Raf1 promotes successful Human Cytomegalovirus replication and is regulated by AMPK-mediated phosphorylation during infection.

Raf1 is a key player in growth factor receptor signaling, which has been linked to multiple viral infections, including Human Cytomegalovirus (HCMV) infection. Although HCMV remains latent in most individuals, it can cause acute infection in immunocompromised populations such as transplant recipients, neonates, and cancer patients. Current treatments are suboptimal, highlighting the need for novel treatments. Multiple points in the growth factor signaling pathway are important for HCMV infection, but the relationship between HCMV and Raf1, a component of the mitogen-activated protein kinase (MAPK) cascade, is not well understood. The AMP-activated protein kinase (AMPK) is a known regulator of Raf1, and AMPK activity is both induced by infection and important for HCMV replication. Our data indicate that HCMV infection induces AMPK-specific changes in Raf1 phosphorylation, including increasing phosphorylation at Raf1-Ser621, a known AMPK phospho-site, which results in increased binding to the 14-3-3 scaffolding protein, an important aspect of Raf1 activation. Inhibition of Raf1, either pharmacologically or via shRNA or CRISPR-mediated targeting, inhibits viral replication and spread in both fibroblasts and epithelial cells. Collectively, our data indicate that HCMV infection and AMPK activation modulate Raf1 activity, which are important for viral replication.

Comparable and Complimentary Modalities for Treatment of Small-Sized HCC: Surgical Resection, Radiofrequency Ablation, and Microwave Ablation.

BACKGROUND: Over the past decade, there has been continual improvement in both ablative and surgical technologies for the treatment of hepatocellular carcinoma (HCC). The efficacy of ablative therapy compared to surgical resection for HCC has not been thoroughly evaluated using multiple large-scale randomized controlled trials. By international consensus, if a patient is eligible, surgery is the primary curative treatment option, as it is believed to confer superior oncologic control. OBJECTIVE: to determine the efficacies of percutaneous ablative therapies and surgical resection (SR) in the treatment of HCC. Data sources, study appraisal, and synthesis methods: A meta-analysis using 5 online databases dating back to 1989 with more than 31,000 patients analyzing patient and tumor characteristics, median follow-up, overall survival, and complication rate was performed. RESULTS: Ablative therapies are suitable alternatives to surgical resection in terms of survival and complication rates for comparable patient populations. For the entire length of the study from 1989-2019, radiofrequency ablation (RFA) produced the highest 5-year survival rates (59.6%), followed by microwave ablation (MWA) (50.7%) and surgical resection (SR) (49.9%). In the most recent era from 2006 to 2019, surgical resection has produced the highest 5-year survival rate of 72.8%, followed by RFA at 61.7% and MWA at 50.6%. Conclusions and key findings: Depending on the disease state and comorbidities of the patient, one modality may offer superior overall survival rates over the other available techniques. Interventional ablative methods and surgical resection should be used in conjunction for the successful treatment of small-sized HCC.