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  • The proteasome activator gamma encodes the

    2018-11-07

    The proteasome activator 28 gamma () encodes the gamma LDC000067 cost subunit of the 11S regulator of the immunoproteasome, a modified proteasome that processes class I MHC peptides. PA28γ is a multifunctional protein, implicated in the degradation of important LDC000067 cost regulatory proteins in an ATP-independent manner. In fact, PA28γ inhibits apoptosis and promotes cell cycle progression (). A homopolymer form of PA28γ interacts with both MDM2 and p53 proteins and facilitates their physical interaction, which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53, thus limiting its accumulation and resulting in inhibited apoptosis after DNA damage. Elimination of endogenous PA28γ in human cancer cells has been shown to abolish MDM2-mediated p53 degradation, increase the activity of p53, and enhance apoptosis (). In the -, Jing Li and colleagues assess immunohistochemically PA28γ expression as a prognostic biomarker in OSCC. For this purpose, a total of 368 patients from three independent cohorts were included in the current study. Moreover, the authors used an independent cohort of 460 patient specimens obtained between 1992 and 2013 in the TCGA database as an external validation cohort to validate the prognostic value of PA28γ expression. Strong PA28γ expression was shown to predict significantly reduced disease-free and overall survival in OSCC patients. More importantly, the unfavorable prognostic value of PA28γ was independent from other prognostic factors such as smoking history, drinking history, cell differentiation, tumor stage, nodal stage, radiotherapy and chemotherapy. Besides the prognostic significance of PA28γ in OSCC, this study provides evidence for the role of PA28γ in oral tumor growth and metastasis. In more detail, silencing in two OSCC cell lines led to a decline in cell viability and colony growth. Moreover, growth of tumor originating from OSCC cells transplanted subcutaneously on the right back of BALB/c nude mice was much slower when was silenced in these tumor cells. The authors also showed that silencing suppresses tumor angiogenesis and increases tumor cell apoptosis in xenograft models. This study opens the door to assess the clinical value of PA28γ expression as a surrogate prognostic biomarker in larger cohorts of OSCC patients as well as to further investigate the role of PA28γ overexpression in the pathobiology and progression of OSCC. The clinical value of several molecules as putative diagnostic, prognostic, and treatment-response biomarkers in OSCC has been widely investigated during the last decades (). The elucidation of the biochemical pathways implicated in oral carcinogenesis, tumor progression, and metastasis, taking also into consideration the heterogeneity of oral tumors, would definitely assist the discovery of novel candidate biomarkers in OSCC. Some molecular biomarkers, including PA28γ, may also have prognostic value in specific OSCC patient subgroups. In conclusion, the dysregulation of gene expression in OSCC tissues compared to benign oral tumors, dysplasias, or normal specimens originating from the oral cavity merits further investigation and validation in independent and large cohorts of OSCC patients. Disclosure
    Standard chemotherapy of tuberculosis (TB), which is caused by infection with () and which primarily affects the lung, consists of a combination of antimicrobial drugs (isoniazid, rifampin, ethambutol and pyrazinamide). Concomitant administration of these antimicrobials helps eradicate active infection and prevents disease relapse (). In most patients suffering from drug-susceptible TB, strong adherence to treatment for at least 6months leads to cure of TB disease. However, poor compliance with the prolonged treatment regime facilitates spread of infection, as active TB patients expectorate bacteria. Prolonged treatment also promotes the development of drug-resistant . Multidrug-resistant (MDR)-TB is clinically difficult to manage and accounted for 3.5% of the 9 million new TB cases in 2013 and about 20.5% of previously treated TB patients (). Shortening the length of TB chemotherapy could thus limit spread of the disease and restrict emergence of drug resistance. In this issue of , Maiga et al. provide pre-clinical evidence that Tofacitinib, an FDA-approved Janus kinase (JAK) inhibitor, accelerates bacterial clearance when co-administered with canonical TB chemotherapy.