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BackgroundThe present study examines the structure and operation of social networks of information and advice and their role in making decisions as to whether to adopt new evidence-based practices (EBPs) among agency directors and other program professionals in 12 California counties participating in a large randomized controlled trial.MethodsInterviews were conducted with 38 directors, assistant directors, and program managers of county probation, mental health, and child welfare departments. Grounded-theory analytic methods were used to identify themes related to EBP adoption and network influences. A web-based survey collected additional quantitative information on members of information and advice networks of study participants. A mixed-methods approach to data analysis was used to create a sociometric data set (n = 176) for examination of associations between advice seeking and network structure.ResultsSystems leaders develop and maintain networks of information and advice based on roles, responsibility, geography, and friendship ties. Networks expose leaders to information about EBPs and opportunities to adopt EBPs; they also influence decisions to adopt EBPs. Individuals in counties at the same stage of implementation accounted for 83% of all network ties. Networks in counties that decided not to implement a specific EBP had no extra-county ties. Implementation of EBPs at the two-year follow-up was associated with the size of county, urban versus rural counties, and in-degree centrality. Collaboration was viewed as critical to implementing EBPs, especially in small, rural counties where agencies have limited resources on their own.ConclusionsSuccessful implementation of EBPs requires consideration and utilization of existing social networks of high-status systems leaders that often cut across service organizations and their geographic jurisdictions.Trial RegistrationNCT00880126

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BackgroundDNA-methyltransferase (DNMT)-3A plays an important role in the development of embryogenesis and the generation of aberrant methylation in carcinogenesis. The aim of this study was to investigate the role of a DNMT3A promoter genetic variant on its transcriptional activity and to evaluate the association between DNMT3A gene polymorphism and the susceptibility to gastric cancer (GC) and oesophagus carcinoma (EC) in the Chinese population.MethodsWe selected one of the single nucleotide polymorphisms (SNPs) -448A>G in the DNMT3A promoter region and evaluated its effect on activity using a luciferase assay. -448A>G polymorphisms of DNMT3A were determined by polymerase chain reaction/restriction fragment length polymorphism and confirmed by sequencing. The distribution of -448A>G polymorphisms was detected in 208 GC patients and 346 healthy controls matched for age and gender. The distribution of -448A>G polymorphisms was also detected in 96 EC patients and matched 241 healthy controls. The association of -448A>G polymorphisms of DNMT3A and the risk of GC and EC was evaluated by stratified analysis according to the patient's age and gender.ResultsIn a promoter assay, carriage of the -448 A allele showed a significantly higher promoter activity (> two fold) compared with the -448G allele (P < 0.001). The allele frequency of -448A among GC patients and controls was 32.9% versus 19.9%, respectively. Overall, we found that, compared with GG carriers, the DNMT3A -448AA homozygotes has a > six fold increased risk of GC. Stratification analysis showed that AA homozygotes have a more profound risk in the subgroups of individuals at the age range ≤ 60 years in GC. However, individuals with -448AG and -448AA were not statistically significantly associated with an increased risk of EC compared with those carried the -448GG genotype.ConclusionsThe DNMT3A -448A>G polymorphism is a novel functional SNP and contributes to its genetic susceptibility to GC. -448A>G can be used as a stratification marker to predict an individual's susceptibility to GC, especially in the subgroups of individuals at the age range ≤ 60 years. However, the relative distribution of -448A>G in EC can not be used as a prediction marker in order to evaluate an individual's susceptibility to EC.

Promoter hypermethylation mediated by DNA methyltransferases (DNMTs) is the main reason for epigenetic inactivation of tumor suppressor genes (TSGs). Previous studies showed that DNMT1 and DNMT3B play an important role in CpG island methylation in tumorigenesis. Little is known about the role of DNMT3A in this process, especially in hepatocellular carcinoma (HCC). In the present study, increased DNMT3A expression in 3 out of 6 HCC cell lines and 16/25 (64%) HCC tissues implied that DNMT3A is involved in hepatocellular carcinogenesis. Depletion of DNMT3A in HCC cell line SMMC-7721 inhibited cell proliferation and decreased the colony formation (about 65%). Microarray data revealed that 153 genes were upregulated in DNMT3A knockdown cells and that almost 71% (109/153) of them contain CpG islands in their 5′ region. 13 of them including PTEN, a crucial tumor suppressor gene in HCC, are genes involved in cell cycle and cell proliferation. Demethylation of PTEN promoter was observed in DNMT3A-depleted cells implying that DNMT3A silenced PTEN via DNA methylation. These results provide insights into the mechanisms of DNMT3A to regulate TSGs by an epigenetic approach in HCC.