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1.
Medicine (Baltimore) ; 100(19): e25773, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106609

RESUMO

RATIONALE: Anti-PD-1 antibody is the standard therapy for treatment-resistant gastric cancer, but only a limited number of patients respond. Additionally, cases of hyper-progressive disease (HPD) in which tumor growth accelerates after anti-PD-1 antibody administration have been reported; however, the biological mechanism has not been elucidated. PATIENT CONCERNS: In the present case, metastatic gastric cancer was treated with the anti-PD-1 antibody, nivolumab, as third-line treatment. DIAGNOSIS: After the initiation of nivolumab therapy, a rapidly enlarging para-aortic lymph nodes were observed leading to the diagnosis of HPD. INTERVENTIONS: Multiplex immunohistochemistry was used to examine immune cells infiltrating in the primary tumor and in liver metastasis which were obtained before nivolumab treatment, and in lymph node metastasis which presented with HPD after nivolumab therapy. OUTCOMES: In the primary tumor, helper T (Th) cells, cytotoxic T lymphocytes (CTLs), regulatory T (Treg) cells, and PD-L1-negative macrophages were observed. On the other hand, in metastatic lymph nodes presenting with HPD, PD-L1-positive macrophages prominently increased, while Treg cells, CTLs, and Th cells decreased. PD-L1 expression was not observed in gastric cancer cells among the three specimens. LESSONS: The findings suggest the possibility that PD-L1-positive M2 macrophage might contribute to acceleration of tumor growth with anti-PD-1 therapy in the present case.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Nivolumabe/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Progressão da Doença , Evolução Fatal , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
2.
Sci Rep ; 10(1): 20896, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262403

RESUMO

Doxorubicin is a first-line therapy for patients with unresectable advanced soft tissue sarcoma (STS). However, because of cardiotoxicities, it is not used for patients with cardiac problems. Eribulin has exhibited efficacy for advanced STS in second- or later-line treatments. In the present study, we retrospectively analyzed the efficacy and safety of first-line eribulin therapy for patients with advanced STS unable to receive doxorubicin. Six of 28 patients who received eribulin as any line treatment received eribulin as a first-line treatment. The reasons for avoiding doxorubicin were as follows: cardiac problems for four patients and advanced age for two. Median progression-free survival (PFS) of the patients who received eribulin as first-line and, second or later-line therapy were 9.7 months (95% CI: 1.0-not reached) and 3.9 months (95% CI: 2.7-5.9), which were not significantly different. The reasons for discontinuation of eribulin were disease progression and adverse events (2 fatigue and 1 neuropathy) for three patients each. No treatment-related cardiotoxicity was observed. The findings of this study indicated that eribulin exhibits meaningful efficacy for the patients with contraindications for doxorubicin as a first-line treatment without cardiac adverse events. However, appropriate safety management is necessary because older patients are typically among those intolerable of doxorubicin.


Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/efeitos adversos , Furanos/uso terapêutico , Cetonas/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Terapia Combinada , Contraindicações , Feminino , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/cirurgia , Análise de Sobrevida
3.
J Pharm Health Care Sci ; 6(1): 24, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33292602

RESUMO

BACKGROUND: While the world's population is growing older, healthy life expectancy is not increasing. The Japanese Orthopedic Association proposed the concept of 'locomotive syndrome,' manifested as a decline in mobility functions, and introduced a short test battery for assessing the risk of this syndrome. The test battery includes the 'stand-up test,' 'two-step test,' and '25-question Geriatric Locomotive Function Scale' (25-question GLFS). The purpose of locomotion training is to improve and sustain standing and gait functions. However, the place where locomotion training can be provided and followed up has not been decided upon. Therefore, a study was conducted to explore the effect of locomotive syndrome improvement by continuous locomotion training provided at community pharmacies. The objective of this study was to evaluate the effect of pharmacists' instructions and follow-up on the compliance and effectiveness of locomotion training. METHODS: The inclusion criteria were 1) age ≥ 65 years and 2) decline in mobility functions. Guidance on how to perform locomotion training was provided by a pharmacist at the pharmacy. The participants performed locomotion training at home. They were tested and instructed at the pharmacy once a month for 3 months. The main outcome measures were test battery results and the percentage of number of days participants who were able to do the training at home. RESULTS: Eleven participants were analysed. The minimum implementation percentage was 78%. Improvements were observed in 25-question GLFS, muscle strength, and standing time on one leg. Three participants no longer showed a noticeable decline in mobility function. CONCLUSION: Continuous locomotion training provided at pharmacies could contribute to locomotive syndrome prevention. TRIAL REGISTRATION: This study was registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification No. UMIN000027963 . Registered 28 June 2017).

4.
Intern Med ; 59(20): 2571-2575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33055471

RESUMO

Drug-induced immune thrombocytopenia (DITP) is an important cause of thrombocytopenia. A 73-year-old man with relapsed rectal carcinoma received S-1, oxaliplatin and bevacizumab combination therapy (SOX+Bev). Dexamethasone was administered as an antiemetic prophylaxis. On day 2 of the first cycle, thrombocytopenia (8,000/µL) was observed. We sequentially omitted any drugs suspected to possibly induce thrombocytopenia and confirmed dexamethasone as the cause of thrombocytopenia. DITP induced by synthetic corticosteroids is very rare and this is the first case report of DITP induced by dexamethasone. Although rare, DITP due to synthetic corticosteroids including dexamethasone should be a differential diagnosis among patients receiving synthetic corticosteroids with thrombocytopenia.


Assuntos
Antieméticos/efeitos adversos , Dexametasona/efeitos adversos , Trombocitopenia/induzido quimicamente , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Idoso , Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Dexametasona/uso terapêutico , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/cirurgia , Trombocitopenia/diagnóstico , Trombocitopenia/imunologia
5.
Biochem Biophys Res Commun ; 530(1): 235-239, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32828292

RESUMO

Fat mass and obesity-associated protein (FTO) is an enzyme that demethylates N6-methyladenosine (m6A), the most abundant RNA modifications in a cell. The upregulated expression of FTO promotes the progression of various types of cancer by modulating cell-intrinsic genes which relate to malignant potential. However, the impact of FTO on the expression of immune-checkpoint molecules in the tumor cells, which are important for immune escape, has not been well understood. We examined the relevance of FTO to programmed cell death-ligand 1 (PD-L1) expression in colon cancer cells. HCT-116 cells showed high expression of both FTO and PD-L1 proteins. The knockdown of FTO by small interfering RNA decreased mRNA and protein levels of PD-L1 in HCT-116 cells. To elucidate the underlying mechanism by which FTO regulates the expression of PD-L1, we depleted FTO in HCT-116 in the presence of IFN-γ, which is a major stimulus to upregulate PD-L1 expression. Depletion of FTO reduced PD-L1 expression in an IFN-γ signaling-independent manner. RNA immunoprecipitation assay revealed the m6A modification of the PD-L1 mRNA and the binding of FTO to the PD-L1 mRNA in HCT-116. Taken together, our results indicated that FTO could regulate PD-L1 expression in colon cancer cells and provides new insights into the regulation of PD-L1 expression by RNA modification.


Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Antígeno B7-H1/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Adenosina/genética , Adenosina/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Desmetilação , Células HCT116 , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
6.
Oncoimmunology ; 9(1): 1724763, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32117589

RESUMO

Tertiary lymphoid structures (TLSs), clusters of immune cells found around tumor tissue, have been shown to be associated with anti-tumor immunity, but the cellular composition within each TLS and whether the cellular composition of a TLS affects a patient's prognosis are poorly understood. In the present study, each TLS was categorized according to its cellular composition determined by a system of multiplex immunohistochemical staining and quantitative analysis, and the correlation between the category and prognosis was examined. Sixty-seven patients with curatively resected stage II/III colorectal cancer (CRC) were enrolled. A TLS, consisting of germinal center B cells, follicular dendritic cells, T helper (Th) cells, B cells, cytotoxic T cells, and macrophages, was confirmed in the tumor tissue of 58 patients (87%). The densities of Th cells and macrophages were significantly higher in relapsed patients than in not-relapsed patients (p = .043 and p = .0076). A higher ratio of Th cells was the most significant independent risk factor for disease relapse on multivariate analysis. The subset increasing in Th cells was GATA3+ Th2. A total of 353 TLSs was divided into five clusters according to immune cell composition. Among them, the Th-rich type TLS was significantly increased (p = .0009) in relapsed patients. These data suggest the possibility that Th cell-dominant composition might disturb the anti-tumor immune response, and the function of each TLS might differ depending on its composition.

7.
Br J Cancer ; 122(10): 1507-1517, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203221

RESUMO

BACKGROUND: Anti-PD-1 monoclonal antibody, nivolumab, has shown efficacy for advanced gastric cancer (AGC). However, the specific immune cell subsets predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. METHODS: Peripheral blood of 30 AGC patients treated with nivolumab was prospectively obtained before the initial and second administrations and at the time of progressive disease (PD). The proportions of immune cell subsets and the serum concentrations of cytokines were systematically analysed by flow cytometry. Associations of subsets and serum cytokines with therapeutic effects were evaluated. RESULTS: After the initial administration, significant increases in activated central/effector memory, activated effector T cells, and activated T-helper 1 subsets were observed. At the time of PD, activated regulatory T cells, LAG3-positive CD4+/CD8+ T cells, and TIM3-positive CD4+/CD8+ T cells increased significantly. Significant positive correlations were shown between progression-free survival and proportions of LAG3-positive CD4+/CD8+ T cells and of OX40-positive CD4+/CD8+ T cells (log-rank p = 0.0008, 0.0003, 0.0035 and 0.0040). CONCLUSIONS: Nivolumab therapy enhances activation of central/effector memory and effector subsets of CD4+/CD8+ T cells. The expression levels of LAG-3 and OX40 on T cells correlated with the efficacy of nivolumab therapy and could be reasonable biomarkers for anti-PD-1 therapy.


Assuntos
Antígenos CD/genética , Nivolumabe/administração & dosagem , Ligante OX40/genética , Receptor de Morte Celular Programada 1/genética , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Linfócitos T Reguladores/efeitos dos fármacos
8.
FEBS Open Bio ; 10(1): 147-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31736281

RESUMO

Epstein-Barr virus (EBV)-associated gastric cancer (GC) is associated with a high degree of DNA methylation. However, the association between chemotherapy susceptibility and tumor DNA methylation in advanced diseases remains unclear. The comprehensive DNA methylation status of GC cells obtained from an advanced EBV-associated GC (EBVGC) case, in which complete response to S-1 plus cisplatin chemotherapy was achieved, was analyzed using a DNA methylation microarray. We compared DNA methylation of GC cells with public data and identified genes with higher methylation in EBVGC cell lines than in normal gastric cells, and genes in which methylation was increased by EBV. Of these genes, ABCG2, AHNAK2, BCL2, FZD1, and TP73 are associated with published evidence for resistance to 5-fluorouracil and cisplatin. Silencing of these genes may be associated with hypersensitivity to chemotherapy.


Assuntos
Metilação de DNA , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Herpesvirus Humano 4/patogenicidade , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Linhagem Celular , Cisplatino/farmacologia , Proteínas do Citoesqueleto/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , DNA de Neoplasias/efeitos dos fármacos , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Receptores Frizzled/genética , Inativação Gênica/efeitos dos fármacos , Herpesvirus Humano 4/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Ácido Oxônico/farmacologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias Gástricas/virologia , Tegafur/farmacologia , Proteína Tumoral p73/genética
9.
Nat Hum Behav ; 4(1): 20-26, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31332300

RESUMO

Long-lasting, romantic partnerships are a universal feature of human societies, but almost as ubiquitous is the risk of instability when one partner strays. Jealous response to the threat of infidelity is well studied, but most empirical work on the topic has focused on a proposed sex difference in the type of jealousy (sexual or emotional) that men and women find most upsetting, rather than on how jealous response varies1,2. This stems in part from the predominance of studies using student samples from industrialized populations, which represent a relatively homogenous group in terms of age, life history stage and social norms3,4. To better understand variation in jealous response, we conducted a 2-part study in 11 populations (1,048 individuals). In line with previous work, we find a robust sex difference in the classic forced-choice jealousy task. However, we also show substantial variation in jealous response across populations. Using parental investment theory, we derived several predictions about what might trigger such variation. We find that greater paternal investment and lower frequency of extramarital sex are associated with more severe jealous response. Thus, partner jealousy appears to be a facultative response, reflective of the variable risks and costs of men's investment across societies.


Assuntos
Comparação Transcultural , Ciúme , Relações Pais-Filho , Parceiros Sexuais/psicologia , Adulto , Relações Extramatrimoniais/psicologia , Feminino , Humanos , Masculino , Fatores Sexuais
10.
Cancer Sci ; 109(9): 2986-2992, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30187676

RESUMO

The liquid biopsy of ascites fluid could be an excellent source of tumor and microenvironment for the study of prognostic biomarkers because of its accessibility. Tumor-infiltrating lymphocytes (TILs) can predict prognosis in multiple malignancies, including the response to immune checkpoint inhibitors, a breakthrough cancer therapy. However, TILs' profiles from malignant ascites have not been extensively studied. Using flow cytometric analysis, we quantified the proportion of exhausted T cells and memory/naive/effector T-cell subsets, among the CD4+ and CD8+ T-cell populations of paired TILs and peripheral blood T cell samples (n = 22). The correlation between CD4+ and CD8+ subset profiles suggested that the combined analysis of CD4+ and CD8+ cells in malignant ascites was clinically significant. We found that cells positive for the exhaustion markers programmed cell death-1 (PD-1), and T-cell immunoglobulin and mucin domain 3 (TIM-3), and cells coexpressing PD-1 and TIM-3 abundantly exist among malignant ascites TILs. Furthermore, patients with high frequency of PD-1+ TIM-3+ cells among the CD4+ and CD8+ T-cell population showed worse clinical outcome in multivariate analysis (n = 27). We propose that exhausted ascites TILs represent a clinically significant prognostic biomarker in advanced gastrointestinal cancer and represent an important target for immune checkpoint inhibitors.


Assuntos
Ascite/imunologia , Neoplasias Gastrointestinais/imunologia , Receptor Celular 2 do Vírus da Hepatite A/análise , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/análise , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Neoplasias Gastrointestinais/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Cancer Sci ; 109(11): 3461-3470, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30142697

RESUMO

Disseminated cancer cells in malignant ascites possess unique properties that differ from primary tumors. However, the biological features of ascites tumor cells (ATC) have not been fully investigated. By analyzing ascites fluid from 65 gastrointestinal cancer patients, the distinguishing characteristics of ATC were identified. High frequency of CD44+ cells was observed in ATC using flow cytometry (n = 48). Multiplex quantitative PCR (n = 15) showed higher gene expression of epithelial-mesenchymal transition (EMT)-related genes and transforming growth factor beta (TGF-beta)-related genes in ATC than in the primary tissues. Immunohistochemistry (n = 10) showed that ATC also had much higher expression of phosphorylated SMAD2 than that in the corresponding primary tissues. TGF-beta 1 was detected in all cases of malignant ascites by enzyme-linked immunoassay (n = 38), suggesting the possible interaction of ATC and the ascites microenvironment. In vitro experiments revealed that these ATC properties were maintained by TGF-beta 1 in cultured ATC(n = 3). Here, we showed that ATCrevealed high frequencies of CD44 and possessed distinct EMT features from primary tissues that were mainly maintained by TGF-beta 1 in the ascites.


Assuntos
Ascite/metabolismo , Neoplasias Gastrointestinais/metabolismo , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Regulação para Cima , Idoso , Idoso de 80 Anos ou mais , Ascite/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo
12.
Cancer Sci ; 109(10): 3032-3042, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30066977

RESUMO

Human anti-programmed death-1 (PD-1) antibody possesses the capability to revitalize host T cells and has been an effective therapy for metastatic malignant melanoma (MM). The precise subsets of T cells predominantly activated by anti-PD-1, however, have not yet been clarified. In this study, peripheral blood mononuclear cells obtained from MM patients scheduled to receive anti-PD-1 (nivolumab) therapy, and healthy subjects (HS), were systematically examined on flow cytometry to identify changes in the proportion of immune cell subsets. Compared with HS, MM patients prior to therapy had an increased proportion of activated CD8+ T cells with effector memory phenotypes (Tem), and PD-1 positive subsets of CD4+ central memory T cells (Tcm) and T-helper (Th)17 cells. After a single course of anti-PD-1 therapy, MM patients had an increase in activated Tem and Tcm subsets of CD4+ and CD8+ T cells, and activated Th1 plus T-helper follicular 1 cells. There was no consistent change in the proportion of Tfh cells, B cells, natural killer cells, or dendritic cells. The observed activated phenotypes were attenuated during the course of therapy, but regulatory T cells belonging to the CD3+CD4+CD45RO+CD25high fraction increased at disease progression. Taken together, anti-PD-1 therapy modulates systemic immune reactions and exerts anti-tumor effects, not only by revitalizing Tem and Tcm of CD4+ and CD8+ T cells, but also via a shift to a Th1 phenotype.


Assuntos
Antineoplásicos/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antineoplásicos/farmacologia , Células Cultivadas , Estudos de Coortes , Citotoxicidade Imunológica/efeitos dos fármacos , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Antígenos Comuns de Leucócito/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Pessoa de Meia-Idade , Nivolumabe , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia
13.
Cancer Chemother Pharmacol ; 82(4): 625-633, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30043209

RESUMO

PURPOSE: Peripheral sensory neuropathy (PSN) and thrombocytopenia are the main dose-limiting toxicities of oxaliplatin for the treatment of advanced gastric cancer (AGC). Because the risk factors for those toxicities in practice have not been clarified, we conducted this prospective study. METHODS: AGC patients who received oxaliplatin-based therapy at any of seven institutions participating in the Kyushu Medical Oncology Group were assessed after we obtained written informed consent. RESULTS: A total of 60 patients including 39 males and 21 females were examined. The median age was 66 years. The numbers of patients receiving oxaliplatin as the first, second, or third and later lines of therapy were 39, 16, and 5, respectively. An initial dose of 130, 100, or < 100 mg/m2 oxaliplatin was administered to 12, 39, and 9 patients, respectively. S-1 or capecitabine as a concomitant drug was administered in 54 and 6 patients, respectively. In multivariate analysis, the comorbidity of diabetes mellitus was associated with ≥ grade 2 thrombocytopenia (p = 0.035). No significant risk factor was associated with ≥ grade 2 PSN. However, the accumulated dose of oxaliplatin exhibited a strong correlation with ≥ grade 2 PSN (p = 0.0043), and the predicted accumulated dose of oxaliplatin in which 10% of patients developed ≥ grade 2 PSN was 800 mg/m2. The frequency of PSN in subsequent paclitaxel therapy in patients with ≥ grade 2 or worse PSN in oxaliplatin-based chemotherapy did not increase compared to those with none or grade 1 PSN in oxaliplatin. CONCLUSION: Thrombocytopenia in AGC patients with diabetes mellitus should be carefully monitored during oxaliplatin-based therapy.


Assuntos
Hipestesia , Oxaliplatina , Doenças do Sistema Nervoso Periférico , Neoplasias Gástricas , Trombocitopenia , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Contagem de Células Sanguíneas/métodos , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipestesia/induzido quimicamente , Hipestesia/diagnóstico , Japão , Masculino , Estadiamento de Neoplasias , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico
15.
J Physiol Anthropol ; 35(1): 23, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27716348

RESUMO

BACKGROUND: Understanding the whole-body patterns of joint flexibility and their related biological and physical factors contributes not only to clinical assessments but also to the fields of human factors and ergonomics. In this study, ranges of motion (ROMs) at limb and trunk joints of young adults were analysed to understand covariation patterns of different joint motions and to identify factors associated with the variation in ROM. METHODS: Seventy-eight healthy volunteers (42 males and 36 females) living on Okinawa Island, Japan, were recruited. Passive ROM was measured at multiple joints through the whole body (31 measurements) including the left and right side limbs and trunk. RESULTS: Comparisons between males and females, dominant and non-dominant sides, and antagonistic motions indicated that body structures influence ROMs. In principal component analysis (PCA) on the ROM data, the first principal component (PC1) represented the sex difference and a similar covariation pattern appeared in the analysis within each sex. Multiple regression analysis showed that this component was associated with sex, age, body fat %, iliospinale height, and leg extension strength. CONCLUSIONS: The present study identified that there is a spectrum of "masculine" and "feminine" types in the whole-body patterns of joint flexibility. This study also suggested that body proportion and composition, muscle mass and strength, and possibly skeletal structures partly explain such patterns. These results would be important to understand individual variation in susceptibility to joint injuries and diseases and in one's suitable and effective postures and motions.


Assuntos
Amplitude de Movimento Articular/fisiologia , Adulto , Fenômenos Biomecânicos , Feminino , Humanos , Masculino , Fatores Sexuais , Adulto Jovem
16.
Masui ; 64(7): 752-5, 2015 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-26422943

RESUMO

BACKGROUND: Residual regurgitation after valve surgery affects patients' long-term prognosis. Whether post-repair regurgitation deteriorates postoperatively or not remains unclear, but this issue is a primary concern of the anesthesiologists responsible for intraoperative evaluation by transesophageal echocardiography (TEE). This study was conducted to assess changes in the severity of residual regurgitation during the early postoperative period. METHODS: Among 160 consecutive patients who underwent valve repair or valve replacement surgery during April 2010-June 2013 at our institution, 38 (24%) were found to have residual regurgitation by intraoperative TEE. We retrospectively evaluated these patients by reviewing follow-up transthoracic echocardiographic examination records. RESULTS: Residual regurgitation improved in 14 (37%), remained unchanged in 21 (55%), and worse in 3 (8%). All three patients showing worse regurgitation had undergone valve repair. Of them, one had reoperation one year later. No worsening of regurgitation, including perivalvular leakage, was found in patients who had undergone valve replacement. CONCLUSIONS: In valve repair, even mild residual regurgitation deteriorates postoperatively. Therefore, it should be observed cautiously. In valve replacement mild residual regurgitation did not deteriorate, irrespective of the regurgitation mechanism.


Assuntos
Ecocardiografia Transesofagiana , Valvas Cardíacas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Valvas Cardíacas/diagnóstico por imagem , Humanos , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico
17.
Mol Cancer Ther ; 14(4): 931-40, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25637314

RESUMO

Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, ß, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinoxalinas/administração & dosagem , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Anesth ; 29(1): 134-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25056257

RESUMO

Myxomas are the most common type of cardiac tumor. Mobile or large left atrial (LA) myxomas frequently cause functional mitral stenosis, and can lead to mitral regurgitation (MR). Difficulties have been associated with detecting masked MR jets and evaluating the severity of MR during LA myxoma surgery due to the presence of a prolapsing tumor and changes in blood flow. We herein presented a case of LA myxoma with significant MR diagnosed on intraoperative transesophageal echocardiography (TEE) prior to cardiopulmonary bypass. Repeated careful observations on TEE led to a confident diagnosis of MR and the selection of an additional appropriate procedure. This case study highlighted the importance of intraoperative TEE in supporting clinical decision-making for optimal mitral valve procedures during LA myxoma surgery.


Assuntos
Ecocardiografia Transesofagiana/métodos , Neoplasias Cardíacas/cirurgia , Complicações Intraoperatórias/diagnóstico por imagem , Insuficiência da Valva Mitral/diagnóstico por imagem , Mixoma/cirurgia , Ponte Cardiopulmonar , Humanos , Complicações Intraoperatórias/diagnóstico , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/diagnóstico
19.
Mol Biol Evol ; 31(11): 2929-40, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25086001

RESUMO

The Ryukyu Islands are located to the southwest of the Japanese archipelago. Archaeological evidence has revealed the existence of prehistoric cultural differentiation between the northern Ryukyu islands of Amami and Okinawa, and the southern Ryukyu islands of Miyako and Yaeyama. To examine a genetic subdivision in the Ryukyu Islands, we conducted genome-wide single nucleotide polymorphism typing of inhabitants from the Okinawa Islands, the Miyako Islands, and the Yaeyama Islands. Principal component and cluster analyses revealed genetic differentiation among the island groups, especially between Okinawa and Miyako. No genetic affinity was observed between aboriginal Taiwanese and any of the Ryukyu populations. The genetic differentiation observed between the inhabitants of the Okinawa Islands and the Miyako Islands is likely to have arisen due to genetic drift rather than admixture with people from neighboring regions. Based on the observed genetic differences, the divergence time between the inhabitants of Okinawa and Miyako islands was dated to the Holocene. These findings suggest that the Pleistocene inhabitants, whose bones have been found on the southern Ryukyu Islands, did not make a major genetic contribution, if any, to the present-day inhabitants of the southern Ryukyu Islands.


Assuntos
Grupo com Ancestrais do Continente Asiático , Deriva Genética , Genoma Humano , Polimorfismo de Nucleotídeo Único , Análise por Conglomerados , Feminino , Genética Populacional , Humanos , Ilhas , Japão , Masculino , Paleontologia , Análise de Componente Principal , Isolamento Reprodutivo
20.
Am J Hum Biol ; 26(4): 538-48, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24838439

RESUMO

OBJECTIVES: Differences in facial height and breadth between Okinawa Islanders and mainland Japanese have been reported in previous craniometric and somatometric studies. This study using three-dimensional (3D) images aimed to identify more detailed characteristics of facial morphology in each population. METHODS: Using a hand-held 3D scanner, we obtained 60 facial surface images each from Okinawa Islanders and mainland Japanese. Twenty-one landmarks were plotted on a computer and 27 measurements of distances and angles between the landmarks were taken. Statistical analyses such as t test, principal component analysis (PCA), regression analysis, and discriminant analysis were performed to identify sex and regional differences, the patterns of facial features, factors explaining the facial patterns, and other features. RESULTS: Okinawa Islanders showed lower facial and nasal heights than mainland Japanese. Furthermore, we identified larger protrusions of the glabella and nasal root in Okinawa Islanders than in mainland Japanese. In the PCA, we observed components of facial shape patterns. These components mainly represented facial size (PC1), facial depth (PC2), the prominence of the glabella and nasal root (PC3), and facial breadth (PC4). We identified that the population difference is strongly associated with PC3. CONCLUSIONS: This study quantitatively identified differences in the facial morphology between Okinawa Islanders and mainland Japanese using 3D digital images, with special emphases on the differences in the nasal height and the prominence of the glabella and nasal root.


Assuntos
Face/anatomia & histologia , Adulto , Cefalometria , Feminino , Humanos , Imageamento Tridimensional , Ilhas , Japão , Masculino , Adulto Jovem
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