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1.
Dev Biol ; 468(1-2): 146-153, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758484

RESUMO

White sponge nevus (WSN) is a benign autosomal dominant disorder characterized by the formation of white spongy plaques in the oral mucosa. Keratin (KRT) 13 is highly expressed in the mucosa, and mutations in this gene have been commonly associated with WSN patients. However, it remains unknown whether there is a causal relationship between KRT13 mutations and WSN and what the underlying mechanisms might be. Here, we use mouse genetic models to demonstrate that Krt13 is crucial for the maintenance of epithelial integrity. Krt13 knockout mice show a WSN-like phenotype in several tissues, including the tongue, buccal mucosa, and esophagus. Transcriptome analyses uncover that Krt13 regulates a cohort of gene networks in tongue epithelial cells, including epithelial differentiation, immune responses, stress-activated kinase signaling, and metabolic processes. We also provide evidence that epithelial cells without Krt13 are susceptible to mechanical stresses experienced during postnatal life, resulting in unbalanced cell proliferation and differentiation. These data demonstrate that Krt13 is essential for maintaining epithelial homeostasis and loss of Krt13 causes the WSN-like phenotype in mice.


Assuntos
Diferenciação Celular , Proliferação de Células , Células Epiteliais , Queratina-13/genética , Leucoceratose da Mucosa Hereditária , Mucosa Bucal , Mutação , Animais , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Queratina-13/metabolismo , Leucoceratose da Mucosa Hereditária/embriologia , Leucoceratose da Mucosa Hereditária/genética , Leucoceratose da Mucosa Hereditária/patologia , Camundongos , Camundongos Knockout , Mucosa Bucal/embriologia , Mucosa Bucal/patologia
2.
Dermatol Online J ; 23(3)2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28329519

RESUMO

TNF-α-inhibitors are known to induce skin adverseeffects including psoriasis and alopecia areata. Here, wedescribe a unique pattern of hair loss that has psoriaticand alopecia areata-like features. Diagnosis requiresclinical-pathologic correlation and is supportedby increased catagen/telogen hairs, psoriasiformepidermal hyperplasia, perifollicular lymphocyticinfiltrate, and the presence of eosinophils and plasmacells. Although there are no treatment consensusguidelines, management options include stoppingtherapy, switching to a different TNF-α inhibitor orustekinumab (in severe cases), or continuing TNF-αinhibitor therapy with addition of topical, intralesional,or systemic immunosuppressants.


Assuntos
Adalimumab/efeitos adversos , Alopecia/induzido quimicamente , Antirreumáticos/efeitos adversos , Doença de Crohn/tratamento farmacológico , Alopecia/diagnóstico , Alopecia/tratamento farmacológico , Alopecia/patologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Injeções Intralesionais , Triancinolona/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto Jovem
3.
Skinmed ; 14(2): 153-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27319967

RESUMO

A 50-year-old woman presented to our clinic for evaluation of numerous recurrent, pruritic papules on her upper extremities. She reported a 2- to 3-year history of up to eight unique lesions on the bilateral upper arms that would initially appear as firm papules before gradually softening and flattening out, leaving residual pink macules (Figure 1A). Her medical history was notable for mild hyperlipidemia. On presentation, she had several erythematous papules with overlying telangiectasias scattered throughout her bilateral upper arms. One lesion of concern over the left deltoid had been present for 5 months without signs of regression (Figure 1B). Pathology of this and a similar lesion showed histiocytes forming Touton giant cells with foamy cytoplasm consistent with a xanthogranuloma (AXG). Results from immunoperoxidase stains were negative for factor XIIIa and CD1a, diffusely positive for CD68, and focally positive for S100 (Figure 2).


Assuntos
Granuloma/patologia , Lúpus Eritematoso Sistêmico/patologia , Xantomatose/patologia , Feminino , Granuloma/complicações , Humanos , Hiperplasia/complicações , Hiperplasia/patologia , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Recidiva , Extremidade Superior , Xantomatose/complicações
4.
Dermatol Online J ; 22(3)2016 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-27136633

RESUMO

It is known that eosinophilic fasciitis can be associated with monoclonal gammopathy. There is clinical similarity between eosinophilic fasciitis and morphea profunda, but it is unclear whether morphea profunda might be associated with monoclonal gammopathy. The temporal quantification of gammopathy in morphea profunda has not been well characterized. We describe four patients with morphea profunda that were associated with monoclonal gammopathy. Three were associated with monoclonal IgG protein and one with IgM. No patients in our series developed myeloma. In conclusion, the association of monoclonal gammopathy is not unique to eosinophilic fasciitis and scleromyxedema. Further studies are necessary to characterize further the relationship between the two conditions.


Assuntos
Gamopatia Monoclonal de Significância Indeterminada/complicações , Esclerodermia Localizada/complicações , Adulto , Idoso , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/imunologia , Esclerodermia Localizada/patologia , Pele/patologia
5.
Dermatol Surg ; 41(6): 685-92, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25984905

RESUMO

BACKGROUND: Eccrine porocarcinoma (EPC) has a poor prognosis after standard wide local excision (WLE), with 20% local recurrence, 20% regional and 12% distant metastatic rates. Mohs micrographic surgery (MMS) has been used as a promising treatment. OBJECTIVE: To review the use of MMS for EPC and assess treatment outcomes. MATERIALS AND METHODS: This was a retrospective case series of 12 EPC patients treated by MMS between 1984 and 2013 in the institution. Furthermore, a literature review revealed an additional 17 cases of EPC managed by MMS. RESULTS: Of 29 cases of EPC treated by MMS, outcome was established in 27 cases. The patients had a significantly longer mean follow-up period of 6 years (range, 4-206 months), as compared with 19 months (range, 2-48 months) in reported cases. Two patients had regional lymph node metastasis after MMS. The regional metastatic rates to lymph nodes were 7% (2/27). There was no local recurrence, distant metastasis, or disease-specific death in the 27 cases studied. CONCLUSION: To the best of the authors' knowledge, this is the single largest case series of EPCs treated by MMS and the authors' data demonstrated that MMS may be superior to the standard WLE.


Assuntos
Porocarcinoma Écrino/cirurgia , Cirurgia de Mohs , Neoplasias das Glândulas Sudoríparas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Porocarcinoma Écrino/patologia , Porocarcinoma Écrino/secundário , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias das Glândulas Sudoríparas/patologia , Resultado do Tratamento
6.
Exp Dermatol ; 23(5): 304-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24646432

RESUMO

Epigenetic regulation of gene expression by DNA methylation is a central mechanism governing the silencing of tumor suppressor genes in many forms of cancer. Current methods have not proven optimal for the quantitative analysis of DNA methylation and corresponding in situ protein expression within cells in small specimens like skin biopsies. We have overcome this limitation by combining and modifying several techniques: target cell enrichment, DNA micro-isolation, one-step denaturation/bisulphite conversion/in-column desulphonation, specially designed PCR amplification, pyrosequencing and multispectral image analysis. Using this approach optimized for small samples, we can quantify minor alterations in gene methylation and protein expression using minimal amounts of tissue. Comparative studies of fresh and processed cells showed that our method is valid for DNA in both fresh and formalin-fixed, paraffin-embedded specimens. We can measure the effects of DNA methylation inhibitors, administered in vitro or in vivo, on the promoter methylation and protein expression of selected genes in specific cells. This novel approach should prove useful for a wide variety of investigative and clinical applications in dermatology and other specialties where the collection of small, routinely processed biopsy specimens is common. We refer to this method as Q-GAME (quantitative gene analysis of methylation and expression).


Assuntos
Metilação de DNA , Epigênese Genética , Linfoma Cutâneo de Células T/genética , Linhagem Celular Tumoral , Ilhas de CpG , Citometria de Fluxo , Formaldeído/química , Inativação Gênica , Humanos , Células Jurkat , Linfoma Cutâneo de Células T/diagnóstico , Inclusão em Parafina , Reação em Cadeia da Polimerase , Processamento de Sinais Assistido por Computador , Fixação de Tecidos
7.
Arch Biochem Biophys ; 563: 136-44, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25107531

RESUMO

Expression of Melanoma AntiGen Encoding (MAGE) genes, particularly MAGE-A3, has been correlated with aggressive clinical course, the acquisition of resistance to chemotherapy and poor clinical outcomes of melanoma and other malignancies. MAGE proteins bind to KAP1, a gene repressor and ubiquitin E3 ligase which also binds KRAB domain containing zinc finger transcription factors (KZNFs), and MAGE expression may affect KZNF mediated gene regulation. To investigate mechanisms for these effects, we tested the hypothesis that differences in KRAB domain composition affect KZNF poly-ubiquitination and determine whether MAGE expression increases, decreases, or has no effect on KZNFs mediated gene repression. Using an integrated reporter gene responsive to repression by KRAB domain fusion proteins, we found that MAGE-A3 relieved KZNF mediated repression and induced KZNF poly-ubiquitination and degradation in association with expression of the A+B box KRAB domain. In contrast, MAGE-A3 enhanced KAP1 mediated repression of KZNFs expressing A or A+b box KRAB domains but caused no increase in poly-ubiquitination or degradation. MAGE-A3 has no significant impact on KZNFs with KRAB domains containing the Scan box motif. These data support our hypothesis by showing that the effects of MAGE-A3 on gene repression depend on the type of KZNF KRAB domain involved.


Assuntos
Antígenos de Neoplasias/metabolismo , Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Repressoras/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Células CHO , Cricetulus , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Melanoma/genética , Modelos Moleculares , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/genética , Proteína 28 com Motivo Tripartido , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
8.
Mod Pathol ; 26(8): 1032-40, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23558570

RESUMO

Angiosarcoma is an aggressive malignancy of endothelial differentiation. Potential roles of the endothelial angiopoietin-tunica interna endothelial cell kinase (ANGPT-TIE) system in angiosarcoma diagnosis, pathogenesis, prognosis and treatment are undefined. To examine the expression and prognostic significance of angiopoietin-1, angiopoietin-2, TIE1 and TEK (TIE2) proteins in angiosarcoma, we immunohistochemically evaluated clinically annotated human angiosarcoma samples. Correlations of protein expression with overall survival and pathological features were explored. The cohort included 51 patients diagnosed with angiosarcoma at the age of 30-86 years (median 67). The 5-year overall survival was 45% with a median of 26 months. Moderate to strong expression of angiopoietin-1, TIE1 and TEK (TIE2) was identified in the majority of angiosarcomas and moderate to strong expression of angiopoietin-2 was observed in 42% of angiosarcomas. Increased angiopoietin-1 expression correlated with improved survival. Non-significant trends toward longer survival were also observed with increased TIE1 and TEK (TIE2) expression. Increased expression of angiopoietin-2, TIE1 and TEK (TIE2) was associated with vasoformative architecture. No differences in expression of these proteins were observed when patients were segregated by age, gender, presence or absence of metastases at diagnosis, primary tumor location, radiation association or the presence of necrosis. We conclude that components of the ANGPT-TIE system are commonly expressed in angiosarcomas. Reduced expression of these proteins is associated with non-vasoformative and clinically more aggressive lesions.


Assuntos
Angiopoietinas/biossíntese , Biomarcadores Tumorais/análise , Hemangiossarcoma/metabolismo , Receptores de TIE/biossíntese , Neoplasias de Tecidos Moles/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiopoietinas/análise , Feminino , Hemangiossarcoma/mortalidade , Hemangiossarcoma/patologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Receptores de TIE/análise , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Análise Serial de Tecidos
9.
Am J Dermatopathol ; 35(1): 113-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22892471

RESUMO

Cutaneous mastocytosis is a rare clinically heterogeneous disorder characterized by mast cell infiltration. Mastocytosis affects both children and adults and has been reported to occur in families. Recent data suggest that mutations in the c-kit proto-oncogene are causative of mastocytosis not only in adults but in children and familial cases as well; however, mutation analysis other than D816V is not widely available, making detection of causative mutations problematic. We present the case of a 33-year-old man with a 30-year history of persistent urticaria pigmentosa and his 2 affected children. Sequencing of KIT exons 8, 10, 11, and 17 was carried out on a skin biopsy specimen and mucosal swabs of the incident case and was negative for known KIT mutations. Additional work-up was deferred by the family. Presentation of this familial case of urticaria pigmentosa demonstrates the complexity of genetic evaluation in clinical settings. It suggests that mutations other than those reported in exons 8, 10, 11, and 17 may also result in familial mastocytosis. Presentation of this case also allows for review of the mechanism of action of causative KIT mutations and the recent literature supporting KIT mutations in childhood and familial mastocytosis.


Assuntos
Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Urticaria Pigmentosa/genética , Adulto , Biópsia , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Linhagem , Fenótipo , Proto-Oncogene Mas , Pele/patologia , Urticaria Pigmentosa/patologia
10.
Dermatol Online J ; 19(11): 20393, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24314770

RESUMO

African tick bite fever (ATBF) is a rickettsial infection that should be considered as the cause of fever in travelers returning from endemic regions of sub-Saharan Africa or the Caribbean. Patients typically present with a flu-like syndrome and may demonstrate one or more cutaneous inoculation eschars as a diagnostic key. We present a case of ATBF in a pregnant woman following her trip to Swaziland. Her symptoms rapidly improved with institution of effective antimicrobial treatment with azithromycin and rifampin; she made a full recovery.


Assuntos
Complicações Infecciosas na Gravidez/microbiologia , Infecções por Rickettsia/microbiologia , Dermatopatias/microbiologia , Picadas de Carrapatos/complicações , Adulto , Essuatíni , Feminino , Humanos , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Infecções por Rickettsia/diagnóstico , Dermatopatias/patologia , Viagem
11.
Cancers (Basel) ; 15(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36672468

RESUMO

Both oncogenic and tumor suppressor roles have been assigned to Notch signaling in melanoma. In clinical trials, Notch inhibitors proved to be ineffective for melanoma treatment. Notch signaling has also been implicated in melanoma transdifferentiation, a prognostic feature in primary melanoma. In this study, we investigated the role of Notch signaling in melanoma tumor development and growth using the genetic model of mouse melanoma by crossing BRAFCA/+/Pten+/+/Tyr-CreER+ (B) and BRAFCA/+/Pten-/-/Tyr-CreER + (BP) mice with Notch1 or Notch2 floxed allele mice. The topical application of tamoxifen induced tumors in BP mice but not in B mice with or without the deletion of either Notch1 or Notch2. These data show that the loss of either Notch1 nor Notch2 can substitute the tumor suppressor function of Pten in BRAFV600E-induced melanomagenesis. However, in Pten-null background, the loss of either Notch1 or Notch2 appeared to accelerate BRAFV600E-induced tumor development, suggesting a tumor suppressor role for Notch1 and Notch2 in BRAFV600E/Pten-null driven melanomagenesis. Quantitative immunochemical analysis of a human cutaneous melanoma tissue microarray that consists of >100 primary tumors with complete clinical history showed a weak to moderate correlation between NOTCH protein levels and clinical and pathological parameters. Our data show that Notch signaling is involved during melanomagenesis and suggest that the identification of genes and signaling pathways downstream of Notch could help devise strategies for melanoma prevention.

12.
Front Immunol ; 13: 1051472, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36741360

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant health/economic burdens. Existing therapies are not fully effective, necessitating development of new approaches for AD management. Here, we report that dietary grape powder (GP) mitigates AD-like symptoms in 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/NgaTndCrlj mice. Using prevention and intervention protocols, we tested the efficacy of 3% and 5% GP-fortified diet in a 13-weeks study. We found that GP feeding markedly inhibited development and progression of AD-like skin lesions, and caused reduction in i) epidermal thickness, mast cell infiltration, ulceration, excoriation and acanthosis in dorsal skin, ii) spleen weight, extramedullary hematopoiesis and lymph nodes sizes, and iii) ear weight and IgE levels. We also found significant modulations in 15 AD-associated serum cytokines/chemokines. Next, using quantitative global proteomics, we identified 714 proteins. Of these, 68 (normal control) and 21 (5% GP-prevention) were significantly modulated (≥2-fold) vs AD control (DNFB-treated) group, with many GP-modulated proteins reverting to normal levels. Ingenuity pathway analysis of GP-modulated proteins followed by validation using ProteinSimple identified changes in acute phase response signaling (FGA, FGB, FGG, HP, HPX, LRG1). Overall, GP supplementation inhibited DNFB-induced AD in NC/NgaTndCrlj mice in both prevention and intervention trials, and should be explored further.


Assuntos
Dermatite Atópica , Dermatopatias , Vitis , Camundongos , Animais , Dermatite Atópica/metabolismo , Dinitrofluorbenzeno , Dieta
13.
Arch Biochem Biophys ; 508(2): 217-21, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21277283

RESUMO

The Class I MAGE proteins are normally expressed only in developing germ cells but are often aberrantly expressed in malignancies, particularly melanoma, making them good therapeutic targets. MAGE proteins promote tumor survival by binding to the RBCC region of KAP-1 and suppressing p53. Although, suppression of MAGE expression, by RNA interference, relieves p53 suppression and inhibits tumor growth, its therapeutic uses are limited by lack of methods for systemic delivery of small interfering RNA. To overcome this barrier, we sought to discover chemical compounds that inhibit binding between MAGE and KAP-1 proteins. Based on previously published effects of MAGE suppression, we developed a strategy for screening a small molecule library based on selective death of MAGE positive cells, activation of p53 and lack of caspase activity. We screened the Maybridge HitFinder library of compounds and eight compounds fulfilled these criteria. Seven of these compounds interfered with co-precipitation of MAGE and KAP-1, and three interfered with binding of MAGE and KAP-1 in a mammalian two hybrid assay. We now report identification of three potential compounds that interfere with MAGE/KAP-1 binding and can be developed as novel chemo-therapeutic agents for treatment of advanced melanoma and other cancers.


Assuntos
Antígenos de Neoplasias/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas Repressoras/metabolismo , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Ligação Proteica/efeitos dos fármacos , Proteínas Repressoras/química , Proteína 28 com Motivo Tripartido
15.
Viruses ; 13(1)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33478104

RESUMO

Merkel cell polyomavirus (MCPyV) is a human polyomavirus causally linked to the development of Merkel cell carcinoma (MCC), an aggressive malignancy that largely arises within the dermis of the skin. In this study, we recapitulate the histopathology of human MCC tumors in vitro using an organotypic (raft) culture system that is traditionally used to recapitulate the dermal and epidermal equivalents of skin in three dimensions (3D). In the optimal culture condition, MCPyV+ MCC cells were embedded in collagen between the epidermal equivalent comprising human keratinocytes and a dermal equivalent containing fibroblasts, resulting in MCC-like lesions arising within the dermal equivalent. The presence and organization of MCC cells within these dermal lesions were characterized through biomarker analyses. Interestingly, co-culture of MCPyV+ MCC together with keratinocytes specifically within the epidermal equivalent of the raft did not reproduce human MCC morphology, nor were any keratinocytes necessary for MCC-like lesions to develop in the dermal equivalent. This 3D tissue culture system provides a novel in vitro platform for studying the role of MCPyV T antigens in MCC oncogenesis, identifying additional factors involved in this process, and for screening potential MCPyV+ MCC therapeutic strategies.


Assuntos
Carcinoma de Célula de Merkel/etiologia , Carcinoma de Célula de Merkel/patologia , Poliomavírus das Células de Merkel/fisiologia , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/virologia , Infecções Tumorais por Vírus/complicações , Infecções Tumorais por Vírus/virologia , Linhagem Celular Tumoral , Imunofluorescência , Humanos , Imuno-Histoquímica , Organoides/patologia , Pele/patologia , Técnicas de Cultura de Tecidos
17.
Cutis ; 85(5): 254-8, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20540416

RESUMO

Several important cutaneous neoplasms present with basaloid cells in the dermis. Desmoplastic trichoepithelioma (DTE), infiltrative/morpheaform basal cell carcinoma (BCC), and microcystic adnexal carcinoma (MAC) are tumors in this category that may be difficult to differentiate, especially when evaluating thin biopsy specimens. An accurate diagnosis has important clinical implications. While DTE is a benign neoplasm with indolent behavior, infiltrative/morpheaform BCC and MAC can be highly aggressive, leading to substantial local destruction and potential metastasis. We present a patient with an unusual tumor demonstrating basaloid cells in the dermis and discuss the diagnostic approach for these lesions, emphasizing the potential role of cytokeratin 20 (CK20) in determining the need for Mohs micrographic surgery.


Assuntos
Carcinoma Basocelular/patologia , Carcinoma de Apêndice Cutâneo/patologia , Cirurgia de Mohs , Neoplasias Cutâneas/patologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Queratina-20 , Masculino , Pessoa de Meia-Idade , Coloração e Rotulagem
18.
Cancer Res ; 67(20): 9954-62, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17942928

RESUMO

The MAGE-A, MAGE-B, and MAGE-C protein families comprise the class-I MAGE/cancer testes antigens, a group of highly homologous proteins whose expression is suppressed in all normal tissues except developing sperm. Aberrant expression of class I MAGE proteins occurs in melanomas and many other malignancies, and MAGE proteins have long been recognized as tumor-specific targets; however, their functions have largely been unknown. Here, we show that suppression of class I MAGE proteins induces apoptosis in the Hs-294T, A375, and S91 MAGE-positive melanoma cell lines and that members of all three families of MAGE class I proteins form complexes with KAP1, a scaffolding protein that is known as a corepressor of p53 expression and function. In addition to inducing apoptosis, MAGE suppression decreases KAP1 complexing with p53, increases immunoreactive and acetylated p53, and activates a p53 responsive reporter gene. Suppression of class I MAGE proteins also induces apoptosis in MAGE-A-positive, p53wt/wt parental HCT 116 colon cancer cells but not in a MAGE-A-positive HCT 116 p53-/- variant, indicating that MAGE suppression of apoptosis requires p53. Finally, treatment with MAGE-specific small interfering RNA suppresses S91 melanoma growth in vivo, in syngenic DBA2 mice. Thus, class I MAGE protein expression may suppress apoptosis by suppressing p53 and may actively contribute to the development of malignancies and by promoting tumor survival. Because the expression of class I MAGE proteins is limited in normal tissues, inhibition of MAGE antigen expression or function represents a novel and specific treatment for melanoma and diverse malignancies.


Assuntos
Antígenos de Neoplasias/metabolismo , Apoptose/imunologia , Proteínas de Ligação a DNA/metabolismo , Melanoma/imunologia , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Processos de Crescimento Celular/imunologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/imunologia , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Melanoma/genética , Melanoma/patologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos DBA , Proteínas Nucleares/imunologia , Ligação Proteica , Proteínas Repressoras/imunologia , Fatores de Transcrição/imunologia , Proteína 28 com Motivo Tripartido , Proteína Supressora de Tumor p53/imunologia
19.
Cutis ; 103(6): 357-360, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31348450

RESUMO

Erythema gyratum repens (EGR) is a rare and poorly understood dermatosis. The relationship of superficial dermatophytic infection to EGR-like eruptions in mycosis fungoides (MF) is unclear. We present a case of an EGR-like eruption in a patient with Sézary syndrome (SS). Histopathologic examination revealed both a superficial dermatophyte (Trichophyton rubrum) and cutaneous T-cell lymphoma (CTCL) in biopsies of the skin, regardless of whether those biopsies showed EGR-like lesions or erythroderma clinically. On 2 occasions, treatment of the superficial dermatophytic infection led to resolution of the EGR-like eruption and associated pruritus but not to resolution of the erythroderma. This case supports a role for dermatophytic superinfection in an EGR-like eruption in SS. Further investigation is necessary to fully understand the impact of dermatophytic infection in this clinical setting.


Assuntos
Eritema/diagnóstico , Linfoma Cutâneo de Células T/diagnóstico , Síndrome de Sézary/patologia , Neoplasias Cutâneas/diagnóstico , Tinha/diagnóstico , Idoso , Biópsia , Eritema/etiologia , Feminino , Humanos , Linfoma Cutâneo de Células T/patologia , Neoplasias Cutâneas/patologia , Tinha/patologia , Trichophyton/isolamento & purificação
20.
J Am Acad Dermatol ; 59(1): 130-6, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18462833

RESUMO

Kikuchi's disease, also known as histiocytic necrotizing lymphadenitis, is a systemic illness with classic clinical findings of cervical lymphadenopathy and fever. Diagnosis is confirmed by lymph node histology, which reveals paracortical foci of necrosis and a histiocytic infiltrate. Kikuchi's disease has been associated with a number of infections, but no single source has been identified. Diverse, often nonspecific, cutaneous findings have been described in up to 40% of cases. Description of the histopathologic findings of skin lesions is limited to single case reports and one case series. We describe a 24-year-old woman with fevers, lymphadenopathy, hepatic and hematologic abnormalities, and a skin eruption involving the face, neck, trunk, and extremities with characteristic lymph node and cutaneous histopathologic findings. We completed a systematic review of the clinical presentations and histopathology of Kikuchi's disease.


Assuntos
Linfadenite Histiocítica Necrosante/diagnóstico , Linfadenite Histiocítica Necrosante/patologia , Adulto , Axila , Biópsia , Feminino , Humanos , Linfonodos/patologia , Pele/patologia
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