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Supplementary Table from Inhibition of LSD1 Attenuates Oral Cancer Development and Promotes Therapeutic Efficacy of Immune Checkpoint Blockade and YAP/TAZ Inhibition

Supplementary Table 1. RNAi used in the study.

Supplementary Figure S3. Gene set enrichment analysis of the YAP/TAZ-activated genes.

Supplementary Figure from Inhibition of LSD1 Attenuates Oral Cancer Development and Promotes Therapeutic Efficacy of Immune Checkpoint Blockade and YAP/TAZ Inhibition

Supplementary Table 2. Antibodies used in the study.

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that contributes to the etiology of oral squamous cell carcinoma (OSCC) in part by promoting cancer stem cell phenotypes. The molecular signals regulated by LSD1, or acting with LSD1, are poorly understood, particularly in the development of OSSC. In this study, we show that conditional deletion of the Lsd1 gene or pharmacologic inhibition of LSD1 in the tongue epithelium leads to reduced development of OSCC following exposure to the tobacco carcinogen 4NQO. LSD1 inhibition attenuated proliferation and clonogenic survival and showed an additive effect when combined with the YAP inhibitor Verteporfin. Interestingly, LSD1 inhibition upregulated the expression of PD-L1, leading to immune checkpoint inhibitor therapy responses.Implications:Collectively, our studies reveal a critical role for LSD1 in OSCC development and identification of tumor growth targeting strategies that can be combined with LSD1 inhibition for improved therapeutic application.

Supplementary Table 5. Gene list from the cluster analysis in Fig 5B.

Supplementary Table 3. qPCR primers used in the study.

Supplementary Table 4. Microarray data from siCTL, siTAZ, siYAP, and siYAP/TAZ-treated SCC2 cells.

Supplementary Table 6. Hyper-enrichment analysis of YAP/TAZ-regulated molecular signature.

Supplementary Figure 1 from Overexpression of DPAGT1 Leads to Aberrant N-Glycosylation of E-Cadherin and Cellular Discohesion in Oral Cancer

Supplementary Figure 2 from Overexpression of DPAGT1 Leads to Aberrant N-Glycosylation of E-Cadherin and Cellular Discohesion in Oral Cancer

Supplementary Figure Legends 1-2 from Overexpression of DPAGT1 Leads to Aberrant N-Glycosylation of E-Cadherin and Cellular Discohesion in Oral Cancer

Tophaceous pseudogout is a rare variant of the calcium pyrophosphate dihydrate (CPPD) disorder, with predilection for the TMJ. It is characterized by calcific deposits composed of rhomboid- or rectangular-shaped crystals that exhibit birefringence when examined under polarized light. We hereby present a case of a 65-year-old man with left pre-auricular tenderness and malocclusion. CT imaging was notable for a left TMJ mineralized mass with erosion of the condylar head. Treatment involved excision of the mass with eminectomy, condylectomy, and a stock total TMJ reconstruction. In this report, important considerations for diagnosis, biopsy, and surgical treatment with emphasis on reconstruction for tophaceous pseudogout of the TMJ have been highlighted by the authors.

Objective Oral hairy leukoplakia (OHL) is a benign Epstein-Barr virus infection typically presenting as a white lesion on the lateral border of the tongue. Historically, OHL was described in patients who are severely immunocompromised, such as those with HIV/AIDS and organ transplant patients. OHL is increasingly seen in patients who are not severely immunocompromised. This study reviews 45 cases of OHL in a single institution and characterizes the clinical features of these relatively immunocompetent patients. Study Design Retrospective study. Results There were 45 cases with 23 male patients (51.1%) and a median age of 64 (range, 24-100 years). The lateral/ventral tongue was the affected site in 41 cases (91.1%), and 5 cases presented bilaterally. A review of the medical history and medications showed the most common conditions were hypertension (53.3%), hyperlipidemia (42.2%), and chronic respiratory conditions (33.3%); 8 patients (17.8%) had diabetes mellitus, and 1 had rheumatoid arthritis. Eleven cases (24.4%) reported no underlying medical conditions or history of medications. The most frequently reported medications included antihypertensive drugs (21.0%), steroid inhalers (14.6%), and cholesterol-lowering drugs (11.0%). Conclusions OHL is not exclusively seen in profoundly immunocompromised patients. Localized immunosuppression (from steroid inhalers) and immunosenescence (aging) are possible contributing factors.

Objective We report the first 4 cases of intraoral nonnecrotizing granulomatous foreign body reactions to diatoms, plausibly as a result of exogenous material introduced following iatrogenic or traumatic injury. Study Design Clinical and histopathologic findings of 4 intraoral cases of nonnecrotizing granulomatous foreign body reaction to diatoms, single-celled algae belonging to the taxonomic phylum Bacillariophyta, are reported. Results The lesions presented either in the jaws or in the soft tissue overlying the alveolar bone, in some instances mimicking an inflammatory lesion of odontogenic etiology. Microscopically, the lesions presented as nonnecrotizing granulomatous inflammation associated with either spherical and radially symmetric or rectangular and bilaterally symmetric diatomaceous foreign material. Conclusion The diagnosis of a diatom-associated foreign body reaction necessitates familiarization with the histopathologic features of these organisms to accurately characterize the nature of such lesions.

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that contributes to the etiology of oral squamous cell carcinoma (OSCC) in part by promoting cancer stem cell phenotypes. The molecular signals regulated by LSD1, or acting with LSD1, are poorly understood, particularly in the development of OSSC. In this study, we show that conditional deletion of the Lsd1 gene or pharmacologic inhibition of LSD1 in the tongue epithelium leads to reduced development of OSCC following exposure to the tobacco carcinogen 4NQO. LSD1 inhibition attenuated proliferation and clonogenic survival and showed an additive effect when combined with the YAP inhibitor Verteporfin. Interestingly, LSD1 inhibition upregulated the expression of PD-L1, leading to immune checkpoint inhibitor therapy responses. Implications: Collectively, our studies reveal a critical role for LSD1 in OSCC development and identification of tumor growth targeting strategies that can be combined with LSD1 inhibition for improved therapeutic application.

Meningiomas are common benign neoplasms developing within the central nervous system and arise from the meningothelial cells. Extracranial (ectopic) meningiomas are rare and may represent an extracranial extension of an intracranial meningioma or distant metastasis from a primary intracranial meningioma, or they may originate from arachnoid cells in the sheaths of the cranial nerves that are exiting the skull through the foramina or sutures. Ectopic meningiomas can also arise as true primary extracranial meningiomas originating from ectopic arachnoid lining cells or multipotential mesenchymal cells. Primary extracranial meningiomas occurring in the jaws are extremely rare, with only 11 reported cases (2 cases in the maxilla and 9 cases in the mandible) in the literature. The infrequent occurrence of this entity presenting in this unusual location of the jaws often poses a diagnostic challenge to the oral pathologist, resulting in misdiagnosis. We present the 10th mandibular case of extracranial meningioma involving the right side of the mandible in a 56-year-old female patient. The clinical and radiographic presentation, histopathologic features, and histopathologic differential and immunohistochemical findings of this case are presented. The proposed pathogenesis, treatment options, and prognosis are also discussed along with a review of the literature.

We report 7 cases of hitherto undescribed keratotic papillary plaques of uncertain etiology involving the gingiva. All 7 cases presented on the anterior maxillary attached gingiva of patients in the second decade. The lesions were asymptomatic and 86% (6 of 7 cases) presented in a bilateral symmetric distribution. Microscopically, the lesions exhibited parakeratosis and papillary acanthosis with parakeratin-filled crypts. No specific etiology such as a factitial habit or a common exogenous agent has been identified. The possibility of a developmental etiology such as an oral epithelial nevus cannot be entirely excluded. We propose the descriptive term idiopathic gingival papillokeratosis with crypt formation (IGPC) for this condition.

Extracellular lysyl oxidases (LOX and LOXL1–LOXL4) are critical for collagen biosynthesis. LOXL2 is a marker of poor survival in oral squamous cell cancer. We investigated mechanisms by which tumor cell secreted LOXL2 targets proximal mesenchymal cells to enhance tumor growth and metastasis. This study identified the first molecular mechanism for LOXL2 in the promotion of cancer via its enzymatic modification of a non-collagenous substrate in the context of paracrine signaling between tumor cells and resident fibroblasts. The role and mechanism of active LOXL2 in promoting oral cancer was evaluated and employed a novel LOXL2 small molecule inhibitor, PSX-S1C, administered to immunodeficient, and syngeneic immunocompetent orthotopic oral cancer mouse models. Tumor growth, histopathology, and metastases were monitored. In vitro mechanistic studies with conditioned tumor cell medium treatment of normal human oral fibroblasts were carried out in the presence and absence of the LOXL2 inhibitor to identify signaling mechanisms promoted by LOXL2 activity. Inhibition of LOXL2 attenuated cancer growth and lymph node metastases in the orthotopic tongue mouse models. Immunohistochemistry data indicated that LOXL2 expression in and around tumors was decreased in mice treated with the inhibitor. Inhibition of LOXL2 activity by administration of PXS-S1C to mice reduced tumor cell proliferation, accompanied by changes in morphology and in the expression of epithelial to mesenchymal transition markers. In vitro studies identified PDGFRβ as a direct substrate for LOXL2, and indicated that LOXL2 and PDGF-AB together secreted by tumor cells optimally activated PDGFRβ in fibroblasts to promote proliferation and the tendency toward fibrosis via ERK activation, but not AKT. Optimal fibroblast proliferation in vitro required LOXL2 activity, while tumor cell proliferation did not. Thus, tumor cell-derived LOXL2 in the microenvironment directly targets neighboring resident cells to promote a permissive local niche, in addition to its known role in collagen maturation.

Background A preponderance of periapical radiolucencies are of inflammatory etiology (radicular cysts or periapical granulomas) secondary to pulpal disease. In some instances, however, a suspected periapical inflammatory lesion is not a consequence of pulpal disease but instead represents a lesion of noninflammatory origin. The differential diagnosis for such lesions is broad, ranging from odontogenic cysts and tumors to metastatic disease. As the biological behavior of such lesions is varied, the distinction between inflammatory odontogenic periapical lesions and lesions of noninflammatory origin in a periapical location is critical. Methods A retrospective study of 5,993 archival periapical biopsies over a span of 15 years from the database of the Oral Pathology Biopsy Service in the Henry M. Goldman School of Dental Medicine at Boston University recorded the incidence of various lesions in a periapical location. Results Of the cases studied, 97.2% represented lesions of inflammatory origin with histopathologic diagnoses as follows: periapical granuloma (60.0%), radicular cyst (36.7%), periapical fibrous scar (0.27 %), and periapical abscess (0.23 %). The remaining 2.8% cases were lesions of noninflammatory origin with histopathologic diagnoses of odontogenic keratocyst (also known as keratocystic odontogenic tumor), benign fibro-osseous lesions, and ameloblastoma. One patient had Langerhans cell disease, and 1 had central giant cell granuloma. Conclusions Although most periapical specimens biopsied represented expected inflammatory periapical lesions, the biological behavior of underdiagnosed lesions may have considerable consequences for both the patient and the clinician. Practical Implications This article serves to inform clinicians regarding the diversity of lesions arising in the periapical region of the jaws, to assist in the formulation of differential diagnoses, and to highlight the importance of submission of lesional tissue for histopathologic evaluation and definitive diagnosis when biopsy is clinically indicated.

Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops from the epithelium of the oral cavity. OSCC is on the rise worldwide, and death rates associated with the disease are particularly high. Despite progress in understanding the mutational and expression landscape associated with OSCC, advances in deciphering these alterations for the development of therapeutic strategies have been limited. Further insight into the molecular cues that contribute to OSCC is therefore required. Here, we show that the transcriptional regulators YAP ( YAP1 ) and TAZ ( WWTR1 ), which are key effectors of the Hippo pathway, drive protumorigenic signals in OSCC. Regions of premalignant oral tissues exhibit aberrant nuclear YAP accumulation, suggesting that dysregulated YAP activity contributes to the onset of OSCC. Supporting this premise, we determined that nuclear YAP and TAZ activity drives OSCC cell proliferation, survival, and migration in vitro , and is required for OSCC tumor growth and metastasis in vivo . Global gene expression profiles associated with YAP and TAZ knockdown revealed changes in the control of gene expression implicated in protumorigenic signaling, including those required for cell cycle progression and survival. Notably, the transcriptional signature regulated by YAP and TAZ significantly correlates with gene expression changes occurring in human OSCCs identified by The Cancer Genome Atlas (TCGA), emphasizing a central role for YAP and TAZ in OSCC biology. Implications: This study defines a YAP/TAZ-regulated transcriptional program in OSCC and reveals novel roles for nuclear YAP/TAZ activity in the onset and progression of this cancer. Mol Cancer Res; 13(6); 957–68. ©2015 AACR . This article is featured in Highlights of This Issue, [p. 955][1] [1]: /lookup/volpage/13/955?iss=6

Objective We report intraoral granulomatous foreign body reactions in patients treated with calcium hydroxylapatite (CHA) or poly- l -lactic acid (PLA). Study Design Clinical and histopathologic data were obtained from 25 patients who developed orofacial nodules or swelling after dermal filler injections. Results All 25 patients were women aged 35 to78 years (median, 55 years). All had a history of injection of CHA (n = 13) or PLA (n = 12) to the lips, nasolabial area, or mental area. Two patients developed cutaneous nodules at the sites of injections; all others presented with intraoral nodules (labial/buccal or vestibular mucosa) distant from the site of injections, suggestive of filler migration. Five of 21 cases presented with pain. Histopathologically, CHA presented as a diffuse mass of mauve-gray or beige, nonrefractile spherules, and PLA as rice- or spindle-shaped, geometric, refractile bodies within circumscribed nodules. Conclusions Cutaneous injections of CHA and PLA fillers may induce granulomatous reactions presenting as intraoral nodules distant from the injection sites.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that has been associated with oncogenic osteomalacia. This tumor secretes fibroblast growth factor-23 (FGF-23). Although other mesenchymal tumors can cause oncogenic osteomalacia, PMT is the most common mesenchymal neoplasm associated with oncogenic osteomalacia and accounts for 80% of such cases. Most patients are adults and the tumor can affect both men and women. The most common location for the tumor is the lower extremities followed by the head and neck area. Patients typically present with diffuse bone pain, bone fractures, and progressive muscle weakness. The laboratory studies usually reveal increased levels of FGF-23, hyperphosphaturia, increased alkaline phosphatase, normal serum calcium and parathyroid hormone levels, normal to low levels of 1,25-dihydroxyvitamin D and hypophosphatemia. The four common phosphaturic mesenchymal tumor microscopic subtypes are: phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, ossifying fibroma-like variant, and non-ossifying fibroma-like variant. The small size of this slow growing tumor and the non-specific clinical presentation may present a diagnostic challenge to clinicians. We present a case of a 48-year-old Haitian male who was diagnosed with PMT in the right angle of the mandible. Fewer than 15 cases of PMT presenting in the oral cavity have been reported in the literature. The clinical presentation, the laboratory findings, imaging characteristics, and the histopathologic features for this case are discussed along with the molecular genetic aspects, treatment and prognosis for this rare neoplasm.

Objectives Benign alveolar ridge keratosis (BARK) is a benign hyperkeratosis that occurs as a poorly demarcated white papule or plaque on the retromolar area or edentulous alveolar ridge mucosa caused by trauma. Histopathologic features are identical to cutaneous lichen simplex chronicus, a condition that results from chronic habitual skin scratching/picking. P53 protein is a tumor suppressor protein that plays a critical role in DNA repair. P53 protein has been shown to be present within 5-25% of the basal cell nuclei in normal oral mucosa and reactive lesions. The objective of this study is to report on the histopathologic features of BARK and to explore P53 expression pattern. Study Design Cases of BARK were identified from the biopsy service of the Harvard School of Dental Medicine from January, 2016 to December, 2017. Randomly selected cases were studied for the presence of P53. Results There were 174 cases comprising 119 males and 55 females (2.2:1; M:F) with a median age of 57 years (range 15-86). The majority were in the sixth (31.0%) and seventh (29.3%) decades. There were 112 (64.4%) cases on the retromolar pad and 62 (35.6%) on the edentulous alveolar mucosa; 27 (15.5%) cases were bilateral. Histopatho-logically, the oral mucosa showed hyperkeratosis often with wedge-shaped hypergranulosis and occasional focal parakeratosis. The epithelium exhibited mild to moderate acanthosis and slight surface undulations or papillomatosis, with tapered rete ridges, often confluent at the tips. The study for P53 performed in 11 cases showed less than 25 % nuclear positivity. Conclusion BARK is a distinct benign clinicopathologic entity caused by friction that is the intraoral counterpart of cutaneous lichen simplex chronicus with which it shares similar histopathologic features. It is not a mere hyperkeratosis which would relegate it to the clinical entity of leukoplakia, and which is a potentially malignant condition.

A preponderance of periapical radiolucencies are of inflammatory etiology (radicular cysts or periapical granulomas) secondary to pulpal disease. In some instances, however, a suspected periapical inflammatory lesion is not a consequence of pulpal disease but instead represents a lesion of noninflammatory origin. The differential diagnosis for such lesions is broad, ranging from odontogenic cysts and tumors to metastatic disease. As the biological behavior of such lesions is varied, the distinction between inflammatory odontogenic periapical lesions and lesions of noninflammatory origin in a periapical location is critical.A retrospective study of 5,993 archival periapical biopsies over a span of 15 years from the database of the Oral Pathology Biopsy Service in the Henry M. Goldman School of Dental Medicine at Boston University recorded the incidence of various lesions in a periapical location.Of the cases studied, 97.2% represented lesions of inflammatory origin with histopathologic diagnoses as follows: periapical granuloma (60.0%), radicular cyst (36.7%), periapical fibrous scar (0.27 %), and periapical abscess (0.23 %). The remaining 2.8% cases were lesions of noninflammatory origin with histopathologic diagnoses of odontogenic keratocyst (also known as keratocystic odontogenic tumor), benign fibro-osseous lesions, and ameloblastoma. One patient had Langerhans cell disease, and 1 had central giant cell granuloma.Although most periapical specimens biopsied represented expected inflammatory periapical lesions, the biological behavior of underdiagnosed lesions may have considerable consequences for both the patient and the clinician.This article serves to inform clinicians regarding the diversity of lesions arising in the periapical region of the jaws, to assist in the formulation of differential diagnoses, and to highlight the importance of submission of lesional tissue for histopathologic evaluation and definitive diagnosis when biopsy is clinically indicated.

Oral lesions associated with premalignant changes and malignancy present in diverse ways. This article discusses the clinical characteristics of such lesions enabling clinicians to identify classical features.Additionally, an effort is made to familiarize clinicians with the significance of red and white lesions, especially those having a high index of suspicion for oral cancer, and to alert clinicians when a biopsy is mandatory.