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2.
Hum Exp Toxicol ; 39(4): 500-513, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31876189

RESUMO

Methotrexate (MTX)-induced intestinal mucosal injury in animals has been studied to understand how MTX can cause gastrointestinal disorders, but the pathogenesis of gastrointestinal disorders is still uncertain. We have attempted to reveal how dietary factors influence intestinal toxicity due to MTX. Mice were fed normal chow (NC) or a high-fat high-sucrose diet (HFHSD) before oral administration of MTX. While MTX significantly decreased the survival rates of mice fed HFHSD, the intestinal epithelial injury was detected. MTX excretion in the feces of mice fed HFHSD was reduced. Change of diets between NC and HFHSD influences the survival. The survival rates of the mice fed a high-sucrose diet or control diet were higher than those fed HFHSD. Higher survival rates were observed in mice fed a high-fat high-sucrose diet modified (HFHSD-M) in which casein was replaced by soybean-derived proteins. The survival rates of mice treated with vancomycin were lower than those administered neomycin. Microbiome and metabolome analyses on feces suggest a similarity of the intestinal environments of mice fed NC and HFHSD-M. HFHSD may modify MTX-induced toxicity in intestinal epithelia on account of an altered MTX distribution as a result of change in the intestinal environment.


Assuntos
Dieta Hiperlipídica , Microbioma Gastrointestinal/efeitos dos fármacos , Enteropatias/dietoterapia , Mucosa Intestinal/efeitos dos fármacos , Metotrexato/toxicidade , Sacarose/administração & dosagem , Animais , Dieta Hiperlipídica/métodos , Modelos Animais de Doenças , Fezes/química , Enteropatias/induzido quimicamente , Enteropatias/microbiologia , Enteropatias/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Metaboloma/efeitos dos fármacos , Metotrexato/farmacocinética , Camundongos Endogâmicos C57BL , Análise de Sobrevida , Distribuição Tecidual
3.
Eur J Dent Educ ; 22(3): e634-e643, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29877022

RESUMO

OBJECTIVES: The purpose of this study was to identify the weak points in the knowledge and attitudes of first-year oral health care and nursing students towards oral health care and to identify the factors associated with their positive willingness to practise oral health care after becoming a health professional in order to develop oral healthcare curricula. MATERIALS AND METHODS: The subjects were 88 first-year dental students (DSs), 64 dental hygiene students (DHSs) and 119 nursing students (NSs) enrolled in schools in Japan, as of April 2017. A questionnaire was distributed to subjects in each school to assess their knowledge and attitudes towards oral health care. RESULTS: Less than half knew that oral health care was also provided in cancer hospitals, hospices, acute care hospitals, maternity wards and psychiatric wards. Only 46.2% knew that oral health care was effective in the prevention of aspiration pneumonia. The level of knowledge and attitudes in NSs regarding oral health care were likely to be lowest amongst the student groups. Only NSs' high interest towards oral health care was associated with their positive willingness to practise oral health care in the future although oral health students' high perceptions and interest regarding oral health care were associated with the willingness. CONCLUSION: This study showed oral healthcare and nursing students' weak points regarding their attitudes and knowledge of oral health care at early stages. Oral health academic staff and professionals should develop effective oral healthcare curricula for oral healthcare students and help nursing staff develop a collaborative nursing oral healthcare curriculum to motivate nursing students.


Assuntos
Atitude do Pessoal de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Motivação , Saúde Bucal/educação , Higiene Bucal/educação , Aprendizagem Baseada em Problemas , Estudantes de Odontologia/psicologia , Estudantes de Ciências da Saúde/psicologia , Estudantes de Enfermagem/psicologia , Adulto , Feminino , Humanos , Masculino , Pneumonia Aspirativa/prevenção & controle , Inquéritos e Questionários , Adulto Jovem
4.
Scand J Immunol ; 87(5): e12655, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29484687

RESUMO

Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through 2 main pathways, immunoglobulin E-dependent and E-independent activation. In the latter pathway, mast cells are activated by a diverse range of basic molecules (collectively known as basic secretagogues) through Mas-related G protein-coupled receptors (MRGPRs). In addition to the known basic secretagogues, here, we discovered several endogenous protein and enzyme fragments (such as chaperonin-10 fragment) that act as bioactive peptides and induce immunoglobulin E-independent mast cell activation via MRGPRX2 (previously known as MrgX2), leading to the degranulation of mast cells. We discuss the possibility that MRGPRX2 responds various as-yet-unidentified endogenous ligands that have specific characteristics, and propose that MRGPRX2 plays an important role in regulating inflammatory responses to endogenous harmful stimuli, such as protein breakdown products released from damaged or dying cells.


Assuntos
Degranulação Celular/imunologia , Imunoglobulina E/imunologia , Mastócitos/imunologia , Proteínas do Tecido Nervoso/imunologia , Fragmentos de Peptídeos/imunologia , Receptores Acoplados a Proteínas G/imunologia , Receptores de Neuropeptídeos/imunologia , Animais , Linhagem Celular Tumoral , Chaperonina 10/imunologia , Células HEK293 , Humanos , Mastócitos/metabolismo , Proteínas do Tecido Nervoso/genética , Células PC12 , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropeptídeos/genética , Suínos
5.
Peptides ; 96: 61-66, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28867075

RESUMO

The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is a member of the GPCR family. The receptor is primate specific and expressed in the sensory neurons of dorsal root ganglion and trigeminal ganglion, where it is considered to be involved in the pain perception. The MRGPRX1 has unusual binding mechanism, as it is activated by several different ligands as well as several different fragments of precursor proteins. Thus, we hypothesize that it is activated by several unknown compounds as well since the receptor is still classified as orphan. Here, we describe the isolation of two novel endogenous ligands for the MRGPRX1 from human platelet preparation. The isolated ligands are hemoglobin ß-chain fragments, known members of the hemorphin family.


Assuntos
Hemoglobinas/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Plaquetas/metabolismo , Humanos
6.
Biochim Biophys Acta Gen Subj ; 1861(11 Pt A): 2530-2534, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28844982

RESUMO

BACKGROUND: Mast cells are important modulators of the human immune system via their release of several inflammatory mediators and proteases. The release can be activated by different pathways: the classical immunoglobulin E-dependent pathway and by the non-immunological immunoglobulin E-independent pathway. MAS-related G protein-coupled receptor X2 (MRGPRX2) is expressed in mast cells and it is one of the endogenous receptor responsible for the IgE-independent activation of human mast cell. The MRGPRX2 is classified as orphan receptor and unlike most GPCRs, the MRGPRX2 recognizes a wide range of basic molecules. Thus, there still might be several unknown ligands for the receptor. METHODS: MRGPRX2 activating peptides were isolated from human plasma using consecutive HPLC purification steps. The isolation process was monitored with MRGPRX2 transfected HEK 293 cells. The isolated peptides were sequenced by MS and synthetized. The synthetic peptides were used to determine degranulation of the human LAD 2 mast cell line by measuring ß-hexosaminidase release. RESULTS: Three endogenous MRGPRX2 activating peptides were isolated from human plasma. These peptides are identified as fragments of albumin. The isolated fragments activate MRGPRX2 and degranulate MRGPRX2 expressing LAD 2 cells in dose-dependent manner. CONCLUSIONS: The isolated basic peptides generated from human albumin are able to degranulate mast cells via the MRGPRX2. GENERAL SIGNIFICANCE: These endogenous albumin fragments, cleaved from albumin by mast cell secreted proteases, provide a possible pathway for self-perpetuating mast cell dependent inflammation.


Assuntos
Imunoglobulina E/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/sangue , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Albumina Sérica Humana/metabolismo , Degranulação Celular/genética , Degranulação Celular/imunologia , Células HEK293 , Humanos , Imunoglobulina E/imunologia , Ligantes , Mastócitos/imunologia , Mastócitos/metabolismo , Proteínas do Tecido Nervoso/imunologia , Biblioteca de Peptídeos , Peptídeos/imunologia , Receptores Acoplados a Proteínas G/imunologia , Receptores de Neuropeptídeos/imunologia , Albumina Sérica Humana/imunologia , Transdução de Sinais , beta-N-Acetil-Hexosaminidases/metabolismo
7.
J Virol ; 91(3)2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27852861

RESUMO

The genome of influenza virus (viral RNA [vRNA]) is associated with the nucleoprotein (NP) and viral RNA-dependent RNA polymerases and forms helical viral ribonucleoprotein (vRNP) complexes. The NP-vRNA complex is the biologically active template for RNA synthesis by the viral polymerase. Previously, we identified human pre-mRNA processing factor 18 (Prp18) as a stimulatory factor for viral RNA synthesis using a Saccharomyces cerevisiae replicon system and a single-gene deletion library of Saccharomyces cerevisiae (T. Naito, Y. Kiyasu, K. Sugiyama, A. Kimura, R. Nakano, A. Matsukage, and K. Nagata, Proc Natl Acad Sci USA, 104:18235-18240, 2007, https://doi.org/10.1073/pnas.0705856104). In infected Prp18 knockdown (KD) cells, the synthesis of vRNA, cRNA, and viral mRNAs was reduced. Prp18 was found to stimulate in vitro viral RNA synthesis through its interaction with NP. Analyses using in vitro RNA synthesis reactions revealed that Prp18 dissociates newly synthesized RNA from the template after the early elongation step to stimulate the elongation reaction. We found that Prp18 functions as a chaperone for NP to facilitate the formation of NP-RNA complexes. Based on these results, it is suggested that Prp18 accelerates influenza virus RNA synthesis as an NP chaperone for the processive elongation reaction. IMPORTANCE: Templates for viral RNA synthesis of negative-stranded RNA viruses are not naked RNA but rather RNA encapsidated by viral nucleocapsid proteins forming vRNP complexes. However, viral basic proteins tend to aggregate under physiological ionic strength without chaperones. We identified the pre-mRNA processing factor Prp18 as a stimulatory factor for influenza virus RNA synthesis. We found that one of the targets of Prp18 is NP. Prp18 facilitates the elongation reaction of viral polymerases by preventing the deleterious annealing of newly synthesized RNA to the template. Prp18 functions as a chaperone for NP to stimulate the formation of NP-RNA complexes. Based on these results, we propose that Prp18 may be required to maintain the structural integrity of vRNP for processive template reading.


Assuntos
Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Influenza Humana/virologia , Nucleoproteínas/metabolismo , Fatores de Processamento de RNA/metabolismo , RNA Viral/biossíntese , Linhagem Celular , Células Cultivadas , Técnicas de Silenciamento de Genes , Humanos , Influenza Humana/genética , Ligação Proteica , Fatores de Processamento de RNA/genética , Ribonucleoproteínas/metabolismo , Elongação da Transcrição Genética , Transcrição Gênica
9.
Pharmacogenomics J ; 16(3): 280-5, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26076924

RESUMO

The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.


Assuntos
Alopecia/induzido quimicamente , Alopecia/genética , Anti-Inflamatórios/efeitos adversos , Azatioprina/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/efeitos adversos , Leucopenia/induzido quimicamente , Leucopenia/genética , Mercaptopurina/efeitos adversos , Pirofosfatases/genética , Adulto , Alopecia/enzimologia , Alopecia/etnologia , Anti-Inflamatórios/administração & dosagem , Povo Asiático/genética , Azatioprina/administração & dosagem , Distribuição de Qui-Quadrado , Colite Ulcerativa/etnologia , Doença de Crohn/etnologia , Relação Dose-Resposta a Droga , Feminino , Fármacos Gastrointestinais/administração & dosagem , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Japão , Estimativa de Kaplan-Meier , Leucopenia/enzimologia , Leucopenia/etnologia , Modelos Logísticos , Masculino , Mercaptopurina/administração & dosagem , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Fenótipo , Pirofosfatases/metabolismo , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
10.
Eur J Dent Educ ; 20(3): 167-73, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26083002

RESUMO

The term 'oral health care for older adults' has various interpretations, and its meaning is not clear among dental school academic staff. Additionally, there are no theoretical or practical stand-alone courses on oral health care for older adults in Japanese dental schools. To improve oral health care education, we investigated the opinions and attitudes toward oral health care education for older adults among academic staff in dental schools. Data were collected in seven dental schools from May to September 2013 via an online questionnaire survey. Five-hundred-fifty-eight academics (428 male, 130 female) participated (response rate 57%). The average number of years since they had completed a university degree was 20.2 (SD 10.2) years. The majority (Over 90%) of participants perceived that oral health care should be provided in nursing facilities, hospitals, and at home. Its treatments and instructions should include, not only methods of keeping good oral hygiene, but also improvement of oral function such as swallowing training and salivary glands massage. The majority (84.2%) suggested oral health care education should be combined as a one-credit, stand-alone course. Findings indicate that dental academics have an understanding the need for a course in oral health care for older adults. Participants supported the need for further development of education in oral health care for older adults' in Japan, as a separate course on its own right. However there were some different views about content by teaching field. The need for a national core program for teaching oral health care education was suggested.


Assuntos
Atitude do Pessoal de Saúde , Assistência Odontológica para Idosos/psicologia , Recursos Humanos em Odontologia/psicologia , Saúde Bucal , Faculdades de Odontologia , Adulto , Idoso , Auxiliares de Odontologia , Educação em Odontologia/estatística & dados numéricos , Feminino , Educação em Saúde Bucal , Hospitais , Humanos , Japão , Masculino , Casas de Saúde , Higiene Bucal , Inquéritos e Questionários
11.
Lung Cancer ; 86(3): 339-43, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25453619

RESUMO

BACKGROUND: S-1, a novel oral fluoropyrimidine, has potent antitumor activity against non-small-cell lung cancer (NSCLC). Meanwhile, leucovorin enhances the efficacy of 5-fluorouracil by inhibiting thymidylate synthase. Therefore, this phase II clinical trial evaluated the safety and efficacy of S-1 plus leucovorin combination therapy for previously treated patients with NSCLC. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were prospectively enrolled if they received 1 or 2 prior chemotherapy regimens. S-1 (40-60 mg) and leucovorin (25mg) were administered together orally twice per day for 7 consecutive days followed by 7 days of rest. This 2-week cycle was repeated for a maximum of 25 cycles until the onset of disease progression or unacceptable adverse events. Endpoints included objective tumor response, progression-free survival, overall survival, and safety. RESULTS: Among 33 patients, 6 (18.2%), 14 (42.4%), and 11 (33.3%) had partial response, stable disease, and progressive disease, respectively. Median progression-free and overall survival times were 3.5 and 11.7 months, respectively. The common grade 3 toxicities included stomatitis (18.2%), anorexia (12.1%), and neutropenia (9.1%). One patient had pneumatosis cystoides intestinalis, and another experienced paralytic ileus. There were no treatment-related deaths. CONCLUSIONS: S-1 plus leucovorin combination therapy demonstrated promising efficacy and an acceptable toxicity profile in previously treated patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Leucovorina/administração & dosagem , Ácido Oxônico/administração & dosagem , Tegafur/administração & dosagem , Administração Oral , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Humanos , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/efeitos adversos , Tegafur/efeitos adversos
12.
Clin Exp Allergy ; 44(11): 1327-34, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25251750

RESUMO

BACKGROUND: It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. OBJECTIVE: To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. METHODS: We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. RESULTS: In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. CONCLUSIONS: Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.


Assuntos
Povo Asiático/genética , Asma/genética , Predisposição Genética para Doença , Glucuronosiltransferase/genética , Adulto , Idoso , Asma/diagnóstico , Estudos de Casos e Controles , Cromossomos Humanos Par 8 , Enganação , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hialuronan Sintases , Japão , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , RNA Mensageiro/genética , Fatores de Risco
13.
Ann Oncol ; 25(10): 1948-1953, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25009007

RESUMO

BACKGROUND: Whether the mutant allele frequency (MAF) may also have predictive implications for tyrosine kinase inhibitor (TKI) therapy in patients with advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (AELAd) remains unknown. PATIENTS AND METHODS: Based on a biobanking system in conjunction with our institution, we assessed EGFR mutation status using pyrosequencing (Py) and by outsourcing laboratory tests, such as the Cycleave (Cy) and the Scorpion ARMS (A). RESULTS: Out of 705 patients enrolled in the Shizuoka Lung Cancer Mutation Study between July 2011 and March 2013, 102 AELAd patients were identified as carrying the L858R mutation (L858Rm) using Py to analyze histological specimens. Of these 102 patients, the EGFR mutation status was assessed using both Py and Cy in 48 patients: the median MAF of L858R (MAFLR) was 18.5% (range: 8%-82%), and 45 patients (94%) were identified as having an L858Rm using both Py and Cy. Three patients (6%) with discrepant L858Rm findings were only identified using Py. The plotting of a receiver operating characteristic curve to identify the discordance in L858Rm findings showed that the area under the curve for MAFLR was 0.967 (95% confidence interval: 0.91-1) and that an MAFLR of 9% resulted in high sensitivity (100%) and specificity (99%). Also, 29 patients with AELAd, excluding those with postoperative recurrences, had their L858R status assessed using Cy or A. The median age, 69 years (range: 47-84 years); male/female, 14 (48%)/15 (52%); smokers/never-smokers 13 (45%)/16 (55%); ECOG PS 0-1/2-3, 26 (90%)/3 (10%); stage IIIB/IV, 4 (14%)/25 (86%); median MAFLR, 18% (range: 8%-63%). Patients with an MAFLR of ≤9% had a significantly shorter progression-free survival (PFS) period after TKI therapy than those with an MAFLR of >9% (mPFS: 92 versus 284 days, P = 0.0027). CONCLUSION: The MAF may be a potential predictive factor of TKI treatment efficacy in patients with AELAd carrying the L858Rm.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/administração & dosagem , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Frequência do Gene , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Inibidores de Proteínas Quinases/efeitos adversos
14.
Bull Entomol Res ; 104(3): 307-13, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24521569

RESUMO

Although apomixis is the most common form of parthenogenesis in diplodiploid arthropods, it is uncommon in the haplodiploid insect order Hymenoptera. We found a new type of spontaneous apomixis in the Hymenoptera, completely lacking meiosis and the expulsion of polar bodies in egg maturation division, on the thelytokous strain of a parasitoid wasp Meteorus pulchricornis (Wesmael) (Braconidae, Euphorinae) on pest lepidopteran larvae Spodoptera litura (Fabricius) (Noctuidae). The absence of the meiotic process was consistent with a non-segregation pattern in the offspring of heterozygous females, and no positive evidence was obtained for the induction of thelytoky by any bacterial symbionts. We discuss the conditions that enable the occurrence of such rare cases of apomictic thelytoky in the Hymenoptera, suggesting the significance of fixed heterosis caused by hybridization or polyploidization, symbiosis with bacterial agents, and occasional sex. Our finding will encourage further genetic studies on parasitoid wasps to use asexual lines more wisely for biological control.


Assuntos
Fenômenos Fisiológicos Bacterianos , Partenogênese , Simbiose , Vespas/microbiologia , Vespas/fisiologia , Animais , Feminino , Genótipo , Japão , Larva/parasitologia , Larva/fisiologia , Meiose , Repetições de Microssatélites , Reação em Cadeia da Polimerase , Reprodução , Especificidade da Espécie , Spodoptera/crescimento & desenvolvimento , Spodoptera/parasitologia , Vespas/genética
15.
Neoplasma ; 61(2): 233-40, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24299320

RESUMO

The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with non-small cell lung cancer (NSCLC). We examined whether progression-free survival (PFS), post-progression survival (PPS), or tumor response could be valid surrogate endpoints for OS after first-line chemotherapies in advanced NSCLC by using individual-level data, given the lack of research in this area. Between April 2009 and June 2011, 50 patients with advanced non-squamous NSCLC treated with cisplatin and pemetrexed as first-line chemotherapy were analyzed. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.89, P < 0.05, R2 = 0.79), PFS was moderately correlated with OS (r = 0.67, P < 0.05, R2 = 0.39), and tumor shrinkage was weakly correlated with OS (r = 0.36, P < 0.05, R2 = 0.14). Performance status at the beginning of second-line treatment, the best response to second-line treatment, and number of regimens used after progression following first-line chemotherapy were significantly associated with PPS (P < 0.05). Analysis of individual-level data suggested that PPS could be used as a surrogate for OS in patients with advanced non-squamous NSCLC with unknown oncogenic driver mutations and therefore limited options for subsequent chemotherapy. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS. These results should be validated in other larger populations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Neoplasias Pulmonares/patologia , Adulto , Idoso , Cisplatino/administração & dosagem , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
17.
J Phys Condens Matter ; 25(21): 216006, 2013 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-23644576

RESUMO

The electric, magnetic, and thermal properties of three perovskite cobaltites with the same 30% hole doping and ferromagnetic ground state were investigated down to very low temperatures. With decreasing size of large cations, the ferromagnetic Curie temperature and spontaneous moments of cobalt are gradually suppressed: TC = 130 K, 55 K and 25 K and m = 0.68 µB, 0.34 µB and 0.23 µB for Nd0.7Sr0.3CoO3, Pr0.7Ca0.3CoO3 and Nd0.7Ca0.3CoO3, respectively. The moment reduction with respect to the moment of the conventional ferromagnet La0.7Sr0.3CoO3 (T(C) = 230 K, m = 1.71 µB) in the so-called low spin/intermediate spin (IS/LS) state for Co(3+)/Co(4+) was originally interpreted using a phase-separation scenario. Based on the present results, mainly the analysis of the Schottky peak originating from Zeeman splitting of the ground-state Kramers doublet of Nd(3+), we find, however, that the ferromagnetic phase in Nd0.7Ca0.3CoO3 and likely also in Pr0.7Ca0.3CoO3 is uniformly distributed over the whole sample volume, despite the severe drop of moments. The ground state of these compounds is identified with the LS/LS-related phase derived theoretically by Sboychakov et al (2009 Phys. Rev. B 80 024423). The ground state of Nd0.7Sr0.3CoO3 with an intermediate cobalt moment is inhomogeneous due to competition between the LS/LS and IS/LS phases. In the theoretical part of the study, the crystal field split levels for 4f(3) (Nd(3+)), 4f(2) (Pr(3+)) and 4f(1) (Ce(3+) or Pr(4+)) are calculated and their magnetic characteristics are presented.

18.
Ann Oncol ; 24(6): 1653-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23413279

RESUMO

BACKGROUND: Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ~20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). PATIENTS AND METHODS: Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. RESULTS: Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC(0-12) compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. CONCLUSION: Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Polimorfismo Genético/genética , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Estudos de Coortes , Citocromo P-450 CYP2C19 , Relação Dose-Resposta a Droga , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/enzimologia , Gastroenteropatias/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Pirrolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Resultado do Tratamento
19.
J Appl Microbiol ; 114(4): 1147-57, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23311468

RESUMO

AIMS: The oral administration of a compost produced by the fermentation of marine animals with thermophiles confers health benefits for fish and pigs. This study aimed to isolate the beneficial bacteria from this compost that would modulate the physiological conditions of host animals. METHODS AND RESULTS: The compost extract was orally administrated to germ-free mice for 21 days, and thereafter, the culturable bacterial population within the caeca was surveyed. Sequence analyses of the 16S rRNA gene from the two predominant thermophilic isolates revealed organisms that were closely related to Bacillus thermoamylovorans and Bacillus coagulans. These bacteria could grow at 37°C, but more abundantly at 50-55°C, and they were minor components of the original compost extract. When an individual bacterial strain or a mixture of strains was administered to the conventionally maintained mice, their levels of faecal immunoglobulin A, an indicator of the gut immune response, were markedly raised. In addition, their feeding efficiency also changed among the tested mouse groups. CONCLUSIONS: These two kinds of thermophilic bacterial species, isolated from the caeca after compost ingestion to the germ-free mice, are candidate probiotics that could function in the mammalian gut. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed that the compost used in agriculture can contain potential probiotic thermophiles.


Assuntos
Bactérias/isolamento & purificação , Ceco/microbiologia , Probióticos , Microbiologia do Solo , Animais , Bacillus/genética , Bacillus/isolamento & purificação , Bactérias/genética , Fezes/microbiologia , Fermentação , Vida Livre de Germes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , RNA Ribossômico 16S/genética , Solo
20.
Neoplasma ; 59(3): 257-63, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22329847

RESUMO

The aim of this study is to examine the relationship between the expression level of excision repair cross-complementation group 1 (ERCC1) and of 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) in various thoracic neoplasm.Three hundreds-eight patients [non-small cell lung cancer (NSCLC)(n=56), malignant pleural mesothelioma (MPM)(n=21), pulmonary metastatic tumors (PMT)(n=148), thymic epithelial tumors (n=49) and pulmonary neuroendocrine tumor (n=34)] who underwent 18F-FDG PET before treatment were included in this study. Tumors sections were stained by immunohistochemistry for ERCC1, glucose transporter 1(Glut1), vascular endothelial growth factor (VEGF) and microvessel density (MVD) by determinate by CD34. The expression of ERCC1 in thoracic neoplasms had a positivity of 49% (152/308), and the positive rates of ERCC1 expression in NSCLC, PMT, thymic epithelial tumor, pulmonary neuroendocrine tumor and MPM were 52, 43, 53, 47 and 85%, respectively. The positivity of ERCC1 expression was significantly higher in MPM and SQC than in the other histological types. A statistically significant correlation between ERCC1 expression and 18F-FDG uptake was observed in thymic epithelial tumors, especially thymoma. Moreover, ERCC1 expression was also closely associated with the expression of Glut1, VEGF and MVD.Our results indicated that 18F-FDG uptake may be an alternative biomarker for predicting ERCC1 expression in patients with thymoma.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Neoplasias Torácicas/diagnóstico por imagem , Neoplasias Torácicas/metabolismo , Idoso , Antígenos CD34/metabolismo , Feminino , Transportador de Glucose Tipo 1/metabolismo , Humanos , Técnicas Imunoenzimáticas , Masculino , Neoplasias Torácicas/patologia , Neoplasias do Timo/diagnóstico por imagem , Neoplasias do Timo/metabolismo , Neoplasias do Timo/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
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