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Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome. Seven patients received transplants without conditioning from HLA-matched family donors (MFDs); the other 8 patients received conditioning and were given transplants either from HLA-mismatched family donors (MMFDs; n = 6) or from matched unrelated donors (MUDs; n = 2). At a mean follow-up period of 12 years (range, 4-22 years), 12 patients are alive with stable and complete immune reconstitution (7 of 7 after MFD, 4 of 6 after MMFD, and 1 of 2 after MUD transplantation). Six of 12 surviving patients show marked neurologic abnormalities, which include mental retardation, motor dysfunction, and sensorineural hearing deficit. We were unable to identify disease or transplantation-related factors correlating with this divergent neurologic outcome. The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease.  相似文献   
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BACKGROUND: There is mounting evidence in the literature that resveratrol is a promising natural compound for prevention and treatment of a variety of human cancers. This overview summarizes recent studies of the major apoptosis and survival pathways regulated by resveratrol. BIOLOGICAL MECHANISMS: Apoptosis or programmed cell death is a key regulator of tissue homeostasis during normal development and also in adult organism under various conditions including adaptive responses to cellular stress. For example, tissue homeostasis is maintained by tight control of signaling events regulating cell death and survival. Thus, uncontrolled proliferation or failure to undergo cell death is involved in pathogenesis and progression of many human diseases, for example in tumorigenesis or in cardiovascular disorders. Moreover, current cancer therapies primarily act by triggering apoptosis programs in cancer cells. THERAPEUTIC APPLICATIONS: Natural products such as resveratrol have gained considerable attention as cancer chemopreventive or cardioprotective agents and also because of their antitumor properties. Among its wide range of biological activities, resveratrol has been reported to interfere with many intracellular signaling pathways, which regulate cell survival or apoptosis. DISCUSSION: Further insights into the signaling network and interaction points modulated by resveratrol may provide the basis for novel drug discovery programs to exploit resveratrol for the prevention and treatment of human diseases.  相似文献   
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Death receptors in chemotherapy and cancer   总被引:18,自引:0,他引:18  
Debatin KM  Krammer PH 《Oncogene》2004,23(16):2950-2966
Apoptosis, the cell's intrinsic death program, is a key regulator of tissue homeostasis. An imbalance between cell death and proliferation may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies such as chemotherapy, gamma-irradiation or ligation of death receptors is predominantly mediated by triggering apoptosis in target cells. In addition to the intrinsic mitochondrial pathway, elements of death receptor signaling pathways have been implied to contribute to the efficacy of cancer therapy. Failure to undergo apoptosis in response to anticancer therapy may lead to resistance. Also, deregulated expression of death receptor pathway molecules may contribute to tumorigenesis and tumor escape from endogenous growth control. Understanding the molecular events that regulate apoptosis induced by anticancer therapy and how cancer cells evade apoptosis may provide new opportunities for pathway-based rational therapy and for drug development.  相似文献   
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BACKGROUND AND OBJECTIVES: Whether von Willebrand factor (vWf) is variably expressed by endothelial cells (EC) of the human vascular tree or not is not known. Studies on animals showed that the varying degrees of vWf expression in pulmonary vessels was a reflection of EC heterogeneity. Neither the influence of age or sex nor that of pathophysiological factors such as pulmonary hypertension (PH) on vWf expression has been systematically analysed up to now. However, such information is essential for the design and delivery of site-selective drugs and genes as well as for the analysis of EC culture systems. METHODS: The variable degrees of vWf expression in lung tissue specimens from 64 patients (age: 6 weeks to 86 years) with and without PH were studied immunohistochemically and analysed statistically. RESULTS: CD31-specific antibody was used as a control stain for EC. It produced equally strong staining reactions in all pulmonary EC. In contrast, vWf-specific antibody yielded negative or weakly positive staining reactions in capillary EC. The staining intensities increased hand in hand with vessel calibres. Besides, they increased statistically significantly with age and PH. Sex had no influence on vWf expression. CONCLUSION: These findings show that (1) vWf expression by pulmonary EC is heterogeneous and specific for individual types of vessels, (2) age and PH enhance vWf expression, (3) vWf expression is indicative of altered EC activation but not of EC defects, and (4) elevated plasma levels of vWf correlate positively with raised coagulatory activities in older patients and in patients with PH.  相似文献   
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Hyperuricemia is part of the "metabolic syndrome". The aim of this study was to investigate the regulation and role of serum uric acid in the cardiovascular risk factor profile of obese children and adolescents. Serum levels of uric acid and selected risk factors and hormones were determined in 269 children aged 10.0-15.9 years with a BMI >90th percentile (mean 24.0 kg/m2, SD 5.43). Stepwise regression adjusted for age and sex revealed that testosterone (p < 0.0001), BMI (p < 0.0001), systolic blood pressure (p < 0.0017), triglycerides (p < 0.0345) and cholesterol/HDL ratio (p < 0.0393) were positively correlated with serum uric acid and accounted for 42.1% of the variance. Additional regression models with the same set of variables indicated that uric acid contributed significantly to levels of cholesterol/HDL, total cholesterol, BMI and systolic blood pressure, respectively. These results suggest a not yet described impact of androgens in the regulation of serum uric acid in obese children and adolescents. Furthermore, they show that uric acid is a reliable indicator for the "pre-metabolic syndrome" in obese youths.  相似文献   
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Stomatin is a widely distributed 32kD membrane protein of unknown function. In biochemical studies it is associated with cholesterol+sphingomyelin-rich 'rafts' in the cytomembrane. Genetic studies in C. elegans, supported by microscopic studies in mammalian tissue and co-expression studies in oocytes, suggest a functional link with the DEG/ENaC (degenerin/epithelial Na+ channel) superfamily of monovalent ion channels. Since ENaC channels play a prominent role in the physiology of the respiratory epithelium, we have studied the immunolocalization of stomatin in mature and developing human airway epithelium by means of Western blot analysis, immunocytochemistry, and immunoelectron microscopy. Stomatin immunoreactivity (stomatin-IR) was found in the ciliated cells of the conductive airway epithelium in a distinct distribution pattern with the strongest signal along the cilia. Immunogold labelling revealed immunogold particles at the basal bodies, along the cilia, and at the membrane of the microvilli. The presence of stomatin-IR paralleled the stages of ciliogenesis in airway development, and its appearance preceded the elongation of the axoneme and the cilial outgrowth. Due to its presence in the different cellular locations in the ciliated cell, we suggest that stomatin is involved in various cellular functions. From its ultrastructural position, stomatin could be a candidate for a membrane-associated mechanotransducer with a role in the control of ciliary motility. Stomatin as a raft protein might be a microtubule associated protein moving along the outer surface of the microtubules to its terminal site of action in the cilia. Stomatin-IR in microvilli supports the hypothesis of a co-localization with beta- and gamma- ENaC and, in conclusion, their potential functional interaction to control the composition of periciliary mucus electrolytes.  相似文献   
50.
Apoptosis, the cell's intrinsic death program, is a key regulator of tissue homeostasis. An imbalance between cell death and proliferation may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies, such as chemotherapy, gamma-irradiation or ligation of death receptors is predominantly mediated by triggering apoptosis in target cells. Death receptor signaling pathways have been implied to contribute to the efficacy of cancer therapy. Failure to undergo apoptosis in response to anticancer therapy may lead to resistance. Understanding the molecular events that regulate apoptosis induced by anticancer therapy and how cancer cells evade apoptosis may provide new opportunities for drug development. Thus, novel strategies targeting tumor cell resistance will be based on insights into the molecular mechanisms of cell death.  相似文献   
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