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1.
Blood Cancer J ; 7(1): e516, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-28157189

RESUMO

Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases. The mutations were then analyzed in a programmed death-1 (PD1)-positive population enriched with tumor cells and CD20-positive B cells purified by laser microdissection from 19 cases. TET2 and DNMT3A mutations were identified in both the PD1+ cells and the CD20+ cells in 15/16 and 4/7 cases, respectively. All the RHOA and IDH2 mutations were confined to the PD1+ cells, indicating that some, including RHOA and IDH2 mutations, being specific events in tumor cells. Notably, we found that all NOTCH1 mutations were detected only in the CD20+ cells. In conclusion, we identified both B- as well as T-cell-specific mutations, and mutations common to both T and B cells. These findings indicate the expansion of a clone after multistep and multilineal acquisition of gene mutations.


Assuntos
Biomarcadores Tumorais , Linfoma Extranodal de Células T-NK/genética , Mutação , Alelos , Substituição de Aminoácidos , Linfócitos B/metabolismo , Linfócitos B/patologia , DNA Metiltransferase 3A , Rearranjo Gênico do Linfócito T , Predisposição Genética para Doença , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica , Imunofenotipagem , Linfoma Extranodal de Células T-NK/metabolismo , Linfoma Extranodal de Células T-NK/patologia , Especificidade de Órgãos/genética , Fenótipo , Análise de Sequência de DNA , Recombinação V(D)J , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
2.
Oncogene ; 36(9): 1276-1286, 2017 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-27546618

RESUMO

The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.


Assuntos
Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Proteína 1 Inibidora de Diferenciação/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinogênese , Feminino , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/genética , Camundongos , Camundongos Nus , NF-kappa B/genética , NF-kappa B/metabolismo , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Transdução de Sinais , Esferoides Celulares , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Placenta ; 22(10): 882-5, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11718577

RESUMO

Though various tissue macrophages possess high glucose-6-phosphate dehydrogenase (G6PD) activity, which plays an important role in their phagocytosis/bactericidal function, the presence of this enzyme in human placental villous macrophages (Hofbauer cells) has not been determined. We examined the ultrastructural localization of glucose-6-phosphate dehydrogenase (G6PD) in Hofbauer cells in first and second trimester placental villi, using a newly developed enzyme-cytochemistry (copper-ferrocyanide) method. Electron-dense deposits indicative of G6PD activity were clearly visible in the cytoplasm and on the cytosolic side of the endoplasmic reticulum of Hofbauer cells. Positive and negative cytochemical controls ensured specific detection of enzyme activity. These observations indicated that Hofbauer cells abundantly possessed enzyme-cytochemically detectable G6PD activity. Hofbauer cell G6PD may play a role in placental defense, by supplying NADPH-dependent enzymes (i.e. nitric oxide synthase or NADPH oxidase) with NADPH. This enzyme may also fuel Hofbauer cells with ribose 5-phosphate during their cell proliferation and cell division.


Assuntos
Glucosefosfato Desidrogenase/análise , Histocitoquímica , Macrófagos/enzimologia , Placenta/citologia , Citoplasma/enzimologia , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/ultraestrutura , Feminino , Ferrocianetos , Idade Gestacional , Glucosefosfato Desidrogenase/metabolismo , Humanos , Indicadores e Reagentes , Membranas Intracelulares/enzimologia , Macrófagos/ultraestrutura , Microscopia Eletrônica , Gravidez
4.
Eur J Histochem ; 47(2): 173-6, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12777215

RESUMO

Although various tissue macrophages possess high glucose-6-phosphate dehydrogenase (G6PD) activity, which is reported to be closely associated with their phagocytotic/bactericidal function, the fine subcellular localization of this enzyme in liver resident macrophages (Kupffer cells) has not been determined. We have investigated the subcellular localization of G6PD in Kupffer cells in rat liver, using a newly developed enzyme-cytochemical (copper-ferrocyanide) method. Electron-dense precipitates indicating G6PD activity were clearly visible in the cytoplasm and on the cytosolic side of the endoplasmic reticulum of Kupffer cells. Cytochemical controls ensured specific detection of the enzymatic activity. Rat Kupffer cells abundantly possessed enzyme-cytochemically detectable G6PD activity. Kupffer cell G6PD may play a role in liver defense by delivering NADPH to NADPH-dependent enzymes. G6PD enzyme-cytochemistry may be a useful tool for the study of Kupffer cell functions.


Assuntos
Glucosefosfato Desidrogenase/metabolismo , Histocitoquímica/métodos , Células de Kupffer/enzimologia , Animais , Citoplasma/enzimologia , Citoplasma/ultraestrutura , Células de Kupffer/ultraestrutura , Masculino , Microscopia Eletrônica , Ratos , Ratos Sprague-Dawley
5.
Dis Aquat Organ ; 33(2): 111-8, 1998 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-9684317

RESUMO

Recurrent outbreaks of a disease leading to mass mortalities in an oyster (Crassostrea gigas) hatchery located in western Japan were investigated. The disease occurred regularly in 2- to 8-d-old larvae and has been experimentally controlled in the hatchery by treating the larval rearing water with streptomycin, without ascertaining the etiological agent. The signs of the disease and the course of infection resembled bacillary necrosis reported in oysters and other bivalve molluscs in the USA and Europe. Quantitative and qualitative examinations of the bacterial flora of hatchery samples including source water, broodstock, larval feed and larvae revealed a very high total bacterial load and presumptive vibrios in diseased larvae. Further, the bacterial profile revealed that Vibrio spp. constituted approximately 60 to 95% of the bacteria isolated from infected larvae and most isolates were identified as V. splendidus biovar II and V. harveyi, suggesting their possible role in the disease. However, experimental challenges proved the pathogenicity of V. splendidus II. Several isolates of V. splendidus II from infected larvae were highly pathogenic, producing 100% mortality at levels of 10(5) cfu ml-1 in 24 h, while isolates from other sources demonstrated a low degree of virulence. Detection of V. splendidus II from broodstock, especially in the gonad of a few breeders, suggests the probability that broodstock could be the source and route of transmission of this pathogen.


Assuntos
Aquicultura , Ostreidae/microbiologia , Frutos do Mar/microbiologia , Vibrio/isolamento & purificação , Animais , Antibacterianos/farmacologia , Japão , Larva/microbiologia , Testes de Sensibilidade Microbiana , Vibrio/efeitos dos fármacos , Vibrio/patogenicidade
6.
Histopathology ; 49(4): 349-57, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16978197

RESUMO

AIMS: To determine the significance of p63 protein expression in the development and progression of lung adenocarcinoma. METHODS AND RESULTS: The expression of p63 was immunohistochemically investigated in 92 cases of lung adenocarcinoma with a maximum diameter of 30 mm or less. p63 expression was observed not only in the nuclei (46/92 cases, 50%), but also in the cytoplasm of neoplastic cells (47/92, 51%). Nuclear localization of p63 was correlated with nuclear accumulation of p53 (P=0.0120), whereas the presence of nuclear p63 had no apparent effect on patient survival. Cytoplasmic localization of p63 was found to be correlated with shorter survival periods by univariate and multivariate analyses (P=0.0486 and P=0.0488, respectively) and the relation was independent of clinicopathological factors. Cytoplasmic localization of p63 was further confirmed by immunoblots of the cytoplasmic fraction of HLC-1, a lung adenocarcinoma cell line which predominately expressed DeltaNp63alpha transcript relative to TAp63 transcript by quantitative reverse transcriptase-polymerase chain reaction. CONCLUSIONS: Cytoplasmic expression of p63 is an adverse prognostic factor in patients with adenocarcinoma of the lung.


Assuntos
Adenocarcinoma/mortalidade , Biomarcadores Tumorais/análise , Citoplasma/metabolismo , Neoplasias Pulmonares/mortalidade , Proteínas de Membrana/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Núcleo Celular/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida , Proteína Supressora de Tumor p53/metabolismo
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