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Cisplatin, 5FU and docetaxel (TPF) are the most common chemotherapy regimen used for advanced OSCC. However, many cancer patients experience relapse, continued tumor growth, and spread due to drug resistance, which leads to treatment failure and metastatic disease. Here, using a CRISPR/Cas9 based kinome knockout screening, Misshapen-like kinase 1 (MINK1) is identified as an important mediator of 5FU resistance in OSCC. Analysis of clinical samples demonstrated significantly higher MINK1 expression in the tumor tissues of chemotherapy non-responder as compared to chemotherapy responders. The in-vitro and xenograft experiments indicate that knocking out MINK1 restores 5FU mediated cell death in chemoresistant OSCC. An antibody based phosphorylation array screen revealed MINK1 as a negative regulator of p53. Mechanistically, MINK1 modulates AKT phosphorylation at Ser473, which enables p-MDM2 (Ser 166) mediated degradation of p53. We also identified lestaurtinib as a potent inhibitor of MINK1 kinase activity. Lestaurtinib significantly induces 5FU mediated cell death in chemoresistant OSCC lines. The patient derived chemoresistant cell based xenograft data suggest that lestaurtinib restores 5FU sensitivity and facilitates a significant reduction of tumor burden. Overall, our study suggests that MINK1 is a major driver of 5FU resistance in OSCC. The novel combination of MINK1 inhibitor lestaurtinib and 5FU needs further clinical investigation in advanced OSCC. One sentence summary Lestaurtinib reverses 5FU sensitivity in drug resistant OSCC.

Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatin-induced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT-glycogen synthase kinase-3β. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.

Background Chemoresistance is one of the major factors for treatment failure in OSCC. Identifying key resistance triggering molecules will be useful strategy for developing novel treatment methods. Methods To identify the causative factors of chemoresistance, we performed RNA sequencing and global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin-resistance patterns. Results From the common set of dysregulated genes from both the analysis, RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is upregulated in chemotherapy-non-responder tumours as compared to chemotherapy-responder tumours. Genetic (knockout) or pharmacological (Radezolid, represses expression of RRBP1) inhibition of RRBP1 restores cisplatin-mediated cell death in chemo-resistant OSCC. Mechanistically, RRBP1 regulates Yes-associated protein1 (YAP1), a key protein in the Hippo pathway to induce chemoresistance. The PDC xenograft data suggests that knockout of RRBP1 induces cisplatin-mediated cell death and facilitates a significant reduction of tumour burden. Conclusion Overall, our data suggests that (I) RRBP1 is a major driver of cisplatin-resistance in OSCC, (II) RRBP1 regulates YAP1 expression to mediate cisplatin-resistance, (III) Radezolid represses RRBP1 expression and (IV) targeting RRBP1 reverses cisplatin-induced chemoresistance in advanced OSCC.

Cisplatin-based chemotherapy still remains as one of the primary treatment modalities for OSCC. Several OSCC patients experience relapse owing to development of chemoresistance. To identify key resistance triggering molecules, we performed global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin resistance patterns. From the proteomic profiling study, human RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is elevated in chemotherapy-non-responder tumors as compared to chemotherapy-naïve tumors. Knocking out RRBP1 resulted in restoring cisplatin mediated cell death in chemoresistant lines and patient derived cells (PDC). Mechanistically, RRBP1 regulates YAP-1 to induce chemoresistance in OSCC. The chemoresistant PDC xenograft data suggests that knock out of RRBP1 induces cisplatin mediated cell death and facilitates a significant reduction of tumor burden. We also found Radezolid, a novel oxazolidinone antibiotic represses the expression of RRBP1 and restores cisplatin-induced cell death in chemoresistant OSCC. This unique combinatorial approach needs further clinical investigation to target advanced OSCC. Here with for the first time, we uncover the novel role of RRBP1 as potential modulator of cisplatin resistance in advanced OSCC.

Chemoresistance is one of the important factors for treatment failure in OSCC, which can culminate in progressive tumor growth and metastatic spread. Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance, which can be achieved by identifying the causative factors for acquired chemoresistance. In this study, to explore the key cisplatin resistance triggering factors, we performed global proteomic profiling of OSCC lines representing with sensitive, early and late cisplatin-resistant patterns. The top ranked up-regulated protein appeared to be CMTM6. We found CMTM6 to be elevated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analyses of OSCC patient samples indicate that CMTM6 expression is upregulated in chemotherapy-non-responder tumors as compared to chemotherapy-naïve tumors. Stable knockdown of CMTM6 restores cisplatin-mediated cell death in chemoresistant OSCC lines. Similarly, upon CMTM6 overexpression in CMTM6KD lines, the cisplatin resistant phenotype was efficiently rescued. Mechanistically, it was found that CMTM6 interacts with membrane bound Enolase-1 and stabilized its expression, which in turn activates the AKT-GSK3β mediated Wnt signaling. CMTM6 triggers the translocation of β-catenin into the nucleus, which elevates the Wnt target pro-survival genes like Cyclin D, c-Myc and CD44. Moreover, incubation with lithium chloride, a Wnt signaling activator, efficiently rescued the chemoresistant phenotype in CMTM6KD OSCC lines. In a patient-derived cell xenograft model of chemoresistant OSCC, knock-down of CMTM6 restores cisplatin induced cell death and results in significant reduction of tumor burden. CMTM6 has recently been identified as a stabilizer of PD-L1 and henceforth it facilitates immune evasion by tumor cells. Herewith for the first time, we uncovered another novel role of CMTM6 as one of the major driver of cisplatin resistance.

Sex determination from unidentified skeletal remains a daunting task in forensic odontology. The mandible is the strongest and most durable of bones available for post-mortem profiling and its morphometric characteristics have been investigated. Less explored is the location of the mandibular canal which in a few populations has shown gender dimorphism.The present cross-sectional study explores sexual dimorphism in an eastern Indian population of Odisha from an analysis of cone-beam CT system (CBCT) images for the relative position of the mandibular canal and its foramina.A total of 120 CBCT images from either gender (1:1 ratio) of adult dentate individuals aged 18-60 years were analysed for the relative position of the mandibular canal. Ten measurements (8- coronal and 2- from axial slices) concerning the mandibular canal; at the level of the mandibular foramen, mandibular first molar and mental foramen were performed. Unpaired Student's t-test was employed to compare variables between the sexes atThe results revealed statistically significant differences (The relative position of the mandibular canal and its associated foramina show sexual dimorphism in an adult eastern Indian population.

The invasive tumor front (ITF) of oral squamous cell carcinoma (OSCC) and the reactive changes in regional lymph nodes (RLNs) are believed to carry integral prognostic information about the tumor's invasive capacity and insight into host immune response, respectively.This study aims to evaluate the reactivity patterns of RLNs in relation to the tumor stage, grade and various histopathological parameters at the ITF of primary tumor, in an attempt to elucidate the nature of host-immune response to tumor.Pattern of invasion (POI) using Bryne's criteria, peritumoral inflammation, and status of connective tissue (CT) stroma of 50 OSCC cases, that underwent selective neck dissection were assessed at the ITF. Immunoreactivity patterns in corresponding 450 RLNs were assessed as proposed by Tsakraklides and Ioachim. Further, 97 metastatic lymph nodes (LNs) were evaluated for degree and pattern of tumor invasion. The datasets were subjected to the Chi-square analysis.There was statistically significant association (P = 0.001) of Type III and Type IV POI as well as mild peritumoral inflammation (P = 0.024) with the advanced stages of OSCC as compared to early stages. Significant association was observed between LN reactivity pattern and tumor stage (P = 0.05), with metastatic nodes exhibiting germinal center predominance (97.9%) and lymphocyte predominance (69.1%) largely observed in nonmetastatic nodes. Majority of metastatic nodes showed Grade 3 invasion (54.7%) in the form of large islands (57.7%), whereas two (2.1%) nodes were totally effaced by tumor metastasis. Statistical significance was observed between CT stroma at ITF and degree of tumor invasion in metastatic LN (P = 0.001). POI also showed significant correlation with peritumoral inflammation (P = 0.002), CT stroma (P = 0.02), and LN reactivity pattern (P = 0.03).This study supports the presence of a strong immunological host-tumor relationship.

Cisplatin alone or in combination with 5FU (5-fluorouracil) and docetaxel (TPF) are common regimen chemotherapeutics for treatment of advanced oral squamous cell carcinoma (OSCC). Despite the initial positive response, several patients experience relapse due to chemoresistance. The potential role of Bcl-2 antiapoptotic members in acquired chemoresistance is yet to be explored. To address this, we designed two different relevant OSCC chemoresistant models: (i) acquired chemoresistant cells, where OSCC lines were treated with conventional chemotherapy for a prolonged period to develop chemoresistance, and (ii) chemoresistant patient-derived cells, where primary cells were established from tumor of neoadjuvant-treated OSCC patients who do not respond to TPF. Among all Bcl-2 antiapoptotic members, Mcl-1 expression (but not Bcl-2 or Bcl-xL) was found to be upregulated in both chemoresistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. Irrespective of all three chemotherapy drugs, Mcl-1 expression was elevated in OSCC cells that are resistant to either cisplatin or 5FU or docetaxel. In chemoresistant OSCC, Mcl-1 mRNA was upregulated by signal transducer and activator of transcription 3 (STAT3) activation, and the protein was stabilized by AKT-mediated glycogen synthase kinase 3 beta (GSK3β) inactivation. Genetic (siRNA) or pharmacological (Triptolide, a transcriptional repressor of Mcl-1) inhibition of Mcl-1 induces drug-mediated cell death in chemoresistant OSCC. In patient-derived xenograft model of advanced stage and chemoresistant OSCC tumor, Triptolide restores cisplatin-mediated cell death and facilitates significant reduction of tumor burdens. Overall, our data suggest Mcl-1 dependency of chemoresistant OSCC. A combination regimen of Mcl-1 inhibitor with conventional chemotherapy deserves further clinical investigation in advanced OSCC.

Background: The routine approach to delve into the organization of mineralized and nonmineralized structures of teeth is by studying whole tooth or slices of it by making thin section which requires laborious grinding or employing specialized equipment and also leads to specimen wastage. Peels hitherto utilized for fossil studies hold promise in overcoming the aforesaid shortcomings. Although the acetate peel technique has been modified for the study of tooth structure, the field remains largely unexplored. Aim: The current study was taken up to explore the usefulness of cellulose acetate peels in reproducing microscopic structures of teeth as seen in routine ground sections and further if they could supplement or replace the same. Materials and Methods: Extracted human teeth were embedded in plaster blocks in longitudinal and transverse orientation, ground and polished with silicon carbide paper. Following etching, washing and drying, the polished surface was wet with acetone and precut cellulose acetate film was placed over it and allowed to dry. As the acetate polymer dissolved in acetone and subsequently re-polymerized after setting into the micro reliefs produced by tooth etching, it registered the microscopic tooth details on its surface. The peels were mounted and secured on a glass slide and subjected to routine light and phase contrast microscopy for observing captured details of the tooth structure. Results and Conclusion: Acetate peels successfully reproduced most of the microscopic tooth details which were better than those observed in ground tooth sections. Hence, this technique could be considered as a quick, durable and inexpensive alternative or supplement to routine thin ground sections of dental hard tissues.

Sclerosing polycystic adenosis (SPA) is an uncommon entity occurring in the salivary glands, with majority of the cases reported in major salivary glands reminiscent of fibrocystic disease of the breast. SPA arising in minor salivary glands of the oral cavity constitutes an exceedingly rare phenomenon. Here, we report a case of SPA that presented as a solitary, submucosal mass on the left lower labial mucosa in a 19-year-old male. The pathology features and a clinicopathologic diagnostic approach highlighting key features are discussed here. Similar cases published in the English literature are reviewed.

Rhinosporidiosis, is a chronic granulomatous disease presenting as a polypoidal mass in the nasal cavity and nasopharynx caused by Rhinosporidium seeberi and is endemic in India and Sri Lanka. Diagnosis is mainly by clinical observations and is confirmed by histopathology. We report a case of atypical rhinosporidiosis that presented as an oropharyngeal mass and mimicked chronic tonsillitis. Hence possibility of this atypical rhinosporidiosis should be included in the clinical differential diagnosis of any posterior oral or oropharyngeal mass, particularly when managing patients from rural endemic areas.

Ameloblastomas are rare histologically benign, locally aggressive tumors arising from the oral ectoderm that occasionally reach a gigantic size. Giant ameloblastomas are a rarity these days with the advent of panoramic radiography in routine dental practice. Furthermore, the granular cell variant is an uncommon histological subtype of ameloblastoma where the central stellate reticulum like cells in tumor follicles is replaced by granular cells. Although granular cell ameloblastoma (GCA) is considered to be a destructive tumor with a high recurrence rate, the significance of granular cells in predicting its biologic behavior is debatable. However, we present a rare case of giant GCA of remarkable histomorphology showing extensive craniofacial involvement and dural extension that rendered a good prognosis following treatment.

The intriguing array of spindle cell lesions occurring, especially in the head and neck region, poses a critical diagnostic challenge not only to the histopathologist but also ultimately to the clinicians for planning an appropriate treatment protocol. Overlapping spectrum of clinico-radiographic and microscopic features further compounds this problem. In such situations, the aid of ancillary techniques like immunohistochemistry (IHC) is sought to clinch the diagnosis. But is the diagnosis based on IHC most decisive? Probably the answer lies in the Pandora's Box. This paper analyzed the potential doubts, apprehensions and the reliability that is singularly based on the morphological spindle appearance of an abnormal cell that has deviated from the usual clinical and microscopic presentation and thus posed a diagnostic dilemma warranting more questions than the answers. We review the etiopathogenesis of this entity and its differential diagnosis from few other spindle cell lesions of head and neck with special reference to use of immunohistochemical markers, with a case study.

Transformation of a normal cell into a cancerous phenotype is essentially backed by genetic mutations that trigger several oncogenic signaling pathways. These signaling pathways rewire the cellular metabolism to meet the bioenergetic and biomass requirement of proliferating cell, which is different from a quiescent cell. Although the change of metabolism in a cancer cell was observed and studied in the mid-20th century, it was not adequate to explain oncogenesis. Now, equipped with a revolution of oncogenes, we have a genetic basis to explain the transformation. Through several studies, it is clear now that such metabolic alterations not only promote cancer progression but also contribute to the chemoresistance of cancer. Targeting specific enzymes and combinations of enzymes can improve the efficacy of cancer therapy and help to overcome the therapeutic resistance.

aBst RaCt Chondrosarcoma (CS) is an uncommon malignant mesenchymal tumour showing cartilaginous differentiation which rarely presents in the jaws. CS represents 10-20% of all malignant bone tumours and less than 5% of tumours in head and neck region. Among the infrequent subtypes of CS, dedifferentiated CS is a sinister variant that presents with singular features and has extremely poor prognosis. We report a unique case of dedifferentiated CS that presented in the temporomandibular joint (TMJ) with extra articular involvement of the infratemporal space. This high grade CS is reviewed due to its rarity and the dentist is implored to take this variant into account when considering the differential diagnosis of destructive TMJ lesions.

Cancer of the oral cavity and pharynx are the most common type of head and neck cancer with annual global incidence estimated at approximately 480,000 cases. More than 90% of oral cancer cases occur in people older than 45 years. Lesions of gingiva account for approximately 10% of the oral squamous cell carcinomas and may clinically present mimicking as benign or inflammatory lesions, leading to delay in definitive diagnosis and treatment with unfavorable outcome. Present case is a 60 year old male patient who presented with chronic periodontal lesion since the past 6 months. However, a through history, clinical and histopathological examination revealed the lesion to be gingival squamous cell carcinoma and treatment was initiated.

Background: The superiority of dentofacial structures as scientific identifiers, particularly in mass disasters is well known. Special techniques like rugoscopy are valuable not only in identification of skeletal remains but can also facilitate population differentiation, as few studies have shown. Aim: The present study is to classify and compare the differences in rugae shape in populations of Andhra Pradesh and Odisha and to evaluate the discriminatory ability of rugae shape in population differentiation. Materials and Methods: One hundred maxillary casts from each group, equally divided between the sexes and in a narrow age range, were classified as per rugae shapes. The incidence of rugae shape was recorded and their association with ethnicity was tested using Chi-square analysis and step wise discriminant function analysis. All analysis was undertaken using SPSS 16.0 (SPSS Inc., Chicago, Illinois, USA) and MS Excel Package. Results: Straight and nonspecific rugae were most prevalent in Andhra Pradesh, whereas the wavy forms and unifications prevailed in Odisha. A hitherto unknown nonspecific plaque pattern was detected in considerable numbers in Andhra Pradesh population. The accuracy of the discriminant function analysis in differentiating the study populations was 93.5%. Conclusion: Significant differences in rugae shape between the two populations emerged that also allowed a fair differentiation, thus validating previous reports of a good discriminatory ability of rugae shapes. Perhaps, more studies in genetically diverse populations as in India could also unearth new rugae patterns and further the identification process.