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1.
Biol Pharm Bull ; 46(3): 427-431, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36858571

RESUMO

Studies have reported an association between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis in patients with melanoma treated with ipilimumab. However, it remains unclear whether NLR is useful in Japanese patients with melanoma, and if so, what is the optimal cut-off value. We retrospectively examined 38 patients who received ipilimumab from August 2015 to November 2021 at Nagoya University Hospital. We divided patients into two groups: 1-2 versus 3-4 cycles of ipilimumab. In univariate analysis, baseline neutrophil count and NLR were significantly higher in patients who discontinued ipilimumab within 2 cycles. With receiver operating characteristic analysis, the optimal NLR cut-off value was found to be 3.4 (area under the curve, 0.75; 95% confidence interval, 0.58-0.92). In multivariate logistic regression analysis, baseline NLR >3.4 was an independent risk factor for ipilimumab discontinuation (odds ratio, 15.6; 95% confidence interval, 3.0-82) that was significantly associated with shorter progression-free survival (PFS) (p = 0.003, log-rank test). In conclusion, NLR >3.4 is useful for selecting Japanese patients with melanoma who might have better PFS with ipilimumab-containing treatment. Because the optimal NLR cut-off value in this study was lower than values in American and European studies, it possibly differs by race. Hence, it should be extrapolated to Japanese patients with caution.


Assuntos
Melanoma , Nivolumabe , Humanos , Ipilimumab , Estudos Retrospectivos , Neutrófilos , Japão , Linfócitos
2.
Cells ; 9(1)2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936650

RESUMO

Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.


Assuntos
Senescência Celular , Transativadores/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Linhagem Celular , DNA/metabolismo , Proteína p300 Associada a E1A/metabolismo , Fibroblastos/metabolismo , Humanos , Modelos Biológicos , Ligação Proteica , Transcrição Gênica , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteína Supressora de Tumor p53/genética
3.
Int J Clin Oncol ; 22(3): 593-599, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28124284

RESUMO

BACKGROUND: Nedaplatin (NDP)-related hypersensitivity reactions (HSRs) trigger adverse clinical events. Prediction and prevention of NDP-HSRs are thus essential to minimize the risk and maximize the benefit of NDP therapy. However, the incidence of NDP-HSRs and the associated risk factors remain unclear. METHODS: We retrospectively examined patients who received NDP monotherapy between April 2011 and July 2015 in Nagoya University Hospital. HSRs severity was defined according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE ver.4). Risk factors for NDP-HSRs were determined using multivariate logistic regression. RESULTS: Of 111 patients who received NDP monotherapy, 90 (81%) were female; median age was 59 years (range, 29-78 years). Eighty-eight patients had gynecological cancer and 20 suffered from head and neck cancer. Eight of 111 patients (7.2%) experienced NDP-HSRs, six of which developed in the second NDP cycle. However, all patients with NDP-HSRs were treated with carboplatin (CBDCA) for more than three cycles. Grade 3 and 4 HSRs developed in 2 patients. NDP-HSRs were significantly associated with a history of CBDCA-HSRs (odds ratio 37.5, 95% confidence interval 5.38-262, p < 0.001) and with the interval between NDP administration and the previous platinum treatment (odds ratio 13.9, 95% confidence interval 1.23-158, p = 0.034). CONCLUSION: The risk of NDP-HSRs increases in patients with a history of CBDCA-HSRs and in those administered NDP for more than 6 months after previous platinum treatment. Such individuals must be closely monitored if given NDP, even if they are expected to benefit from the treatment.


Assuntos
Antineoplásicos/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Compostos Organoplatínicos/efeitos adversos , Adulto , Idoso , Carboplatina/uso terapêutico , Hipersensibilidade a Drogas/etiologia , Feminino , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
4.
Sci Rep ; 6: 35483, 2016 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-27759037

RESUMO

Transforming growth factor ß (TGF-ß) signaling facilitates tumor development during the advanced stages of tumorigenesis, but induces cell-cycle arrest for tumor suppression during the early stages. However, the mechanism of functional switching of TGF-ß is still unknown, and it is unclear whether inhibition of TGF-ß signaling results amelioration or exacerbation of cancers. Here we show that the tumor suppressor p53 cooperates with Smad proteins, which are TGF-ß signal transducers, to selectively activate plasminogen activator inhibitor type-1 (PAI-1) transcription. p53 forms a complex with Smad2/3 in the PAI-1 promoter to recruit histone acetyltransferase CREB-binding protein (CBP) and enhance histone H3 acetylation, resulting in transcriptional activation of the PAI-1 gene. Importantly, p53 is required for TGF-ß-induced cytostasis and PAI-1 is involved in the cytostatic activity of TGF-ß in several cell lines. Our results suggest that p53 enhances TGF-ß-induced cytostatic effects by activating PAI-1 transcription, and the functional switching of TGF-ß is partially caused by p53 mutation or p53 inactivation during cancer progression. It is expected that these findings will contribute to optimization of TGF-ß-targeting therapies for cancer.


Assuntos
Inibidor 1 de Ativador de Plasminogênio/genética , Regiões Promotoras Genéticas , Proteínas Smad/metabolismo , Ativação Transcricional , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular , Humanos , Complexos Multiproteicos/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Elementos de Resposta , Sialoglicoproteínas/metabolismo , Transdução de Sinais , Proteínas Smad/química , Proteína Supressora de Tumor p53/química
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