Pancreatic STAT3 protects mice against caerulein-induced pancreatitis via PAP1 induction.

The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that controls expressions of several genes involved in cell survival, proliferation and differentiation, and tissue inflammation. However, the significance of pancreatic STAT3 in acute pancreatitis remains unclear. We generated conditional STAT3 knockout (stat3(Δ/Δ)) mice by crossing stat3(flox/flox) mice with Pdx1-promoter Cre transgenic mice.

Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression.

Signal transducers and activators of transcription (STAT) 1 plays a pivotal role in cell-cycle and cell-fate determination, and vascular endothelial growth factor (VEGF) also contributes tumor growth. Recently, interferon (IFN) α has been reported to be effective for prevention of hepatocellular carcinomas (HCCs) recurrence, but the detailed mechanisms remain elusive. In vitro, cobalt chloride-treated VEGF induction and hypoxia responsive element (HRE) promoter activity were inhibited by IFNs and this abrogation was cancelled by introduction of small interfering RNA for STAT1.

Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet.

Background: Invariant natural killer T (iNKT) cells have been suggested to play critical roles in a wide range of immune responses by acting in a proinflammatory or anti-inflammatory manner. Nonalcoholic steatohepatitis (NASH) is a chronic liver disease progressing to advanced cirrhosis and hepatocellular carcinoma. Despite the abundance of iNKT cells in the liver, their role in the pathogenesis of NASH remains obscure.

Fatal exacerbation of type B chronic hepatitis triggered by changes in relaxed circular viral DNA synthesis and virion secretion.

Virological features of fulminant liver disease-causing hepatitis B virus (HBV) have not been fully elucidated. We studied longitudinally the viruses obtained before and after fulminant liver disease in a patient with chronic HBV infection showing fatal exacerbation. HBV strains were obtained before and after exacerbation (designated as FEP1 and FEP2).

Natural killer cell is a major producer of interferon gamma that is critical for the IL-12-induced anti-tumor effect in mice.

Although the anti-tumor effect of IL-12 is mediated mostly by IFNgamma, which cell types most efficiently produce IFNgamma and therefore initiate or promote the anti-tumor effect of IL-12 has not been clearly determined. In the present study, we demonstrated hydrodynamic injection of the IL-12 gene led to prolonged IFNgamma production, NK-cell activation and complete inhibition of liver metastasis of CT-26 colon cancer cells in wild-type mice, but not in IFNgamma knockout mice. NK cells expressed higher levels of STAT4 and upon IL-12 administration displayed stronger STAT4 phosphorylation and IFNgamma production than non-NK cells.

Mutations associated with the therapeutic efficacy of adefovir dipivoxil added to lamivudine in patients resistant to lamivudine with type B chronic hepatitis.

Factors influencing the therapeutic efficacy of adefovir dipivoxil added to continuing lamivudine have not been elucidated in lamivudine-resistant patients with type B chronic hepatitis. The viral mutations influencing the efficacy of treatment with adefovir dipivoxil were investigated by sequencing analysis of the whole virus genome. Thirty patients resistant to lamivudine receiving adefovir dipivoxil therapy added to lamivudine were studied.

Supportive role played by precore and preS2 genomic changes in the establishment of lamivudine-resistant hepatitis B virus.

Background: Hepatitis B virus (HBV) establishes lamivudine resistance via the resistance-causative rtM204V/I mutation and the replication-compensatory rtL180M mutation. However, both lamivudine-resistant viruses with and those without rtL180M can exist in clinical settings. To elucidate the differences between viruses with and those without rtL180M, we conducted full-length sequencing analysis of HBV derived from patients with type B chronic hepatitis showing lamivudine resistance.

Dendritic cell-based vaccines suppress metastatic liver tumor via activation of local innate and acquired immunity.

Background: Dendritic cell (DC)-based vaccines have been applied clinically in the setting of cancer, but tumor-associated antigens (TAAs) have not yet been enough identified in various cancers. In this study, we investigated whether preventive vaccination with unpulsed DCs or peptide-pulsed DCs could offer anti-tumor effects against MC38 or BL6 liver tumors.

Methods: Mice were subcutaneously (s.

Early emergence of entecavir-resistant hepatitis B virus in a patient with hepatitis B virus/human immunodeficiency virus coinfection.

The efficacy of entecavir for patients with hepatitis B virus/human immunodeficiency virus coinfection has not been fully elucidated. Here we examined a patient coinfected with both viruses in whom entecavir-resistant hepatitis B virus appeared. The 60-year-old Japanese male with the coinfection received antiretroviral therapy including lamivudine.

Type B fulminant hepatitis is closely associated with a highly mutated hepatitis B virus strain.

Objective: Genome-wide sequences of hepatitis B virus strain associated with type B fulminant hepatitis have not been compared with those of acute self-limited hepatitis. We carried out full-length sequencing analysis of viral strains derived from patients with type B acute liver injury.

Methods: Nine acute self-limited hepatitis and 6 fulminant hepatitis patients were the subjects of this study.

Immunotherapy of murine colon cancer using receptor tyrosine kinase EphA2-derived peptide-pulsed dendritic cell vaccines.

Background: Further optimization of dendritic cell (DC)-based vaccines is required clinically against advanced stage cancer. Given the broad range of expression levels observed in the recently defined tumor antigen EphA2 in a diverse types of cancers, especially in advanced stage or metastatic cancers, the authors evaluated the effectiveness of vaccination using DCs pulsed with EphA2-derived peptides (Eph-DCs) in a murine colon cancer model.

Methods: EphA2 protein expression levels were evaluated in advanced colorectal carcinoma tissues from 10 patients by Western blot analysis.

Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor.

Unlabelled: Alpha-galactosylceramide, a glycosphingolipid, mediates interaction of dendritic cells (DCs) and NKT cells, leading to activation of both innate and acquired immunity. For cancer treatment, conventional DC-based vaccine has been tried, but its clinical efficacy is limited against liver cancer. Intrahepatic injection of alpha-Galactosylceramide-pulsed DCs (alphaGCDC) has not yet been tested in the liver that contains abundant immune cells such as NK, NKT, and T cells.

Natural killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFNalpha gene to mice.

Interferon (IFN) alpha is a pleiotropic cytokine acting as an antiviral substance, cell growth inhibitor and immunomodulator. To evaluate the therapeutic efficacy and mechanisms of IFNalpha on hepatic metastasis of tumor cells, we hydrodynamically injected naked plasmid DNA encoding IFNalpha1 (pCMV-IFNa1) into Balb/cA mice having 2 days hepatic metastasis of CT-26 cells. Single injection of pCMV-IFNa1 efficiently enhanced the natural killer (NK) activity of hepatic mononuclear cells, induced production of IFNgamma in serum and led to complete rejection of tumors in the liver.