Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice.

Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho (KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks.

The Effect of Genetic Polymorphism in Response to Body Weight Reduction in Japanese Patients with Nonalcoholic Fatty Liver Disease.

Background: weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of rs738409 and rs6834314 variants in response to diet therapy in Japanese patients with NAFLD.

Methods: we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to and genotypes.

PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat.

We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient L-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups.

Attenuated effect of PNPLA3 on hepatic fibrosis by HSD17B13 in Japanese patients with non-alcoholic fatty liver disease.

Background & Aims: PNPLA3 rs738409 has been associated with increased risks of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Recently, carriage of the rs6834314 G allele, which is in high linkage with rs72613567 of 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13), was reported to be associated with a reduced risk of liver injury in NAFLD patients. We estimated the impact of these genetic variants on hepatic fibrosis in Japanese patients with NAFLD.

Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high-fat diet fed mice.

Background & Aims: Mice fed high-fat diet (HFD) demonstrate obesity-related systemic insulin resistance (IR). Aim of this study is to clarify the role of interleukin (IL)-6 in IR in vivo focusing on skeletal muscle, adipose tissue and liver.

Methods: Plasma markers of IR and hepatic IL-6 signalling were examined in eight-week HFD feeding C57/BL6 mice.

High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells.

P300 impacts the transcription of several genes involved in biological behavior of human malignancies including hepatocellular carcinomas (HCC). We found p300 is highly expressed in 47% of surgically resected HCC specimens by immunohistochemistry, which correlated with advanced TNM staging (P = 0.034), vascular invasion (P = 0.

Transformation of dendritic cells from plasmacytoid to myeloid in a leukemic plasmacytoid dendritic cell line (PMDC05).

We investigated the transformation from pDCs to mDCs in a pDC line (PMDC05) which was established from a patient with pDC leukemia in our laboratory. PMDC05 cells were separated into two fractions according to the expression of BDCA1 and CD123. BDCA1(-)CD123(+) cells were found to be pDC-like cells by their morphology, surface phenotypes, mRNA expression and the function.

WT1 peptide vaccination in a CML patient: induction of effective cytotoxic T lymphocytes and significance of peptide administration interval.

Although antigen-specific immune responses including cytotoxic T cells (CTLs) against antigen peptide could be enhanced after tumor antigen peptide vaccinations, the immune responses do not necessarily result in a decrease or eradication of tumor cells in the vaccination trials. We focused on whether antigen-specific CTLs could be damaged by the repeated stimulation of antigenic peptide and whether regulatory T (Treg) cells would be increased by the administration of WT1 peptide. We administered WT1 peptide 22 times over 18 months in a CML patient who was being treated with imatinib.

A leukemic plasmacytoid dendritic cell line, PMDC05, with the ability to secrete IFN-alpha by stimulation via Toll-like receptors and present antigens to naïve T cells.

We established a plasmacytoid dendritic cell (pDC) line (PMDC05) from leukemia cells of pDC leukemia. PMDC05 cells were positive for CD4, CD56, CD33, HLA-DR, CD123 (IL-3Ralpha) and CD86 in the absence of lineage markers. mRNA of TLR1, TLR2, TLR4, TLR7 and TLR9 was clearly expressed and among these TLRs, TLR7 was prominent.

Induction of antigen-specific cytotoxic T lymphocytes by using monocyte-derived DCs transfected with in vitro-transcribed WT1 or SART1 mRNA.

To evaluate the usefulness of monocyte-derived dendritic cells transfected with tumor antigen mRNA for dendritic cell-based antitumor immunotherapy, we attempted to generate antigen-specific cytotoxic T cells by priming lymphocytes with monocyte-derived dendritic cells transfected with in vitro-transcribed tumor antigen mRNA. Mature monocyte-derived dendritic cells were generated from microbeads-separated CD14(+) cells by culturing with GM-CSF/IL-4 for 7 days and with TNF-alpha, IL-1alpha, IL-6, and PGE(2) for the last one day. Monocyte-derived dendritic cells, lymphocytes, and target cells, which were positive for HLA-A24, were used in the present study.

Plasmacytoid dendritic cell leukemia with potent antigen-presenting ability.

We report 2 patients with plasmacytoid dendritic cell leukemia (pDCL) expressing CD4, CD56, CD33, CD36, HLA-DR, CD123, CD86 and CD83 in the absence of lineage markers (myeloid, B, T or natural killer cells) except for CD33. Culturing leukemic blasts of both cases with IL-3 for 4 days increased the expression of surface molecules associated with antigen presentation, e.g.

Anti-tumor cytotoxicity of gammadelta T cells expanded from peripheral blood cells of patients with myeloma and lymphoma.

In order to establish an efficient gammadelta T cell-mediated immunotherapy for hematological malignancies, we attempted to evaluate cytotoxicity against tumor cells by gammadelta T cells, which were generated from blood cells of patients with myeloma and lymphoma by culturing with zoledronate and a low dose of IL-2. Although gammadelta T cells were expanded in patients with myeloma and lymphoma as well as normal persons, the amplification rates of gammadelta T cells before and after culturing varied from patient to patient in myeloma and lymphoma. gammadelta T cells generated in patients with myeloma and lymphoma showed a potent cytotoxic ability against myeloma/lymphoma cell lines as shown in gammadelta T cells generated in normal subjects.

Enhancement of anti-tumor cytotoxicity of expanded gammadelta T Cells by stimulation with monocyte-derived dendritic cells.

In order to establish the method of generating powerful gammadelta T cells for anti-tumor immunotherapy, we investigated the effects of monocyte-derived dendritic cells (mo-DCs) on anti-tumor cytotoxicity of expanded gammadelta T cells. Activation of gammadelta T cells co-cultured for 2-3 days with immature or mature mo-DCs was evaluated by CD69 expression and anti-tumor cytotoxicity using two assays : the 5- (and 6-) carboxyfluorescein diacetate, succinimidyl ester-based cytotoxicity assay and the calcein-AM-based Terascan assay. gammadelta T cells were used as effector cells and myeloma cell line (RPMI8226) or chronic myelogenous leukemia blastic crisis cell line (C2F8) were used as target cells.