Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection with the human immunodeficiency virus (HIV) invariably leads to the development of acquired immunodeficiency syndrome (AIDS) in most infected humans, yet does so rarely, if at all, in HIV-infected chimpanzees. The differences between the two species are not due to differences in cellular receptors or an inability of the chimpanzee to be infected, but rather to the lack of pan-immune activation in the infected primate. This results in reduced apoptotic death in CD4+ T-helper lymphocytes and a lower viral load. In humans the degree of chronic immune activation correlates with virus load and clinical outcome with high immune activation leading to high viral loads and the more rapid progression to AIDS and death. The type of immune perturbation seen in HIV-associated AIDS is similar to that of chronic graft-versus-host disease (GVHD) where reduced cell-mediated immune (CMI) responses occur early in the course of the disease and where humoral responses (HI) predominate. A reduced CMI response occurs in a number of chronic infectious diseases, including tuberculosis and leishmaniasis. More recently, it has become increasingly apparent that the CMI response is suppressed in virtually all malignant diseases, including melanoma and colorectal and prostate cancer. This raises the possibility that, as the malignant process develops, the cancer cells evolve to subvert the CMI response. Moreover, the reduced CMI response seen in colorectal cancer (CRC) patients is completely reversed following curative surgery strongly supporting the hypothesis that CRC can suppress the systemic immune response. Wound healing, ovulation, embryo implantation, and fetal growth are all associated with suppressed CMI and neovascularization (the formation of new blood vessels) or angiogenesis (the formation of new blood vessels from an existing vasculature). If unresolved, wound healing results in chronic inflammation, which can give rise to the phenomenon of "scar cancers." Indeed all the chronic inflammatory conditions known to be associated with the subsequent development of malignant disease, including chronic obstructive airway disease (COPD), ulcerative colitis (UC), and asbestosis, give rise to similar proangiogenic, suppressed CMI, and HI-predominant environments. In keeping with this CMI-associated cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma tend to be antiangiogenic, whereas HI cytokines such as IL-6 tend to be proangiogenic. Furthermore, chronic immune activation leads to the synthesis and release of factors such as macrophage inflammatory protein (MIP)-1 that inhibit apoptosis through suppression of p53 activity. The "Golden Triangle" of suppressed CMI, angiogenesis, and reduced apoptosis would provide the ideal environment for the serial mutations to occur that are required for the development of malignant disease. If the observed association is relevant to carcinogenesis, then treatments aimed at reducing the components of these inflammatory conditions may be useful both in the setting of chemoprevention and the therapeutic management of established disease.
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PMID:Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. 1188 29

Infection of a human melanoma cell line by a retroviral vector resulted in transmission of a mouse VL30 (mVL30-1) retroelement RNA to some of the cells infected by the retrovirus, followed by synthesis, integration, and expression of the mVL30-1 cDNA. One vector carried a tissue factor (TF) transgene that generated high TF melanoma clones, and another vector was a control without the TF transgene that generated low TF clones. Some high TF melanoma clones contained the mVL30-1 retroelement and others did not, and some low TF melanoma clones contained the mVL30-1 retroelement and others did not. Each type of melanoma clone was tested for its metastatic potential in severe combined immunodeficient (SCID) mice, by i.v. injection of the cells to generate lung tumors. None of the low TF clones that either contained or lacked the mVL30-1 retroelement generated lung tumors, consistent with earlier results showing that high TF expression promoted metastasis. The high TF clones containing the mVL30-1 retroelement were strongly metastatic, in contrast to the high TF clones lacking the mVL30-1 retroelement, which were weakly metastatic. Southern hybridization analyses showed that the mVL30-1 cDNA integrated into different genomic sites in different melanoma clones, suggesting that the effect of the mVL30-1 retroelement on metastasis depends not on integration per se but instead on expression of the mVL30-1 RNA. A role for the mVL30-1 RNA in metastasis and possibly other cell functions is an unexpected finding, because the RNA appears to lack significant coding potential for a functional protein. The metastatic effect might be mediated directly by a noncoding mVL30-1 RNA or by a peptide or small protein encoded by one of the short ORFs in the mVL30-1 RNA.
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PMID:Retroviral-mediated transmission of a mouse VL30 RNA to human melanoma cells promotes metastasis in an immunodeficient mouse model. 1195 15

Subtraction hybridization identified melanoma differentiation-associated gene-7 (mda-7) as a gene induced during terminal differentiation in human melanoma cells. On the basis of structure, chromosomal localization and cytokine-like properties, mda-7 is classified as IL-24. Administration of mda-7/IL-24 by means of a replication-incompetent adenovirus (Ad.mda-7) induces apoptosis selectively in diverse human cancer cells without inducing harmful effects in normal fibroblast or epithelial cells. The present studies investigated the mechanism underlying this differential apoptotic effect. Infection of melanoma cells, but not normal immortal melanocytes, with Ad.mda-7 induced a time- and dose-dependent increase in expression, mRNA and protein, of a family of growth arrest and DNA damage (GADD)-inducible genes, which correlated with induction of apoptosis. Among the members of the GADD family of genes, GADD153, GADD45 alpha, and GADD34 displayed marked, and GADD45 gamma showed minimal induction. Treatment of melanoma cells with SB203580, a selective inhibitor of the p38 mitogen-activated protein kinase (MAPK) pathway, effectively inhibited Ad.mda-7-induced apoptosis. Additional support for an involvement of the p38 MAPK pathway in Ad.mda-7-mediated apoptosis was documented by using an adenovirus expressing a dominant negative mutant of p38 MAPK. Infection with Ad.mda-7 increased the phosphorylation of p38 MAPK and heat shock protein 27 in melanoma cells but not in normal immortal melanocytes. In addition, SB203580 effectively inhibited Ad.mda-7-mediated induction of the GADD family of genes in a time- and dose-dependent manner, and it effectively blocked Ad.mda-7-mediated down-regulation of the antiapoptotic protein BCL-2. Inhibition of GADD genes by an antisense approach either alone or in combination also effectively blocked Ad.mda-7-induced apoptosis in melanoma cells. These results support the hypothesis that Ad.mda-7 mediates induction of the GADD family of genes by means of the p38 MAPK pathway, thereby resulting in the selective induction of apoptosis in human melanoma cells.
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PMID:mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. 1211 39

Several systems have been tested for introduction of Ags into human dendritic cells (DC). Most of them to date, however, are complex and possess limited efficiency. Recent advances in HIV trans-activating (TAT) fusion protein technology permit extremely high transduction efficiencies for a majority of mammalian cell types. Here we report our attempts to develop a simple, but highly efficient, protocol for loading of antigenic protein into DC using TAT fusion technology. A TAT-minigene fusion protein was generated, encoding both the HLA-A2-restricted influenza matrix protein-derived epitope (GILVFTFTL, Flu-M1) and a melanoma Ag gp100-derived modified epitope (YLEPGPVTV, G9(280)-9V). In addition, both a TAT-Her2/neu extracellular domain (ECD) fusion protein and a TAT-green fluorescence protein fusion protein were generated. Over 95% of DC stained positively for TAT-green fluorescence protein within 20 min of coculture. DC treated with TAT-minigene were efficiently recognized by both Flu-M1 and G9(280)-9V-specific T cells in cytotoxicity assays and IFN-gamma ELISPOT assays. In contrast, DC pulsed with minigene fusion protein lacking TAT were either poorly recognized or not recognized by the T cells. DC pulsed with TAT-minigene also efficiently induced Flu-M1-specific T cells from naive lymphocytes. Similarly, DC treated with TAT-Her2/neu ECD stimulated patient-derived lymphocytes that specifically recognized Her2/neu(+) ovarian and breast cancer cell lines. The CTL induced by TAT-Her2/neu ECD-pulsed DC specifically recognized the Her2/neu ECD-derived immunogenic peptide E75 (KIFGSLAFL). Our data suggest that TAT fusion proteins efficiently transduce DC and induce Ag-specific T cells. This could prove to be a useful method for treatment of infectious diseases and cancer.
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PMID:Induction of antigen-specific CTL by recombinant HIV trans-activating fusion protein-pulsed human monocyte-derived dendritic cells. 1253 88

Human activity has contributed to climate change. The relationship between climate and child health has not been well investigated. This review discusses the role of climate change on child health and suggests 3 ways in which this relationship may manifest. First, environmental changes associated with anthropogenic greenhouse gases can lead to respiratory diseases, sunburn, melanoma, and immunosuppression. Second, climate change may directly cause heat stroke, drowning, gastrointestinal diseases, and psychosocial maldevelopment. Third, ecologic alterations triggered by climate change can increase rates of malnutrition, allergies and exposure to mycotoxins, vector-borne diseases (malaria, dengue, encephalitides, Lyme disease), and emerging infectious diseases. Further climate change is likely, given global industrial and political realities. Proactive and preventive physician action, research focused on the differential effects of climate change on subpopulations including children, and policy advocacy on the individual and federal levels could contain climate change and inform appropriate prevention and response.
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PMID:The impact of climate change on child health. 1254 Feb 54

Therapeutic cancer vaccination is based on the finding that tumors in both humans and experimental animals, such as mice, express potential immunological targets, some of which have high selectivity for cancer cells. In contrast to the successful vaccination against some infectious diseases, where most vaccines induce neutralizing antibodies that act prophylactically, the aim of therapeutic cancer vaccines is to treat established tumors (primarily micrometastases). Since most tumor-destructive immune responses are cell-mediated, therapeutic cancer vaccination needs to induce and expand such responses and also to overcome "escape" mechanisms that allow tumors to evade immunological destruction. Tumor antigens (as with other antigens) are presented by "professional" antigen-presenting cells, most notably dendritic cells (DC). Therefore DC that have been transfected or "pulsed" to present antigen provide a logical source of tumor vaccines, and some encouraging results have been obtained clinically as well as in preclinical models. An alternative and more physiological approach is to develop vaccines that deliver tumor antigen for in vivo uptake and presentation by the DC. Vaccines of the latter type include tumor cells that have been modified to produce certain lymphokines or express costimulatory molecules, as well as cDNAs, recombinant viruses, proteins, peptides and glycolipids which are often given together with an adjuvant. Several studies over the past 5 years have demonstrated dramatic therapeutic responses against established mouse tumors as a result of repeated injections of agonistic monoclonal antibodies (MAbs) to the costimulatory molecule CD137 (4-1BB). However, the clinical use of such MAbs may be problematic since they depress antibody formation, for example, to infectious agents. The alternative approach to transfect tumor cells to express the CD137 ligand (CD137L) increases their immunogenicity, but vaccination with tumor cells expressing CD137L is ineffective in several systems where injection of anti-CD137 MAb produces tumor regression. Recent findings indicate that a more effective way to engage CD137 towards tumor destruction is to transfect tumor cells to express a cell-bound form of anti-CD137 single-chain Fv fragments (scFv). Notably, tumors from melanoma K1735, growing either subcutaneously or in the lung, could be eradicated following vaccination with K1735 cells that expressed anti-CD137 scFv. This was in spite of the fact that K1735, as with many human neoplasms, expresses very low levels of MHC class I and has low immunogenicity. Similar results were subsequently obtained with other tumors of low immunogenicity, including sarcoma Ag104. We hypothesize that the concomitant expression of tumor antigen and anti-CD137 scFv effectively engages NK cells, monocytes and dendritic cells, as well as activated CD4(+) and CD8(+) T cells (all of which express CD137) so as to induce and expand a tumor-destructive Th1 response. While vaccines in the form of transfected tumor cells can be effective, at least in mouse models, the logical next step is to construct vaccines that combine genes that encode molecularly defined tumor antigens with a gene that encodes anti-CD137 scFv. Before planning any clinical trials, vaccines that engage CD137 via scFv need to be compared in demanding mouse models for efficacy and side effects with vaccines that are already being tested clinically, including transfected DC and tumor cells producing granulocyte-macrophage colony-stimulating factor.
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PMID:Therapeutic vaccination with tumor cells that engage CD137. 1260 23

Metastasis to the penis is an unusual event. Bladder and prostate tumors are the main sources of penile metastasis. Other sites include the rectosigmoid, kidney, and, less frequently, the pancreas, liver, nasopharynx, and lung. Other sources include malignant melanoma and Burkitt's lymphoma. The differential diagnosis includes idiopathic priapism, venereal or infectious disease, tuberculosis, Peyronie's disease, and primary penile tumor. Chondrosarcoma of the jaw is responsible for 10% of all chondrosarcomas that originate with craniofacial bones. Its behavior is usually characterized by local aggression; however, distant metastasis is uncommon. We report a case of chondrosarcoma of the jaw with penile metastasis. This is the first case described in published medical reports.
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PMID:Penile metastasis of chondrosarcoma of the jaw. 1267 May 83

Adoptive immunotherapy holds promise as a treatment for cancer and infectious diseases, but its development has been impeded by the lack of reproducible methods for generating therapeutic numbers of antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs). As a result, there are only limited reports of expansion of antigen-specific CTLs to the levels required for clinical therapy. To address this issue, artificial antigen-presenting cells (aAPCs) were made by coupling a soluble human leukocyte antigen-immunoglobulin fusion protein (HLA-Ig) and CD28-specific antibody to beads. HLA-Ig-based aAPCs were used to induce and expand CTLs specific for cytomegalovirus (CMV) or melanoma. aAPC-induced cultures showed robust antigen-specific CTL expansion over successive rounds of stimulation, resulting in the generation of clinically relevant antigen-specific CTLs that recognized endogenous antigen-major histocompatibility complex complexes presented on melanoma cells. These studies show the value of HLA-Ig-based aAPCs for reproducible expansion of disease-specific CTLs for clinical approaches to adoptive immunotherapy.
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PMID:Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells. 1270 85

Terminal differentiation and senescence share several common properties, including irreversible cessation of growth and changes in gene expression profiles. To identify molecules that converge in both processes, an overlapping pathway screening was employed that identified old-35, which is human polynucleotide phosphorylase (hPNPaseold-35), a 3',5'-exoribonuclease. We previously demonstrated that hPNPaseold-35 is a type I interferon-inducible gene that is also induced in senescent fibroblasts. In vitro RNA degradation assays confirmed its exoribonuclease properties, and overexpression of hPNPaseold-35 resulted in growth suppression in HO-1 human melanoma cells. The present study examined the molecular mechanism of the growth-arresting property of hPNPaseold-35. When overexpressed by means of a replication-incompetent adenoviral vector (Ad.hPNPaseold-35), hPNPaseold-35 inhibited cell growth in all cell lines tested. Analysis of cell cycle revealed that infection of HO-1 cells with Ad.hPNPaseold-35 resulted in arrest in the G1 phase and eventually apoptosis accompanied by marked reduction in the S phase. Infection with Ad.hPNPaseold-35 resulted in reduction in expression of the c-myc mRNA and Myc protein and modulated the expression of proteins regulating G1 checkpoint and apoptosis. In vitro mRNA degradation assays revealed that hPNPaseOLD-35 degraded c-myc mRNA. Overexpression of Myc partially but significantly protected HO-1 cells from Ad.hPNPaseold-35-induced growth arrest, indicating that Myc down-regulation might directly mediate the growth-inhibitory properties of Ad.hPNPaseold-35. Inhibition of hPNPaseold-35 by an antisense approach provided partial but significant protection against interferon-beta-mediated growth inhibition, thus demonstrating the biological significance of hPNPaseold-35 in interferon action.
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PMID:Down-regulation of Myc as a potential target for growth arrest induced by human polynucleotide phosphorylase (hPNPaseold-35) in human melanoma cells. 1272 1

There are currently over 150 medical centers worldwide enrolling patients in randomized, controlled Phase III clinical trials testing autologous cancer-derived heat-shock protein (HSP)-peptide complexes for the treatment of renal cell carcinoma and melanoma. In addition, autologous HSP-peptide complexes have been or are being tested in Phase I and II trials of chronic myelogenous leukemia, lymphoma and pancreatic, gastric and colorectal cancers. The door has more recently opened to clinical testing of off-the-shelf HSP-based treatments for infectious diseases. This review recounts the long history of basic research on HSPs in immune response. A keen understanding of how these ancient molecules orchestrate the immune response to cancer and infections has been gained, providing a clear rationale for translating this knowledge into clinical medicine.
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PMID:Vaccination with heat shock protein-peptide complexes: from basic science to clinical applications. 1290 2


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