Research Spotlight

Ehlers, S.A., Bozanich, J.M., Arashlow, M.T., Liang, H. and Nair, M.K. (2020). “Large airway-obstructing retropharyngeal lipoma in an asymptomatic patient: a case report.” Int J Implant Dent 6(1): 38.

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BACKGROUND: Lipomas are common benign mesenchymal tumors that appear in the head and neck region in approximately 25% of cases where they are noted. Lipomas of the airway region are exceedingly rare, accounting for less than 1% of airway obstruction tumors. Correlation of radiographic findings from cone beam computed tomography (CBCT), multi-detector computed tomography (MDCT), and magnetic resonance imaging (MRI) of a rare retropharyngeal lipoma has not been previously reported. CBCT studies acquired for implant and/or other diagnostic purposes may be the first line of detection as an incidental finding. CASE PRESENTATION: A 66-year-old female presented for a pre-implant CBCT with no history of other complaints or signs/symptoms. CBCT imaging depicts a large, well-defined, low-attenuation/soft tissue density lesion with an undulating appearance extending from the posterior left pharyngeal wall and occluding two-thirds of the airway from C2 to C4. The lesion extends laterally into the left parapharyngeal space and inferiorly beyond the field of view of the study. Evidence of faint internal septations was noted. The patient was immediately referred for an ENT consult. Laryngoscopy, MRI, and contrast-enhanced MDCT imaging were conducted to determine the full extent and nature of the lesion, as well as to potentially plan for biopsy and/or surgical resection. Removal of the lesion was successful, and histopathologic evaluation confirmed lipoma. Periodic follow-up was recommended to monitor for possible recurrence. DISCUSSION: The slower growth pattern of some benign lesions may obscure any symptoms as changes the patient may normally notice take place over an extended period. Furthermore, soft tissue lesions and especially those in the posterior midline, such as in this case, may not be easily visible on routine panoramic imaging or clinical exam, allowing for substantially large growth before detection. While the soft tissue contrast of the CBCT volume is poor, enough information was present to establish an initial differential diagnosis and the need for more advanced imaging modalities. With the growing popularity and adoption of CBCT in maxillofacial imaging, a thorough understanding of the appearance of hard and soft tissue lesions, as well as a strong understanding of the baseline appearance of normal anatomy, is important to ensure no incidental pathoses go undiagnosed.

Francis, M., Gopinathan, G., Salapatas, A., Nares, S., Gonzalez, M., Diekwisch, T.G.H. and Luan, X. (2020). “SETD1 and NF-κB Regulate Periodontal Inflammation through H3K4 Trimethylation.” J Dent Res: 22034520939029

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The inflammatory response to periodontal pathogens is dynamically controlled by the chromatin state on inflammatory gene promoters. In the present study, we have focused on the effect of the methyltransferase SETD1B on histone H3 lysine K4 (H3K4) histone trimethylation on inflammatory gene promoters. Experiments were based on 3 model systems: 1) an in vitro periodontal ligament (PDL) cell culture model for the study of SETD1 function as it relates to histone methylation and inflammatory gene expression using Porphyromonas gingivalis lipopolysaccharide (LPS) as a pathogen, 2) a subcutaneous implantation model to determine the relationship between SETD1 and nuclear factor κB (NF-κB) through its activation inhibitor BOT-64, and 3) a mouse periodontitis model to test whether the NF-κB activation inhibitor BOT-64 reverses the inflammatory tissue destruction associated with periodontal disease. In our PDL progenitor cell culture model, P. gingivalis LPS increased H3K4me3 histone methylation on IL-1β, IL-6, and MMP2 gene promoters, while SETD1B inhibition decreased H3K4me3 enrichment and inflammatory gene expression in LPS-treated PDL cells. LPS also increased SETD1 nuclear localization in a p65-dependent fashion and the nuclear translocation of p65 as mediated through SETD1, suggestive of a synergistic effect between SETD1 and p65 in the modulation of inflammation. Confirming the role of SETD1 in p65-mediated periodontal inflammation, BOT-64 reduced the number of SETD1-positive cells in inflamed periodontal tissues, restored periodontal tissue integrity, and enhanced osteogenesis in a periodontal inflammation model in vivo. Together, these results have established the histone lysine methyltransferase SETD1 as a key factor in the opening of the chromatin on inflammatory gene promoters through histone H3K4 trimethylation. Our studies also confirmed the role of BOT-64 as a potent molecular therapeutic for the restoration of periodontal health through the inhibition of NF-κB activity and the amelioration of SETD1-induced chromatin relaxation.

Francis, M., Gopinathan, G., Foyle, D., Fallah, P., Gonzalez, M., Luan, X. and Diekwisch, T.G.H. (2020). “Histone Methylation: Achilles Heel and Powerful Mediator of Periodontal Homeostasis.” J Dent Res: 22034520932491.

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The packaging of DNA around nucleosomes exerts dynamic control over eukaryotic gene expression either by granting access to the transcriptional machinery in an open chromatin state or by silencing transcription via chromatin compaction. Histone methylation modification affects chromatin through the addition of methyl groups to lysine or arginine residues of histones H3 and H4 by means of histone methyl transferases or histone demethylases. Changes in histone methylation state modulate periodontal gene expression and have profound effects on periodontal development, health, and therapy. At the onset of periodontal development, progenitor cell populations such as dental follicle cells are characterized by an open H3K4me3 chromatin mark on RUNX2, MSX2, and DLX5 gene promoters. During further development, periodontal progenitor differentiation undergoes a global switch from the H3K4me3 active methyl mark to the H3K27me3 repressive mark. When compared with dental pulp cells, periodontal neural crest lineage differentiation is characterized by repressive H3K9me3 and H3K27me3 marks on typical dentinogenesis-related genes. Inflammatory conditions as they occur during periodontal disease result in unique histone methylation signatures in affected cell populations, including repressive H3K9me3 and H3K27me3 histone marks on extracellular matrix gene promoters and active H3K4me3 marks on interleukin, defensin, and chemokine gene promoters, facilitating a rapid inflammatory response to microbial pathogens. The inflammation-induced repression of chromatin on extracellular matrix gene promoters presents a therapeutic opportunity for the application of histone methylation inhibitors capable of inhibiting suppressive trimethylation marks. Furthermore, inhibition of chromatin coregulators through interference with key inflammatory mediators such as NF-kB by means of methyltransferase inhibitors provides another avenue to halt the exacerbation of the inflammatory response in periodontal tissues. In conclusion, histone methylation dynamics play an intricate role in the fine-tuning of chromatin states during periodontal development and harbor yet-to-be-realized potential for the treatment of periodontal disease.

Malek, A. J., C. L. Isbell, M. M. Mrdutt, S. A. Zamin, E. M. Allen, S. E. Coulson, J. L. Regner and H. T. Papaconstantinou (2020). “Resident-Championed Quality Improvement Provides Value: Confronting Prolonged Mechanical Ventilation.” J Surg Res Jul 16;256:36-42. [Epub ahead of print.].

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BACKGROUND: The Quality In-Training Initiative (QITI) provides hands-on quality improvement education for residents. As our institution has ranked in the bottom quartile for prolonged mechanical ventilation (PMV) according to the National Surgical Quality Improvement Program (NSQIP), we sought to illustrate how our resident-led QITI could be used to determine perioperative contributors to PMV. MATERIALS AND METHODS: The Model for Improvement framework (developed by Associates in Process Improvement) was used to target postoperative ventilator management. However, baseline findings from our 2016 NSQIP data suggested that preoperative patient factors were more likely contributing to PMV. Subsequently, a retrospective one-to-one case-control study was developed, comparing preoperative NSQIP risk calculator profiles for PMV patients to case-matched patients for age, sex, procedure, and emergent case status. Chart review determined ventilator time, 30-d outcomes, and all-cause mortality. RESULTS: Forty-five patients with PMV (69% elective) had a median ventilator time of 134 h (interquartile range 87-254). The NSQIP calculator demonstrated increased preoperative risk percentages in PMV patients when compared to case-matched patients for any complication (includes PMV), predicted length of stay, and death (all P < 0.05). Thirty-day outcomes were worse for the PMV group in categories for sepsis, pneumonia, unplanned reoperation, 30-d mortality, rehab facility discharge, and length of stay (all P < 0.05). All-cause mortality was also significantly higher for PMV patients (P < 0.05). CONCLUSIONS: Resident-led QITI projects enhance resident education while exposing opportunities for improving care. Preoperative patient factors play a larger-than-anticipated role in PMV at our institution. Ongoing efforts are aimed toward preoperative identification and optimization of high-risk patients.

Men, Y., Y. Wang, Y. Yi, D. Jing, W. Luo, B. Shen, W. Stenberg, Y. Chai, W. P. Ge, J. Q. Feng and H. Zhao (2020). “Gli1+ Periodontium Stem Cells Are Regulated by Osteocytes and Occlusal Force.” Dev Cell.

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Teeth are attached to alveolar bone by the periodontal ligament (PDL), which contains stem cells supporting tissue turnover. Here, we identified Gli1+ cells in adult mouse molar PDL as multi-potential stem cells (PDLSCs) giving rise to PDL, alveolar bone, and cementum. They support periodontium tissue turnover and injury repair. Gli1+ PDLSCs are surrounding the neurovascular bundle and more enriched in the apical region. Canonical Wnt signaling is essential for their activation. Alveolar bone osteocytes negatively regulate Gli1+ PDLSCs activity through sclerostin, a Wnt inhibitor. Blockage of sclerostin accelerates the PDLSCs lineage contribution rate in vivo. Sclerostin expression is modulated by physiological occlusal force. Removal of occlusal force upregulates sclerostin and inhibits PDLSCs activation. In summary, Gli1+ cells are the multipotential PDLSCs in vivo. Osteocytes provide negative feedback to PDLSCs and inhibit their activities through sclerostin. Physiological occlusal force indirectly regulates PDLSCs activities by fine-tuning this feedback loop