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  1. Article ; Online: Elevated Serum Leptin Levels are Associated With an Increased Risk of Sentinel Lymph Node Metastasis in Cutaneous Melanoma.

    Oba, Junna / Wei, Wei / Gershenwald, Jeffrey E / Johnson, Marcella M / Wyatt, Cynthia M / Ellerhorst, Julie A / Grimm, Elizabeth A

    Medicine

    2016  Volume 95, Issue 11, Page(s) e3073

    Abstract: The metabolic hormone leptin has been implicated in the pathogenesis of various malignancies and may contribute to the high rate of cancer in obese individuals. We reported that leptin and its receptor are expressed by melanoma tumors and cell lines, and ...

    Abstract The metabolic hormone leptin has been implicated in the pathogenesis of various malignancies and may contribute to the high rate of cancer in obese individuals. We reported that leptin and its receptor are expressed by melanoma tumors and cell lines, and that leptin stimulates proliferation of cultured melanoma cells. Here, we tested the hypothesis that leptin contributes to early melanoma progression by assessing its association with sentinel node positivity in cutaneous melanoma patients. The study enrolled 72 patients who were scheduled to undergo lymphatic mapping and sentinel node biopsy. Fasting blood was obtained before surgery, and serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA) with a "raw" (assay value) and an "adjusted" value (raw value divided by body mass index). Leptin levels and other clinicopathologic parameters were compared between sentinel node positive and negative groups. Logistic regression models were used to predict sentinel node status using leptin and other relevant clinical parameters. The raw and adjusted leptin levels were significantly higher in the 15 patients with positive sentinel nodes. These findings could not be attributed to differences in body mass indices. Univariate models revealed raw leptin, adjusted leptin, Breslow thickness, and mitotic rate as significant predictors of sentinel node status. Leptin levels and Breslow thickness remained significant in multivariate models. Survival and follow-up analysis revealed more aggressive disease in diabetic patients. Elevated serum leptin levels predict sentinel node metastasis in melanoma. Validation of this finding in larger cohorts should enable better stratification of early stage melanoma patients.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Diabetes Complications/blood ; Diabetes Complications/mortality ; Diabetes Complications/pathology ; Female ; Humans ; Leptin/blood ; Lymphatic Metastasis ; Male ; Melanoma/blood ; Melanoma/mortality ; Melanoma/pathology ; Middle Aged ; Prospective Studies ; Sentinel Lymph Node Biopsy ; Skin Neoplasms/blood ; Skin Neoplasms/mortality ; Skin Neoplasms/pathology ; Texas/epidemiology
    Chemical Substances Leptin
    Language English
    Publishing date 2016-03
    Publishing country United States
    Document type Journal Article ; Observational Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80184-7
    ISSN 1536-5964 ; 0025-7974
    ISSN (online) 1536-5964
    ISSN 0025-7974
    DOI 10.1097/MD.0000000000003073
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: NF-kappaB mediates mitogen-activated protein kinase pathway-dependent iNOS expression in human melanoma.

    Uffort, Deon G / Grimm, Elizabeth A / Ellerhorst, Julie A

    The Journal of investigative dermatology

    2008  Volume 129, Issue 1, Page(s) 148–154

    Abstract: Tumor expression of inducible nitric oxide synthase (iNOS) predicts poor outcomes for melanoma patients. We have reported the regulation of melanoma iNOS by the mitogen-activated protein kinase (MAPK) pathway. In this study, we test the hypothesis that ... ...

    Abstract Tumor expression of inducible nitric oxide synthase (iNOS) predicts poor outcomes for melanoma patients. We have reported the regulation of melanoma iNOS by the mitogen-activated protein kinase (MAPK) pathway. In this study, we test the hypothesis that NF-kappaB mediates this regulation. Western blotting of melanoma cell lysates confirmed the constitutive expression of iNOS. Western blot detected baseline levels of activated nuclear extracellular signal-regulated kinase and NF-kappaB. Indirect immunofluorescence confirmed the presence of NF-kappaB p50 and p65 in melanoma cell nuclei, with p50 being more prevalent. Electrophoretic mobility shift assay demonstrated baseline NF-kappaB activity, the findings confirmed by supershift analysis. Treatment of melanoma cells with the MEK inhibitor U0126 decreased NF-kappaB binding to its DNA recognition sequence, implicating the MAPK pathway in NF-kappaB activation. Two specific NF-kappaB inhibitors suppressed iNOS expression, demonstrating regulation of iNOS by NF-kappaB. Several experiments indicated the presence of p50 homodimers, which lack a transactivation domain and rely on the transcriptional coactivator Bcl-3 to carry out this function. Bcl-3 was detected in melanoma cells and co-immunoprecipitated with p50. These data suggest that the constitutively activated melanoma MAPK pathway stimulates activation of NF-kappaB hetero- and homodimers, which, in turn, drive iNOS expression and support melanoma tumorigenesis.
    MeSH term(s) B-Cell Lymphoma 3 Protein ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Dimerization ; Enzyme Inhibitors/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Enzymologic ; Humans ; MAP Kinase Signaling System ; Melanocytes/metabolism ; Melanoma/enzymology ; Melanoma/metabolism ; Models, Biological ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Proto-Oncogene Proteins/metabolism ; Transcription Factors/metabolism ; Transcriptional Activation
    Chemical Substances B-Cell Lymphoma 3 Protein ; BCL3 protein, human ; Enzyme Inhibitors ; NF-kappa B ; Proto-Oncogene Proteins ; Transcription Factors ; Nitric Oxide Synthase Type II (EC 1.14.13.39)
    Language English
    Publishing date 2008-07-31
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1038/jid.2008.205
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Association of activated c-Met with NRAS-mutated human melanomas.

    Chattopadhyay, Chandrani / Ellerhorst, Julie A / Ekmekcioglu, Suhendan / Greene, Victoria R / Davies, Michael A / Grimm, Elizabeth A

    International journal of cancer

    2012  Volume 131, Issue 2, Page(s) E56–65

    Abstract: Cutaneous melanomas can be divided into three mutually exclusive genetic subsets: tumors with mutated BRAF, tumors with mutated NRAS and tumors wild type at both loci (wt/wt). Targeted therapy for melanoma has been advancing with agents directed to ... ...

    Abstract Cutaneous melanomas can be divided into three mutually exclusive genetic subsets: tumors with mutated BRAF, tumors with mutated NRAS and tumors wild type at both loci (wt/wt). Targeted therapy for melanoma has been advancing with agents directed to mutated BRAF, accounting for 50% of melanoma patients. The c-Met pathway is known to play a role in melanoma tumorigenesis and preliminary data from our laboratory suggested that this pathway is preferentially activated in NRAS-mutated tumors. The objective of this study was to test the hypothesis that melanomas carrying the mutated NRAS genotype are uniquely sensitively to c-Met inhibition, thus providing rationale for therapeutic targeting of c-Met in this patient cohort. Using primary human melanomas with known BRAF/NRAS genotypes, we observed greater immunostaining for phosphorylated (activated) c-Met in NRAS-mutated and wt/wt tumors, compared to BRAF-mutated tumors. NRAS-mutated and wt/wt cell lines also demonstrated more robust c-Met activation in response to hepatocyte growth factor (HGF). Knock-down of mutated N-Ras, but not wild type N-Ras, by RNA interference resulted in decreased c-Met phosphorylation. Compared to BRAF mutants, NRAS-mutated melanoma cells were more sensitive to pharmacologic c-Met inhibition in terms of c-Met activation, Akt phosphorylation, tumor cell proliferation, migration and apoptosis. This enhanced sensitivity was observed in wt/wt cells as well, but was a less consistent finding. On the basis of these experimental results, we propose that c-Met inhibition may be a useful therapeutic strategy for melanomas with NRAS mutations, as well as some tumors with a wt/wt genotype.
    MeSH term(s) Apoptosis/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Female ; Genes, ras ; Hepatocyte Growth Factor/metabolism ; Humans ; Indoles/pharmacology ; Male ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Middle Aged ; Mutation ; Phosphorylation ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; RNA Interference ; RNA, Small Interfering ; Signal Transduction ; Sulfones/pharmacology
    Chemical Substances 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one ; Indoles ; RNA, Small Interfering ; Sulfones ; Hepatocyte Growth Factor (67256-21-7) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2012-01-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.26487
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Trends in hepatocyte growth factor, insulin-like growth factor 1, thyroid-stimulating hormone, and leptin expression levels in uveal melanoma patient serum and tumor tissues: correlation to disease progression.

    Oba, Junna / Esmaeli, Bita / Ellerhorst, Julie A / Lyons, Genevieve R / Milton, Denái R / Wang, Wei-Lien / Macedo, Mariana P / Lazar, Alexander J / Grimm, Elizabeth A / Chattopadhyay, Chandrani

    Melanoma research

    2017  Volume 27, Issue 2, Page(s) 126–133

    Abstract: This exploratory study was carried out to determine the expression levels of hepatocyte growth factor (HGF), insulin-like growth factor 1, thyroid-stimulating hormone (TSH), and leptin in serum and tumor samples from patients with uveal melanoma and to ... ...

    Abstract This exploratory study was carried out to determine the expression levels of hepatocyte growth factor (HGF), insulin-like growth factor 1, thyroid-stimulating hormone (TSH), and leptin in serum and tumor samples from patients with uveal melanoma and to investigate the potential association of these expression levels with disease progression and patient survival. Seventeen patients, including nine nonmetastatic and eight metastatic, were included in the study. Eighteen healthy individuals served as controls. The levels of these four proteins in serum and tissue samples were determined by enzyme-linked immunosorbent assays and immunohistochemical staining, respectively. Associations between protein levels and survival, disease progression, and other clinicopathological factors were analyzed statistically. Serum levels of HGF were significantly higher and TSH levels were lower in uveal melanoma patients than in healthy individuals, but the level of neither protein differed significantly between metastatic and nonmetastatic groups. Of the four proteins tested, only serum TSH was significantly associated with patient survival. No correlation was observed between the tissue and serum levels of each protein. The levels of HGF in serum may be markers of uveal melanoma development. The prognostic and predictive values of these potential markers need to be determined in a larger cohort.
    MeSH term(s) Adult ; Aged ; Biomarkers, Tumor/blood ; Disease Progression ; Female ; Hepatocyte Growth Factor/blood ; Humans ; Insulin-Like Growth Factor I/metabolism ; Leptin/blood ; Male ; Melanoma/blood ; Melanoma/secondary ; Middle Aged ; Survival Rate ; Thyrotropin/blood ; Uveal Neoplasms/blood ; Uveal Neoplasms/pathology
    Chemical Substances Biomarkers, Tumor ; IGF1 protein, human ; Leptin ; Hepatocyte Growth Factor (67256-21-7) ; Insulin-Like Growth Factor I (67763-96-6) ; Thyrotropin (9002-71-5)
    Language English
    Publishing date 2017-01-24
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1095779-0
    ISSN 1473-5636 ; 0960-8931
    ISSN (online) 1473-5636
    ISSN 0960-8931
    DOI 10.1097/CMR.0000000000000329
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Lack of maturation with anti-leptin receptor antibody in melanoma but not in nevi.

    Diwan, A Hafeez / Dang, Shyam M / Prieto, Victor G / Ellerhorst, Julie A

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

    2008  Volume 22, Issue 1, Page(s) 103–106

    Abstract: We have previously shown thryotropin-releasing hormone expression in nevi and melanoma. Thryotropin-releasing hormone regulation by leptin has been shown in the hypothalamus. The present study was therefore undertaken to evaluate leptin and leptin ... ...

    Abstract We have previously shown thryotropin-releasing hormone expression in nevi and melanoma. Thryotropin-releasing hormone regulation by leptin has been shown in the hypothalamus. The present study was therefore undertaken to evaluate leptin and leptin receptor in nevi and melanoma. Leptin receptor expression as assessed using an anti-leptin receptor antibody showed uniform expression throughout the lesion in 14 of 17 melanomas; 3 melanomas lacked leptin receptor immunoreactivity. In contrast, out of 15 nevi, 10 showed weak to moderate leptin receptor immunoreactivity, with positivity present only in the superficial dermal component. Thus, maturation was present in nevi but not in melanoma with the anti-leptin receptor antibody (P<0.0001). Anti-leptin antibody, in contrast, did not show a significant difference in maturation between nevi and melanoma. We also compared leptin receptor in Spitz nevi and melanoma, as the two can sometimes be difficult to distinguish. Spitz nevi showed moderate to strong immunopositivity. Of 19 Spitz nevi, 7 showed lack of maturation, a finding statistically significant from both melanoma and nevi. Our results suggest a role for leptin receptor in melanoma, and we show for the first time that melanomas show more intense immunoreactivity as compared to nevi (but not Spitz nevi) and that maturation with anti-leptin receptor antibody may be a diagnostically useful tool in distinguishing melanomas, especially nevoid ones, from nevi in difficult cases.
    MeSH term(s) Antibodies ; Biomarkers, Tumor/analysis ; Diagnosis, Differential ; Humans ; Immunohistochemistry ; Leptin/biosynthesis ; Melanoma/metabolism ; Melanoma/pathology ; Nevus/metabolism ; Nevus/pathology ; Receptors, Leptin/biosynthesis ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology
    Chemical Substances Antibodies ; Biomarkers, Tumor ; Leptin ; Receptors, Leptin
    Language English
    Publishing date 2008-10-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 645073-8
    ISSN 1530-0285 ; 0893-3952
    ISSN (online) 1530-0285
    ISSN 0893-3952
    DOI 10.1038/modpathol.2008.166
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  6. Article ; Online: Frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase in cutaneous melanoma.

    Greene, Victoria R / Johnson, Marcella M / Grimm, Elizabeth A / Ellerhorst, Julie A

    The Journal of investigative dermatology

    2008  Volume 129, Issue 6, Page(s) 1483–1488

    Abstract: A lack of consensus exists with regards to the relative rates of NRAS and BRAF mutations in the radial (RGP) and vertical (VGP) growth phases of individual melanoma tumors. This study was conducted to test the hypothesis that mutations are acquired with ... ...

    Abstract A lack of consensus exists with regards to the relative rates of NRAS and BRAF mutations in the radial (RGP) and vertical (VGP) growth phases of individual melanoma tumors. This study was conducted to test the hypothesis that mutations are acquired with progression from RGP to VGP. Using laser capture microdissection, pure tumor DNA was obtained from 15 in situ melanomas, and from the RGP and VGP of 29 invasive tumors. NRAS exon 2 and BRAF exon 15 DNA were amplified by PCR and sequenced. Mutations were present in 6 of 15 in situ melanomas (40%). Of 29 invasive tumors, 16 exhibited RGP mutations (55.2%); 22 showed VGP mutations (75.9%). Paired RGP/VGP mutation analysis revealed a trend toward discordance in the distribution of mutations, favoring VGP localization (P=0.07). Of 15 samples, 12 with mutations in both phases had an increased proportion of mutated DNA in the VGP, measured on DNA chromatograms (P=0.08). Limitations of this study include a relatively small sample cohort selected for technical reasons from a larger population, presenting the risk of selection bias. These concerns notwithstanding our findings support the hypothesis that NRAS and BRAF mutations increase with tumor progression from superficial to invasive disease. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclub.
    MeSH term(s) Cell Line, Tumor ; DNA Mutational Analysis ; Disease Progression ; Exons ; Female ; Genes, ras ; Humans ; Male ; Melanoma/genetics ; Melanoma/metabolism ; Mutation ; Neoplasm Invasiveness ; Proto-Oncogene Proteins B-raf/genetics ; Sequence Analysis, DNA ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; ras Proteins/genetics
    Chemical Substances BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2008-11-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1038/jid.2008.374
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Constitutive intracellular production of iNOS and NO in human melanoma: possible role in regulation of growth and resistance to apoptosis.

    Grimm, Elizabeth A / Ellerhorst, Julie / Tang, Chi-Hui / Ekmekcioglu, Suhendan

    Nitric oxide : biology and chemistry

    2008  Volume 19, Issue 2, Page(s) 133–137

    Abstract: Human melanoma tumors cells are known to express the enzyme, inducible nitric oxide synthase (iNOS), which is responsible for cytokine induced nitric oxide (NO) production during immune responses. This constitutive expression of iNOS in many patients' ... ...

    Abstract Human melanoma tumors cells are known to express the enzyme, inducible nitric oxide synthase (iNOS), which is responsible for cytokine induced nitric oxide (NO) production during immune responses. This constitutive expression of iNOS in many patients' tumor cells, as well as its strong association with poor patient survival, have led to the consideration of iNOS as a molecular marker of poor prognosis, as well as a possible target for therapy. The expression of iNOS in patient tumors was found to associate with nitrotyrosine, COX2, pSTAT3, and arginase. Using human melanoma patients' samples as well as cell lines, we have further evidence supporting intracellular NO production by detection of nitrotyrosine and also by use of DAF-2DA staining. Experiments were performed to scavenge the endogenous NO (with c-PTIO) resulting in melanoma cell growth inhibition; this was restored with SIN-1 (NO and O2-donor) providing data to support a functional role of this gas. Our goal is to understand the aberrant biology leading to this curious phenomenon, and to regulate it in favor of patient treatments.
    MeSH term(s) Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Cyclooxygenase 2/analysis ; Humans ; Melanoma/metabolism ; Melanoma/pathology ; Neoplasm Proteins/analysis ; Nitric Oxide/physiology ; Nitric Oxide Synthase Type II/analysis ; STAT3 Transcription Factor/analysis ; Tumor Cells, Cultured ; Tyrosine/analogs & derivatives ; Tyrosine/analysis
    Chemical Substances Neoplasm Proteins ; STAT3 Transcription Factor ; STAT3 protein, human ; Nitric Oxide (31C4KY9ESH) ; 3-nitrotyrosine (3604-79-3) ; Tyrosine (42HK56048U) ; NOS2 protein, human (EC 1.14.13.39) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Cyclooxygenase 2 (EC 1.14.99.1) ; PTGS2 protein, human (EC 1.14.99.1)
    Language English
    Publishing date 2008-04-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1362794-6
    ISSN 1089-8611 ; 1089-8603
    ISSN (online) 1089-8611
    ISSN 1089-8603
    DOI 10.1016/j.niox.2008.04.009
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  8. Article ; Online: Genetic deficiency of complement isoforms C4A or C4B predicts improved survival of metastatic renal cell carcinoma.

    Zafar, Ghazal I / Grimm, Elizabeth A / Wei, Wei / Johnson, Marcella M / Ellerhorst, Julie A

    The Journal of urology

    2009  Volume 181, Issue 3, Page(s) 1028–34; discussion 1034

    Abstract: Purpose: Autoimmune phenomena during immunotherapy are associated with favorable outcomes in patients with metastatic renal cell carcinoma. We have reported improved survival in patients with stage IV renal cell carcinoma who carry autoimmunity ... ...

    Abstract Purpose: Autoimmune phenomena during immunotherapy are associated with favorable outcomes in patients with metastatic renal cell carcinoma. We have reported improved survival in patients with stage IV renal cell carcinoma who carry autoimmunity associated HLA class II haplotypes. We propose that the clinical benefit is mediated by products of other autoimmunity associated genes linked to these haplotypes. A candidate gene is complement C4, which replicates as part of the RCCX module, can be present in multiple copies and exists as C4A and C4B isoforms. Deficiencies of either isoform are associated with autoimmunity. In the current study we tested the hypothesis that C4A or C4B deficiency predicts improved survival of patients with RCC.
    Materials and methods: The total C4 copy number was determined by simultaneous amplification of RP1 and TNXA/RP2 to quantitate RCCX modules. C4A and C4B alleles were distinguished by PshAI restriction fragment length polymorphism.
    Results: Genetic complotypes were determined in 61 patients. Individuals with a solitary copy of either C4 isoform experienced longer survival. Median survival from the diagnosis of metastatic disease in patients with a solitary copy of C4A or C4B was 7.75 years vs 1.25 in the comparison group (p = 0.001). This was independent of the benefit derived from autoimmune class II genotypes.
    Conclusions: Improved survival is seen in patients with C4A or C4B deficiency and renal cell carcinoma treated with cytokine therapy with or without surgery. These data support our hypothesis that patients with renal cell carcinoma who have autoimmune genotypes have favorable outcomes resulting from autoimmune mechanisms directed to the tumor.
    MeSH term(s) Adult ; Aged ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/mortality ; Carcinoma, Renal Cell/secondary ; Complement C4a/genetics ; Complement C4b/genetics ; Female ; Humans ; Kidney Neoplasms/genetics ; Kidney Neoplasms/mortality ; Kidney Neoplasms/pathology ; Male ; Middle Aged ; Protein Isoforms ; Survival Rate
    Chemical Substances Protein Isoforms ; Complement C4a (80295-49-4) ; Complement C4b (80295-50-7)
    Language English
    Publishing date 2009-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3176-8
    ISSN 1527-3792 ; 0022-5347
    ISSN (online) 1527-3792
    ISSN 0022-5347
    DOI 10.1016/j.juro.2008.11.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Promotion of melanoma growth by the metabolic hormone leptin.

    Ellerhorst, Julie A / Diwan, A H / Dang, Shyam M / Uffort, Deon G / Johnson, Marilyn K / Cooke, Carolyn P / Grimm, Elizabeth A

    Oncology reports

    2010  Volume 23, Issue 4, Page(s) 901–907

    Abstract: We have previously shown that melanoma cells proliferate in response to the metabolic hormones TRH and TSH. The objective of the present study was to test the hypothesis that a third metabolic hormone, leptin, serves as a growth factor for melanoma. ... ...

    Abstract We have previously shown that melanoma cells proliferate in response to the metabolic hormones TRH and TSH. The objective of the present study was to test the hypothesis that a third metabolic hormone, leptin, serves as a growth factor for melanoma. Using western blotting, indirect immunofluorescence, and RT-PCR, leptin receptors were found to be expressed by human melanoma cells. In contrast, cultured melanocytes expressed message for the receptor without detectable protein. Melanoma cells responded to treatment with leptin by activating the MAPK pathway and proliferating. Melanoma cells but not melanocytes, also expressed leptin protein, creating a potential autocrine loop. Examination of human melanoma tumors by immunohistochemistry revealed that melanomas and nevi expressed leptin at a high frequency. Melanomas also strongly expressed the leptin receptor, whereas nevi expressed this receptor to a much lesser degree. We conclude that leptin is a melanoma growth factor and that a leptin autocrine-loop may contribute to the uncontrolled proliferation of these cells.
    MeSH term(s) Blotting, Western ; Cell Line, Tumor ; Cell Proliferation ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; Intercellular Signaling Peptides and Proteins/metabolism ; Leptin/metabolism ; Melanoma/metabolism ; Melanoma/pathology ; Mitogen-Activated Protein Kinases/metabolism ; Nevus/metabolism ; Receptors, Leptin/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/physiology ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology
    Chemical Substances Intercellular Signaling Peptides and Proteins ; Leptin ; Receptors, Leptin ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2010-03-04
    Publishing country Greece
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1222484-4
    ISSN 1791-2431 ; 1021-335X
    ISSN (online) 1791-2431
    ISSN 1021-335X
    DOI 10.3892/or_00000713
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  10. Article ; Online: Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma.

    Eton, Omar / Ross, Merrick I / East, Mary Jo / Mansfield, Paul F / Papadopoulos, Nicholas / Ellerhorst, Julie A / Bedikian, Agop Y / Lee, Jeffrey E

    Journal of translational medicine

    2010  Volume 8, Page(s) 9

    Abstract: Background: Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective ... ...

    Abstract Background: Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma.
    Methods: Patients with a Karnofsky Performance Status >70% and stage III or stage IV melanoma had to have a metastasis >3 cm in diameter resectable as part of routine clinical management. HSPPC-96 tumor-derived vaccines were prepared in one of three dose levels (2.5, 25, or 100 microg/dose) and administered as an intradermal injection weekly for 4 consecutive weeks. In vivo induction of immunity was evaluated using delayed-type hypersensitivity (DTH) to HSPPC-96, irradiated tumor, and dinitrochlorobenzene (DNCB). The gamma-interferon (IFNgamma) ELISPOT assay was used to measure induction of a peripheral blood mononuclear cell response against autologous tumor cells at baseline and at the beginning of weeks 3, 4, and 8.
    Results: Among 36 patients enrolled, 72% had stage IV melanoma and 83% had received prior systemic therapy. The smallest tumor specimen from which HSPPC-96 was prepared weighed 2 g. Twelve patients (including 9 with stage IV and indicator lesions) had a negative DNCB skin test result at baseline. All 36 patients were treated and evaluable for toxicity and response. There were no serious toxicities. There were no observed DTH responses to HSPPC-96 or to autologous tumor cells before or during treatment. The IFNgamma-producing cell count rose modestly in 5 of 26 patients and returned to baseline by week 8, with no discernible association with HSPPC-96 dosing or clinical parameters. There were no objective responses among 16 patients with stage IV disease and indicator lesions. Among 20 patients treated in the adjuvant setting, 11 with stage IV melanoma at baseline had a progression-free and overall survival of 45% and 82%, respectively, with a median follow-up of 10 years.
    Conclusion: Treatment with autologous tumor-derived HSPPC-96 was feasible and safe at all doses tested. Observed immunological effects and antitumor activity were modest, precluding selection of a biologically active dose. Nevertheless, the 25-microg dose level was shown to be practical for further study.
    MeSH term(s) Adolescent ; Adult ; Aged ; Animals ; Cancer Vaccines/immunology ; Cancer Vaccines/therapeutic use ; Heat-Shock Proteins/immunology ; Heat-Shock Proteins/therapeutic use ; Humans ; Immunotherapy/methods ; Kaplan-Meier Estimate ; Leukocytes, Mononuclear/cytology ; Leukocytes, Mononuclear/immunology ; Male ; Melanoma/immunology ; Melanoma/pathology ; Melanoma/prevention & control ; Middle Aged ; Neoplasm Metastasis ; Young Adult
    Chemical Substances Cancer Vaccines ; Heat-Shock Proteins ; vitespin (492448-75-6)
    Language English
    Publishing date 2010-01-29
    Publishing country England
    Document type Clinical Trial ; Journal Article
    ISSN 1479-5876
    ISSN (online) 1479-5876
    DOI 10.1186/1479-5876-8-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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