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1.
Nat Med ; 26(12): 1865-1877, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33077955

RESUMO

An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.

3.
Cienc. tecnol. salud ; 7(1): 47-52, 2020.
Artigo em Espanhol | LILACS | ID: biblio-1120310

RESUMO

Los estudios de melanoma en Guatemala han sido pocos y únicamente se ha evaluado el aspecto clínico e histológico. El objetivo del presente estudio fue determinar la proporción de casos de melanoma cutáneo por morfología, inmunohistoquímica y mutación del gen BRAF en pacientes con diagnóstico de melanoma en dos centros de referencia, Instituto de Cancerología e Instituto de Dermatología en Guatemala. El estudio es de tipo descriptivo, retrospectivo, transversal. El tipo de muestreo es no probabilístico, con una muestra por conveniencia de 100 casos de tejidos de piel de pacientes, caracterizados por edad, sexo y localización del tumor. Los estudios moleculares incluyeron la determinación de la mutación de la proteína BRAF, por la técnica de PCR-RT. Los resultados muestran que el sexo más afectado es el femenino (54 %). El grupo etario con mayor número de casos es entre 56-75 años (44 %). El tipo histológico predominante es el melanoma lentiginoso acral (59 %) y la localización más frecuente es en miembro inferior (71 %). No se encontraron casos de melanoma lentigo maligno. La mutación del gen BRAF se encontró en el 6 % de los casos, lo que representa un dato importante para el pronóstico y tratamiento del paciente. Por ser uno de los primeros estudios que incluyen el factor molecular, abre paso a una línea de investigación que permita dar continuidad a los pacientes con melanoma en Guatemala, lo que permitirá determinar factores pronóstico y predictivos, así como tratamientos de los casos en estudio.


Studies of melanoma in Guatemala have been few and only the clinical and histological aspects have been evaluated. The objective of this study was to determine the proportion of cases of cutaneous melanoma by morphology, immunohistochemistry and mutation of the BRAF gene in patients diagnosed with Melanoma in two important reference centers, Institute of Cancerology (Incan) and Institute of Dermatology of Guatemala (Inderma). The study is descriptive, retrospective, transversal. The type of sampling is non-probabilistic, with a convenience sample calculation of 100 cases of patient skin biopsies, characterized by age, sex and tumor anatomic location. Molecular studies included the determination of the BRAF protein mutation by means of the RT-PCR technique. Results show that the most affected sex is the female (54 %). Age group with the highest number of cases is between 56 and 75 years old (44 % of cases). The histological type that predominated is acral lentiginous melanoma (59 %) and the most frequent location is in the lower limb (71 %). No cases of malignant lentigo melanoma were found in the cases studied. The BRAF gene mutation was found in 6 % of the cases, which represents an important data for the prognosis and treatment of the patient. In addition, being one of the first studies that include the molecular factor, it opens the way to a line of research that allows patients with melanoma to continue in Guatemala. This would allow to determine prognostic and predictive factors, as well as treatments of the cases under study.


Assuntos
Imuno-Histoquímica/métodos , Melanoma/diagnóstico , Mutação/genética , Neoplasias Cutâneas , Hospitais de Doenças Crônicas , Melanoma/patologia
4.
J Exp Med ; 216(5): 1061-1070, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30975894

RESUMO

Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis. The assessment of surrogate markers of tumor progression in circulating extracellular vesicles could be a powerful non-invasive approach in this setting. We have characterized extracellular vesicles purified from the lymphatic drainage also known as exudative seroma (ES) of stage III melanoma patients obtained after lymphadenectomy. Proteomic analysis showed that seroma-derived exosomes are enriched in proteins resembling melanoma progression. In addition, we found that the BRAFV600E mutation can be detected in ES-derived extracellular vesicles and its detection correlated with patients at risk of relapse.


Assuntos
Progressão da Doença , Vesículas Extracelulares/metabolismo , Exsudatos e Transudatos/metabolismo , Melanoma/genética , Melanoma/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Seroma/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Intervalo Livre de Doença , Drenagem , Exossomos/metabolismo , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Proteômica/métodos , Neoplasias Cutâneas/patologia
6.
Cancer Cell ; 35(1): 46-63.e10, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30581152

RESUMO

Modulators of mRNA stability are not well understood in melanoma, an aggressive tumor with complex changes in the transcriptome. Here we report the ability of p62/SQSTM1 to extend mRNA half-life of a spectrum of pro-metastatic factors. These include FERMT2 and other transcripts with no previous links to melanoma. Transcriptomic, proteomic, and interactomic analyses, combined with validation in clinical biopsies and mouse models, identified a selected set of RNA-binding proteins (RBPs) recruited by p62, with IGF2BP1 as a key partner. This p62-RBP interaction distinguishes melanoma from other tumors where p62 controls autophagy or oxidative stress. The relevance of these data is emphasized by follow-up analyses of patient prognosis revealing p62 and FERMT2 as adverse determinants of disease-free survival.


Assuntos
Melanoma/metabolismo , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , RNA Mensageiro/química , Proteínas de Ligação a RNA/metabolismo , Proteína Sequestossoma-1/metabolismo , Animais , Linhagem Celular Tumoral , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/genética , Proteínas de Membrana/química , Camundongos , Proteínas de Neoplasias/química , Transplante de Neoplasias , Mapas de Interação de Proteínas , Proteômica/métodos , Estabilidade de RNA , Análise Serial de Tecidos
7.
PLoS One ; 13(6): e0198477, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29894486

RESUMO

Differentiating early mycosis fungoides (MF) from inflammatory dermatitis is a challenge. We compare the differential expression profile of early-stage MF samples and benign inflammatory dermatoses using microRNA (miRNA) arrays. 114 miRNAs were found to be dysregulated between these entities. The seven most differentially expressed miRNAs between these two conditions were further analyzed using RT-PCR in two series comprising 38 samples of early MFs and 18 samples of inflammatory dermatitis. A series of 51 paraffin-embedded samples belonging to paired stages of 16 MF patients was also analyzed. MiRNAs 26a, 222, 181a and 146a were differentially expressed between tumoral and inflammatory conditions. Two of these miRNAs (miRNA-181a and miRNA-146a) were significantly deregulated between early and advanced MF stages. Bioinformatic analysis showed FOXP3 expression to be regulated by these miRNAs. Immunohistochemistry revealed the level of FOXP3 expression to be lower in tumoral MFs than in plaque lesions in paraffin-embedded tissue. A functional study confirmed that both miRNAs diminished FOXP3 expression when overexpressed in CTCL cells. The data presented here suggest that the analysis of a restricted number of miRNAs (26a, 222, 181a and 146a) could be sufficient to differentiate tumoral from reactive conditions. Moreover, these miRNAs seem to be involved in MF progression.


Assuntos
Fatores de Transcrição Forkhead/genética , MicroRNAs/genética , Micose Fungoide/genética , Neoplasias Cutâneas/genética , Regiões 3' não Traduzidas , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Micose Fungoide/metabolismo , Neoplasias Cutâneas/metabolismo
8.
Front Neurol ; 9: 272, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755400

RESUMO

Epidemiological associations linking between obstructive sleep apnea and poorer solid malignant tumor outcomes have recently emerged. Putative pathways proposed to explain that these associations have included enhanced hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) cell expression in the tumor and altered immune functions via intermittent hypoxia (IH). Here, we examined relationships between HIF-1α and VEGF expression and nocturnal IH in cutaneous melanoma (CM) tumor samples. Prospectively recruited patients with CM tumor samples were included and underwent overnight polygraphy. General clinical features, apnea-hypopnea index (AHI), desaturation index (DI4%), and CM characteristics were recorded. Histochemical assessments of VEGF and HIF-1α were performed, and the percentage of positive cells (0, <25, 25-50, 51-75, >75%) was blindly tabulated for VEGF expression, and as 0, 0-5.9, 6.0-10.0, >10.0% for HIF-1α expression, respectively. Cases with HIF-1α expression >6% (high expression) were compared with those <6%, and VEGF expression >75% of cells was compared with those with <75%. 376 patients were included. High expression of VEGF and HIF-1α were seen in 88.8 and 4.2% of samples, respectively. High expression of VEGF was only associated with increasing age. However, high expression of HIF-1α was significantly associated with age, Breslow index, AHI, and DI4%. Logistic regression showed that DI4% [OR 1.03 (95% CI: 1.01-1.06)] and Breslow index [OR 1.28 (95% CI: 1.18-1.46)], but not AHI, remained independently associated with the presence of high HIF-1α expression. Thus, IH emerges as an independent risk factor for higher HIF-1α expression in CM tumors and is inferentially linked to worse clinical CM prognostic indicators.

9.
Am J Dermatopathol ; 40(7): 506-510, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29077579

RESUMO

Congenital melanocytic nevi (CMN) are benign melanocytic proliferations that are usually present at birth. A somatic mosaicism for an NRAS point mutation is responsible for the several phenotypic abnormalities that may be associated with congenital nevi. We report the case of a 7-year-old boy with a proliferative nodule (PN) arising in a Giant CMN completely excised and with several visceral and intraspinal melanoma metastases with no evidence of primary cutaneous melanoma. The careful analysis of the clinical, morphologic, and molecular features allowed the distinction of between the benign PN (BPN) and the melanoma. The BPN showed a characteristic comparative genomic hybridization pattern with gains or losses of whole chromosomes, whereas the melanoma displayed gains or losses involving complex partial chromosomal copy number gains or losses. Leptomeningeal melanocytes are more susceptible to transformation by oncogenic NRAS than cutaneous melanocytes, and central nervous system melanomas are more common than cutaneous melanomas in the setting of CMN. Thus, it has been recommended to characterize the congenital disease in patients with 2 CMN at birth, independently of size and site, with a single magnetic resonance imaging screening younger than the age of 1 year.


Assuntos
GTP Fosfo-Hidrolases/genética , Melanoma/genética , Proteínas de Membrana/genética , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética , Criança , Humanos , Masculino , Melanoma/patologia , Mutação , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia
10.
Nat Commun ; 8(1): 2249, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29269732

RESUMO

Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer.


Assuntos
Proteínas CELF1/fisiologia , Melanoma/genética , Oncogenes , Biologia de Sistemas , Regiões 3' não Traduzidas , Biópsia , Proteínas CELF1/genética , Proteínas CELF1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Cromossômicas não Histona/metabolismo , Humanos , Imunoprecipitação , Melanoma/patologia , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Prognóstico , Proteômica , RNA Neoplásico/genética , Análise de Sobrevida , Transcriptoma
11.
Melanoma Res ; 27(6): 558-564, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28885396

RESUMO

Melanoma is a highly prevalent cancer that is associated with substantial mortality. Although clinical staging procedures can serve as relatively robust prognostic indicators, we aimed to determine whether assessments of the abundance of hypoxia inducible factor-1α (HIF-1α) or vascular endothelial growth factor (VEGF) in postexcisional melanoma tumor tissues may enable more accurate determination of tumor aggressiveness. We carried out a multicenter prospective study, in which we systematically evaluated 376 consecutive patients diagnosed with melanoma, and performed histochemical assessments for both HIF-1α and VEGF immunoreactivity in the tumor biopsies. Multivariate analyses showed that higher HIF-1α expression, but not high VEGF, were associated significantly and independently with increased tumor aggressiveness as derived from several well-established aggressiveness criteria. A limitation of this study was that this was a descriptive prospective study lacking a post-hoc verification arm. Thus, the presence of increased numbers of positively labeled HIF-1α cells in melanoma tumors may potentially serve as an indicator of tumor phenotype and prognosis, and accordingly guide therapy.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Estudos de Coortes , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fator A de Crescimento do Endotélio Vascular/genética
12.
Nature ; 546(7660): 676-680, 2017 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-28658220

RESUMO

Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis. However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma. Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress. Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma. Still, the identities and prognostic value of lymphangiogenic mediators remain unclear. Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches. Injectable lymphatic tracers have been developed, but their limited diffusion precludes whole-body imaging at visceral sites. Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer. Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.


Assuntos
Citocinas/metabolismo , Vasos Linfáticos/metabolismo , Metástase Neoplásica/diagnóstico por imagem , Metástase Neoplásica/patologia , Imagem Corporal Total/métodos , Animais , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/metabolismo , Feminino , Genes Reporter , Humanos , Linfangiogênese , Vasos Linfáticos/patologia , Masculino , Melanoma/diagnóstico por imagem , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Midkina , Comunicação Parácrina , Prognóstico , Recidiva , Reprodutibilidade dos Testes , Serina-Treonina Quinases TOR/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Am J Dermatopathol ; 39(4): 291-295, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28323782

RESUMO

Therapies targeting the BRAF oncogene have improved the overall and disease-free survival of patients with advanced melanomas. An unresolved issue in clinical practice is the existence (or not) of BRAF-mutated and BRAF-nonmutated tumors in individual patients (intrapatient BRAF mutation heterogeneity), which may serve as a mechanism of resistance to BRAF inhibitors or lead to diagnostic problems. Different research groups have reported differing results after analyzing the BRAF mutation statuses of multiple melanoma tumors. Herein, we present a brief revision of the literature on this controversial topic and propose a theory to justify the divergence of the results found in the literature.


Assuntos
Análise Mutacional de DNA/métodos , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Humanos
16.
Appl Immunohistochem Mol Morphol ; 25(3): 209-212, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-26894645

RESUMO

Fordyce spots are a frequent condition under which sebaceous glands are found in the oral mucosa. There are 2 studies in the literature that have found an association between Fordyce spots and either Muir-Torre syndrome or Lynch syndrome. Despite this, no study on the expression of mismatch repair (MMR) proteins has been performed on biopsies of Fordyce granules. In this study, we intend to study the expression of MMR proteins under Fordyce condition. We investigated 9 cases of Fordyce spots of the oral mucosa from 6 men and 3 women, using immunohistochemistry with antibodies for the MutS protein homolog 6 (MSH6), MutS protein homolog 2 (MSH2), MutL protein homolog 1 (MLH1), and postmeiotic segregation increased 2 (PMS2). All cases showed the preservation of the expression of all markers. Even though a strong association has been demonstrated between Lynch syndrome and Fordyce spots, our study suggests that studying the biopsies of Fordyce condition by immunohistochemistry for MMR proteins might not be necessary.


Assuntos
Reparo de Erro de Pareamento de DNA , Mucosa Bucal/patologia , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Muir-Torre/patologia
17.
Pigment Cell Melanoma Res ; 30(2): 194-202, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27893188

RESUMO

DEK is an oncoprotein involved in a variety of cellular functions, such as DNA repair, replication, and transcriptional control. DEK is preferentially expressed in actively proliferating and malignant cells, including melanoma cell lines in which DEK was previously demonstrated to play a critical role in proliferation and chemoresistance. Still, the impact of this protein in melanoma progression remains unclear. Thus, we performed a comprehensive analysis of DEK expression in different melanocytic tumors. The immunostaining results of 303 tumors demonstrated negligible DEK expression in benign lesions. Conversely, malignant lesions, particularly in metastatic cases, were largely positive for DEK expression, which was partially associated with genomic amplification. Importantly, DEK overexpression was correlated with histological features of aggressiveness in primary tumors and poor prognosis in melanoma patients. In conclusion, our study provides new insight into the involvement of DEK in melanoma progression, as well as proof of concept for its potential application as a marker and therapeutic target of melanoma.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Regulação Neoplásica da Expressão Gênica , Melanoma/patologia , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Biomarcadores Tumorais/genética , Proliferação de Células , Proteínas Cromossômicas não Histona/genética , Progressão da Doença , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Melanoma/genética , Melanoma/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Oncogênicas/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
18.
Laryngoscope ; 127(3): 561-567, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27859294

RESUMO

OBJECTIVE: Acquired tracheal stenosis (ATS) is an unusual disease often secondary to prolonged mechanical trauma. Acquired tracheal stenosis pathogenesis involves inflammation and subsequent fibrosis with narrowing of the tracheal lumen. Transforming growth factor-ß1 (TGF-ß) represents a pivotal factor in most fibrotic processes, and therefore a potential target in this context. The aim of this study is to analyze the role of TGF-ß as a target for anti-fibrotic interventions in tracheal stenosis. METHODS: Human stenotic tracheobronchial tissues from patients with benign airway stenosis and normal controls from pneumonectomy specimens were analyzed. Tracheal stenosis was induced in adult NZ rabbits by a circumferential thermal injury to the mucosa during open surgery and re-anastomosis. Rabbits were treated postoperatively with a peritracheal collagen sponge containing a TGF-ß peptide antagonist (p17) or vehicle. Fibrosis was determined by Masson's trichrome staining, and smooth muscle cell α-actin+ (α-SMA+ Confirm accuracy.) myofibroblasts, connective tissue growth factor (CTGF), and p-Smad2/3 expression by immunohistochemistry. RESULTS: Human and rabbit stenotic tissues showed extensive submucosal fibrosis, characterized by significantly increased α-SMA+ myofibroblasts and CTGF expression. In human stenotic lesions, increased p-Smad2/3+ nuclei were also observed. p17 treatment significantly reduced the fibrotic thickness, as well as the density of α-SMA+ myofibroblasts and CTGF+ cells in rabbit stenotic lesions, but failed to improve the luminal area. CONCLUSION: ATS is characterized by a TGF-ß dependent fibrotic process, but reduction of the fibrotic component by TGF-ß1 antagonist therapy was not sufficient to improve tracheal narrowing, suggesting that fibrosis may not be the main contributor to luminal stenosis. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:561-567, 2017.


Assuntos
Estenose Traqueal/tratamento farmacológico , Estenose Traqueal/patologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Adolescente , Animais , Biópsia por Agulha , Criança , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Fibrose/tratamento farmacológico , Fibrose/patologia , Humanos , Imuno-Histoquímica , Masculino , Coelhos , Valores de Referência , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Técnicas de Cultura de Tecidos , Adulto Jovem
19.
Nat Commun ; 7: 13418, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27857118

RESUMO

Nuclear 3'-end-polyadenylation is essential for the transport, stability and translation of virtually all eukaryotic mRNAs. Poly(A) tail extension can also occur in the cytoplasm, but the transcripts involved are incompletely understood, particularly in cancer. Here we identify a lineage-specific requirement of the cytoplasmic polyadenylation binding protein 4 (CPEB4) in malignant melanoma. CPEB4 is upregulated early in melanoma progression, as defined by computational and histological analyses. Melanoma cells are distinct from other tumour cell types in their dependency on CPEB4, not only to prevent mitotic aberrations, but to progress through G1/S cell cycle checkpoints. RNA immunoprecipitation, sequencing of bound transcripts and poly(A) length tests link the melanoma-specific functions of CPEB4 to signalling hubs specifically enriched in this disease. Essential in these CPEB4-controlled networks are the melanoma drivers MITF and RAB7A, a feature validated in clinical biopsies. These results provide new mechanistic links between cytoplasmic polyadenylation and lineage specification in melanoma.


Assuntos
Melanoma/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Melanoma/genética , Camundongos , Neoplasias Experimentais , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética
20.
J Am Acad Dermatol ; 75(6): 1176-1186.e4, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27502312

RESUMO

BACKGROUND: Previously, using imaging mass spectrometry (IMS), we discovered proteomic differences between Spitz nevi and Spitzoid melanomas. OBJECTIVE: We sought to determine whether IMS can assist in the classification of diagnostically challenging atypical Spitzoid neoplasms (ASN), to compare and correlate the IMS and histopathological diagnoses with clinical behavior. METHODS: We conducted a retrospective collaborative study involving centers from 11 countries and 11 US institutions analyzing 102 ASNs by IMS. Patients were divided into clinical groups 1 to 4 representing best to worst clinical behavior. The association among IMS findings, histopathological diagnoses, and clinical groups was assessed. RESULTS: There was a strong association between a diagnosis of Spitzoid melanoma by IMS and lesions categorized as clinical groups 2, 3, and 4 (recurrence of disease, metastases, or death) compared with clinical group 1 (no recurrence or metastasis beyond a sentinel node) (P < .0001). Older age and greater tumor thickness were strongly associated with poorer outcome (P = .01). CONCLUSIONS: IMS diagnosis of ASN better predicted clinical outcome than histopathology. Diagnosis of Spitzoid melanoma by IMS was strongly associated with aggressive clinical behavior. IMS analysis using a proteomic signature may improve the diagnosis and prediction of outcome/risk stratification for patients with ASN.


Assuntos
Espectrometria de Massas , Melanoma/diagnóstico por imagem , Melanoma/secundário , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Nevo de Células Epitelioides e Fusiformes/diagnóstico por imagem , Nevo de Células Epitelioides e Fusiformes/patologia , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/química , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/química , Nevo de Células Epitelioides e Fusiformes/química , Proteínas/análise , Estudos Retrospectivos , Medição de Risco , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/química , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
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