Rapamycin Blocks Production of KSHV/HHV8: Insights into the Anti-Tumor Activity of an Immunosuppressant Drug

Infection with Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) often results in the development of fatal tumors in immunocompromised patients. Studies of renal transplant recipients show that use of the immunosuppressant drug rapamycin, an mTOR inhibitor, both prevents and can induce the regression of Kaposi's sarcoma (KS), an opportunistic tumor that arises within a subset of this infected population. In light of rapamycin's marked anti-KS activity, we tested whether the drug might directly inhibit the KSHV life cycle. We focused on the molecular switch that triggers this predominantly latent virus to enter the lytic (productive) replication phase, since earlier work links this transition to viral persistence and tumorigenesis.In latently infected human B cell lines, we found that rapamycin inhibited entry of the virus into the lytic replication cycle, marked by a loss of expression of the lytic switch protein, replication and transcription activator (RTA). To test for viral-specific effects of rapamycin, we focused our studies on a B cell line with resistance to rapamycin-mediated growth inhibition. Using this line, we found that the drug had minimal effect on cell cycle profiles, cellular proliferation, or the expression of other cellular or latent viral proteins, indicating that the RTA suppression was not a result of global cellular dysregulation. Finally, treatment with rapamycin blocked the production of progeny virions.These results indicate that mTOR plays a role in the regulation of RTA expression and, therefore, KSHV production, providing a potential molecular explanation for the marked clinical success of rapamycin in the treatment and prevention of post-transplant Kaposi's sarcoma. The striking inhibition of rapamycin on KSHV lytic replication, thus, helps explain the apparent paradox of an immunosuppressant drug suppressing the pathogenesis of an opportunistic viral infection

Mini-invasive video-assisted surgery of the thyroid and parathyroid glands: A 2011 update

Abstract: Thyroid surgery during the last century was characterized by a development of Kocher's concepts: through a relentless work of surgeons from all over the world thyroidectomy reached a standard of quality in terms of overall results which was unimaginable in the first half of the XX century. The flattering data collected in the literature until the 90's were all concordant in assuming that there would be little space for a real improvement in the quality standard of thyroid surgery. The introduction of laparoscopic surgery, though, changed very quickly the attitude of surgeons towards their operative behavior and countless new mini-invasive techniques were soon proposed for almost any field of surgery. In 1994, Gagner published the first series of laparoscopic adrenalectomies. Soon after, parathyroid adenomas seemed to offer an ideal field of application of these new surgical concepts. The first report of an endoscopic parathyroidectomy was in 1996. One year later other videoscopic procedures were described whose results seemed quite encouraging so as to push surgeons to try the same access and the same technique also for operations on thyroid. During the following decade several endoscopic or video-assisted approaches were proposed for the removal of thyroid gland. This paper aims to evaluate the results of minimally invasive thyroid and parathyroid surgery through an extensive review of the literature, in particular as far as minimally invasive video-assisted thyroidectomy is concerned. (J. Endocrinol. Invest. 34: 473-480, 2011) (C) 2011, Editrice Kurti

Endocytosis of hepatitis C virus non-enveloped capsid-like particles induces MAPK-ERK1/2 signaling events

Although HCV is an enveloped virus, naked nucleocapsids have been reported in the serum of infected patients. The HCV core particle serves as a protective capsid shell for the viral genome and recombinant in vitro assembled HCV core particles induce strong specific immunity. We investigated the post-binding mechanism of recombinant core particle uptake and its intracellular fate. In hepatic cells, these particles are internalized, most likely in a clathrin-dependent pathway, reaching early to late endosomes and finally lysosomes. The endocytic acidic milieu is implicated in trafficking process. Using specific phosphoantibodies, signaling pathway inhibitors and chemical agents, ERK(1/2) was found to be activated in a sustained way after endocytosis, followed by downstream immediate early genes (c-fos and egr-1) modulation. We propose that the intriguing properties of cellular internalization of HCV non-enveloped particles can induce specific ERK(1/2)-MAPKs events that could be important in HCV life cycle and pathogenesis of HCV infection