High antitumor activity of pladienolide B and its derivative in gastric cancer.

The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6-4.0) and 1.2 ± 1.1 (range, 0.4-3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction.

Novel des-γ-carboxy prothrombin in serum for the diagnosis of hepatocellular carcinoma.

BACKGROUND AND AIM: Serum des-γ-carboxy prothrombin (DCP) levels using a newly developed electrochemiluminescence immunoassay (ECLIA, novel DCP [NX-DCP]) were measured, and the utility of NX-DCP and DCP/NX-DCP ratio for the diagnosis of hepatocellular carcinoma (HCC) was investigated. Antigenic differences in DCP between HCC and non-HCC patients were elucidated. METHODS: The subjects included 170 patients with HCC, 61 with benign liver disease, 12 with obstructive jaundice, and 10 warfarin users. NX-DCP was quantitated by sandwich ECLIA employing novel anti-DCP monoclonal antibodies, P11 and P16. Conventional DCP was quantitated by standard ECLIA. DCP extracted from serum by affinity-chromatography was analyzed by Western blotting. RESULTS: Conventional serum DCP levels were high in patients with HCC and obstructive jaundice, and in warfarin users, consistent with previous reports. Serum NX-DCP levels were high only in warfarin users and obstructive jaundice patients (vitamin K-deficient patients) but not in HCC patients. The DCP/NX-DCP ratio was significantly higher in the HCC group than in the benign liver disease, obstructive jaundice, and warfarin groups (P < 0.001). Receiver operating characteristic analysis showed significant superiority of the DCP/NX-DCP ratio over conventional DCP as a marker for HCC diagnosis (P < 0.05). Western blot analysis showed that P11 and P16 reacted strongly with DCP from a warfarin user and an obstructive jaundice patient but very faintly with DCP from an HCC patient. Immunohistochemistry on HCC samples and autopsied normal liver tissues from warfarin users showed similar results. CONCLUSIONS: The DCP/NX-DCP ratio is very useful for diagnosing HCC. DCP in HCC patients is distinct from that in vitamin K-deficient patients.

Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue.

OBJECTIVES: The purpose of this report was to assess the link between macrophage polarization in epicardial adipose tissue and atherosclerosis in patients with coronary artery disease (CAD). BACKGROUND: Macrophage accumulation enhances chronic inflammation in adipose tissue, but macrophage phenotypic change in human epicardial adipose tissue and its role in atherogenesis are unknown. METHODS: Samples were obtained from epicardial and subcutaneous adipose tissue during elective cardiac surgery (CAD, n = 38; non-CAD, n = 40). Infiltration of M1/M2 macrophages was investigated by immunohistochemical staining with antibodies against CD11c and CD206, respectively. Expression of pro- and anti-inflammatory adipocytokines in adipose tissue was evaluated by real-time quantitative polymerase chain reaction. RESULTS: Infiltration of macrophages and expression of pro- and anti-inflammatory cytokines were enhanced in epicardial fat of patients with CAD compared with that in non-CAD patients (p < 0.05). The ratio of M1/M2 macrophages was positively correlated with the severity of CAD (r = 0.312, p = 0.039). Furthermore, the expression of pro-inflammatory cytokines was positively correlated, and the expression of anti-inflammatory cytokines was negatively correlated with the ratio of M1/M2 macrophages in epicardial adipose tissue of CAD patients. By contrast, there was no significant difference in macrophage infiltration and cytokine expression in subcutaneous adipose tissue between the CAD and non-CAD groups. CONCLUSIONS: The ratio of M1/M2 macrophages in epicardial adipose tissue of CAD patients is changed compared with that in non-CAD patients. Human coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue.

Background exposure to PCDDs/PCDFs/PCBs and its potential health effects: a review of epidemiologic studies.

Here we review epidemiologic studies dealing with the dietary intake and the body burden of polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzo-furans (PCDFs)/ polychlorinated biphenyls (PCBs) in the general population, and potential adverse health effects of these substances, especially on the risk of diabetes mellitus and endometriosis, and on thyroid function and the neurodevelopment of infants. The mean or median intake of dioxin-related compounds among the general populations of various countries is lower than the maximum tolerable daily intake (TDI) set by the WHO in 1998 (4pg TEQ/kg/day). However, there have been few reports on the distribution of intake and the proportion of subjects whose exposure levels exceed the maximum TDL. At present, it remains unclear whether background exposure to dioxin-related compounds is associated with increased risk of diabetes (because of lack of longitudinal studies), endometriosis (because of lack of studies with sufficient statistical power), or altered thyroid function (because of inconsistent results on humans). Consistent results have been reported for the association between exposure to background levels of PCBs/dioxins, especially trans-placental PCBs, and defective neurodevelopment of infants in the U.S. and Europe. Thus, efforts should be made to further decrease the body burden among women of reproductive age by reducing the release of PCDDs/PCDFs/PCBs into the environment.