Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

Regulatory T Cells

Since the 1970s, the epidemic of hepatocellular carcinoma (HCC) has spread beyond the Eastern Asian predominance and has been increasing in Northern hemisphere, especially in the United States (US) and Western Europe. It occurs more commonly in males in the fourth and fifth decades of life. Among all cancers, HCC is one of the fastest growing causes of death in the US and poses a significant economic burden on healthcare. Chronic liver disease due to hepatitis B virus or hepatitis C virus and alcohol accounts for the majority of HCC cases. Incidence of nonalcoholic fatty liver disease has been on the risem and it has also been associated with the development of HCC. Its pathogenesis varies based on the underlying etiological factor although majority of cases develop in the setting of background cirrhosis. Carcinogenesis of HCC includes angiogenesis, chronic inflammation, and tumor macroenvironment and microenvironment. There is a significant role of both intrinsic genetic risk factors and extrinsic influences such as alcohol or viral infections that lead to the development of HCC. Understanding its etiopathogenesis helps select appropriate diagnostic tests and treatments.

Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis.

Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma

More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin-proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration

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Deubiquitylating enzymes and drug discovery: emerging opportunities.

Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy.

Immunological landscape and immunotherapy of hepatocellular carcinoma

Role of the microenvironment in hepatocellular carcinoma development and progression.

Association between PON1 activity and coronary heart disease risk: A meta-analysis based on 43 studies

Ubiquitin carboxyl-terminal hydrolase 37 (UCH37), a member of the DUBs, was found to play an important role in oncogenesis through promoting some Proto-oncogenes’ expression and stem cell-like characteristics in the cell in previous research. The aim of this study was to assess the value of UCH37 in predicting tumor recurrence after curative resection in esophageal squamous cell carcinoma (ESCC) patients. We analyzed UCH37 protein expression in 111 clinicopathologically characterized ESCC cases, from those who underwent curative resection between 2007 and 2008, by immunohistochemistry. The prognostic significance was assessed using Kaplan–Meier survival estimates and log-rank tests. We found that UCH37 expression was higher in the cancer tissue than in non-tumorous control tissue at protein level and was overexpressed in tumor tissues of recurrent patients. There was a significant difference of UCH37 expression in patients categorized according to TNM stage (p = 0.038) and lymph nodes metastasis condition (p = 0.009). Univariate analyses revealed that UCH37 was a significant predictor for overall survival and disease-free survival, and multivariate analyses showed that UCH37 was an independent prognostic marker for ESCC recurrence. A prognostic significance of UCH37 was also found in the subgroup of lymph nodes metastasis condition classification. About 90 % of the recurrent patients recurred within 2 years, of which 84.4 % were predicted by UCH37. UCH37 is associated with outcome and recurrence of ESCC and can be a novel predictor for poor prognosis of ESCC patients after curative resection.

Expression and Clinical Significance of UCH37 in Human Esophageal Squamous Cell Carcinoma

Characterized by immunosuppression regulatory T cells (Tregs) play a key role in maintaining immune tolerance. A growing number of tumours have been found with Tregs accumulating in microenvironment and patients with high density of Tregs in tumour stroma get a worse prognosis, which suggests that Tregs may inhibit anti-tumour immunity in stroma, resulting in a poor prognosis. In this paper, we demonstrate the accumulation of Tregs in tumour stroma and the possible suppressive mechanisms. We also state the immunotherapy that has being used in animal and clinical trials.

Regulatory T cell: a protection for tumour cells.

Background
Melatonin receptor 1B (MTNR1B) belongs to the seven-transmembrane G protein-coupled receptor superfamily involved in insulin secretion, which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) since it was first identified as a loci associated with fasting plasma glucose level through genome wide association approach. The relationship between MTNR1B and T2D has been reported in various ethnic groups. The aim of this study was to consolidate and summarize published data on the potential of MTNR1B polymorphisms in T2D risk prediction.

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Yushui Ma

Papers

Role of the microenvironment in hepatocellular carcinoma development and progression.

Association between PON1 activity and coronary heart disease risk: A meta-analysis based on 43 studies

Expression and Clinical Significance of UCH37 in Human Esophageal Squamous Cell Carcinoma

Regulatory T cell: a protection for tumour cells.

Association between the melatonin receptor 1B gene polymorphism on the risk of type 2 diabetes, impaired glucose regulation: a meta-analysis.