Recurrent UBE3C-LRP5 translocations in head and neck cancer with therapeutic implications.

Head and neck cancer is a major cause of morbidity and mortality worldwide. The identification of genetic alterations in head and neck cancer may improve diagnosis and treatment outcomes. In this study, we report the identification and functional characterization of UBE3C-LRP5 translocation in head and neck cancer. Our whole transcriptome sequencing and RT-PCR analysis of 151 head and neck cancer tumor samples identified the LRP5-UBE3C and UBE3C-LRP5 fusion transcripts in 5.3% of patients of Indian origin (n = 151), and UBE3C-LRP5 fusion transcripts in 1.2% of TCGA-HNSC patients (n = 502). Further, whole genome sequencing identified the breakpoint of UBE3C-LRP5 translocation. We demonstrate that UBE3C-LRP5 fusion is activating in vitro and in vivo, and promotes the proliferation, migration, and invasion of head and neck cancer cells. In contrast, depletion of UBE3C-LRP5 fusion suppresses the clonogenic, migratory, and invasive potential of the cells. The UBE3C-LRP5 fusion activates the Wnt/ß-catenin signaling by promoting nuclear accumulation of ß-catenin, leading to upregulation of Wnt/ß-catenin target genes, MYC, CCND1, TCF4, and LEF1. Consistently, treatment with the FDA-approved drug, pyrvinium pamoate, significantly reduced the transforming ability of cells expressing the fusion protein and improved survival in mice bearing tumors of fusion-overexpressing cells. Interestingly, fusion-expressing cells upon knockdown of CTNNB1, or LEF1 show reduced proliferation, clonogenic abilities, and reduced sensitivity to pyrvinium pamoate. Overall, our study suggests that the UBE3C-LRP5 fusion is a promising therapeutic target for head and neck cancer and that pyrvinium pamoate may be a potential drug candidate for treating head and neck cancer harboring this translocation.

Assessment of quality of life in thyroid cancer patients using the EORTC thyroid-specific questionnaire: a prospective cross-sectional study.

BACKGROUND: Many studies on the quality of life (QoL) among the thyroid cancer survivors have shown conflicting results. This may be since many of these studies have not used thyroid cancer-specific questionnaires. PATIENTS AND METHODS: In our study we have translated the EORTC THY-34, validated and served it in a cross-sectional study to the assess the QoL among thyroid cancer patients free of disease during their routine follow-up. Patients were categorized based on the duration from treatment completion, ATA risk stratification, treatment received, number of RAI sessions and thyroid function status during analysis. RESULTS: Overall, 220 thyroid cancer survivors were included in this study. In general, in the EORTC QLQ-C30, the global QoL of thyroid cancer patients were good with a mean score of 72.99. The highest score was that for social functioning (89.55). In the EORTC-THY34 all the patients in the cohort had relatively lower scores (on symptom scales). Overall, there was no difference in the QLQ-C30 and THY-34 QoL with respect to any of the categorization mentioned above. However, our thyroid cancer patients QoL scores were better and/or comparable to those in published literature and they were also better or comparable to the QoL of the general population those were available in literature. CONCLUSIONS: There was no difference in the QoL scores based on various categories. To better understand the quality of life of these patients a prospective longitudinal study with baseline values and values at regular intervals might give us a better insight.

Osteomielite maxilar associada ao COVID-19: mucormicose ou não? Uma série de casos / Maxillary osteomyelitis associated with COVID-19: mucormycosis or not? A series of cases

Aim: A series of cases have been presented involving the oral cavity focusing on the presentation, diagnosis and treatment of mucormycosis that can form a basis for successful therapy. Background: The management of severe coronavirus disease (COVID-19) in conjunction with comorbidities such as diabetes mellitus, hematological malignancies, organ transplants, and immunosuppression have led to a rise of mucormycosis which is an opportunistic infection. Cases Description: The various forms that have been enlisted till date are rhino-cerebral, rhino-orbital, gastrointestinal, cutaneous, and disseminated mucormycosis. From the dentistry and maxillofacial surgery perspective, the cases depicting extension of mucormycosis into the oral cavity have been less frequently recorded and thus, require a detailed study. The patients that reported to our private practice had non-tender swelling, draining sinuses and mobility of teeth. A similarity was observed in the clinical signs both in osteomyelitis and mucormycosis. Thus, a histopathological examination was used to establish the definitive diagnosis. Conclusion: Mucormycosis is a life threatening pathology that requires intervention by other branches to make an early diagnosis and commence the treatment. The characteristic ulceration or necrosis is often absent in the initial stage and thus, histopathological examination and radiographic assessment are required to formulate a definitive diagnosis. Early intervention is a necessity to avoid morbidity. The treatment involves surgical debridement of the necrotic infected tissue followed by systemic antifungal therapy. Mucormycosis has recently seen a spike in its prevalence, post the second-wave of coronavirus pandemic in India. It was seen commonly in patients with compromised immunity, diabetes mellitus, hematological malignancies, or on corticosteroid therapy. Mucormycosis invading the palate mostly via maxillary sinus has been less frequently described. In the post-COVID era the features associated with mucormycosis involving oral cavity, should warrant a possible differential diagnosis and managed appropriately. (AU)

Objetivo: Apresentar uma série de casos com enfâse na apresentação, diagnóstico e tratamento da mucormicose oral, assim como uma revisão sistemática que sirva como base para estabelecimento de terapias de sucesso. Introdução: A forma severa da infecção por coronavirus (COVID-19) associada a diabetes mellitus, doenças hematológicas malignas, transplante de órgãos e imunossupressão levaram a um aumento das infecções oportunistas de mucormicose. Descrição dos Casos: As diversas apresentações clínicas que foram descritas até o momento são a rinocerebral, rino-orbital, gastrointestinal, cutânea e mucormicose disseminada. No que concerne a odontologia e a cirurgia maxillofacial, os casos que apresentam extensão de mucormicose para cavidade oral tem sido menos reportados e assim requerem mais estudos. Os pacientes que compareceram a nossa clínica apresentavam aumento de volume endurecido, drenagem de fluidos dos seios maxilares e mobilidade dentária. Clinicamente tanto a osteomielite quanto a mucormicose apresentaram-se de forma semelhante. Assim, análise histopatológica foi utilizada para estabelecimento do diagnóstico definitivo. Conclusão: A mucormicose é uma patologia grave que requer intervenção precoce para estabelecimento do tratamento. A ulceração e necrose características usualmente estão ausentes nos estágios iniciais da lesão, assim análise histopatológica e radiográfica são necessárias para o diagnóstico final. Intervenção precoce é necessária para diminuir a morbidade. O tratamento envolve o debridamento cirúrgico da área necrosada seguida de terapia antifúngica sistêmica. Recentemente, houve um aumento nos casos de mucormicose, após a Segunda onda da pandemia de COVID-19 na índia. Os casos acometiam principalmente pacientes imunocomprometidos, com diabetes mellitus, doenças hematológicas malignas e em uso de corticosteróides. A mucormicose invadindo o palato pelos seios maxilares foi raramente descrita. Na era pós-COVID a mucormicose envolvendo a cavidade oral deve entrar no painel de diagnósticos diferenciais para que o tratamento adequado possa ser instituído precocemente.(AU)

Role of miR-944/MMP10/AXL- axis in lymph node metastasis in tongue cancer.

Occult lymph-node metastasis is a crucial predictor of tongue cancer mortality, with an unmet need to understand the underlying mechanism. Our immunohistochemical and real-time PCR analysis of 208 tongue tumors show overexpression of Matrix Metalloproteinase, MMP10, in 86% of node-positive tongue tumors (n = 79; p < 0.00001). Additionally, global profiling for non-coding RNAs associated with node-positive tumors reveals that of the 11 significantly de-regulated miRNAs, miR-944 negatively regulates MMP10 by targeting its 3'-UTR. We demonstrate that proliferation, migration, and invasion of tongue cancer cells are suppressed by MMP10 knockdown or miR-944 overexpression. Further, we show that depletion of MMP10 prevents nodal metastases using an orthotopic tongue cancer mice model. In contrast, overexpression of MMP10 leads to opposite effects upregulating epithelial-mesenchymal-transition, mediated by a tyrosine kinase gene, AXL, to promote nodal and distant metastasis in vivo. Strikingly, AXL expression is essential and sufficient to mediate the functional consequence of MMP10 overexpression. Consistent with our findings, TCGA-HNSC data suggests overexpression of MMP10 or AXL positively correlates with poor survival of the patients. In conclusion, our results establish that the miR-944/MMP10/AXL- axis underlies lymph node metastases with potential therapeutic intervention and prediction of nodal metastases in tongue cancer patients.

Expression of Gata Binding Protein 3 as a Prognostic Factor in Urogenital Lesions and Its Association With Morphology.

BACKGROUND: Urogenital malignancies, encompassing urinary bladder cancer, prostate cancer, and renal cell carcinoma, pose significant diagnostic challenges due to overlapping histopathological features. GATA binding protein 3 (GATA3), a transcription factor associated with urothelial tissue, has shown promise as a potential diagnostic marker. This study aimed to investigate the incidence of these malignancies, explore GATA3's involvement in urothelial cancer (UC), and determine its role in distinguishing urogenital malignancies. MATERIALS AND METHODS: A cross-sectional, retro-prospective, hospital-based study was conducted from May 2019 to April 2021. The surgical samples of patients who underwent transurethral resection of bladder tumour (TURBT), transurethral resection of the prostate (TURP), radical cystoprostatectomy, total and partial radical nephrectomy specimens during the study period were reviewed. Patients diagnosed with urinary bladder neoplasm and high-grade prostate neoplasm along with chromophobe, oncocytic, sarcomatoid variant and clear cell carcinoma, renal cell carcinoma were included. Immunohistochemical analysis of GATA3 expression was performed, with scoring based on nuclear staining intensity and percentage of tumor cells labeled. RESULTS: The study included 64 patients, predominantly males over 60 years. Personal habits revealed a high prevalence of smoking (85.9%). The most prevalent symptom was hematuria (75.0%), followed by hematuria with urgency (20.3%). The most common site of lesion was posterolateral (31.3%). Urothelial cancer was the most common malignancy, primarily high-grade. Strong positive GATA3 expression was significantly associated with high-grade UC (p=0.01) and invasion (p=0.01). However, low-grade UC and papillary urothelial neoplasm of low malignant potential exhibited moderate GATA3 expression. GATA3 demonstrated potential for distinguishing UC from other histological types. CONCLUSION: GATA3 expression correlates with high-grade urothelial cancer and invasive behavior, suggesting its utility as a diagnostic marker in challenging cases.

Identifying cancer driver genes from functional genomics screens.

With the emerging advances made in genomics and functional genomics approaches, there is a critical and growing unmet need to integrate plural datasets in order to identify driver genes in cancer. An integrative approach, with the convergence of multiple types of genetic evidence, can limit false positives through a posterior filtering strategy and reduce the need for multiple hypothesis testing to identify true cancer vulnerabilities. We performed a pooled shRNA screen against 906 human genes in the oral cancer cell line AW13516 in triplicate. The genes that were depleted in the screen were integrated with copy number alteration and gene expression data and ranked based on ROAST analysis, using an integrative scoring system, DepRanker, to compute a Rank Impact Score (RIS) for each gene. The RIS-based ranking of candidate driver genes was used to identify the putative oncogenes AURKB and TK1 as essential for oral cancer cell proliferation. We validated the findings, showing that shRNA mediated genetic knockdown of TK1 or pharmacological inhibition of AURKB by AZD-1152 HQPA in AW13516 cells could significantly impede their proliferation. Next we analysed alterations in AURKB and TK1 genes in head and neck cancer and their association with prognosis using data on 528 patients obtained from TCGA. Patients harbouring alterations in AURKB and TK1 genes were associated with poor survival. To summarise, we present DepRanker as a simple yet robust package with no third-party dependencies for the identification of potential driver genes from a pooled shRNA functional genomic screen by integrating results from RNAi screens with gene expression and copy number data. Using DepRanker, we identify AURKB and TK1 as potential therapeutic targets in oral cancer. DepRanker is in the public domain and available for download at http://www.actrec.gov.in/pi-webpages/AmitDutt/DepRanker/DepRanker.html.

Customized Implant Full-Mouth Rehabilitation: A Biomechanical Depiction.

The rationale for implant full-mouth rehabilitation is believed to present the better quality of life to the older population. This type of modalities preserves the soft and hard tissue of oral cavity. It is also helpful to check the temporomandibular joint disease. Literature exposes that implant full-mouth fixed rehabilitation is one of the taxing procedures in the field of prosthodontics. The current clinical report discusses a customized biomechanical approach for the fabrication of implant complete-mouth rehabilitation. A systematic approach in managing this patient can lead to a predictable and favorable prognosis. This article also presents the stages of prosthodontic rehabilitation from diagnosis to final treatment planning as a customized radiographical Gutta Percha template, precise implant surgery of 12 implants (ADIN, Dental Implant System, Israel) over the both the arches and provisional restorations with group function occlusion. Lastly, full-mouth restorations were fabricated as cement-retained (open hole) metal-ceramic restoration. Advocated patient is absolutely happy with customized implant full-mouth rehabilitation.