Regulation of UDP-glucose:ceramide glucosyltransferase-1 by ceramide

AbstractWe report that the expression of mRNA and the activity of UDP-glucose:ceramide (Cer) glucosyltransferase-1 (GlcT-1) of human hepatoma Huh7 and mouse melanoma B16 cells increases after treatment with bacterial sphingomyelinase or upon addition of short-chain Cer. Interestingly, however, GlcT-1 gene transcription was not increased by Cer when GlcT-1 cDNA was introduced with the CMV promoter in GlcT-1-deficient GM95 cells, suggesting that the normal promoter region of GlcT-1 gene is essential for the response. The conversion of C6-Cer to C6-GlcCer occurred much more rapidly in GlcT-1-overexpressing Huh7 cells than in mock transfectants. As a result, GlcT-1-overexpressing cells acquired a greater resistance to C6-Cer-mediated cell death

<症例>マムシ (Agkistrodon halys Blomhoffii) 咬傷における少量抗毒素血清投与の経験 : 43症例の検討

Forty-three consecutive patients of venomous snakebite by the Japanese viper (Agkistrodon halys Blomhoffii, "Mamushi" in Japanese) were treated with an uniformly scheduled therapy from 1990 and 1994. The therapy was mainly composed of minimal dose of antivenin, methylprednisolon and cepharanthin. There were two clinical courses, i.e., the minimal envenomation course (Group A, n=14) and the severe one (Group B, n=29). Our treatment was so satisfactory that all patients of both groups fully recovered activities of daily living with neither organic disorders nor sequelae of the bitten extremities. The high appearance ratio of atypical lymphocytes (P < 0. 05) and the increased ratio of lymphocyte count to White blood cell count (P<0. 02) could be indicators that predict hich clinical courses the patients take.1990年から1994年までの5年間に当院で治療したマムシ咬傷43例について検討した. 当院では原則として抗毒素血清, ステロイド, セファランチンの投与を行っているが, 死亡例はなく, 咬傷部の機能障害を示した症例もなかった. 4例（9. 3%）に即効型過敏反応が認められた. 1例は anaphylaxy shock を呈したが治療により即時改善をみた. 遅延型血清病は入院期間中観察されなかった. McCollough らの分類により軽症例（n=14）と重症例（n=29）に分け予後因子を検討した. 治療開始前の WBC, CPK, LDH, BUN, Cr はいずれも重症化指標とはなりえなかったが, 白血球中のリンパ球比率（P<0. 02）, 異型リンパ球出現率（P<0. 05）が高い程, 重症化することが示唆された. 死亡報告が散見されるマムシ咬傷に対し受傷早期の抗毒素血清投与は有用であり, 即効型過敏反応に即座に対応すれば比較的安全に投与できるものと考えられた. しかし, 軽症例に対しての抗毒素血清投与には疑問が残り, 今後は重症化が危倶される症例を的確に選択する必要があると思われた

Identification of Physiologically Active Substances as Novel Ligands for MRGPRD

Mas-related G-protein coupled receptor member D (MRGPRD) is a G protein-coupled receptor (GPCR) which belongs to the Mas-related GPCRs expressed in the dorsal root ganglia (DRG). In this study, we investigated two novel ligands in addition to beta-alanine: (1) beta-aminoisobutyric acid, a physiologically active substance, with which possible relation to tumors has been seen together with beta-alanine; (2) diethylstilbestrol, a synthetic estrogen hormone. In addition to the novel ligands, we found that transfection of MRGPRD leads fibroblast cells to form spheroids, which would be related to oncogenicity. To understand the MRGPRD novel character, oncogenicity, a large chemical library was screened in order to obtain MRGPRD antagonists to utilize in exploring the character. The antagonist in turn inhibited the spheroid proliferation that is dependent on MRGPRD signaling as well as MRGPRD signals activated by beta-alanine. The antagonist, a small-molecule compound we found in this study, is a potential anticancer agent

Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34$^{+}$ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)- and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor-mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs

MRGD, a MAS-related G-protein Coupled Receptor, Promotes Tumorigenisis and Is Highly Expressed in Lung Cancer

To elucidate the function of MAS-related GPCR, member D (MRGD) in cancers, we investigated the in vitro and in vivo oncogenic function of MRGD using murine fibroblast cell line NIH3T3 in which MRGD is stably expressed. The expression pattern of MRGD in clinical samples was also analyzed. We found that overexpression of MRGD in NIH3T3 induced focus formation and multi-cellular spheroid formation, and promoted tumors in nude mice. In other words, overexpression of MRGD in NIH3T3 induced the loss of contact inhibition, anchorage-independent growth and in vivo tumorigenesis. Furthermore, it was found that the ligand of MRGD, beta-alanine, enhanced spheroid formation in MRGD-expressing NIH3T3 cells. From investigation of clinical cancer tissues, we found high expression of MRGD in several lung cancers by immunohistochemistry as well as real time PCR. Based on these results, MRGD could be involved in tumorigenesis and could also be a novel anticancer drug target

Environmental radiation monitoring utilizing solid state dosimeters

A personal glass dosimeter (GD) based on the radiophotoluminescence phenomenon in Ag+-doped phosphate glass was evaluated for its applicability to the measurement of environmental natural background radiation. To investigate the potential of the personal GD, we measured the monthly data of environmental natural background radiation at seven points in Ishikawa prefecture. The results indicated that the personal GD is suitable and reasonable for monitoring environmental natural background radiation. It is very important to monitor environmental natural background radiation to detect changes in environmental radiation dose such as experiments using an atomic bomb or an accidental leakage of radioactivity from a radiation facility. The personal GD will be a very useful tool to monitor both the environmental natural background radiation dose and personal radiation dose