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1.
Proc Natl Acad Sci U S A ; 111(10): E914-23, 2014 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-24567380

RESUMO

Radiation dose rates were evaluated in three areas neighboring a restricted area within a 20- to 50-km radius of the Fukushima Daiichi Nuclear Power Plant in August-September 2012 and projected to 2022 and 2062. Study participants wore personal dosimeters measuring external dose equivalents, almost entirely from deposited radionuclides (groundshine). External dose rate equivalents owing to the accident averaged 1.03, 2.75, and 1.66 mSv/y in the village of Kawauchi, the Tamano area of Soma, and the Haramachi area of Minamisoma, respectively. Internal dose rates estimated from dietary intake of radiocesium averaged 0.0058, 0.019, and 0.0088 mSv/y in Kawauchi, Tamano, and Haramachi, respectively. Dose rates from inhalation of resuspended radiocesium were lower than 0.001 mSv/y. In 2012, the average annual doses from radiocesium were close to the average background radiation exposure (2 mSv/y) in Japan. Accounting only for the physical decay of radiocesium, mean annual dose rates in 2022 were estimated as 0.31, 0.87, and 0.53 mSv/y in Kawauchi, Tamano, and Haramachi, respectively. The simple and conservative estimates are comparable with variations in the background dose, and unlikely to exceed the ordinary permissible dose rate (1 mSv/y) for the majority of the Fukushima population. Health risk assessment indicates that post-2012 doses will increase lifetime solid cancer, leukemia, and breast cancer incidences by 1.06%, 0.03% and 0.28% respectively, in Tamano. This assessment was derived from short-term observation with uncertainties and did not evaluate the first-year dose and radioiodine exposure. Nevertheless, this estimate provides perspective on the long-term radiation exposure levels in the three regions.


Assuntos
Radioisótopos de Césio/análise , Exposição Ambiental/análise , Acidente Nuclear de Fukushima , Neoplasias/epidemiologia , Doses de Radiação , Monitoramento de Radiação/estatística & dados numéricos , Previsões , Geografia , Humanos , Japão/epidemiologia , Fatores de Risco
2.
Int J Cancer ; 132(4): 813-23, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22821812

RESUMO

Bone marrow-derived mesenchymal stem cells (MSCs) are reported to contribute to formation of tumor-promoting stromal cells. We reported recently that, in an orthotopic nude mice model of colon cancer, MSCs traveled to tumor stroma, where they differentiated into carcinoma-associated fibroblast (CAF)-like cells. We also found that CAFs express platelet-derived growth factor receptor (PDGFR) at a high level and that imatinib therapy targeting PDGFR in CAFs inhibits growth and metastasis of human colon cancer. These findings led us to examine whether the tumor-promoting effect of MSCs is impaired by blockade of PDGFR signaling achieved with imatinib. Orthotopic transplantation and splenic injection of human MSCs along with KM12SM human colon cancer cells, in comparison with transplantation of KM12SM cells alone, resulted in significantly greater promotion of tumor growth and liver metastasis. The KM12SM + MSC xenograft enhanced cell proliferation and angiogenesis and inhibited tumor cell apoptosis. When tumor-bearing animals were treated with imatinib, there was no significant increase in primary tumor volume or total volume of liver metastases, despite the KM12SM+MSC xenograft, and survival in the mixed-cell group was prolonged by imatinib treatment. Moreover, the ability of MSCs to migrate to tumor stroma was impaired, and the number of MSCs surviving in the tumor microenvironment was significantly decreased. In in vitro experiments, treatment with imatinib inhibited migration of MSCs. Our data suggest that blockade of PDGF signaling pathways influences the interaction between bone marrow-derived MSCs and tumor cells in the tumor microenvironment and, hence, inhibits the progressive growth of colon cancer.


Assuntos
Células da Medula Óssea/fisiologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células-Tronco Mesenquimais/fisiologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Apoptose , Benzamidas , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Feminino , Humanos , Mesilato de Imatinib , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neovascularização Patológica , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo , Microambiente Tumoral/efeitos dos fármacos
3.
Int J Cancer ; 128(9): 2050-62, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21387285

RESUMO

Recent studies have revealed that platelet-derived growth factor (PDGF) plays a role in promoting progressive tumor growth in several organs; however, whether PDGF plays such a role in gastric carcinoma is undetermined. We examined whether inhibition of PDGF receptor (PDGF-R) tyrosine kinase signaling by imatinib affects tumor growth and metastasis in an orthotopic nude mouse model of human gastric carcinoma. TMK-1 human gastric carcinoma cells were injected into the gastric wall of nude mice. Groups of mice (n = 10 each) received sterile water (control), low-dose imatinib (50 mg/kg/day), high-dose imatinib (200 mg/kg/day), cancer chemotherapeutic agent irinotecan (5 mg/kg/week), or imatinib (50 mg/kg/day or 200 mg/kg/day) and irinotecan (5 mg/kg/week) in combination for 28 days. Tumor growth and metastasis were assessed. Resected tumors were analyzed immunohistochemically. Carcinoma-associated fibroblasts, pericytes and lymphatic endothelial cells in stroma expressed high levels of PDGF-R; carcinoma cells did not. Treatment with imatinib alone did not inhibit tumor growth and metastasis; however, treatment with irinotecan alone or combined with imatinib significantly inhibited tumor growth. Only treatment with high-dose imatinib and irinotecan in combination inhibited lymph node and peritoneal metastases. Immunohistochemically, only imatinib alone or in combination with irinotecan was shown to significantly decrease the stromal reaction, microvessel area and pericyte coverage of tumor microvessels. These effects were marked with high-dose imatinib. In conclusion, administration of PDGF-R tyrosine kinase inhibitor in combination with irinotecan appears to impair the progressive growth of gastric carcinoma by blockade of PDGF-R signaling pathways in stromal cells.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Benzamidas , Western Blotting , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Imunofluorescência , Humanos , Mesilato de Imatinib , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Irinotecano , Masculino , Camundongos , Camundongos Nus , Microscopia Confocal , Metástase Neoplásica/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Hepatol ; 54(5): 872-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21145818

RESUMO

BACKGROUND & AIMS: The current treatment regimen for chronic hepatitis C virus (HCV) infection is peg-interferon plus ribavirin combination therapy. The majority of developing therapeutic strategies also contain peg-interferon with or without ribavirin. However, interferon is expensive and sometimes intolerable for some patients because of severe side effects. METHODS: Using human hepatocyte chimeric mice, we examined whether a short term combination therapy with the HCV NS3-4A protease inhibitor telaprevir and the RNA polymerase inhibitor MK-0608 with or without interferon eradicates the HCV from infected mice. The effect of telaprevir and MK-0608 combination therapy was examined using subgenomic HCV replicon cells. RESULTS: Combination therapy with the two drugs enhanced inhibition of HCV replication compared with either drug alone. In in vivo experiments, early emergence of drug resistance was seen in mice treated with either telaprevir or MK-0608 alone. However, emergence was prevented by the combination of these drugs. Mice treated with a triple combination therapy of telaprevir, MK-0608, and interferon became negative for HCV RNA soon after commencement of the therapy, and HCV RNA was not detected in serum of these mice 12 weeks after cessation of the therapy. Furthermore, all mice treated with a high dose telaprevir and MK-0608 combination therapy for 4 weeks became negative for HCV RNA 1 week after the beginning of the therapy and remained negative after 18 weeks. CONCLUSIONS: Eradication of HCV from mice with only 4 weeks of therapy without interferon points the way to future combination therapies for chronic hepatitis C patients.


Assuntos
Antivirais/farmacologia , Quimerismo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/farmacologia , Tubercidina/análogos & derivados , Animais , Células Cultivadas , Modelos Animais de Doenças , Quimioterapia Combinada , Hepatite C Crônica/virologia , Hepatócitos/transplante , Humanos , Camundongos , Camundongos SCID , Tubercidina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
5.
Cancer Sci ; 101(9): 1984-9, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20624165

RESUMO

Recent study of murine fibrosarcoma has revealed that platelet-derived growth factor (PDGF) plays a direct role in promoting lymphangiogenesis and metastatic spread to lymph nodes. Thus, we investigated the relation between PDGF and PDGF receptor (PDGF-R) expression and lymphatic metastasis in human gastric carcinoma. We examined PDGF-B and PDGF-Rß expression in four human gastric carcinoma cell lines (TMK-1, MKN-1, MKN-45, and KKLS) and in 38 surgical specimens of gastric carcinoma. PDGF-B and PDGF-Rß expression was examined by immunofluorescence in surgical specimens and in human gastric carcinoma cells (TMK-1) implanted orthotopically in nude mice. Groups of mice (n = 10, each) received saline (control) or PDGF-R tyrosine kinase inhibitor imatinib. PDGF-B and PDGF-Rß mRNA expression was significantly higher in patients with lymph node metastasis than in those without and was also significantly higher in diffuse-type carcinoma than in intestinal-type carcinoma. In surgical specimens, tumor cells expressed PDGF-B, but PDGF-Rß was expressed predominantly by stromal cells. Under culture conditions, expression of PDGF-B mRNA was found in all of the gastric cell lines, albeit at different levels. In orthotopic TMK-1 tumors, cancer cells expressed PDGF-B but not PDGF-Rß. PDGF-Rß was expressed by stromal cells, including lymphatic endothelial cells. Four weeks of treatment with imatinib significantly decreased the area of lymphatic vessels. Our data indicate that secretion of PDGF-B by gastric carcinoma cells and expression of PDGF-Rß by tumor-associated stromal cells are associated with lymphatic metastasis. Blockade of PDGF-R signaling pathways may inhibit lymph node metastasis of gastric carcinoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-sis/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Gástricas/genética , Idoso , Animais , Benzamidas , Western Blotting , Linhagem Celular Tumoral , Feminino , Humanos , Mesilato de Imatinib , Imuno-Histoquímica , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-sis/metabolismo , Pirimidinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Células Estromais/metabolismo
6.
Clin Vaccine Immunol ; 14(6): 678-84, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17460114

RESUMO

N-Formyl peptide receptor-like 1 (fPRL1) is a member of the chemoattractant subfamily of G protein-coupled receptors and plays a key role in inflammation via chemotaxis and the regulation of mediator release from leukocytes. Activated fPRL1 has recently been shown to induce a complicated pattern of cellular signaling in vitro, but the details of the regulation and alteration of leukocyte cellular fPRL1 during inflammation in vivo remain unclear. To clarify the alteration of neutrophil fPRL1 during inflammation in vivo, the immunohistochemical staining of neutrophil fPRL1 in samples from patients with purulent dermatitis was performed. The in vitro morphological alteration of neutrophil fPRL1 on cellular membranes by stimulation with N-formylmethionyl-leucyl-phenylalanine (fMLP) was also examined. Both the cytoplasm and the cellular membranes of blood neutrophils stained strongly for fPRL1. On the other hand, the cellular membranes of neutrophils in dermatitis tissue stained strongly for fPRL1 but the cytoplasm stained weakly. The enhancement of neutrophil fPRL1 on cellular membranes by stimulation with fMLP indicates the exocytosis of neutrophil fPRL1-containing granules. In conclusion, we for the first time confirmed the alteration of neutrophil fPRL1 in clinical cases of purulent dermatitis. Cytoplasm that was weakly stained and cellular membranes that were well stained for fPRL1 were considered to be distinctive features of activated neutrophils in purulent dermatitis tissue.


Assuntos
Regulação para Baixo , Exocitose , Neutrófilos/metabolismo , Pioderma/metabolismo , Receptores de Formil Peptídeo , Receptores de Lipoxinas , Idoso , Estudos de Casos e Controles , Células Cultivadas , Citoplasma/metabolismo , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neutrófilos/fisiologia
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