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Although 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has been shown to inhibit the growth of certain malignant cells, its hypercalcemic effect has prevented clinical application. We have recently developed a novel vitamin D3 analog, 22-oxa-1,25-(OH)2D3 (OCT), that is capable of promoting differentiation and inhibiting proliferation without inducing hypercalcemia. The present study was undertaken to determine whether OCT could be applied for the treatment of breast cancer with or without estrogen receptor (ER). OCT inhibited the proliferation of both ER-positive (MCF-7, T-47D, and ZR-75-1) and ER-negative breast cancer cells (MDA-MB-231 and BT-20) in vitro in a time- and dose-dependent manner, as determined by cell number and [3H]thymidine uptake. The antiproliferative effect was observed with a concentration as low as 10(-11) M OCT, and treatment of MCF-7 cells with 10(-8) M OCT for 8 days caused more than a 50% reduction in cell number compared with that of vehicle-treated cells. OCT was approximately 1 order of magnitude more potent than 1,25-(OH)2D3 in inhibiting the proliferation of MCF-7 cells. The in vivo effect of OCT was examined in athymic mice implanted with ER-negative MX-1 tumor, which was established as the xenograft derived from human breast carcinoma. Intratumor administration of OCT three times a week remarkably delayed the growth of MX-1 tumor in a time- and dose-dependent manner. The antitumor effect of 1 microgram/kg BW OCT was greater than that of 500 microgram/kg BW adriamycin, and the relative tumor weights in each group on day 26 were 29.7% and 50.5% of that in the vehicle-treated group, respectively. The effects of OCT and adriamycin were additive, and the relative tumor weight after 26 days of combined treatment was 21.7% of that in the vehicle-treated group. Oral administration of OCT was also effective, and the relative tumor weight in the OCT-treated group (1 microgram/kg BW) was 54.6 +/- 0.1% (mean +/- SEM) of that in the vehicle-treated group. Neither intratumor nor oral administration of OCT raised the serum calcium level in these animals. These results demonstrate that OCT is a potent inhibitor of the proliferation of breast cancer cells with or without ER and that OCT inhibits the growth of breast cancer in vivo without inducing hypercalcemia. We suggest that OCT may provide a new strategy for the treatment of breast carcinoma regardless of ER status.

Primary biliary cirrhosis (PBC) primarily affects females and is rarely complicated by hepatocellular carcinoma (HCC). Although the HCC incidence in PBC patients is low, several characteristics and risk factors associated with its development have been reported. In this study, national data concerning the current status of carcinogenesis in PBC patients in Japan are reviewed. Using data from two national questionnaire surveys, we investigated the clinicopathological findings associated with HCC in PBC patients. According to the data of all reviewed PBC patients, the HCC incidence was 2.4% (71/2946). The HCC incidence by gender was 5.1% (19/370) in males and 2.0% (52/2576) in females, and the proportion of males was 26.7%. Prognosis was significantly poorer in the PBC patients with HCC than in those without. Multivariate analysis of risk factors associated with HCC by gender revealed histological stage at the time of PBC diagnosis as an independent risk factor associated with the development of HCC in females, but not in males. Furthermore, data from another national survey of 178 PBC patients with HCC (male/female 5 49/129; proportion of males 27.5%) revealed that the duration between the diagnosis of PBC and that of HCC was significantly shorter in males than in females. In addition, histological stage at the time of HCC diagnosis was an independent risk factor for HCC in females, whereas no risk factors were identified in males. Conclusion: these data indicate that males are at risk of developing HCC at any histological stage of PBC. Therefore, male PBC patients in particular should be carefully screened for HCC from the early stages of PBC. (HEPATOLOGY 2013;57:1942-1949

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an energy metabolism-related enzyme in the glycolytic pathway. Recently, it has been reported that GAPDH has other physiological functions, such as apoptosis, DNA repair and autophagy. Some in vitro studies have indicated immunological aspects of GAPDH function, although there is no definite study discussing the advantage of GAPDH as a therapeutic target. Here, we show that GAPDH has an anti-inflammatory function by using a lipopolysaccharide (LPS)-induced, sepsis-related severe acute lung injury (ALI) mouse model, which is referred to as acute respiratory distress syndrome (ARDS) in humans. GAPDH pre-injected mice were protected from septic death, and their serum levels of proinflammatory cytokines were significantly suppressed. In lung tissue, LPS-induced acute injury and neutrophil accumulation were strongly inhibited by GAPDH pre-injection. Pulmonary, proinflammatory cytokine gene expression and serum chemokine expression in GAPDH pre-injected mice were also reduced. These data suggest the therapeutic potential of GAPDH for sepsis-related ALI/ARDS.

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A recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) is one of the major concerns reflecting the higher mortality of HCC. This study aimed to explore the impact of circulating exosomes on HCC development and recurrence. One-shot transfusion of hepatoma serum to naïve rats induced liver cancer development with gradual elevation of alpha-fetoprotein (AFP), but exosome-free hepatoma serum failed to induce AFP elevation. The microarray analysis revealed miR-92b as one of the highly expressing microribonucleic acids in hepatoma serum exosomes. Overexpression of miR-92b enhanced the migration ability of liver cancer cell lines with active release of exosomal miR-92b. The hepatoma-derived exosomal miR-92b transferred to natural killer (NK) cells, resulting in the downregulation of CD69 and NK cell-mediated cytotoxicity. Furthermore, higher expression of miR-92b in serum exosomes was confirmed in HCC patients before LDLT, and its value at 1 month after LDLT was maintained at a higher level in the patients with posttransplant HCC recurrence. In summary, we demonstrated the impact of circulating exosomes on liver cancer development, partly through the suppression of CD69 on NK cells by hepatoma-derived exosomal miR-92b. The value of circulating exosomal miR-92b may predict the risk of posttransplant HCC recurrence. K E Y W O R D Sbasic (laboratory) research/science, biomarker, cancer/malignancy/neoplasia: risk factors, cellular biology, immunobiology, liver transplantation/hepatology, microarray/gene array, molecular biology: micro RNA, natural killer (NK) cells/NK receptors, translational research/ science 1 | INTRODUC TI ON Hepatocellular carcinoma (HCC) is the second leading cause of death from cancer in the world. 1 In general, malignant tumor regions are treated by radiofrequency ablation (RFA) or transarterial embolization (TAE) and/or removed by surgical resection.Our group compared the disease-free survival of HCC patients between surgical resection and RFA in the Barcelona Clinic Liver

The Notch signaling pathway regulates the development of various cell types and organs, and also contributes to disease mechanisms in adults. Accumulating evidence suggests its role in cardiovascular and metabolic diseases. Notch signaling components also control the phenotype of immune cells. Delta-like ligand 4 (Dll4) of the Notch pathway promotes pro-inflammatory activation of macrophages in vitro and in vivo. Dll4 blockade attenuates chronic atherosclerosis, vein graft disease, vascular calcification, insulin resistance and fatty liver in mice. The Dll4-Notch axis may thus participate in the shared mechanisms for cardiometabolic disorders, serving as a potential therapeutic target for ameliorating these global health problems.

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