Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection disturbs glucose and lipid metabolism contributing to the development of liver steatosis, insulin resistance and type 2 diabetes mellitus. On the other hand, insulin resistance and steatosis have been found to be associated with increased rates of fibrosis progression and lower rates of response to interferon therapy in chronic hepatitis C (CHC). The molecular mechanisms contributing to insulin resistance in CHC are not well understood. We have shown previously that protein phosphatase 2A (PP2A) is over-expressed in biopsies from patients with CHC. In this study, we tested if PP2A over-expression leads to insulin resistance. METHODS: We studied insulin signalling in cell lines that allow the regulated over-expression of HCV proteins and of the PP2A catalytic subunit (PP2Ac). Insulin signalling and PP2Ac expression were also studied in HCV transgenic mice and in liver biopsies from patients with CHC. RESULTS: Over-expression of PP2Ac in cells inhibited insulin signalling by dephosphorylation of PKB/Akt. PP2Ac over-expression and impaired insulin signalling were found in the liver of HCV transgenic mice and in liver biopsies of patients with CHC. CONCLUSIONS: HCV-induced over-expression of PP2A in the liver contributes to the pathogenesis of insulin resistance in patients with CHC.     

Functional Characterization of Novel Mutations Affecting Survivin (BIRC5)‐Mediated Therapy Resistance in Head and Neck Cancer Patients

Survivin (BIRC5) is an acknowledged cancer therapy‐resistance factor and overexpressed in head and neck squamous cell carcinomas (HNSCC). Driven by its nuclear export signal (NES), Survivin shuttles between the nucleus and the cytoplasm, and is detectable in both cellular compartments in tumor biopsies. Although predominantly nuclear Survivin is considered a favorable prognostic disease marker for HNSCC patients, the underlying molecular mechanisms are not resolved. Hence, we performed immunohistochemical and mutational analyses using laser capture microdissection on HNSCC biopsies from patients displaying high levels of nuclear Survivin. We found somatic BIRC5 mutations, c.278T>C (p.Phe93Ser), c.292C>T (p.Leu98Phe), and c.288A>G (silent), in tumor cells, but not in corresponding normal tissues. Comprehensive functional characterization of the Survivin mutants by ectopic expression and microinjection experiments revealed that p.Phe93Ser, but not p.Leu98Phe inactivated Survivin's NES, resulted in a predominantly nuclear protein, and attenuated Survivin's dual cytoprotective activity against chemoradiation‐induced apoptosis. Notably, in xenotransplantation studies, HNSCC cells containing the p.Phe93Ser mutation responded significantly better to cisplatin‐based chemotherapy. Collectively, our results underline the disease relevance of Survivin's nucleocytoplasmic transport, and provide first evidence that genetic inactivation of Survivin's NES may account for predominantly nuclear Survivin and increased therapy response in cancer patients.     

The significance of histological diagnosis in renal allograft biopsies in 2014

In 2014, the renal allograft biopsy still represents the best available diagnostic ‘gold’ standard to assess reasons for allograft dysfunction. However, it is well recognized that histological lesion observed in the biopsy is of limited diagnostic specificity and that the Banff classification as the international diagnostic standard represents mere expert consensus. Here, we review the role of the renal allograft biopsy in different clinical and diagnostic settings. To increase diagnostic accuracy and to compensate for lack of specificity, the interpretation of biopsy pathology needs to be within the clinical context, primarily defined by time post‐transplantation and patient‐specific risk profile. With this in mind, similar histopathological patterns will lead to different conclusions with regard to diagnosis, disease grading and staging and thus to patient‐specific clinical decision‐making. Consensus generation for such integrated diagnostic approach, preferably including new molecular tools, represents the next challenge to the transplant community on its way to precision medicine in transplantation.