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Zinc(II) complexes of alpha-amino acids and their derivatives with a Zn(N2O2) coordination mode were found to have in vitro insulinomimetic activity as estimated with the inhibition of free fatty acid release in isolated rat adipocytes treated with epinephrine. It was revealed that the insulinomimetic activities of zinc(II) complexes with over-all stability constants (log beta) less than 10.5 are higher than those of ZnSO4 and VOSO4. The high blood glucose level of KK-Ay mice with type 2 diabetes mellitus was lowered by daily intraperitoneal injections of a zinc(II) complex, cis-[Zn(L-Thr)2(H2O)2], for 14 d. The improvement of diabetes mellitus was confirmed with the oral glucose tolerance test.

Objectives. The influence of the histology of adenocarcinoma on recurrence and survival for patients treated with radical hysterectomy and diagnosed as having pathologic stage Ib cervical cancer was investigated. Methods. Five hundred and nine patients (405 squamous cell carcinomas, 104 adenocarcinomas) with pathologic stage Ib cervical cancer treated initially at the Aichi Cancer Center between 1976 and 1995 were studied. Results. Multivariate analysis identified the prognostic variables as histology of adenocarcinoma, number of lymph nodes involved, and tumor size beyond 4 cm. Five-year overall survival and disease-free survival of patients with adenocarcinoma in the presence of lymph node metastasis were 63.2 and 47.4%, respectively, significantly poorer than for squamous cell carcinoma (83.6 and 80.6%; P P = 0.002, respectively). These were not different in the absence of lymph node metastasis (adenocarcinoma, 93.9 and 92.7%; squamous cell carcinoma, 97.9% and 96.1%; P = 0.067 and P = 0.250, respectively). Conclusions. The independent significant risk factors for the recurrence and survival of pathologic stage Ib cervical cancer were the presence of lymph node metastasis, large tumor size beyond 4 cm, and histology of adenocarcinoma. The prognosis of patients with adenocarcinoma was poorer than of patients with squamous cell carcinoma in the presence of lymph node metastasis, while the prognosis of pathologic stage Ib cervical cancer was equivalent when there was no metastasis.

A method to analyze in vivo metabolites in blood obtained from the hepatic vein after the intraportal injection of a drug was established. This method includes cannulation into the portal vein, hepatic vein and bile duct, followed by TLC-autoradioluminography of a non-extracted sample. Either [14C]diazepam, L-3,4-dihydroxyphenyL[3-(14)C]alanine or [14C]inulin was administered on the day following the surgical operation to avoid the influence of anesthesia. Radioactive concentrations of [14C]DOPA decreased rapidly in the first 1 min, then decreased gradually. The concentrations of [14C]diazepam increased within the first 1 min and then decreased gradually. The concentration of [14C]inulin was approximately 10 times higher than that of [14C]DOPA, and both decreased gradually. These results show that the uptake levels of the drugs to the liver varied depending on the drugs. The metabolites of [14C]diazepam and [14C]DOPA were detected as early as 5 s after administration. These results suggest that the in vivo hepatic first pass effect of drugs in the early period of injection (5 s) can be studied using these techniques.

Angiogenesis plays critical roles during development and progression of cancer. Members of the bone morphogenetic protein (BMP) family are involved in TGF-beta superfamily, and have been implicated in the development and maintenance of vascular systems. While BMP-9 and 10 have been recently reported to bind to ALK-1 in endothelial cells, the roles of BMP-9/ALK-1 signaling in the regulation of endothelial cells have not yet been fully elucidated. Here, we examined the effects of BMP-9 on the proliferation of endothelial cells using various systems. Vascular tube formation from ex vivo allantoic explants of mouse embryos was promoted by BMP-9. BMP-9 also induced the proliferation of in vitro-cultured mouse embryonic stem cell-derived endothelial cells (MESEC) by inducing the expression of vascular endothelial growth factor receptor 2 and Tie2, a receptor for Angiopoietin-1. Decrease in ALK-1 expression and expression of constitutively active ALK-1 in MESEC abrogated and mimicked the effects of BMP-9 on the proliferation of MESEC, respectively, suggesting that BMP-9 promotes their proliferation via ALK-1. Furthermore, in vivo angiogenesis was promoted by BMP-9 in a Matrigel plug assay and a BxPC3 human pancreatic cancer xenograft model. In consistent with these in vivo findings, BMP-9 enhanced the proliferation of in vitro cultured normal endothelial cells from dermal tissues of adult mice and tumor-associated endothelial cells isolated from tumor xenografts in host mice. These findings suggest that BMP-9 signaling activates the endothelium via ALK-1. In this presentation, the roles of BMP-9 signals in the formation of lymphatic vessels will also be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5276. doi:1538-7445.AM2012-5276

Fabry disease is an X-linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (EC 3.2.1.22). The causative mutations are diverse, include both large rearrangements and single-base substitutions, and are dispersed throughout the 7 exons of the alpha-galactosidase A gene (GLA). Mutation hotspots for Fabry disease do not exist. We examined 62 Fabry patients in Japan and found 24 GLA mutations, including 11 novel ones. A potential treatment reported for Fabry disease is active site specific chaperone (ASSC) therapy using 1-deoxygalactonojirimycin (DGJ), an inhibitor of alpha-galactosidase A, at subinhibitory concentrations. We transfected COS-7 cells with the 24 mutant GLAs and analyzed the alpha-galactosidase A activities. We then treated the transfected COS-7 cells with DGJ and analyzed its effect on the mutant enzyme activities. The activity of 11 missense mutants increased significantly with DGJ. Although ASSC therapy is useful only for misfolding mutants and therefore not applicable to all cases, it may be useful for treating many Japanese patients with Fabry disease.

We present a case of fetal liver failure caused by the activation of lamivudine-resistant hepatitis B virus (HBV) nine months after lamivudine treatment. A 57-year old man visited our hospital for the treatment of decompensated chronic hepatitis B. Lamivudine was started in December 2001. Subsequently, serum HBV was negative for HBV DNA with seroconversion from HBeAg to anti-HBe and improvement of liver function. However, HBV DNA and HBeAg were again detected in September 2002. He was complicated by breakthrough hepatitis and admitted to our hospital in November for severely impaired liver function. Vidarabine treatment was started and serum HBV DNA and alanine aminotransferase (ALT) decreased transiently. However, after the start of alpha-interferon treatment, HBV DNA level increased and liver function deteriorated. He died 1 mo after admission. An analysis of amino acid sequences in the polymerase region revealed that rtM204I/V with rtL80I/V occurred at the time of viral breakthrough. After the start of antiviral treatment, rtL180M was detected in addition to rtM204I/V and rtL80I/V, and became predominant in the terminal stage of the disease. HBV clone with a high replication capacity may be produced by antiviral treatment leading to the worsening of liver function. Antiviral therapy for patients with breakthrough hepatitis in advanced liver disease should be carefully performed.

Zinc oxide (ZnO) nanoparticles have been widely used in industry, cosmetics, and biomedicine. Recent studies suggested that these nanoparticles could have a major impact on the cardiovascular system. Endothelial progenitor cells (EPCs) contribute to postnatal endothelial repair and regeneration. The present study dissected the effects of ZnO nanoparticles on vasculogenesis using human endothelial colony forming cells (ECFCs), which participate in post-natal vasculogenesis. Two types of ZnO particles were used (nano and micro), in addition to zinc chloride solutions with zinc ion concentrations equal to those in ZnO nanoparticles. Twenty-four-hour exposure induced cytotoxicity in a dose-dependent manner and increased ECFCs apoptosis in all groups. The exposure also reduced the functional capacity of ECFCs on Matrix gel to form tubules, compared with the control cells. These effects were associated with downregulation of expression of vascular endothelial growth factor receptor, VEGFR2 and CXC chemokine receptor, CXCR4. The results suggest that ZnO nanoparticles suppress vasculogenesis from ECFCs through downregulation of the expression of receptors related to vasculogenesis. These effects are based the concentration of released Zn(II).

Background Carcinoma of the oral tongue (OTSCC) is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival. The last three decades has witnessed a change in the OTSCC epidemiological profile, with increasing incidence in younger patients, females and never-smokers. Here, we sought to characterize the OTSCC genomic landscape and to determine factors that may delineate the genetic basis of this disease, inform prognosis and identify targets for therapeutic intervention. Methods Seventy-eight cases were subjected to whole-exome (n = 18) and targeted deep sequencing (n = 60). Results While the most common mutation was in TP53, the OTSCC genetic landscape differed from previously described cohorts of patients with head and neck tumors: OTSCCs demonstrated frequent mutations in DST and RNF213, while alterations in CDKN2A and NOTCH1 were significantly less frequent. Despite a lack of previously reported NOTCH1 mutations, integrated analysis showed enrichments of alterations affecting Notch signaling in OTSCC. Importantly, these Notch pathway alterations were prognostic on multivariate analyses. A high proportion of OTSCCs also presented with alterations in drug targetable and chromatin remodeling genes. Patients harboring mutations in actionable pathways were more likely to succumb from recurrent disease compared with those who did not, suggesting that the former should be considered for treatment with targeted compounds in future trials. Conclusions Our study defines the Asian OTSCC mutational landscape, highlighting the key role of Notch signaling in oral tongue tumorigenesis. We also observed somatic mutations in multiple therapeutically relevant genes, which may represent candidate drug targets in this highly lethal tumor type. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0219-2) contains supplementary material, which is available to authorized users.

Background Long-term treatment with antibiotics containing pivalic acid may decrease serum carnitine concentration and can sometimes be associated with severe hypoglycemia and encephalopathy in infants. Little has been reported, however, on severe hypocarnitinemia induced by acute administration in older children. Case presentation We describe a 6-year-old Japanese girl with Fukuyama-type congenital muscular dystrophy who lost consciousness after 3 days of treatment with an antibiotic containing pivalic acid (cefditoren pivoxil). Investigations at the onset of unconsciousness revealed hypoglycemia (free plasma glucose concentration: 31 mg/dL) and hypocarnitinemia (serum free carnitine concentration: 6.2 μmol/L). Intravenous administration of glucose rapidly improved her symptoms without any complications. Serum free carnitine concentration was 29.0 μmol/L immediately prior to the initiation of cefditoren pivoxil. Computed tomography scanning showed severe peripheral skeletal muscle atrophy, indicating the likelihood of decreased carnitine stores in skeletal muscle. Conclusions Although serum carnitine concentration can appear deceptively normal, skeletal muscle carnitine stores can be reduced in patients with severe muscular atrophy. Even a short course of a pivalate-containing antibiotic can lead to life-threatening hypocarnitinemia in older children with severe muscular dystrophy.

Biodiversity patterns in nature are often heterogeneous across space. Individual organ-isms can be influenced by spatial constraints via dispersal processes and interactions with the environment, and thus connectivity among patches is a key aspect of spatial structure that can influence the community processes controlling biodiversity patterns. Although the connectivity concept has fostered a large body of theory, many theoretical results are derived assuming simplified spatial structures, which are often not capturing the complexity of natural systems. Network metacommunity models, where patches are connected in potentially heterogeneous ways, can be used to build a theoretical basis for how different landscape and seascape structures may affect metacommunity dynamics. Likewise, recent technical advances permit a better estimation of connectivity in natural systems, such as networks of coral reefs or hydrothermal vents. To fill the knowledge gap about the role of space in ecology, this thesis investigates how the spatial structure drives metacommunity dynamics and biodiversity patterns and stability of metacommunities by utilizing computer simulations and marine connectivity data. In particular, I analyze the two aspects of metacommunity systems: biodiversity assembly and stability, both of which can contribute to biodiversity patterns. First, I examine the role of spatial topology (i.e. the pattern of dispersal linkages among patches) in the interplay between different metacommunity processes, including species sorting and mass effects. I find that network topology strongly mediates the balance of different dynamics in ways that are not captured by simplified spatial models that form the basis of metacommunity theory. Second, I examine the contribution of different aspects of spatial structure to metacommunity stability and find that the size of the network, rather than topology, is the dominant factor driving stability on the metacommunity level. Third, I combine these two simulation analyses with empirical marine connectivity networks and provide a better understanding of spatial processes applicable to natural systems. Overall, these analyses dissect the complexity in connectivity and reveal key aspects of connectivity in regulating biodiversity and stability. This study provides a better understanding of spatial processes and specifically reveals how and which spatial features control biodiversity patterns and metacommunity stability, contributing to a metacommunity theory that can ultimately inform conservation planning.