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The cell population within the periodontal ligament (PDL) tissue is remarkably heterogeneous1. Fibroblasts, a mixed population of cells, are the main cellular component of the PDL and the cell type most often studied for periodontal regeneration. Osteoblasts and osteoclasts are found on the bone side, while fibroblasts, macrophages, undifferentiated adult/mesenchymal stem cells, neural elements, and endothelial cells are found throughout the PDL. Epithelial rests of Malassez cells and cementoblasts are focused near the root surface. PDL tissue also includes loose connective tissue between dense fiber bundles that contain branches of the periodontal blood vessels and nerves2. The complexity of the PDL tissue, with its various cell types and cell progenitor components, explains the challenges involved in therapies to restore tissue following periodontal disease. Cementoblasts, osteoblasts, and endothelial cells must migrate, differentiate, and coordinately interact with a variety of soluble mediators to regenerate the periodontium3. Stem cells located in the PDL tissue are key contributors to this process4. Stem cells in the PDL are important not only for formation and maintenance of the tissue but also for repair, remodeling, and regeneration of adjacent alveolar bone and cementum5. Our laboratory has shown that progenitor cells isolated from PDL tissue by selection with cell surface markers STRO-1+ and CD146+ are capable of differentiating into chondrogenic, osteogenic, and adipogenic phenotypes under appropriate culture conditions

Perineural invasion is a phenotype in which cancer surrounds or invades the nerves. It is associated with poor clinical outcome for head and neck squamous cell carcinoma and other cancers. Mechanistic studies have shown that the molecular crosstalk between nerves and tumor cells occurs prior to physical interaction. There are only a few in vivo models to study perineural invasion, especially to investigate early progression, before physical nerve-tumor interactions occur. The chick chorioallantoic membrane model has been used to study cancer invasion, because the basement membrane of the chorionic epithelium mimics that of human epithelial tissue. Here we repurposed the chick chorioallantoic membrane model to investigate perineural invasion, grafting rat dorsal root ganglia and human head and neck squamous cell carcinoma cells onto the chorionic epithelium. We have demonstrated how this model can be useful to evaluate the ability of cancer cells to invade neural tissue in vivo.

Perineural invasion (PNI) is a mechanism of tumor dissemination that can provide a challenge to tumor eradication and that is correlated with poor survival. Squamous cell carcinoma, the most common type of head and neck cancer, has a high prevalence of PNI. This review provides an overview of clinical studies on the outcomes and factors associated with PNI in head and neck cancer and on findings on cancer-nerve crosstalk.

Background: In this study, we use a bioinformatics-based strategy to nominate a tumor suppressor gene cadherin-11 (CDH11) and investigate its role in growth and invasion in head and neck squamous cell carcinoma (HNSCC)., Methods: Using the Oncomine ™ database to compare HNSCC and normal specimens, CDH11 was nominated as having a role in HNSCC. CDH11 expression in HNSCC was evaluated by immunohistochemistry on a tissue microarray (TMA) and immunoblotting and immunofluorescence of cell lines. The functional impact of CDH11 on proliferation and invasion was evaluated after siRNA-mediated knockdown., Results: In silico analysis suggested that CDH11 is overexpressed in HNSCC compared to normal specimens. HNSCC TMA exhibited a small but significant increase in intensity and proportion of CDH11. By immunoblot analysis, CDH11 was higher in 4/7 HNSCC cell lines compared to normal keratinocytes; CDH11 was highly upregulated in UM-SCC-47 and UM-SCC-74A and detectable in UM-SCC-14A and UM-SCC-29 cell lines. Downregulation of CDH11 in both UM-SCC-29 and UM-SCC-47 using two different siRNAs enhanced proliferation and invasion., Conclusion: CDH11 inhibits cell proliferation and invasion of HNSCC. This suggests that CDH11 functions as a tumor suppressor gene in head and neck cancer. Our findings emphasize the importance of verifying in silico findings with functional studies., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Perineural invasion (PNI) is an indicator of poor survival in multiple cancers. Unfortunately, there is no targeted treatment for PNI since the molecular mechanisms are largely unknown. PNI is an active process, suggesting that cancer cells communicate with nerves. However, nerve-tumour crosstalk is understudied due to the lack of in vivo models to investigate the mechanisms. Here we developed an in vivo model of PNI to characterize this interaction. We show that the neuropeptide galanin (GAL) initiates nerve-tumour crosstalk via activation of its G protein-coupled receptor, GALR2. Our data reveal a novel mechanism by which GAL from nerves stimulates GALR2 on cancer cells to induce NFATC2-mediated transcription of cyclooxygenase-2 and GAL. Prostaglandin E2 promotes cancer invasion, and in a feedback mechanism, GAL released by cancer induces neuritogenesis, facilitating PNI. This study describes a novel in vivo model for PNI and reveals the dynamic interaction between nerve and cancer.

Head and neck squamous cell carcinomas (HNSCC) are malignant tumors that arise from the surface epithelium of the oral cavity, oropharynx and larynx, primarily due to exposure to chemical carcinogens or the human papilloma virus. Due to their location, dental practitioners are well-positioned to detect the lesions. Deadlier than lymphoma or melanoma, HNSCC is incompletely understood. For these reasons, dental practitioners and researchers are focused on understanding HNSCC and the processes driving it. One of these critical processes is invasion, the degradation of the basement membrane by HNSCC cells with subsequent movement into the underlying connective tissue, blood vessels or nerves. Cancer cells metastasize to distant sites via the blood vessels, lymphatics and nerves. Metastasis is associated with poor survival. Since invasion is essential for development and metastasis of HNSCC, it is essential to understand the mechanism(s) driving this process. Elucidation of the mechanisms involved will facilitate the development of targeted treatment, thereby accelerating development of precision/personalized medicine to treat HNSCC. Robust in vitro and in vivo assays are required to investigate the mechanistic basis of invasion. This review will focus on in vitro and in vivo assays used to study invasion in HNSCC, with special emphasis on some of the latest assays to study HNSCC., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Roburic acid (ROB) is a newly discovered tetracyclic triterpene acid extracted from oak galls, which has anti-inflammatory effects, but the mechanism of its anticancer effect is not clear. Our study focuses on exploring the potential mechanism of action of ROB in the treatment of lung cancer using a combination of network pharmacological prediction, molecular docking technique and experimental validation. Methods: A network pharmacology approach was used to screen the protein targets of ROB and lung cancer, and PPI network analysis and enrichment analysis were performed on the intersecting genes. The tissue and organ distribution of the targets was also evaluated based on the BioGPS database. To ensure the reliability of the network pharmacology prediction results, we proceeded to use molecular docking technique to determine the relationship between drugs and targets. Finally, in vitro experiments with cell lines were performed to further reveal the potential mechanism of ROB for the treatment of lung cancer. Results: A total of 83 potential targets of ROB in lung cancer were collected and further screened by using Cytoscape software, and 7 targets of PTGS2, CYP19A1, PTGS1, AR, CYP17A1, PTGES and SRD5A1 were obtained as hub genes and 7 hub targets had good binding energy with ROB. GO and KEGG analysis showed that ROB treatment of lung cancer mainly involves Arachidonic acid metabolism, Notch signaling pathway, cancer pathway and PPAR signaling pathway. The results of in vitro experiments indicated that ROB may inhibit the proliferation and metastasis of lung cancer cells and activate the PPARg signaling pathway, as well as induce cellular autophagy. Conclusions: The results of this study comprehensively elucidated the potential targets and molecular mechanisms of ROB for the treatment of lung cancer, providing new ideas for further lung cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Colon cancer, a frequently encountered malignancy, exhibits a comparatively poor survival prognosis. Perineural invasion (PNI), highly correlated with tumor progression and metastasis, is a substantial effective predictor of stage II-III colon cancer. Nonetheless, the lack of effective and facile predictive methodologies for detecting PNI prior operation in colon cancer remains a persistent challenge. Method: Pre-operative computer tomography (CT) images and clinical data of patients diagnosed with stage II-III colon cancer between January 2015 and December 2023 were obtained from two sub-districts of Sun Yat-sen Memorial Hospital (SYSUMH). The LASSO/RF/PCA filters were used to screen radiomics features and LR/SVM models were utilized to construct radiomics model. A comprehensive model, shown as nomogram finally, combining with radiomics score and significant clinical features were developed and validated by area under the curve (AUC) and decision curve analysis (DCA). Result: The total cohort, comprising 426 individuals, was randomly divided into a development cohort and a validation cohort as a 7:3 ratio. Radiomics scores were extracted from LASSO-SVM models with AUC of 0.898/0.726 in the development and validation cohorts, respectively. Significant clinical features (CA199, CA125, T-stage, and N-stage) were used to establish combining model with radiomics scores. The combined model exhibited superior reliability compared to single radiomics model in AUC value (0.792 vs. 0.726, p = 0.003) in validation cohorts. The radiomics-clinical model demonstrated an AUC of 0.918/0.792, a sensitivity of 0.907/0.813 and a specificity of 0.804/0.716 in the development and validation cohorts, respectively. Conclusion: The study developed and validated a predictive nomogram model combining radiomics scores and clinical features, and showed good performance in predicting PNI pre-operation in stage II-III colon cancer patients. [ABSTRACT FROM AUTHOR]

Bruton tyrosine kinase inhibitor (BTKi) combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is the major cause of relapse and death of DLBCL. In this study, we conducted a comprehensive analysis BTKi-resistance related genes (BRRGs) and established a 10-gene (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) signature for early identifying high-risk DLBCL patients. The resistance scores based on the BRRGs signature were associated with prognosis. Furthermore, we developed a nomogram incorporating the BRRGs signature, which demonstrated excellent performance in predicting the prognosis of DLBCL patients. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Additionally, we identified TRIP13 as a key gene in our model. TRIP13 was found to be overexpressed in DLBCL and BTKi-resistant DLBCL cell lines, knocking down TRIP13 suppresses cell proliferation, promotes cell apoptosis, and enhances the apoptosis effect of BTKi on DLBCL cells by regulating the Wnt/β-catenin pathway. In conclusion, our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL, and TRIP13 might be a potential therapeutic target for resistant DLBCL. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the head and neck (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor patient survival. Galanin receptor 2 (GALR2) is a G protein-coupled receptor that induces aggressive tumor growth in SCCHN. The objective of this study was to investigate the mechanism by which GALR2 promotes angiogenesis, a critical oncogenic phenotype required for tumor growth. The impact of GALR2 expression on secretion of proangiogenic cytokines in multiple SCCHN cell lines was investigated by ELISA and in vitro angiogenesis assays. Chemical inhibitor and genetic knockdown strategies were used to understand the key regulators. The in vivo impact of GALR2 on angiogenesis was investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically relevant mouse orthotopic floor-of-mouth models. GALR2 induced angiogenesis via p38-MAPK-mediated secretion of proangiogenic cytokines, VEGF, and interleukin-6 (IL-6). Moreover, GALR2 activated small-GTP-protein, RAP1B, thereby inducing p38-mediated inactivation of tristetraprolin (TTP), which functions to destabilize cytokine transcripts. This resulted in enhanced secretion of proangiogenic cytokines and angiogenesis in vitro and in vivo. In SCCHN cells overexpressing GALR2, inactivation of TTP increased secretion of IL-6 and VEGF, whereas inhibition of p38 activated TTP and decreased cytokine secretion. Here, we report that GALR2 stimulates tumor angiogenesis in SCCHN via p38-mediated inhibition of TTP with resultant enhanced cytokine secretion. Given that p38 inhibitors are in clinical use for inflammatory disorders, GALR2/p38-mediated cytokine secretion may be an excellent target for new adjuvant therapy in SCCHN.

Tristetraprolin (TTP) is an RNA-binding protein which downregulates multiple cytokines that mediate progression of head and neck squamous cell carcinoma (HNSCC). We previously showed that HNSCC cells with shRNA-mediated knockdown of TTP are more invasive than controls. In this study, we use control and TTP-deficient cells to present a novel subsurface non-linear optical molecular imaging method using a three-dimensional (3D) organotypic construct, and compare the live cell imaging data to histology of fixed tissue specimens. This manuscript describes how to prepare and image the novel organotypic system that closely mimics HNSCC in a clinical setting. The oral cancer equivalent (OCE) system allows HNSCC cells to stratify and invade beyond the basement membrane into underlying connective tissue prepared from decellularized human dermal tissue. The OCE model was inspired by tissue engineering strategies to prepare autologous transplants from human keratinocytes. Advantages of this method over previously used in vitro cancer models include the simulation of the basement membrane and complex connective tissue in the construct, in addition to the ability to track the 3D movement of live invading cells and quantify matrix destruction over time. The OCE model and novel live cell imaging strategy may be applied to study other types of 3D tissue constructs.

Current in vivo models for head and neck squamous cell carcinoma (HNSCC) have limitations in simulating some essential tumorigenic phenotypes, such as invasion. Most mouse models of human HNSCC are inadequate because tumor cells are injected directly into the connective tissue, thereby bypassing the basement membrane of the surface epithelium, the first barrier to invasion. In this manuscript, we establish the chick chorioallantoic membrane (CAM) assay as an in vivomodel of human HNSCC tumor progression. Using the CAM model of HNSCC, we investigated the role of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, in multiple aspects of HNSCC tumor progression. We found that knockdown of EZH2 reduced tumor size, angiogenesis, invasion, and metastasis of tumors produced by grafting human HNSCC cells onto the CAM. In addition, we demonstrate that EZH2 expression mediates a mesenchymal phenotype in HNSCC cell lines and mouse tumors. These findings demonstrate the advantages of the newly proposed CAM model of human HNSCC and highlight the emerging role of EZH2 in HSNCC tumor progression.

Antibody signatures may become sophisticated screening tools for early diagnosis and the development of personalized anticancer treatments. We used biopanning to enrich the immune response of head and neck squamous cell carcinoma (HNSCC) patients. This method revealed a HNSCC-specific antibody signature and allowed for the discovery of a novel oncogene, L23 .

An understanding of the process by which tumor cells destroy the basement membrane of the surface epithelium, invade, and metastasize is essential to the development of novel treatment of head and neck squamous cell carcinoma (HNSCC). In recent years, there has been increased interest in the role of epithelial-mesenchymal transition (EMT) in invasion. EMT is a process that describes the development of motile, mesenchymal-like cells from non-motile parent epithelial cells. There are 3 known types of EMT that mediate development, wound healing, and carcinogenesis. This review summarizes studies of known EMT biomarkers in the context of HNSCC progression. The biomarkers discussed come from a wide range of proteins, including cell-surface proteins (E-cadherin, N-cadherin, and Integrins), cytoskeletal proteins (α-Smooth Muscle Actin, Vimentin, and β-catenin), extracellular matrix proteins (Collagens, Fibronectin, and Laminin), and transcription factors (SNAIL1, SNAIL2, TWIST, and LEF-1). Overall, the findings of these studies suggest that EMT mediates HNSCC progression. The mechanistic role of the EMT markers that have been associated with HNSCC should be more clearly defined if new anti-HNSCC therapies to block EMT progression are to be developed.

The periodontal ligament (PDL) is a key contributor to the process of regeneration of the periodontium. The heterogeneous nature of the PDL tissue, its development during early adulthood, and the different conditions to which the PDL tissue is exposed to in vivo impart on the PDL unique characteristics that may be of consequence during its cultivation in vitro. Several factors affecting the in vivo setting influence the behaviour of PDL fibroblasts in culture. The purpose of this review is to address distinct factors that influence the behaviour of PDL fibroblasts in culture -in vivo-in vitro transitions, cell identification/isolation markers, primary PDL cultures and cell lines, tooth-specific factors, and donor-specific factors. Based on the reviewed studies, the authors recommendations include the use of several identification markers to confirm cell identity, use of primary cultures at early passage to maintain unique PDL heterogeneic characteristics, and noting donor conditions such as age, systemic health status, and tooth health status. Continued efforts will expand our understanding of the in vitro and in vivo behaviour of cells, with the goal of orchestrating optimal periodontal regeneration. This understanding will lead to improved evidence-based rationales for more individualized and predictable periodontal regenerative therapies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor with a high metastatic potential. Perineural invasion (PNI) occurs in the early stages of PDAC with a high incidence rate and is directly associated with a poor prognosis. It involves close interaction among PDAC cells, nerves and the tumor microenvironment. In this review, we detailed discuss PNI-related pain, six specific steps of PNI, and treatment of PDAC with PNI and emphasize the importance of novel technologies for further investigation. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the most common malignant tumor. In the present study, we identified a long non‐coding RNA (lncRNA) AC100826.1 (simplify to Lnc1), which was highly expressed in non‐small cell lung cancer (NSCLC) tissues compared with the paracancerous tissues. We also observed the critical role of Lnc1 in regulating the metastasis ability of NSCLC cells. Methods: RNA sequencing was performed to detect differential expression levels of lncRNAs in NSCLC tissues and its paracancerous tissues. Effects of Lnc1 on cell proliferation, invasion, and migration were determined by CCK‐8, transwell and scratch assays. The xenograft experiment confirmed the effect of Lnc1 on NSCLC cells proliferation and migration abilities in vivo. RT‐qPCR and western blots were performed to determine the expression levels of mRNAs and proteins. Results: The expression level of Lnc1 was related to multiple pathological results, knockdown of Lnc1 can inhibit the proliferation and metastasis abilities of NSCLC cells. silencing phospholipase C, β1(PLCB1) can reverse the promoting effects of overexpression Lnc1 on NSCLC cells proliferation and migration abilities. In addition, the Rap1 signaling pathway was implicated in the regulation of Lnc1 in NSCLC metastasis. Conclusion: Our results suggest that Lnc1 regulated the metastatic ability of NSCLC cells through targeting the PLCB1/Rap1 signal pathway. [ABSTRACT FROM AUTHOR]

Perineural invasion (PNI) leads to the poor prognosis of head and neck squamous cancer (HNSCC) patients, but the mechanism of PNI remains unclear. Dickkopf‐1 (DKK1), a secretory protein in the Wnt signaling pathway, was found indeed upregulated in HNSCC cells and tissues. Higher expression of DKK1 was statistically relevant to T stage, N stage, PNI, and poor prognosis of HNSCC. DKK1 overexpression enhanced the migration abilities of cancer cells. Moreover, DKK1‐overexpressing cancer cells promoted cancer cells invasion of peripheral nerves in vitro and in vivo. Mechanistically, DKK1 could promote the PI3K–AKT signaling pathway. The migration abilities of neuroblastoma cells, which were enhanced by DKK1‐overexpressing HNSCC cell lines, could be reversed by an inhibitor of Akt (MK2206). The association of DKK1 with PNI was also confirmed in HNSCC samples. Variables, including T stage, N stage, DKK1 expression, and PNI, were used to establish a nomogram to predict the survival probability and disease‐free probability at 3 and 5 years. In summary, DKK1 can promote the PI3K–AKT signaling pathway in tumor cells and then could induce neuritogenesis and facilitate PNI. MK2206 may be a potential therapeutic target drug for HNSCC patients with PNI. [ABSTRACT FROM AUTHOR]

Background: Bone or brain metastases may develop in 20–40% of individuals with late‐stage non‐small‐cell lung cancer (NSCLC), resulting in a median overall survival of only 4–6 months. However, the primary lung cancer tissue's distinctions between bone, brain and intrapulmonary metastases of NSCLC at the single‐cell level have not been underexplored. Methods: We conducted a comprehensive analysis of 14 tissue biopsy samples obtained from treatment‐naïve advanced NSCLC patients with bone (n = 4), brain (n = 6) or intrapulmonary (n = 4) metastasis using single‐cell sequencing originating from the lungs. Following quality control and the removal of doublets, a total of 80 084 cells were successfully captured. Results: The most significant inter‐group differences were observed in the fraction and function of fibroblasts. We identified three distinct cancer‐associated fibroblast (CAF) subpopulations: myofibroblastic CAF (myCAF), inflammatory CAF (iCAF) and antigen‐presenting CAF (apCAF). Notably, apCAF was prevalent in NSCLC with bone metastasis, while iCAF dominated in NSCLC with brain metastasis. Intercellular signalling network analysis revealed that apCAF may play a role in bone metastasis by activating signalling pathways associated with cancer stemness, such as SPP1‐CD44 and SPP1‐PTGER4. Conversely, iCAF was found to promote brain metastasis by activating invasion and metastasis‐related molecules, such as MET hepatocyte growth factor. Furthermore, the interaction between CAFs and tumour cells influenced T‐cell exhaustion and signalling pathways within the tumour microenvironment. Conclusions: This study unveils the direct interplay between tumour cells and CAFs in NSCLC with bone or brain metastasis and identifies potential therapeutic targets for inhibiting metastasis by disrupting these critical cell–cell interactions. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to process and assess the effect of hydrated amnion chorion membrane and dehydrated amnion chorion membrane on proliferation of periodontal ligament (PDL) fibroblast cells. The amnion chorion membrane (ACM) from placenta of 18 systemically healthy patients was obtained from the Department of Obstetrics and Gynaecology. They were processed as hydrated and dehydrated based on different processing methods. The Periodontal ligament cells were obtained from periodontal ligament of freshly extracted premolars of systemically healthy patients, due to orthodontic reasons. The PDL cells were further cultured in laboratory and were exposed to hydrated and dehydrated amnion chorion membrane. The MTT assay was performed to assess the proliferation of PDL fibroblast cells after 24 and 48 h. The hydrated and dehydrated amnion chorion membrane showed proliferation of PDL fibroblasts after 24 and 48 h. The proliferation of PDL fibroblasts in hydrated (p = 0.043) and dehydrated (p = 0.050) amnion chorion membrane was statistically significant at the end of 24 and 48 h respectively. On inter-group comparison dehydrated ACM showed significant proliferation of PDL fibroblasts after 24 (p=0.014) and 48 h (p=0.019). Within the limits of the present study, it can be concluded: both hydrated and dehydrated amnion chorion membrane showed proliferationof PDL fibroblast cells. However, dehydrated ACM showed significant proliferation of PDL fibroblasts. [ABSTRACT FROM AUTHOR]

Communication between the nervous system and the immune system has evolved to optimally respond to potentially dangerous stimuli both from within and outside the body. Tumors pose a severe threat to an organism and current therapies are insufficient for tumor regression in the majority of cases. Studies show that tumors are innervated by peripheral nerves from the sensory, parasympathetic and sympathetic nervous systems. Interactions between cancer cells, nerves and immune cells regulate overall tumor progression. Clinical studies have indicated the potential of targeting the peripheral nervous system for promoting anti-tumor immune responses. This view point provides an opinion on the current evidence and therapeutic potential of manipulating neuro-immune communications in cancer., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Aim: 2,3-bisphosphoglycerate mutase (BPGM) is traditionally recognized for its role in modulating oxygen affinity to hemoglobin in erythrocytes. Recent transcriptomic analyses, however, have indicated a significant upregulation of BPGM in acutely injured murine and human kidneys, suggesting a potential renal function for this enzyme. Here we aim to explore the physiological role of BPGM in the kidney., Methods: A tubular-specific, doxycycline-inducible Bpgm-knockout mouse model was generated. Histological, immunofluorescence, and proteomic analyses were conducted to examine the localization of BPGM expression and the impact of its knockout on kidney structure and function. In vitro studies were performed to investigate the metabolic consequences of Bpgm knockdown under osmotic stress., Results: BPGM expression was localized to the distal nephron and was absent in proximal tubules. Inducible knockout of Bpgm resulted in rapid kidney injury within 4 days, characterized by proximal tubular damage and tubulointerstitial fibrosis. Proteomic analyses revealed involvement of BPGM in key metabolic pathways, including glycolysis, oxidative stress response, and inflammation. In vitro, Bpgm knockdown led to enhanced glycolysis, decreased reactive oxygen species elimination capacity under osmotic stress, and increased apoptosis. Furthermore, interactions between nephron segments and immune cells in the kidney suggested a mechanism for propagating stress signals from distal to proximal tubules., Conclusion: BPGM fulfills critical functions beyond the erythrocyte in maintaining glucose metabolism in the distal nephron. Its absence leads to metabolic imbalances, increased oxidative stress, inflammation, and ultimately kidney injury., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: Proline-rich tyrosine kinase 2 (PYK2) is involved in the occurrence, proliferation, migration, and invasion of various tumors. However, few studies have reported the role of PYK2 in colorectal cancer (CRC)., Aim: To explore the effects of PYK2 on CRC metastasis and elucidate the detailed molecular mechanisms involved., Methods: The expression and prognosis value of PYK2 in CRC prognosis were analyzed using data from The Cancer Genome Atlas (TCGA). PYK2 was knocked down or overexpressed in human CRC cell line, HCT116. Cell proliferation, migration, invasion, and cycle changes were analyzed using CCK-8, Transwell, and flow cytometry assays. Western blotting and quantitative real-time PCR were performed to detect the mRNA and protein levels of cell proliferation and epithelial-mesenchymal transition (EMT) indicators. Fluorescence staining was performed to examine the cytoskeleton., Results: Lower expression of PYK2 was observed in CRC tissues and associated with poor prognosis and metastasis in patients with CRC in TCGA database. PYK2 knockdown significantly induced the migration and invasion of CRC cells but did not affect cell proliferation or cycle. Immunofluorescence staining of phalloidin showed that the downregulation of PYK2 increased the cytoskeleton in CRC cells. Moreover, low expression of PYK2 induced the downregulation of E-cadherin and upregulation of snail and vimentin by activating Wnt/β-catenin signaling, thus promoting EMT in CRC cells., Conclusions: Low PYK2 expression was found in tumor tissues, especially metastases, and significantly correlated with patient prognosis. Moreover, decreased PYK2 induces EMT by activating Wnt/β-catenin signaling, which is the potential mechanism of CRC metastasis. Regulating the expression of PYK2 to suppress tumor cell metastasis may represent a promising therapeutic strategy for metastatic CRC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and cancer cells plays a critical role in tumor initiation and progression. Perineural invasion (PNI) occurs when tumor cells invade the nerve sheath and/or encircle more than 33% of the nerve circumference. PNI is a common feature in various malignancies and is associated with tumor invasion, metastasis, cancer-related pain, and unfavorable clinical outcomes. The colon and rectum are highly innervated organs, and accumulating studies support PNI as a histopathologic feature of colorectal cancer (CRC). Therefore, it is essential to investigate the role of nerves in CRC and comprehend the mechanisms of PNI to impede tumor progression and improve patient survival. Conclusion: This review elucidates the clinical significance of PNI, summarizes the underlying cellular and molecular mechanisms, introduces various experimental models suitable for studying PNI, and discusses the therapeutic potential of targeting this phenomenon. By delving into the intricate interactions between nerves and tumor cells, we hope this review can provide valuable insights for the future development of CRC treatments. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated phytic acid (IP6) effect on the viability, alkaline phosphatase (ALP) activity and calcium release of human periodontal ligament (HPDL) cells in optimal (OGL) and elevated glucose level (EGL) in cell culture media. Materials and methods: Cells were seeded in OGL (1000mg/L) or EGL (4500 mg/L) media. IP6 was added at 0.005%, 0.01% or 0.02% concentrations for 24 or 48h, and XTT assay was performed. Cell differentiation and calcium release in presence of 0.02% IP6 in OGL or EGL in non-osteogenic or osteogenic media were analyzed using ALP assay and alizarin red staining, respectively. Results: In OGL, IP6 enhanced the viability of the cells at both exposure times (P<0.05). However, IP6 lowered the viability of the cells with the presence of EGL compared to the control at both exposure times, except for 0.02% IP6 which showed comparable viability to the control at 48 h. In OGL and EGL, ALP activity of the cells was not affected by the presence of IP6 in non-osteogenic media; however, in osteogenic media IP6 lowered the ALP activity. Meanwhile, calcium release was the highest with IP6 within osteogenic media of EGL. Conclusions: IP6 effects on the HPDL cells were dependent on IP6 concentration, time of exposure, glucose levels and the osteogenic condition of the media. Clinical relevance: This study gives insights on the potential therapeutic effect of IP6 as adjunctive periodontal therapy in patients with diabetes. [ABSTRACT FROM AUTHOR]

Aberrant mRNA expression is implicated in uterine corpus endometrial carcinoma (UCEC) oncogenesis and progression. However, effective prognostic biomarkers for UCEC remain limited. We aimed to construct a reliable multi-gene risk model using gene expression profiles. Utilizing TCGA data (543 UCEC samples, 35 controls), we identified 1517 differentially acting genes. Weighted gene co-expression complex analysis (WGCCA), hub gene screening, and risk regression analysis (RRA) were employed to determine prognosis-related genes and construct the risk model. Nomograms visualized risk scores and receiver operator characteristic (ROC) curves assessed model performance. Seven novel prognosis-related hub genes (ANGPT1, ASB2, GAL, GDF7, ONECUT2, SV2B, TRPC6) were identified. The model's concordance index (C index) by multivariate Cox regression analysis was 0.79. ROC curves yielded AUCs of 0.811 (3-year) and 0.79 (5-year), demonstrating the model's efficacy in predicting UCEC survival. Our study proposes a promising seven-biomarker risk model for predicting UCEC prognosis, offering potential clinical utility., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Institute of Plant Genetics Polish Academy of Sciences.)

Background: Oral squamous cell carcinoma (SCC) is associated with oral microbial dysbiosis. In this unique study, we compared pre- to post-treatment salivary microbiome in patients with SCC by 16S rRNA gene sequencing and examined how microbiome changes correlated with the expression of an anti-microbial protein. Results: Treatment of SCC was associated with a reduction in overall bacterial richness and diversity. There were significant changes in the microbial community structure, including a decrease in the abundance of Porphyromonaceae and Prevotellaceae and an increase in Lactobacillaceae. There were also significant changes in the microbial community structure before and after treatment with chemoradiotherapy, but not with surgery alone. In patients treated with chemoradiotherapy alone, several bacterial populations were differentially abundant between responders and non-responders before and after therapy. Microbiome changes were associated with a change in the expression of DMBT1, an anti-microbial protein in human saliva. Additionally, we found that salivary DMBT1, which increases after treatment, could serve as a post-treatment salivary biomarker that links to microbial changes. Specifically, post-treatment increases in human salivary DMBT1 correlated with increased abundance of Gemella spp., Pasteurellaceae spp., Lactobacillus spp., and Oribacterium spp. This is the first longitudinal study to investigate treatment-associated changes (chemoradiotherapy and surgery) in the oral microbiome in patients with SCC along with changes in expression of an anti-microbial protein in saliva. Conclusions: The composition of the oral microbiota may predict treatment responses; salivary DMBT1 may have a role in modulating the oral microbiome in patients with SCC. After completion of treatment, 6 months after diagnosis, patients had a less diverse and less rich oral microbiome. Leptotrichia was a highly prevalent bacteria genus associated with disease. Expression of DMBT1 was higher after treatment and associated with microbiome changes, the most prominent genus being Gemella -6tcCpfJtMWsEpEDBUWdC3 Video Abstract [ABSTRACT FROM AUTHOR]

Mechanisms of sex-dependent orofacial pain are widely understudied. A significant gap in knowledge exists about comprehensive regulation of tissue-specific trigeminal sensory neurons in diseased state of both sexes. Using RNA sequencing of FACS sorted retro-labeled sensory neurons innervating tongue tissue, we determined changes in transcriptomic profiles in males and female mice under naïve as well as tongue-tumor bearing conditions Our data revealed the following interesting findings: (1) FACS sorting obtained higher number of neurons from female trigeminal ganglia (TG) compared to males; (2) Naïve female neurons innervating the tongue expressed immune cell markers such as Csf1R, C1qa and others, that weren't expressed in males. This was validated by Immunohistochemistry. (3) Accordingly, immune cell markers such as Csf1 exclusively sensitized TRPV1 responses in female TG neurons. (4) Male neurons were more tightly regulated than female neurons upon tumor growth and very few differentially expressed genes (DEGs) overlapped between the sexes, (5) Male DEGs contained higher number of transcription factors whereas female DEGs contained higher number of enzymes, cytokines and chemokines. Collectively, this is the first study to characterize the effect of sex as well as of tongue-tumor on global gene expression, pathways and molecular function of tongue-innervating sensory neurons. [ABSTRACT FROM AUTHOR]

Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively target and kill cancer cells while sparing normal ones. Among them, engineered Herpes simplex virus type 1 (HSV-1) has been proposed as a potential treatment for cancer and was moved to phase III clinical trials. Previous studies showed that design of OV therapy combined with p53 gene therapy increases the anti-cancer activities of OVs. Here, the UL39 gene of the ICP34.5 deleted HSV-1 was manipulated with the insertion of the EGFP-p53 expression cassette utilizing CRISPR/ Cas9 editing approach to enhance oncoselectivity and oncotoxicity capabilities. The ΔUL39/Δγ34.5/HSV1-p53 mutant was isolated using the chorioallantoic membrane (CAM) of fertilized chicken eggs as a complementing membrane to support the growth of the viruses with gene deficiencies. Comparing phenotypic features of ΔUL39/Δγ34.5/HSV1-p53-infected cells with the parent Δγ34.5/HSV-1 in vitro revealed that HSV-1-P53 had cytolytic ability in various cell lines from different origin with different p53 expression rates. Altogether, data presented here illustrate the feasibility of exploiting CAM model as a promising strategy for isolating recombinant viruses such as CRISPR/Cas9 mediated HSV-1-P53 mutant with less virus replication in cell lines due to increased cell mortality induced by exogenous p53. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study is to determine the possibility of isolation and characterization of the human periodontal ligament stem cells (hPDLSCs) using limited harvested periodontal ligament (PDL) tissue of only one patient's wisdom teeth (2--4 teeth) under the more compatible terms of use in clinical application without using the fetal bovine serum (FBS). Materials and Methods: In this pilot study, hPDLSCs were isolated from the impacted third molar, and tissue was scraped from the roots of the impacted third molar of 10 volunteers to enzymatically digest using collagenase. The cells were sub-cultured. The samples of the first seven patients and half of the eighth patient's sample were cultured in alpha modified of Eagle's medium (α-MEM) (FBS) medium and the other part of the eighth patient's sample was cultured with prior medium supplemented with +FBS 15% as a control of the cultivation protocol. While for the past two patients (9th and 10th the α-MEM medium was supplemented with L-Glutamine, anti/anti 2X, and 20% knock-out serum replacement (KSR). Two more nutritious supplements (N2 and B27) were added to the medium of the tenth sample. Flow-cytometric analysis for the mesenchymal stem cell surface markers CD105, CD45, CD90, and CD73 was performed. Subsequent polymerase chain reaction was undertaken on three samples cultured with two growth media. Results: Cultivation failed in some of the samples because of the lack of cell adhesion to the culturing dish bottom (floating cells), but it was successful for the 9th and 10th patients, which were cultured in the α-MEM serum supplemented with KSR 20%. Flow cytometry analysis was positive for CD105, CD90, and CD73 and negative for CD45. The PDL stem cells (PDLSCs) expressed CD105, CD45, and CD90 but were poor for CD73. Conclusion: According to the limited number of sample tests in this study, isolation and characterization of PDLSCs from collected PDL tissue of one patient's wisdom teeth (2--4) may be possible by the proper setup in synthetic FBS-free serum. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate the prognostic significance of the preoperative controlling nutritional status (CONUT) score in patients with resectable advanced hypopharyngeal cancer. Methods: This retrospective study included 113 advanced hypopharyngeal cancer patients who underwent curative resection in our hospital from 2013 to 2017. The association between the CONUT score and clinicopathological variables was evaluated. The association between CONUT score and survival was analyzed using Kaplan–Meier survival curves and Cox regression. The efficacy of the CONUT score and other immune‐nutritional markers to predict prognosis was compared using a time‐dependent receiver operating characteristic (ROC). Results: Patients were divided into the high‐CONUT score group (≥3) and the low‐CONUT score group (≤2) according to ROC analysis. The CONUT score was associated with body mass index (p = 0.047), monocyte (p = 0.021), pharyngocutaneous fistula (p = 0.045), flap repairment (p = 0.034), tumor (T) classification (p = 0.034), node (N) classification (p = 0.036), subsite of tumor (p = 0.035), and negative pathologic factors (p < 0.001). Tumor, node, metastasis (TNM) stage, negative pathologic factors, adjuvant radiotherapy, postoperative chemoradiotherapy, and CONUT score were independent prognostic factors for survival. Patients with a higher CONUT score had worse overall survival (OS) (hazard ratio: 2.76, 95% confidence interval [CI]: 1.44–5.29, p = 0.002) and disease‐free survival (hazard ratio: 2.51, 95% CI: 1.28–4.91, p = 0.007). The area under the curve of the CONUT score (0.799) to predict 5‐year OS was greater than those of Preoperative Nutritional Index (0.769), platelet‐to‐lymphocyte ratio (0.643), neutrophil‐to‐lymphocyte ratio (0.565), and lymphocyte‐to‐monocyte ratio (0.577). Conclusion: The CONUT score is a prognostic marker for patients with resectable advanced hypopharyngeal cancer. Level of Evidence: 3 Laryngoscope, 133:2613–2620, 2023 [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate solubility, pH value, chemical structure, radiopacity, and cytotoxicity of AH Plus BC, TotalFill BC, AH Plus, and AH Plus Jet sealers. Materials and methods: Cytotoxicity analysis with direct and extraction tests at 3 different concentrations (1:1, 1:2, 1:4 v/v%) and time (24 h, 48 h, and 72 h) on Saos-2, PdLF, and THP-1 cell lines, chemical structure with scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) analysis, solubility, pH, and radiopacity values of AH Plus BC, TotalFill BC, AH Plus, and AH Plus Jet were evaluated. For statistical analyses of the groups, repeated measures, factorial, and one-way ANOVA tests were used. The statistical significance level was set at p <.05. Results: Resin-based sealers showed higher cytotoxicity values than the bioceramic-based sealers (p < 0.05). Time and concentrations were effective on the cell viabilities for cell lines. Higher peaks of calcium were detected bioceramic-based sealers and higher amount of zirconium was detected in AH Plus BC (p < 0.05). AH Plus BC showed similar radiopacity value with AH Plus, AH Plus Jet, whereas TotalFill BC showed the lowest radiopacity (p < 0.05). Bioceramic-based sealers had higher pH values in all experiment periods, and the difference between resin- and bioceramic-based sealer groups was significant (p < 0.05). However, the solubility values of the tested root canal sealers revealed no differences (p > 0.05). Conclusions: The newly produced AH Plus BC Sealer showed similar properties with TotalFill BC, and their biological properties were better than AH Plus and AH Plus Jet. Clinical relevance: AH Plus BC could be a possible alternative to other bioceramic- or resin-based sealers. [ABSTRACT FROM AUTHOR]

Despite their critical roles in tissue repair and pathological processes such as fibrosis, tumor invasion, and metastasis, the origins of mesenchymal cells remain poorly understood. Among the likely routes, epithelial-to-mesenchymal transitions (EMTs) emerge as important source of these cells. EMTs manifest themselves as a phenotypic transition in terminally differentiated epithelial cells into mesenchymal cells which are closely related to embryogenesis and organ development as well as in chronically inflamed tissues and neoplasia. There exists a potential for successful engineering of biomimetic environments that closely reflects and reciprocates the dynamic changes in the cellular microenvironment during EMT and relies on integrating the mechanical sensing mechanisms found in the native tissues into the synthetic scaffolds to understand cellular plasticity. Extracellular matrix (ECM) has complex structures composed of a collection of extracellular molecules including fibrous proteins and glycoproteins in a hydrated mixture of glycosaminoglycans and proteoglycans. Therefore, fibrous materials have been increasingly applied in tissue engineering applications since biomaterials need to restore ECM structures to provide physical, biochemical, and biomechanical signals to define cellular behaviors and tissue functions. This review summarizes materials used for fibrous scaffolds including natural and synthetic materials, highlights recent development of fabrication techniques, characteristic architectures, and properties and different applications of fibrous scaffolds in tissue engineering. The prospects and challenges about fibrous materials in tissue engineering applications are also discussed. Finally, we summarized relevant bioengineering approaches to modulate each type of EMT as potential avenues to consider toward future biomaterials design. [ABSTRACT FROM AUTHOR]

Tubular epithelial cell fate following exposure to various types of injurious stimuli can be decided at distinct cell cycle checkpoints. One such checkpoint occurs during mitosis, known as the spindle assembly checkpoint, and is tightly regulated through the actions of cell division cycle protein 20 (CDC20). Due to our paucity of knowledge about the role of CDC20 in the kidney, the present study was designed to investigate the expression levels and distribution of CDC20 within the kidney and how pharmacological inhibition of CDC20 function affects kidney recovery using various rodent models of kidney injury. CDC20 is normally detected in distal tubules, but upon injury by either cisplatin administration or ureter obstruction, CDC20 accumulation is considerably elevated. Blockade of CDC20 activity using a selective pharmacological inhibitor, Apcin, lowered serum creatinine, tubular damage, and DNA injury following acute kidney injury compared with vehicle-treated mice. In unilateral ureteral obstruction, Apcin reduced tissue kidney injury molecule-1 levels, sirius red staining, and tubulointerstitial α-smooth muscle actin staining in the tissue. The findings in the present study demonstrated that elevations in CDC20 levels in the kidney are associated with kidney injury and that inhibition of CDC20 can alleviate and reverse some of the pathological effects on the architecture and function of kidney. NEW & NOTEWORTHY To our knowledge, this is the first study to characterize the expression and localization of cell division cycle 20 protein (CDC20) in normal and acute, and chronically injured kidneys. Tubular epithelial cell damage was markedly reduced through the administration of a selective inhibitor of CDC20, Apcin. This study provides new evidence that CDC20 can be induced in damaged kidney cells and negatively impact the recovery of the kidney following acute kidney injury. [ABSTRACT FROM AUTHOR]

Purpose: Neuropeptide Y (NPY) is a pleiotropic peptide, which is involved in many biological mechanisms important in regulation of cell growth and survival. The aim of this study was a comprehensive analysis of the NPY system in prostate pathology. Methods: The study was based on immunohistochemical analysis of NPY and its receptors, Y1R, Y2R and Y5R, in tissue samples from benign prostate (BP), primary prostate cancer (PCa) and PCa bone metastases. Tissue microarray (TMA) technique was employed, with analysis of multiple cores from each specimen. Intensity of the immunoreactivity and expression index (EI), as well as distribution of the immunostaining in neoplastic cells and stromal elements were evaluated. Perineural invasion (PNI) and extraprostatic extension (EPE) were areas of special interests. Moreover, a transwell migration assay on the LNCaP PCa cell line was used to assess the chemotactic properties of NPY. Results: Morphological analysis revealed homogeneous membrane and cytoplasmic pattern of NPY staining in cancer cells and its membrane localization with apical accentuation in BP glands. All elements of the NPY system were upregulated in pre-invasive prostate intraepithelial neoplasia, PCa and metastases. EI and staining intensity of NPY receptors were significantly higher in PCa then in BP with correlation between Y2R and Y5R. The strength of expression of the NPY system was further increased in the PNI and EPE areas. In bone metastases, Y1R and Y5R presented high expression scores. Conclusion: The results of our study suggest that the NPY system is involved in PCa, starting from early stages of its development to disseminated states of the disease, and participates in the invasion of PCa into the auto and paracrine matter. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prognostic significance of MR-detected mandibular nerve involvement (MNI) and its value for induction chemotherapy (IC) administration in patients with nasopharyngeal carcinoma (NPC) and T4 disease. Methods: This retrospective study enrolled 792 non-metastatic, biopsy-proven NPC patients. Univariate and multivariate analysis were used to evaluate potential prognosticators. The inter-observer agreement was assessed by the kappa values. Results: MR-detected MNI was observed in 141 (72.3%) patients among 195 patients with T4 disease, with excellent agreement between the readers (kappa = 0.926). Patients with MR-detected MNI presented better 5-year overall survival (OS) (hazard ratio [HR], 0.40; P = 0.006) than those with MR-negative MNI. Of these patients, IC treatment was verified as an independent factor (HR: 0.35; P = 0.014) with preferable effect on OS. Conclusion: MR-detected MNI could serve as an independent favorable prognostic predictor for OS in NPC patients with stage T4, which should be considered for stratifying these patients for IC administration. [ABSTRACT FROM AUTHOR]

Background: Although nerve involvement can predict recurrence and prognosis in oral squamous cell carcinomas, there still have controversies and limitations regarding the standardization for its detection. In this study, we explore the impact of neural invasion in oral squamous cell carcinomas prognosis, comparing intraneural invasion (tumor cells inside nerve structure) and perineural invasion (cells involving the nerve, but not invading its sheath). Methods: Surgical slides stained with hematoxylin and eosin from 235 patients with oral squamous cell carcinomas were carefully verified for the presence of intraneural invasion and perineural invasion. The location in the tumor (intratumoral vs. peritumoral) and number of foci (unifocal or multifocal) were also explored. Survival analyses for cancer‐specific survival and disease‐free survival were performed with Cox proportional model. Results: Neural invasion was identified in 74 cases, 64.9% displayed intraneural invasion and 35.1% displayed perineural invasion. Univariate analysis revealed a significantly poorer cancer‐specific survival, but not disease‐free survival, in patients with intraneural invasion, in contrast to cases with perineural invasion that did not achieve significant association with both cancer‐specific survival and disease‐free survival. Further analyses revealed that the location in the tumor and number of foci had little impact on discriminatory ability of intraneural invasion. Multivariate analysis confirmed that intraneural invasion is significantly and independently associated with poor cancer‐specific survival (hazard ratio: 2.50, 95% CI: 1.31–3.79, p = 0.003). Conclusion: This study provides evidence that intraneural invasion, but not perineural invasion, is a relevant predictor of survival in patients with oral squamous cell carcinomas, suggesting that its association with other clinical and pathological prognostic factors should be consider in determining the optimal treatment protocol and prognosis of these patients. [ABSTRACT FROM AUTHOR]

Objectives: Perineural invasion (PNI) in head and neck cancer (HNC) is a distinct pathological feature used to indicate aggressive tumor behavior and drive treatment strategies. Our study examined the prevalence and predictors of PNI in HNC patients stratified by tumor site. Study design and methods: A retrospective analysis of head and neck squamous cell carcinoma (HNSCC) patients who underwent surgical resection at the University of Pittsburgh Medical Center between 2015 and 2018 was performed. Pretreatment pain was assessed at least 1 week before surgery using the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N). Demographics, clinical characteristics, and concomitant medications were obtained from medical records. Patients with cancers at the oropharynx and non-oropharynx (i.e., cancer at oral cavity, mandible, larynx) sites were separately analyzed. Tumor blocks were obtained from 10 patients for histological evaluation of intertumoral nerve presence. Results: A total of 292 patients (202 males, median age = 60.94 ± 11.06) were assessed. Pain and PNI were significantly associated with higher T stage (p < 0.001) and tumor site (p < 0.001); patients with non-oropharynx tumors reported more pain and had a higher incidence of PNI compared to oropharynx tumors. However, multivariable analysis identified pain as a significant variable uniquely associated with PNI for both tumor sites. Evaluation of nerve presence in tumor tissue showed 5-fold higher nerve density in T2 oral cavity tumors compared to oropharyngeal tumors. Conclusions: Our study finds that PNI is associated with pretreatment pain and tumor stage. These data support the need for additional research into the impact of tumor location when investigating targeted therapies of tumor regression. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is one of the most common malignancy in the oral cancer threatening human health and the survival rate of OSCC has not been effectively improved in recent decades, so more effective biomarkers for the targeted therapy of OSCC are needed. Moreover, the role of CDH11 in OSCC has not been intensively investigated. We here show that the CDH11 protein and mRNA expression levels in the OSCC tissues were all significantly higher than in the non-cancerous tissues using RT-qPCR and western blot. This study also revealed that patients with higher CDH11 levels showed a higher incidence of perineural invasion and lymph node metastasis. By using data available from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ArrayExpress databases, overexpressed CDH11 in OSCC that associated with patients'history of alcohol, negative Human Papilloma Virus (HPV) status, perineural invasion, infiltration of multiple immune cells, and Single-cell functional states including quiescence and angiogenesis, possessed an excellent discriminatory capability in the OSCC patients. Moreover, the majority of the biological processes or pathways were significantly clustered by co-expressed genes, including extracellular matrix organization, the epithelial to mesenchymal transition, carbon metabolism, and the PI3K-Akt signaling pathway, and the upstream transcriptional regulation mechanism of CDH11 in OSCC was showed on a transcription factor/miRNA-mRNA network with the online tool NetworkAnalyst. Finally, frequent mutation of CDH11 was observed on a mouse OSCC model through whole-genome sequencing. CDH11 might serve as a valuable biomarker in OSCC, as it was identified to be overexpressed in OSCC and related to its clinical progression. [ABSTRACT FROM AUTHOR]

Objective: This study to evaluate clinicopathological parameters such as age, tumor location, tumor size, grade, depth of invasion (DOI), lymphovascular space invasion (LVSI), lymph node metastasis, and stage that predict peri-neural invasion (PNI) in oral squamous cell carcinoma (OSCC). Material and Methods: A retrospective study on 1716 postoperative OSCC patients who satisfied the eligibility criteria and treated from January 2009 to December 2019 was analyzed using IBM SPSS V23. Mean and percentage were assessed using descriptive statistics. Wilcoxon--Mann--Whitney U-test was used to compare continuous variables, while Chi-square test was used to compare discrete variables between PNI-positive and PNI-negative groups. Two-tailed P < 0.05 was considered to be statistically significant. Results: Out of 1716 patients, 553 were PNI positive. The mean age was 48.76 ± 12.42 years in PNI-positive patients while 51.52 ± 12.51 years in PNI-negative patients. Males outnumbered females. The most common primary was carcinoma buccal mucosa (204, 36.9%), followed by carcinoma of oral tongue (161,29.1%). Maximum tumor size was 3.14 ± 1.20 cm in PNI-positive patients whereas 2.78 ± 1.22 cm in PNI-negative patients. Sixty (10.84%) patients in PNI-positive group and 51 (4.38%) in PNI-negative group had LVSI positive. Lymph node involvement was observed in 305 (55.13%) patients in PNI-positive group whereas 358 (30.78%) patients in PNI-negative group. Maximum number 228 (41.3%) in PNI-positive patients were in Stage IVA disease. Conclusion: PNI is one of the important adverse prognostic factors having a definite correlation with anatomical subsite, tumor size, grade, DOI, LVSI, lymph node involvement, and stage of the disease. PNI should be analyzed in postoperative histopathology report of OSCC that guides the clinician for adjuvant therapy. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the prognostic impact of lymphovascular and perineural invasions in patients with squamous cell carcinoma of the tongue who received surgery-based treatment at our institution between January 2013 and December 2020. Patients were divided into four groups based on the presence of perineural (P−/P +) and lymphovascular invasions (V−/V +): P–V−, P–V + , P + V−, and P + V +. Log-rank and Cox proportional hazard models were used to evaluate the association between perineural /lymphovascular invasion and overall survival (OS). Altogether, 127 patients were included, and 95 (74.8%), 8 (6.3%), 18 (14.2%), and 6 (4.7%) cases were classified as P–V−, P–V + , P + V−, and P + V + , respectively. Pathologic N stage (pN stage), tumor stage, histological grade, lymphovascular invasion, perineural invasion, and postoperative radiotherapy were significantly associated with OS (p < 0.05). OS was significantly different among the four groups (p < 0.05). Significant between-group differences in OS were detected for node-positive (p < 0.05) and stage III–IV (p < 0.05) cases. OS was the worst in the P + V + group. Lymphovascular and perineural invasions are independent negative prognostic factors for squamous cell carcinoma of the tongue. Patients with lymphovascular and/or perineural invasion may have significantly poorer overall survival than those without neurovascular involvement. [ABSTRACT FROM AUTHOR]

Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here, we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting that unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. Perineural invasion induced afterdischarge in A high-threshold mechanoreceptors (HTMRs), mechanical sensitization (ie, decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low-threshold mechanoreceptors. Perineural invasion resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically insensitive and electrically unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.