Chronic hepatitis C virus infection associated with autonomic dysfunction

Background: Impaired autonomic function has been described in patients with chronic liver diseases from different aetiologies, and has proven to be a poor prognostic indicator. To date, it is not known how chronic hepatitis C virus (HCV) infection affects the autonomic nervous system. Aims: In the present study, we compared cardiovagal autonomic function in patients with chronic HCV infection and healthy controls and examined the relation between autonomic function and serum levels of aminotransferases, HCV RNA, cryoglobulins, albumin and glucose. Methods: Autonomic function was assessed in 45 treatment-naı¨ve patients with chronic HCV infection and in 40 healthy controls by determining spontaneous baroreflex sensitivity (BRS) and heart rate variability (HRV) indices. The R–R interval was determined by electrocardiogramrecording; continuous radial artery pressure was monitored simultaneously by applanation tonometry. Laboratory analyses and quantitative polymerase chain reaction for serum HCV RNA level were performed by standard procedures. Results: BRS and HRV time and frequency domain indices were lower in patients with HCV infection compared with healthy controls [7.1+/-3.4 vs. 11.5+/-6.5 ms/mmHg for BRS, 168.5+/-160.9 vs. 370.7+/-349.4 ms2 for low-frequency HRV (mean+/-SD); Po0.01]. Multivariate analysis showed that autonomic dysfunction in HCV-infected patients correlated with elevated alanine aminotransferase levels, but was not associated with serum HCV RNA levels and cryoglobulins. Conclusion: Our results suggest that impaired autonomic function is caused by chronic HCV infection. Further studies are needed, however, to identify the underlying mechanisms

A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma.

BackgroundClinical trials of therapies directed against nodes of the signaling axis of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) in glioblastoma (GBM) have had disappointing results. Resistance to mTOR inhibitors limits their efficacy.MethodsTo determine mechanisms of resistance to chronic mTOR inhibition, we performed tandem screens on patient-derived GBM cultures.ResultsAn unbiased phosphoproteomic screen quantified phosphorylation changes associated with chronic exposure to the mTOR inhibitor rapamycin, and our analysis implicated a role for glycogen synthase kinase (GSK)3B attenuation in mediating resistance that was confirmed by functional studies. A targeted short hairpin RNA screen and further functional studies both in vitro and in vivo demonstrated that microtubule-associated protein (MAP)1B, previously associated predominantly with neurons, is a downstream effector of GSK3B-mediated resistance. Furthermore, we provide evidence that chronic rapamycin induces microtubule stability in a MAP1B-dependent manner in GBM cells. Additional experiments explicate a signaling pathway wherein combinatorial extracellular signal-regulated kinase (ERK)/mTOR targeting abrogates inhibitory phosphorylation of GSK3B, leads to phosphorylation of MAP1B, and confers sensitization.ConclusionsThese data portray a compensatory molecular signaling network that imparts resistance to chronic mTOR inhibition in primary, human GBM cell cultures and points toward new therapeutic strategies

A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma

Background:Clinical trials of therapies directed against nodes of the signaling axis of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) in glioblastoma (GBM) have had disappointing results. Resistance to mTOR inhibitors limits their efficacy. Methods:To determine mechanisms of resistance to chronic mTOR inhibition, we performed tandem screens on patient-derived GBM cultures. Results:An unbiased phosphoproteomic screen quantified phosphorylation changes associated with chronic exposure to the mTOR inhibitor rapamycin, and our analysis implicated a role for glycogen synthase kinase (GSK)3B attenuation in mediating resistance that was confirmed by functional studies. A targeted short hairpin RNA screen and further functional studies both in vitro and in vivo demonstrated that microtubule-associated protein (MAP)1B, previously associated predominantly with neurons, is a downstream effector of GSK3B-mediated resistance. Furthermore, we provide evidence that chronic rapamycin induces microtubule stability in a MAP1B-dependent manner in GBM cells. Additional experiments explicate a signaling pathway wherein combinatorial extracellular signal-regulated kinase (ERK)/mTOR targeting abrogates inhibitory phosphorylation of GSK3B, leads to phosphorylation of MAP1B, and confers sensitization. Conclusions:These data portray a compensatory molecular signaling network that imparts resistance to chronic mTOR inhibition in primary, human GBM cell cultures and points toward new therapeutic strategies