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101.
In legal proceedings on the subject of occupational diseases concerning comparatively rare pneumoconioses, additional analyses such as energy dispersive x-ray microanalysis (EDX) and electron energy loss spectroscopy (EELS) offer decisive information for the pathologist in establishing causal connections between occupational exposure to hazardous substances, foreign particle deposits in lung tissue and pulmonary reaction patterns. Using the example of silver finisher's lung, dental technician's lung and talcosis, the connections between foreign particle deposits in lung tissue and granulomatous and fibrosing pulmonary changes are shown. 相似文献
102.
103.
Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression 总被引:17,自引:0,他引:17
Primary or acquired resistance to current treatment protocols remains a major concern in clinical oncology and may be caused by defects in apoptosis programs. Since recent data suggest that TRAIL can bypass apoptosis resistance caused by Bcl-2, we further investigated the role of Bcl-2 in TRAIL-induced apoptosis. Here we report that overexpression of Bcl-2 conferred protection against TRAIL in neuroblastoma, glioblastoma or breast carcinoma cell lines. Bcl-2 overexpression reduced TRAIL-induced cleavage of caspase-8 and Bid indicating that caspase-8 was activated upstream and also downstream of mitochondria in a feedback amplification loop. Importantly, Bcl-2 blocked cleavage of caspases-9, -7 and -3 into active subunits and cleavage of the caspase substrates DFF45 or PARP. Also, Bcl-2 blocked cleavage of XIAP and overexpression of XIAP conferred resistance against TRAIL indicating that apoptosis was also amplified through a feedforward loop between caspases and XIAP. In contrast, in SKW lymphoblastoid cells, TRAIL-induced activation of caspase-8 directly translated into full activation of caspases, cleavage of XIAP, DFF45 or PARP and apoptosis independent of Bcl-2 overexpression, although Bcl-2 similarly inhibited loss of mitochondrial membrane potential and the release of cytochrome c, AIF and Smac from mitochondria in all cell types. By demonstrating a cell type dependent regulation of the TRAIL signaling pathway at different level, e.g. by Bcl-2 and by XIAP, these findings may have important clinical implication. Thus, strategies targeting the molecular basis of resistance towards TRAIL may be necessary in some tumors for cancer therapy with TRAIL. 相似文献
104.
The clinical benefit of suicide gene therapy of tumors has been marginal, mostly due to the low gene transfer efficiency in vivo. The death-inducing ligand, TRAIL, effectively kills many tumor cell types, while sparing most normal tissues. We hypothesized that TRAIL may enhance HSV thymidine kinase/ganciclovir (TK/GCV) gene therapy of tumor cells by augmenting both target and bystander cell kill. Human SH-EP neuroblastoma cells expressing TK as well as bystander cells were effectively killed by apoptosis, and their clonogenicity was ablated following GCV. Human TRAIL enhanced TK/GCV-induced cell death and decreased clonogenicity of TK-expressing cells and also of bystander cells. Cooperation between TRAIL and TK/GCV depended both on caspase activation and on mitochondrial apoptogenic function because both the broad-spectrum caspase inhibitor zVAD.fmk and overexpression of Bcl-2 decreased enhancement of cell kill by TRAIL. Facilitation of TRAIL signalling by up-regulation of TRAIL receptors did not contribute to enhancement because cell surface expression of the agonistic TRAIL receptors 1 and 2 was not increased by TK/GCV. In conclusion, the concerted activation of caspases and the mitochondrial amplification of caspase activation by TK/GCV may explain the cooperative effect of TK/GCV and TRAIL on the kill of neuroblastoma cells. Because combined treatment also augmented the bystander cell kill, the addition of TRAIL may increase the efficacy of TK/GCV gene therapy of neuroblastoma. 相似文献
105.
Chemotherapy: targeting the mitochondrial cell death pathway 总被引:11,自引:0,他引:11
One of the mechanisms by which chemotherapeutics destroy cancer cells is by inducing apoptosis. Apoptosis can be activated through several different signalling pathways, but these all appear to converge at a single event - mitochondrial membrane permeabilization (MMP). This 'point-of-no-return' in the cell death program is a complex process that is regulated by the composition of the mitochondrial membrane and pre-mitochondrial signal-transduction events. MMP is subject to a complex regulation, and local alterations in the composition of mitochondrial membranes, as well as alterations in pre-mitochondrial signal-transducing events, can determine chemotherapy resistance in cancer cells. Detecting MMP might thus be useful for detecting chemotherapy responses in vivo. Several cytotoxic drugs induce MMP by a direct action on mitochondria. This type of agents can enforce death in cells in which upstream signals normally leading to apoptosis have been disabled. Cytotoxic components acting on mitochondria can specifically target proteins from the Bcl-2 family, the peripheral benzodiazepin receptor, or the adenine nucleotide translocase, and/or act by virtue of their physicochemical properties as steroid analogues, cationic ampholytes, redox-active compounds or photosensitizers. Some compounds acting on mitochondria can overcome the cytoprotective effect of Bcl-2-like proteins. Several agents which are already used in anti-cancer chemotherapy can induce MMP, and new drugs specifically designed to target mitochondria are being developed. 相似文献
106.
TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB 总被引:16,自引:0,他引:16
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in cancer cells. Examining primary cells of children with untreated acute leukemia, TRAIL induced apoptosis in 50% of cells, but to our surprise attenuated spontaneous apoptosis in the remaining samples or, most importantly, even mediated proliferation. We therefore examined tumor cell lines of leukemic and nonleukemic origin with apoptosis resistance towards TRAIL because of absent Caspase-8 or dysfunctional FADD. In all cell lines tested, TRAIL treatment increased cell numbers in average to 163% within 4 days and accelerated doubling time from 24 to 19 h. TRAIL-mediated proliferation was completely abrogated by blockade of NF-kappaB activation using proteasome inhibitors or in RIP-negative, IKKgamma-negative cells or in cells overexpressing dominant-negative IkappaBalpha. Our data describe the biological significance of TRAIL-mediated activation of NF-kappaB in cancer cells resistant to TRAIL-mediated apoptosis: TRAIL leads to an increase in tumor cell count by a prosurvival and possibly mitogenic function. Given the promising therapeutic potential of TRAIL as a novel anticancer drug, TRAIL-mediated survival or proliferation of target cells may restrict its use to apoptosis-sensitive tumors. 相似文献
107.
108.
Cario H Pahl HL Schwarz K Galm C Hoffmann M Burdelski M Kohne E Debatin KM 《British journal of haematology》2003,123(2):346-352
Polycythemia vera is a myeloproliferative disorder that, in most cases, occurs sporadically with a median age at presentation of 60 years. Familial cases are very rare and usually manifest in elderly family members. The Budd-Chiari syndrome, characterized by the obstruction and occlusion of the suprahepatic veins, is a rare typical complication in polycythemia vera patients. To date, only two children or adolescents with polycythemia vera and Budd-Chiari syndrome have been described. Here, we report an 11-year-old girl with Budd-Chiari syndrome as the initial symptom of familial polycythemia vera, which was also found in the girl's grandmother. Details of the diagnostic procedures used and the clinical course are reported. The patient underwent orthotopic liver transplantation and is being treated with hydroxyurea. The available literature on familial polycythemia vera and polycythemia vera in childhood with and without Budd-Chiari syndrome is reviewed. 相似文献
109.
Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases 总被引:4,自引:0,他引:4
Dorfmüller P Humbert M Perros F Sanchez O Simonneau G Müller KM Capron F 《Human pathology》2007,38(6):893-902
Pulmonary arterial hypertension is a severe complication of connective tissue diseases. It is currently well established that pulmonary arterial hypertension associated with connective tissue diseases such as systemic sclerosis is frequently less responsive or even refractory to pulmonary vasodilator therapies. In that setting, pulmonary venoocclusive disease is believed to contribute to treatment failures. We therefore hypothesized that pulmonary arterial hypertension associated with connective tissue diseases may be associated with obstructive lesions of pulmonary veins. Lung samples from 8 patients with pulmonary arterial hypertension associated with connective tissue disease (4 limited systemic sclerosis, 2 systemic lupus erythematosus, 1 mixed connective tissue diseases, and 1 rheumatoid arthritis) were studied by light microscopy and analyzed by immunohistochemistry (5 postmortem samples, 3 explants after lung transplantation). Findings were compared with 29 pulmonary arterial hypertension cases from patients displaying neither connective tissue diseases nor associated conditions. We found that (a) 6 (75%) of 8 patients with pulmonary arterial hypertension associated with connective tissue diseases showed significant obstructive pulmonary vascular lesions predominating in veins/preseptal venules, as compared with 5 (17.2%) of 29 non-connective tissue diseases control pulmonary arterial hypertension; (b) lesions of small muscular arteries were consistently present in pulmonary arterial hypertension associated with connective tissue diseases, showing mostly intimal fibrosis and thrombotic lesions; and (c) 6 of 8 lung samples from patients with pulmonary arterial hypertension associated with connective tissue diseases revealed perivascular inflammatory infiltration. In conclusion, our study highlights the fact that pulmonary arterial hypertension complicating the course of connective tissue diseases may be characterized by a more frequent involvement of pulmonary veins and may thus explain why these patients are less prone to respond to specific pulmonary arterial hypertension treatment as compared with idiopathic pulmonary arterial hypertension. 相似文献
110.