Disruption of H3K36 methylation provokes cellular plasticity to drive aberrant glandular formation and squamous carcinogenesis.

Chromatin organization is essential for maintaining cell-fate trajectories and developmental programs. Here, we find that disruption of H3K36 methylation dramatically impairs normal epithelial differentiation and development, which promotes increased cellular plasticity and enrichment of alternative cell fates. Specifically, we observe a striking increase in the aberrant generation of excessive epithelial glandular tissues, including hypertrophic salivary, sebaceous, and meibomian glands, as well as enhanced squamous tumorigenesis. These phenotypic and gene expression manifestations are associated with loss of H3K36me2 and rewiring of repressive H3K27me3, changes we also observe in human patients with glandular hyperplasia. Collectively, these results have identified a critical role for H3K36 methylation in both in vivo epithelial cell-fate decisions and the prevention of squamous carcinogenesis and suggest that H3K36 methylation modulation may offer new avenues for the treatment of numerous common disorders driven by altered glandular function, which collectively affect large segments of the human population.

A Periodontal Perspective on the Successful Treatment of Recurrent Benign Gingival Lesions Affecting the Anterior Dentition: Two Case Reports.

Recurrent benign gingival lesions occurring in the anterior dentition are clinical dilemmas. While complete removal of such lesions is required to prevent recurrence, this can result in a poor esthetic outcome. Relative to this conundrum, this report discusses the diagnosis, psychologic management, and clinical treatment of two patients with recurring lesions on the facial gingiva of the mandibular and maxillary incisors, respectively. Patient A, a 55-year-old woman, presented with a recurrent peripheral ossifying fibroma (POF); Patient B, a 76-year-old man, presented with a recurrent pyogenic granuloma (PG). Both patients underwent multiple procedures and were ultimately treated without lesion recurrence. The efficacious surgical treatment of recurrent gingival lesions like POF and PG requires an aggressive approach involving lesion removal of the lesion as well as a 1.0- to 2.0-mm margin of normal tissue, underlying alveolar bone, and associated periodontal ligament (PDL). The rationale for this approach stresses the potential periodontal and esthetic ramifications that were considered. In summary, when recurrent benign gingival lesions are localized to the anterior part of the mouth, the approach to their surgical removal should be modified to minimize the extent of gingival recession and other potential esthetic issues.

Iron oxide nanozymes stabilize stannous fluoride for targeted biofilm killing and synergistic oral disease prevention.

Dental caries is the most common human disease caused by oral biofilms despite the widespread use of fluoride as the primary anticaries agent. Recently, an FDA-approved iron oxide nanoparticle (ferumoxytol, Fer) has shown to kill and degrade caries-causing biofilms through catalytic activation of hydrogen peroxide. However, Fer cannot interfere with enamel acid demineralization. Here, we show notable synergy when Fer is combined with stannous fluoride (SnF2), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, we discover that the stability of SnF2 is enhanced when mixed with Fer in aqueous solutions while increasing catalytic activity of Fer without any additives. Notably, Fer in combination with SnF2 is exceptionally effective in controlling dental caries in vivo, even at four times lower concentrations, without adverse effects on host tissues or oral microbiome. Our results reveal a potent therapeutic synergism using approved agents while providing facile SnF2 stabilization, to prevent a widespread oral disease with reduced fluoride exposure.

Iron oxide nanozymes stabilize stannous fluoride for targeted biofilm killing and synergistic oral disease prevention.

Dental caries (tooth decay) is the most prevalent human disease caused by oral biofilms, affecting nearly half of the global population despite increased use of fluoride, the mainstay anticaries (tooth-enamel protective) agent. Recently, an FDA-approved iron oxide nanozyme formulation (ferumoxytol, Fer) has been shown to disrupt caries-causing biofilms with high specificity via catalytic activation of hydrogen peroxide, but it is incapable of interfering with enamel acid demineralization. Here, we find notable synergy when Fer is combined with stannous fluoride (SnF 2 ), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, our data show that SnF 2 enhances the catalytic activity of Fer, significantly increasing reactive oxygen species (ROS) generation and antibiofilm activity. We discover that the stability of SnF 2 (unstable in water) is markedly enhanced when mixed with Fer in aqueous solutions without any additives. Further analyses reveal that Sn 2+ is bound by carboxylate groups in the carboxymethyl-dextran coating of Fer, thus stabilizing SnF 2 and boosting the catalytic activity. Notably, Fer in combination with SnF 2 is exceptionally effective in controlling dental caries in vivo , preventing enamel demineralization and cavitation altogether without adverse effects on the host tissues or causing changes in the oral microbiome diversity. The efficacy of SnF 2 is also enhanced when combined with Fer, showing comparable therapeutic effects at four times lower fluoride concentration. Enamel ultrastructure examination shows that fluoride, iron, and tin are detected in the outer layers of the enamel forming a polyion-rich film, indicating co-delivery onto the tooth surface. Overall, our results reveal a unique therapeutic synergism using approved agents that target complementary biological and physicochemical traits, while providing facile SnF 2 stabilization, to prevent a widespread oral disease more effectively with reduced fluoride exposure.

Oral involvement of cutaneous T-cell lymphoma: A rare entity.

Mycosis fungoides (MF) is a rare cutaneous T-cell lymphoma (CTCL) with significant morbidity and mortality rates. Involvement of MF in the oral cavity is uncommon, often follows cutaneous involvement, and is usually associated with a poor prognosis. Herein, we describe a case of a 72-year-old White male with biopsy-proven oral T-cell lymphoma (TCL) in the setting of MF with systemic disease progression. Mycosis fungoides with oral involvement can often prove challenging to diagnose and manage. Thorough medical history intake and clinical examination supported by histopathologic and immunohistochemical analysis are imperative because delay in the diagnosis can lead to disease progression.

Gingival Overgrowth in an Adult Male Patient.

Pyogenic granuloma (PG) is an oral reactive inflammatory hyperplasia of connective tissue that can occur in response to hormonal changes and local irritation such as calculus, fractured teeth, rough dental restorations, and foreign materials. It is nonneoplastic and predominant in the second decade of life in young adult females. The most common site of involvement is the gingiva. Lesions are more common in the maxillary than mandibular gingiva and mainly occur on the facial or buccal aspect. Pyogenic granuloma rarely grows more than 2 cm in diameter and is rarely associated with bone loss. This article presents a rare case of an abnormally large pyogenic granuloma affecting both the labial and palatal gingiva sustaining occlusal trauma due to its size and associated with severe alveolar bone loss that was managed successfully with surgical excision in a 40-year-old male.

Immediate impact of dental prophylaxis and oral hygiene improvement on multifocal pyogenic granulomas: a case report.

A 31-year-old man presented with gingival mass-like lesions. The patient reported occasional bleeding from lesions; otherwise, the lesions were asymptomatic. Intraoral examination revealed multiple interdental red/purple soft, sessile, nodular lesions involving both the maxillary and mandibular buccal and lingual gingivae, with poor oral hygiene. After performing incisional biopsy, the patient was diagnosed with pyogenic granuloma. Subsequently, the patient underwent cleaning of his teeth and within only 3 days of dental cleaning, the patient reported rapid regression of all his lesions.

NF-κB perturbation reveals unique immunomodulatory functions in Prx1+ fibroblasts that promote development of atopic dermatitis.

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor κB (NF-κB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-κB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-κB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions.

Hypoxia enhances basal autophagy of epithelial-derived ameloblastoma cells.

Ameloblastoma is a locally aggressive odontogenic tumor. Etiopathogenesis and locally aggressive growth properties of ameloblastoma can be attributed to a hypoxic microenvironment conducive to tumor cell survival. Epithelial-derived follicular ameloblastoma cells (EP-AMCs) display enhanced basal autophagy, but the interplay of hypoxia and autophagy in EP-AMCs survival and ameloblastoma recurrence is unclear. We evaluated differential expression of autophagic markers in primary and recurrent ameloblastomas and hypothesized that hypoxia-induced autophagy supports EP-AMC survival. Primary and recurrent ameloblastomas were comparatively assessed for expression levels of pan-cytokeratin, Vimentin, and autophagic markers SQSTM1/p62, LC3, and pS6. EP-AMCs compared with human odontoma-derived cells (HODCs) were subjected to severe hypoxia to determine the interplay of hypoxia and autophagic process in posthypoxia survival. Pan-cytokeratin and SQSTM1/p62 were expressed by both primary and recurrent ameloblastoma epithelial cells while the ameloblastoma connective tissues displayed weak reactivity to vimentin. Under hypoxia, EP-AMC expression levels of hypoxia-inducible factor (HIF)-1α, p62, and LC3 were increased while pS6 was decreased posthypoxia. The combined decrease in pS6 and enhanced LC3 in EP-AMCs under hypoxia indicate that EP-AMCs re-establish basal autophagy under hypoxia. Taken together, these suggest a possible role of LC3-associated phagocytosis (LAP) in ameloblastoma cell survival.

EBV-positive B-cell ulcerative proliferation in the oral cavity associated with EBV-negative follicular lymphoma in a patient with common variable immunodeficiency: A case report and review of the literature.

Lymphoproliferative disorders (LPDs) are a group of conditions characterized by excessive production of lymphocytes manifested in various patterns including lymphadenopathy, tumor-like lesions, and lymphomas. LPD may be stimulated by Epstein-Barr virus (EBV) infection that most commonly appears in the setting of immunocompromised status such as long-term use of immunosuppressive medications and in individuals with primary immunodeficiency disorders. EBV mucocutaneous ulcer is a benign LPD reaction that mostly regresses spontaneously but sometimes requires medical or surgical intervention. This article presents a case of oral EBV mucocutaneous ulceration that affected an individual with a history of complex primary immunodeficiency disorders consisted of common variable immunodeficiency disease associated with T-cell dysfunction. This case is unique because the oral lesions led to the diagnosis of concurrent widespread EBV-negative follicular lymphomas, seemingly unrelated to her EBV-positive LPD oral disease. Yet, both occurred in the setting of severe immunosuppression from the primary immunodeficiency disorders.

High-Dose-Rate Brachytherapy for Primary Treatment of Refractory Proliferative Verrucous Leukoplakia of the Hard Palate.

Oral proliferative verrucous leukoplakia (PVL) is a rare, progressive form of leukoplakia with a high rate of malignant transformation. No therapies are known to lower the rate of malignant transformation and prevent a recurrence. An 84-year-old patient with a years-long history of symptomatic PVL of the hard palate refractory to CO2 laser ablation presented to the radiation oncology clinic for consideration of non-surgical management. High dose rate brachytherapy was used to deliver 36 Gy in 12 fractions to the hard palate using an Ir-192 source with a custom-molded applicator. By three months of follow-up, the patient had complete regression of the PVL and resolution of acute mucositis. With 18 months of follow-up, the patient remains disease- and symptom-free without toxicities of treatment. High dose rate surface applicator brachytherapy is a feasible and potentially effective treatment for oral PVL, yielding durable control with low long-term toxicity.

Primary Syphilis of the Oral Cavity, a Rare Presentation of a Re-Emerging Disease.

Syphilis is a sexually transmitted disease caused by microaerophilic spirochete Treponema pallidum. After contact, T. pallidum infiltrates the genital or oral mucosa and spreads systemically throughout the blood and lymphatic systems. Syphilis is classified into stages, with varying signs and symptoms associated with each stage. Primary syphilis has an incubation period of up to 90 days following the sexual transmission of T. pallidum, and is characterized by the development of chancres at the site of inoculation. Rarely, primary syphilis presents in the tongue, which can mimic many other conditions that affect the oral cavity. In this article, we discuss a rare oral manifestation of primary syphilis.

Oral lesions containing amyloid-like material.

During oral pathology daily practice, true amyloid may be identified in oral amyloidosis and several odontogenic tumors. However, histologic examination often reveals other oral and perioral diseases with similar eosinophilic, acellular, amorphous substances. These include extensive areas of collagenous sclerosis, fibrin deposition, elastic fiber degeneration, and dentinoid material, which may resemble amyloid under light microscopic examination. These materials are often termed "amyloid-like" due to their close histologic resemblance to true amyloid. The rarity of most of these conditions and their strong histologic similarity may hamper an accurate diagnosis. Definitive diagnosis of these lesions may require clinical correlation; laboratory evaluation; histochemical or immunohistochemical reactions; and, in some cases, genetic investigation. In this review, we describe the main clinicopathologic features of this group of diseases that may manifest in the oral and/or perioral regions and that have in common the presence of amyloid-like material deposition.