Geotechnical Properties of Kanto Alluvial Soils based on Geochemical Survey

Chemical properties of pore water in soils have a great influence on interparticle bonding among clayey particles and, as a result, not only on their soil structure but also on their geotechnical properties. In this study, we analyzed ionic compositions in pore water extracted from alluvial soils deposited under different sedimentary environments in Kanto lowland area, Japan, and investigated the effect of the chemical compositions of pore water on the geotechnical properties such as compressibility and sensitivity. The following results were obtained: The ion concentrations of pore water measured by different extraction methods showed that the concentration of Na+ by the dilution method was higher than that by the centrifugation method, while the concentrations of Ca2+, Cl- and SO42- by the dilution method are significantly smaller than those by centrifugation method. The centrifugation method was recommended for evaluating geochemistry of the soils since the rotation speeds in the centrifugation method did not significantly affect the pore-water compositions. The geotechnical properties were highly related to the ion concentrations of pore water. Higher compression index and sensitivity were observed for the alluvial soils with higher monovalent/divalent ion ratio. In addition, more strong dependency of monovalent/divalent ion ratio on geotechnical properties was obtained for the alluvial soils with plasticity index larger than 30

Deep Vascular Imaging in Wounds by Two-Photon Fluorescence Microscopy

Deep imaging within tissue (over 300 mu m) at micrometer resolution has become possible with the advent of two-photon fluorescence microscopy (2PFM). The advantages of 2PFM have been used to interrogate endogenous and exogenous fluorophores in the skin. Herein, we employed the integrin (cell-adhesion proteins expressed by invading angiogenic blood vessels) targeting characteristics of a two-photon absorbing fluorescent probe to image new vasculature and fibroblasts up to approximate to 1600 mu m within wound (neodermis)/granulation tissue in lesions made on the skin of mice. Reconstruction revealed three dimensional (3D) architecture of the vascular plexus forming at the regenerating wound tissue and the presence of a fibroblast bed surrounding the capillaries. Biologically crucial events, such as angiogenesis for wound healing, may be illustrated and analyzed in 3D on the whole organ level, providing novel tools for biomedical applications

Liposomal Fasudil, a Rho-Kinase Inhibitor, for Prolonged Pulmonary Preferential Vasodilation in Pulmonary Arterial Hypertension

Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal fasudil formulations was between 68.1 ± 0.8% and 73.6 ± 2.3%, and the cumulative release at 37 °C was 98–99% over a period of 5 days. Compared to intravenous (IV) fasudil, a ~ 10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols. The t1/2 of IV fasudil was 0.39 ± 0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71 ± 0.72 h. One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6 ± 5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH

Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma

The microRNA MIR211 is an important regulator of melanoma tumor cell behavior. Previous studies suggested that in certain tumors, MIR211 acted as a tumor suppressor while in others it behaved as an oncogenic regulator. When MIR211 is expressed in BRAFV600E-mutant A375 melanoma cells in mouse xenografts, it promotes aggressive tumor growth accompanied by increased cellular proliferation and angiogenesis. We demonstrate that MIR211 is transferred to adjacent cells in the tumor micro-environment via exosomes. Cross-species genome-wide transcriptomic analysis showed that human tumor-derived MIR211 interacts with the mouse transcriptome in the tumor microenvironment, and activates ERK5 signaling in human tumor cells via the modulation of a feedback loop. Human miR211 directly inhibits human DUSP6 protein phosphatase at the post-transcriptional level. We provide support for the hypothesis that DUSP6 inhibition conferred resistance of the human tumor cells to the BRAF inhibitor vemurafenib and to the MEK inhibitor cobimetinib, with associated increases in ERK5 phosphorylation. These findings are consistent with a model in which MIR211 regulates melanoma tumor proliferation and BRAF inhibitor resistance by inducing ERK5 signaling within the complex tumor microenvironment. We propose that the MIR211-ERK5 axis represents an important and sensitive regulatory arm in melanoma with potential theranostic applications

Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma

The microRNA MIR211 is an important regulator of melanoma tumor cell behavior. Previous studies suggested that in certain tumors, MIR211 acted as a tumor suppressor while in others it behaved as an oncogenic regulator. When MIR211 is expressed in BRAFV600E-mutant A375 melanoma cells in mouse xenografts, it promotes aggressive tumor growth accompanied by increased cellular proliferation and angiogenesis. We demonstrate that MIR211 is transferred to adjacent cells in the tumor micro-environment via exosomes. Cross-species genome-wide transcriptomic analysis showed that human tumor-derived MIR211 interacts with the mouse transcriptome in the tumor microenvironment, and activates ERK5 signaling in human tumor cells via the modulation of a feedback loop. Human miR211 directly inhibits human DUSP6 protein phosphatase at the post-transcriptional level. We provide support for the hypothesis that DUSP6 inhibition conferred resistance of the human tumor cells to the BRAF inhibitor vemurafenib and to the MEK inhibitor cobimetinib, with associated increases in ERK5 phosphorylation. These findings are consistent with a model in which MIR211 regulates melanoma tumor proliferation and BRAF inhibitor resistance by inducing ERK5 signaling within the complex tumor microenvironment. We propose that the MIR211-ERK5 axis represents an important and sensitive regulatory arm in melanoma with potential theranostic applications

トクシマシ イシカイ ノ トウニョウビョウ タイサク

Tokushima City Medical Association has founded the committee for the means to prevent diabetesmellitus, because the mortality rate by diabetes mellitus in Tokushima Prefecture remainedranked first for 14 years from 1993 to 2006. It has enlightened a large number of people, such asdiabetic patients and candidates for diabetes, and also healthy citizens in Tokushima for preventingdiabetes mellitus. For this aim, Tokushima City Medical Association has made the home pagenamed Tokushima City Diabetic Network to show clearly the means to prevent diabetes mellitusfor the citizens. By this Web site, the citizens can get a correct knowledge about diabetes mellitus,a useful information about the treatments including exercises, diets and medications, and an informationabout medical institutions by utilizing the search page to receive a proper diabetic treatment.Tokushima City Medical Association held several events, such as Tokushima citizens’extension courses and diabetes forums for the citizens to understand diabetes mellitus clearly.Fortunately, in 2007, Tokushima got out of the first rank of diabetic mortality rate. TokushimaCity Medical Association will continue efforts to prevent diabetes mellitus by approaching the citizensof all ages from various aspects

Multifunctional activities and contribution to metastasis of sialomucin complex

One of the hallmarks of neoplastic cells is aberrant properties of their cell surfaces. Progressive changes in the phenotypes of tumor cells are often associated with alterations in composition as well as abundance of surface molecules. Highly metastatic acites sublines of 13762 rat mammary adenocarcinoma cells express abundantly a large glycoprotein complex called sialomucin complex (SMC). However, in spite of the fact that the molecule had been suggested to play significant roles in tumor progression and malignancy, the functional characterization of the glycoprotein has been limited. Recent advances in molecular cloning and gene expression technologies, such as tetracycline-regulated inducible expression, enabled us to examine the roles that SMC plays in cancer and in normal tissues. To investigate the role of SMC in tumor metastasis at the molecular level, recombinant cDNAs for SMC were transfected and expressed in mammalian cell lines. To examine the biological consequences of this multifunctionality, we tested whether the metastasis of cancer cells in the animal can be modulated by regulating SMC levels. For this purpose, SMC-transfected A375 melanoma cells were injected i.v. into the tail vein of nude mice, and the SMC expression level in these cancer cells was regulated by the oral administration of tetracycline. In this experimental metastasis assay, lung metastases, were found to be substantially greater in both number and colony size in mice bearing SMC-overexpressing cancer cells than in mice under tetracycline therapy to repress SMC expression. These observations confirmed that overexpression of SMC can contribute significantly to the metastatic ability of the tumor cells. We therefore propose that SMC is a multifunctional complex which confers anti-adhesive properties and immune resistance as well as altered cellular signaling, all of which may be critical characteristics of metastatic cancer.SMC is also expressed in normal secretory epithelial cells. Immunological analyses using monoclonal antibodies revealed the presence of the glycoprotein in many glands/tissues of human and rat, suggesting a diversity in its physiological roles. In contrast to the membrane association in 13762 ascites tumor cells, SMC is produced in normal tissues as both membrane-associated and secreted/soluble forms. The soluble SMC is a truncated isoform that lacks the transmembrane and cytoplasmic domains. Since the membrane association is a critical feature of tumor SMC for its contribution to malignancy, it is of interest to investigate how SMC is produced as a secreted form in normal tissues. Analysis of SMC mRNA by RT-PCR argues against alternative splicing as a mechanism for production of the secreted isoform. Here, we tested a mechanism involving specific proteolytic cleavage of membrane-bound isoform to release the extracellular portion of the SMC molecule. (Abstract shortened by UMI.)</p