Association of Functional Gene Polymorphisms of Interleukin-1β and Transforming Growth Factor-β1 with the Progression of Liver Fibrosis in Japanese Patients with Hepatitis C Virus-Related Chronic Liver Disease

Interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1RN) are key cytokines in an inflammatory response, and transforming growth factor β1 (TGF-β1) promotes hepatic fibrogenesis. The association of polymorphisms in the genes for these cytokines with liver fibrosis is controversial. The aim of this study was to examine the possible association of IL-1β, IL-1RN and TGF-β1 polymorphisms with the progression of liver fibrosis in the Japanese population using cross-sectional and longitudinal study designs. We examined 183 patients with hepatitis C virus (HCV)-related chronic liver disease (93 chronic hepatitis and 90 with cirrhosis). Some of the chronic hepatitis cases were divided into progressive fibrosis and non-progressive fibrosis. IL-1β ?31T/C, IL-1RN variable number of tandem repeats (VNTR) and TGF-β1 +869 T/C polymorphisms were analyzed using a polymerase-chain reaction-based assay. In the cross-sectional study, there were no significant differences in the genotype distributions of IL-1β, IL-1RN and TGF-β1 between chronic hepatitis and liver cirrhosis. No significant differences were found among Child-Pugh grades in cirrhosis patients. In the longitudinal study, there were no significant differences in the genotype distributions of IL-1β, IL-1RN and TGF-β1 between progressive fibrosis and non-progressive fibrosis. No significant differences in the speed at which liver fibrosis develop were found among the genotypes of IL-1β, IL-1RN and TGF-β1. In disagreement with other studies, the functional gene polymorphisms of IL-1β, IL-1RN and TGF-β1 were not associated with the progression of liver fibrosis in Japanese patients with HCV-related chronic liver disease

Crystalline Inclusions in Hepatocyte Mitochondria of a Patient with Porphyria Cutanea Tarda

Intramitochondrial crystalline inclusions were found in hepatocytes of a patient with porphyria cutanea tarda (PCT). They were composed of parallel filamentous structures which measured approximately 12 nm in diameter. Each filament was separated from an adjacent filament by a space measuring approximately 5 nm. The mitochondria containing such inclusions were usually elongated and enlarged. It seemed likely that these changes are not particular in PCT, but indicate one reversible pathological finding in the liver

Nationwide retrospective observational study of idiopathic dendriform pulmonary ossification : clinical features with a progressive phenotype

Background: Diffuse pulmonary ossification is a specific lung condition that is accompanied by underlying diseases. However, idiopathic dendriform pulmonary ossification (IDPO) is extremely rare, and the clinical features remain unclear. In this study, we aimed to report the clinical characteristics of IDPO. Methods: We conducted a nationwide survey of patients with IDPO from 2017 to 2019 in Japan and evaluated the clinical, radiological, and histopathological findings of patients diagnosed with IDPO. Results: Twenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22-56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1s). Two cases with rapid decline of 10% /year in %FVC predicted were observed.)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1s). Two cases with rapid decline of 10% /year in %FVC predicted were observed. )) at diagnosis. Nearly 80% of the subjects wereasymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1s). Two cases with rapid decline of 10% /year in %FVC predicted were observed. Conclusions: IDPO develops at a young age with gradually progressive phenotype. Further research and long-term (>20 years) follow-up are required to clarify the pathogenesis and clinical findings in IDPO

Biomarkers for novel targeted therapies of hepatocellular carcinoma

Increasing insights into molecular alterations of signalling pathways have led to the development of specific targeted therapies for cancer. Due to the high specificity of monoclonal antibodies or small molecule inhibitors, identification of patients who will benefit from these therapeutics is crucial for treatment success. Furthermore, as classical endpoints of clinical trials are not fully applicable to targeted therapies, biomarkers for monitoring treatment response have to be identified. The recent introduction of a multi-kinase inhibitor for the treatment of liver cancer has accelerated efforts in the field of biomarker research. As further novel targeted therapies are on the horizon for liver cancer therapy, we will here review candidate markers for new hepatocellular carcinoma therapies, with a focus on EGF- and VEGF-receptor related pathways

miR-29b, miR-205 and miR-221 enhance chemosensitivity to gemcitabine in HuH28 human cholangiocarcinoma cells.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is highly resistant to chemotherapy, including gemcitabine (Gem) treatment. MicroRNAs (miRNAs) are endogenous, non-coding, short RNAs that can regulate multiple genes expression. Some miRNAs play important roles in the chemosensitivity of tumors. Here, we examined the relationship between miRNA expression and the sensitivity of CCA cells to Gem. METHODS: Microarray analysis was used to determine the miRNA expression profiles of two CCA cell lines, HuH28 and HuCCT1. To determine the effect of candidate miRNAs on Gem sensitivity, expression of each candidate miRNA was modified via either transfection of a miRNA mimic or transfection of an anti-oligonucleotide. Ontology-based programs were used to identify potential target genes of candidate miRNAs that were confirmed to affect the Gem sensitivity of CCA cells. RESULTS: HuCCT1 cells were more sensitive to Gem than were HuH28 cells, and 18 miRNAs were differentially expressed whose ratios over ± 2log2 between HuH28 and HuCCT1. Among these 18 miRNAs, ectopic overexpression of each of three downregulated miRNAs in HuH28 (miR-29b, miR-205, miR-221) restored Gem sensitivity to HuH28. Suppression of one upregulated miRNA in HuH28, miR-125a-5p, inhibited HuH28 cell proliferation independently to Gem treatment. Selective siRNA-mediated downregulation of either of two software-predicted targets, PIK3R1 (target of miR-29b and miR-221) or MMP-2 (target of miR-29b), also conferred Gem sensitivity to HuH28. CONCLUSIONS: miRNA expression profiling was used to identify key miRNAs that regulate Gem sensitivity in CCA cells, and software that predicts miRNA targets was used to identify promising target genes for anti-tumor therapies