CMTM6 attenuates cisplatin-induced cell death in OSCC by regulating AKT/c-Myc-driven ribosome biogenesis.

CMTM6, a type 3 transmembrane protein, is known to stabilize the expression of programmed cell death ligand 1 (PD-L1) and hence facilitates the immune evasion of tumor cells. Recently, we demonstrated that CMTM6 is a major driver of cisplatin resistance in oral squamous cell carcinomas (OSCC). However, the detailed mechanism of how CMTM6 rewires cisplatin resistance in OSCC is yet to be explored. RNA sequencing analysis of cisplatin-resistant OSCC lines stably expressing Nt shRNA and CMTM6 shRNA revealed that CMTM6 might be a potential regulator of the ribosome biogenesis network. Knocking down CMTM6 significantly inhibited transcription of 47S precursor rRNA and hindered the nucleolar structure, indicating reduced ribosome biogenesis. When CMTM6 was ectopically over-expressed in CMTM6KD cells, almost all ribosomal machinery components were rescued. Mechanistically, CMTM6 induced the expression of C-Myc, which promotes RNA polymerase I mediated rDNA transcription. In addition to this, CMTM6 was also found to regulate the AKT-mTORC1-dependent ribosome biogenesis and protein synthesis in cisplatin-resistant lines. The nude mice and zebrafish xenograft experiments indicate that blocking ribosome synthesis either by genetic inhibitor (CMTM6KD) or pharmacological inhibitor (CX-5461) significantly restores cisplatin-mediated cell death in chemoresistant OSCC. Overall, our study suggests that CMTM6 is a major regulator of the ribosome biogenesis network and targeting the ribosome biogenesis network is a viable target to overcome chemoresistance in OSCC. The novel combination of CX-5461 and cisplatin deserves further clinical investigation in advanced OSCC.

RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway.

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.

DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG.

Platinum based drugs alone or in combination with 5FU and docetaxel are common regimen chemotherapeutics for the treatment of advanced OSCC. Chemoresistance is one of the major factors of treatment failure in OSCC. Human RNA helicase DDX3 plays an important role in cell proliferation, invasion, and metastasis in several neoplasms. The potential role of DDX3 in chemoresistance is yet to be explored. Enhanced cancer stem cells (CSCs) population significantly contributes to chemoresistance and recurrence. A recent study showed that m6A RNA regulates self-renewal and tumorigenesis property in cancer. In this study we found genetic (shRNA) or pharmacological (ketorolac salt) inhibition of DDX3 reduced CSC population by suppressing the expression of FOXM1 and NANOG. We also found that m6A demethylase ALKBH5 is directly regulated by DDX3 which leads to decreased m6A methylation in FOXM1 and NANOG nascent transcript that contribute to chemoresistance. Here, we found DDX3 expression was upregulated in both cisplatin-resistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. In a patient-derived cell xenograft model of chemoresistant OSCC, ketorolac salt restores cisplatin-mediated cell death and facilitates a significant reduction of tumor burdens. Our work uncovers a critical function of DDX3 and provides a new role in m6 demethylation of RNA. A combination regimen of ketorolac salt with cisplatin deserves further clinical investigation in advanced OSCC.

STAT3- and GSK3ß-mediated Mcl-1 regulation modulates TPF resistance in oral squamous cell carcinoma.

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 (GSK3ß) 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.

Evaluation of micrometastasis and isolated tumor cells in node-negative early-stage oral tongue squamous cell carcinoma: a cross-sectional study in tertiary-level hospitals in eastern India.

OBJECTIVE: The present study aimed to investigate the incidence of micrometastasis (MMs) and isolated tumor cells (ITCs) in node-negative early-stage oral tongue squamous cell carcinoma (T1-T2 N0). The secondary objective was to correlate the incidence with the clinicopathologic parameters of age, sex, depth of invasion, pattern of invasion, host lymphocytic response, and size and grade of primary tumor. STUDY DESIGN: Micrometastasis and ITCs in cervical nodes of 30 patients with early-stage oral tongue squamous cell carcinoma were detected and compared using 3 methods: routine hematoxylin and eosin staining, serial-sectioning at intervals of 150 microns employing hematoxylin and eosin, and serial sectioning pan-cytokeratin immunostaining. Associations with clinicopathological variables were analyzed. RESULTS: Metastatic tumor cells were detected in the cervical nodes of 2 patients using serial sectioning and immunohistochemistry, resulting in upstaging of 6.6% of all cases. Level I and II lymph nodes were primarily involved. CONCLUSIONS: Early-stage oral tongue squamous cell carcinoma has a significant potential for MMs that frequently go undetected in routine histopathologic examination. However, laborious and technique-sensitive, serial sectioning in combination with pan-cytokeratin staining (AE1/AE3) may aid in detecting MMs and ITCs in patients with early-stage OTSCC.

Immunohistochemical evaluation of yes-associated protein molecule in the odontogenic epithelium of different histopathological variants of ameloblastoma and unicystic ameloblastoma.

Background: Ameloblastoma is one of the major odontogenic neoplasms with an invasive and recurrence potential. Its tumourigenesis and proliferative capacity can be attributed to the activation or inactivation of certain molecular signalling pathways. Hippo signalling pathway is known to regulate diverse physiological processes related to mitosis and organ growth and is an emerging tumour suppressor pathway, the dysfunction of which is implicated in various diseases including cancers. Yes-associated protein1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the downstream effectors in the Hippo cascade, which on nuclear activation leads to cellular proliferation in various tumours. Aim: The current study was undertaken to evaluate the expression of YAP in various histopathological variants of ameloblastoma and unicystic ameloblastoma. Materials and Methods: Fifty formalin-fixed paraffin-embedded tissue samples of histopathologically diagnosed cases of ameloblastoma, and 10 histopathologically diagnosed cases of unicystic ameloblastoma were obtained from the departmental archives to evaluate the immunohistochemical expression of YAP both manually and by software analysis. Results: More than 90% of cases of conventional ameloblastoma and unicystic ameloblastoma elicited positive expression of YAP. No statistical difference was found among different histopathological variants of conventional ameloblastoma. Significant difference between the means of all four quantitative score groups was observed. Conclusion: In view of the modulating effect of YAP in tumourigenesis and its higher expression in ameloblastoma, further exploration of this molecule appears to be a promising area of research.

Understanding the approach to interpretation and challenges in measurement of pathological depth of invasion in oral squamous cell carcinoma: A cross-sectional survey of oral and maxillofacial pathologists in India.

Objectives: To understand the approach to interpretation along with challenges encountered in assessing pathological depth of invasion (pDOI) in oral squamous cell carcinoma (OSCC) as per 8th Edition of TNM-AJCC staging among oral and maxillofacial pathologists in India. Method and Materials: A cross-sectional web-based survey was conducted (May 2021-October 2021) with a pre-validated 21-item questionnaire. Responses were stored in a Microsoft Excel worksheet and analysed by descriptive statistics using SPSS v 25.0. Results: About 69.7% of the 267 respondents correctly defined pDOI while 13.1% measured the same from tumour surface. Among those not reporting pDOI, one-third of respondents (36.6%) lacked requisite awareness about 8th edition staging while more than half of them (55.4%) lacked proper tools to measure. The vst majority of the oral pathologists found pDOI measurement practically challenging (85.8%), mostly with difficulty in obtaining adjacent normal mucosa (77.9%). Selection of reference points of adjacent normal mucosa was divided between deepest point of rete ridge (43.1%), the closest rete ridge (28.8%) and the tip of highest submucosal papilla (15%). Conclusion: Underreporting of pDOI was observed owing to inherent challenges in measurement, thus ostensibly substituted with tumour thickness. Elaboration on reference points of adjacent normal mucosa is awaited.

Sexual dimorphism of inferior alveolar canal location: A record- based CBCT Study in Eastern India.

Background: 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. Aim: 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. Method and Materials: 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 at P < 0.05 level of significance. Results: The results revealed statistically significant differences (P < 0.05) between the genders in most of the variables (8/10), with higher mean values in males compared to females except in the distance between mandibular foramen and anterior border of the ramus (2.648 ± 0.67 mm in females, 2.527 ± 0.75 mm in males) and in the distance between the canal and lingual cortical plate in the region of the first molar (14.515 ± 1.33 mm in females, 14.288 ± 2.01 mm in males). Conclusion: The relative position of the mandibular canal and its associated foramina show sexual dimorphism in an adult eastern Indian population.

Interaction between peritumoral reactivity and histomorphological pattern of lymph node reactivity in oral squamous cell carcinoma: A host immune status indicator.

Background: 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. Aim: 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. Materials and Methods: 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. Results: 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). Conclusion: This study supports the presence of a strong immunological host-tumor relationship.

Histomorphometric Analysis of Residual Alveolar Ridge Preserved using Collagen Cell Occlusive Membrane Alone and Along with Demineralized Bone Matrix Following Tooth Extraction: A Randomized Control Trial.

Context: The changes in the volume and dimensions of the alveolar bone after tooth extraction often lead to challenges in prosthetic rehabilitation of the same necessitating ridge preservation procedures (RPP). Aim: The aim of this randomized clinical trial was to evaluate and compare the dimensional and histomorphometric changes of the sites preserved using the collagen membrane with and without demineralized bone matrix (DMBM). Settings and Design: Interventional, parallel-design, double blinded, randomized controlled trail. Materials and Methods: A randomized controlled trial was designed with 45 participants having at least 2 teeth indicated for were enrolled in this study. The sites were randomly assigned to the control group (RPP using collagen membrane) and the test group (RPP using collagen membrane with DMBM). The clinical parameters assessed were alveolar bone width and alveolar bone height. Histomorphometric analysis was carried out on tissue trephined from the preserved sites to evaluate the percentage of bone and connective tissue (CT %) formed 8 months postRPP. Statistical Analysis Used: Shapiro - Wilk test and paired and unpaired t-test. Results: Horizontal resorption was significantly less in the test group (7.375 ± 1.64). Histomorphometry of these sites revealed a complete absence of residual graft particles, presence of trabecular bone, and a more mineralized matrix (63.256%) as compared to the control sites (46.833%). Conclusions: The use of DMBM along with the collagen membrane for RPP yielded better results both clinically and histomorphometically.

CRISPR-based kinome-screening revealed MINK1 as a druggable player to rewire 5FU-resistance in OSCC through AKT/MDM2/p53 axis.

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-responders as compared to chemotherapy responders. The nude mice and zebrafish 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. The patient derived TPF resistant 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.

Peels as an alternative to ground sections - An in vitro microscopic study.

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.

CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3ß axis.

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-3ß. 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.

SARI inhibits growth and reduces survival of oral squamous cell carcinomas (OSCC) by inducing endoplasmic reticulum stress.

AIMS: SARI (suppressor of activator protein (AP)-1, regulated by interferon (IFN) was identified as a novel tumor suppressor by applying subtraction hybridization to terminally differentiating human melanoma cells. The anti-tumor activity of SARI and the correlation between expression and cancer aggression and metastasis has been examined in multiple cancers, but its potential role in oral squamous cell carcinomas (OSCC) has not been explored. METHODS: SARI expression was monitored in tumor tissues of OSCC patients by performing immunohistochemistry. Ectopic expression of SARI was achieved using a replication defective adenovirus expressing SARI (Ad.SARI). A nude mouse xenograft model was used to evaluate the in vivo efficacy of SARI. Endoplasmic reticulum (ER) stress was monitored in SARI infected OSCC cells by confocal microscopy. KEY FINDING: In this study, we demonstrate that SARI expression is significantly lower in OSCC tumor tissue as compared to normal adjacent tissue. Ectopic expression of SARI induces cancer-specific cell death in human OSCC cell lines and in a paclitaxel plus cisplatin non-responder OSCC patient-derived (PDC1) cell line. Mechanistically, SARI inhibits zinc finger protein GLI1 expression through induction of endoplasmic reticulum (ER) stress. Using a nude mouse xenograft model, we show that intratumoral injections of Ad.SARI significantly reduce PDC1 tumor burden, whereas treatment with an ER stress inhibitor efficiently rescues tumors from growth inhibition. SIGNIFICANCE: Overall, our data provides a link between induction of ER stress and inhibition of the GLI1/Hedgehog signaling pathway and the tumor suppressive activity of SARI in the context of OSCC.

Sclerosing polycystic adenosis of minor salivary glands: Report of a rare case with diagnostic approach and review of literature.

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.

Bcl-2 Antiapoptotic Family Proteins and Chemoresistance in Cancer.

Cancer is a daunting global problem confronting the world's population. The most frequent therapeutic approaches include surgery, chemotherapy, radiotherapy, and more recently immunotherapy. In the case of chemotherapy, patients ultimately develop resistance to both single and multiple chemotherapeutic agents, which can culminate in metastatic disease which is a major cause of patient death from solid tumors. Chemoresistance, a primary cause of treatment failure, is attributed to multiple factors including decreased drug accumulation, reduced drug-target interactions, increased populations of cancer stem cells, enhanced autophagy activity, and reduced apoptosis in cancer cells. Reprogramming tumor cells to undergo drug-induced apoptosis provides a promising and powerful strategy for treating resistant and recurrent neoplastic diseases. This can be achieved by downregulating dysregulated antiapoptotic factors or activation of proapoptotic factors in tumor cells. A major target of dysregulation in cancer cells that can occur during chemoresistance involves altered expression of Bcl-2 family members. Bcl-2 antiapoptotic molecules (Bcl-2, Bcl-xL, and Mcl-1) are frequently upregulated in acquired chemoresistant cancer cells, which block drug-induced apoptosis. We presently overview the potential role of Bcl-2 antiapoptotic proteins in the development of cancer chemoresistance and overview the clinical approaches that use Bcl-2 inhibitors to restore cell death in chemoresistant and recurrent tumors.

Assessment of Demirjian's 8-teeth technique of age estimation and Indian-specific formulas in an East Indian population: A cross-sectional study.

BACKGROUND: The age of an individual can be assessed by a plethora of widely available tooth-based techniques, among which radiological methods prevail. The Demirjian's technique of age assessment based on tooth development stages has been extensively investigated in different populations of the world. AIM: The present study is to assess the applicability of Demirjian's modified 8-teeth technique in age estimation of population of East India (Odisha), utilizing Acharya's Indian-specific cubic functions. MATERIALS AND METHODS: One hundred and six pretreatment orthodontic radiographs of patients in an age group of 7-23 years with representation from both genders were assessed for eight left mandibular teeth and scored as per the Demirjian's 9-stage criteria for teeth development stages. Age was calculated on the basis of Acharya's Indian formula. Statistical analysis was performed to compare the estimated and actual age. All data were analyzed using SPSS 20.0 (SPSS Inc., Chicago, Illinois, USA) and MS Excel Package. RESULTS: The results revealed that the mean absolute error (MAE) in age estimation of the entire sample was 1.3 years with 50% of the cases having an error rate within ± 1 year. The MAE in males and females (7-16 years) was 1.8 and 1.5, respectively. Likewise, the MAE in males and females (16.1-23 years) was 1.1 and 1.3, respectively. CONCLUSION: The low error rate in estimating age justifies the application of this modified technique and Acharya's Indian formulas in the present East Indian population.

Alteration of cellular metabolism in cancer cells and its therapeutic prospects.

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.

Multifocal Head and Neck Neurofibromas with Osseous Abnormalities and Muscular Hypoplasia in a Child with Neurofibromatosis: Type I.

Neurofibromatosis type 1 (NF1) is a clinically and genetically distinct disease involving both neuroectodermal and mesenchymal derivatives. Orofacial manifestations in NF1 have been documented before but occurrence of multifocal intraosseous (IO) and extraosseous (EO) neurofibromas is rare. The present case highlights the importance of imaging findings in the diagnosis and management of multifocal jaw, infratemporal, and parotid neurofibromas with muscular hypoplasia in an eight-year-old girl with NF1. Apart from orthopantomograms (OPG), three-dimensional computed tomography (3D CT) and cross-sectional reformations were valuable in delineating the extent of the lytic lesion and identifying additional bony deformities of the mandible. Magnetic resonance imaging (MRI) helped to identify the solid nature of the lesion and true extent of the soft tissue mass.