TLRs, Alcohol, HCV, and Tumorigenesis

Chronic liver damage caused by viral infection, alcohol, or obesity can result in increased risk for hepatocellular carcinoma (HCC). Ample epidemiological evidence suggests that there is a strong synergism between hepatitis C virus (HCV) and alcoholic liver diseases (ALD). The Toll-like receptor (TLR) signaling pathway is upregulated in chronic liver diseases. Alcoholism is associated with endotoxemia that stimulates expression of proinflammatory cytokine expression and inflammation in the liver and fat tissues. Recent studies of HCC have centered on cancer-initiating stem cell (CSC), including detection of CSC in cancer, identification of CSC markers, and isolation of CSC from human HCC cell lines. Synergism between alcohol and HCV may lead to liver tumorigenesis through TLR signaling

Idiopathic Pneumonia Syndrome Refractory to Ruxolitinib after Post-Transplant Cyclophosphamide-based Haploidentical Hematopoietic Stem Cell Transplantation: Lung Pathological Findings from an Autopsy Case

A 69-year-old Japanese man with acute leukemia received post-transplant cyclophosphamide-based haploidentical stem cell transplantation (PTCY-haplo-SCT) but was readmitted with dyspnea and ground-glass-opacities of the lungs. Bronchoscopy showed inflammatory changes with no signs of infection. He received steroids but required intubation as his condition deteriorated. In addition to antithymocyte globulin and cyclophosphamide, we administered ruxolitinib but failed to save him. Autopsy findings revealed fibrotic nonspecific interstitial pneumonia (NSIP) without evidence of organizing pneumonia or infection. Thus, we diagnosed idiopathic pneumonia syndrome (IPS). As far as our knowledge, this is the first case of IPS with NSIP histology after PTCY-haplo-SCT

Hepatitis C Virus-Related Lymphomagenesis in a Mouse Model

B cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with hepatitis C virus (HCV) infection. The mechanism by which HCV infection leads to lymphoproliferative disorder remains unclear. Our group established HCV transgenic mice that expressed the full HCV genome in B cells (RzCD19Cre mice). We observed a 25.0% incidence of diffuse large B cell non-Hodgkin lymphomas (22.2% in male and 29.6% in female mice) within 600 days of birth. Interestingly, RzCD19Cre mice with substantially elevated serum-soluble interleukin-2 receptor α-subunit (sIL-2Rα) levels (>1000 pg/mL) developed B cell lymphomas. Another mouse model of lymphoproliferative disorder was established by persistent expression of HCV structural proteins through disruption of interferon regulatory factor-1 (irf-1_/_/CN2 mice). Irf-1_/_/CN2 mice showed extremely high incidences of lymphomas and lymphoproliferative disorders. Moreover, these mice showed increased levels of interleukin (IL)-2, IL-10, and Bcl-2 as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes

A Disseminated Fusarium fujikuroi Species Complex Infection Prior to Allogeneic Hematopoietic Stem Cell Transplantation

A 53-year-old man was diagnosed with acute myeloid leukemia, which was refractory to chemotherapies. Systemic papules appeared afterward. The skin biopsies revealed filamentous fungal infection including fusariosis. Despite antifungal therapy, the infection did not resolve, because neutropenia persisted with the leukemia. He underwent hematopoietic stem cell transplantation (HSCT) to overcome the leukemia and restore normal hematopoiesis but died from fusariosis just before engraftment. Fusarium fujikuroi species complex was detected in blood cultures with poor antifungal susceptibility. Because restoring normal hematopoiesis is important in the treatment of fusariosis, HSCT might be considered for patients with persistent pancytopenia

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific transgenic (Tg) expression of the HCV nonstructural protein NS5A, and this induction mediates synergistic liver damage and tumor formation by alcohol-induced endotoxemia. We also identify Nanog, the stem/progenitor cell marker, as a novel downstream gene up-regulated by TLR4 activation and the presence of CD133/Nanog-positive cells in liver tumors of alcohol-fed NS5A Tg mice. Transplantation of p53-deficient hepatic progenitor cells transduced with TLR4 results in liver tumor development in mice following repetitive LPS injection, but concomitant transduction of Nanog short-hairpin RNA abrogates this outcome. Taken together, our study demonstrates a TLR4-dependent mechanism of synergistic liver disease by HCV and alcohol and an obligatory role for Nanog, a TLR4 downstream gene, in HCV-induced liver oncogenesis enhanced by alcohol

Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis

BACKGROUND & AIMS: Steatohepatitis (SH) is associated with mitochondrial dysfunction and excessive production of superoxide, which can then be converted into H(2)O(2) by SOD2. Since mitochondrial GSH (mGSH) plays a critical role in H(2)O(2) reduction, we explored the interplay between superoxide, H(2)O(2), and mGSH in nutritional and genetic models of SH, which exhibit mGSH depletion. METHODS: We used isolated mitochondria and primary hepatocytes, as well as in vivo SH models showing mGSH depletion to test the consequences of superoxide scavenging. RESULTS: In isolated mitochondria and primary hepatocytes, superoxide scavenging by SOD mimetics or purified SOD decreased superoxide and peroxynitrite generation but increased H(2)O(2) following mGSH depletion, despite mitochondrial peroxiredoxin/thioredoxin defense. Selective mGSH depletion sensitized hepatocytes to cell death induced by SOD mimetics, and this was prevented by RIP1 kinase inhibition with necrostatin-1 or GSH repletion with GSH ethyl ester (GSHee). Mice fed the methionine-choline deficient (MCD) diet or MAT1A(-/-) mice exhibited reduced SOD2 activity; in vivo treatment with SOD mimetics increased liver damage, inflammation, and fibrosis, despite a decreased superoxide and 3-nitrotyrosine immunoreactivity, effects that were ameliorated by mGSH replenishment with GSHee, but not NAC. As a proof-of-principle of the detrimental role of superoxide scavenging when mGSH was depleted transgenic mice overexpressing SOD2 exhibited enhanced susceptibility to MCD-mediated SH. CONCLUSIONS: These findings underscore a critical role for mGSH in the therapeutic potential of superoxide scavenging in SH, and suggest that the combined approach of superoxide scavenging with mGSH replenishment may be important in SH

Truncating Mutation in the Autophagy Gene \u3cem\u3eUVRAG\u3c/em\u3e Confers Oncogenic Properties and Chemosensitivity in Colorectal Cancers

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAGFS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAGFS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAGFS can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAGFS expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response