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1.
Environ Res ; 184: 109279, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32113023

RESUMO

To estimate the mortality risk from haze and the modifying effects by three characteristics of haze (intensity, duration and timing), data on haze and mortality in the Pearl River Delta region from 2013 to 2016 were collected. We first estimated mortality risk during haze days compared with non-haze days. Then we classified haze into several categories by considering one or any two of the three haze characteristics together, and further calculated the mortality risks separately. The mortality risk increased 5.0% (95% confidence intervals (CI): 3.1%-6.9%) during hazy days compared with non-haze days, with larger effect for the elderly ≥ 85 years old (Excess risk (ER): 8.7%, 95% CI: 3.9%-13.6%) than other age groups. Mortality risk increased in longer haze (ER: 4.4%, 95% CI: 2.9%-6.0%) compared with shorter haze (ER: 1.9%, 95% CI: 0.7%-3.2%). The greatest effect of any two of haze characteristics was observed when haze was intense and long (ER: 4.8%, 95% CI: 3.0%-6.6%). Our study indicates that haze significantly increased mortality risk in the Pearl River Delta. The health effects of haze may be under-estimated when using a single air pollutant concentration during haze periods to assess health risk of haze events. The haze intensity, duration, and time of occurrence should be accounted for in appropriate risk assessment of haze.

2.
Lung Cancer ; 142: 98-105, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32120230

RESUMO

OBJECTIVES: The efficacy of immunotherapy in epidermal growth factor receptor (EGFR)-activating non-small cell lung cancer (NSCLC) is limited. However, a series of patients with uncommon EGFR alterations was reported to derive clinical benefit from PD-1 blockade. To characterize the tumor immune microenvironment, we retrospectively evaluated tumor PD-L1 expression and T cells infiltration among NSCLC patients with uncommon EGFR mutations. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expression of PD-L1 and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs). Chi-square test and Cox proportional hazards regression were conducted to investigate the correlations between the immune microenvironment features and clinicopathological variables and survival, as well as to explore the potential of immunotherapy in this patient population. RESULTS: Among 600 NSCLC patients with EGFR alterations, we identified 49 (8.2 %) bearing uncommon mutations, including G719X, L861Q, S768I, and Ex20 ins. In total, 49.0 % (24/49) of these patients showed positive PD-L1 expression in tumor cells, markedly higher than the proportion in patients with classic sensitive mutations (19del and L858R, 12.2 % [67/551], P < 0.05). Furthermore, PD-L1 expression was associated with relatively short overall survival (OS; 15.2 vs 29.3 months, P = 0.006) and was identified as an independent predictor of OS (hazard ratio=2.57, 95 % confidence interval: 1.03-7.12, P = 0.045). Additionally, PD-L1 positivity was predominantly observed among tumors with CD8+ TILs infiltration (P = 0.001). Uncommon EGFR-mutant tumors had a high frequency (36.7 %) of concurrent PD-L1 expression and abundant CD8 + TILs infiltration. Moreover, this dual-positive group exhibited the most unfavorable prognosis (P = 0.023). Notably, patients with PD-L1 and CD8 dual positivity showed a favorable response to PD-1 inhibitors. CONCLUSIONS: High rates of concomitant PD-L1 expression and CD8 + TILs within the tumor microenvironment were observed in NSCLC patients with uncommon EGFR mutations. Further investigations are needed to confirm the therapeutic sensitivity to PD-1 blockade in this subgroup.

3.
Insect Biochem Mol Biol ; : 103361, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32199887

RESUMO

Insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) can provide safe and effective control of some major pests, but evolution of resistance by pests diminishes these benefits. Better understanding of the genetics and mechanisms of resistance is urgently needed to improve methods for monitoring, managing, and countering pest resistance to Bt toxins. Here we used CRISPR-mediated knockouts to evaluate the role of five genes encoding candidate Bt toxin receptors in Spodoptera exigua (beet armyworm), a devastating pest of vegetable, field and flower crops. We compared susceptibility to Bt toxins Cry1Ac, Cry1Fa, and Cry1Ca between the parent susceptible strain and each of five strains homozygous for the knockout of one of the candidate genes (SeAPN1, SeCad1, SeABCC1, SeABCC2 or SeABCC3). The results from the 15 pairwise comparisons reveal that SeABCC2 has a major role and SeCad1 a minor role in mediating toxicity of Cry1Ac and Cry1Fa. SeABCC2 also has a minor role in toxicity of Cry1Ca. In addition, the results imply little or no role for the other three candidate receptors in toxicity of Cry1Ac or Cry1Fa; or for the four candidate receptors other than SeABCC2 in toxicity of Cry1Ca.

4.
Can J Physiol Pharmacol ; : 228-235, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32207632

RESUMO

To test if magnitudes of the beneficial actions of CO2 water bath therapy on blood flow and vascular density are dependent upon temperature, ischemia in the hind limb of rats was induced by occluding the left femoral artery for 2 weeks and the animals were exposed to water bath therapy with or without CO2 at 34 or 41 °C for 4 weeks (20 min treatment each day for 5 days/week). CO2 water bath therapy at 34 °C increased peak, minimal, and mean blood flow by 190%-600% in the ischemic limb. On the other hand, CO2 water bath treatment at 41 °C increased these parameters of blood flow by 37%, 55%, and 41%, respectively, in the ischemic limb. The small blood vessel count, an index of vascular density, in the ischemic limb was increased by CO2 water bath therapy at 34 and 41 °C by 32% and 122%, respectively. No changes in the ischemic animals by CO2 water bath therapy at 34 or 41 °C were observed in the heart rate, R-R interval, and plasma lipid or glucose levels. These data indicate that the beneficial effect of CO2 water bath therapy at 34 °C on blood flow in the ischemic muscle is greater whereas that on vascular density is smaller than changes in these parameters at 41 °C.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32077806

RESUMO

A QuEChERS method with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was modified and validated for the determination of florasulam and pyroxsulam residues in wheat grain and straw. The validated method was applied to cereals including oat, millet, corn and rice. Average recoveries were 76-113% with RSDs 2-15%. The limits of quantitation (LOQ) were 0.005 mg/kg for wheat grain and 0.01 mg/kg for wheat straw and four cereals. Ion suppression for florasulam (-28% to -76%) was observed in all the matrices except corn, whereas ion enhancement were shown for pyroxsulam (44% to 83%). Degradation rates of florasulam and pyroxsulam were 6% and 23%, respectively, in wheat grain and straw after eight-week storage at -20°C. The ultimate residues in field trials in ten regions were all ≤0.05 mg/kg, and long term dietary risk assessment indicated that hazard quotients were 0.02% and 0.001% for florasulam and pyroxsulam, respectively, which shows that it is safe to spray the two herbicides on wheat.

6.
Eur Radiol ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020400

RESUMO

OBJECTIVES: This prospective trial was performed to verify whether microwave ablation (MWA) in combination with chemotherapy could provide superior survival benefit compared with chemotherapy alone. MATERIALS AND METHODS: From March 1, 2015, to June 20, 2017, treatment-naïve patients with pathologically verified advanced or recurrent non-small cell lung cancer (NSCLC) were randomly assigned to MWA plus chemotherapy group or chemotherapy group. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), time to local progression (TTLP), and objective response rate (ORR). The complications and adverse events were also reported. RESULTS: A total of 293 patients were randomly assigned into the two groups. One hundred forty-eight patients with 117 stage IV tumors were included in the MWA plus chemotherapy group. One hundred forty-five patients with 113 stage IV tumors were included in the chemotherapy group. The median follow-up period was 13.1 months and 12.4 months, respectively. Median PFS was 10.3 months (95% CI 8.0-13.0) in the MWA plus chemotherapy group and 4.9 months (95% CI 4.2-5.7) in the chemotherapy group (HR = 0.44, 95% CI 0.28-0.53; p < 0.0001). Median OS was not reached in the MWA plus chemotherapy group and 12.6 months (95% CI 10.6-14.6) in the chemotherapy group (HR = 0.38, 95% CI 0.27-0.53; p < 0.0001) using Kaplan-Meier analyses with log-rank test. The median TTLP was 24.5 months, and the ORR was 32% in both groups. The adverse event rate was not significantly different in the two groups. CONCLUSIONS: In patients with advanced NSCLC, longer PFS and OS can be achieved with the treatment of combined MWA and chemotherapy than chemotherapy alone. KEY POINTS: • Patients treated with MWA plus chemotherapy had superior PFS and OS over those treated with chemotherapy alone. • The ORR of patients treated with MWA plus chemotherapy was similar to that of those treated with chemotherapy alone. • Complications associated with MWA were common but tolerable and manageable.

7.
Can J Physiol Pharmacol ; 98(2): 103-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31369714

RESUMO

Lysophosphatidic acid (LPA) is an important lipid molecule for signal transduction in cell proliferation. Although the effects of LPA on vascular smooth muscle (VSM) cell growth have been reported previously, the underlying mechanisms of its action are not fully understood. The present study was undertaken to investigate the effects of some inhibitors of different protein kinases and other molecular targets on LPA-induced DNA synthesis as well as gene expression in the aortic VSM cells. The DNA synthesis was studied by the [3H]thymidine incorporation method and the gene expression was investigated by the real-time PCR technique. It was observed that the LPA-induced DNA synthesis was attenuated by inhibitors of protein kinase C (PKC) (staurosporine, calphostin C, and bisindolylmaleimide), phosphoinositide 3-kinase (PI3K) (wortmannin and LY294002), and ribosomal p70S6 kinase (p70S6K) (rapamycin). The inhibitors of guanine protein coupled receptors (GPCR) (pertussis toxin), phospholipase C (PLC) (U73122 and D609), and sodium-hydrogen exchanger (NHE) (amiloride and dimethyl amiloride) were also shown to depress the LPA-induced DNA synthesis. Furthermore, gene expressions for PLC ß1 isoform, PKC δ and ε isoforms, casein kinase II ß isoform, and endothelin-1A receptors were elevated by LPA. These results suggest that the LPA-induced proliferation of VSM cells is mediated through the activation of GPCR and multiple protein kinases as well as gene expressions of some of their specific isoforms.

8.
Brief Bioinform ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31799597

RESUMO

Drug sensitivity has always been at the core of individualized cancer chemotherapy. However, we have been overwhelmed by large-scale pharmacogenomic data in the era of next-generation sequencing technology, which makes it increasingly challenging for researchers, especially those without bioinformatic experience, to perform data integration, exploration and analysis. To bridge this gap, we developed RNAactDrug, a comprehensive database of RNAs associated with drug sensitivity from multi-omics data, which allows users to explore drug sensitivity and RNA molecule associations directly. It provides association data between drug sensitivity and RNA molecules including mRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) at four molecular levels (expression, copy number variation, mutation and methylation) from integrated analysis of three large-scale pharmacogenomic databases (GDSC, CellMiner and CCLE). RNAactDrug currently stores more than 4 924 200 associations of RNA molecules and drug sensitivity at four molecular levels covering more than 19 770 mRNAs, 11 119 lncRNAs, 438 miRNAs and 4155 drugs. A user-friendly interface enriched with various browsing sections augmented with advance search facility for querying the database is offered for users retrieving. RNAactDrug provides a comprehensive resource for RNA molecules acting in drug sensitivity, and it could be used to prioritize drug sensitivity-related RNA molecules, further promoting the identification of clinically actionable biomarkers in drug sensitivity and drug development more cost-efficiently by making this knowledge accessible to both basic researchers and clinical practitioners. Database URL: http://bio-bigdata.hrbmu.edu.cn/RNAactDrug.

9.
Brief Bioinform ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31792500

RESUMO

Numerous studies have shown that copy number variation (CNV) in lncRNA regions play critical roles in the initiation and progression of cancer. However, our knowledge about their functionalities is still limited. Here, we firstly provided a computational method to identify lncRNAs with copy number variation (lncRNAs-CNV) and their driving transcriptional perturbed subpathways by integrating multidimensional omics data of cancer. The high reliability and accuracy of our method have been demonstrated. Then, the method was applied to 14 cancer types, and a comprehensive characterization and analysis was performed. LncRNAs-CNV had high specificity in cancers, and those with high CNV level may perturb broad biological functions. Some core subpathways and cancer hallmarks widely perturbed by lncRNAs-CNV were revealed. Moreover, subpathways highlighted the functional diversity of lncRNAs-CNV in various cancers. Survival analysis indicated that functional lncRNAs-CNV could be candidate prognostic biomarkers for clinical applications, such as ST7-AS1, CDKN2B-AS1 and EGFR-AS1. In addition, cascade responses and a functional crosstalk model among lncRNAs-CNV, impacted genes, driving subpathways and cancer hallmarks were proposed for understanding the driving mechanism of lncRNAs-CNV. Finally, we developed a user-friendly web interface-LncCASE (http://bio-bigdata.hrbmu.edu.cn/LncCASE/) for exploring lncRNAs-CNV and their driving subpathways in various cancer types. Our study identified and systematically characterized lncRNAs-CNV and their driving subpathways and presented valuable resources for investigating the functionalities of non-coding variations and the mechanisms of tumorigenesis.

10.
Aging (Albany NY) ; 11(24): 12428-12451, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852840

RESUMO

Long noncoding RNAs (lncRNAs) have multiple regulatory roles and are involved in many human diseases. A potential therapeutic strategy based on targeting lncRNAs was recently developed. To gain insight into the global relationship between small molecule drugs and their affected lncRNAs, we constructed a small molecule lncRNA network consisting of 1206 nodes (1033 drugs and 173 lncRNAs) and 4770 drug-lncRNA associations using LNCmap, which reannotated the microarray data from the Connectivity Map (CMap) database. Based on network biology, we found that the connected drug pairs tended to share the same targets, indications, and side effects. In addition, the connected drug pairs tended to have a similar structure. By inferring the functions of lncRNAs through their co-expressing mRNAs, we found that lncRNA functions related to the modular interface were associated with the mode of action or side effects of the corresponding connected drugs, suggesting that lncRNAs may directly/indirectly participate in specific biological processes after drug administration. Finally, we investigated the tissue-specificity of drug-affected lncRNAs and found that some kinds of drugs tended to have a broader influence (e.g. antineoplastic and immunomodulating drugs), whereas some tissue-specific lncRNAs (nervous system) tended to be affected by multiple types of drugs.

11.
Wei Sheng Yan Jiu ; 48(6): 907-912, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31875814

RESUMO

OBJECTIVE: To investigate the prevalence and change of growth retardation, weight loss and malnutrition among children and adolescents aged 6-17 years in Guangdong Province in 2002-2012. METHODS: A total of 7264 children and adolescents(3804 boys and 3460 girls) aged 6-17 years were selected in thirteen monitoring points of Guangdong for nutritional survey in 2002, and a total of 2319 children and adolescents(1158 boys and 1161 girls) aged 6-17 years were selected in nine counties/districts of Guangdong for nutritional survey during 2009-2012 through multistage random cluster sampling. The body height and weight of all the children and adolescents were measured. RESULTS: The prevalence of growth retardation, weight loss and malnutrition decreased from 10. 0% to 1. 6%, 18. 1% to 8. 0%, and 24. 7% to 9. 3%among children and adolescents in Guangdong from 2002 to 2009-2012. The result of2009-2012 survey indicated the average prevalence of growth retardation were higher in boys(1. 9%) than in girls(1. 1%), and the average prevalence of weight loss and malnutrition was higher in girls(10. 4% and 11. 3%) than in boys(6. 0% and 7. 7%). And the average prevalence of growth retardation, weight loss and malnutrition were all higher in those living in rural area(2. 5%, 12. 4% and 14. 5%) than in city area(0. 8%, 4. 4% and 5. 1%). CONCLUSION: Compared with 2002, the prevalence of growth retardation, weight loss and malnutrition in children and adolescents aged 6-17 in Guangdong Province all decreased significantly. The prevalence was still high in girls and those living in rural, and children aged 6-17, thus more attention should be paid to them.


Assuntos
Desnutrição , Inquéritos Nutricionais , Adolescente , Peso Corporal , Criança , China , Feminino , Humanos , Masculino , Estado Nutricional , Prevalência
12.
Hepatology ; 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31677282

RESUMO

Free and bioavailable 25-hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival. We included 1031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort (GLCC) enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum free 25OHD levels were measured using a two-step enzyme-linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer-specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C-reactive protein, Barcelona Clinic Liver Cancer (BCLC) stage, and cancer treatment. The multivariable-adjusted HRs in the highest vs. lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend=0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend=0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS. CONCLUSION: Higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population-based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis.

13.
Med Ultrason ; 21(3): 327-335, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31476213

RESUMO

AIM: To evaluate the diagnostic accuracy of real-time elastography as a method for detecting prostate cancer. MATERIAL AND METHODS: Relevant studies applying real-time elastography as the diagnostic modality and biopsy as the reference standard, published by March 1, 2018 were retrieved from PubMed, EMBASE, Web of Science and Cochrane Library databases. Two independent reviewers inspected all these articles to confirm the matching of the inclusion criteria. One reviewer with methodological expertise extracted the data from the included studies. Sensitivity, specificity and diagnostic odds ratio (DOR) were used to obtain overall estimates. Randomized effect method, meta-regression and subgroup analysis were performed. RESULTS: Twenty-four studies out of 1156 identified articles met the inclusion criteria. Three groups were set: analysisby patient (Group 1), by core (Group 2), and by image (Group 3) and subgroups set in Group 1. The pooled estimate ofreal-time elastography sensitivity/ specificity/ DOR calculated with the identical P-value 0.00. Within subgroups "Asia" and"PSA>=10 ng/ml", the pooled sensitivity, specificity and DOR were 0.83, 0.65 (p=0.01, I2=73.40%; p=0.02, I2=69.5%), 0.80, 0.82 (p=0.66, I2=0.00%; p=0.58, I2=0.00%) and 20.2, 8.67 (p=0.09, I2=54.2%; p=0.20, I2=35.5%), respectively. In these three groups, the areas under the SROC curve were 0.7417, 0.9246, and 0.6213 independently. CONCLUSIONS: Real-time elastography is a promising, reliable modality for the non-invasive diagnosis of patients with prostate cancer. The diagnostic accuracy of real-time elastography correlates tightly to the presence of higher PSA level and may help avoid unnecessary biopsy. It seems to be a useful tool in systemic biopsy.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Neoplasias da Próstata/diagnóstico por imagem , Humanos , Masculino , Próstata/diagnóstico por imagem , Sensibilidade e Especificidade
14.
Br J Cancer ; 121(8): 640-646, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31523058

RESUMO

BACKGROUND: Small-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies. METHODS: Eligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate. RESULTS: Forty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand-foot syndrome, increased L-gamma-glutamyltransferase. CONCLUSIONS: Apatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted. TRIAL REGISTRATION: NCT02945852.

15.
J Transl Med ; 17(1): 255, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387579

RESUMO

BACKGROUND: Individualized drug response prediction is vital for achieving personalized treatment of cancer and moving precision medicine forward. Large-scale multi-omics profiles provide unprecedented opportunities for precision cancer therapy. METHODS: In this study, we propose a pipeline to identify subpathway signatures for anticancer drug response of individuals by integrating the comprehensive contributions of multiple genetic and epigenetic (gene expression, copy number variation and DNA methylation) alterations. RESULTS: Totally, 46 subpathway signatures associated with individual responses to different anticancer drugs were identified based on five cancer-drug response datasets. We have validated the reliability of subpathway signatures in two independent datasets. Furthermore, we also demonstrated these multi-omics subpathway signatures could significantly improve the performance of anticancer drug response prediction. In-depth analysis of these 46 subpathway signatures uncovered the essential roles of three omics types and the functional associations underlying different anticancer drug responses. Patient stratification based on subpathway signatures involved in anticancer drug response identified subtypes with different clinical outcomes, implying their potential roles as prognostic biomarkers. In addition, a landscape of subpathways associated with cellular responses to 191 anticancer drugs from CellMiner was provided and the mechanism similarity of drug action was accurately unclosed based on these subpathways. Finally, we constructed a user-friendly web interface-CancerDAP ( http://bio-bigdata.hrbmu.edu.cn/CancerDAP/ ) available to explore 2751 subpathways relevant with 191 anticancer drugs response. CONCLUSIONS: Taken together, our study identified and systematically characterized subpathway signatures for individualized anticancer drug response prediction, which may promote the precise treatment of cancer and the study for molecular mechanisms of drug actions.

16.
Genes (Basel) ; 10(9)2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466383

RESUMO

Breast cancer has become the most common cancer that leads to women's death. Breast cancer is a complex, highly heterogeneous disease classified into various subtypes based on histological features, which determines the therapeutic options. System identification of effective drugs for each subtype remains challenging. In this work, we present a computational network biology approach to screen precision drugs for different breast cancer subtypes by considering the impact intensity of candidate drugs on the pathway crosstalk mediated by miRNAs. Firstly, we constructed and analyzed the subtype-specific risk pathway crosstalk networks mediated by miRNAs. Then, we evaluated 36 Food and Drug Administration (FDA)-approved anticancer drugs by quantifying their effects on these subtype-specific pathway crosstalk networks and combining with survival analysis. Finally, some first-line treatments of breast cancer, such as Paclitaxel and Vincristine, were optimized for each subtype. In particular, we performed precision screening of subtype-specific therapeutic drugs and also confirmed some novel drugs suitable for breast cancer treatment. For example, Sorafenib was applicable for the basal subtype treatment, Irinotecan was optimum for Her2 subtype treatment, Vemurafenib was suitable for the LumA subtype treatment, and Vorinostat could apply to LumB subtype treatment. In addition, the mechanism of these optimal therapeutic drugs in each subtype of breast cancer was further dissected. In summary, our study offers an effective way to screen precision drugs for various breast cancer subtype treatments. We also dissected the mechanism of optimal therapeutic drugs, which may provide novel insight into the precise treatment of cancer and promote researches on the mechanisms of action of drugs.


Assuntos
Neoplasias da Mama/genética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Redes Reguladoras de Genes , Genômica/métodos , MicroRNAs/genética , Medicina de Precisão/métodos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos
17.
Environ Int ; 130: 104882, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31202028

RESUMO

BACKGROUND: Experimental studies have indicated that alterations in the gut microbiota might play a role in the pathway of diabetes induction resulting from particulate matter pollution with aerodynamic diameters < 2.5 µm (PM2.5). However, few human studies have examined such experimental findings. Here, we examine the mediating effects of gut microbial dysbiosis on the associations between PM2.5 and particulate matter pollution with aerodynamic diameters < 1 µm (PM1) on diabetes using the Guangdong Gut Microbiome Project (GGMP) dataset. METHODS: A multistage cluster sampling method was employed to recruit adult participants from communities in Guangdong. Each participant was interviewed using a questionnaire, fasting blood and stool samples were collected, and the exposure to air pollutants was assessed using a spatiotemporal land-use regression model. The mediation analysis was conducted to estimate the associations among air pollutants, gut microbiota diversity and diabetes. RESULTS: Both PM2.5 and PM1 were positively associated with the risks of impaired fasting glucose (IFG) or type 2 diabetes and negatively associated with alpha diversity indices of the gut microbiota. The mediation analyses indicated that the associations of PM2.5 and PM1 with the risk of type 2 diabetes were partially mediated by the decrease in gut microbiota diversity. Moreover, we found that 79 (PM2.5 on IFG), 84 (PM2.5 on type 2 diabetes), 83 (PM1 on IFG) and 89 (PM1 on type 2 diabetes) bacterial taxa could partially mediate the associations of PM2.5 and PM1 with IFG and type 2 diabetes, respectively. The relative abundance of most Firmicutes, Proteobacteria and Verrucomicrobia bacteria were negatively associated with particulate matter (PM) concentrations and the risks of diabetes. CONCLUSIONS: Long-term exposure to PM may increase the risk of diabetes, and alterations in the gut microbiota partially explained these associations.

18.
Brief Bioinform ; 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31155677

RESUMO

Alterations of biological pathways can lead to oncogenesis. An overview of these oncogenic pathways would be highly valuable for researchers to reveal the pathogenic mechanism and develop novel therapeutic approaches for cancers. Here, we reviewed approximately 8500 literatures and documented experimentally validated cancer-pathway associations as benchmarking data set. This data resource includes 4709 manually curated relationships between 1557 paths and 49 cancers with 2427 upstream regulators in 7 species. Based on this resource, we first summarized the cancer-pathway associations and revealed some commonly deregulated pathways across tumor types. Then, we systematically analyzed these oncogenic pathways by integrating TCGA pan-cancer data sets. Multi-omics analysis showed oncogenic pathways may play different roles across tumor types under different omics contexts. We also charted the survival relevance landscape of oncogenic pathways in 26 tumor types, identified dominant omics features and found survival relevance for oncogenic pathways varied in tumor types and omics levels. Moreover, we predicted upstream regulators and constructed a hierarchical network model to understand the pathogenic mechanism of human cancers underlying oncogenic pathway context. Finally, we developed `CPAD' (freely available at http://bio-bigdata.hrbmu.edu.cn/CPAD/), an online resource for exploring oncogenic pathways in human cancers, that integrated manually curated cancer-pathway associations, TCGA pan-cancer multi-omics data sets, drug-target data, drug sensitivity and multi-omics data for cancer cell lines. In summary, our study provides a comprehensive characterization of oncogenic pathways and also presents a valuable resource for investigating the pathogenesis of human cancer.

19.
BMC Public Health ; 19(1): 599, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101032

RESUMO

BACKGROUND: Drowning is a leading cause of accidental death in children under 14 years of age in Guangdong, China. We developed a statistical model to classify the risk of drowning among children based on the risk factors. METHODS: A multiple-stage cluster random sampling was employed to select the students in Grades 3 to 9 in two townships in Qingyuan, Guangdong. Questionnaire was a self-reported measure consisting of general information, knowledge, attitudes and activities. A univariate logistic regression model was used to preliminarily select the independent variables at a P value of 0.1 for multivariable model. Three-quarters of the participants were randomly selected as a training sample to establish the model, and the remaining were treated as a testing sample to validate the model. RESULTS: A total of 8390 children were included in this study, about 12.18% (1013) experienced drowning during the past one year. In the univariate logistic regression model, introvert personality, unclear distributions of water areas on the way to school, and bad relationships with their classmates and families were positively associated with drowning. However, females, older age and lower swimming skills were negatively associated with drowning. After employing the prediction model with these factors to estimate drowning risk of the students in the testing samples, the results of Hosmer-Lemeshow tests showed non-significant differences between the predictive results and actual risk (χ2 = 5.97, P = 0.65). CONCLUSIONS: Male, younger children, higher swimming skills, bad relationship with their classmates and families, introvert personality and unclear distributions of water areas on the way to school were important risk factors of non-fatal drowning among children. The prediction model based on these variables has an acceptable predictive ability.


Assuntos
Afogamento/etiologia , Modelos Estatísticos , Medição de Risco/métodos , Estudantes/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , China , Análise por Conglomerados , Feminino , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Fatores de Risco , Instituições Acadêmicas , Autorrelato , Natação
20.
Sci Rep ; 9(1): 6989, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061470

RESUMO

Obesity is a progressive, chronic disease, which can be caused by long-term miscommunication between organs. It remains challenging to understand how chronic dysfunction in a particular tissue remotely impairs other organs to eventually imbalance organismal energy homeostasis. Here we introduce RNAi Pulse Induction (RiPI) mediated by short hairpin RNA (shRiPI) or double-stranded RNA (dsRiPI) to generate chronic, organ-specific gene knockdown in the adult Drosophila fat tissue. We show that organ-restricted RiPI targeting Stromal interaction molecule (Stim), an essential factor of store-operated calcium entry (SOCE), results in progressive fat accumulation in fly adipose tissue. Chronic SOCE-dependent adipose tissue dysfunction manifests in considerable changes of the fat cell transcriptome profile, and in resistance to the glucagon-like Adipokinetic hormone (Akh) signaling. Remotely, the adipose tissue dysfunction promotes hyperphagia likely via increased secretion of Akh from the neuroendocrine system. Collectively, our study presents a novel in vivo paradigm in the fly, which is widely applicable to model and functionally analyze inter-organ communication processes in chronic diseases.

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