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: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pigmented actinic keratosis is one of the simulators of early melanoma in situ from severely sun-damaged skin. Close scrutiny of the hematoxylin and eosin stained section does not always allow an unequivocal diagnosis, because it is sometimes difficult to distinguish pigmented keratinocytes from melanocytes. Immunohistochemical stains, such as S-100 and HMB-45, are used routinely to address this problem. Melan-A, also known as MART-1, is an additional melanocytic marker and has proved to be useful in identifying metastatic tumors of melanocytic origin. The usefulness of this marker to discriminate pigmented actinic keratosis from early melanoma in situ, however, has not yet been a subject of investigation. In this study we evaluated Melan-A expression in ten unequivocal cases of pigmented actinic keratosis and compared the staining pattern with that of S-100, HMB-45, and tyrosinase. In all ten cases the number of cells highlighted with Melan-A was by far larger than those labeled with S-100, HMB-45, and tyrosinase. Four cases showed clusters of Melan-A positive cells being suggestive of melanocytic nests. Even areas of normal skin adjacent to the actinic keratosis featured prominent staining of Melan-A, but only inconsistent labeling of intraepidermal melanocytes with S-100, HMB-45, and tyrosinase. We therefore believe that Melan-A is a more sensitive marker for intraepidermal melanocytes than S-100, HMB-45, and tyrosinase. In addition there may be expression of Melan-A in keratinocytes and nonmelanocytic cells. To avoid an erroneous diagnosis of malignant melanoma one should therefore interpret results obtained from Melan-A stained slides carefully and in the context with other melanocytic markers.
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PMID:Melan-A: not a helpful marker in distinction between melanoma in situ on sun-damaged skin and pigmented actinic keratosis. 1536 66

To improve diagnostic accuracy, a number of novel techniques have been developed to assist in the evaluation of melanocytic tumours. Dematologists have begun to explore the use of new instruments, such as dermoscopy or confocal scanning laser microscopy, in their clinical assessment of pigmented lesions. They have also benefited from advances in digital photography and applied this technique to monitor patients with numerous atypical naevi. Likewise, the diagnostic armamentarium of pathologists has been enriched over the past decade. A number of new reagents have become available for immunohistochemical analysis of melanocytes in archival material, such as antibodies to tyrosinase, Melan-A/Mart-1, micropthalmia-associated transcription factor and PNL2. These markers have allowed improvements in the sensitivity and specificity in the diagnosis of melanoma and its distinction from histological mimics. However, some pitfalls in the use of various reagents have also become apparent. Most recently, molecular techniques are being explored for their potential use in the diagnosis of melanoma. In this review, various modalities are discussed with regard to their application in the evaluation of melanocytic neoplasms.
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PMID:The use and application of special techniques in assessing melanocytic tumours. 1537 Jan 17

We report a case of an unusual basomelanocytic tumor from the scalp of a 56-year-old man. A 56-year-old white man presented with a scalp lesion that was biopsied and interpreted as a basal cell carcinoma. Fourteen months later, metastatic melanoma was discovered in a cervical lymph node and the liver. A subsequent biopsy from the area of the previously biopsied basal cell carcinoma of the scalp showed an invasive malignant melanoma. Immunohistochemical stains performed on the original scalp specimen showed biphasic immunohistochemical profile. A population of neoplastic cells was strongly positive for the melanocytic markers Melan-A, HMB-45, and tyrosinase and showed weak focal immunoreactivity for S-100. A second population of cells was strongly immunoreactive for keratin (wide-spectrum polyclonal antibody) and BerEp4. To our knowledge, this is the first description of a malignant basomelanocytic tumor complicated by metastatic melanoma.
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PMID:Malignant basomelanocytic tumor manifesting as metastatic melanoma. 1537 58

Dendritic cells (DCs) show promise as adjuvants in anticancer immunotherapeutic strategies. Flt3 ligand (FL) is a hematopoietic growth factor that increases the number of immature DCs in the blood and other tissues. We treated 27 patients with metastatic or high-risk resected melanoma with s.c. FL daily for 14 d in three 28 d cycles. Eighteen of these patients also received vaccination with influenza (Flu), Melan-A (Mel), tyrosinase (Tyr), and NY-ESO-1 peptides. To induce local DC maturation, 8 of the vaccinated patients had imiquimod, a Toll-like receptor-7 ligand (TLR7L), applied topically to their vaccine sites. Patients were monitored for clinical and hematological effects. Immune responses were assessed by cutaneous reactivity to vaccination and by the induction of peptide-specific CD8+ T-cells. Eight patients did not complete the protocol due to adverse events related to their cancer. The treatment was generally safe and well tolerated, although some patients developed clinically significant toxicities related to FL. FL induced increases in immature CD11c+ and CD123+ peripheral blood (PB) DCs. Other hematological effects included monocytosis, granulocytosis, and thrombocytosis, which were marked in some patients. Cutaneous reactions to peptide vaccination and circulating peptide-specific CD8+ T-cells were more frequent in imiquimod-treated patients. FL treatment of melanoma patients has pleiotropic clinical and hematological effects. In vivo maturation of FL-generated DCs using imiquimod may increase immune responses to tumor antigens.
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PMID:The impact of imiquimod, a Toll-like receptor-7 ligand (TLR7L), on the immunogenicity of melanoma peptide vaccination with adjuvant Flt3 ligand. 1538 29

Great attention has been recently given to a flavonoid of the anthocyanin class, cyanidin-3-O-beta-glucopyranoside (C-3-G), which is widely spread throughout the plant kingdom, and is present in both fruits and vegetables of human diets. In this study, we investigated the effect of C-3-G on proliferation and differentiation of human melanoma cells. Both morphological and functional parameters were evaluated, using electron and confocal microscopy, cytofluorometric analysis, HPLC assay, Western blot analysis, and enzymatic assay, as appropriate. A treatment with a single dose of C-3-G decreased cell proliferation without affecting cell viability and without inducing apoptosis or necrosis. The mitotic index and cell percentage in S phase were significantly lower in C-3-G treated cells compared with untreated control. C-3-G treatment induced, in a dose- and time-dependent manner, melanoma cell differentiation characterized by a strong increase in dendrite outgrowth accompanied with a remodeling of the microtubular network, a dramatic increase of focal adhesion and an increased expression of "brain specific" cytoskeletal components such as NF-160 and NF-200 neurofilament proteins. C-3-G treatment also induced increase of cAMP levels and up-regulation of tyrosinase expression and activity resulting in an enhanced melanin synthesis and melanosome maturation. Up-regulation of the melanoma differentiation antigen Melan-A/MART-1 in treated cells respect to the untreated control was also recorded. Data obtained provide evidence that a single treatment with C-3-G is able to revert the human melanoma cells from the proliferating to the differentiated state. We conclude that C-3-G is a very promising molecule to include in the strategies for treatment of melanoma; also because of its nutritional relevance.
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PMID:Differentiation of human melanoma cells induced by cyanidin-3-O-beta-glucopyranoside. 1545 88

Hermansky-Pudlak Syndrome-type 3 (HPS-3) is a relatively mild subtype of HPS with minimal cutaneous and ocular depigmentation. The HPS-3 gene encodes a novel protein of unknown function with a predicted molecular weight of 114 kd. To assess the role of the HPS3 protein in melanization, cultured melanocytes developed from HPS-3 patients were evaluated biochemically and histologically for activity and localization of melanocyte-specific proteins. Endogenous tyrosinase activity of HPS-3 melanocytes was substantial, but tyrosinase activity and melanin synthesis was suppressed in intact melanocytes. However, the level of suppression, as well as extent to which up-regulation by isobutylmethylxanthine and cholera toxin was muted, was less that in HPS-1 melanocytes. Ultrastructurally, HPS-3 melanocytes contained morphologically normal melanosomes, predominantly of stage I and II with minimal stage III and few stage IV melanosomes. Dihydroxyphenylalanine (DOPA) histochemistry demonstrated an increase in melanization of melanosomes. Unique to HPS-3 melanocytes were numerous DOPA-positive 50-nm vesicles and tubular elements present throughout the cell body and dendrites. Tyrosinase, tyrosinase-related protein-1 (Tyrp1), dopachrome tautomerase (Dct), and LAMP1 and 3 localization in HPS-3 melanocytes, as evaluated by immunocytochemistry and confocal microscopy, demonstrated a fine, floccular distribution in contrast to the coarse, granular distribution characteristic of control melanocytes. The localization profile of other proteins expressed by melanocytes (ie, Silver/Pmel17, Melan-A/MART-1, LAMP2, Rab 27, transferrin, c-kit, adaptin-3, and the HPS1 protein) appeared normal. These results suggest that a specific subset of melanocyte proteins are aberrantly trafficked throughout the HPS-3 melanocyte and may be responsible for the reduction in melanin synthesis.
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PMID:Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrome-type 3. 1563 15

Heat shock has been shown to have pleiotropic effects on tumor physiology besides a direct cytotoxic effect. In the present study, we address the question whether heat shock treatment has an impact on the antigenicity of human melanoma cells and their specific recognition by cytotoxic lymphocytes. The heat shock response was induced by treating the cells with two different thermal isoeffect doses, which resulted in equivalent clonogenic survival, mimicking doses achieved during clinical hyperthermia treatment of tumors. Antigen expression and immune recognition by cytotoxic T cells was studied using the human melanoma cell lines 624.38-MEL, SK-MEL23, WM115 and WM266-4, which naturally express, process and present tyrosinase and Melan-A/melanoma antigen recognized by T cells (MART)-1-derived peptides in the context of HLA-A2 molecules. We demonstrate that during the heat shock response following the two thermal doses, heat shock protein 70 (Mr 72 kDa) (HSP70) was induced with differential kinetics; tyrosinase protein and mRNA levels dissociated with a significant increase in tyrosinase protein and a decrease in transcript levels. A similar dissociation was not observed for Melan-A/MART-1. Furthermore, tyrosinase-specific T-cell recognition did not correlate with changes in HSP70 and antigen protein levels. These results suggest that caution has to be taken when considering protein levels as a marker for the antigenic status of a tumor. Moreover, these results document the maintenance of immunological homeostasis during recovery from heat treatment, thus challenging the view that tumor cells subjected to heat shock become resistant to CTL recognition.
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PMID:Melanoma-associated antigen tyrosinase but not Melan-A/MART-1 expression and presentation dissociate during the heat shock response. 1564 53

Human melanomas can express unique tumor antigens, resulting from mutated proteins, and shared epitopes encoded for by normal genes, but these two classes of antigens have not been previously compared for immunogenicity and retention in metastatic cells. Here, we identified a new unique antigen generated by a point mutation in the peroxiredoxin 5 (Prdx5) gene in an HLA-A*0201(+) human metastatic melanoma lacking the wild-type allele. An antioxidant assay, with recombinant Prdx5 proteins, and evaluation of peroxide accumulation in transiently transfected cells, indicated that the mutant protein retained its enzymatic activity. The mutation in the Prdx5 protein did not generate a new HLA agretope but yielded an HLA-A*0201-restricted T cell epitope (Prdx5(110-119)). By HLA-tetramer analysis, in a tumor-invaded lymph node, >50% of mutant Prdx5-specific CD8(+) T cells (frequency 0.37%/CD8(+)) showed a CCR7(+/-) CD45RA(-) "T(CM)" or "T(EM)" phenotype, as found in Melan-A/MART-1-specific T cells (frequency 0.68%/CD8(+)) in the same tissue. In agreement with their memory phenotype, the Prdx5-specific T cells readily expanded in vitro in mixed lymphocyte-tumor culture, as did the Melan-/MART-1-specific T cells. By immunohistochemistry of the invaded lymph node, the mutant Prdx5 protein was expressed in all neoplastic cells, in contrast with the heterogeneous expression of shared antigens as Melan-A/MART-1, gp100 and tyrosinase. Thus, a unique tumor antigen can be as immunogenic as the melanoma differentiation antigens but, in contrast to the latter, may be retained in all metastatic cells possibly as result of the relevant cellular function exerted by the mutated protein.
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PMID:Immunogenicity without immunoselection: a mutant but functional antioxidant enzyme retained in a human metastatic melanoma and targeted by CD8(+) T cells with a memory phenotype. 1569 8

PNL2 is a novel monoclonal antibody, which has recently been introduced as an immunohistochemical reagent to stain melanocyte and tumors derived thereof. In the present study, we analyzed the immunoreactivity of this mAb in various normal tissues, melanocytic nevi, primary and metastatic melanoma, nonmelanocytic tumors, including histologic mimickers of melanoma as well as angiomyolipoma, and multiple cell lines derived from different tumors types. We used several tissue microarray panels as well as selected conventional sections from tissue blocks. For metastatic melanoma, immunoreactivity for PNL2 was compared with A103 (Melan-A/MART-1), T311 (tyrosinase), HMB45 (gp100), and D5 (MITF). Positive staining with PNL2 was found in normal melanocytes and neutrophils, but no other normal cell type. Among melanocytic lesions, both benign nevi as well as primary malignant melanomas, especially epithelioid variants thereof, were commonly immunopositive. Only 1 of 13 desmoplastic melanomas reacted with PNL2. PNL2 showed high sensitivity for metastatic melanoma (87%). In comparison, 82% of metastatic melanomas were positive for A103, 76% for HMB45, 92% for T311, and 84% for D5. The combined use of all five reagents minimized the number of immunonegative cases. None of the selected nonmelanocytic tumors (carcinomas or soft tissue neoplasms) was positive for PNL2 in this series except for angiomyolipomas and chronic myeloid leukemias and 1 single case of a malignant peripheral nerve sheath tumor with heterologous differentiation (malignant Triton tumor). Despite its reactivity with neutrophils, PNL2 appears to be a valuable supplementary reagent for the diagnosis of melanocytic tumors.
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PMID:Immunohistochemical analysis of novel monoclonal antibody PNL2 and comparison with other melanocyte differentiation markers. 1572 10

Desmoplastic melanoma (DM) is a fibrosing variant of spindle cell melanoma. It most often presents as an indurated lesion in chronically sun-damaged skin. Due to the lack of characteristic clinical features, early detection is uncommon. At the time of excision, the tumors usually extend into the reticular dermis or deeper. DM is prone to misdiagnosis. It may simulate histologically sclerosing melanocytic nevi as well as various benign and malignant nonmelanocytic lesions. There is significant morphologic variability among tumors classified as DM. Desmoplasia may be prominent throughout the entire tumor ("pure" DM) or represent a portion of an otherwise nondesmoplastic melanoma ("combined" DM). Some tumors show neuroma-like features with prominent nerve involvement, in which case the term "desmoplastic neurotropic melanoma" is used. Immunophenotypically, DMs are usually strongly and homogeneously positive for S-100 protein but are often negative or only focally positive for melanocyte differentiation antigens such as tyrosinase, gp100, Melan-A, and microphthalmia transcription factor. DM differs from conventional melanoma in its clinical course. It is associated with a higher tendency for local recurrence, but metastases to regional lymph nodes are less common. Evidence is also emerging that for patients with thick melanomas, the presence of a paucicellular fibrosing tumor histology (pure DM) is a favorable prognostic factor for survival.
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PMID:Cutaneous desmoplastic melanoma. 1573 77


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