Publications by authors named "T E Van Dyke"

546 Publications

Host Modulation and Treatment of Periodontal Disease.

J Dent Res 2021 Mar 3:22034521995157. Epub 2021 Mar 3.

Center for Clinical and Translational Research, Forsyth Institute, Cambridge, MA, USA.

Periodontitis is the sixth-most prevalent disease in the world and the first cause for tooth loss in adults. With focus shifted to the inflammatory/immune response in the pathogenesis of periodontitis, there is a critical need to evaluate host modulatory agents. Synthetic and biological disease-modifying antirheumatic drugs are a cornerstone for the treatment of inflammatory diseases. Recent prospective cohort studies showed that synthetic disease-modifying antirheumatic drugs improved periodontal clinical parameters following nonsurgical periodontal treatment in patients with rheumatoid arthritis. Treatment with recombinant humanized monoclonal antibodies against CD20 (rituximab) and IL-6 receptor (tocilizumab), the latter also in clinical trials for the treatment of COVID-19 pneumonia, resulted in decreased periodontal inflammation and improved periodontal status. Studies on the effect of TNF-α inhibitors in patients with periodontitis yielded inconsistent results. Recent data suggest that probiotics provide anti-inflammatory clinical benefit, as do nutritional supplements, such as n-3 fatty acids, when combined with periodontal therapy. Probiotics reduce the production of proinflammatory cytokines/chemokines by suppressing NF-κB pathways and promote the accumulation of T regulatory cells. Statins, like aspirin, have been shown to exhibit anti-inflammatory and bone-preserving actions by upregulating production of Specialized Proresolving Mediators (SPMs). Currently, there is insufficient scientific support for the topical delivery of statins or bisphosphonates as adjuncts to periodontal therapy. Here, we present a critical review of the most recent host modulatory agents applied in humans and the key immune pathways that they target. Emerging evidence from novel drug candidates, including SPMs and complement inhibitors as previously studied in animal models and currently in human clinical trials, suggests future availability of adjunctive therapeutic strategies for the management of periodontitis.
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http://dx.doi.org/10.1177/0022034521995157DOI Listing
March 2021

A Novel Animal Model for Simulating Scarring After Cleft Lip Repair.

Facial Plast Surg Aesthet Med 2021 Feb 24. Epub 2021 Feb 24.

Department of Otolaryngology-Head and Neck Surgery, Tufts University School of Medicine, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1089/fpsam.2020.0525DOI Listing
February 2021

The use of amnion-derived cellular cytokine solution for the treatment of gingivitis: A two week safety, dose-ranging, proof-of-principle randomized trial.

J Periodontol 2021 Feb 15. Epub 2021 Feb 15.

The Forsyth Institute, Center for Clinical and Translational Research, Cambridge, MA.

Background: A 6-week Phase I clinical trial was performed to primarily evaluate the safety and secondarily determine the preliminary efficacy of a novel biological solution, ST266, comprised of a mixture of cytokines, growth factors, nucleic acids, and lipids secreted by cultured Amnion-derived Multi-potent Progenitor cells on gingival inflammation.

Methods: Fifty-four adults with gingivitis/periodontitis were randomly assigned to 1X ST266 or diluted 0.3X ST266 or saline topically applied on facial/lingual gingiva (20μL/tooth). Safety was assessed through oral soft/hard tissue exam, adverse events, and routine laboratory tests. Efficacy was assessed by modified gingival index (MGI), bleeding on probing (BOP), plaque index (PI), pocket depth (PD) and clinical attachment level (CAL). Assessments were performed on Day 0, 8, 12 and 42. ST266 and saline applied daily starting at Day 0 through Day-12 except weekend days. Plasma was analyzed for safety and pro-inflammatory cytokines, interleukin 1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon gamma (IFN-γ). Gingival crevicular fluid (GCF) was analyzed for the same cytokines. Subgingival plaque was primarily analyzed by Checkerboard DNA-DNA hybridization. Comparisons with saline were modeled through a generalized estimating equations method adjusting for baseline.

Results: No safety concern was found related to ST266. Statistically significant reduction in MGI was noted at Day 42 by 1X ST266 compared with saline (p = 0.044). PD and CAL were reduced by both doses of ST266 at Day 42 (p<0.01) and by 1X ST266 at Day 12 (p<0.05). GCF IL-1β and IL-6 levels were reduced by both doses of ST266 at Day 12 (p<0.05, p<0.01, respectively). IL-6 was also significantly reduced in plasma of both ST266 groups (p<0.05). Significant reductions in red complex bacteria were detected in both ST266 doses.

Conclusions: In this "first in human oral cavity" study, topical ST266 was safe and effective in reducing gingival inflammation in 6 weeks. Longitudinal studies with large sample sizes are warranted to assess the therapeutic value of this novel host modulatory compound in the treatment of periodontal diseases. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/JPER.20-0800DOI Listing
February 2021

TLR2 and TLR4 Differentially Regulate the Osteogenic Capacity of Human Periodontal Ligament Fibroblasts.

J Int Acad Periodontol 2021 Jan 1;23(1):3-10. Epub 2021 Jan 1.

Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA. E-mail address:

Aims: To test that the osteogenic capacity of periodontal ligament (PDL) fibroblasts can be mediated by TLR2 and TLR4 activation.

Materials And Methods: Human PDL fibroblasts were cultured in osteogenic medium and treated with TLR2 and TLR4 agonists (Pam3CSK4 and monophosphoryl Lipid A (MPLA), respectively). Cell proliferation was measured by MTT and BrdU incorporation. Osteogenic differentiation was measured by alkaline phosphatase (ALP) activity. Nodule formation was measured for osteoblast function. The expression of markers of potential signaling pathways (RUNX2, OCN, BSP and Osterix) was evaluated by quantitative PCR.

Results: PDL fibroblasts grew at the same rate during the first 5 days in response to both Pam3CSK5 and MPLA. On day 7, cells cultured in the presence of Pam3CSK4 had a significantly higher rate of DNA replication, while cells in MPLA group had a significantly lower DNA replication rate (one-third) compared to the control (p less than 0.05). Pam3CSK4 induced significantly higher ALP activity and larger calcified nodules. TLR4 activation significantly reduced the expression of RUNX2 and osterix and enhanced OCN. Neither TLR2 nor TLR4 affected BSP expression.

Conclusions: These data suggest that the activation of TLR2 and TLR4 differentially and perhaps antagonistically modulate osteogenesis by human PDL fibroblasts and have a direct role of TLR-mediated PDL function during periodontal regeneration as a potential target for therapeutics.
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January 2021

In Memoriam Sebastian G. Ciancio, DDS, MS (1937-2020).

J Int Acad Periodontol 2021 Jan 1;23(1):1-2. Epub 2021 Jan 1.

Department of Applied Oral Sciences, Centre for Periodontology,The Forsyth Institute, Cambridge, Massachusetts, USA.

Periodontology lost another giant in our field this past October when Sebastian Ciancio passed away. Seb was a true leader in our field and his impact on the profession was immeasurable. He was recognized worldwide for his expertise in research and clinical applications of Periodontology and Pharmacology. The impact of Dr. Sebastian G. Ciancio on the field of Periodontology is impossible to quantify. He was one of the earliest contributors to the scientific era of clinical research in periodontology going far beyond descriptive studies and case reports into modern concepts of evaluating treatments for disease. His leadership changed the way we practice. He was a leader in education and science, and he will be missed. Seb was 83.
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January 2021

Inflammation of the periodontium associates with risk of future cardiovascular events.

J Periodontol 2021 Mar 13;92(3):348-358. Epub 2021 Feb 13.

Cardiovascular Imaging Research Center, Boston, MA.

Background: While growing evidence suggests a link between periodontal disease (PD) and cardiovascular disease (CVD), the independence of this association and the pathway remain unclear. Herein, we tested the hypotheses that: (1) inflammation of the periodontium (PD ) predicts future CVD independently of disease risk factors shared between CVD and PD, and (2) the mechanism linking the two diseases involves heightened arterial inflammation.

Methods: F-fluorodeoxyglucose positron emission tomography/computed tomography ( F-FDG-PET/CT) imaging was performed in 304 individuals (median age 54 years; 42.4% male) largely for cancer screening; individuals without active cancer were included. PD and arterial inflammation were quantified using validated F-FDG-PET/CT methods. Additionally, we evaluated the relationship between PD and subsequent major adverse cardiovascular events (MACE) using Cox models and log-rank tests.

Results: Thirteen individuals developed MACE during follow-up (median 4.1 years). PD associated with arterial inflammation, remaining significant after adjusting for PD and CVD risk factors (standardized β [95% CI]: 0.30 [0.20-0.40], P < 0.001). PD predicted subsequent MACE (standardized HR [95% CI]: 2.25 [1.47 to 3.44], P <0.001, remaining significant in multivariable models), while periodontal bone loss did not. Furthermore, mediation analysis suggested that arterial inflammation accounts for 80% of the relationship between PD and MACE (standardized log odds ratio [95% CI]: 0.438 [0.019-0.880], P = 0.022).

Conclusion: PD is independently associated with MACE via a mechanism that may involve increased arterial inflammation. These findings provide important support for an independent relationship between PD and CVD.
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http://dx.doi.org/10.1002/JPER.19-0441DOI Listing
March 2021

Maresin-1 and Resolvin E1 Promote Regenerative Properties of Periodontal Ligament Stem Cells Under Inflammatory Conditions.

Front Immunol 2020 25;11:585530. Epub 2020 Sep 25.

The Forsyth Institute, Cambridge, MA, United States.

Maresin-1 (MaR1) and Resolvin E1 (RvE1) are specialized pro-resolving lipid mediators (SPMs) that regulate inflammatory processes. We have previously demonstrated the hard and soft tissue regenerative capacity of RvE1 in an model of the periodontal disease characterized by inflammatory tissue destruction. Regeneration of periodontal tissues requires a well-orchestrated process mediated by periodontal ligament stem cells. However, limited data are available on how SPMs can regulate the regenerative properties of human periodontal ligament stem cells (hPDLSCs) under inflammatory conditions. Thus, we measured the impact of MaR1 and RvE1 in an model of hPDLSC under stimulation with IL-1β and TNF-α by evaluating pluripotency, migration, viability/cell death, periodontal ligament markers (α-smooth muscle actin, tenomodulin, and periostin), cementogenic-osteogenic differentiation, and phosphoproteomic perturbations. The data showed that the pro-inflammatory milieu suppresses pluripotency, viability, and migration of hPDLSCs; MaR1 and RvE1 both restored regenerative capacity by increasing hPDLSC viability, accelerating wound healing/migration, and up-regulating periodontal ligament markers and cementogenic-osteogenic differentiation. Protein phosphorylation perturbations were associated with the SPM-induced regenerative capacity of hPDLSCs. Together, these results demonstrate that MaR1 and RvE1 restore or improve the regenerative properties of highly specialized stem cells when inflammation is present and offer opportunities for direct pharmacologic treatment of lost tissue integrity.
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http://dx.doi.org/10.3389/fimmu.2020.585530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546375PMC
September 2020

Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo.

Br J Pharmacol 2021 Jan 18;178(2):280-297. Epub 2020 Dec 18.

Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA.

Background And Purpose: Adiponectin (APN) is an adipokine secreted from adipocytes that binds to APN receptors AdipoR1 and AdipoR2 and exerts an anti-inflammatory response through mechanisms not fully understood. There is a need to develop small molecules that activate AdipoR1 and AdipoR2 and to be used to inhibit the inflammatory response in lipopolysaccharide (LPS)-induced endotoxemia and other inflammatory disorders.

Experimental Approach: We designed 10 new structural analogues of an AdipoR agonist, AdipoRon (APR), and assessed their anti-inflammatory properties. Bone marrow-derived macrophages (BMMs) and peritoneal macrophages (PEMs) were isolated from mice. Levels of pro-inflammatory cytokines were measured by reverse transcription and real-time quantitative polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and microarray in LPS-induced endotoxemia mice and diet-induced obesity (DIO) mice in which systemic inflammation prevails. Western blotting, immunohistochemistry (IHC), siRNA interference and immunoprecipitation were used to detect signalling pathways.

Key Results: A novel APN receptor agonist named adipo anti-inflammation agonist (AdipoAI) strongly suppresses inflammation in DIO and endotoxemia mice, as well as in cultured macrophages. We also found that AdipoAI attenuated the association of AdipoR1 and APPL1 via myeloid differentiation marker 88 (MyD88) signalling, thus inhibiting activation of nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and c-Maf pathways and limiting the production of pro-inflammatory cytokines in LPS-induced macrophages.

Conclusion And Implications: AdipoAI is a promising alternative therapeutic approach to APN and APR to suppress inflammation in LPS-induced endotoxemia and other inflammatory disorders via distinct signalling pathways.
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http://dx.doi.org/10.1111/bph.15277DOI Listing
January 2021

Omega-3 Fatty Acids and Low-Dose Aspirin in the Treatment of Periodontitis and Metabolic Syndrome: Case Report.

J Int Acad Periodontol 2020 10 1;22(4):223-230. Epub 2020 Oct 1.

Division of Periodontics, São Paulo State University (Unesp), Institute of Science and Technology, Brazil. E-mail:

Aims: To investigate the use of ω-3 fatty acids and low-dose aspirin as adjuncts to periodontal debridement in a patient with periodontitis and metabolic syndrome.

Methods: Periodontal and systemic parameters were assessed at baseline and 6 months. Gingival crevicular fluid was analyzed for interleukin (IL)-1β, IL-6 and interferon (IFN)-γ levels by multiplex ELISA at baseline, 3 and 6 months.

Results: The treatment was effective in reducing probing depth, clinical attachment level, bleeding on probing and plaque index, and glycated hemoglobin, triglycerides IL-1β, IL-6 and IFN-γ levels over time.

Conclusions: The adjunctive use of ω-3 and low-dose aspirin to periodontal debridement might have potential benefits in the treatment of periodontitis in a patient with metabolic syndrome.
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October 2020

Investigating the Response of Human Neutrophils to Hydrophilic and Hydrophobic Micro-Rough Titanium Surfaces.

Materials (Basel) 2020 Aug 3;13(15). Epub 2020 Aug 3.

Department of Periodontics, Indiana University School of Dentistry, Indianapolis, IN 46202, USA.

Various treatments have been used to change both the topography and chemistry of titanium surfaces, aiming to enhance tissue response and reduce healing times of endosseous implants. Most studies to date focused on bone healing around dental implants occurring later during the healing cascade. However, the impact of the initial inflammatory response in the surgical wound site on the success and healing time of dental implants is crucial for implant integration and success, yet it is still poorly understood. The purpose of this study was to investigate the effect of titanium surface hydrophilicity on the response of human neutrophils by monitoring oxygen radical production, which was measured as chemiluminescence activity. Materials and Methods: Neutrophils were isolated from human donors' blood buffy coats using the double sucrose gradient method. Neutrophils were exposed to both hydrophilic and hydrophobic titanium surfaces with identical topographies in the presence and absence of human serum. This resulted in six experimental groups including two different implant surfaces, with and without exposure to human serum, and two control groups including an active control with cells alone and a passive control with no cells. Two samples from each group were fixed and analyzed by SEM. Comparisons between surface treatments for differences in chemiluminescence values were performed using analysis of variance ANOVA. Results and Conclusion: In the absence of exposure to serum, there was no significant difference noted between the reaction of neutrophils to hydrophilic and hydrophobic surfaces. However, there was a significant reduction in the mean and active chemiluminescence activity of neutrophils to serum-coated hydrophilic titanium surfaces than to serum-coated hydrophobic titanium surfaces. This suggests that surface hydrophilicity promotes enhanced adsorption of serum proteins, which leads to decreased provocation of initial immune cells and reduction of local oxygen radical production during wound healing. This can help explain the faster osseointegration demonstrated by hydrophilic titanium implants.
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http://dx.doi.org/10.3390/ma13153421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435731PMC
August 2020

Distinct Profiles of Specialized Pro-resolving Lipid Mediators and Corresponding Receptor Gene Expression in Periodontal Inflammation.

Front Immunol 2020 25;11:1307. Epub 2020 Jun 25.

Department of Periodontics and Dental Hygiene, The University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, United States.

Polyunsaturated fatty acid-derived specialized pro-resolving lipid mediators (SPMs) play an important role in modulating inflammation. The aim of the study was to compare profiles of SPMs, SPM related lipid mediators and SPM receptor gene expression in gingiva of subjects with periodontitis to healthy controls. A total of 28 subjects were included; 13 periodontally healthy and 15 periodontitis before or after non-surgical periodontal therapy. Gingival tissues were collected from two representative posterior teeth prior to and 8 weeks after scaling and root planning; only once in the healthy group. Lipid mediator-SPM metabololipidomics was performed to identify metabolites in gingiva. qRT-PCR was performed to assess relative gene expression (2) of known SPM receptors. Intergroup comparisons were made using Wilcoxon tests. Thirty-six omega-6 or omega-3 fatty acid-derived lipid mediators and seven receptor genes were identified in gingiva. Profiles of lipid mediators and receptor gene expression were significantly different between the three groups. Levels of six lipid mediators, 5-HETE, 15-HETE, 15(S)-HEPE, 4-HDHA, 7-HDHA, and 17-HDHA in periodontitis before treatment were significantly higher than in periodontitis after treatment. The expression of in the healthy group was significantly higher than periodontitis subjects before and after treatment. The expression of in periodontitis before treatment was significantly higher than in periodontitis after treatment while the expression of in periodontitis before treatment was significantly lower than in periodontitis after treatment. Elevated levels of SPM biosynthetic pathway markers in periodontitis subjects before treatment indicated inflammation induced pro-resolution activity in gingiva, but receptors for these molecules were deficient in periodontitis pre-treatment suggesting that failure of resolution of inflammation contributes to excess, chronic inflammation in periodontitis.
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http://dx.doi.org/10.3389/fimmu.2020.01307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330171PMC
June 2020

Steven Offenbacher, DDS, PhD, MMSc: The gifts of a giant in science and the father of periodontal medicine.

J Periodontol 2020 10;91 Suppl 1:S1-S3

The Forsyth Institute, Cambridge, MA.

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http://dx.doi.org/10.1002/JPER.20-0494DOI Listing
October 2020

Shifting the paradigm from inhibitors of inflammation to resolvers of inflammation in periodontitis.

J Periodontol 2020 10 20;91 Suppl 1:S19-S25. Epub 2020 Jun 20.

Clinical and Translational Research, Forsyth Institute, Cambridge, MA.

An initial shift in our understanding of the basis of periodontal disease occurred early in the 2000s. The host response, rather than the bacterial burden, was the principal determinant of the disease. Microbial dysbiosis that occurs in periodontal disease results from a hyperinflammatory state in the host. A second shift in periodontal disease is taking place. This time in the realm of treatment strategies. Rather than targeting antimicrobials or inhibitors of individual inflammatory mediators, preclinical studies support using resolution pharmacology to convert the pro-inflammatory condition into a non-inflammatory one, thereby resolving both the local and systemic inflammation associated with periodontal disease. Here, I describe the bases for these shifts in paradigms.
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http://dx.doi.org/10.1002/JPER.20-0088DOI Listing
October 2020

Activation of PPAR-γ induces macrophage polarization and reduces neutrophil migration mediated by heme oxygenase 1.

Int Immunopharmacol 2020 Jul 7;84:106565. Epub 2020 May 7.

Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic, Laboratoy of Neuroimmune Interface of Pain Research, Campinas, SP, Brazil; Department of Physiology Sciences, Laboratory of Orofacial Pain, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil. Electronic address:

Natural or synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-γ) represent an interesting tool for pharmacological interventions to treat inflammatory conditions. In particular, PPAR-γ activation prevents pain and inflammation in the temporomandibular joint (TMJ) by decreasing cytokine release and stimulating the synthesis of endogenous opioids. The goal of this study was to clarify whether PPAR-γ activation induces macrophage polarization, inhibiting inflammatory cytokine release and leukocyte recruitment. In addition, we investigated the involvement of heme oxygenase 1 (HO-1) in downstream events after PPAR-γ activation. Our results demonstrate that PPAR-γ activation ablates cytokine release by Bone Marrow-Derived Macrophages (BMDM) in vitro. 15d-PGJ induces the PPAR-γ heterodimer activation from rat macrophages, with macrophage polarization from M1-like cells toward M2-like cells. This response is mediated through HO-1. PPAR-γ activation diminished neutrophil migration induced by carrageenan, which was also HO-1 dependent. Ca/calmodulin expression did not change after PPAR-γ activation indicating that is not required for the activation of the intracellular L-arginine/NO/cGMP/K channel pathway. In summary, the anti-inflammatory actions induced by PPAR-γ activation involve macrophage polarization. HO-1 expression is increased and HO-1 activity is required for the suppression of neutrophil migration.
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http://dx.doi.org/10.1016/j.intimp.2020.106565DOI Listing
July 2020

The role of the microbiota in periodontal disease.

Periodontol 2000 2020 06;83(1):14-25

Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA.

The last decade has witnessed unparalleled advances in our understanding of the complexity of the oral microbiome and the compositional changes that occur in subgingival biofilms in the transition from health to gingivitis and to destructive periodontal disease. The traditional view, which has held sway for the last 2 decades, that disease is characterized by the outgrowth of a consortium, or consortia, of a limited number of potentially pathogenic organisms, has given way to an alternative paradigm. In this new view, the microbiological changes associated with disease represent whole-scale alterations to the overall microbial population structure and to the functional properties of the entire community. Thus, and in common with other microbially mediated diseases of the gastrointestinal tract, the normally balanced, symbiotic, and generally benign commensal microbiome of the tooth-associated biofilm undergoes dysbiosis to a potentially deleterious microbiota. Coincident with progress in defining the microbiology of these diseases, there have been equally important advances in our understanding of the inflammatory systems of the periodontal tissues, their control, and how inflammation may contribute both to the development of dysbiosis and, in a deregulated state, the destructive disease process. One can therefore speculate that the inflammatory response and the periodontal microbiome are in a bidirectional balance in oral health and a bidirectional imbalance in periodontitis. However, despite these clear insights into both sides of the host/microbe balance in periodontal disease, there remain several unresolved issues concerning the role of the microbiota in disease. These include, but are not limited to, the factors which determine progression from gingivitis to periodontitis in a proportion of the population, whether dysbiosis causes disease or results from disease, and the molecular details of the microbial stimulus responsible for driving the destructive inflammatory response. Further progress in resolving these issues may provide significant benefit to diagnosis, treatment, and prevention.
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http://dx.doi.org/10.1111/prd.12296DOI Listing
June 2020

The role of inflammation and genetics in periodontal disease.

Periodontol 2000 2020 06;83(1):26-39

Center for Clinical and Translational Research, Forsyth Institute, Cambridge, Massachusetts, USA.

Periodontitis is a complex disease: (a) various causative factors play a role simultaneously and interact with each other; and (b) the disease is episodic in nature, and bursts of disease activity can be recognized, ie, the disease develops and cycles in a nonlinear fashion. We recognize that various causative factors determine the immune blueprint and, consequently, the immune fitness of a subject. Normally, the host lives in a state of homeostasis or symbiosis with the oral microbiome; however, disturbances in homeostatic balance can occur, because of an aberrant host response (inherited and/or acquired during life). This imbalance results from hyper- or hyporesponsiveness and/or lack of sufficient resolution of inflammation, which in turn is responsible for much of the disease destruction seen in periodontitis. The control of this destruction by anti-inflammatory processes and proresolution processes limits the destruction to the tissues surrounding the teeth. The local inflammatory processes can also become systemic, which in turn affect organs such as the heart. Gingival inflammation also elicits changes in the ecology of the subgingival environment providing optimal conditions for the outgrowth of gram-negative, anaerobic species, which become pathobionts and can propagate periodontal inflammation and can further negatively impact immune fitness. The factors that determine immune fitness are often the same factors that determine the response to the resident biofilm, and are clustered as follows: (a) genetic and epigenetic factors; (b) lifestyle factors, such as smoking, diet, and psychosocial conditions; (c) comorbidities, such as diabetes; and (d) local and dental factors, as well as randomly determined factors (stochasticity). Of critical importance are the pathobionts in a dysbiotic biofilm that drive the viscious cycle. Focusing on genetic factors, currently variants in at least 65 genes have been suggested as being associated with periodontitis based on genome-wide association studies and candidate gene case control studies. These studies have found pleiotropy between periodontitis and cardiovascular diseases. Most of these studies point to potential pathways in the pathogenesis of periodontal disease. Also, most contribute to a small portion of the total risk profile of periodontitis, often limited to specific racial and ethnic groups. To date, 4 genetic loci are shared between atherosclerotic cardiovascular diseases and periodontitis, ie, CDKN2B-AS1(ANRIL), a conserved noncoding element within CAMTA1 upstream of VAMP3, PLG, and a haplotype block at the VAMP8 locus. The shared genes suggest that periodontitis is not causally related to atherosclerotic diseases, but rather both conditions are sequelae of similar (the same?) aberrant inflammatory pathways. In addition to variations in genomic sequences, epigenetic modifications of DNA can affect the genetic blueprint of the host responses. This emerging field will yield new valuable information about susceptibility to periodontitis and subsequent persisting inflammatory reactions in periodontitis. Further studies are required to verify and expand our knowledge base before final cause and effect conclusions about the role of inflammation and genetic factors in periodontitis can be made.
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http://dx.doi.org/10.1111/prd.12297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319430PMC
June 2020

The Nexus Between Periodontal Inflammation and Dysbiosis.

Front Immunol 2020 31;11:511. Epub 2020 Mar 31.

Melbourne Dental School, The University of Melbourne, Melbourne, VIC, Australia.

The nexus between periodontal inflammation and the polymicrobial biofilm in the gingival sulcus is critical to understanding the pathobiology of periodontitis. Both play a major role in the etiology and pathogenesis of periodontal diseases and each reinforces the other. However, this nexus is also at the center of a significant conundrum for periodontology. For all mucosal polymicrobial biofilms, the most confounding issue is the paradoxical relationship between inflammation, infection, and disease. Despite significant advances made in both periodontal microbiology and periodontal pathobiology, the issue of which comes first, the inflammatory response or the change to a dysbiotic subgingival microbiota, is still debated. In this paper, we present a model for the pathogenesis of periodontitis based on the central role of inflammation and how this modulates the polymicrobial biofilm within the context of the continuum of health, gingivitis, and periodontitis. We propose a new model termed "Inflammation-Mediated Polymicrobial-Emergence and Dysbiotic-Exacerbation" (IMPEDE), which is designed to integrate into and complement the 2017 World Workshop Classification of Periodontitis.
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http://dx.doi.org/10.3389/fimmu.2020.00511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136396PMC
March 2021

Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy.

Nat Med 2020 05 13;26(5):781-791. Epub 2020 Apr 13.

Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.
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http://dx.doi.org/10.1038/s41591-020-0818-3DOI Listing
May 2020

Proposal of a Clinical Endpoint for Periodontal Trials: The Treat-to-Target Approach.

J Int Acad Periodontol 2020 04 1;22(2):41-53. Epub 2020 Apr 1.

Department of Periodontology, Dental Research Division, Guarulhos University, Guarulhos, São Paulo, Brazil.

Objective: The selection of proper outcome measures is a critical step in clinical research. Most randomized clinical trials (RCTs) assessing the effects of initial anti-infective periodontal therapies use surrogate outcomes as primary outcome variables, such as mean changes in probing depth (PD) or in clinical attachment. However, these parameters do not reflect disease remission/control at patient level, which has led to subjective interpretations of the data from RCTs and Systematic Reviews. Based on a comprehensive analysis of 724 patients from USA, Germany and Brazil treated for periodontitis, this paper suggests that the clinical endpoint of "≤4 sites with PD≥5mm" is effective in determining disease remission/control after active periodontal treatment and therefore, may represent a pertinent endpoint for applying the treat-to-target concept in RCTs. Furthermore, regression models showed that the presence of >10% and >20% sites with bleeding on probing in the mouth post-treatment increases the risk of a patient leaving the endpoint from 1-2 years (OR=3.5 and 8.7, respectively). Researchers are encouraged to present results on this outcome when reporting their trials, as this will allow for an objective comparison across studies and facilitate systematic reviews, and consequently, the extrapolation of data from research to clinical practice.
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April 2020

Omega-3 PUFA and aspirin as adjuncts to periodontal debridement in patients with periodontitis and type 2 diabetes mellitus: Randomized clinical trial.

J Periodontol 2020 10 21;91(10):1318-1327. Epub 2020 Jun 21.

Division of Periodontics, Unesp - São Paulo State University, Institute of Science and Technology, São José dos Campos, São Paulo, Brazil.

Background: Supplementation with omega-3 polyunsaturated fatty acids (ω-3 PUFA) and low-dose aspirin (ASA) have been proposed as a host modulation regimen to control chronic inflammatory diseases. The aim of this study was to investigate the clinical and immunological impact of orally administered ω-3 PUFA and ASA as adjuncts to periodontal debridement for the treatment of periodontitis in patients type 2 diabetes.

Methods: Seventy-five patients (n = 25/group) were randomly assigned to receive placebo and periodontal debridement (CG), ω-3 PUFA + ASA (3 g of fish oil/d + 100 mg ASA/d for 2 months) after periodontal debridement (test group [TG]1), or ω-3 PUFA + ASA (3 g of fish oil/d + 100 mg ASA/d for 2 months) before periodontal debridement (TG2). Periodontal parameters and GCF were collected at baseline (t0), 3 months after periodontal debridement and ω-3 PUFA + ASA or placebo for TG1 and CG (t1), after ω-3 PUFA + ASA (before periodontal debridement) for TG2 (t1), and 6 months after periodontal debridement (all groups) (t2). GCF was analyzed for cytokine levels by multiplex ELISA.

Results: Ten patients (40%) in TG1 and nine patients (36%) in TG2 achieved the clinical endpoint for treatment (less than or equal to four sites with probing depth ≥ 5 mm), as opposed to four (16%) in CG. There was clinical attachment gain in moderate and deep pockets for TG1. IFN-γ and interleukin (IL)-8 levels decreased over time for both test groups. IL-6 levels were lower for TG1. HbA1c levels reduced for TG1.

Conclusion: Adjunctive ω-3 and ASA after periodontal debridement provides clinical and immunological benefits to the treatment of periodontitis in patients with type 2 diabetes.
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http://dx.doi.org/10.1002/JPER.19-0613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483813PMC
October 2020

Inactivation of TRP53, PTEN, RB1, and/or CDH1 in the ovarian surface epithelium induces ovarian cancer transformation and metastasis.

Biol Reprod 2020 04;102(5):1055-1064

Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA.

Ovarian cancer (OvCa) remains the most common cause of death from gynecological malignancies. Genetically engineered mouse models have been used to study initiation, origin, progression, and/or mechanisms of OvCa. Based on the clinical features of OvCa, we examined a quadruple combination of pathway perturbations including PTEN, TRP53, RB1, and/or CDH1. To characterize the cancer-promoting events in the ovarian surface epithelium (OSE), Amhr2cre/+ mice were used to ablate floxed alleles of Pten, Trp53, and Cdh1, which were crossed with TgK19GT121 mice to inactivate RB1 in KRT19-expressing cells. Inactivation of PTEN, TRP53, and RB1 with or without CDH1 led to the development of type I low-grade OvCa with enlarged serous papillary carcinomas and some high-grade serous carcinomas (HGSCs) in older mice. Initiation of epithelial hyperplasia and micropapillary carcinoma started earlier at 1 month in the triple mutations of Trp53, Pten, and Rb1 mice as compared to 2 months in quadruple mutations of Trp53, Pten, Rb1, and Cdh1 mice, whereas both genotypes eventually developed enlarged proliferating tumors that invaded into the ovary at 3-4 months. Mice with triple and quadruple mutations developed HGSC and/or metastatic tumors, which disseminated into the peritoneal cavity at 4-6 months. In summary, inactivation of PTEN, TRP53, and RB1 initiates OvCa from the OSE. Additional ablation of CDH1 further increased persistence of tumor dissemination and ascites fluid accumulation enhancing peritoneal metastasis.
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http://dx.doi.org/10.1093/biolre/ioaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305658PMC
April 2020

Understanding resolution of inflammation in periodontal diseases: Is chronic inflammatory periodontitis a failure to resolve?

Periodontol 2000 2020 02;82(1):205-213

Harvard School of Dental Medicine, Boston, Massachusetts, USA.

Periodontitis is an infectious-inflammatory disease that results from loss of balance between the commensal microbiome and the host response. The hyper-inflammatory, uncontrolled inflammatory immune lesion promotes tissue damage and impedes effective bacterial clearance. In this review, the relationship between the microbiome and the inflammatory/immune response is explored in the context of a bi-directional pathogenesis; bacteria induce inflammation and inflammation modifies the growth environment causing shifts in the composition of the microbiome. Resolution of inflammation is an active, receptor-mediated process induced by specialized pro-resolving lipid mediators. Inflammatory disease may, therefore, be the result of failure of resolution. Failure to resolve inflammation coupled with resultant microbiome changes is hypothesized to drive development of periodontitis. Re-establishment of microbiome/host homeostasis by specialized pro-resolving lipid mediator therapy suggests that microbiome dysbiosis, the host hyperinflammatory phenotype, and periodontitis can be reversed.
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http://dx.doi.org/10.1111/prd.12317DOI Listing
February 2020

Omega-3 Fatty Acids Effects on Inflammatory Biomarkers and Lipid Profiles among Diabetic and Cardiovascular Disease Patients: A Systematic Review and Meta-Analysis.

Sci Rep 2019 12 11;9(1):18867. Epub 2019 Dec 11.

Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, USA.

The purpose of this systematic review and meta-analysis was to investigate omega-3 fatty acids' influence on 12 inflammatory biomarkers-LDL, HDL, total cholesterol, TG, HbA1c, Apo AI, Apo AII, Apo B, CRP, TNF-α, glucose, and fasting blood glucose among diabetic and cardiovascular disease (CVD) patients. We searched articles in six database engines, and 16 of the 696 articles reviewed met the inclusion criteria. Among these, lipid and inflammatory biomarkers investigated commonly included total cholesterol (11 studies), LDL, and TG (10 studies each). Overall, omega-3 was associated with a significant reduction in Apo AII among diabetic patients, as compared to different controls (-8.0 mg/dL 95% CI: -12.71, -3.29, p = 0.0009), triglycerides (-44.88 mg/dL 95% CI: -82.6, -7.16, p < 0.0001), HDL (-2.27 mg/dL 95% CI: -3.72, -0.83, p = 0.002), and increased fasting blood glucose (16.14 mg/dL 95% CI: 6.25, 26.04, p = 0.001). Omega-3 also was associated with increased LDL among CVD patients (2.10 mg/dL 95% CI: 1.00, 3.20, p = 0.0002). We conclude that omega-3 fatty acids may be associated with lower inflammatory biomarkers among diabetic and cardiovascular patients. Clinicians should be aware of these potential benefits; however, it is essential to recommend that patients consult with clinicians before any omega-3 intake.
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http://dx.doi.org/10.1038/s41598-019-54535-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906408PMC
December 2019

Characterization of periodontitis in people with type 1 diabetes of 50 years or longer duration.

J Periodontol 2019 06 13;90(6):565-575. Epub 2019 May 13.

Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

Background: Periodontitis is more common and severe in people with diabetes than the general population. We have reported in the Joslin Medalist Study that people with type 1 diabetes of ≥50 years (Medalists) may have endogenous protective factors against diabetic nephropathy and retinopathy.

Methods: In this cross-sectional study, the prevalence of periodontitis according to the Centers for Disease Control/American Academy of Periodontology classification in a subset (n = 170, mean age = 64.6 ± 6.9 years) of the Medalist cohort, and its associations to various criteria of periodontitis and diabetic complications were assessed.

Results: The prevalence of severe periodontitis in Medalists was only 13.5% which was lower than reported levels in diabetic patients of similar ages. Periodontal parameters, including bleeding on probing, plaque index, gingival index, and demographic traits, including male sex, chronological age, and age at diagnosis were significantly associated with severity of periodontitis, which did not associate with diabetes duration, hemoglobin A1c (HbA1c), body mass index, and lipid profiles. Random serum C-peptide levels inversely associated with severity of periodontitis (P = 0.03), lower probing depth (P = 0.0002), and clinical attachment loss (P = 0.03). Prevalence of cardiovascular diseases (CVD) and systemic inflammatory markers, plasma interleukin-6 (IL-6), and serum immunoglobulin G titer against Porphyromonas gingivalis positively associated with severity of periodontitis (P = 0.002 and 0.02, respectively). Antibody titer to P. gingivalis correlated positively and significantly with CVD, serum IL-6, and high-sensitivity C-reactive protein.

Conclusions: Some Medalists could be protected from severe periodontitis even with hyperglycemia. Endogenous protective factors for periodontitis could possibly be related to residual insulin production and lower levels of chronic inflammation.
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http://dx.doi.org/10.1002/JPER.18-0735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087383PMC
June 2019

Development and validation of a predictive model for periodontitis using NHANES 2011-2012 data.

J Clin Periodontol 2019 04 19;46(4):420-429. Epub 2019 Mar 19.

Center for Clinical and Translational Research, Forsyth Institute, Cambridge, Massachusetts.

Aim: To develop and validate a predictive model for moderate-to-severe periodontitis in the adult USA population, with data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) cycle.

Material And Methods: A subset of 3017 subjects aged >30 years, with >14 teeth present and having received a periodontal examination in addition to data collected on cardio-metabolic risk measures (smoking habit, body mass index [BMI], blood pressure, total cholesterol and glycated haemoglobin [HbA1c]) were used for model development by multivariable logistic regression.

Results: The prevalence of moderate and severe periodontitis using CDC/AAP classification was 37.1% and 13.2%, respectively. A multivariable logistic regression model revealed that HbA1c ≥5.7% was significantly associated with moderate-to-severe periodontitis (odds ratio, OR = 1.29; p < 0.01). A predictive model including age, gender, ethnicity, HbA1c and smoking habit as variables had 70.0% sensitivity and 67.6% specificity in detecting moderate-to-severe periodontitis in US adults.

Conclusions: Periodontitis is a common disease in North American adults, and its prevalence is significantly higher in individuals with pre-diabetes or diabetes. The present study demonstrates that a model including age, gender, ethnicity, HbA1c and smoking habit could be used as a reliable screening tool for periodontitis in primary medical care settings to facilitate referral of patients at risk for periodontal examination and diagnosis.
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http://dx.doi.org/10.1111/jcpe.13098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050186PMC
April 2019

Resolvin D2 Induces Resolution of Periapical Inflammation and Promotes Healing of Periapical Lesions in Rat Periapical Periodontitis.

Front Immunol 2019 26;10:307. Epub 2019 Feb 26.

Department of Pathophysiology-Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Periapical periodontitis results from pulpal infection leading to pulpal necrosis and resorption of periapical bone. The current treatment is root canal therapy, which attempts to eliminate infection and necrotic tissue. But, in some cases periapical inflammation doesn't resolve even after treatment. Resolvins belongs to a large family of specialized pro-resolving lipid mediators that actively resolves inflammation signaling via specific receptors. Resolvin D2 (RvD2), a metabolite of docosahexaenoic acid (DHA), was tested as an intracanal medicament in rats . Mechanism was evaluated in rat primary dental pulp cells (DPCs) . The results demonstrate that RvD2 reduces inflammatory cell infiltrate, periapical lesion size, and fosters pulp like tissue regeneration and healing of periapical lesion. RvD2 enhanced expression of its receptor, GPR18, dentin matrix acidic phosphoprotein 1 (DMP1) and mineralization and . Moreover, RvD2 induces phosphorylation of Stat3 transcription factor in dental pulp cells. We conclude that intracanal treatment with RvD2 resolves inflammation and promoting calcification around root apex and healing of periapical bone lesions. The data suggest that RvD2 induces active resolution of inflammation with pulp-like tissue regeneration after root canal infection and thus maybe suitable for treating periapical lesions.
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http://dx.doi.org/10.3389/fimmu.2019.00307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399419PMC
September 2020

Function of Pro-Resolving Lipid Mediator Resolvin E1 in Type 2 Diabetes.

Crit Rev Immunol 2018 ;38(5):343-365

Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA, 02115, USA.

Programming of inflammation resolution is governed by a class of specialized pro-resolving lipid mediators (SPMs) that act in concert to modulate epithelial, endothelial, and immune cell function for restoration of homeostasis. The resolution circuits are altered in obesity and associated morbidities, including type 2 diabetes mellitus (T2D), through reduced production and/or action of SPMs, which can be rescued by therapeutic SPM delivery or up-regulation of SPM receptors. Resolvin E1 (RvE1), an eicosapentaenoic acid derivative, has potent pro-resolving and insulin-sensitizing actions mediated by BLT1 and ERV1 receptors in the vasculature and metabolic organs. Nonetheless, the RvE1-mediated increase in protective adipokines such as adiponectin in white adipose tissues, the enhancement of monocyte patrolling function in the vasculature, as well as the macrophage-clearing functions improve metabolic control in obese-prone conditions. RvE1-enhanced resolving function in obesity prevents dysbiosis of the gut microflora and increased gut permeability. These functions suggest that RE1 has therapeutic potential for immunometabolic alterations associated with T2D in patients with reduced inflammation resolving capacity. SPM profiling in individuals at risk for T2D and associated complications will help to advance personalized disease management and precision medicine.
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http://dx.doi.org/10.1615/CritRevImmunol.2018026750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392080PMC
September 2019