellular carcinoma co-occurring with hepatitis C virus infection: A mathematical model

AIM: To develop a mathematical model for the early detection of hepatocellular carcinoma(HCC) with a panel of serum proteins in combination with α-fetoprotein(AFP).METHODS: Serum levels of interleukin(IL)-8, soluble intercellular adhesion molecule-1(s ICAM-1), soluble tumor necrosis factor receptor Ⅱ(s TNF-RⅡ), proteasome, and β-catenin were measured in 479 subjects categorized into four groups:(1) HCC concurrent with hepatitis C virus(HCV) infection(n = 192);(2) HCV related liver cirrhosis(LC)(n = 96);(3) Chronic hepatitis C(CHC)(n = 96); and(4) Healthy controls(n = 95). The R package and different modules for binary and multi-class classifiers based on generalized linear models were used to model the data. Predictive power was used to evaluate the performance of the model. Receiver operating characteristic curve analysis over pairs of groups was used to identify the best cutoffs differentiating the different groups. RESULTS: We revealed mathematical models, based on a binary classifier, made up of a unique panel of serum proteins that improved the individual performance of AFP in discriminating HCC patients from patients with chronic liver disease either with or without cirrhosis. We discriminated the HCC group from the cirrhotic liver group using a mathematical model(-11.3 + 7.38 × Prot + 0.00108 × s ICAM + 0.2574 ×β-catenin + 0.01597 × AFP) with a cutoff of 0.6552, which achieved 98.8% specificity and 89.1% sensitivity. For the discrimination of the HCC group from the CHC group, we used a mathematical model [-10.40 + 1.416 × proteasome + 0.002024 × IL + 0.004096 × s ICAM-1 +(4.251 × 10-4) × s TNF + 0.02567 ×β-catenin + 0.02442 × AFP] with a cutoff 0.744 and achieved 96.8% specificity and 89.7% sensitivity. Additionally, we derived an algorithm, based on a binary classifier, for resolving the multi-class classification problem by using three successive mathematical model predictions of liver disease status. CONCLUSION: Our proposed mathematical model may be a useful method for the early detection of different statuses of liver disease co-occurring with HCV infection.

Molecular analysis of the sex chromosomes of the platyfish Xiphophorus maculatus: Towards the identification of a new type of master sexual regulator in vertebrates

In contrast to mammals and birds,fish display an amazing diversity of genetic sex determination systems,with frequent changes during evolution possibly associated with the emergence of new sex chromosomes and sex-determining genes.To better understand the molecular and evolutionary mechanisms driving this diversity,several fish models are studied in parallel.Besides the medaka(Oryzias latipes Temminck and Schlegel,1846)for which the master sex-determination gene has been identified,one of the most advanced models for studying sex determination is the Southern platyfish(Xiphophorus maculatus,Günther 1966).Xiphophorus maculatus belongs to the Poeciliids,a family of live-bearing freshwater fish,including platyfish,swordtails and guppies that perfectly illustrates the diversity of genetic sex-determination mechanisms observed in teleosts.For X.maculatus,bacterial artificial chro-mosome contigs covering the sex-determination region of the X and Y sex chromosomes have been constructed.Initial molecular analysis demonstrated that the sex-determination region is very unstable and frequently undergoes duplications,deletions,inversions and other rearrangements.Eleven gene candidates linked to the master sex-determining gene have been identified,some of them corresponding to pseudogenes.All putative genes are present on both the X and the Y chromosomes,suggesting a poor degree of differentiation and a young evolutionary age for platyfish sex chromosomes.When compared with other fish and tetrapod genomes,syntenies were detected only with autosomes.This observation supports an independent origin of sex chromosomes,not only in different vertebrate lineages but also between different fish species.

Understanding and therapeutically modulating the stability of regulatory T cells to treat inflammatory diseases

Forkhead box P3(FOXP3)^+regulatory T(Treg)cells are crucial for the homeostasis of the immune system,and harbor suppressive capacities of which are maintained by or inherited with distinct epigenetic signatures.The functional features of Treg cells are facilitated by multiple T cell differentiation-related transcription factors that therefore endow them with adaption capability to dynamic microenvironments.Recent studies also recalled the importance of immune cell metabolism,which is intimately linked with Treg cell differentiation,proliferation and function.Understanding the molecular mechanism underlying the functional stability of Treg cells could provide therapeutic opportunities to treat major human inflammatory diseases including infection,autoimmunity,allergy and cancer.

Th17 Cells in autoimmune diseases

Th17 cells are a new subset of CD4^＋ T cells fungi. Accumulating evidence suggests that Tb17 cells involved in the clearance of extracellular pathogens and and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren＇s syndrome, inflammatory bowel disease, and multiple sclerosis.