ABSTRACT
Innate immunity controls pathogen replication and spread. Yet, certain pathogens, such as Hepatitis C Virus (HCV), escape immune elimination and establish persistent infections that promote chronic inflammation and related diseases. Whereas HCV regulatory proteins that attenuate antiviral responses are known, those that promote inflammation and liver injury remain to be identified. Here, we show that transient expression of HCV RNA-dependent RNA polymerase (RdRp), NS5B, in mouse liver and human hepatocytes results in production of small RNA species that activate innate immune signaling via TBK1-IRF3 and NF-κB and induce cytokine production, including type I interferons (IFN) and IL-6. NS5B-expression also results in liver damage.
Subject(s)
Hepacivirus , Hepatitis C, Chronic , Immunity, Innate , Liver , Viral Nonstructural Proteins , Animals , Hepacivirus/genetics , Hepacivirus/metabolism , Hepacivirus/pathogenicity , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/metabolism , Hepatitis C, Chronic/virology , Hepatocytes/metabolism , Humans , Interferon Regulatory Factor-3/metabolism , Interferon Type I/biosynthesis , Interferon Type I/metabolism , Interleukin-6/biosynthesis , Interleukin-6/metabolism , Liver/injuries , Liver/metabolism , Liver/virology , Mice , NF-kappa B/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolismABSTRACT
A convenient one-pot synthesis of chelating bis-N-heterocyclic carbene-ligated P(I) salts is described. The solid state structures of these remarkably stable phosphamethine cyanine dyes with various N-alkyl groups and counter-anions are reported, and initial reactivity results are discussed.
ABSTRACT
BACKGROUND: Helical tomotherapy is a novel intensity-modulated radiotherapy modality with a helical 360° radiation delivery system and CT imaging ability. The purpose of this report is to review our initial experiences and to assess the toxicity and efficacy of helical tomotherapy for esophageal cancer. METHODS: Twenty patients with locally advanced esophageal cancer (T3-4 and/or N+ and/or M1a/b) were treated with helical tomotherapy. Radiotherapy included simultaneous 50 Gy to gross tumorous areas and 45 Gy to areas of suspected subclinical disease. All received combination chemotherapy. Ten patients underwent surgical resection after completion of chemoradiation. Ten patients were ineligible for surgery. RESULTS: The treatment was well-tolerated. There were no treatment-related deaths or Grade 4 toxicity. Grade 3 toxicities were noted in 9 of 20 patients (45%). Down-staging was noted in 7 of 10 patients (70%) who underwent surgery. The median follow-up time was 24.5 months. Eight patients, including 3 with surgery and 5 without surgery, have died. The 1-year overall survival rates for the entire group, patients with and without surgical resection are 80.0%, 100.0% and 60.0% respectively (log-rank p = 0.244, surgery versus no surgery). CONCLUSIONS: The regimen of combined chemoradiation by helical tomotherapy for locally advanced esophageal cancer is well-tolerated. The toxicity profile compares favorably with that of protocols based on conventional approach and the preliminary indications of efficacy are encouraging.