Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-ß Autocrine Stimulation.

Since the discovery of oncogenes, there has been tremendous interest to understand their mechanistic basis and to develop broadly actionable therapeutics. Some of the most frequently activated oncogenes driving diverse cancers are c-MYC, EGFR, HER2, AKT, KRAS, BRAF, and MEK. Using a reductionist approach, we explored how cellular proteomes are remodeled in isogenic cell lines engineered with or without these driver oncogenes. The most striking discovery for all oncogenic models was the systematic downregulation of scores of antiviral proteins regulated by type 1 interferon. These findings extended to cancer cell lines and patient-derived xenograft models of highly refractory pancreatic cancer and osteosarcoma driven by KRAS and MYC oncogenes. The oncogenes reduced basal expression of and autocrine stimulation by type 1 interferon causing remarkable convergence on common phenotypic and functional profiles. In particular, there was dramatically lower expression of dsRNA sensors including DDX58 (RIG-I) and OAS proteins, which resulted in attenuated functional responses when the oncogenic cells were treated with the dsRNA mimetic, polyI:C, and increased susceptibility to infection with an RNA virus shown using SARS-CoV-2. Our reductionist approach provides molecular and functional insights connected to immune evasion hallmarks in cancers and suggests therapeutic opportunities.

Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium.

BACKGROUND: Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity. METHODS: In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined. RESULTS: The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50 = 5-11 µM) of rhinovirus-induced type I IFNß, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities. CONCLUSIONS: The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with anti-inflammatory, antibacterial and antiviral activity and show surprising versatility depending on the clinical need.

Surgical care checklists to optimize patient care following postoperative complications.

BACKGROUND: Postoperative complications are common. Inconsistency in the care of complications is reflected in variable rates of failure to rescue. This study aims to develop and validate checklists for treatment of common postoperative complications. METHODS: Initial checklists were based on best evidence, with expert clinician review. Casenote review was performed, comparing checklist item completion with outcomes. Logistic regression was performed for risk of further morbidity, considering American Society of Anesthesiology grade, age, sex, and checklist compliance. Checklists were finalized through end user multidisciplinary review. RESULTS: Evidence-based checklists were developed. Retrospective casenote review revealed management of 86% (31/37) of these complications to be noncompliant with checklist-mandated care. This resulted in delays and errors in 65% (24/37) of cases, with median treatment delay of 6 hours (interquartile range 5.4 hours). Regression analysis revealed poor checklist compliance to be to only significant factor (odds ratio 6.75, 95% confidence interval 1.11 to 41.00, P = .038) for developing further morbidity. CONCLUSIONS: Management of complications is highly variable, with failure to adhere to best practice principles significantly associated with an increased risk of further morbidity. This study presents an evidence-based framework for the development of checklists to standardize care.

Obesity and susceptibility to severe outcomes following respiratory viral infection.

During the 2009 H1N1 influenza pandemic, obesity was convincingly identified as a novel, independent risk factor for multiple markers of disease severity. Associations between numerous nosocomial and community-acquired clinical infections have previously been established; yet, little is known about the mechanisms underpinning the increased susceptibility to severe outcomes following pandemic H1N1/09 infection in obesity. Here, we present a brief synthesis of the recent advances in our understanding of the immunomodulatory effects of obesity on outcomes following respiratory viral infection, with a particular focus on pandemic influenza.

Influenza-related pneumonia.

Influenza-related pneumonia encompasses both primary viral pneumonia and secondary bacterial pneumonia, which may be difficult to differentiate clinically. A high index of suspicion, prompt initiation of antiviral and antibiotic therapy, and appropriate escalation to secondary/critical care are key to improving outcome.

Pathogenesis of influenza: virus-host interactions.

Since their inception in March 1972, Keystone Symposia on Molecular and Cellular Biology have brought together scientists from across the globe to discuss key biological topics. Now in its 40th year, it is a completely independent, nonprofit organization devoted solely to providing outstanding scientific conferences in all areas of the biological and biomedical sciences. Towards the end of May 2011, over 200 virologists and immunologists came to Hong Kong, an appropriate setting given the emergence of H5N1, to discuss influenza virus and host interactions. The meeting, expertly organized by Siamon Gordon (University of Oxford, Oxofrd, UK), Malik Peiris (University of Hong Kong, Hong Kong, China) and Kanta Subbarao (NIAID, NIH, MD, USA), took place in the aftermath of the first pandemic in 40 years and provided great insight into both pandemic H1N1 and H5N1. This article focuses on some of the recurring themes that were discussed during the week.