Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in certain tumor cells. In addition, TRAIL and chemotherapy can act cooperatively, possibly as a result of chemotherapy-induced increases in expression of a TRAIL receptor, DR5. We used cell lines derived from a highly chemoresistant tumor, malignant mesothelioma, to learn whether TRAIL was effective alone or together with chemotherapy and whether cooperativity depended on increases in DR5 expression. TRAIL (codons 95-285) was expressed in a bacterial expression vector and purified by nickel affinity chromatography. TRAIL alone (25 to 500 ng/ml) had little effect on mesothelioma cells. TRAIL plus chemotherapy (doxorubicin, cis-platinum, etoposide, or gemcitabine) acted cooperatively to induce apoptosis in mesothelioma cells (M28, REN, VAMT, and MS-1). For example, in M28 cells treated for 18 h, apoptosis from TRAIL (100 ng/ml) plus doxorubicin (0.6 microg/ml; 71 +/- 11%) greatly exceeded that from TRAIL alone (21 +/- 8%) or from doxorubicin alone (6 +/- 2%) (means +/- standard deviation; P < 0.03). Mesothelioma cells treated with chemotherapy showed no change in DR5 protein by Western analysis or by immunocytochemistry. TRAIL plus chemotherapy was associated with an increase in mitochondrial cytochrome c release and mitochondrial depolarization. We conclude that TRAIL and chemotherapy act cooperatively to kill mesothelioma cell lines, not by increases in DR5 receptor but in association with mitochondrial amplification of apoptotic signals.
Am J Respir Cell Mol Biol 2001 Jul
PMID:Tumor necrosis factor-related apoptosis-inducing ligand and chemotherapy cooperate to induce apoptosis in mesothelioma cell lines. 1147 83

The National Cancer Institute is sponsoring a phase I clinical trial by the University of Pennsylvania involving administration of recombinant adenovirus containing the HSV-tk gene and subsequent tumor kill by ganciclovir, for the gene therapy of malignant mesothelioma. Twenty one patients have been enrolled into the trial.
Curr Opin Mol Ther 1999 Aug
PMID:Technology evaluation: gene therapy (mesothelioma), NCI. 1171 68

The aim of this study was to evaluate whether the presence of simian virus-40 (SV40) is associated with increased release of vascular endothelial growth factor (VEGF) in human malignant mesothelioma (MM) cells. We studied nine cell lines derived from pleural effusion (PE) of patients with MM, and three different cultures of normal human mesothelial cells (NHMC) derived from pleural fluid of patients with congestive heart failure. NHMC were transfected with full length SV40 (NHMC-FL) or large T antigen (NHMC Tag) DNAs. High levels of VEGF were detected in conditioned media of each of two MM cells that tested positive for SV40 by PCR amplification and Southern blot hybridization and for Tag transcript by reverse transcription- polymerase chain reaction (RT-PCR) and immunoprecipitation. We also found that NHMC-FL released high amounts of VEGF. Conditioned media from SV40-positive MM cells and from FL-NHMC increased proliferation of human umbilical vein cells (HUVEC) and this effect was partially abrogated by adding specific blocking antibodies against VEGF. These results offer the first evidence that SV40 can cause VEGF release in SV40-positive MM cells and that entire viral genome is required for this effect.
Am J Respir Cell Mol Biol 2002 Feb
PMID:The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular endothelial growth factor. 1180 65

Differentiating reactive mesothelial cells from malignant mesotheliomas and from adenocarcinomas can be diagnostically challenging when based solely on the morphologic examination of serous fluids. The diagnosis even after the use of standard immunohistochemical stains may at times be inconclusive because of the variable reactivity of mesothelial cells for these markers. Pathologists and cytologists underutilize reactivity for desmin, a feature of mesothelial cells apparently not shared by adenocarcinomas. The purpose of this study was to evaluate the extent to which mesothelial cells express muscle differentiation and to assess the diagnostic utility of muscle markers in distinguishing reactive mesothelial cells from malignant mesotheliomas and adenocarcinomas. Archival paraffin-embedded cell blocks of serous fluids from 24 cases of reactive mesothelial cells, 14 cases of malignant mesothelioma, and 56 cases (14 cases from each) of metastatic adenocarcinoma from the lung, breast, ovary, and gastrointestinal tract were retrieved. Five cases of omentum with unremarkable mesothelial cells were also included in the study. All cases were stained for desmin, actin, myoglobin, and myogenin and evaluated independently by two observers. Strong cytoplasmic reactivity for desmin was noted in 22 of 24 cases (92%) of reactive mesothelial cells. The reactive mesothelial cells did not express actin, myoglobin, or myogenin. All cases of malignant mesothelioma and metastatic adenocarcinoma were negative for the four muscle markers. The mesothelial lining and scattered subserosal cells in the omental sections were positive for desmin. Because desmin was expressed only in benign mesothelial cells, it may serve as a reliable marker in distinguishing reactive mesothelial cells from mesothelioma or from adenocarcinoma. Awareness of this staining pattern is also important to avoid pitfalls when evaluating body fluid specimens from patients with a history of tumors expressing muscle differentiation.
Appl Immunohistochem Mol Morphol 2002 Jun
PMID:Diagnostic use of muscle markers in the cytologic evaluation of serous fluids. 1205 38

One promising therapeutic approach to intracavitary tumors, such as malignant mesothelioma and ovarian cancer, is immuno-gene therapy. In a previous study, intraperitoneal (i.p.) instillation of an adenoviral vector encoding the mouse interferon-beta gene (Ad.muIFN-beta) was shown to eradicate established mesothelioma tumors in the peritoneal cavity of immune competent, but not immunodeficient mice. The goal of this study was to understand more completely the kinetics and mechanisms of this immune-mediated response. Two days after a single intraperitoneal (i.p.) injection of Ad.muIFN-beta into BALB/c mice with established tumors, the response in the peritoneum was characterized by an influx of activated natural killer (NK) cells, polymorphonuclear (PMN) cells, and macrophages with minimal infiltration into the tumor nodules. However, depletion of PMN or NK cells after Ad.IFN-beta treatment had only minimal effects. At later time points (up to 10 days after Ad.IFN-beta i.p.), a large influx of CD4(+) and activated CD8(+) T cells was present in the peritoneal fluid and within the tumor nodules. The CD8(+) T cells had cytolytic activity, and adoptive transfer of peritoneal exudate cells (obtained by peritoneal lavage) resulted in effective tumor cell killing. Antitumor effects of Ad.IFN-beta may be different in different tumor types or in different anatomic locations. However, these results demonstrate that tumor-specific CD4(+) and CD8(+) T cells are the key effector cells for tumor eradication in this model.
Mol Ther 2002 Aug
PMID:Analysis of the immunologic response generated by Ad.IFN-beta during successful intraperitoneal tumor gene therapy. 1216 Nov 87

Besides acting complexly on both normal and tumor cells, transforming growth factor-beta (TGF-beta) can determine the nature of the response to the antigen, strongly inhibiting the differentiation of naive CD4+ T-cells toward a T helper-1 (Th-1) phenotype; in a number of experimental models, TGF-beta also appeared to be a potent immunosuppressant factor. TGF-beta was shown to be released by some human malignant mesothelioma (MMe) cells, which affects the immune response to this tumor. Thus, for a better understanding of the role of TGF-beta in the immune response to MMe cells, we evaluated the production of a Th-1 cytokine (IFN-gamma) and of a Th-2 cytokine (IL-4), following Purified Protein Derivative (PPD) recall antigen presentation by human MMe cells to a class-II major histocompatibility complex (MHC-II)-matched PPD clone (PPD clone). Our data confirm that human MMe cells possess the unusual capability of presenting a common recall antigen to CD4+ lymphocytes but also show that these tumor cells can abrogate Th-1 immune response, as evidenced by a shift in favor of the production of IL-4 over that of IFN-gamma, through a TGF-beta-mediated pathway; only the simultaneous block of TGF-beta1 and beta2 effects can significantly restore a typical Th-1 pattern of cytokine production by PPD clone in response to PPD presentation by MMe. Even though the role of TGF-beta in the promotion of MMe growth should be further and better defined, this effect should be considered when designing new therapeutical approaches aimed at improving the immune response to MMe.
Int J Mol Med 2003 Feb
PMID:Transforming growth factor-beta released by PPD-presenting malignant mesothelioma cells inhibits interferon-gamma synthesis by an anti-PPD CD4+ T-cell clone. 1252 71

The presence of c-Kit immunoreactivity in gastrointestinal stromal tumor (GIST), currently guides treatment with the selective c-Kit inhibitor STI571 (or Gleevec) in clinical trials and establishes a precedent of immunohistochemistry-guided treatment decisions. Thus, the optimization of detection conditions for c-Kit and the determination of its incidence in other malignancies have clinical bearing. Aims of our study were: 1) to determine the incidence of c-Kit expression in formalin-fixed paraffin-embedded tissue (FFPE) in pulmonary small cell carcinoma (SCC) and non small cell carcinoma (NSCC), pulmonary carcinoid, and malignant mesothelioma (MM); and 2) to test the feasibility of c-Kit determination using commercially available antibodies and routine immunohistochemical settings, comparing the performance of two commercially available antibodies, Dako and Santa Cruz. The Dako antibody detected positive stain in 10/22 SCC, 3/8 carcinoids, 1/57 NSCC (1/30 adenocarcinomas, 0/24 squamous cell carcinomas, 0/3 large cell undifferentiated carcinomas), and 7/33 MM. The Santa Cruz antibody detected c-kit in 8/22 SCC, 0/57 NSCC, 1/8 carcinoids, and 0/33 MM. HIER increased the performance of both antibodies. We conclude that c-Kit can routinely be detected in FFPE tissue with commercially available antibodies, and that the Dako anti-c-Kit has a higher sensitivity than the Santa Cruz antibody. C-Kit expression is common in SCC and carcinoids, very rare in NSCC, and infrequent in MM. The frequent c-Kit expression in SCC highlights that this molecule plays an important role in the biology of this malignancy, and that it could be targeted in subsets of patients for therapy with c-Kit inhibitors.
Appl Immunohistochem Mol Morphol 2003 Mar
PMID:Immunohistochemistry frequently detects c-Kit expression in pulmonary small cell carcinoma and may help select clinical subsets for a novel form of chemotherapy. 1261 Mar 57

The epidemiologic association between asbestos exposure and human malignant mesothelioma is well established. However, the molecular mechanisms linking asbestos exposure of humans and the subsequent mesothelioma formation is not well understood. The most frequent genetic changes found so far in human malignant mesothelioma (HMM) are deletions and point mutations in the tumor suppressor genes p16INK4a and NF2. Whereas homozygous deletions appear to be the predominant mechanism leading to p16/CDKN2A inactivation, inactivating point mutations coupled with allelic loss mainly occur at the NF2 locus. In the present study, asbestos-treated human mesothelial cells (HMC), SV40-transformed human mesothelial cells (MeT-5A) and a human mesothelioma cell line (COLO) were investigated for genetic changes of cell cycle genes (cyclin D1, p16INK4a, RB1, CDK2) using multicolor fluorescence in situ hybridization (mFISH) in interphase cells. The results show that cyclin D1 is unaffected in all investigated cells. The p16INK4a gene locus was shown to be mutated in COLO cells but not in HMC. After labeling of CDK2 and RB1, hemizygous loss of one allele of each gene was observed in asbestos-treated HMC whereas gene amplification of these genes was detectable in MeT-5A and COLO cells. Our data indicate that disarrangement of the RB1 dependent pathway seems to be involved in mesothelioma formation.
Cell Mol Biol (Noisy-le-grand) 2002
PMID:Interphase fish analysis of cell cycle genes in asbestos-treated human mesothelial cells (HMC), SV40-transformed HMC (MeT-5A) and mesothelioma cells (COLO). 1264 44

Gene delivery of CD40 Ligand (CD40L) has shown promise in murine models of melanoma and adenocarcinoma; however, its potential for thoracic malignancies such as malignant mesothelioma remains unclear. In this study, we investigated the hypothesis that CD40L gene therapy would be effective in local and distant tumor suppression in mesothelioma using an immunocompetent murine model. Using a recombinant adenovirus encoding murine CD40L (AdCD40L), we demonstrated no suppression of in vitro cell growth for the AC29 (mesothelioma) cell line. However, inoculation of immunocompetent CBA/J mice with AC29 cells treated ex vivo with AdCD40L resulted in significant suppression of tumor formation in vivo when compared with controls (P < 0.001). Intratumoral inoculation of AdCD40L into previously established AC29 tumors yielded similar antitumor results and was associated with increased recruitment of intratumoral CD8+ T cells. Adoptive transfer of CD8+ T cells from AdCD40L-treated tumor bearing mice conferred protection to naive mice given an AC29 tumor challenge. Finally, in mice with two synchronous tumors, treatment of one of the tumors with AdCD40L resulted in a regression of both tumors. These findings demonstrate the development of tumor specific CD8+ T cells by AdCD40L and support the further development of AdCD40L for the treatment of malignant mesothelioma.
Am J Respir Cell Mol Biol 2003 Sep
PMID:Efficacy of CD40 ligand gene therapy in malignant mesothelioma. 1267 4

Asbestos fibers are biopersistent particles that are capable of stimulating chronic inflammatory responses in the pleura of exposed individuals. Exposure of pleural mesothelial cells, the progenitor cell of malignant mesothelioma, to asbestos induces an array of cellular responses. The present studies investigated whether the p38 mitogen-activated protein kinase cascade was induced under asbestos-exposed conditions. p38 plays a vital role in the response to stressful stimuli and enables the cell to enter an inflammatory state characterized by cytokine production. Western blot and in vitro kinase assays showed increases in dual phosphorylation and actual activity of p38 after exposure to fibrous and nonfibrous (milled) crocidolite; in contrast, polystyrene beads and iron (III) oxide had no such effects. In common with other asbestos-induced events, this was shown to be an oxidative stress-sensitive effect, inasmuch as preincubation with N-acetyl-L-cysteine or -tocopherol (vitamin E) ameliorated the effect. The present studies show that p38 activity is important for crocidolite-induced activator protein-1 DNA binding, inasmuch as an inhibitor of p38, SB-203580, reduced this activity. Crocidolite-induced cytotoxicity was also reduced with SB-203580, indicating a role for p38 in asbestos-mediated cell death. Our studies suggest that p38 activity could be a crucial factor in the chronic immune response elicited by asbestos and may represent a target for future pharmacological intervention.
Am J Physiol Lung Cell Mol Physiol 2004 Apr
PMID:Activation of p38 MAP kinase by asbestos in rat mesothelial cells is mediated by oxidative stress. 1461 14


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