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991.
Natural killer (NK) cells can mediate the rejection of bone marrow allografts and exist as subsets based on expression of inhibitory/activating receptors that can bind MHC. In vitro data have shown that NK subsets bearing Ly49 receptors for self-MHC class I have intrinsically higher effector function, supporting the hypothesis that NK cells undergo a host MHC-dependent functional education. These subsets also play a role in bone marrow cell (BMC) allograft rejection. Thus far, little in vivo evidence for this preferential licensing across mouse strains with different MHC haplotypes has been shown. We assessed the intrinsic response potential of the different Ly49(+) subsets in BMC rejection by using β2-microglobulin deficient (β2m(-/-)) mice as donors. Using congenic and allogeneic mice as recipients and depleting the different Ly49 subsets, we found that NK subsets bearing Ly49s, which bind "self-MHC" were found to be the dominant subset responsible for β2m(-/-) BMC rejection. This provides in vivo evidence for host MHC class I-dependent functional education. Interestingly, all H2(d) strain mice regardless of background were able to resist significantly greater amounts of β2m(-/-), but not wild-type BMC than H2(b) mice, providing evidence that the rheostat hypothesis regarding Ly49 affinities for MHC and NK-cell function impacts BMC rejection capability. 相似文献
992.
Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is a common type of leukemia in infants, which is associated with a high relapse rate and poor prognosis. IL24 selectively induces apoptosis in cancer cells and exerts immunomodulatory and antiangiogenic effects. We examined the effects of adeno-associated virus type 8 (AAV8) vector-mediated muscle-directed systemic gene therapy in MLL/AF4-positive ALL using IL24. In a series of in vitro studies, we examined the effects of AAV8-IL24-transduced C2C12 cell-conditioned medium. We also examined the effects of AAV8-IL24 in MLL/AF4 transgenic mice. The results revealed the effects of AAV8-IL24 in MLL/AF4-positive ALL both in vitro and in vivo. With regard to the mechanism of therapy using AAV8-IL24 in MLL/AF4-positive ALL, we demonstrated the antiangiogenicity and effects on the ER stress pathway and unreported pathways through inhibition of S100A6 and HOXA9, which is specific to MLL/AF4-positive ALL. Inhibition of S100A6 by IL24 was dependent on TNF-α and induced acetylation of p53 followed by activation of the caspase 8-caspase 3 apoptotic pathway. Inhibition of HOXA9 by IL24, which was independent of TNF-α, induced MEIS1 activation followed by activation of the caspase 8-caspase 3 apoptotic pathway. Thus, gene therapy using AAV8-IL24 is a promising treatment for MLL/AF4-positive ALL. 相似文献
993.
Ma CS Avery DT Chan A Batten M Bustamante J Boisson-Dupuis S Arkwright PD Kreins AY Averbuch D Engelhard D Magdorf K Kilic SS Minegishi Y Nonoyama S French MA Choo S Smart JM Peake J Wong M Gray P Cook MC Fulcher DA Casanova JL Deenick EK Tangye SG 《Blood》2012,119(17):3997-4008
T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients. 相似文献
994.
Hypertension is associated with cardiac noradrenergic hyperactivity, although it is not clear whether this precedes or follows the development of hypertension itself. We hypothesized that Ca(2+) homeostasis in postganglionic sympathetic neurons is impaired in spontaneously hypertensive rats (SHRs) and may occur before the development of hypertension. The depolarization-induced rise in intracellular free calcium concentration ([Ca(2+)](i); measured using fura-2-acetoxymethyl ester) was significantly larger in cultured sympathetic neurons from prehypertensive SHRs than in age matched normotensive Wistar-Kyoto rats. The decay of the [Ca(2+)](i) transient was also faster in SHRs. The endoplasmic reticulum Ca(2+) content and caffeine-induced [Ca(2+)](i) amplitude were significantly greater in the young SHRs. Lower protein levels of phospholamban and more copies of ryanodine receptor mRNA were also observed in the young SHRs. Depleting the endoplasmic reticulum Ca(2+) store did not alter the difference of the evoked [Ca(2+)](i) transient and decay time between young SHRs and Wistar-Kyoto rats. However, removing mitochondrial Ca(2+) buffering abolished these differences. A lower mitochondrial membrane potential was also observed in young SHR sympathetic neurons. This resulted in impaired mitochondrial Ca(2+) uptake and release, which might partly be responsible for the increased [Ca(2+)](i) transient and faster decay in SHR sympathetic neurons. This Ca(2+) phenotype seen in early development in cardiac stellate and superior cervical ganglion neurons may contribute to the sympathetic hyperresponsiveness that precedes the onset of hypertension. 相似文献
995.
996.
997.
Shimizu H Kimura F Yoshidome H Ohtsuka M Kato A Yoshitomi H Nozawa S Furukawa K Mitsuhashi N Takeuchi D Takayashiki T Suda K Miyazaki M 《Hepato-gastroenterology》2012,59(116):1023-1025
Interventional procedure via percutaneous transhepatic route is often performed, as an initial treatment, in patients with benign bilioenteric anastomotic stricture. However, surgical management is required in most cases in which radiological intervention is unsuccessful. In this report, we describe a case of a 67-year-old woman with recurrent bilioenteric anastomotic stricture, accompanying bilateral hepatolitiasis after several times of transhepatic interventions. The patient underwent intrahepatic cholangiojejunostomy (Longmire procedure) and cholangioscopic lithotomy after resection of an atrophic left lateral segment resulting from hepatolithiasis. Although the damaged hilar bile duct had to be isolated and divided from the corresponding vasculature for re-anastomosis, it was quite impossible due to severe inflammatory change at the hepatic hilus. We, therefore, anastomosed the intact biliary stump on the cut surface of the left lateral segment to the jejunal loop with a stent tube. The patient's postoperative course was uneventful and she exhibited no evidence of cholangitis during follow-up period of 1 year after surgery. At present, the indications for intrahepatic cholangiojejunostomy for biliary obstruction, are quite limited, but biliary surgeons should keep this procedure in mind at the time of biliary reconstruction for benign proximal bile duct stricture, particularly in cases of multiply operated hilum. 相似文献
998.
999.
Background/Aims: Abnormalities in cell cycle regulation are reported to be strongly associated with tumorigenesis and progression of tumors. Wnt/β-catenin signaling pathway and cell cycle play key roles during the genesis and development of hepatocellular carcinoma (HCC). Current studies indicated that expressions of cyclin A, E and D1 were affected after silencing of β-catenin gene in HCC, but it is unclear if other cyclins are affected. Methodology: To determine the relation, small interference RNA (siRNA) against β-catenin was transfected into HCC cell lines HepG2 and SMMC-7721, and cell cycle and cyclin B1 and cyclin C protein expression were detected. Results: Cell cycle was arrested in G0/G1 at 72h after transfection and the cell cycle began to transfer from G0/G1 to G2/M through S and had a trend to revert at 96h. In addition, β-catenin protein expression was decreased at both 72 and 96h, although the level was slightly higher at 96h than that at 72h. However, cyclin B1 expression decreased at 72h and increased at 96h, cyclin C expression increased at 72h and decreased at 96h. Conclusions: These findings suggest that silencing β-catenin gene may induce the changes of cell cycle and cyclin B1 and cyclin C protein expression. Wnt/β-catenin signaling pathway probably takes part in the genesis and development of HCC through regulating cell cycle and the expression of cyclin B1 and cyclin C. 相似文献
1000.
Angenete E Asplund D Bergström M Park PO 《International journal of colorectal disease》2012,27(5):665-670