Background: Recent data support the implication of accelerated titanium dissolution products in peri-implantitis. It is unknown whether these dissolution products have an effect on the peri-implant microbiome, the target of existing peri-implantitis therapies. Purpose: This study assessed the relationship between the peri-implant microbiome, dissolved titanium levels, and peri-implantitis. Materials and methods: Clinical, microbiome, and titanium data were collected from a periodontal population having implants in function for 10 years. Clinical examinations were performed, and submucosal plaque samples were collected from the deepest site per implant. An aliquot of the sample was used for 16S rRNA gene sequencing, with the remainder analyzed for titanium quantity using mass spectrometry. Sequences were clustered into taxonomic units at 97% minimum sequence similarity using the QIIME pipeline approach. Results: Fifteen implants were assessed. According to established case definitions, six had a diagnosis of peri-implantitis; nine were healthy. The genera Streptococcus, Prevotella and Haemophilus characterized peri-implant health. Peri-implantitis was associated with a marked increase in Veillonella. Quantities of dissolved titanium were identified in 40% of sites. Titanium presence was associated with peri-implant disease status (p=0.02) and correlated to the 1st principal component of the microbiome (rho=0.552) and its alpha-diversity (rho=−0.496). Canonical correlation analyses found that titanium levels, but not health or disease status of the implant, were significantly associated with the microbiota composition (p=0.045). Conclusion: These findings suggest an association between titanium dissolution products and peri-implantitis and support a role for these products in modifying the peri-implant microbiome structure and diversity.
Introduction: Epigenetic changes are associated with various inflammatory diseases and are influenced by environmental factors. Recent data support an association between titanium dissolution products and peri-implantitis. We hypothesize that site-specific changes in gene methylation, a form of epigenetic regulation, around dental implants may be influenced by local environmental factors, such as titanium dissolution particles. Objectives: The primary purpose of this study was to assess global methylation patterns related to the disease status of dental implants and the concentration of titanium particles. Methods: We assessed peri-implantitis cases defined according to established definitions from a cross-sectional study that had implants in function for at least 2 y. Controls were sampled from the same population and had healthy implants. Peri-implant crevicular fluid samples were collected and prepared for immunohistochemical analysis of 5-methylcytosine (5mC), and submucosal plaque samples were collected and subjected to inductively coupled plasma mass spectrometry (ICP-MS) for measuring titanium. Data were analyzed via generalized estimating equation models to account for multiple implants per participant.
Key Points Teriflunomide, the active metabolite of leflunomide, downregulates c-Myc expression through inhibition of PIM kinases. Leflunomide together with lenalidomide significantly extended survival in an in vivo MM model.
BackgroundOur previous study found that more than 500 transcripts significantly increased in abundance in the zebrafish and mouse several hours to days postmortem relative to live controls. The current literature suggests that most mRNAs are post-transcriptionally regulated in stressful conditions. We rationalized that the postmortem transcripts must contain sequence features (3- to 9- mers) that are unique from those in the rest of the transcriptome and that these features putatively serve as binding sites for proteins and/or non-coding RNAs involved in post-transcriptional regulation.ResultsWe identified 5117 and 2245 over-represented sequence features in the mouse and zebrafish, respectively, which represents less than 1.5% of all possible features. Some of these features were disproportionately distributed along the transcripts with high densities in the 3′ untranslated regions of the zebrafish (0.3 mers/nt) and the open reading frames of the mouse (0.6 mers/nt). Yet, the highest density (2.3 mers/nt) occurred in the open reading frames of 11 mouse transcripts that lacked 3′ or 5′ untranslated regions. These results suggest the transcripts with high density of features might serve as ‘molecular sponges’ that sequester RNA binding proteins and/or microRNAs, and thus indirectly increase the stability and gene expression of other transcripts. In addition, some of the features were identified as binding sites for Rbfox and Hud proteins that are also involved in increasing transcript stability and gene expression.ConclusionsOur results are consistent with the hypothesis that transcripts involved in responding to extreme stress, such as organismal death, have sequence features that make them different from the rest of the transcriptome. Some of these features serve as putative binding sites for proteins and non-coding RNAs that determine transcript stability and fate. A small number of the transcripts have high density sequence features, which are presumably involved in sequestering RNA binding proteins and microRNAs and thus preventing regulatory interactions among other transcripts. Our results provide baseline data on post-transcriptional regulation in stressful conditions that has implications for regulation in disease, starvation, and cancer.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5042-x) contains supplementary material, which is available to authorized users.
The post-translational modification of proteins by ubiquitinating enzymes plays a central role in a number of cellular functions, such as cell proteolysis, DNA repair, and cell signaling and communication. Deubiquitinating enzymes (DUBs) disassemble ubiquitin chains and remove ubiquitin moieties from proteins. Targeting DUBs in cancer models has revealed an important role for these enzymes in tumorigenesis, and they therefore have emerged as attractive therapeutic targets. In the present study, the effects of three DUB inhibitors, PR-619, RA-9 and LDN-91946, on a non-small cell lung cancer cell line (A549) and a mesothelioma cell line (H2373) were investigated. PR-619 significantly inhibited cell adhesion and the proliferation of both cell lines. RA-9 exerted an inhibitory effect on the adhesion and proliferation of H2373 cells, whereas it had no effect on A549 cells. Notably, however, while PR-619 attenuated the proliferation of both cell lines, it exerted an opposite effect on cell motility; in the case of A549 cells, there was a significant increase in cell motility, while for the H2373 cells, there was a significant decrease. Furthermore, protein phosphorylation kinetic analyses revealed that the effects were cell line-specific. In H2373 cells, the phosphorylation of only one peptide corresponding to the P85A protein was significantly affected, and while LDN-91946 treatment increased phosphorylation, treatment with RA-9 or PR-619 decreased its phosphorylation compared to the DMSO control. By contrast, in the case of A549 cells, the phosphorylation of 21 peptides was significantly affected by the same compounds. In light of the potential for the negative side-effects of DUB inhibition, such as increased cancer cell motility, the data presented herein underscore the dire need for the development of specific DUB inhibitors and to elucidate the individual role of DUB family members in cancer biology before they can be specifically pharmacologically targeted.
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