Correlation between mutation of the p53 suppressor gene and the presence of the Human Papilloma Virisuses (PHV) in oral squamous cell cancer

Oral squamous cell carcinoma is one of the ten most frequent cancers of the body, which is more common in men and its frequency increases with age. Human papillomaviruses (HPV) have been implicated in uterine cervical cancer development, however, their role in oral squamous cell carcinoma (OSCC) development is less well defined. The E6 and E7 proteins of HPV are known to bind to the p53 protein and pRB respectively, thus inactivating the tumor suppressor activity of both proteins. The p53 gene has been indicated to be a tumor suppressor gene that is mutated in all human cancers. The aim of this study was to examine the incidence of human papillomavirus infection and p53 alterations in oral squamous cell carcinoma and to investigate a possible correlation between HPV infection and p53 alteration in the development of the disease. For this purpose we examined 60 specimens of primary oral SCCs and 30 cell smears of normal oral mucosa of controls for detection of p53 mutations and HPV DNAs. Exons 5 through 8 of the p53 gene were examined using the PCR-SSCP analysis. Mutations in the p53 gene were observed in 26 out of 60 tumor specimens (43,3%). All mutations were detected in exon 8 while 3 were in found in both exons 7 and 8. P53 mutations were only observed in oral squamous cell carcinomas. Tobacco use and alcohol intake were strongly associated (P0,05). Thirty nine out of 60 tumor specimens were found to harbor HPV 16 or 18 DNA or p53 gene mutations. These data suggest that HPV 16 infection and p53 mutations reveal a significant association with oral squamous cell carcinoma. No correlation exists between oncogenic HPV infection and p53 alterations in OSSC. HPV infection was not related to age, gender or use of alcohol and/or smoking. Conversely, we observed a strong association between alcohol and tobacco consumption and mutations of the p53 gene. These findings probably indicate that p53 mutations and HPV 16 contribute independently in the process of oral epithelial carcinogenesis.Ο καρκίνος της στοματικής κοιλότητας είναι ένας από τους δέκα πιο συχνούς όγκους του σώματος. Οι ανθρώπειοι θηλωματοϊοί (HPV) έχουν συνδεθεί με την ανάπτυξη του καρκίνου του τραχήλου της μήτρας, ωστόσο ο ρόλος τους στην ανάπτυξη του ακανθοκυτταρικού καρκινώματος της στοματικής κοιλότητας δεν έχει διευκρινιστεί επαρκώς. Οι Ε6 και Ε7 ογκοπρωτεΐνες των υψηλού κινδύνου HPV είναι γνωστό, ότι αλληλεπιδρούν με τις ογκοκατασταλτικές πρωτεΐνες pRB και p53 αντίστοιχα και τις απενεργοποιούν. Το γονίδιο p53 ανευρίσκεται ως το πιο συχνά μεταλλαγμένο γονίδιο στους περισσότερους τύπους καρκίνου, ωστόσο στον καρκίνο του τραχήλου της μήτρας, όπου ο ογκογενετικός ρόλος των HPV θεωρείται ως ιδιαίτερα σημαντικός, οι μεταλλάξεις του γονιδίου p53 είναι εξαιρετικά σπάνιες. Βάσει αυτών των δεδομένων σκοπός της μελέτης ήταν να διερευνηθεί κατά πόσο η παρουσία των ιών HPV συνδέεται με την ανάπτυξη ακανθοκυτταρικού καρκινώματος στη στοματική κοιλότητα, κατά πόσο το ογκοκατασταλτικό γονίδιο p53 βρίσκεται συχνά μεταλλαγμένο στο αντίστοιχο καρκίνωμα καθώς επίσης τη διερεύνηση της συσχέτισης της παρουσίας των υψηλού κινδύνου HPV με τις μεταλλάξεις του γονιδίου p53. Για τον σκοπό αυτό διερευνήσαμε 60 ιστικά δείγματα από ακανθοκυτταρικά καρκινώματα της στοματικής κοιλότητας που προήλθαν από ισάριθμους αρρώστους και 30 κυτταρικά επιχρίσματα από υγιή άτομα που αποτέλεσαν την ομάδα αναφοράς. Με την εφαρμογή της μεθόδου PCR-SSCP μεταξύ των εξονίων 5-8 του γονιδίου p53 ανιχνεύτηκαν μεταλλάξεις σε 26 από τα 60 καρκινικά δείγματα (43,3%). Όλες οι μεταλλάξεις εντοπίστηκαν στο εξόνιο 8, ενώ 3 ήταν κοινές στα εξόνια 7 και 9. Η στατιστική διαφορά σε σύγκριση με την ομάδα αναφοράς ήταν σημαντική (p<0,01). Με τη μέθοδο της PCR 27 δείγματα (45%) αποδείχτηκε, ότι ήταν θετικά για την παρουσία των HPV. Με την περαιτέρω τυποποίηση των ιών με υβριδισμό κατά Southern, καθώς και με τη μέθοδο PCR-RFLP οι υψηλού κινδύνου θηλωματοϊοί ανιχνεύτηκαν σε 17 περιπτώσεις αποτελώντας το 63% των ανιχνευθέντων HPV (17/27) ή το 28% του συνόλου των δειγμάτων (17/60). Ο HPV 16 ήταν ο συχνότερος τύπος ιού που ανιχνεύθηκε (16/17). Η διαφορά στη συχνότητα του γονιδιώματος των HPV μεταξύ των φυσιολογικών και καρκινικών δειγμάτων ήταν στατιστικά σημαντική (p<0,01). Από την σύγκριση της συχνότητας τόσο των μεταλλάξεων του γονιδίου p53 όσο και της παρουσίας των HPV στα καρκινικά δείγματα προέκυψε, ότι η συχνότητα και των δύο ήταν το ίδιο σημαντική (p<0,01). Οι μεταλλάξεις στο γονίδιο φαίνεται να συνδέονται με τη συνήθεια του καπνίσματος p=0,05, αλλά πολύ περισσότερο με την ταυτόχρονη λήψη αλκοόλ και χρήση καπνού (p<0,01). Από τα ευρήματά μας προκύπτει, ότι τόσο οι ανθρώπειοι θηλωματοϊοί υψηλού κινδύνου και ιδιαίτερα ο τύπος HPV16, όσο και οι μεταλλάξεις του ογκοκατασταλτικού γονιδίου p53 παρουσιάζουν σημαντική συσχέτιση με το ακανθοκυτταρικό καρκίνωμα του στόματος. Επίσης από την συσχέτιση της παρουσίας των υψηλού κινδύνου ογκογόνων HPV και των μεταλλάξεων του ογκοκατασταλτικού γονιδίου p53 προκύπτει, ότι η ανεξάρτητη παρουσία των δύο παραγόντων στα ενδοστοματικά καρκινώματα είναι εξίσου σημαντική. Έτσι η παρουσία των μεταλλάξεων του γονιδίου p53 και η παρουσία των υψηλού κινδύνου HPV που με διαφορετικούς μηχανισμούς αδρανοποιούν τελικά την ογκοκατασταλτική λειτουργία του γονιδίου p53 ανέρχονταν στο 72% του συνόλου των μελετηθέντων ακανθοκυτταρικών καρκινωμάτων

Hybrid Nanogel Drug Delivery Systems: Transforming the Tumor Microenvironment through Tumor Tissue Editing

The future of drug delivery offers immense potential for the creation of nanoplatforms based on nanogels. Nanogels present a significant possibility for pharmaceutical advancements because of their excellent stability and effective drug-loading capability for both hydrophobic and hydrophilic agents. As multifunctional systems, composite nanogels demonstrate the capacity to carry genes, drugs, and diagnostic agents while offering a perfect platform for theranostic multimodal applications. Nanogels can achieve diverse responsiveness and enable the stimuli-responsive release of chemo-/immunotherapy drugs and thus reprogramming cells within the TME in order to inhibit tumor proliferation, progression, and metastasis. In order to achieve active targeting and boost drug accumulation at target sites, particular ligands can be added to nanogels to improve the therapeutic outcomes and enhance the precision of cancer therapy. Modern “immune-specific” nanogels also have extra sophisticated tumor tissue-editing properties. Consequently, the introduction of a multifunctional nanogel-based drug delivery system improves the targeted distribution of immunotherapy drugs and combinational therapeutic treatments, thereby increasing the effectiveness of tumor therapy

Peripheral Osteoma of the Mandibular Condyle&mdash;Case Series

The purpose of this article is to present four new cases of peripheral osteoma of the mandibular condyle and the literature review. A retrospective study of files from our Department of Oral and Maxillofacial Surgery over the last 6 years revealed four cases of peripheral osteomas located in the area of the mandibular condyle. Diagnostic procedure included clinical, radiographic, and histologic criteria. Gardner&rsquo;s syndrome was excluded from patient history and clinical evaluation. One patient had only an aesthetic disturbance, with facial swelling, and the other three patients presented disturbances of the mandibular function, including deviation during mouth opening along with malocclusion. Three of the patients were male and one was female; all were of middle age (45&ndash;65 years old). The proposed surgical treatment was accepted by half of the patients, while the remaining half declined the operation after a confirmation of the diagnosis. Peripheral osteomas of the maxillofacial region are uncommon, and some cases with multiple osteomas are related to Gardner&rsquo;s syndrome. An osteoma of the mandibular condyle is very rare and surgical treatment is challenging for the surgeon with regards to the approach selection and the related complications. In the two cases that accepted the proposed surgical treatment, no recurrence and no complication was observed

Molecular and Immune Phenotypic Modifications during Metastatic Dissemination in Lung Carcinogenesis

The tumor microenvironment plays a key role in the progression of lung tumorigenesis, progression, and metastasis. Recent data reveal that disseminated tumor cells (DTCs) appear to play a key role in the development and progression of lung neoplasiaby driving immune system dysfunction and established immunosuppression, which is vital for evading the host immune response. As a consequence, in this review we will discuss the role and function of DTCs in immune cell signaling routes which trigger drug resistance and immunosuppression. We will also discuss the metabolic biology of DTCs, their dormancy, and their plasticity, which are critical for metastasis and drive lung tumor progression. Furthermore, we will consider the crosstalk between DTCs and myeloid cells in tumor-related immunosuppression. Specifically, we will investigate the molecular immune-related mechanisms in the tumor microenvironment that lead to decreased drug sensitivity and tumor relapse, along with strategies for reversing drug resistance and targeting immunosuppressive tumor networks. Deciphering these molecular mechanisms is essential for preclinical and clinical investigations in order to enhance therapeutic efficacy. Furthermore, a better understanding of these immune cell signaling pathways that drive immune surveillance, immune-driven inflammation, and tumor-related immunosuppression is necessary for future personalized therapeutic approaches

Tumor-Infiltrating Dendritic Cells: Decisive Roles in Cancer Immunosurveillance, Immunoediting, and Tumor T Cell Tolerance

The tumor microenvironment plays a key role in progression of tumorigenesis, tumor progression, and metastasis. Accumulating data reveal that dendritic cells (DCs) appear to play a key role in the development and progression of metastatic neoplasia by driving immune system dysfunction and establishing immunosuppression, which is vital for tumor evasion of host immune response. Consequently, in this review, we will discuss the function of tumor-infiltrating DCs in immune cell signaling pathways that lead to treatment resistance, tumor recurrence, and immunosuppression. We will also review DC metabolism, differentiation, and plasticity, which are essential for metastasis and the development of lung tumors. Furthermore, we will take into account the interaction between myeloid cells and DCs in tumor-related immunosuppression. We will specifically look into the molecular immune-related mechanisms in the tumor microenvironment that result in reduced drug sensitivity and tumor relapse, as well as methods for combating drug resistance and focusing on immunosuppressive tumor networks. DCs play a crucial role in modulating the immune response. Especially, as cancer progresses, DCs may switch from playing an immunostimulatory to an inhibitory role. This article&rsquo;s main emphasis is on tumor-infiltrating DCs. We address how they affect tumor growth and expansion, and we highlight innovative approaches for therapeutic modulation of these immunosuppressive DCs which is necessary for future personalized therapeutic approaches

Association of LOXL1 polymorphisms with pseudoexfoliation, glaucoma, intraocular pressure, and systemic diseases in a Greek population. The Thessaloniki eye study.

PurposeTo investigate the association of the two single-nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation syndrome (PEX), pseudoexfoliative glaucoma (PEXG), and primary open-angle glaucoma (POAG) in a Greek population-based setting, from the Thessaloniki Eye study.MethodsA total of 233 subjects with successful DNA extraction, PCR amplification, and genotyping were included in the genetic analysis of G153D and R141L SNPs of LOXL1 gene and classified into four groups: controls (n = 93); subjects with PEX (n = 40); POAG (n = 66); and PEXG (n = 34). Multinomial logistic regression was used to test their association with LOXL1 SNPs with adjustment for covariates. The association of LOXL1 with IOP (in untreated subjects) and with systemic diseases was explored.ResultsBoth LOXL1 SNPs were present in high frequencies in controls and cases. The G153D was strongly associated with both PEX (odds ratio [OR] = 23.2, P = 0.003 for allele G) and PEXG (OR = 24.75, P = 0.003 for allele G) and was not associated with POAG (P = 0.451). In contrast, the R141L was not associated with PEX (P = 0.81), PEXG (P = 0.063), or POAG (P = 0.113). No association of the G153D with either intraocular pressure (IOP) or systemic diseases was found.ConclusionsIn the Thessaloniki Eye Study, the G153D SNP of LOXL1 gene was strongly associated with both PEX and PEXG, whereas the R141L was not associated. No association of the LOXL1 with IOP or with systemic diseases was found. These findings further support the hypothesis that the LOXL1 gene contributes to onset of PEXG through PEX. Gene variants of LOXL1 do not help to identify those with PEX at increased risk for glaucoma development

Association of LOXL1 polymorphisms with pseudoexfoliation, glaucoma, intraocular pressure, and systemic diseases in a Greek population. The Thessaloniki eye study.

PurposeTo investigate the association of the two single-nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation syndrome (PEX), pseudoexfoliative glaucoma (PEXG), and primary open-angle glaucoma (POAG) in a Greek population-based setting, from the Thessaloniki Eye study.MethodsA total of 233 subjects with successful DNA extraction, PCR amplification, and genotyping were included in the genetic analysis of G153D and R141L SNPs of LOXL1 gene and classified into four groups: controls (n = 93); subjects with PEX (n = 40); POAG (n = 66); and PEXG (n = 34). Multinomial logistic regression was used to test their association with LOXL1 SNPs with adjustment for covariates. The association of LOXL1 with IOP (in untreated subjects) and with systemic diseases was explored.ResultsBoth LOXL1 SNPs were present in high frequencies in controls and cases. The G153D was strongly associated with both PEX (odds ratio [OR] = 23.2, P = 0.003 for allele G) and PEXG (OR = 24.75, P = 0.003 for allele G) and was not associated with POAG (P = 0.451). In contrast, the R141L was not associated with PEX (P = 0.81), PEXG (P = 0.063), or POAG (P = 0.113). No association of the G153D with either intraocular pressure (IOP) or systemic diseases was found.ConclusionsIn the Thessaloniki Eye Study, the G153D SNP of LOXL1 gene was strongly associated with both PEX and PEXG, whereas the R141L was not associated. No association of the LOXL1 with IOP or with systemic diseases was found. These findings further support the hypothesis that the LOXL1 gene contributes to onset of PEXG through PEX. Gene variants of LOXL1 do not help to identify those with PEX at increased risk for glaucoma development

Association of LOXL1

PURPOSE. To investigate the association of the two single-nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation syndrome (PEX), pseudoexfoliative glaucoma (PEXG), and primary open-angle glaucoma (POAG) in a Greek population–based setting, from the Thessaloniki Eye study. METHODS. A total of 233 subjects with successful DNA extraction, PCR amplification, and genotyping were included in the genetic analysis of G153D and R141L SNPs of LOXL1 gene and classified into four groups: controls (n = 93); subjects with PEX (n = 40); POAG (n = 66); and PEXG (n = 34). Multinomial logistic regression was used to test their association with LOXL1 SNPs with adjustment for covariates. The association of LOXL1 with IOP (in untreated subjects) and with systemic diseases was explored. RESULTS. Both LOXL1 SNPs were present in high frequencies in controls and cases. The G153D was strongly associated with both PEX (odds ratio [OR] = 23.2, P = 0.003 for allele G) and PEXG (OR = 24.75, P = 0.003 for allele G) and was not associated with POAG (P = 0.451). In contrast, the R141L was not associated with PEX (P = 0.81), PEXG (P = 0.063), or POAG (P = 0.113). No association of the G153D with either intraocular pressure (IOP) or systemic diseases was found. CONCLUSIONS. In the Thessaloniki Eye Study, the G153D SNP of LOXL1 gene was strongly associated with both PEX and PEXG, whereas the R141L was not associated. No association of the LOXL1 with IOP or with systemic diseases was found. These findings further support the hypothesis that the LOXL1 gene contributes to onset of PEXG through PEX. Gene variants of LOXL1 do not help to identify those with PEX at increased risk for glaucoma development