Search

Objective We aimed to assess which metabolic pathways would be implicated in the phenotypic changes of the epithelial lining of odontogenic keratocyst after marsupialization, comparing pre- and post-marsupialized lesions with adjacent oral mucosa. Materials and methods Eighteen formalin-fixed and paraffin-embedded tissues from six subjects were divided into three paired groups: odontogenic keratocyst pre (n=6) and post marsupialization (n=6), and adjacent oral mucosa (n=6). The metabolic pathways found in these groups were obtained by high-performance liquid chromatography-mass spectrometry-based untargeted metabolomics performed. Results Through putative metabolite annotation followed by pathway enrichment and predictive analysis with automated algorithms (Mummichog and Gene Set Enrichment Analysis), we found differences in many cellular processes that may be involved in inflammation, oxidative stress response, keratinocyte-basal membrane attachment, differentiation, and proliferation functions, all relevant to odontogenic keratocyst pathobiology and the phenotype acquired after marsupialization. Conclusion Our study was able to identify several metabolic pathways potentially involved in the metaplastic changes induced by marsupialization of odontogenic keratocysts. An improved comprehension of this process could pave the way for the development of targeted therapies.

Giant cell granuloma of the jaws are benign osteolytic lesions of the jaws. These lesions are genetically characterized by mutually exclusive somatic mutations at TRPV4, KRAS, and FGFR1, and a fourth molecular subgroup which is wild-type for the three mutations. Irrespective of the molecular background, giant cell granulomas show MAPK/ERK activation. However, it remains unclear if these mutations lead to differences in their molecular signaling in giant cell granulomas.Metabolomics, proteomics, and phosphoproteomics analyses were carried out in formalin-fixed paraffin-embedded samples of giant cell granuloma of the jaws. The study cohort consisted of five lesions harboring mutations in FGFR1, six in KRAS, five in TRPV4, and five that were wild-type for these mutations.Lesions harboring KRAS or FGFR1 mutations showed overall similar proteomics and metabolomics profiles. In all four groups, metabolic pathways showed similarity in apoptosis, cell signaling, gene expression, cell differentiation, and erythrocyte activity. Lesions harboring TRPV4 mutations showed a greater number of enriched pathways related to tissue architecture. On the other hand, the wild-type group presented increased number of enriched pathways related to protein metabolism compared to the other groups.Despite some minor differences, our results revealed an overall similar molecular profile among the groups with different mutational profile at the metabolic, proteic, and phosphopeptidic levels.

OBJECTIVE Odontogenic keratocyst (OKC) is a benign lesion that tends to recur after surgical treatment. In an attempt to clarify the molecular basis underlining the OKC pathobiology, we aimed to analyze its proteomic profile. MATERIALS AND METHODS We compared the proteomic profiles of five OKC and matched normal oral mucosa by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Then, we performed enrichment analysis and a literature search for the immunoexpression of the proteomics targets. RESULTS We identified 1,150 proteins and 72 differently expressed proteins (log2 fold change ≥ 1.5; p

Odontogenic cysts and tumors are heterogeneous lesions, originating from elements or remnants of the odontogenic apparatus. Although the majority of these lesions are benign and never undergo malignant transformation, rare malignant tumors may arise de novo or from benign precursors. The molecular basis of these lesions is still poorly understood. This article summarizes and discusses studies using small, medium, and large-scale and/or "-omic" techniques to describe the molecular characteristics of benign and malignant odontogenic lesions and briefly debates strategies to increase the use of "-omic" and multi-omic approaches or integrative analyses in the research of these lesions. A comprehensive understanding of the molecular aspects of odontogenic lesions by using large-scale approaches will enable us to refine the classification of this heterogeneous group of disorders and provide more accurate biomarkers for precise diagnosis, prognosis, and development of molecular tools in the management of patients with these conditions.

Background: Fibrous dysplasia (FD) and cemento-ossifying fibroma (COF) are the most common gnathic fibro-osseous lesions. These diseases exhibit remarkable overlap of several clinicopathological aspects, and differential diagnosis depends on the combination of histopathological, radiographic, and clinical aspects. Their molecular landscape remains poorly characterized, and herein, we assessed their proteomic and phosphoproteomic profiles. Methods: The quantitative differences in protein profile of FD and COF were assessed by proteomic and phosphoproteomic analyses of formalin-fixed paraffin-embedded tissue samples. Pathway enrichment analyses with differentially regulated proteins were performed. Results: FD and COF exhibited differential regulation of pathways related to extracellular matrix organization, cell adhesion, and platelet and erythrocytes activities. Additionally, these lesions demonstrated distinct abundance of proteins involved in osteoblastic differentiation and tumorigenesis and differential abundance of phosphorylation of Ser61 of Yes-associated protein 1 (YAP1). Conclusions: In summary, despite the morphological similarity between these diseases, our results demonstrated that COF and DF present numerous quantitative differences in their proteomic profiles. These findings suggest that these fibro-osseous lesions trigger distinct molecular mechanisms during their pathogenesis. Moreover, some proteins identified in our analysis could serve as potential biomarkers for differential diagnosis of these diseases after further validation.

Background Pyogenic granuloma (PG) is a benign nodular lesion with a prominent vascular component which may affect different sites. Recently, BRAF, KRAS, HRAS, NRAS, GNA11, and GNA14 mutations were reported on PGs of the skin. The present study assessed the role of the MAPK/ERK pathway in oral PG pathogenesis. Methods Mutations in hotspot regions of genes involved in the MAPK/ERK pathway activation were investigated by Sanger sequencing. The expression of phospho-ERK1/2 was evaluated by immunohistochemistry. Results Oral PGs did not show mutations in the sequenced regions of the genes BRAF, KRAS, HRAS, NRAS, GNA11, or GNA14. Our results also showed activation of the MAPK/ERK pathway demonstrated by phospho-ERK1/2 immunohistochemical positivity. Conclusions Although oral PG shows MAPK/ERK pathway activation, the driver molecular event remains to be elucidated.

Head and neck cancers are the seventh most common type of cancer worldwide, with almost half of the cases affecting the oral cavity. Oral squamous cell carcinoma (OSCC) is the most common form of oral cancer, showing poor prognosis and high mortality. OSCC molecular pathogenesis is complex, resulting from a wide range of events that involve the interplay between genetic mutations and altered levels of transcripts, proteins, and metabolites. Metabolomics is a recently developed sub-area of omics sciences focused on the comprehensive analysis of small molecules involved in several biological pathways by high throughput technologies. This review summarizes and evaluates studies focused on the metabolomics analysis of OSCC and oral premalignant disorders to better interpret the complex process of oral carcinogenesis. Additionally, the metabolic biomarkers signatures identified so far are also included. Moreover, we discuss the limitations of these studies and make suggestions for future investigations. Although many questions about the metabolic features of OSCC have already been answered in metabolomic studies, further validation and optimization are still required to translate these findings into clinical applications.

Introduction: Pyogenic granuloma (PG) is a common nodular lesion with a prominent vascular component which may affect different sites. BRAF and RAS mutations were reported on a set of PGs of the skin. Objective: To evaluate the presence of BRAF and RAS mutations in PG. Study Design: The present study assessed the role of the MAPK/ERK pathway in oral PG pathogenesis. Mutations in hotspot regions of oncogenes components of the MAPK/ERK pathway were investigated by Sanger sequencing. The immunoexpression of phospho-ERK1/2 was assessed by immunohistochemistry. Results: Oral PGs showed no mutations in the sequenced regions of the genes BRAF, KRAS, HRAS, and NRAS. Our results also showed that activation of MAPK/ERK pathway demonstrated phospho-ERK1/2 immunohistochemical positivity. Conclusion: In conclusion, although oral PG shows MAPK/ERK pathway activation, the driven molecular event remains to be elucidated.

Odontogenic myxoma (OM) occasionally responds poorly to surgical treatment. The MAPK pathway is constitutively activated in several neoplasms and we aimed to test if the MAPK pathway is activated in OM, in order to pave the way for an alternative therapy for aggressive and recurrent cases. The immunoexpression of phosphorylated ERK1/2 (pERK1/2) was assessed in OM. We established a 3D organotypic culture model for the in vitro study and patient-derived xenografts (PDX) in mice for the in vivo study. The MEK inhibitor U0126 was used to inhibit phosphorylation of ERK1/2 in the in vitro and in vivo models. All OM showed strong pERK1/2 immunoexpression, consistent with MAPK pathway activation. Treatment of the 3D culture with U0126 resulted in a reduced pERK1/2/ERK1/2 ratio. Consistent with the in vitro results, all PDX of animals treated with U0126 showed a decreased volume fold change compared with controls. The MAPK pathway is activated in OM and its inhibition leads to tumor shrinkage in PDX and cell culture models. Our results offer a pre-clinical frame for OM-targeted therapy. Further work is needed to determine if this initial finding holds clinical promise.

Pyogenic granuloma (PG) is a benign nodular lesion with a prominent vascular component which may affect different sites. Recently, BRAF, KRAS, HRAS, NRAS, GNA11, and GNA14 mutations were reported on PGs of the skin. The present study assessed the role of the MAPK/ERK pathway in oral PG pathogenesis.Mutations in hotspot regions of genes involved in the MAPK/ERK pathway activation were investigated by Sanger sequencing. The expression of phospho-ERK1/2 was evaluated by immunohistochemistry.Oral PGs did not show mutations in the sequenced regions of the genes BRAF, KRAS, HRAS, NRAS, GNA11, or GNA14. Our results also showed activation of the MAPK/ERK pathway demonstrated by phospho-ERK1/2 immunohistochemical positivity.Although oral PG shows MAPK/ERK pathway activation, the driver molecular event remains to be elucidated.

Background Oral Lichen Planus is a chronic inflammatory disorder that affects the oral mucosa, with the reticular and erosive forms representing the primary clinical variants of the disease. Previous studies have shown that metabolic alterations may well be involved in the pathogenesis of the disease; however, the molecular mechanisms related to the clinicopathological differences between erosive and reticular forms remain unknown. Methods A comparative metabolomic analysis was performed on formalin-fixed and paraffin-embedded tissue samples of erosive (n = 6) and reticular (n = 10) oral lichen planus using gas chromatography-mass spectrometry. Results The metabolomic analysis showed a distinct profile between the two clinical variants. Five metabolites (cyclohexanamine, glycine, mannitol/sorbitol, methyl palmitate and trehalose) were significantly diminished in erosive oral lichen planus as compared to the reticular form. Conclusions Reticular and erosive forms of oral lichen planus have a distinct metabolic profile. However, further studies using a large number of fresh tissue samples are necessary to confirm this data.

Background Ameloblastoma is a locally infiltrative, aggressive epithelial odontogenic neoplasm. BRAF-V600E mutation is frequently found in this tumor and has a pivotal role in its pathogenesis, but the consequences of this alteration need to be addressed. An untargeted metabolomics approach was applied to verify whether metabolic disturbances are related to tumor biology and whether BRAF-V600E mutation contributes to these alterations. Methods Formalin-fixed and paraffin-embedded tissue specimens from thirteen ameloblastoma and six dental follicles were included in this study. BRAF mutational status was determined by competitive allele-specific real-time PCR. Metabolite extracts were analyzed using gas chromatography coupled to mass spectrometry. Univariate and multivariate statistical methods were employed to compare the metabolic profiles of the samples. Results The abundance of eleven metabolites was significantly higher in ameloblastoma in relation to dental follicles, including amino acids, fatty acids, carbohydrates, inorganic acids, and organoheterocyclic compounds. The presence of BRAF-V600E mutations in ameloblastoma was related to decreased levels of glycerol in comparison with tumors carrying only wild-type alleles of this gene. No metabolic differences were observed between recurrent and primary manifestations of ameloblastoma. Conclusions Ameloblastoma exhibits a distinct metabolic profile from normal odontogenic epithelium. BRAF-V600E may contribute to metabolic alterations in ameloblastoma. Collectively, our findings suggest that metabolic alterations might play a role in tumor pathogenesis.

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive impairment in behavior, executive function, and language. The behavioral variant (bvFTD) is the most clinical common form and requires differential diagnosis with atypical Alzheimer's disease (AD) cases. This study aimed to investigate the plasma metabolite profile of patients with bvFTD compared to AD patients and cognitively healthy individuals using gas chromatography coupled to mass spectrometry (GCMS). This study included nine patients with bvFTD, 17 with AD and 15 cognitively healthy controls (training set), whose data were validated on a testing set (eight bvFTD, 14 AD and ten controls). The metabolites were detected by GCMS. A tendency towards a reduction in the levels of palmitoleic, oleic and lauric acids was found in the bvFTD group compared to the AD group; however, no significance after multiple comparison correction was observed. However, bvFTD group showed reduced levels of creatinine, glycine, tryptophan, uric acid, hypoxanthine, serine, valine, threonine, isoleucine, homoserine, methionine, glutamic acid, capric acid, tartronic acid, fumaric acid, and myo-inositol, metabolites related to glycine/serine/threonine, alanine/aspartate/glutamate pathways and aminoacyl-tRNA biosynthesis, when compared to controls. The data suggest that bvFTD patients may present an impairment of amino acid metabolism and the translation process. This pioneering study on bvFTD and its plasma metabolomic signature can be useful to provide new ideas about pathophysiological mechanisms, as well as guide more robust studies in search of possible biomarkers for the diagnosis of this important dementia.