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Objective: The aim of this report was to review oral follicular lymphoid hyperplasia, with emphasis on palatal lesions., Method and Materials: A comprehensive search was performed on PubMed for case reports and case series of palatal follicular lymphoid hyperplasia published in the English language literature. Relevant data from collated articles was sought, including patient demographics, clinical manifestations, imaging modalities and findings, comorbidities, etiopathogenesis, lesional management, and lesional outcome. A new palatal case has also been provided to illustrate several features of this lesion., Results: In total, 32 cases were assembled to establish clinicopathologic correlations, representing the largest aggregation of published cases. Most of the affected patients were at least 60 years old and with a decisive female predilection. The majority of lesions were ≤ 3 cm, appearing as normal color, purple-red or red, and varied from soft to firm. Notably, 32% of palatal follicular lymphoid hyperplasias were associated with denture wear, and lesional recurrence was recorded in 16% of cases. To date, none of the reported cases of palatal follicular lymphoid hyperplasia has undergone malignant transformation., Conclusions: Palatal follicular lymphoid hyperplasias often arise as a reactive process. Critical histopathologic and histochemical assessments are necessary to establish benignity. Postoperatively, clinicians should follow patients for at least 5 years for recurrence and remain vigilant for neoplastic change as several published accounts of non-oral follicular lymphoid hyperplasias have undergone malignant transformation, usually to lymphoma.

Introduction: Oral squamous cell carcinoma (OSCC) is the most prevalent oral malignancy, with emerging interest in the characterization of its tumor microenvironment. Herein, we present a comprehensive histological analysis of OSCC stromal density and inflammation and their relationship with patient demographics, clinicopathologic features and immuno-oncologic signatures., Materials-Methods: Eighty-seven completely excised OSCC tissues were prospectively collected and scored for histopathologic inflammatory subtypes [HIS]-inflamed (INF), immune-excluded (IE) and immune-desert (ID), peritumoral stromal inflammation (PTSI), and peritumoral stromal fibrosis (PTSF). Scoring of inflammation was complemented by Semaphorin 4D immunohistochemistry. NanoString differential gene expression (DGE) analysis was conducted for eight OSCC cases representative of the inflammatory and stromal subtypes and the demographic groups., Results: PTSF correlated with male gender ( p  = 0.0043), smoking ( p  = 0.0455), alcohol consumption ( p  = 0.0044), increased tumor size ( p  = 0.0054), and advanced stage ( p  = 0.002). On the contrary, PTSI occurred predominantly in females ( p  = 0.0105), non-drinkers ( p  = 0.0329), and small tumors ( p  = 0.0044). Transcriptionally, decreased cytokine signaling, and oncogenic pathway activation were observed in HIS-IE. Smokers and males displayed decreased global immune-cell levels and myeloid-cell predominance., Conclusion: Our work describes OSCC stromal and inflammatory phenotypes in correlation with distinct patient groups and DGE, highlighting the translational potential of characterizing the tumor microenvironment for optimal patient stratification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Theofilou, Ghita, Elnaggar, Chaisuparat, Papadimitriou, Bentzen, Dyalram, Lubek, Ord and Younis.)

Introduction: Oral squamous cell carcinoma (OSCC) is often preceded by oral epithelial dysplasia (OED). The role of ribosomal protein S6 (RPS6) and programmed cell death ligand-1 (PD-L1) in the progression of OED to OSCC remains unclear. This study aimed to investigate the expression of phosphorylated RPS6 (p-RPS6) and PD-L1 in OSCC and OED and to examine its relationship with clinicopathological features., Methods: Fifty-two OSCC and 48 OED cases were recruited for immunohistochemical analysis of p-RPS6 and PD-L1 expression. The expression of markers was correlated with clinicopathological features of OSCC and OED., Results: We found p-RPS6 expression in all cases of OSCC and OED, whereas PD-L1 was expressed in 42/48 (87%) OED and in 28/52 (53%) OSCC. The patients with mild OED presented higher expression level of PD-L1 and p-RPS6 significantly, when compared to moderate-differentiated OSCC patients ( p  < 0.05). Moreover, we found a significant positive correlation between PD-L1 and p-RPS6 expression in OED and OSCC patients ( p  < 0.01). The PD-L1 expression was significantly related to more than 2 cm tumor size in OSCC patients ( p  =   0.007)., Discussion: Our findings suggest the upregulation of PD-L1 may be related with activation of the mTOR pathway in the early events of tumor progression and the pathogenesis of OSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Hanroongsri, Amornphimoltham, Younis and Chaisuparat.)

The odontoma is regarded as a hamartomatous process of the jaws. Most are discovered as an incidental radiographic finding, averaging 15 mm in size. This report describes a case of a diminutive odontoma that was surgically removed before the onset of eruptive and pathologic consequences. A compilation of documented complications and syndromes associated with odontomas is also presented., Competing Interests: No conflicts of interest reported.

Objective: The purpose of this study is to identify the immuno-oncologic (IO) signature at the surgical tumor margin (TM) of oral squamous cell carcinoma (OSCC) that is involved in the process of malignant transformation., Study Design: Under institutional review board approval, TM of 73 OSCC were investigated using immunohistochemistry for the immune biomarker, programmed death ligand-1 (PD-L1). NanoString 770 IO-focused gene set was analyzed in 5 pairs of TM and invasive tumor (T). PD-L1 regulation in response to interferon-gamma (IFN-γ) was investigated in an oral potentially malignant cell line (OPMC)., Results: Programmed death ligand-1 expression in the epithelial margin directly correlated with its expression in the underlying immune cells (P = .0082). Differential gene expression showed downregulation of PD-L1 and IFN-γ 6 gene signature in the TM relative to T pair.CD8 and macrophages were higher in TM. CNTFR, LYZ, C7, RORC, and FGF13 downregulation in T relative to TM. TDO2, ADAM12, MMP1, LAMC2, MB21D1, TYMP, OASL, COL5A1, exhausted&#95;CD8, Tregs,and NK&#95;CD56dim were upregulated in T relative to TM. Finally, IFN-γ induced upregulation of PD-L1 in the OPMC., Conclusions: Our work suggests a role for IFN-γ in PD-L1 upregulation in OPMC and presents novel IO transcriptional signatures for frankly invasive OSCC relative to TM., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Plasma cell gingivitis (PCG) is an inflammatory condition that affects the gingival mucosa of the oral cavity. It is characterized by polyclonal dense plasma cell infiltrate in the connective tissue. Lesions do not respond to prophylactic treatment. Etiology is most likely hypersensitivity to certain antigens (eg, toothpastes, oral rinses, chewing gums, spices). Differential diagnosis of PCG includes reactive, granulomatous, and neoplastic lesions. The diagnostic workup is based on patient's history and the clinicopathologic correlation to rule out mimics of PCG. Dermatologic patch test may be indicated in chronic conditions to identify the allergen., Competing Interests: Conflict of interest The authors have no conflict of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) can be classified according to the histological inflammatory subtype (HIS) into inflamed (HIS-INF) or immune excluded (HIS-IE). HIS-IE was previously associated with higher levels of soluble Semaphorin 4D (HsS4D) in plasma, and higher transcriptional levels of osteopontin (OPN) in the tumor tissue, compared to HIS-INF. The goal of the current study is to investigate whether the HIS inflammatory subtype can be distinguished by a differential cytokine panel in peripheral blood. Retrospectively collected five HIS-INF and five HIS-IE tumor tissue with paired plasma were included in the study. Five healthy donors (HD) and five autoimmune/chronic inflammatory conditions (AI/CI) were controls. The ELISA-Luminex™ system was used to detect 40 traditional cytokines in plasma. Human cytokine array (104 cytokines) was used for the conditioned medium (CM) of the HNSCC HN6 cell line. Semaphorin 4D (Sema4D) siRNA and recombinant human osteopontin (rh-OPN) were used to investigate the effect of OPN on Sema4D expression. The HIS-IE cytokine profile was higher than HIS-INF but comparable to AI/CI. HIS-INF had the lowest cytokine levels. HIS-IE was differentially higher in IP-10 and IL8 compared to HD, while HIS-INF was higher in IL-10. Sema4D inhibition in HN6 resulted in a decrease of OPN in the CM of HN6, and treatment with rh-OPN rescued Sema4D in HN6 cell lysate and associated CM. In conclusion, the current work demonstrates a novel association between the HIS subtypes and a differential pattern of cytokine expression in plasma. These findings can open new avenues for HNSCC patient stratification and hence provide better personalized treatment., Competing Interests: US patent application number 17/379,909, a method for measuring cytokines in plasma of HNSCC patients and linking that to a tumor histological inflammatory profile, filed on July 19, 2021, by RY and the office of technology transfer, University of Maryland Baltimore, is related to the current work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Ghita, Piperi, Atamas, Ord, Dyalram, Lubek and Younis.)

Ghost cell odontogenic carcinoma (GCOC) is a rare malignant tumor of odontogenic origin, with only about 50 cases reported in the English literature so far. Histologically, it is characterized by ghost cells, dentinoid deposits, high grade malignant cellular features, and areas of necrosis and invasion. Having common histological features with other odontogenic ghost cell lesions (OGCL) like calcifying odontogenic cyst (COC) and dentinogenic ghost cell tumors, it is crucial to recognize GCOC malignant features, as it can be destructive and invasive, sometimes showing distant metastases and high recurrence rate. For this reason, it may entail more aggressive surgical approach and multimodal therapeutic regimen. Here we present a case report of GCOC arising in a previous COC, treated with surgical excision that showed persistence and recurrence after two years. The clinical and histological features of this rare occurrence are presented, in addition to the surgical approach, and a summary of literature review of OGCL., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Central osteomas of the jaws have been infrequently reported, mostly presenting as a well-defined opacity on conventional radiography projections and as a hyperdensity on computed tomography scans. To increase the knowledge of the phenotypic expression of gnathic central osteomas, an unusual case has been described, including the clinical, radiographic, cone beam computed tomography (CBCT) and histopathologic findings. The lesion was initially discovered 4 years prior as an asymptomatic ovoid radiolucency in the posterior mandible. A 25-year-old female presented with a hyperdense expansile mass with a hypodense rim on a CBCT scan. The enucleated mass was diagnosed as a compact central osteoma. A literature search has identified 4 other cases with similar hypodense borders on CT scans. We propose that a subset of central osteomas should be considered in the differential diagnosis of osteopathologies of the jaws with hyperdense internal architecture and hypodense borders, as seen on CT images., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The pathogenesis of oral cancer is a complex and multifactorial process that requires a deep understanding of the underlying mechanisms involved in the development and progress of malignancy. The ever-improving comprehension of the diverse molecular characteristics of cancer, the genetic and epigenetic alterations of tumor cells, and the complex signaling pathways that are activated and frequently cross talk open up promising horizons for the discovery and application of diagnostic molecular markers and set the basis for an era of individualized management of the molecular defects underlying and governing oral premalignancy and cancer. The purpose of this article is to review the key molecular concepts that are implicated in oral carcinogenesis, especially focusing on oral squamous cell carcinoma, and to review selected biomarkers that play a substantial role in controlling the so-called "hallmarks of cancer," with special reference to recent advances that shed light on their deregulation during the different steps of oral cancer development and progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Francisella tularensis ( Ft ) is a Gram-negative, facultative intracellular bacterium that is a Tier 1 Select Agent of concern for biodefense for which there is no licensed vaccine. A subfamily of 9 Francisella phagosomal transporter ( fpt ) genes belonging to the Major Facilitator Superfamily of transporters was identified as critical to pathogenesis and potential targets for attenuation and vaccine development. We evaluated the attenuation and protective capacity of LVS derivatives with deletions of the fptA and fptF genes in the C57BL/6J mouse model of respiratory tularemia. LVSΔ fptA and LVSΔ fptF were highly attenuated with LD 50 values of >20 times that of LVS when administered intranasally and conferred 100% protection against lethal challenge. Immune responses to the fpt mutant strains in mouse lungs on day 6 post-infection were substantially modified compared to LVS and were associated with reduced organ burdens and reduced pathology. The immune responses to LVSΔ fptA and LVSΔf ptF were characterized by decreased levels of IL-10 and IL-1β in the BALF versus LVS, and increased numbers of B cells, αβ and γδ T cells, NK cells, and DCs versus LVS. These results support a fundamental requirement for FptA and FptF in the pathogenesis of Ft and the modulation of the host immune response.

Semaphorin 4D (Sema4D) is a glycoprotein that is expressed by several tumors and immune cells. It can function as a membrane bound protein or as a cleaved soluble protein (sSema4D). We sought to investigate the translational potential of plasma sSema4D as an immune marker in plasma of patients with head and neck squamous cell carcinoma (HNSCC). Paired peripheral blood and tumor tissue samples of 104 patients with HNSCC were collected at the same time point to allow for real time analysis. Scoring of the histological inflammatory subtype (HIS) was carried out using Sema4D immunohistochemistry on the tumor tissue. sSema4D was detected in plasma using direct ELISA assay. Defining elevated sSema4D as values above the 95 th percentile in healthy controls, our data showed that sSema4D levels in plasma were elevated in 25.0% (95% CI, 16.7-34.9%) of the patients with HNSCC and showed significant association with HIS immune excluded (HIS-IE) (p = 0.007), Sema4D +ve tumor cells (TCs) (p = 0.018) and PD-L1 +ve immune cells (ICs) (p = 0.038). A multi-variable logistic regression analysis showed that HIS was significantly (P = 0.004) associated with elevated sSema4D, an association not explained by available patient-level factors. Using the IO-360 nanoString platform, differential gene expression (DGE) analysis of 10 HNSCC tumor tissues showed that patients with high sSema4D in plasma (HsS4D) clustered as IFN- γ negative tumor immune signature and were mostly HIS-IE. The IC type in the HsS4D paired tumor tissue was predominantly myeloid, while the lymphoid compartment was higher in the low sSema4D (LsS4D). The Wnt signaling pathway was upregulated in the HsS4D group. Further analysis using the IO-360, 770 gene set, showed significant non-inflamed profile of the HsS4D tumors compared to the LsS4D. In conclusion, our data reveals an association between sSema4D and the histological inflammatory subtype., Competing Interests: TW is CEO of WebbCures, LLC, co-founder of Screen Therapeutics and serves as an advisor for Immunaccel Labs, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Younis, Ghita, Elnaggar, Chaisuparat, Theofilou, Dyalram, Ord, Davila, Tallon, Papadimitriou, Webb, Bentzen and Lubek.)

Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI., Competing Interests: Competing interests: TM is a consultant for AstraZeneca, Genentech, Boehringe Ingelheim, Atara, and Regeneron. And receives research grant support from Bristol Myers Squibb, Regeneron, Merck, and Boehringer Ingelheim. AER receives sponsored research support from Janssen, AbbVie, Bristol Myers Squibb, Celgene SMR receives consulting fees from Eli Lilly, Daiichi Sankyo and Silverback Therapeutics and research support from Cancer Prevention and Research Institute of Texas RR190020. MER-R receives research grant support from ROCHE and Highlight Therapeutics. SC and CF are employees and shareholder at NanoString Technologies. DHA has received royalties from the University of Illinois and has received consulting fees from Boehringer Ingelheim. JG is a consultant for Glaxo-Smith Kline (GSK), Array BioPharma, Codagenix, Verseau Therapeutics and Kymera and receives sponsored research support from GSK, Eli Lilly and Array BioPharma., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

The success of immunotherapy in the treatment of patients with advanced melanoma has paved the way for unprecedented successes in the treatment of many other malignancies. We present a case of extensively metastatic oral mucosal melanoma that responded successfully to combined immune checkpoint blockade with ipilimumab and nivolumab but developed multiple immune-related adverse events, including myocarditis, a rare event associated with immunotherapy of elderly melanoma patients. Though the acute myocarditis was managed successfully, the patient succumbed to sudden cardiac death. This case highlights the fact, that autoimmune carditis must be considered when working up the sudden onset of shortness of breath in patients on immune checkpoint blockade. After controlling the acute myocarditis with high-dose steroids, which should be tapered over 6 weeks, further cardiology care is needed, and a defibrillator might have to be implanted. Understanding the pathophysiology of immune-related adverse events could make cancer immunotherapy both more effective and safer.

Benign fibro-osseous lesions within the maxillofacial region represent a heterogeneous group of benign entities with overlapping histologic features. Ossifying fibroma, the rarest of these entities, represents a true neoplasm. Juvenile ossifying fibroma (JOF) is considered an aggressive rapidly growing sub-type. It tends to occur in the first or second decades of life. Based on histological and clinical features it can further be classified into two variants, namely juvenile trabecular ossifying fibroma (JTOF) and juvenile psammomatoid ossifying fibroma (JPOF). JTOF features a proliferation of cellular fibroblastic tissue admixed with woven bone trabeculae with varying histologic presentations. Correlation with clinical and radiographic features is essential to differentiate it from other fibro-osseous lesions. A case of JTOF of the mandible is exemplified in this Sine Qua Non Radiology-Pathology article.

Mycosis fungoides (MF) accounts for approximately 50% of all primary cutaneous lymphomas. MF occurrence in the oral cavity is extremely rare with approximately 45 cases reported to date. We present a case of a 68 year-old man with a raised nodular lesion of the ventral tongue with clinical impression of irritational fibroma. Histopathologic and immunohistochemical (IHC) examination revealed a phenotype consistent with MF with large cell transformation in the context of Sezary syndrome. The histological diagnosis of oral MF requires a high index of suspicion and IHC panel to rule out large cell transformation. To our knowledge, only four cases of large cell transformation of oral MF have been reported in the English literature. The clinical and histopathologic features of a rare case of intra-oral MF with large cell transformation are exemplified in this article.

Xanthoma is a common, self-limiting cutaneous lesion of non-Langerhans cell, lipid-laden foamy histiocytes that is often concomitant with hyperlipidemia. The intraosseous counterpart is rarely encountered and typically presents as a painless, expansile osteolytic process in the context of hyperlipidemia or normolipidemia. Only a scant number of gnathic xanthomas have been reported in the otolaryngologic literature. We report the clinical, laboratory, radiographic, histopathologic, immunohistochemical, and ultrastructural studies of a mandibular lesion discovered in an asymptomatic 16-year-old male, and associated with 2 previously unreported comorbidities, namely hyperlipidemia and vitamin D deficiency., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The search for stromal biomarkers in carcinoma patients is a challenge in the field. Semaphorin 4D (Sema4D), known for its various developmental, physiological and pathological effects, plays a role in pro and anti-inflammatory responses. It is expressed in many epithelial tumors including head and neck squamous cell carcinoma (HNSCC). Recently, we found that HNSCC-associated Sema4D modulates an immune-suppressive, tumor-permissible environment by inducing the expansion of myeloid derived suppressor cells. The purpose of this study was to determine the value of Sema4D as a biomarker for the peri-tumoral stromal phenotype in human HNSCC. Our data showed Sema4D +ve/high tumor cells in 34% of the studied cohort with positive correlation to Stage III (p=0.0001). Sema4D +ve/high tumor cells correlated directly with dense fibrotic peri-tumoral stroma (p=0.0001) and inversely with infiltrate of Sema4D +ve/high tumor-associated inflammatory cells (TAIs) (p=0.01). Most of the Sema4D +ve/high TAIs were co-positive for the macrophage biomarker CD163. Knockdown of Sema4D in WSU-HN6 cells inhibited collagen production by fibroblasts, and decreased activated TGF-β1 levels in culture medium of HNSCC cell lines. In a stratification model of HNSCC using combined Sema4D and the programmed death ligand 1 (PDL-1), Sema4D +ve/high tumor cells represented a phenotype distinct from the PDL-1 positive tumors. Finally,Sema4D was detected in plasma of HNC patients at significantly higher levels (115.44, ± 39.37) compared to healthy donors (38.60± 12.73) (p <0.0001). In conclusion, we present a novel HNSCC tumor stratification model, based on the expression of the biomarker Sema4D. This model opens new avenues to novel targeted therapeutic strategies., Competing Interests: CONFLICTS OF INTEREST T.J.W. is the founder and CEO of WebbCures, LLC. The other authors declare no conflicts of interest.

Clear cell squamous cell carcinoma (CCSCC) is a rare histological subtype of squamous cell carcinoma (SCC) that was originally described in the skin. Here, we report a case of a 66-year-old female patient who presented with a fungating ulcerative mass of the left lateral tongue extending anteriorly to the floor of the mouth, and posteriorly to the left retromolar fossa and the oropharynx. The patient had a history of SCC of the left posterior tongue that was treated with partial glossectomy and adjuvant radiotherapy. Representative biopsies were obtained from the floor of the mouth, tongue and retromolar fossa. The examined biopsies showed various degrees of dysplastic surface epithelium with transition into infiltrating epithelial tumor nests and cords with clear cytoplasm and malignant cellular features. Pancytokeratin, CK5/6, and p63 were all diffusely positive. S-100, Calponin, and smooth muscle actin (SMA) were negative. PAS stain was diffusely positive and diastase labile in the tumor clear cells. Sparse areas of mucicarmine positivity were noted. Based on these findings a final diagnosis of a glycogen-rich CCSCC was given. This case represents a very rare histological variant of oral SCC, which is significant for the histological differential diagnosis of clear cell tumors of the oral cavity.

One of the mechanisms by which malignancies can induce immune suppression is through the production of cytokines that affect the maturation and differentiation of inflammatory cells in the tumor microenvironment. Semaphorin 4D (Sema4D) is a proangiogenic cytokine produced by several malignancies, which has been described in the regulation of the immune system. In the present study, we examined the role of human head and neck squamous cell carcinoma (HNSCC)-secreted Sema4D on myeloid cell differentiation. CD33(+) cells cultured in HNSCC cell line-derived conditioned medium differentiated into myeloid derived suppressor cells (MDSC) (CD33(+)CD11b(+)HLA-DR(-/low)). The addition of anti-Sema4D Ab to HNSCC conditioned medium significantly reduced the expansion of the MDSC population. Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28. Importantly, CD33(+) myeloid and T cells cultured in conditioned medium of HNSCC cells in which Sema4D was knocked down promoted antitumor inflammatory profile, through recovery of the effector T cells (CD4(+)T-bet(+) and CD8(+)T-bet(+)), as well as a decrease in regulatory T cells (CD4(+)CD25(+)FOXP3(+)). We also showed that Sema4D was comparable to GM-CSF in its induction of MDSC. Collectively, this study describes a novel immunosuppressive role for Sema4D in HNSCC through induction of MDSC, and it highlights Sema4D as a therapeutic target for future studies to enhance the antitumorigenic inflammatory response in HNSCC and other epithelial malignancies., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background: Recent evidence indicates that metformin, a biguanide used as first-line treatment for type 2 diabetes, prevents the conversion of carcinogen-induced oral dysplasias into head and neck squamous cell carcinomas (HNSCC), most likely by inhibiting mammalian target of rapamycin complex 1 (mTORC1) oncogenic signaling. Whether metformin acts directly at the primary tumor site or indirectly by modulating hormonal secretion from extratumoral organs remains unknown. As organic cation transporters (OCT) belonging to the solute carrier 22A gene family, including OCT-1, OCT-2, and OCT-3, mediate metformin uptake and activity, it is critical to define what role they play in the antineoplastic activity of metformin., Methods: Immunohistochemical and immunoblotting techniques were used in normal, dysplastic and HNSCC tissues, and HNSCC cell lines, respectively, to determine OCTs expression levels., Results: We report that only OCT-3 was highly expressed in a number of HNSCC cell lines, oral epithelial dysplasias, and well to moderately differentiated HNSCC. Indeed, inhibition of OCT-3 expression and activity in HNSCC cells prevented metformin-induced AMP-activated protein kinase activation and mTORC1 pathway inhibition. Moreover, in oral dysplasias, high OCT-3 expression localized to epithelial compartments where mTORC1 signaling was also upregulated suggestive of a potential local effect of metformin., Conclusions: The concept of using metformin as a chemopreventive agent to control head and neck carcinogenesis is promising. Further work is warranted to elucidate largely unexplored mechanisms of metformin uptake and pharmacologic action that may ultimately influence the selection of the most suitable patients who can benefit from metformin in head and neck cancer chemoprevention., (© 2012 John Wiley & Sons A/S.)

Schistosomiasis is a common chronic helminthic infection of the liver that causes hepatic fibrosis and portal hypertension,contributing to the death of over half a million people a year. Infusion of autologous bone marrow cells into patients with hepatic cirrhosis has been reported to ameliorate symptoms of portal hypertension and improve liver function, either by conversion of the infused mesenchymal stem cells (MSCs) to hepatocytes or by modulating of the hepatic fibrosis. Here,we have investigated the antifibrotic effect of mesenchymal stem cells (MSCs) using S. mansoni-induced liver fibrosis in mice, which causes an intense, stable fibrosis. MSCs derived from bone marrow of male mice were then infused intravenously into female mice that had received intraperitoneal injection of S.mansoni cercariae. Mice were divided into 4 groups: Untreated control; MSCs infusion only; Schistosomiasis only; and Schistosomiasis plus MSCs infusion. Serum alanine aminotransferase (ALT) and liver histopathology were evaluated. Expression of the collagen gene (type I),transforming growth factor (TGF-β), matrix metalloproteinase (MMP2), tissue inhibitor of metalloproteinase (TIMP-1),stromal cell-derived factor-1(SDF-1) and its receptor (CXCR4) were analyzed. MSC infusion resulted in significant decrease in liver collagen and TGF-β gene expression in the Schistosomiasis mice. The ratio of MMP-2 to TIMP-1 expression increased. SDF-1 and CXCR4 mRNA expression also increased. There was overall improvement of liver histology and a statistically significant reduction of serum ALT level. MSCs infusion ameliorated S. mansoni-induced liver fibrosis, probably by modulating the relative expression of MMP and TIMP. The findings support the hypothesis that MSCs participate in liver regeneration and functional improvement by reducing liver fibrosis.

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. The recent identification of the mTOR complex 1 (mTORC1) signaling pathway as a highly prevalent molecular signature underlying HNSCC pathogenesis has provided the foundation to search for novel therapeutic approaches to prevent and treat HNSCC. Here, we asked whether metformin, the most widely used medication for the treatment of type II diabetes, which acts in part by stimulating the AMP-activated protein kinase (AMPK) signaling pathway thereby reducing mTORC1 activity, may lower the risk of HNSCC development. Indeed, we show that metformin reduces the growth of HNSCC cells and diminishes their mTORC1 activity by both AMPK-dependent and -independent mechanisms. We also optimized an oral-specific carcinogenesis mouse model that results in the accumulation of multiple oral premalignant lesions at the end of the carcinogen exposure, some of which then spontaneously progress into HNSCC. Using this mouse model, we observed that metformin specifically inhibits mTORC1 in the basal proliferating epithelial layer of oral premalignant lesions. Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions and by preventing their spontaneous conversion to squamous cell carcinomas. Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression., (2012 AACR)

Objective: Lung cancer remains number one cause of cancer related deaths worldwide. Cell cycle deregulation plays a major role in the pathogenesis of Non-Small Cell Lung Cancer (NSCLC). CDC25A represents a critical cell cycle regulator that enhances cell cycle progression. In this study we aimed to investigate the role of a novel CDC25A transcriptional variant, CDC25A(Q110del), on the regulation of the CDC25A protein, and its impact on prognosis of NSCLC patients., Methodology/principal Findings: Here we report a novel CDC25A transcript variant with codon 110 (Glutamine) deletion, that we termed CDC25A(Q110del) in NSCLC cells. In 9 (75%) of the 12 NSCLC cell lines, CDC25A(Q110del) expression accounted for more than 20% of the CDC25A transcripts. Biological effects of CDC25A(Q110del) were investigated in H1299 and HEK-293F cells using UV radiation, flowcytometry, cyclohexamide treatment, and confocal microscopy. Compared to CDC25A(wt), CDC25A(Q110del) protein had longer half-life; cells expressing CDC25A(Q110del) were more resistant to UV irradiation and showed more mitotic activity. Taqman-PCR was used to quantify CDC25A(Q110del) expression levels in 88 primary NSCLC tumor/normal tissue pairs. In patients with NSCLC, Kaplan Meier curves showed tumors expressing higher levels of CDC25A(Q110del) relative to the adjacent lung tissues to have significantly inferior overall survival (P = .0018)., Significance: Here we identified CDC25A(Q110del) as a novel transcriptional variant of CDC25A in NSCLC. The sequence-specific nature of the abnormality could be a prognostic indicator in NSCLC patients as well as a candidate target for future therapeutic strategies.

Oral leukoplakia (OL) is the most common premalignancy in the oral cavity. A small proportion of OLs progresses to oral squamous cell carcinoma (OSCC). To assess OSCC risk of OLs, we investigated the role of the transcriptional repressor enhancer of zeste homolog 2 (EZH2) in oral tumorigenesis and its clinical implication as an OSCC risk predictor. Immunohistochemistry was used to measure EZH2 expression in OLs from 76 patients, including 37 who later developed OSCC and 39 who did not. EZH2 expression was associated with clinicopathologic parameters and clinical outcomes. To determine the biological role of EZH2 in OL, EZH2 level was reduced using EZH2 siRNAs in Leuk-1 cells, its impact on cell cycle, anchorage-dependent/independent growth, and invasion was assessed. We observed strong EZH2 expression in 34 (45%), moderate expression in 26 (34%), and weak/no expression in 16 (21%) of the OLs. The higher EZH2 levels were strongly associated with dysplasia (P < 0.001) and OSCC development (P < 0.0001). Multivariate analysis indicated that EZH2 expression was the only independent factor for OSCC development (P < 0.0001). At 5 years after diagnosis, 80% of patients whose OLs expressed strong EZH2 developed OSCC whereas only 24% patients with moderate and none with weak/no EZH2 expression did so (P < 0.0001). In Leuk-1 cells, EZH2 downregulation resulted in G(1) arrest; decreased invasion capability, decreased anchorage-independent growth; downregulation of cyclin D1 and upregulation of p15(INK4B). Our data suggest that EZH2 plays an important role in OL malignant transformation and may be a biomarker in predicting OSCC development in patients with OLs.

Introduction: The lateral periodontal cyst is an uncommon odontogenic developmental lesion and chiefly arises in the alveolar bone between the roots of a pair of erupted teeth or lateral to a tooth root. Two atypical cases of the lateral periodontal cyst occurring in periapical sites are reported., Methods: Both lesions presented as an incidental radiographic finding, appearing as an apical radiolucency with well-circumscribed sclerotic borders. One lesion, initially suspected to be of pulpal origin, persisted after endodontic therapy; the other case was first considered to be an odontogenic keratocyst. A biopsy was performed on each patient for lesional identity., Results: Histopathologic assessment of each lesion was consistent with a lateral periodontal cyst and revealed thin, nonkeratinized epithelial linings containing nodular plaques and clear cells. The cyst walls were thickened and had minimal inflammation., Conclusions: The featured cases show that the lateral periodontal cyst is not always confined to the interradicular region and can masquerade as a lesion of endodontic origin. Aberrant cases warrant long-term surveillance., (Copyright © 2010 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

The mammalian target of rapamycin (mTOR) signaling network is frequently hyperactivated in patients with head and neck squamous cell carcinoma (HNSCC). Recent studies suggest that hypoxia, a common microenvironmental stress found in tumors, blocks this mitogenic pathway. Here, we demonstrate that in HNSCC cell lines, the expression of the phosphorylated forms of the mTOR downstream targets S6 kinase and S6 (pS6) decreased after hypoxia. These events were associated with a marked up-regulation of the regulated in development and DNA damage 1 (REDD1), a recently characterized hypoxia-induced protein that negatively controls mTOR activity. Conversely, pS6 levels were retained under hypoxia in REDD1 knock-down cells and in HNSCC cells lacking endogenous REDD1 expression. Furthermore, we observed that prolonged hypoxia induced an energy-depleting response as evidenced by decreased cellular ATP levels and AMP-activated protein kinase (AMPK) activation. Interestingly, AMPK inhibition before prolonged hypoxia prevented REDD1 expression, thereby sustaining mTOR activity. These results suggest a novel mechanism by which AMPK activation after hypoxia-induced energy stress may be crucial in regulating REDD1 expression to control the mTOR pathway in HNSCC. Furthermore, we found that, in some HNSCC cells, the reduced mTOR activity in response to hypoxia through AMPK/REDD1 was deregulated, which hence might contribute to the persistent activation of the mTOR pathway in this cancer type.

Central odontogenic fibroma (COF) is a rare benign ectomesenchymal tumor of the jaws. Only 12 cases of COF with giant cell granuloma (GCG)-like lesion have been reported in the English literature. Here, we present a new case of COF epithelium rich type with a GCG-like component. Radiographically, this lesion presented as a well defined unilocular radiolucency in the body of the mandible. Histologically, the lesion showed a unique confluence of odontogenic epithelial rests with multinucleated giant cells (MNGCs) in a highly cellular fibrous connective tissue stroma, with osteoid and cementoid deposits. A distinct area showed the typical histological picture of each component separately. Immunohistochemical staining with pancytokeratin (CK) highlighted the odontogenic epithelial component merging with the GCG component throughout most of the lesion. The significance of GCG-like areas within COF is the reported increased risk of recurrence following curettage, possibly necessitating more aggressive therapy.