RESUMO
ABSTRACT: Objective To analyze the genetic phenotypes of Y-chromosome STR and SNP in Han male population of Wujiang area, Suzhou City and explore the genetic structure of population of Wujiang area for further examination of regional-specific Y-SNP genetic markers ancestor haplogroups. Methods Blood samples of 472 Wujiang area Han males were randomly collected and genotyped by YfilerTM Plus PCR Amplification Kit. The allele frequencies and haplotype frequencies of each locus were obtained using the direct calculation method. Y-SNP haplogroups of each sample were estimated using Y-Predictor software and verified through experiments by amplification refractory mutation system-polymerase chain reaction ï¼ARMS-PCRï¼. Results A total of 453 haplotypes were found in the 27 Y-STR genetic markers in 472 Han males of Wujiang area. The haplotype diversity ï¼HDï¼ was 0.997 696 93, among which, the highest gene diversity ï¼GDï¼ value was DYF387S1a/b ï¼GD=0.953 1ï¼ and the lowest was DYS438 ï¼GD=0.321 8ï¼. Based on genotyping data of 27 Y-STRs and 472 samples, 132 haplogroups from C, D, N, O and Q, etc downstream Y-SNP haplogroups were estimated and then verified through experiments. Conclusion This study is based on Y-chromosome STR haplotypes, and predicts Y-SNP haplogroups by Y-Predictor software, then uses ARMS-PCR to verify. Y-SNP genetic markers were introduced to achieve precise analysis of the genetic structure of male families in population of three towns in Wujiang area.
Assuntos
Cromossomos Humanos Y/genética , Genética Populacional , China , Cidades , Frequência do Gene , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Cardiomiopatia Dilatada , Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Insuficiência Cardíaca , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/etiologia , Síndrome de Churg-Strauss/complicações , Síndrome de Churg-Strauss/diagnóstico , Eosinófilos , Insuficiência Cardíaca/etiologia , HumanosRESUMO
BACKGROUND: While efficacy of combination treatment with methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ) ('triple therapy') has been shown in clinical trials, few studies have examined its longevity in a real-life setting. AIM: Our aim was to assess the tolerability, longevity and efficacy of a triple disease-modifying anti-rheumatic drug (DMARD) regimen initiated in new-onset rheumatoid arthritis (RA) patients. METHODS: Patients who met 1987 American College of Rheumatology criteria for RA with disease duration less than 2 years were offered triple therapy upon diagnosis. Treatment was intensified according to a response-driven step-up algorithm, which included progression to leflunomide (LEF) or a biologic agent. RESULTS: Of 181 new-onset RA patients, 119 commenced triple therapy. Median duration of triple therapy was 39 weeks, and 23.5% remained on it at last follow up, with median follow up 104 weeks. Continuous therapy with any three-DMARD combination (including LEF) occurred in 32% at last follow up, with median duration of 70 weeks. Cessation of at least one of MTX, SSZ or HCQ occurred because of an adverse event in 38%, remission in 7% and incomplete response in 28% of patients. SSZ accounted for 49% of initial drug withdrawals for an adverse event. Continuation of three-drug therapy did not significantly influence the proportion of patients achieving remission or low disease activity (LDA). CONCLUSIONS: Triple therapy in new-onset RA was reasonably well tolerated, persisting for median 39 weeks. SSZ intolerance commonly reduces longevity of triple therapy. Treating to the target of remission or LDA is more important than the number of DMARD continued.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Isoxazóis/administração & dosagem , Metotrexato/administração & dosagem , Sulfassalazina/administração & dosagem , Adulto , Idoso , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Leflunomida , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Malignant pleural effusion (MPE) is a useful specimen allowing for the evaluation of EGFR status in nonsmall cell lung cancer (NSCLC). However, direct sequencing of genomic DNA from MPE samples was found not to be sensitive for EGFR mutation detection. To test whether EGFR analysis from RNA is less prone to interference from nontumour cells that have no or lower EGFR expression, we compared three methods (sequencing from cell-derived RNA versus sequencing and mass-spectrometric analysis from genomic DNA), in parallel, for EGFR mutation detection from MPE samples in 150 lung adenocarcinoma patients receiving first-line tyrosine kinase inhibitors (TKIs). Among these MPE samples, EGFR mutations were much more frequently identified by sequencing using RNA than by sequencing and mass-spectrometric analysis from genomic DNA (for all mutations, 67.3 versus 44.7 and 46.7%; for L858R or exon 19 deletions, 61.3 versus 41.3 and 46.7%, respectively). The better mutation detection yield of sequencing from RNA was coupled with the superior prediction of clinical efficacy of first-line TKIs. In patients with acquired resistance, EGFR sequencing from RNA provided satisfactory detection of T790M (54.2%). These results demonstrated that EGFR sequencing using RNA as template greatly improves sensitivity for EGFR mutation detection from samples of MPE, highlighting RNA as the favourable source for analysing EGFR mutations from heterogeneous MPE specimens in NSCLC.
Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA/métodos , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Derrame Pleural Maligno/genética , RNA/química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma de Pulmão , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Éxons , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Derrame Pleural Maligno/tratamento farmacológico , Quinazolinas/uso terapêuticoRESUMO
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the expression of antibodies to DNA. These antibodies form immune complexes that can stimulate cytokine production as well as deposit in the tissues to incite inflammation and damage. For the formation of immune complexes, the availability of extracellular DNA in an immunologically relevant form is essential. While apoptosis has been implicated as the source of this nuclear material in SLE, as shown with in vitro or in vivo systems, extracellular DNA can originate from apoptotic as well as necrotic cells. In experimental models, the release of DNA occurs with the administration of cells induced to die, in vitro as well as the administration of agents to induce cell death in situ. This release can be influenced by the presence of inflammatory cells such as macrophages that can interact with dead and dying cells to modulate the translocation of DNA from the inside to the outside of cells. In vivo, both glucocorticoids and oestrogens can modify the extent of DNA release from the administration of dead and dying cells. Together, these findings indicate that the generation of extracellular DNA in SLE can result from cell death and that steps in this process represent potential targets for new therapies.
Assuntos
Anticorpos Antinucleares/imunologia , Apoptose , DNA/imunologia , Inflamação/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/imunologia , Animais , Anticorpos Antinucleares/sangue , Autoimunidade , DNA/metabolismo , Humanos , Inflamação/metabolismo , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Macrófagos/metabolismo , Fatores SexuaisRESUMO
HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1-Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1-Src complex might provide a promising molecular model for developing new anticancer strategies.
Assuntos
Proteínas de Choque Térmico HSP40/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Quinases da Família src/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP40/química , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/farmacologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Modelos Moleculares , Mutação , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/genética , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Interferência de RNA , RNA Interferente Pequeno/genética , Domínios de Homologia de src , Quinases da Família src/química , Quinases da Família src/metabolismoRESUMO
Neoglycoalbumin (NGA), a special ligend of asialoglycoprotein receptor on the hepatocyte, was linked via a butanediacyl bridge to acyclovir to form a conjugate NGA-ACV. By using DTA (Differential thermoanalysis) and HPLC analysis, ACV was shown to be connected with NGA by covalent bonds and stable in blood. The radio-biodistribution of 131I-NGA-ACV with high drug density in vivo was carried out in mice. The maximum absorption of 131I-NGA-ACV in liver was 81.7 +/- 10.4% at 5 min. The radioimage of 131I-NGA-ACV with high or low drug density in rabbit showed no significant difference in liver targeting property. The competitive connection tests indicated that 131I-NGA-ACV was concentrated in liver through receptor mediated mechanism. A tentative test of antihepatitis B of NGA-ACV and ACV in vitro showed that the effective dose of the former was significantly lower than that of the latter.
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Aciclovir/farmacocinética , Albuminas/farmacocinética , Antivirais/farmacocinética , Imunotoxinas/farmacocinética , Fígado/metabolismo , Aciclovir/administração & dosagem , Albuminas/administração & dosagem , Animais , Antivirais/administração & dosagem , Ligação Competitiva , Feminino , Fígado/diagnóstico por imagem , Masculino , Camundongos , Coelhos , Cintilografia , Distribuição Aleatória , Distribuição TecidualRESUMO
To assess the efficacy of sibutramine 15 mg once daily as weight reduction in overweight and obese (body mass index > 25 kg/m2) Chinese female type 2 diabetic patients and to evaluate the influence of weight loss on diabetic control, a randomised, double-blind, placebo-control, 12-week study was conducted. Chinese female type 2 diabetic patients, poorly controlled glucose levels and HbA(1C) > 8% were randomly assigned to two groups. In addition to their hypoglycaemic agents (maximal doses of sulphonylureas and metformin), one group (n = 30) received a sibutramine 15 mg once daily for 12 weeks, and the other (n = 30) received placebo for the same period. Comparing the changes that occurred after 12 weeks in the sibutramine and placebo groups, the former showed significantly greater reduction in body weight (2.5 vs. 0.1 kg, p < 0.05), fasting plasma insulin level (28.8 vs. 2.4 pmol/l, p < 0.01), 2-h postprandial blood glucose after standard test meal (3.2 vs. 1.1 mmol/l, p < 0.01), insulin resistance (5.1 vs. 0.2, p < 0.01), HbA1C (1.7% vs. 0.2%, p < 0.05), triglyceride (0.43 vs. 0.12 mmol/l, p < 0.05) and total cholesterol (0.52 vs. 0.08 mmol/l, p < 0.05). No significant differences were found between treatment groups in blood pressure and heart rate. The addition of sibutramine to diet and oral hypoglycaemic therapy resulted in significant weight loss and improvement in metabolic parameters in the treatment group. Sibutramine should be considered for use alongside diet and oral hypoglycaemic therapy in Chinese overweight and obese women with poorly controlled type 2 diabetes.