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2.
Adv Exp Med Biol ; 1232: 291-297, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893423

RESUMO

We present an IoT-based monitoring system for healthcare that allows for long-term measurements of blood pressure (BP), heart rate (HR), and body weight (BW), as well as near-infrared spectroscopy (NIRS) for measurement of prefrontal cortex (PFC) activity. To verify the applicability of the system, it was set up in a local fitness gym for a preliminary study. A total of 39 subjects, selected from members of the gym, participated in the study. We analyzed the BP, HR, and BW data, collected from the subjects over one half-year. In addition, to assess the degree of mental stress of the subjects, we analysed left-right asymmetry of the PFC activity using the laterality index at rest (LIR) of the NIRS parameter. Results show that the subjects were able to measure their physiological data by themselves when they visited the gym, after being instructed how to perform the measurements. Furthermore, the results also indicate that ordinary people can continuously monitor physiological functions such as brain function in a non-medical facility, such as a fitness gym.


Assuntos
Monitorização Fisiológica , Córtex Pré-Frontal , Espectroscopia de Luz Próxima ao Infravermelho , Idoso , Feminino , Lateralidade Funcional , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Autoexame/normas , Estresse Psicológico
3.
Adv Exp Med Biol ; 1232: 315-322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893426

RESUMO

We present an unobtrusive cuff-less sphygmomanometer based on contact-type and optical pulse sensors for continuous and minimally invasive monitoring of blood pressure (BP). We developed a cuff-less sphygmomanometer that utilizes the pulse arrival time (PAT) to estimate continuous BP. To assess its accuracy, we recruited 10 healthy subjects in whom we carried out BP studies using the cuff-less sphygmomanometer compared with a standard cuff-type device in a stationary sitting patient. Preliminary results showed that the mean difference (MD) of estimated systolic blood pressure and diastolic blood pressure were 0.96 ± 9.6 (mean ± SD) mmHg and 1.14 ± 7.5 mmHg, respectively, compared to the control. The corresponding correlation between the estimated BP values and controls were 0.78 for systolic blood pressure (p < 0.01) and 0.69 for diastolic blood pressure (p < 0.01); thus, there were significant correlations. These results suggest that the developed cuff-less sphygmomanometer has the potential for continuous BP monitoring. Finally, we conducted a preliminary study of simultaneous monitoring of cuff-less BP and near-infrared spectroscopy to evaluate the potential for assessment of autonomic nervous system functions during mental stress tasks.


Assuntos
Determinação da Pressão Arterial , Esfigmomanômetros , Adulto , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea , Determinação da Pressão Arterial/instrumentação , Eletrocardiografia , Frequência Cardíaca , Humanos , Masculino , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/normas , Esfigmomanômetros/normas , Adulto Jovem
4.
Int Endod J ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730263

RESUMO

AIM: To assess whether Epstein-Barr virus (EBV) reactivation is triggered by persistent apical periodontitis-related microbes using in vitro and ex vivo methodologies. METHODOLOGY: Surgically removed human periapical granulomas (n = 50) and healthy gingival tissues (n = 10) were analysed to determine the presence of EBV and seven persistent apical periodontitis-related microbes. In addition, real-time polymerase chain reaction was used to detect the mRNA expression of BZLF-1, an immediate-early gene of EBV. Expression of latent membrane protein (LMP)-1 and ZEBRA, an early lytic protein of EBV encoded by BZLF-1, was also examined using triple-colour immunofluorescence staining. n-Butyric acid produced by the microbes was quantified, and luciferase assays were performed in association with bacterial lysates. In addition, Daudi cells were cultured with bacterial lysates, and the expression levels of BZLF-1 mRNA and ZEBRA protein were determined. RESULTS: EBV DNA and BZLF-1 mRNA were detected in 47 out of 50 periapical granulomas, but not in healthy gingival tissues. The EBV DNA copy number and the number of Fusobacterium nucleatum were significantly positively correlated with BZLF-1 expression in periapical granulomas. The number of Prevotella intermedia was slightly correlated with BZLF-1 expression; however, the other microbes were not. CD79a-positive B cells in periapical granulomas, but not those in healthy gingival tissues, expressed both LMP-1 and ZEBRA. n-Butyric acid production was the highest in F. nucleatum and the lowest in P. intermedia. Enterococcus faecalis, Candida albicans and the other tested microbes did not produce n-butyric acid. An F. nucleatum lysate exhibited significantly increased BZLF-1-luciferase activity in the same manner of commercial butyric acid, whereas P. intermedia did not. F. nucleatum also induced the expression of BZLF-1 mRNA and ZEBRA protein by Daudi cells, indicating that EBV reactivation was induced. CONCLUSION: Among the persistent apical periodontitis-related bacteria that were tested, F. nucleatum most strongly reactivated latent EBV, whereas E. faecalis and C. albicans as well as the other microbes did not.

5.
Int J Obstet Anesth ; 40: 32-38, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31353177

RESUMO

BACKGROUND: This study aimed to compare the postoperative analgesic effects of ultrasound-guided posterior quadratus lumborum block with spinal morphine, after cesarean section, using the visual analogue scale pain score. METHODS: One-hundred-and-seventy-six pregnant women scheduled for elective cesarean section with spinal anesthesia were randomly allocated into four groups to receive spinal morphine 0.1 mg (group M+); spinal saline (M-); posterior quadratus lumborum block using either 0.3% ropivacaine (0.45 mL/kg each side, maximum 150 mg) group pQ+); or saline (pQ-). All patients received 11-13 mg hyperbaric bupivacaine 0.5% and 10 µg fentanyl. Intravenous droperidol, fentanyl and acetaminophen were administered during surgery. Bilateral posterior quadratus lumborum block was performed immediately after surgery. Postoperative pain was assessed at 0.5, 1, 2, 4, 6, 18 and 24 h after surgery, and the pain score 6 h after surgery was the primary endpoint. RESULTS: One-hundred-and-forty-six patients were included in the final analysis. Pain scores 6 h after surgery, both at rest and when moving, were significantly different when comparing the M+pQ+ group with the M-pQ+ or M-pQ- groups, and when comparing the M+pQ- group with the M- pQ+ or M- pQ- groups (all P <0.05). There was no significant difference between the M+pQ+ and M+pQ- groups, or between the M-pQ+ and M-pQ- groups. CONCLUSION: Spinal morphine improved postoperative analgesia but the combination of posterior quadratus lumborum block with spinal morphine did not lead to further improvement.

6.
Genes Brain Behav ; 18(2): e12481, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29665250

RESUMO

Individuals use coping behaviors to deal with unpleasant daily events. Such behaviors can moderate or mediate the pathway between psychosocial stress and health-related outcomes. However, few studies have examined the associations between coping behaviors and genetic variants. We conducted a genome-wide association study (GWAS) on coping behaviors in 14088 participants aged 35 to 69 years as part of the Japan Multi-Institutional Collaborative Cohort Study. Five coping behaviors (emotional expression, emotional support seeking, positive reappraisal, problem solving and disengagement) were measured and analyzed. A GWAS analysis was performed using a mixed linear model adjusted for study area, age and sex. Variants with suggestive significance in the discovery phase (N = 6403) were further examined in the replication phase (N = 7685). We then combined variant-level association evidence into gene-level evidence using a gene-based analysis. The results showed a significant genetic contribution to emotional expression and disengagement, with an estimation that the 19.5% and 6.6% variance in the liability-scale was explained by common variants. In the discovery phase, 12 variants met suggestive significance (P < 1 × 10-6 ) for association with the coping behaviors and perceived stress. However, none of these associations were confirmed in the replication stage. In gene-based analysis, FBXO45, a gene with regulatory roles in synapse maturation, was significantly associated with emotional expression after multiple corrections (P < 3.1 × 10-6 ). In conclusion, our results showed the existence of up to 20% genetic contribution to coping behaviors. Moreover, our gene-based analysis using GWAS data suggests that genetic variations in FBXO45 are associated with emotional expression.


Assuntos
Adaptação Psicológica , Emoções Manifestas , Proteínas F-Box/genética , Polimorfismo Genético , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Oncogene ; 37(1): 75-85, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-28869604

RESUMO

Hepatocellular carcinoma (HCC) is a frequent form of cancer with a poor prognosis and with limited possibilities for medical intervention. Recent evidence has accumulated that long noncoding RNAs (lncRNAs) are important regulators of disease processes including cancer. Chromatin remodeling in cancer cells may result in an unusual expression of lncRNAs and indeed it has been shown that more than 7000 unannotated lncRNAs are expressed in HCCs. We identified a novel long intergenic noncoding RNA, Linc00176, that plays a role in proliferation and survival of HCC. Linc00176 regulates expression of more than 200 genes by the sponge function for tumor suppressor miRNAs, miR-9 and miR-185. Linc00176 is expressed at a high level only in HCC, and is activated by Myc, Max and AP-4 transcription regulators. Myc also upregulates miR-9 and miR-185. In Linc00176-depleted HCC, these miRNAs were released from Linc00176 and downregulated their target mRNAs. Thus, depletion of Linc00176 disrupted the cell cycle and induced necroptosis in HCC via released tumor suppressor miRNAs. These data indicate that atypically expressed lncRNAs may be useful targets for cancer therapy.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/metabolismo , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Conjuntos de Dados como Assunto , Regulação para Baixo , Genes Supressores de Tumor , Humanos , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/metabolismo , Regulação para Cima
9.
Ann Oncol ; 28(11): 2698-2706, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29045553

RESUMO

Background: Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients and methods: Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m2 in Japan, 75 mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. Results: A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. Conclusion: S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. Clinical trial number: Japan Pharmaceutical Information Center, JapicCTI-101155.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Salvação , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Docetaxel , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Prognóstico , Taxa de Sobrevida , Taxoides/administração & dosagem , Tegafur/administração & dosagem , Adulto Jovem
10.
Ann Oncol ; 27(12): 2242-2250, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27765756

RESUMO

BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. RESULTS: As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. CONCLUSIONS: Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. CLINICAL TRIALS NUMBER: Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Estadiamento de Neoplasias , Nivolumabe , Paclitaxel/administração & dosagem , Pemetrexede/administração & dosagem , Taxoides/administração & dosagem
11.
Nat Commun ; 7: 12577, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27552365

RESUMO

A fourth production region for the globally important Antarctic bottom water has been attributed to dense shelf water formation in the Cape Darnley Polynya, adjoining Prydz Bay in East Antarctica. Here we show new observations from CTD-instrumented elephant seals in 2011-2013 that provide the first complete assessment of dense shelf water formation in Prydz Bay. After a complex evolution involving opposing contributions from three polynyas (positive) and two ice shelves (negative), dense shelf water (salinity 34.65-34.7) is exported through Prydz Channel. This provides a distinct, relatively fresh contribution to Cape Darnley bottom water. Elsewhere, dense water formation is hindered by the freshwater input from the Amery and West Ice Shelves into the Prydz Bay Gyre. This study highlights the susceptibility of Antarctic bottom water to increased freshwater input from the enhanced melting of ice shelves, and ultimately the potential collapse of Antarctic bottom water formation in a warming climate.

12.
Ann Oncol ; 27(8): 1539-46, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27177863

RESUMO

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Japão , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Modelos de Riscos Proporcionais , Resultado do Tratamento
13.
Diabetes Metab ; 42(5): 368-371, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27161346

RESUMO

AIM: As a low-pigment skin type is prevalent in men and women with type 1 diabetes, it is possible that skin pigmentation may be associated with insulin resistance. This study aimed to cross-sectionally examine this association in healthy women. METHODS: Study participants were 792 Japanese women who attended a health examination and were not taking any medication for diabetes. Skin pigmentation on the inner upper and lower arms and forehead was measured using a Mexameter® skin colorimeter, a narrow-band reflective spectrophotometer. Data are expressed as a melanin index, which quantifies melanin content. Fasting blood glucose and insulin levels were also measured, and homoeostasis model assessment for insulin resistance (HOMA-IR) scores were calculated. Information on medical history and lifestyle factors were obtained by a self-administered questionnaire, while data on sun exposure were collected through interviews. Plasma 25-hydroxyvitamin D levels were measured in a subsample of women (n=464). RESULTS: Melanin indices at the inner upper and lower arms were significantly and inversely associated with fasting insulin levels and HOMA-IR after controlling for age, body mass index, smoking status, indicators for rater effects, cumulative sun exposure and season at the time of measurement. Additional adjustment for plasma 25-hydroxyvitamin D levels did not alter the results. CONCLUSION: These data suggest that skin pigmentation is associated with insulin resistance, and encourage future studies into the potential role of melanin and related factors in glucose homoeostasis.


Assuntos
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Resistência à Insulina/fisiologia , Pigmentação da Pele/fisiologia , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Análise de Regressão , Luz Solar , Vitamina D/sangue , Adulto Jovem
14.
Cell Death Dis ; 7: e2207, 2016 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-27124581

RESUMO

In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein-protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP-Htt axis in the process of the transcriptional repression-induced necrosis.


Assuntos
Apoptose , Proteínas de Drosophila/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Proteína Huntingtina/metabolismo , Amanitinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Drosophila/crescimento & desenvolvimento , Drosophila/metabolismo , Proteínas de Drosophila/genética , Embrião de Mamíferos/citologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Proteína Huntingtina/antagonistas & inibidores , Proteína Huntingtina/genética , Larva/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Pupa/metabolismo , Processamento de RNA/efeitos dos fármacos , Ratos , Ratos Wistar , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteínas Contendo Repetições de beta-Transducina/genética , Proteínas Contendo Repetições de beta-Transducina/metabolismo
15.
Heredity (Edinb) ; 116(2): 135-45, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26328757

RESUMO

Ommochromes are major insect pigments involved in coloration of compound eyes, eggs, epidermis and wings. In the silkworm Bombyx mori, adult compound eyes and eggs contain a mixture of the ommochrome pigments such as ommin and xanthommatin. Here, we identified the gene involved in ommochrome biosynthesis by positional cloning of B. mori egg and eye color mutant pink-eyed white egg (pe). The recessive homozygote of pe has bright red eyes and white or pale pink eggs instead of a normal dark coloration due to the decrease of dark ommochrome pigments. By genetic linkage analysis, we narrowed down the pe-linked region to ~258 kb, containing 17 predicted genes. RNA sequencing analyses showed that the expression of one candidate gene, the ortholog of Drosophila haem peroxidase cardinal, coincided with egg pigmentation timing, similar to other ommochrome-related genes such as Bm-scarlet and Bm-re. In two pe strains, a common missense mutation was found within a conserved motif of B. mori cardinal homolog (Bm-cardinal). RNA interference-mediated knockdown and transcription activator-like effector nuclease (TALEN)-mediated knockout of the Bm-cardinal gene produced the same phenotype as pe in terms of egg, adult eye and larval epidermis coloration. A complementation test of the pe mutant with the TALEN-mediated Bm-cardinal-deficient strain showed that the mutant phenotype could not be rescued, indicating that Bm-cardinal is responsible for pe. Moreover, knockdown of the cardinal homolog in Tribolium castaneum also induced red compound eyes. Our results indicate that cardinal plays a major role in ommochrome synthesis of holometabolous insects.


Assuntos
Bombyx/genética , Proteínas de Insetos/genética , Fenotiazinas/metabolismo , Pigmentação/genética , Animais , Clonagem Molecular , Olho , Feminino , Técnicas de Inativação de Genes , Genes de Insetos , Teste de Complementação Genética , Ligação Genética , Proteínas de Insetos/metabolismo , Larva , Masculino , Óvulo , Fenótipo , Filogenia , Interferência de RNA , Tribolium/genética
16.
Oncogene ; 35(29): 3872-9, 2016 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-26549021

RESUMO

Hepatocellular carcinoma (HCC) is a frequent form of cancer with a poor prognosis and with limited possibilities of medical intervention. It has been shown that over 100 putative driver genes are associated with multiple recurrently altered pathways in HCC, suggesting that multiple pathways will need to be inhibited for any therapeutic method. mRNA processing is regulated by a complex RNA-protein network that is essential for the maintenance of homeostasis. THOC5, a member of mRNA export complex, has a role in less than 1% of mRNA processing, and is required for cell growth and differentiation, but not for cell survival in normal fibroblasts, hepatocytes and macrophages. In this report, we show that 50% depletion of THOC5 in human HCC cell lines Huh7 and HepG2 induced apoptosis. Transcriptome analysis using THOC5-depleted cells revealed that 396 genes, such as transmembrane BAX inhibitor motif containing 4 (TMBIM4), transmembrane emp24-like trafficking protein 10 (Tmed10) and D-tyrosyl-tRNA deacylase 2 (Dtd2) genes were downregulated in both cell lines. The depletion of one of these THOC5 target genes in Huh7 or HepG2 did not significantly induce cell death, suggesting that these may be fine tuners for HCC cell survival. However, the depletion of a combination of these genes synergistically increased the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive HCC. It must be noted that the depletion of these genes did not induce cell death in the hepatocyte cell line, THLE-2 cells. THOC5 expression was enhanced in 78% of cytological differentiation grading G2 and G3 tumor in primary HCC. Furthermore, the expression of a putative glycoprotein, Tmed10, is correlated to THOC5 expression level in primary HCCs, suggesting that this protein may be a novel biomarker for HCC. These data imply that the suppression of the multiple THOC5 target genes may represent a novel strategy for HCC therapy.


Assuntos
Apoptose/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Interferência de RNA , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Immunoblotting , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Nucleares/metabolismo , Transporte de RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Ann Oncol ; 27(1): 185-92, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26487585

RESUMO

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. PATIENTS AND METHODS: In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. RESULT: ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. CONCLUSIONS: Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. REGISTRATION NUMBER: JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carbazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Fusão Oncogênica/metabolismo , Piperidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
18.
Insect Mol Biol ; 24(6): 671-80, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26426866

RESUMO

The induction of apoptosis in vivo is a useful tool for investigating the functions and importance of particular tissues. B-cell leukaemia/lymphoma 2-associated X protein (Bax) functions as a pro-apoptotic factor and induces apoptosis in several organisms. The Bax-mediated apoptotic system is widely conserved from Caenorhabditis elegans to humans. In order to establish a tissue-specific cell death system in the domestic silkworm, Bombyx mori, we constructed a transgenic silkworm that overexpressed mouse Bax (mBax) in particular tissues by the Gal4-upstream activation sequence system. We found that the expression of mBax induced specific cell death in the silk gland, fat body and sensory cells. Fragmentation of genomic DNA was observed in the fat body, which expressed mBax, thereby supporting apoptotic cell death in this tissue. Using this system, we also demonstrated that specific cell death in sensory cells attenuated the response to the sex pheromone bombykol. These results show that we successfully established a tissue-specific cell death system in vivo that enabled specific deficiencies in particular tissues. The inducible cell death system may provide useful means for industrial applications of the silkworm and possible utilization for other species.


Assuntos
Bombyx/genética , Proteína X Associada a bcl-2/genética , Animais , Animais Geneticamente Modificados , Apoptose , Bombyx/citologia , Bombyx/crescimento & desenvolvimento , Glândulas Exócrinas/fisiologia , Corpo Adiposo/metabolismo , Álcoois Graxos/farmacologia , Feminino , Larva/crescimento & desenvolvimento , Masculino , Camundongos , Neurônios Receptores Olfatórios/citologia , Neurônios Receptores Olfatórios/efeitos dos fármacos , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Atrativos Sexuais/farmacologia , Transgenes
19.
Ann Oncol ; 26(10): 2066-72, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26153496

RESUMO

BACKGROUND: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). METHODS: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. RESULTS: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). CONCLUSIONS: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR. TRIAL REGISTRATION NUMBER: NCT01377376.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Taxa de Sobrevida
20.
Oral Dis ; 21(6): 807-13, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26011111

RESUMO

OBJECTIVE: To examine the association between an IL6 (Interleukin-6) polymorphism (C-634G or rs1800796) and tooth loss, and an interaction between the polymorphism and smoking habits for the loss. MATERIAL AND METHODS: Our subjects were 4917 check-up examinees ages 35-69. They reported tooth loss and lifestyle in a questionnaire. We regressed the number of teeth on the IL6 genotype, gender, age, smoking, drinking, diabetes, hypertension, physical activity, energy intake, education, and brushing. We further estimated multivariate-adjusted odds ratios (ORs) for having <20 teeth. RESULTS: Participants with a GG genotype tended to have less teeth than those with CC; ß = -0.798 (95% confidence interval [CI] = -1.501--0.096). Subjects with a GG genotype were more likely to have <20 teeth than those with CC; OR was 1.56 (95% CI = 1.08-2.25). Association between current smoking and tooth loss was stronger among those with GG than among those with CC. In a multiple regression analysis, a significant interaction was found between GG genotype and current smoking in the prediction of tooth loss (P = 0.018). CONCLUSION: The IL6 C-634G polymorphism was significantly associated with tooth loss. Our results suggest greater effects of smoking on tooth loss in GG genotype individuals.


Assuntos
Interleucina-6/genética , Fumar/efeitos adversos , Perda de Dente/genética , Adulto , Idoso , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fumar/epidemiologia , Perda de Dente/epidemiologia
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