Research Spotlight

Luan, X., Zhou, X., Fallah, P., Pandya, M., Lyu, H., Foyle, D., Burch, D. and Diekwisch, T.G.H. (2021). “MicroRNAs: Harbingers and shapers of periodontal inflammation.” Semin Cell Dev Biol Jun 10;S1084-9521(21)00139-7. [Epub ahead of print].

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Periodontal disease is an inflammatory reaction of the periodontal tissues to oral pathogens. In the present review we discuss the intricate effects of a regulatory network of gene expression modulators, microRNAs (miRNAs), as they affect periodontal morphology, function and gene expression during periodontal disease. These miRNAs are small RNAs involved in RNA silencing and post-transcriptional regulation and affect all stages of periodontal disease, from the earliest signs of gingivitis to the regulation of periodontal homeostasis and immunity and to the involvement in periodontal tissue destruction. MiRNAs coordinate periodontal disease progression not only directly but also through long non-coding RNAs (lncRNAs), which have been demonstrated to act as endogenous sponges or decoys that regulate the expression and function of miRNAs, and which in turn suppress the targeting of mRNAs involved in the inflammatory response, cell proliferation, migration and differentiation. While the integrity of miRNA function is essential for periodontal health and immunity, miRNA sequence variations (genetic polymorphisms) contribute toward an enhanced risk for periodontal disease progression and severity. Several polymorphisms in miRNA genes have been linked to an increased risk of periodontitis, and among those, miR-146a, miR-196, and miR-499 polymorphisms have been identified as risk factors for periodontal disease. The role of miRNAs in periodontal disease progression is not limited to the host tissues but also extends to the viruses that reside in periodontal lesions, such as herpesviruses (human herpesvirus, HHV). In advanced periodontal lesions, HHV infections result in the release of cytokines from periodontal tissues and impair antibacterial immune mechanisms that promote bacterial overgrowth. In turn, controlling the exacerbation of periodontal disease by minimizing the effect of periodontal HHV in periodontal lesions may provide novel avenues for therapeutic intervention. In summary, this review highlights multiple levels of miRNA-mediated control of periodontal disease progression, (i) through their role in periodontal inflammation and the dysregulation of homeostasis, (ii) as a regulatory target of lncRNAs, (iii) by contributing toward periodontal disease susceptibility through miRNA polymorphism, and (iv) as periodontal microflora modulators via viral miRNAs.

Abufarwa, M., Noureldin, A., Campbell, P.M. and Buschang, P.H. (2021). “How different time intervals between repeated applications of CPP-ACP fluoride varnish effect smooth surface enamel demineralization?” J Dent 112: 103742.

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OBJECTIVES: To evaluate the preventive effects of different time intervals between repeated applications of the CPP-ACP fluoride varnish on enamel demineralization. METHODS: Human teeth were sectioned and randomly allocated to three groups: 4-week, 6-week, and 12-week (N = 22/group). Baseline images of the enamel surfaces were obtained using the FluoreCam recording the area, intensity, and impact of baseline enamel demineralization. All groups received fluoride varnish applications at the beginning of the experiment. The varnish was reapplied every 4 or 6 weeks in the 4-week and 6-week groups, respectively. Following each application, the groups underwent thermo-cycling, tooth brushing and pH cycling to simulate the time effect. After 12 weeks, the enamel surfaces were reimaged using the FluoreCam. Within and between-group differences in the area, intensity and impact of demineralization were evaluated. RESULTS: At baseline, there were no significant between-group differences for area, intensity, or impact. Statistically significant (p<0.001) enamel demineralization occurred over time within each group. There were significant between-group differences in the changes that occurred in area (P = 0.004), impact (P = 0.022), but not intensity. The 12-week had significantly larger areas of demineralization than the 6-week (P = 0.041) and 4-week (P = 0.001) groups. Changes in impact was significantly (P = 0.007) greater in the 12-week group than 4-week group, but not greater than the 6-week group. There were no statistically significant differences between 4- and 6-week groups in the changes of area, intensity, or impact. CONCLUSION: Reapplication of the CPP-ACP fluoride varnish every 4-6 weeks, is more effective in reducing enamel demineralization compared to every 12 weeks.

De, A., Zhou, J., Liu, P., Huang, M., Gunewardena, S., Mathur, S.C., Christenson, L.K., Sharma, M., Zhang, Q. and Bansal, A. (2021). “Forkhead box F1 induces columnar phenotype and epithelial-to-mesenchymal transition in esophageal squamous cells to initiate Barrett’s like metaplasia.” Lab Invest 101(6): 745-759.

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Multiple genome-wide association studies (GWAS) have linked Forkhead Box F1 (FOXF1) to Barrett’s esophagus (BE). Understanding whether FOXF1 is involved in initiation of Barrett’s metaplasia could allow FOXF1 to be used for risk stratification and for therapy. Two-dimensional cell cultures and three-dimensional organoid cultures and well-annotated human biopsies were used to determine the role of FOXF1 in BE pathogenesis. Multiple established esophageal squamous and BE cell lines were tested in gain- and loss-of-function studies. Initiation of a BE-like metaplastic change was evaluated by measuring characteristic cytokeratins and global gene expression profiling and by culturing organoids. Epithelial-mesenchymal transition (EMT) was evaluated by immunostaining for E-cadherin, vimentin and Snail, and by cell motility assay. Columnar esophageal epithelium of BE patients exhibited higher expression of FOXF1 compared to normal squamous esophageal epithelium of GERD patients (P < 0.001). Acidic bile salts induced nuclear FOXF1 in esophageal squamous cells. FOXF1 overexpression in normal esophageal squamous cells: (a) increased columnar cytokeratins and decreased squamous cytokeratins, (b) converted squamous organoids to glandular organoids, and (c) switched global gene profiles to resemble that of human BE epithelium (P = 2.1685e - 06 for upregulated genes and P = 8.3378e - 09 for downregulated genes). FOXF1 inhibition in BE cell lines led to loss of BE differentiation markers, CK7, and mucin 2. Also, FOXF1 induced EMT and promoted cell motility in normal esophageal squamous epithelial cells. FOXF1-induced genes mapped to pathways such as Cancer, Cellular Assembly and Organization, DNA Replication, Recombination, and Repair. In conclusion, FOXF1 promotes a BE-like columnar phenotype and cell motility in esophageal squamous epithelial cells, which may have a critical role in BE development. FOXF1 should be studied further as a biomarker for BE and as a target for BE treatment.

Georgevsky, D., Li, Y., Pather, S., Tejada-Berges, T., Robinson, D., Laurence, J., Campbell, N., Wyburn, K., Liyanagama, K., Narayan, R., Lutz, T., Chan, A., Heaney, S.A., Kitzing, Y.X., Anderson, L., Testa, G., Johannesson, L. and Marren, A. (2021). “Uterus transplantation and pregnancy induction: Approved protocol at the Royal Prince Alfred Hospital.” Aust N Z J Obstet Gynaecol may 6. [Epub ahead of print].

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Absolute uterine factor infertility (AUFI) is defined as the absence of a uterus or the presence of a non-functional uterus. Before the first live birth from a uterus transplant in 2014, the only fertility options for women with AUFI were surrogacy and adoption. In November 2019, our team was granted approval for the first uterus transplant trial in Australia using known living donors. Our program is based on that of our overseas collaborators in Dallas, Texas; this team will also be proctoring us for our first two cases.

Szerlip, M., Spargias, K.S., Makkar, R., Kar, S., Kipperman, R.M., O’Neill, W.W., Ng, M.K.C., Smith, R.L., Fam, N.P., Rinaldi, M.J., Raffel, O.C., Walters, D.L., Levisay, J., Montorfano, M., Latib, A., Carroll, J.D., Nickenig, G., Windecker, S., Marcoff, L., Cohen, G.N., Schäfer, U., Webb, J.G. and Lim, D.S. (2021). “2-Year Outcomes for Transcatheter Repair in Patients With Mitral Regurgitation From the CLASP Study.” JACC Cardiovasc Interv May 7;S1936-8798(21)00675-0. [Epub ahead of print].

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OBJECTIVES: The study reports 2-year outcomes from the multicenter, prospective, single-arm CLASP study with functional mitral regurgitation (FMR) and degenerative MR (DMR) analysis. BACKGROUND: Transcatheter repair is a favorable option to treat MR. Long-term prognostic impact of the PASCAL transcatheter valve repair system in patients with clinically significant MR remains to be established. METHODS: Patients had clinically significant MR ≥3+ as evaluated by the echocardiographic core laboratory and were deemed candidates for transcatheter repair by the heart team. Assessments were performed by clinical events committee to 1 year (site-reported thereafter) and core laboratory to 2 years. RESULTS: A total of 124 patients (69% FMR, 31% DMR) were enrolled with a mean age of 75 years, 56% were male, 60% were New York Heart Association functional class III to IVa, and 100% had MR ≥3+. At 2 years, Kaplan-Meier estimates showed 80% survival (72% FMR, 94% DMR) and 84% freedom from heart failure (HF) hospitalization (78% FMR, 97% DMR), with 85% reduction in annualized HF hospitalization rate (81% FMR, 98% DMR). MR ≤1+ was achieved in 78% of patients (84% FMR, 71% DMR) and MR ≤2+ was achieved in 97% (95% FMR, 100% DMR) (all p < 0.001). Left ventricular end-diastolic volume decreased by 33 ml (p < 0.001); 93% of patients were in New York Heart Association functional class I to II (p < 0.001). CONCLUSIONS: The PASCAL repair system demonstrated sustained favorable outcomes at 2 years in FMR and DMR patients. Results showed high survival and freedom from HF rehospitalization rates with a significantly reduced annualized HF hospitalization rate. Durable MR reduction was achieved with evidence of left ventricular reverse remodeling and significant improvement in functional status. The CLASP IID/IIF randomized pivotal trial is ongoing.