Antithrombogenic therapy after heart valve replacement - Effect of anti-platelet drug on aggregation-

人工弁置換患者の血栓塞栓症（TE）は，長期予後の成績を左右する。　TEを減少させるために凝固因子を抑制するwarfarinと抗血小板剤による抗血栓療法が行われている。人工弁置換患者103例を対象に，抗血小板剤であるtrapidil（TP）とdipyridamole（DP）の血小板凝集能に与える効果を検討した。36ヵ月間検討したが，warfarin単独群は血小板凝集能に変化がなく，TP，DP共にADP凝集能を抑制した。しかし有意差の見られたのは全経過ではなく，凝集能抑制は強力かつ持続的ではなかった。またコラーゲン誘導凝集能は変化を認めなかった。TPとDPの抗血小板効果は同等と思われる。期間中の血栓塞栓発生は，warfarin単独群9.5％，TP群4.3％，DP群7.7％であった。臨床的に抗血小板剤の併用は有効と思われるが，血小板凝集抑制には投与量の増量，あるいは他の薬剤の検討が必要であろう。To evaluate the effect of anti-thrombotic thrapy after valve replacement, serial platelet aggregation measurememnts were carried out in 103 patients. Patients were divided into three groups. e. i. warfarin alone (control), warfarin with trapidil (TP) of 300mg/day and dipyridamole (DP) of 300mg/day. The aggregation of platelet of the control group did not change through 36 months. TP group showed a decrease in platelet aggregation at 24 and 30 months from the pretreatment value. The aggregation of 24 month in TP was significantly lower than that of control. There was no difference of platelet aggregation between TP and DP group. The incidence of thromboembolism of control, TP and DP group were 9.5%, 4.3% and 7.7%, respectively. These data suggest that the supression of platelet aggregation .by TP and DP is not adequate to continue for long time and TP has similar anti-thrombotic effect to DP

Clinical significance of side population in ovarian cancer cells

Recently, accumulating evidence has suggested that tumors, including ovarian cancer, are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. The emergence of drug resistance is one of the most difficult problems in the treatment of ovarian cancer, which has been explained recently by the potential of CSCs to have superior resistance against anti-cancer drugs than conventional cancer cells. In this study, we expanded this line of study to examine whether this phenomenon is also observed in clinical specimens of ovarian cancer cells. In total we could analyze 28 samples out of 60 obtained from ovarian cancer patients. The clinical samples were subjected to testing of the expression of side population (SP) as a CSC marker, and according to the presence of SP (SP+) or absence of SP (SP−), clinicopathological significances were analyzed. Although there was no statistical significance, there were more SP+s in recurrent cases as well as in ascitic and peritoneal dissemination than in primary tumor of the ovary. There was no correlation between SP status and FIGO staging. In 19 cases of those who could be followed more than 6 months from initial therapy, there were 8 cases of recurrence or death from disease, and all of these were SP+. On the other hand, in 11 cases of disease-free survivors, 6 were SP+. There was a significant difference in prognosis between SP+ and SP− (p = 0.017). Although this study was limited, it revealed that SP could be contained more in recurrent or metastatic tumors than in primary tumors, and also that the presence of SP could be a risk factor of recurrence in ovarian cancer. Therefore, a novel therapeutic strategy targeting SP could improve the prognosis of ovarian cancer

Mouse models of human INAD by Pla2g6 deficiency

Infantile neuroaxonal dystrophy (INAD) is a severe neurodegenerative disease characterized by its early onset. PLA2G6, which encodes a phospholipase A2, iPLA2ß, has been identified as a causative gene of INAD. iPLA2ß has been shown to be involved in various physiological and pathological processes, including immunity, cell death, and cell membrane homeostasis. Gene targeted mice with a null mutation of Pla2g6 develop the INAD phenotype as late as approximately 1 to 2 years after birth. Recently, another INAD mouse model, Pla2g6-INAD mice line, has been established. The Pla2g6-INAD mice bear a point mutation in the ankyrin repeat domain of Pla2g6 generated by N-ethylN-nitrosourea mutagenesis. These mutant mice develop severe motor dysfunction and hematopoietic abnormality in a manner following Mendelian law. The mice showed the abnormal gait and poor performance as early as 7 to 8 weeks of age, detected by hanging grip test. Neuropathological examination revealed widespread formation of spheroids containing tubulovesicular membranes similar to human INAD. Molecular and biochemical analysis revealed that the mutant mice expressed Pla2g6 mRNA and protein, but the mutated Pla2g6 protein had no glycerophospholipid-catalyzing enzyme activity. When analyzed the offspring which bear Pla2g6 knockout allele and Pla2g6-INAD allele, abnormal gait appeared slightly later than Pla2g6-INAD homozygotes but with earlier onset than the Pla2g6 knockout homozygotes. This result suggests that mutant Pla2g6 protein contributes to early onset of INAD symptoms in the absence of intact Pla2g6 protein. The analysis of various INAD mouse models may help to understand the pathogenesis of neurodegenerative diseases, including INAD

BLT1受容体シグナルは好中球の過剰な集積を阻害することでアセトアミノフェン肝障害に対して防御的に作用する

2016(平成28)年

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in iNKT cells

Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells