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6.
PLoS One ; 13(6): e0198789, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29920526

RESUMO

The CXCR4/CXCL12 axis has been extensively associated with different types of cancer correlating with higher aggressiveness and metastasis. In diffuse large B-cell lymphoma (DLBCL), the expression of the chemokine receptor CXCR4 is involved in the dissemination of malignant B cells and is a marker of poor prognosis. CXCR7 is a chemokine receptor that binds to the same ligand as CXCR4 and regulates de CXCR4-CXCL12 axis. These findings together with the report of CXCR7 prognostic value in several tumor types, led us to evaluate the expression of CXCR7 in diffuse large B-cell lymphoma biopsies. Here, we describe that CXCR7 receptor is an independent prognostic factor that associates with good clinical outcome. Moreover, the expression of CXCR7 associates with increased survival in CXCR4+ but not in CXCR4- DLBCL patients. Thus, the combined immunohistochemical evaluation of both CXCR7 and CXCR4 expression in DLBCL biopsies may improve their prognostic value as single markers. Finally, we show that CXCR7 overexpression in vitro is able to diminish DLBCL cell survival and increase their sensitivity to antitumor drugs. Hence, further studies on the CXCR7 receptor may establish its role in DLBCL and the molecular mechanisms that modulate CXCR4 activity.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Proteínas de Neoplasias/biossíntese , Receptores CXCR4/análise , Receptores CXCR/biossíntese , Adulto , Idoso , Biomarcadores Tumorais , Biópsia , Linhagem Celular Tumoral , Quimiocina CXCL12/fisiologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Prognóstico , Modelos de Riscos Proporcionais , Receptores CXCR/genética , Receptores CXCR/fisiologia
7.
Am J Dermatopathol ; 40(11): 846-848, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29672362

RESUMO

Mucocutaneous candidiasis is a common infection affecting both immunocompetent and immunosuppressed individuals. Diversity in the clinical and histopathological presentation of mucocutaneous candidiasis is well known. However, the occurrence of cutaneous verrucous lesions and giant yeast-like structures has been rarely reported. In this article, we describe a case of disseminated mucocutaneous candidiasis in an immunosuppressed patient who presented as a verrucous plaque on the scrotum with giant Candida blastoconidia. This peculiar presentation expands the clinicopathological spectrum of mucocutaneous candidiasis and highlights the wide range of clinical manifestations and great morphologic variability of this common fungal infection.


Assuntos
Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospedeiro Imunocomprometido , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Candida , Humanos , Masculino , Escroto/microbiologia , Escroto/patologia , Esporos Fúngicos
9.
Blood ; 128(8): 1101-11, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-27257180

RESUMO

Pediatric-type follicular lymphoma (PTFL) is a variant of follicular lymphoma (FL) with distinctive clinicopathological features. Patients are predominantly young males presenting with localized lymphadenopathy; the tumor shows high-grade cytology and lacks both BCL2 expression and t(14;18) translocation. The genetic alterations involved in the pathogenesis of PTFL are unknown. Therefore, 42 PTFL (40 males and 2 females; mean age, 16 years; range, 5-31) were genetically characterized. For comparison, 11 cases of conventional t(14:18)(-) FL in adults were investigated. Morphologically, PTFL cases had follicular growth pattern without diffuse areas and characteristic immunophenotype. All cases showed monoclonal immunoglobulin (IG) rearrangement. PTFL displays low genomic complexity when compared with t(14;18)(-) FL (mean, 0.77 vs 9 copy number alterations per case; P <001). Both groups presented 1p36 alterations including TNFRSF14, but copy-number neutral loss of heterozygosity (CNN-LOH) of this locus was more frequently observed in PTFL (40% vs 9%; P =075). TNFRSF14 was the most frequently affected gene in PTFL (21 mutations and 2 deletions), identified in 54% of cases, followed by KMT2D mutations in 16%. Other histone-modifying genes were rarely affected. In contrast, t(14;18)(-) FL displayed a mutational profile similar to t(14;18)(+) FL. In 8 PTFL cases (19%), no genetic alterations were identified beyond IG monoclonal rearrangement. The genetic landscape of PTFL suggests that TNFRSF14 mutations accompanied by CNN-LOH of the 1p36 locus in over 70% of mutated cases, as additional selection mechanism, might play a key role in the pathogenesis of this disease. The genetic profiles of PTFL and t(14;18)(-) FL in adults indicate that these are two different disorders.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Linfoma Folicular/genética , Mutação/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Células Clonais , Análise Citogenética , Variações do Número de Cópias de DNA/genética , Análise Mutacional de DNA , Éxons/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Perda de Heterozigosidade/genética , Linfoma Folicular/patologia , Masculino , Pseudolinfoma , Translocação Genética , Adulto Jovem
10.
Int J Gynecol Pathol ; 34(3): 257-65, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25844549

RESUMO

Breast carcinomas rarely metastasize to the ovary and are even more rarely present clinically as primary ovarian tumors. However, patients with breast cancer not infrequently develop independent primary ovarian carcinomas. In these cases, distinction between independent primaries and metastatic tumors is crucial. Several comparative immunohistochemical studies have been reported, but few included significant clinicopathologic data and none investigated cases of ovarian and breast carcinomas from the same patients. In this study, we compared 18 cases of patients with bona fide independent breast and ovarian carcinomas (15 high-grade serous and 3 clear cell carcinomas), with 9 cases of patients with known mammary carcinomas (7 lobular and 2 ductal carcinomas) metastatic to the ovary. Immunohistochemical stains for Pax-8, WT-1, and GATA3 were carried out on tissue microarrays (TMA). Most primary ovarian carcinomas were larger than the metastatic tumors (P=0.001) and were diagnosed at an advanced stage. All primary ovarian tumors showed marked nuclear pleomorphism, whereas only 2 metastatic breast carcinomas had Grade 3 nuclei (P=0.000). The vast majority of ovarian metastases (7/9) showed the typical pattern of lobular breast carcinoma. Pax-8 and WT-1 expression were found in 16 of 18 (88%) and 13 of 18 (72%) primary ovarian carcinomas, respectively. In contrast, all primary ovarian carcinomas were negative for GATA3. The 2 Pax-8-negative ovarian carcinomas were also negative for WT-1. With the exception of 3 triple-negative carcinomas, all primary breast carcinomas were positive for GATA3. All metastatic breast carcinomas were positive for GATA3 and negative for Pax-8. WT-1 expression was seen in only 1 of 9 metastatic breast carcinomas (11%). Patients with ovarian metastases had worse prognosis than patients with independent breast and ovarian carcinomas (P=0.000). Pax-8, WT-1, and GATA3 immunoreactions are useful in the distinction between independent primaries and metastatic mammary carcinomas to the ovary in the light of clinicopathologic findings.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Metástase Neoplásica/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Fator de Transcrição GATA3/análise , Fator de Transcrição GATA3/biossíntese , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Fator de Transcrição PAX8 , Fatores de Transcrição Box Pareados/análise , Fatores de Transcrição Box Pareados/biossíntese , Análise Serial de Tecidos , Proteínas WT1/análise , Proteínas WT1/biossíntese
11.
J Pathol ; 235(3): 445-55, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25231113

RESUMO

The chemokine receptor CXCR4 has been implicated in the migration and trafficking of malignant B cells in several haematological malignancies. Over-expression of CXCR4 has been identified in haematological tumours, but data concerning the role of this receptor in diffuse large B cell lymphoma (DLBCL) are lacking. CXCR4 is a marker of poor prognosis in various neoplasms, correlating with metastatic disease and decreased survival of patients. We studied CXCR4 involvement in cell migration in vitro and dissemination in vivo. We also evaluated the prognostic significance of CXCR4 in 94 biopsies of DLBCL patients. We observed that the level of expression of CXCR4 in DLBCL cell lines correlated positively with in vitro migration. Expression of the receptor was also associated with increased engraftment and dissemination, and decreased survival time in NOD/SCID mice. Furthermore, administration of a specific CXCR4 antagonist, AMD3100, decreased dissemination of DLBCL cells in a xenograft mouse model. In addition, we found that CXCR4 expression is an independent prognostic factor for shorter overall survival and progression-free survival in DLBCL patients. These results show that CXCR4 mediates dissemination of DLBCL cells and define for the first time its value as an independent prognostic marker in DLBCL patients.


Assuntos
Movimento Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/fisiopatologia , Receptores CXCR4/fisiologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Humanos , Técnicas In Vitro , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Invasividade Neoplásica/fisiopatologia , Prognóstico , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Hum Pathol ; 45(5): 942-51, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24746199

RESUMO

Micro-RNA (miRNA) signatures influence the prognosis of cancer, but little is known about their role in myometrial invasion in endometrioid endometrial adenocarcinoma (EEC). We studied miRNA expression signatures in noninvasive and invasive EEC focusing on the alteration of miR-27 and its main target, FOXO1 as well as their relationship with the clinicopathological parameters and other genetic alterations such as PIK3CA mutations. In 25 tumors and 5 normal endometria, unsupervised hierarchical clustering analysis showed that normal endometria and noninvasive EEC were grouped together and separately from invasive and advanced stage tumors. Of the 20 miRNAs differentially expressed in noninvasive (stage IA) and myoinvasive adenocarcinomas (stage IB and IC), miR27 was overexpressed in invasive adenocarcinomas, and its expression increased linearly according to stage. Results were validated by quantitative real-time reverse transcription polymerase chain reaction in an independent series of 44 EEC. By in situ hybridization, miR-27 expression was limited to the stroma. Using quantitative real-time reverse transcription polymerase chain reaction, the expression of proapoptotic transcription factor FOXO1 was down-regulated in invasive compared with noninvasive tumors. Furthermore, we found that the expression of active caspase 3 was higher in noninvasive than invasive EEC. When stratified by PIK3CA mutations, all invasive tumors down-regulated FOXO1, but only nonmutated adenocarcinomas showed miR-27 overexpression. In conclusion, we propose that the miR27-FOXO1 tandem inhibits apoptosis and represents an alternative pathway for tumor cell survival in PIK3CA-nonmutated EEC.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Fatores de Transcrição Forkhead/fisiologia , MicroRNAs/genética , Invasividade Neoplásica/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/patologia , Caspase 3/biossíntese , Classe I de Fosfatidilinositol 3-Quinases , Regulação para Baixo , Neoplasias do Endométrio/patologia , Feminino , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/biossíntese , Humanos , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética
13.
Mod Pathol ; 27(4): 631-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24263966

RESUMO

The pattern of myometrial invasion in endometrioid endometrial carcinomas varies considerably; ie, from widely scattered glands and cell nests, often associated with a fibromyxoid stromal reaction (desmoplasia) and/or a lymphocytic infiltrate, to invasive glands with little or no stromal response. Recently, two distinct stromal signatures derived from a macrophage response (colony-stimulating factor 1, CSF1) and a fibroblastic response (desmoid-type fibromatosis, DTF) were identified in breast carcinomas and correlated with clinicopathologic features including outcome. In this study, we explored whether these stromal signatures also apply to endometrioid carcinomas and how their expression patterns correlated with morphologic changes. We studied the stromal signatures both by immunohistochemistry and in situ hybridization in 98 primary endometrioid carcinomas with (87 cases) and without (11 cases) myometrial invasion as well as in the corresponding regional lymph nodes metatases of 9 myoinvasive tumors. Desmoplasia correlated positively with the DTF expression signature. Likewise, mononuclear infiltrates were found in the stroma of tumors expressing CSF1. Twenty-four out of eighty-seven (27%) myoinvasive endometrioid carcinomas were positive for the macrophage signature and thirteen out of eighty-seven (15%) expressed the fibroblast signature. Eleven additional cases were positive for both DTF and CSF1 signatures (11/87; 13%). However, over half of the cases (39/87; 45%) and the majority of the non-myoinvasive tumors (8/11; 73%) failed to express any of the two stromal signatures. The macrophage response (CSF1) was associated with higher tumor grade, lymphovascular invasion, and PIK3CA mutations (P<0.05). There was a concordance in the expression of the CSF1 signature in the primary tumors and their corresponding lymph node metastases. This study is the first characterization of stromal signatures in endometrioid carcinomas. Our findings shed new light on the relationship between genetically different endometrioid carcinomas and various stromal responses. Preservation of the CSF1 macrophage stromal response in the metastases leds support to targeting the CSF1 pathway in endometrioid endometrial carcinomas.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Endometrioide/química , Neoplasias do Endométrio/química , Fibroblastos/química , Macrófagos/química , Células Estromais/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/secundário , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Fator Estimulador de Colônias de Macrófagos/análise , Macrófagos/patologia , Pessoa de Meia-Idade , Mutação , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/genética , Valor Preditivo dos Testes , Células Estromais/patologia , Microambiente Tumoral
15.
Hum Pathol ; 44(1): 20-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22939961

RESUMO

The origin of the primary tumor is sometimes difficult to determine in peritoneal and ovarian metastases. A series of 25 metastatic tumors to the ovary and 7 cases of peritoneal carcinomatosis of suspected gynecologic origin were collected. Total RNA was extracted from frozen tumor tissue and studied by the Tissue of Origin-Frozen test, a microarray-based gene expression test from Pathwork Diagnostics (Redwood City, CA). Independently, formalin-fixed, paraffin-embedded tumor tissue was subjected to pathologic analysis. Immunohistochemical stains included keratins 7 and 20, estrogen and progesterone receptors, CDX2, villin, CEA, WT-1, TTF-1, mammoglobin, GCDF-15, and CD31. Clinical data were considered as gold standard, and after clinicopathologic evaluation, the tissue of origin was found in 29 cases. The Tissue of Origin-Frozen test correctly identified the ovary as site of origin in 7 of 7 peritoneal carcinomatosis cases, whereas immunohistochemical stains only allowed appropriate recognition in 5. In addition, the Tissue of Origin-Frozen test identified correctly the site of origin in 18 of the 22 metastatic tumors to the ovary with known origin. In the remaining 4 tumors, the correct origin was the second option in 2 cases and was not determined in the other 2. Immunohistochemistry correctly identified the site of origin in 17 of these 22 ovarian metastases. A combination of Tissue of Origin-Frozen and immunohistochemistry correctly identified the site of origin in 19 of 22 ovarian metastases of known origin. Although conventional pathologic examination and immunohistochemistry are commonly used for assessing the tumor site of origin, Tissue of Origin testing can be useful in difficult cases.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/secundário , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/secundário , Neoplasias Peritoneais/secundário , Biomarcadores Tumorais/genética , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Primárias Múltiplas/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Reprodutibilidade dos Testes , Estudos Retrospectivos
16.
Hum Pathol ; 43(5): 632-43, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21940036

RESUMO

Epithelial to mesenchymal transition is thought to be implicated in tumor invasion and metastasis. To investigate its role in myometrial invasion, samples from 42 stage I (confined to the corpus) endometrioid endometrial carcinomas were analyzed. All E-cadherin repressors (SNAI1, SNAI2 (SLUG), ZEB1, HMGA2, and TWIST1) had a higher expression in endometrioid endometrial carcinomas than in normal endometrium (P < .0001), whereas CDH1 (E-cadherin gene) tended to be lower. In comparison with nonmyoinvasive (stage IA) tumors, those with deep myometrial invasion (stage IC) had increased messenger RNA expression of SLUG, ZEB1, and HMGA2 (P < .001). Furthermore, samples from the myoinvasive front of deeply invasive tumors had higher levels of SLUG, ZEB1, and HMGA2 than the corresponding superficial samples. Immunohistochemical analysis of these cases revealed that the decrease in E-cadherin was concordant with an increase in Snail and Twist protein expression. Trying to induce epithelial to mesenchymal transition in endometrioid endometrial carcinomas, we initially produced persistent activation of this pathway in Ishikawa cells. The cell line was infected with lentiviruses carrying the V600E mutation of BRAF, inducing loss of ß-catenin, E-cadherin, and cytokeratin and increase in vimentin and Snail. These changes were mediated by ERK1/2 phosphorylation, which was also increased at the myoinvasive front. Furthermore, MEK1/2 inhibitor UO126 reversed the mesenchymal phenotype. Our findings suggest that epithelial to mesenchymal transition regulators are implicated in myometrial invasion of endometrioid endometrial carcinoma and may be potential therapeutic targets through the MAPK/ERK pathway.


Assuntos
Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Transição Epitelial-Mesenquimal , Adulto , Idoso , Idoso de 80 Anos ou mais , Caderinas/genética , Caderinas/metabolismo , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Progressão da Doença , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , beta Catenina/genética , beta Catenina/metabolismo
17.
Acta otorrinolaringol. esp ; 62(5): 392-394, sept.-oct. 2011. ilus
Artigo em Espanhol | IBECS | ID: ibc-92551

RESUMO

La afectación del conducto auditivo externo (CAE) por la amiloidosis es extremadamente rara. Presentamos el caso de un hombre de 76 años de edad que consultó por otorrea e hipoacúsia de 6 meses de evolución. El examen mostró un nódulo subcutáneo que ocupaba la luz del CAE y que tras su extirpación se diagnosticó de amiloidosis localizada unilateral. En estos casos es primordial descartar una amiloidosis sistémica (AU)


Amyloidosis involving the external ear is extremely rare. We present the case of a76-year-old man who referred unilateral otorrhea and hypoacusis of six months’ duration. The external auditory canal (EAC) was narrowed by a subcutaneous nodule. After its extirpation, unilateral localised amyloidosis of the EAC was diagnosed. In these rare cases, it is crucial to rule out systemic amyloidosis (AU)


Assuntos
Humanos , Masculino , Idoso , Meato Acústico Externo , Amiloidose/diagnóstico , Otopatias/diagnóstico
18.
Am J Pathol ; 179(5): 2601-10, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21907693

RESUMO

Activation of the endoplasmic reticulum (ER) stress pathway is associated with poor response to doxorubicin-containing regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine and prednisone (R-CHOP), in patients with diffuse large B-cell lymphoma (DLBCL). Bortezomib, a proteasome inhibitor, interferes with ER responses and improves survival in patients with aggressive hematologic malignant tumors, although its use in DLBCL patients remains controversial. The 78-kDa glucose-regulated protein (GRP78), also known as immunoglobulin heavy chain binding protein (BiP), is an ER stress sensor involved in the resistance to doxorubicin and bortezomib, but its role in the response to chemotherapy in DLBCL has not been explored before. We show that high BiP/GRP78 expression is related to worse overall survival (median overall survival, 5.2 versus 3.4 years). Moreover, cell death after R-CHOP in DLCBL cell lines is associated with decreased BiP/GRP78 expression. Conversely, DLBCL cell lines are primarily resistant to bortezomib, probably owing to BiP/GRP78 overexpression. Small-interfering RNA silencing of BiP/GRP78 renders all cell lines sensitive to bortezomib. R-CHOP with bortezomib (R-CHOP-BZ) reduces BiP/GRP78 expression and overcomes bortezomib resistance, mimicking the small-interfering RNA silencing of BiP/GRP78. Accordingly, R-CHOP-BZ is the most effective treatment, providing a rationale for the use of this combinational therapy to improve DLBCL patient survival. Moreover, this study provides preclinical evidence that the germinal center B-cell-like subtype DLBCL is sensitive to bortezomib combined with immunochemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Receptores de Neuropeptídeos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ácidos Borônicos/administração & dosagem , Bortezomib , Linhagem Celular Tumoral , Ciclofosfamida/administração & dosagem , Regulação para Baixo , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Pirazinas/administração & dosagem , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/fisiologia , Análise de Sobrevida , Resultado do Tratamento , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Vincristina/administração & dosagem , Adulto Jovem
19.
Mod Pathol ; 24(10): 1360-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21623383

RESUMO

Recently, mutation of the FOXL2 gene has been consistently identified in adult granulosa cell tumors of the ovary. The purpose of this study is to investigate whether the FOXL2 mutation and mRNA expression have a role in the pathogenesis of juvenile and adult granulosa cell tumors and influence tumor progression. Thirty-four adult granulosa cell tumors and 20 juvenile granulosa cell tumors were examined for the presence of the FOXL2 (C402G) mutation. Expression levels were studied by quantitative PCR and immunohistochemistry. We found that FOXL2 (C402G) mutation was present in 19/27 (70%) of the adult type tumors but in none of the juvenile granulosa cell tumors (0/18). No correlation was encountered between the presence of FOXL2 mutation and various clinicopathologic parameters except for the presence of a different sex-cord component, which was more frequently found in the subgroup of wild-type adult granulosa cell tumors than in the mutated tumors. Patients with tumors harboring the FOXL2 (C402G) mutation had a worse disease-free survival than those with the wild-type gene. Expression levels of FOXL2 mRNA had an impact on disease-free survival in both adult and juvenile granulosa cell tumors. We also found that the mutated tumors had a higher immunohistochemical expression of the FOXL2 protein, and there was a linear correlation between mRNA and immunohistochemical FOXL2 expression in both adult and juvenile granulosa cell tumors. Patients with juvenile granulosa cell tumors and higher FOXL2 protein expression had worse overall survival and disease-free survival than those with negative or weakly immunoreactive tumors. Our data suggest that FOXL2 mutation and mRNA expression are of prognostic importance in both adult and juvenile granulosa cell tumors.


Assuntos
Biomarcadores Tumorais/genética , Fatores de Transcrição Forkhead/genética , Tumor de Células da Granulosa/genética , Mutação , Neoplasias Ovarianas/genética , RNA Mensageiro/análise , Adolescente , Adulto , Fatores Etários , Idoso , Biomarcadores Tumorais/análise , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Proteína Forkhead Box L2 , Fatores de Transcrição Forkhead/análise , Tumor de Células da Granulosa/química , Tumor de Células da Granulosa/mortalidade , Tumor de Células da Granulosa/patologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Fatores de Tempo , Regulação para Cima , Adulto Jovem
20.
Blood ; 117(4): 1270-9, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21106982

RESUMO

Despite the promising introduction of the proteasome inhibitor bortezomib in the treatment of mantle cell lymphoma (MCL), not all patients respond, and resistance often appears after initial treatment. By analyzing a set of 18 MCL samples, including cell lines with constitutive or induced resistance to bortezomib, we found a high correlation between loss of sensitivity to the proteasome inhibitor and up-regulation of the prosurvival chaperone BiP/Grp78. BiP/Grp78 stabilization was ensured at a posttranscriptional level by an increase in the chaperoning activity of heat shock protein of 90 kDa (Hsp90). In bortezomib-resistant cells, both BiP/Grp78 knockdown and cell pretreatment with the Hsp90 inhibitor of the ansamycin class, IPI-504, led to synergistic induction of apoptotic cell death when combined with bortezomib. Cell exposure to the IPI-504-bortezomib combination provoked the dissociation of Hsp90/BiP complexes, leading to BiP/Grp78 depletion, inhibition of unfolded protein response, and promotion of NOXA-mediated mitochondrial depolarization. The IPI-504-bortezomib combination also prevented BiP/Grp78 accumulation, thereby promoting apoptosis and inhibiting the growth of bortezomib-resistant tumors in a mouse model of MCL xenotransplantation. These results suggest that targeting unfolded protein response activation by the inhibition of Hsp90 may be an attractive model for the design of a new bortezomib-based combination therapy for MCL.


Assuntos
Benzoquinonas/farmacologia , Ácidos Borônicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Lactamas Macrocíclicas/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Bortezomib , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico/metabolismo , Humanos , Lactamas Macrocíclicas/uso terapêutico , Linfoma de Célula do Manto/genética , Masculino , Camundongos , Camundongos SCID , Camundongos Transgênicos , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Receptores Estrogênicos/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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