Mast cell infiltration and subtype promote malignant transformation of oral precancer and progression of oral cancer.

The role of mast cell (MC), a common myeloid-derived immune cell, in the development of oral squamous cell carcinoma (OSCC) is unclear and the aim of this study was to investigate MC infiltration in oral precancer and oral cancer. Evaluation of immune cell infiltration and association with prognosis in OSCC using RNA sequencing and multiple public datasets. Multiplex immunofluorescence was used to explore the infiltration of MC in the microenvironment of OSCC and oral precancer and the interaction with CD8+ cells. The role of MC in OSCC progression was verified by in vivo experiments. The resting MC infiltration was mainly present in oral precancer, while activated MC infiltration was significantly higher in OSCC. Activated MC was associated with malignant transformation of oral precancer and poor prognosis of OSCC. In vivo studies showed that MC promoted the growth of OSCC. The infiltration of activated MC was negatively correlated with the infiltration of CD8+ T cells. The subtype of MC containing tryptase without chymase (MCT) was significantly higher in OSCC compared to oral precancer and was associated with poor survival. Furthermore, spatial distance analysis revealed a greater distance between MCT and CD8+ cells that was also linked to poor prognosis in OSCC. Cox regression analysis showed that MCT could be a potential diagnostic and prognostic biomarker. This study provides new insights into the role of MC in the immune microenvironment of OSCC. It might enhance the immunotherapeutic efficacy of OSCC through developing targeted therapies against MC.

Head and neck carcinoma in children: A clinicopathological study of 42 cases.

Background/purpose: Cancer is an important part of the global burden of childhood diseases. Head and neck carcinoma in children is rare and related research is limited. This study aimed to investigate the clinicopathological features of childhood head and neck carcinoma. Materials and methods: Forty-two cases of childhood head and neck carcinoma treated in our institution were reviewed and analyzed. Results: Median age overall was 11 years. Twenty-three patients (54.8%) were male and 19 (45.2%) were female. Parotid gland location was most common (54.8%). Mucoepidermoid carcinoma and squamous cell carcinoma were the most common histological types (57.1% and 11.9%, respectively). Two patients had a history of bone marrow transplantation and two had a history of odontogenic keratocyst. The recurrence rate after treatment was 8.6%. Conclusion: Early diagnosis and treatment and close follow-up of childhood head and neck carcinoma are warranted to prevent recurrence and improve clinical outcome.

Bibliometric analysis of immunotherapy for head and neck squamous cell carcinoma.

Background/purpose: Head and neck squamous cell carcinoma (HNSCC) is a serious disease endangering the health of patients, and the application of immunotherapy in HNSCC is gradually emerging. However, there is no bibliometric analysis in this research field. This study aims to provide a comprehensive overview of the knowledge structure and research hotspots of immunotherapy for HNSCC. Materials and methods: Publications related to immunotherapy for HNSCC from 2002 to 2021 were searched in the Web of Science Core Collection database. The software VOSviewers, CiteSpace, and the R package 'bibliometrix' were used to perform this bibliometric analysis. Results: A total of 1297 publications were from 63 countries, led by the USA and China. The number of publications related to immunotherapy for HNSCC has increased rapidly from 2015. University of Pittsburgh and The University of Texas M.D. Anderson Cancer Center are the main research institutions. Oral Oncology is the most popular journal in this field, and the Journal of Clinical Oncology is the most highly co-cited journal. These publications were from 7569 authors, with Robert L. Ferris publishing the most papers and being the most frequently co-cited. Clinical trials related to nivolumab and pembrolizumab have attracted wide attention. 'Immune checkpoint inhibitors', 'human papillomavirus', 'programmed cell death-ligand 1', and 'programmed cell death protein 1' are the main keywords of emerging research hotspots. Conclusion: This study presents a comprehensive summary of the trends and development of immunotherapy for HNSCC, identifies the research frontier and hotspot direction, and could provide a valuable reference for researchers in this field.

Expressions of GLUT-1, PK-M2 and HIF-1α and Mutation Status of BRAF in Odontogenic Keratocysts.

OBJECTIVE: To investigate the expressions and clinicopathological features of glucose transporter 1 (GLUT-1), pyruvate kinase M2 (PK-M2) and hypoxia-inducible factor 1α (HIF-1α) in odontogenic keratocysts (OKCs), and to investigate the mutation status of v-raf murine sarcoma viral oncogene homolog B1 (BRAF). METHODS: Following a retrospective review of the clinicopathological data of 28 OKC cases, the expressions of GLUT-1, PK-M2 and HIF-1α in these tissue samples were detected through immunohistochemistry. The BRAF mutation statuses of all cases were examined using polymerase chain reaction amplification and direct sequencing. RESULTS: The expression levels of HIF-1α varied in 96.4% of OKC tissues, and there were higher positive rates of PKM2 (100%) and GLUT-1 (100%) in these tissues. None of the 28 OKC samples carried the BRAF mutation. CONCLUSION: The positive expressions of GLUT-1, PK-M2 and HIF-1α indicate that patients with OKCs undergo anaerobic glycolysis to a certain extent, but these processes appear to be irrelevant to clinicopathological features and to the BRAF mutation.

Emerging Role of High Glucose Levels in Cancer Progression and Therapy.

Extensive research has indicated that high glucose levels play an important role in cancer. A high glycaemic index, glycaemic load diet, high sugar intake, high blood glucose and diabetes mellitus all increase the risk of cancer. Various signals are involved in high glucose-induced tumorigenesis, cancer proliferation, apoptosis, invasion and multidrug resistance. Reactive oxygen species might be important targets in cancer progression that are induced by high glucose levels. Drugs such as metformin and resveratrol may inhibit high glucose-induced cancer. As the impact of high glucose levels on cancer progression and therapy is a novel finding, further research is required.

The role of circular RNAs in brain and stroke.

Circular RNAs are single-stranded RNAs which are closed by covalent bonds during splicing. Different from other RNAs, circular RNAs are well known due to their circular structure. In recent years, many researches were conducted to investigate the role of circular RNAs in multiple diseases. To better understand the structure of circular RNAs, we reviewed the biogenesis and related regulation at first. Mechanisms by which circular RNAs exert effects were summarized then. Due to the conserved and brain-specific characteristic, circular RNAs in brain were depicted next. At last, considering the high mortality rate and disability rate caused by stroke globally, we reviewed related articles and summarized the results of original articles. Circular RNAs are suggested to be involved in the pathogenesis of stroke as well as some other neurological diseases which provides new insights and potential targets in clinical application.

Genetic polymorphisms in pri-let-7a-2 are associated with ischemic stroke risk in a Chinese Han population from Liaoning, China: a case-control study.

Ischemic stroke is a complicated disease, and its pathogenesis has been attributed to the occurrence of genetic polymorphisms. Evidence has suggested that the microRNA let-7a is involved in the pathogenesis of ischemic stroke. Pri-miRNA is the primary transcript, which undergoes several processing steps to generate pre-miRNA and, later, mature miRNAs. In this case-control study, we analyzed the distribution of pri-let-7a-2 variants in patients at a high risk for ischemic stroke and the interactions of pri-let-7a-2 variants and environmental factors. Blood samples and clinical information were collected from 1086 patients with ischemic stroke and 836 healthy controls between December 2013 and December 2015 at the First Affiliated Hospital of China Medical University. We found that the rs1143770 CC genotype and the C allele were associated with a decreased risk of ischemic stroke, whereas the rs629367 CC genotype was associated with an increased risk for ischemic stroke. Moreover, these two single-nucleotide polymorphisms were in linkage disequilibrium in this study sample. We analyzed gene-environment interactions and found that rs1143770 exerted a combined effect on the pathogenesis of ischemic stroke, together with alcohol use, smoking, and a history of hypertension. Therefore, the detection of pri-let-7a-2 polymorphisms may increase the awareness of ischemic stroke risk. This study was approved by the Institutional Ethics Committee of the First Affiliated Hospital of China Medical University, China (approval No. 2012-38-1) on February 20, 2012, and was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-COC-17013559) on December 27, 2017.

miR-762 Promotes Malignant Development of Head and Neck Squamous Cell Carcinoma by Targeting PHLPP2 and FOXO4.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is among the most common malignant tumors worldwide. This study, investigated the role of microRNA (miR)-762 in regulating HNSCC progression. MATERIALS AND METHODS: The expression levels of miR-762 in HNSCC tissues were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Statistical analyses were performed to investigate the association of miR-762 with clinicopathological features in patients with HNSCC. Cell proliferation and migration were examined by cell counting (CCK-8) and IncuCyte assays. Target genes of miR-762 were screened using bioinformatics tools and microarrays, and confirmed using a luciferase activity reporter assay, qRT-PCR and Western blot analysis. Recuse experiments were performed to detect whether target genes mediated the effects of miR-762 on HNSCC cells. The in vivo effects of miR-762 were verified using tumor xenografts. RESULTS: HNSCC clinical specimens showed high expression levels of miR-762, which positively correlated with tumor-node-metastasis (TNM) stage and poor prognosis of HNSCC. miR-762 overexpression promoted the proliferation and migration of HNSCC cells in vitro. In addition, overexpression of miR-762 upregulated the expression of phosphorylated AKT (p-AKT) and mesenchymal markers (N-cadherin and vimentin), but suppressed epithelial marker (E-cadherin) expression. miR-762 also promoted HNSCC tumor growth in vivo. PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) and Forkhead box O4 (FOXO4) were direct target genes of miR-762. HNSCC tissues had low expression levels of PHLPP2 and FOXO4, showing a negative correlation with miR-762 expression. Moreover, silencing of PHLPP2 and FOXO4 mimicked the tumor-promotive effects of miR-762 on HNSCC cells. Notably, overexpression of PHLPP2 and FOXO4 abolished the pro-tumoral function of miR-762 on cell proliferation and migration. CONCLUSION: miR-762 promotes HNSCC progression by targeting PHLPP2 and FOXO4. Therefore, miR-762 might be a potential diagnostic or therapeutic target for HNSCC.

RUNX1 and RUNX2 upregulate Galectin-3 expression in human pituitary tumors.

Galectin-3 is expressed in a cell-type specific manner in human pituitary tumors and may have a role in pituitary tumor development. In this study, we hypothesized that Galectin-3 is regulated by RUNX proteins in pituitary tumors. Transcription factor prediction programs revealed several putative binding sites in the LGALS3 (Galectin-3 gene) promoter region. A human pituitary cell line HP75 was used as a model to study LGALS3 and RUNX interactions using Chromatin immunoprecipitation assay and electrophoresis mobility shift assay. Two binding sites for RUNX1 and one binding site for RUNX2 were identified in the LGALS3 promoter region. LGALS3 promoter was further cloned into a luciferase reporter, and the experiments showed that both RUNX1 and RUNX2 upregulated LGALS3. Knock-down of either RUNX1 or RUNX2 by siRNA resulted in a significant downregulation of Galectin-3 expression and decreased cell proliferation in the HP 75 cell line. Immunohistochemistry showed a close correlation between Galectin-3 expression and RUNX1/RUNX2 level in pituitary tumors. These results demonstrate a novel binding target for RUNX1 and RUNX2 proteins and suggest that Galectin-3 is regulated by RUNX1 and RUNX2 in human pituitary tumor cells by direct binding to the promoter region of LGALS3 and thus may contribute to pituitary tumor progression.

Association of DNA methylation and epigenetic inactivation of RASSF1A and beta-catenin with metastasis in small bowel carcinoid tumors.

We analyzed promoter methylation of RASSF1A, CTNNB1, CDH1, LAMB3, LAMC2, RUNX3, NORE1A, and CAV1 using methylation-specific PCR in 33 cases of small bowel carcinoid with both matched primary and metastatic tumors. The methylation status of RASSF1A and CTNNB1 were also determined in six primary appendiceal carcinoid tumors. Two neuroendocrine cell lines, NCI-H727 and HTB-119, were analyzed for promoter methylation. Immunohistochemical analyses for RASSF1A and beta-catenin were performed in 28 matched primary and metastatic tumors. Western blot analysis for RASSF1A and beta-catenin was also performed. Normal enterochromaffin cells were unmethylated in all eight genes examined. RASSF1A and CTNNB1 were unmethylated in appendiceal carcinoids. Methylation of RASSF1A and CTNNB1 promoters was more frequent in metastatic compared to primary tumors (p = 0.013 and 0.004, respectively). The NCI-H727 and HTB-119 cells lines were methylated in the RASSF1A promoter region, and after treatment with 5-aza-2'-deoxycytidine (5-AZA), RASSF1A mRNA was expressed in both cell lines. Western blot results for RASSF1A and beta-catenin supported the methylation-specific PCR findings. The other six genes did not show significant differences. These results suggest that increased methylation of RASSF1A and CTNNB1 may play important roles in progression and metastasis of small bowel carcinoid tumors.