Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human melanoma cells growth arrest irreversibly, lose tumorigenic potential and terminally differentiate after treatment with a combination of fibroblast interferon (IFN-beta) and the protein kinase C activator mezerein (MEZ). Applying subtraction hybridization to this model differentiation system permitted cloning of melanoma differentiation associated gene-7, mda-7. Expression of mda-7 inversely correlates with melanoma development and progression, with elevated expression in normal melanocytes and nevi and increasingly reduced expression in radial growth phase, vertical growth phase and metastatic melanoma. When expressed by means of a replication incompetent adenovirus (Ad.mda-7) growth of melanoma, but not normal early passage or immortal human melanocytes, is dramatically suppressed and cells undergo programmed cell death (apoptosis). Infection of metastatic melanoma cells with Ad.mda-7 results in an increase in cells in the G(2)/M phase of the cell cycle and changes in the ratio of pro-apoptotic (BAX, BAK) to anti-apoptotic (BCL-2, BCL-XL) proteins. Ad.mda-7 infection results in a temporal increase in mda-7 mRNA and intracellular MDA-7 protein in most of the melanocyte/melanoma cell lines and secretion of MDA-7 protein is readily detected following Ad.mda-7 infection of both melanocytes and melanoma cells. The present studies document a differential response of melanocytes versus melanoma cells to ectopic expression of mda-7 and support future applications of mda-7 for the gene-based therapy of metastatic melanoma.
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PMID:The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells. 1185 Jul 99

Melanoma is a significant health problem. Despite public education and free cancer screenings, the incidence and mortality of melanoma continues to rise; however, many currently diagnosed melanomas are thin lesions, suggesting that education and awareness is having an impact. In addition, there are still subsets of patients who need increased surveillance in order to increase their survival. Although large congenital nevi may be precursors of melanoma, small and medium congenital nevi have an insignificant risk for melanoma development. Large congenital nevi, which are axial in location, appear to be more likely to develop melanoma and are associated with melanocytosis and melanoma of the CNS, both of which portend a poor prognosis. Recently, the recommended margins of excision have become more conservative so that many of the surgical defects can be closed primarily. Lymphoscintigraphy and sentinel node biopsy have replaced elective node dissections, thus decreasing the morbidity associated with the surgical management of melanoma. Although controversy still exists as to whether or not sentinel lymph node biopsy alters a patient's prognosis, it has been shown to be a powerful prognostic indicator. Although most melanomas are managed by routine surgical excision, other modalities are sometimes employed. For example, cryosurgery or radiation therapy may be indicated in the frail, elderly individual with a large facial lentigo maligna. Mohs surgery is the treatment of choice for head and neck melanomas and those located in areas where maximum preservation of tissue is required and for desmoplastic and acral lentiginous melanomas. Much more work remains in the area of adjuvant therapy, chemotherapy, and immunotherapy. Dacarbazine remains the drug of choice in disseminated melanoma, but remissions are usually short lived. Interleukin and biochemotherapy has yielded good results but the percentage benefiting is small. Although high dose interferon increases disease-free and overall survival in some patients, it remains a controversial drug which is not easily tolerated. In the new staging system for melanoma, ulceration is second only to Breslow's thickness. In transit (satellite) lesions have also been included in this new system. The new system also recognizes that patients with only microscopic metastatic nodal disease fare better than patients with clinically enlarged metastatic nodes and that it is the number of nodes involved with metastases, not their size, that determines the patient's prognosis. Except for lesions <1mm thick, the Clark's level of invasion has been de-emphasized.
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PMID:Current concepts in the management of patients with melanoma. 1211 49

Homozygous deletions of human chromosomal region 9p21 occur frequently in malignant melanoma and are associated with the loss of the tumor suppressor genes p16(INK4a) and p15(INK4b). In the same chromosomal region the methylthioadenosine phosphorylase (MTAP) gene is localized and therefore may also serve as a tumor suppressor gene. The aim of this study was to analyze MTAP mutations and expression patterns in malignant melanomas. To examine the MTAP gene and expression of MTAP protein we screened 9 human melanoma cell lines and primary human melanocytes by reverse transcriptase-polymerase chain reaction, sequencing, and immunoblotting. Analyzing the melanoma cell lines we found significant down-regulation of MTAP mRNA expression. In only one cell line, HTZ19d, this was due to homozygous deletion of exon 2 to 8 whereas in the other cell lines promoter hypermethylation was detected. MTAP expression was further analyzed in vivo by immunohistochemical staining of 38 tissue samples of benign melanocytic nevi, melanomas, and melanoma metastases. In summary, we demonstrate significant inverse correlation between MTAP protein expression and progression of melanocytic tumors as the amount of MTAP protein staining decreases from benign melanocytic nevi to metastatic melanomas. Our results suggest an important role of MTAP inactivation in the development of melanomas. This finding may be of great clinical significance because recently an association between MTAP activity and interferon sensitivity has been suggested.
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PMID:Characterization of methylthioadenosin phosphorylase (MTAP) expression in malignant melanoma. 1287 87

Blue rubber bleb nevus is a rare entity consisting of distinctive angiomas in the skin and gastrointestinal tract, leading to occult or profound gastrointestinal bleeding and chronic anemia. The efficacy has been documented of systemic treatment with corticoids, interferon, vincristine, and, more recently, subcutaneous octreotide in the presence of active lesion proliferation or disseminated intravascular coagulation. A case of blue rubber bleb nevus syndrome with oral hemangiomas in a 24-year-old woman is reported. The surgical specimens were subjected to immunohistochemical study, which showed all of the hemangiomas to be in an inactive phase.
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PMID:Blue rubber bleb nevus syndrome: immunohistochemical study. 1290 87

Cytokine resistance is a well-established feature of melanoma cell progression and represents also a major obstacle in immunotherapy of patients with metastatic melanoma. To check whether suppressors of cytokine signalling (SOCS) play a role in cytokine resistance and tumor progression of melanoma, we investigated the expression and regulation of SOCS-1, an established negative regulator of interleukin-6 (IL-6) and interferon (IFN) signalling. In vitro SOCS-1 transcripts were detectable by RT-PCR in 8 out of 8 human melanoma cell lines derived from different tumor stages. Normal human melanocytes also expressed SOCS-1 mRNA in the presence or absence of artificial growth factors. Both IL-6 and alpha-IFN induced rapid and transient SOCS-1 mRNA expression in WM35 and WM9 melanoma cells. At the protein level, SOCS-1 was undetectable in normal human melanocytes whereas uniformly expressed in all tested melanoma cell lines. The aberrant SOCS-1 protein expression in melanoma cells was recapitalized in situ as shown by immunohistochemical analysis. SOCS-1 immunoreactivity was closely related to tumor invasion (Clark level), tumor thickness according to Breslow, and stage of the disease. In contrast, melanocytes in normal skin or melanocytic nevi lacked SOCS-1 protein expression. Our findings show that melanoma cells express a member of the SOCS family, SOCS-1, in vitro and in situ. SOCS-1 is a progression marker of human melanoma and may downregulate biological responses by endogenous and/or therapeutically administered cytokines.
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PMID:Expression of SOCS-1, suppressor of cytokine signalling-1, in human melanoma. 1537 79

We studied 253 primary melanomas of the skin for histologic signs of regression. Detailed immunohistologic analyses, including expression of MxA (an antiviral protein specifically induced by type I interferons), the chemokine IP10/CXCL10, the chemokine receptor CXCR3, and the cytotoxic molecule granzyme B, were performed for 14 typical regressive tumors and 20 control samples (congenital nevi, halo nevi, unaffected skin). We found high expression of MxA, indicating local type I interferon production, in inflamed regressive melanocytic lesions, along with large numbers of natural interferon-producing plasmacytoid dendritic cells, CXCR3+ lymphocytes, and granzyme B+ lymphocytes. We also detected high expression of the interferon-induced chemokine IP10/CXCL10, linking type I interferon production and recruitment of CXCR3+ lymphocytes. Our results provide evidence that endogenous activation of type I interferons, infiltration of plasmacytoid dendritic cells, and recruitment of CXCR3+ and granzyme B+ lymphocytes are involved in spontaneous regression of melanoma and other melanocytic lesions. We believe this cytotoxic immune response represents an evolutionarily conserved pathway against intracellular pathogens.
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PMID:Type I interferon-associated recruitment of cytotoxic lymphocytes: a common mechanism in regressive melanocytic lesions. 1592 72

We report on a child with blue rubber bleb nevus syndrome (BRBNS) presenting during the first days of life with severe bleeding from the upper gastrointestinal tract. Medical treatment with methylprednisolone, cyklokapron, interferon 1 alpha and numerous blood transfusions were given to control bleeding during the first 3 years of life. Afterwards repeated endoscopic electrocoagulation were performed over a period of one year resulting in a termination of bleeding episodes. At ten years of age the patient developed spastic diplegia with slight walking disabilities, coordination and fine motor problems. The case is unique because 1) it is the first neonatal case with BRBNS and severe gastrointestinal bleeding; 2) the patient was successfully treated by endoscopic electrocoagulation; and 3) the long-term follow-up. The use of electrocoagulation appears to have been effective and ablation of the stomach could be avoided until now.
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PMID:Severe blue rubber bleb nevus syndrome in a neonate. 1862 72

Malignant blue nevi are a rare variant of cutaneous melanoma often associated with metastatic disease and poor prognosis. Information on the treatment of this condition is limited. This case study reports the use of intralesional interferon -alpha2b (IFN-alpha2b) as a salvage option in a male patient with a congenital blue nevus on the right buttock. After initial diagnosis, the primary lesion (lesion 1) was partially resected and the patient received aggressive treatment with radiotherapy and concomitant polychemotherapy (cisplatin, vinblastine, and dacarbazine). However, the lesion progressed and the patient was treated second-line with carboplatin, paclitaxel, and sorafenib. Although this treatment stabilized the primary lesion, at cycle 6, the patient developed a measurable locoregional metastasis (lesion 2). At this stage, the patient was treated with intralesional IFN-alpha2b twice weekly at lesion 2, followed by weekly intralesional IFN-alpha2b therapy to both lesions, which resulted in partial disease regression. Biweekly maintenance therapy with IFN-alpha2b administered to both lesions maintained a partial response (ongoing at 23+ mo) and allowed complete occupational rehabilitation. Thus, intralesional therapy with IFN-alpha2b may be a viable treatment option in patients with locally advanced melanoma who have progressed on prior radiotherapy, polychemotherapy, and/or multikinase antiangiogenic-based therapy.
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PMID:Intratumoral therapy with interferon-alpha in a locoregional advanced malignant blue nevus: a brief communication. 1995 52

Despite advancements in protocols, a subset of melanocytic lesions continues to pose diagnostic challenges. This is particularly true in the pediatric population where certain congenital nevi mimic melanoma. Recently, comparative genomic hybridization (CGH) has been utilized to support diagnoses of melanocytic lesions based on DNA copy number changes. Because distinct differences in copy number changes have been shown to occur in malignant melanoma and benign nevi, CGH can be a useful adjunct when diagnosis based on histology alone is indeterminate. The authors discuss the benefits of using CGH to aid in the diagnosis of melanocytic lesions that are difficult to characterize as malignant or benign based on clinical and histologic features alone. This paper presents a brief clinical report and review of the literature. A 13-year-old Caucasian male presented to an academic tertiary care medical center after a shave biopsy unexpectedly revealed malignant melanoma with positive deep margins. Following complete excisional biopsy, the diagnosis of malignant melanoma with depth of 0.92 mm was confirmed, both by the home institution's pathologist and by consultant dermatopathologists at two separate academic tertiary medical centers. Sentinel lymph node biopsy revealed a small focus of metastatic melanoma, this lead to a left-sided modified radical neck dissection. All nodes removed were negative for disease, and surgical and postsurgical care was uncomplicated. Before proceeding with interferon therapy, CGH was performed on the tissue from the primary lesion. Other than a slight amplification of chromosome 16p, no other aberrations were detected favoring a benign lesion. Ultimately, the diagnosis was amended to compound melanocytic nevus of the nose with benign nevus cell rest in the sentinel node. While histopathologic evaluation is the current gold standard for the diagnosis of melanoma, there are many cases where it is inaccurate. The use of CGH in the evaluation of histologically equivocal lesions may allow certain patients to avoid invasive procedures and associated morbidities. The authors propose that, in these select diagnostically challenging cases, tissue analyses by CGH may be beneficial before proceeding to more invasive procedures such as sentinel node biopsy and complete lymphadenectomy.
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PMID:Comparative genomic hybridization for the diagnosis of melanoma. 2023 25

Using tissue microarrays assembling 465 nevi, primary melanomas and metastases, we investigated whether expression of methylthioadenosine phosphorylase (MTAP), a recently suggested biomarker of malignant melanoma, has prognostic significance and may predict responsiveness to adjuvant interferon therapy in patients with melanoma. Because of its association with MTAP activity and interferon signalling pathways, signal transducer and activator of transcription 1 (STAT1) immunohistochemistry was analysed, too. MTAP expression was significantly reduced in melanomas and metastases compared with nevi (P < 0.001); STAT1 expression significantly increased. In melanomas, loss of MTAP expression was significantly related to Clark level (P < 0.05) and tumor thickness (P < 0.01); whereas STAT1 immunoreactivity was significantly related to gender (p < 0.05) and tumor thickness (P < 0.05). Interestingly, subgroup analysis of patients with a tumor thickness of 1.5-4.0 mm revealed a significant survival benefit from adjuvant interferon treatment regarding recurrence-free survival (RFS; P < 0.05) if MTAP expression was observed in the primary melanoma. Patients with STAT1-positive melanomas also tended to benefit from interferon concerning RFS (P = 0.074) and showed a significant benefit concerning overall survival (OS; P < 0.05). According to Cox analysis, MTAP expression in contrast to STAT1 was an independent positive prognostic marker for RFS and OS. In conclusion, MTAP represents a highly promising immunohistochemical marker for prognosis and interferon response of patients with malignant melanoma.
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PMID:Methylthioadenosine phosphorylase represents a predictive marker for response to adjuvant interferon therapy in patients with malignant melanoma. 2050 Jul 69


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