Aim Variations in the expression of cytokines during the progression of periodontitis remain ill-defined. We evaluated the expression of 19 cytokine genes related to T cell phenotype/function during initiation, progression, and resolution of periodontitis, and related these to the expression of soft and bone tissue destruction genes (TDGs). Materials and Methods A ligature-induced periodontitis model was used in rhesus monkeys (M. mulatta) (n=18). Gingival tissues were taken at baseline pre-ligation, 2 weeks and 1 month (Initiation), and 3 months (Progression) post-ligation. Ligatures were removed and samples taken 2 months later (Resolution). Total RNA was isolated and the Rhesus Gene 1.0 ST (Affymetrix) used for gene expression analysis. Significant expression changes were validated by qRT-PCR. Results Disease Initiation/Progression was characterized by over-expression of Th17/Treg cytokine genes (IL-1β, IL-6, TGFβ, and IL-21) and down-regulation of Th1/Th2 cytokine genes (IL-18, and IL-25). Increased IL-2 and decreased IL-10 levels were seen during disease resolution. Several Th17/Treg cytokine genes positively correlated with TDGs, whereas most Th1/Th2 genes exhibited a negative correlation. Conclusion Initiation, progression and resolution of periodontitis involve over- and under-expression of cytokine genes related to various T-helper subsets. In addition, variations in individual T-helper response subset/genes during disease progression correlated to protective/destructive outcomes.
Prostate cancer (PCa) with neuroendocrine differentiation (NED) is tightly associated with hormone refractory PCa (HRPC), an aggressive form of cancer that is nearly impossible to treat. Determining the mechanism of the development of NED may yield novel therapeutic strategies for HRPC. Here, we first demonstrate that repressor element-1 silencing transcription factor (REST), a transcriptional repressor of neuronal genes that has been implicated in androgen-deprivation and IL-6 induced NED, is essential for hypoxia-induced NED of PCa cells. Bioinformatics analysis of transcriptome profiles of REST knockdown during hypoxia treatment demonstrated that REST is a master regulator of hypoxia-induced genes. Gene set enrichment analysis (GSEA) of hypoxia and REST knockdown co-upregulated genes revealed their correlation with HRPC. Consistently, gene ontology (GO) analysis showed that REST reduction potential associated with hypoxia-induced tumorigenesis, NE development, and AMPK pathway activation. Emerging reports have revealed that AMPK activation is a potential mechanism for hypoxia-induced autophagy. In line with this, we demonstrate that REST knockdown alone is capable of activating AMPK and autophagy activation is essential for hypoxia-induced NED of PCa cells. Here, making using of in vitro cell-based assay for NED, we reveal a new role for the transcriptional repressor REST in hypoxia-induced NED and characterized a sequential molecular mechanism downstream of REST resulting in AMPK phosphorylation and autophagy activation, which may be a common signaling pathway leading to NED of PCa.
Apoptotic processes are important for physiologic renewal of an intact epithelial barrier and contribute some antimicrobial resistance for bacteria and viruses, as well as anti-inflammatory effects that benefits the mucosa. The oral cavity presents a model of host-bacterial interactions at mucosal surfaces, in which a panoply of microorganisms colonizes various niches in the oral cavity and creates complex multispecies biofilms that challenge the gingival tissues. This report details gene expression in apoptotic pathways that occur in oral mucosal tissues across the lifespan, using a nonhuman primate model. Macaca mulatta primates from 2 to 23 years of age (n = 23) were used in a cross-sectional study to obtain clinical healthy gingival tissues specimens. Further, mRNA was prepared and evaluated using the Affymetrix Rhesus GeneChip and 88 apoptotic pathway genes were evaluated. The results identified significant positive correlations with age in 12 genes and negative correlations with an additional five genes. The gene effects were predicted to alter apoptosis receptor levels, extrinsic apoptotic pathways through caspases, cytokine effects on apoptotic events, Ca+2-induced death signaling, cell cycle checkpoints, and potential effects of survival factors. Both the positively and negatively correlated genes within the apoptotic pathways provided evidence that healthy tissues in aging animals exhibit decreased apoptotic potential compared to younger animals. The results suggested that decreased physiologic apoptotic process in the dynamic septic environment of the oral mucosal tissues could increase the risk of aging tissues to undergo destructive disease processes through dysregulated inflammatory responses to the oral microbial burden.
This paper proposes consistent testing methods for examining the effect of a policy treatment on the whole distribution of a response outcome within the setting of a regression discontinuity design. These methods are particularly useful when a policy is expected to produce treatment effects that are heterogeneous along some unobserved characteristics. The test statistics are Kolmogorov-Smirnov-type and are asymptotically distribution-free when the data are i.i.d. The proposed tests are applied to three seminal RD studies (Pop-Eleches labor supply theory. Similarly, in an RD design, the policy effects identified through mean analysis could potentially miss such treatment heterogeneity. To address this issue, Frolich and Melly (2010) and Frandsen, Frolich, and Melly (2012) propose a nonparametric estimator for the local quantile treatment effect and apply the proposed estimator to study the effect of a universal pre-K program in Oklahoma. They find that participation in the pre-K program significantly raises the lower end and the middle of the test score distribution.The contribution of this paper is to propose consistent uniform tests for distributional effects, which are not discussed in Frolich and Melly (2010) or Frandsen, Frolich, and Melly (2012). The tests will allow researchers to determine quickly whether an identified positive or negative mean effect is also unambiguous along the whole outcome distribution given a pre-determined confidence level, or whether an insignificant mean effect can be generalized to the whole distribution. Both sharp and fuzzy RD designs are considered. The test statistics are constructed as Kolmogorov-Smirnov type functionals of local linear estimators of the reduced-form distributional effect, or the change in the conditional outcome distribution at the threshold value of the running variable. The tests are easy to implement. When the data are i.i.d., the tests are distribution-free, meaning that the critical values and pvalues can be easily tabulated. The proposed tests also produce, as byproducts, confidence regions for the parts of the conditional outcome distribution on which the policy has a positive or negative effect and estimates of the reduced-form distributional effect of the policy intervention. Programs for carrying out the proposed distributional tests are provided for use in both R and Stata and are available on the authors' websites. 2 The proposed tests relate to a large literature in stochastic dominance testing (Barrett and Donald
SUMMARY The molecular changes underlying the higher risk of chronic inflammatory disorders during aging remain incompletely understood. Molecular variations in the innate immune response related to recognition and interaction with microbes at mucosal surfaces could be involved in aging-related inflammation. We developed an ontology analysis of 20 NOD-like receptors (NLRs) and 7 inflammasome-related genes (IRGs) in healthy and inflamed/periodontitis oral mucosal tissues from young, adolescent, adult and aged nonhuman primates (Macaca mulatta) using the GeneChip® Rhesus Macaque Genome array. Validation of some of the significant changes was done by qRT-PCR. The expression of NLRB/NAIP, NLRP12, and AIM2 increased with aging in healthy mucosa whereas NLRC2/NOD2 expression decreased. Although higher expression levels of some NLRs were generally observed with periodontitis in adult mucosal tissues (e.g., NLRB/NAIP, NLRP5, and NLRX1), various receptors (e.g., NLRC2/NOD2, and NLRP2) and the inflammasome adaptor protein ASC, exhibited a significant reduction in expression in aged periodontitis tissues. Accordingly, the expression of NLR-activated innate immune genes, such as HBD3 and IFNB1, was impaired in aged but not adult periodontitis tissues. Both adult and aged tissues showed significant increase in IL-1β expression. These findings suggest that the expression of a subset of NLRs appears to change with aging in healthy oral mucosa, and that aging-related oral mucosal inflammation could involve an impaired regulation of the inflammatory and antimicrobial response associated with down-regulation of specific NLRs and IRGs.
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