Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 79
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Artigo em Inglês | MEDLINE | ID: mdl-31463717

RESUMO

PURPOSE: To determine the frequency of co-occurring genes in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and the predictive effect of co-mutations on the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). METHODS: 54 patients with advanced NSCLC were tested for 422 clinically relevant genes by next-generation sequencing (NGS) before treatment. Among them, patients with EGFR mutation received first-line treatment of EGFR-TKIs. Progression-free survival (PFS) and objective response rate (ORR) were evaluated using Kaplan-Meier methods and compared between two groups using log-rank test. RESULTS: Among 24 EGFR mutant and 30 EGFR wild-type patients, co-mutation rate was lower in patients with EGFR mutation (62.5% [15/24] vs 93.3% [28/30], p = 0.005). There was lower frequency for co-alterations in BRAF (0% [0/24] vs 20% [7/30], p = 0.033), NF1 (4.2% [1/24] vs 30% [9/30], p = 0.038) and RAS-RAF-MAPK pathway genes (16.6% [4/24] vs 56.7% [17/30], p = 0.003) in EGFR mutation group. 24 patients with EGFR mutation received first-line treatment of gefitinib or erlotinib, with an ORR of 83.3% and a median PFS of 12.3 months (95% CI 10.00-14.60). Co-mutation was associated with shorter median PFS (10.2 months [95% CI 5.20-15.20] vs 15.3 months [95% CI 12.09-15.81]; HR 0.29 [95% CI 0.10-0.82]; p = 0.014) in EGFR mutation cohort. Among patients with EGFR mutation and distant metastasis, median PFS was decreased in those with co-mutations (6.3 months [95% CI 3.25-9.35] vs 22.0 months[95% CI 12.10-31.90]; HR 0.12 [95% CI 0.00-5.87]; p = 0.007) and frequency of PIK3CA (0% [0/12] vs 41.7% [5/12], p = 0.037) and PI3K/AKT/mTOR pathway genes (0% [0/12] vs 50% [6/12], p = 0.014) was lower. CONCLUSION: The presence of co-mutations was lower in the EGFR mutation patients and reduces the efficacy of EGFR-TKI, especially in patients with distant metastases. Lower frequency of co-mutation in PIK3CA and PI3K/AKT/mTOR pathway genes may be responsible for promoting metastasis and limiting the efficacy of EGFR-TKIs.

2.
Hepatology ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393024

RESUMO

Hepatic ischemia-reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation (LTx). Effective strategies to improve liver function after hepatic I/R injury are limited. Six-transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R-induced liver damage remains largely unclear. In the present study, we found that Steap3 expression was significantly upregulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation (H/R) insult. Subsequently, global Steap3 knockout mice (Steap3-KO mice), hepatocyte-specific Steap3 transgenic mice (Steap3-HTG mice) and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that compared with the control mice, the Steap3-KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas the Steap3-HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit TAK1 activation and downstream JNK and p38 signaling during hepatic I/R injury. Conclusion: Steap3 is a novel mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis via TAK1-dependent activation of the JNK/p38 pathways. Targeting hepatocytes Steap3 may be a promising approach to protect the liver against I/R injury. This article is protected by copyright. All rights reserved.

3.
Transl Oncol ; 12(4): 656-660, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30822722

RESUMO

The platinum-based, two-drug, 3-week regimen is currently the main first-line chemotherapy program for the treatment of advanced squamous cell lung cancer. The aim of this phase II clinical study was to evaluate the efficacy and adverse events of the bi-weekly program of liposomal paclitaxel combined with nedaplatin as a first-line treatment for advanced squamous cell lung cancer. A total of 52 cases of advanced squamous cell lung cancer were included in this phase II clinical trial. Patients received intravenous infusion of liposomal paclitaxel (100 mg/m2) and nedaplatin (50 mg/m2) on days 1 and 15 of a 4-week cycle. Each patient received two to six cycles of chemotherapy, consistent with the regimen of combined liposomal paclitaxel and nedaplatin. The total effective rate of this chemotherapy program was 37.5%. The median progression-free survival time was 8.5 months (95% confidence interval: 7.8-9.2). The median survival time was 16 months (95% confidence interval: 14.1-17.9). The main adverse event was myelosuppression. Grade 3 leukopenia was noted in seven patients (13.5%), and no grade 4 leukopenia was observed. Grade 3 anemia was noted in four patients (7.7%), and no grade 4 anemia was observed. In addition, no grade 2 or higher thrombocytopenia and no grade 3 or 4 non-bone marrow toxicity was detected. The bi-weekly program of liposomal paclitaxel combined with nedaplatin is effective for the treatment of advanced squamous cell lung cancer, with high safety and few adverse events. However, additional studies are warranted to confirm these results. The trial was registered under the number ChiCTR-OIN-17011423.

4.
Zhongguo Gu Shang ; 32(2): 136-140, 2019 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-30884929

RESUMO

OBJECTIVE: To observe the effect of anti-osteoporosis drugs on the curative effect of femoral head replacement in the elderly patients with proximal humerus fracture. METHODS: From November 2012 to June 2016, 38 patients with proximal humeral fractures received humeral head replacement were divided into the treatment group and the control group according to whether the anti-osteoporosis drugs were used after the operation. The treatment group included 19 cases, of which 11 cases were three part fractures, 18 cases were four part fractures, and bone density was(0.58±0.14) g/cm²; the control group involved 19 cases, of which 10 cases were the three part fractures, 9 cases were four part fractures, and bone density was(0.58±0.11) g/cm². Periprosthetic bone mineral density(BMD) was measured at 4, 8, 12, 24 and 48 weeks after operation, and visual analogue scale(VAS) was used to evaluate the pain and Neer score was used to evaluate the function of the shoulder joint. RESULTS: The incisions of all patients were healed with grade A and no complications occurred. Thirty-five patients were followed up for 1 year. The bone density around the prosthesis of treatment group was higher than that of control group, the difference was statistically significant(P<0.05);VAS in two groups had no statistical significance(P>0.05). The total score and functional score of Neer in the treatment group were better than those in the control group, the difference was statistically significant(P<0.05), and there was no significant difference in pain and activity score between the two groups(P>0.05). According to the Neer score, the results of treatment group was excellent in 10 cases, good in 5 cases, fair in 3 cases;in the control group, 3 cases were excellent, 9 cases were good, and 5 cases were fair;the difference between the two groups was statistically significant(P<0.05). CONCLUSIONS: Artificial humeral head replacement combined with anti-osteoporosis drugs in the treatment of proximal humeral fractures in elderly patients can effectively improve the bone density around the prosthesis and restore shoulder function. The early clinical effect is satisfactory.


Assuntos
Calcitonina/uso terapêutico , Cabeça do Úmero , Fraturas do Ombro , Articulação do Ombro , Idoso , Fixação Interna de Fraturas , Humanos , Período Pós-Operatório , Fraturas do Ombro/prevenção & controle , Resultado do Tratamento
5.
Int J Rheum Dis ; 22(4): 599-607, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729755

RESUMO

AIM: To evaluate the overall diagnostic value of anti-citrullinated fibrinogen (ACF) antibody in patients with rheumatoid arthritis (RA). METHODS: Published studies were systematically retrieved from PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, China Biology Medicine (CBM) disc, and Chinese VIP databases. QUADAS-2 tool was applied to evaluate the quality of eligible studies. Subgroup analysis and meta-regression were used to explore the sources of heterogeneity. Egger's test was used to evaluate for the presence of publication bias. RESULTS: Seven studies were included in this meta-analysis. The pooled sensitivity, specificity, pooled positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of ACF were 0.61 (95% CI: 0.57-0.64), 0.93 (95% CI: 0.92-0.94), 9.33 (95% CI: 5.15-16.92), 0.39 (95% CI: 0.30-0.53) and 24.58 (95% CI: 11.47-52.64), respectively. The area under the curve was 0.8018. The results of subgroup analysis and meta-regression indicated that the factors we analyzed might not be the leading causes of heterogeneity. No significant publication bias was found. CONCLUSION: The ACF antibody had a moderate diagnostic accuracy on RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/diagnóstico , Fibrinogênio/imunologia , Peptídeos Cíclicos/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Humanos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes
6.
Thorac Cancer ; 10(3): 472-482, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628189

RESUMO

BACKGROUND: According to the current clinical guidelines, chemoradiotherapy is considered the standard treatment for locally advanced non-small cell lung cancer (NSCLC). We analyzed the prognostic effect of adjuvant chemotherapy (ACT) in resected patients using the new eighth tumor node metastasis (TNM) staging systems based on the Surveillance, Epidemiology and End Results database. METHODS: We identified 3008 patients with stage IIIA NSCLC (T4N0M0) who underwent sublobar resection, lobectomy, or pneumonectomy. Covariates affecting treatment selection or survival were included as part of propensity score models for matching and weighting. The effect of ACT on survival was assessed, stratified by postoperative radiation therapy (PORT) use, tumor size, and age. RESULTS: Analyses of 2016 patients were conducted with standardized differences in covariates < 10% after matching. ACT was associated with significantly improved five-year overall survival (51.1% vs. 39.7%; P = 0.0260) in patients aged 21-65 with > 7 cm tumors, even after adjusting for the presence or absence of the superior sulcus (P = 0.0003). No significant outcomes were observed using other stratifications in the matched analysis. Moreover, ACT with PORT conferred a potential survival benefit in 21-65-year-old patients with 0-7 cm tumors (for all causes of death: hazard ratio 0.414, 95% confidence interval 0.251-0.684). CONCLUSION: In this population-based cohort, ACT prolonged the survival of patients aged 21-65 with a tumor > 7 cm, with or without PORT. Inverse probability of treatment weighting can estimate the treatment effect and is suitable for use with survival data.

7.
Mol Carcinog ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30457164

RESUMO

Breast cancer (BC) is a common malignancy worldwide. More than 3700 000 women die of BC every year. DSCAM-AS1 was overexpressed several kinds of cancer and miR-204-5p was lowly expressed, which indicated that miR-204-5p had anti-tumor activity and DSCAM-AS1 had pro-tumor activity. We intended to analyze DSCAM-AS1, miR-204-5p and ribonucleotide reductase M2 (RRM2). Microarray analysis and quantitative Real Time fluorescence Polymerase Chain Reaction (qRT-PCR) were employed to determine DSCAM-AS1 and miR-204-5p expression. Luciferase reporter assay was applied to examine the target relationship between DSCAM-AS1, miR-204-5p and RRM2. Cell Counting Kit-8 (CCK-8 assay), transwell assay and flow cytometry were used to detect cell proliferation, invasion and apoptosis. The expression of DSCAM-AS1, miR-204-5p and RRM2 were confirmed by Western blot. We also conducted in vivo assay to verify the effect of DSCAM-AS1. DSCAM-AS1 was up-regulated, while miR-204-5p was down-regulated in BC tissues and cells. DSCAM-AS1 directly targeted miR-204-5p. DSCAM-AS1 promoted the proliferation and invasion of BC cells by reducing miR-204-5p and inhibiting miR-204-5p expression. DSCAM-AS1 expression was related to the expression of RRM2, and miR-204-5p could reverse the function of DSCAM-AS1. RRM2 was up-regulated in BC cells, and miR-204-5p inhibited RRM2 expression by targeting RRM2. Overexpression of RRM2 stimulated proliferation and cell invasion and impeded apoptosis. In vivo experiments showed that knockdown of DSCAM-AS1 decreased the tumorigenesis of BC cells, increased the expression of miR-204-5p. DSCAM-AS1 promoted proliferation and impaired apoptosis of BC cells by reducing miR-204-5p and enhancing RRM2 expression. DSCAM-AS1/miR-204-5p/RRM2 may serve as novel therapeutic targets for BC. This article is protected by copyright. All rights reserved.

8.
Huan Jing Ke Xue ; 39(10): 4727-4734, 2018 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-30229621

RESUMO

The discovery of the complete ammonia-oxidizing microbes, Comammox Nitrospira, had fundamentally changed our perspective on traditional nitrification. The microbe also played a potentially under-appreciated role in the biogeochemical N cycle and provided a new dimension for the research of nitrification. To investigate the abundance of Comammox in different ecosystems was urgently needed. In the present study, three treatments with different quantities of fertilization in a paddy soil (blank control, NPK and 1.5 NPKS) to investigate the nitrification and amoA gene abundance for nitrifying microorganisms, especially for the complete ammonia oxidizing bacteria (Comammox Nitrospira). The results showed that:① Both Comammox Clade A and Comammox Clade B were detected in all three treatments, and the abundance of Comammox Clade A were 9.0×107, 1.7×108, 7.2×108 copies·g-1 (dry soil), respectively, and for Comammox Clade B were 1.5×107, 1.2×107, 1.7×107 copies·g-1 (dry soil), respectively. ② The abundances of both ammonia-oxidizing archaea (AOA)in the three fertilizers was 1.5×107-1.2×108 copies·g-1 (dry soil), and the ammonia-oxidizing bacteria (AOB) in the three fertilizers was 2.0×105-9.3×107 copies·g-1 (dry soil), lower than the abundance of the Comammox. The ratio of Comammox to AOA was 7.2, and the ratio for Comammox to AOB was 524.4 for blank control, were greater than NPK and 1.5 NPKS treatments. ③ The ratio of Comammox Clade A to Comammox Clade B showed an increasing trend with the increase in fertilizer application, at 6.1, 14.4 and 43.1, respectively. ④ For NPK and 1.5 NPKS treatments, Comammox Clade A amoA gene copies were 1.9 and 8.0 times higher than that of the blank control treatment respectively, and the numbers for AOA significantly increased to 3.2 and 7.2 times that of the blank control. The AOB gene copy numbers increased by two orders of magnitude compared with the blank control. In addition, the nitrification potential increased with the increase in N fertilizer application; however, the effects of different fertilizer treatments on Comammox Clade B were not significant. Results indicated that Comammox was widely distributed in the neutral purple paddy soil and was higher in abundance than AOA or AOB, which implied that Comammox-especially Clade A-may contribute to the nitrification of paddy soil.

9.
Clin Rheumatol ; 37(11): 2999-3007, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29980876

RESUMO

To systematically evaluate the diagnostic accuracy of miRNAs as potential biomarkers for systemic lupus erythematosus (SLE). Studies were searched in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and China Biology Medicine (CBM) disc database, and languages were limited in English and Chinese. QUADAS-2 tool was applied to assess the quality of eligible studies. Random-effect model was applied to calculate pooled effects of miRNAs on diagnosing SLE. Subgroup analysis was used to explore the sources of heterogeneity. All data were calculated and analyzed by Meta-Disc 1.4 and RevMan 5.3 software. Six eligible studies were included in this meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratio of miRNAs were 0.75(95% CI 0.71-0.79), 0.72(95% CI 0.66-0.78), and 8.79(95% CI 4.91-15.73), respectively. The pooled positive likelihood ratio was 2.71(95% CI 2.20-3.33) and negative likelihood ratio was 0.34(95% CI 0.24-0.48). The area under the curve was 0.787. The subgroup analysis showed that the number of healthy controls might be the sources of heterogeneity. MiRNAs in blood have moderate accuracy and influence on diagnosing SLE, and the exact diagnostic value should be confirmed by further studies.

10.
Clin Chim Acta ; 484: 105-110, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29842856

RESUMO

BACKGROUND: Cyclophilin A (CyPA) is a potential mediator of inflammation. We assessed the predictive value of the first-trimester maternal serum CyPA concentrations for complicated pregnancy. METHODS: The first-trimester serum CyPA concentrations were quantified in 100 women with normal pregnancy and in 351 women with complicated pregnancy, including 102 pre-eclampsia women, 131 gestational hypertension (GH) women and 118 gestational diabetes mellitus (GDM) women. Its association with complicated pregnancy was ascertained using multivariate analysis. RESULTS: Median CyPA concentrations were significantly higher in women developing complicated pregnancy as pre-eclampsia, GH or GDM than in women with normal pregnancy. CyPA concentrations were independently correlated with C-reactive protein concentrations in complicated pregnancy as pre-eclampsia, GH or GDM women. Serum CyPA and body mass index were independently associated with the development of complicated pregnancy as pre-eclampsia, GH or GDM. Serum CyPA possessed significantly high area under receiver operating characteristic curve. Meanwhile, CyPA significantly improved the predictive value of body mass index. CONCLUSIONS: Serum CyPA might be utilized as a potential inflammatory biomarker for complicated pregnancy and assessment of serum CyPA might aid in the prediction of complicated pregnancy.

12.
Bioorg Chem ; 76: 380-385, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29241110

RESUMO

WDR5, a subunit of the SET/MLL complex, plays critical roles in various biological progresses and are abnormally expressed in many cancers. Here we report the design, synthesis, and biochemical characterization of a new chemical tool to capture WDR5 protein. The probe is a biotinylated version of compound 30 that is a potent WDR5 inhibitor we previously reported. Importantly, the probe displayed high affinity to WDR5 protein in vitro binding potency and showed the ability in specifically and real time monitoring WDR5 protein. Further, the biotinylated tag of the probe enabled selectively "chemoprecipitation" of WDR5 from whole cell lysates of MV4-11. This probe provided a new approach to identify the overexpressed WDR5 protein in different cancer cells and applications to proteomic analysis of WDR5 and WDR5-binding partners.

13.
Bioorg Med Chem ; 26(2): 356-365, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29254892

RESUMO

The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia. Hence, disrupting the interactions between MLL1 and the reciprocal proteins has been considered to be a new treatment strategy for leukemia. Here, we reviewed potential protein-protein interactions (PPIs) between MLL1 and its reciprocal proteins, and summarized the inhibitors to target MLL1 PPIs. The druggability of MLL1 PPIs for leukemia were also discussed.


Assuntos
Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Leucemia/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Histona-Lisina N-Metiltransferase/química , Humanos , Leucemia/genética , Estrutura Molecular , Proteína de Leucina Linfoide-Mieloide/química , Proteínas de Neoplasias/química , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Cancer Manag Res ; 9: 671-677, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29200887

RESUMO

Objective: To evaluate the efficacy and safety of pemetrexed and nedaplatin followed by pemetrexed maintenance therapy in advanced lung adenocarcinoma. Methods: A total of 53 advanced lung adenocarcinoma patients hospitalized between July 2013 and June 2016 with a performance status ≤2 were enrolled in this study. All patients received 4-6 cycles of combination chemotherapy comprising pemetrexed (500 mg/m2 dL) and nedaplatin (80 mg/m2 dL). Each chemotherapy cycle consisted of 21 days. After the efficacy of the combination chemotherapy was assessed, patients with stable disease, partial remission, or complete remission received pemetrexed maintenance therapy (500 mg/m2 dL) until disease progression or intolerable side effects occurred. Each pemetrexed maintenance therapy cycle was 28 days. Results: After completion of the pemetrexed and nedaplatin combination chemotherapy, 26 (49.1%), 15 (28.3%), and 12 (22.6%) patients exhibited partial remission, stable disease, and progressive disease, respectively. Complete remission was not achieved in any patient. Therefore, the response and disease control percentages were 49.1% and 77.4%, respectively. A total of 38 patients were further administered pemetrexed maintenance chemotherapy for an average of 9.8 cycles. The median progression-free survival and overall survival of the 38 patients receiving the pemetrexed maintenance therapy were 9.3 (95% confidence interval: 8.6-10) months and 16.3 (95% confidence interval: 14.5-18.2) months, respectively. The major adverse effects included bone marrow suppression and gastrointestinal reactions, which were well tolerated. Conclusions: Combination chemotherapy based on pemetrexed and nedaplatin is effective for the treatment of advanced lung adenocarcinoma with a high tolerance by patients. In addition, pemetrexed maintenance therapy of advanced lung adenocarcinoma is safe and effective for the treatment of advanced lung adenocarcinoma following pemetrexed and nedaplatin combination chemotherapy.

15.
Ther Adv Med Oncol ; 9(2): 68-74, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28203299

RESUMO

BACKGROUND: In this multi-institutional prospective study, we aimed to assess the safety and efficacy of nedaplatin plus S-1 (NS) chemotherapy for patients with recurrent and metastatic nasopharyngeal carcinoma (NPC) when platinum-containing regimens failed. METHODS: A total of 52 recurrent and metastatic NPC patients who previously received, but failed with platinum-containing chemotherapy, had oral S-1 chemotherapy (twice daily from the first day to the fourteenth day) and nedaplatin (80 mg/ m2, day 1) every 3 weeks. The body surface area (BSA) decided the dose of S-1: 40 mg twice a day when BSA < 1.25 m2; 50 mg twice daily when 1.25 m2 ⩽ BSA < 1.5 m2; and 60 mg twice daily when BSA ⩾ 1.5 m2. RESULTS: Treatment was well tolerated. The main hematological adverse event was neutropenia. Five patients (9.6%) had grade 3 neutropenia. Three patients were found with grade 3 anemia (5.8%). One patient was found with grade 3 thrombocytopenia (1.9%). No patient was found with grade 3 or 4 nonhematological toxicity. The rates of complete response, partial response and overall response were 3.8%, 38.5% and 42.3%, respectively. Median time to progression was 6.2 months and median survival was 14.6 months. The rates of 1-year survival and 2-year survival were 63% and 27%, respectively. CONCLUSIONS: NS chemotherapy provides a satisfactory and safe clinical activity for patients with recurrent and metastatic NPC after platinum-containing chemotherapy failed.

16.
Curr Cancer Drug Targets ; 17(6): 555-568, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27174055

RESUMO

BACKGROUND: G9a is the primary enzyme for mono- and dimethylation at Lys 9 of histone H3 and forms predominantly the heteromeric complex as a G9a-GLP (G9a-like protein) that is a functional histone lysine methltransferase in vivo. Mounting evidence suggests that G9a catalyzes methylation of histone and nonhistone proteins, which plays a crucial role in diverse biological processes and human diseases. METHODS: In this study, the current knowledge on biological functions of G9a and inhibitors were summarized. RESULTS: we review the current knowledge on biological functions of G9a, with particular emphasis on regulating gene expression and cell processes, and involvement in human diseases. We outline a perspective on various classes of G9a inhibitors to date from both articles and patents with an emphasis on their discovery, activity and the current research status. CONCLUSION: We highlight the key knowledge on potential biological functions and various human diseases. We also reviewed the discovery and characterization of the reported G9a inhibitors. However, we also propose the challenges and future opportunities in study of G9a. This review could make a crucial contribution to the long journey to develop drug-like molecules targeting G9a.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Azepinas/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Metilação de DNA , Inibidores Enzimáticos/química , Antígenos de Histocompatibilidade/química , Histona-Lisina N-Metiltransferase/química , Humanos , Terapia de Alvo Molecular , Quinazolinas/farmacologia
17.
Oncotarget ; 8(63): 106833-106843, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29290992

RESUMO

Bromodomain and Extra-Terminal Domain (BET) inhibitors, such as JQ1 have emerged as novel drug candidates and are being enthusiastically pursued in clinical trials for the treatment of cancer. However, many solid cancers are resistance to BET inhibitors. To explore methods for improving the therapeutic potential of BET inhibitors, we investigated the combinational activity of JQ1 with Oridonin, a bioactive molecules derived from Traditional Chinese Medicine in hepatocellular carcinoma (HCC) cells. Our results showed that Oridonin synergistically enhanced the abilities of JQ1 to inhibit cell viability in HCC cells and, significantly augmented JQ1-triggered apoptosis in HCC cells and in HCC cancer stem-like cells. Moreover, Oridonin dose-dependently inhibited the expression of several anti-apoptotic proteins, such as Bcl-2, Mcl-1, and x-linked inhibitor of apoptosis (xIAP) in HCC cells. Cell fractionation and western blotting analysis showed that the enhancement of apoptosis by Oridonin was associated with cytochrome c release, activation of caspase-9, -3 and cleavage of PARP, indicating the activation of mitochondrial apoptosis pathway. Altogether, our findings demonstrate that Oridonin may be used to effectively enhance the sensitivity of BET inhibitors in HCC therapy via downregulation of the expression of multiple anti-apoptotic proteins.

18.
Ying Yong Sheng Tai Xue Bao ; 28(5): 1515-1521, 2017 May 18.
Artigo em Chinês | MEDLINE | ID: mdl-29745187

RESUMO

Acidic forest peat soil in Xiaoxing'an Mountain was used to investigate the type and key drivers of nitrification by carrying out nitrification incubation after adding 10 mL·L-1 C2H2 and different amounts of (NH4)2SO4(0, 1.2, 6.0 mmol N·kg-1). Results showed that strong mineralization (0.9-1.4 mg N·kg-1·d-1) and nitrification (0.4-0.6 mg N·kg-1·d-1) after 2 weeks of incubation were observed for both nitrogen and no nitrogen treatments, and no significant difference was observed for different (NH4)2SO4 application treatments. For C2H2 treatment, there was relatively stronger mineralization (0.8 mg N·kg-1·d-1), but no obvious nitrification (0 mg N·kg-1·d-1). These results indicated that the nitrification in acidic peat soil was mainly autotrophic, and inorganic nitrogen application did not affect nitrification rate significantly. Results also implied that the substrate (NH3) for nitrification was from the organic N mineralization, rather than the (NH4)2SO4 application. Both ammonia-oxidizing bacteria (AOB) and archaea (AOA) abundances increased significantly during 0-14 d regardless of nitrogen application. However, no significant difference in AOB and AOA abundances for different (NH4)2SO4 application treatments was observed, indicating that ammonia oxidizers did not respond positively to (NH4)2SO4 application. Compared with the treatments without C2H2, AOB and AOA abundances did not change significantly during the incubation in C2H2 treatment, suggesting that both AOA and AOB were likely the key players in nitrification in the acidic peat soil.


Assuntos
Nitrificação , Solo , Amônia , Archaea , Bactérias , China , Oxirredução , Microbiologia do Solo
19.
Ying Yong Sheng Tai Xue Bao ; 28(1): 345-352, 2017 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-29749220

RESUMO

Nitrification is the process of microbial oxidation of ammonia to nitrate, completed by the ammonia oxidizers (AOB and AOA) and nitrite oxidizing bacteria (NOB), sequentially. For a century, we have been learning and studying the established two-step process as the unique way for nitrification. According to the kinetic theory, there should be a one-step nitrification in the environment, that is, the whole process of nitrification (from NH3 to NO3-) was completed by one microorganism, but no study could give a direct proof for the existence of this microorganism. Until the end of 2015, three different cultivated bacteria (Candidatus Nitrospira nitrosa, Candidatus Nitrospira nitrificans and Candidatus Nitrospira inopinata) and an uncultivated bacterium (Nitrospira-like orga-nism) respectively found in different environments by three research teams, were defined as complete ammonia oxidizing microorganisms (Comammox), because all of them could carry out the complete oxidation of ammonia to nitrate. The discovery of one-step nitrification and Comammox ended the 100-year-old dogma, and triggered many important scientific issues of the global nitrogen cycle, such as the ecological niche of these microorganisms in the environment and their relative contribution in nitrification. This paper made a brief overview of the discovery of one-step nitrification and Comammox.


Assuntos
Amônia , Nitrificação , Archaea , Bactérias , Nitratos , Nitritos , Oxirredução
20.
J Med Chem ; 59(23): 10498-10519, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27933959

RESUMO

Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.


Assuntos
Antineoplásicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Células HCT116 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA