Secular changes in dental development of Korean children aged 4 to 16 years over a 10-year period

This study evaluated 10-year secular changes in dental maturity and dental development among Korean children. A retrospective analysis of panoramic radiograph samples from Korean children (4–16 years old) taken in 2010 and 2020 was conducted. The 2010 group consisted of 3491 radiographs (1970 boys and 1521 girls), and the 2020 group included 5133 radiographs (2825 boys and 2308 girls). Using Demirjian’s method, dental maturity scores and dental developmental stages were assessed. For intra-observer reliability, Weighted Cohen’s kappa was used, and Mann-Whitney U tests were performed to compare the 2020 and 2010 groups. A slight acceleration in dental maturity was observed in both boys and girls, with the difference being more noticeable in boys at an earlier age. Statistically significant differences were noted at ages 4, 5 and 7 for boys, and at age 6 for girls. Despite these differences, the individual dental development stages of 2020 and 2010 showed inconsistent trends with limited differences. Generally, girls demonstrate more advanced dental maturity than boys. A slight acceleration in Korean children’s dental maturity was observed over a 10-year period when comparing the 2020 groups to the 2010 groups

Whole-exome sequencing in 168 Korean patients with inherited retinal degeneration

Background To date, no genetic analysis of inherited retinal disease (IRD) using whole-exome sequencing (WES) has been conducted in a large-scale Korean cohort. The aim of this study was to characterise the genetic profile of IRD patients in Korea using WES. Methods We performed comprehensive molecular testing in 168 unrelated Korean IRD patients using WES. The potential pathogenicity of candidate variants was assessed using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant interpretation guidelines, in silico prediction tools, published literature, and compatibility with known phenotypes or inheritance patterns. Results Causative variants were detected in 86/168 (51.2%) IRD patients, including 58/107 (54.2%) with retinitis pigmentosa, 7/15 (46.7%) with cone and cone-rod dystrophy, 2/3 (66.6%) with Usher syndrome, 1/2 (50.0%) with congenital stationary night blindness, 2/2 (100.0%) with Leber congenital amaurosis, 1/1 (100.0%) with Bietti crystalline dystrophy, 1/1 (100.0%) with Joubert syndrome, 9/10 (90.0%) with Stargardt macular dystrophy, 1/10 (10.0%) with vitelliform macular dystrophy, 1/11 (9.1%) with other forms of macular dystrophy, and 3/4 (75.0%) with choroideraemia. USH2A, ABCA4, and EYS were the most common causative genes associated with IRD. For retinitis pigmentosa, variants of USH2A and EYS were the most common causative gene mutations. Conclusions This study demonstrated the distribution of causative genetic mutations in Korean IRD patients. The data will serve as a reference for future genetic screening and development of treatment modalities for Korean IRD patients.This study was supported by the Korean Association of Retinal Degenera‑tion, by a Grant Number 2620170060 from the SNUH Research Fund, and by a grant of the Korea Research-Driven Hospital (Grant Number: HI14C1277) through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare (MHW), Republic of Korea. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript

Characterization of Side Populations in HNSCC: Highly Invasive, Chemoresistant and Abnormal Wnt Signaling

Side Population (SP) cells, a subset of Hoechst-low cells, are enriched with stem cells. Originally, SP cells were isolated from bone marrow but recently have been found in various solid tumors and cancer cell lines that are clonogenic in vitro and tumorigenic in vivo. In this study, SP cells from lymph node metastatic head and neck squamous cell carcinoma (HNSCC) cell lines were examined using flow cytometry and Hoechst 3342 efflux assay. We found that highly metastatic HNSCC cell lines M3a2 and M4e contained more SP cells compared to the low metastatic parental HNSCC cell line 686LN. SP cells in HNSCC were highly invasive in vitro and tumorigenic in vivo compared to non-SP cells. Furthermore, SP cells highly expressed ABCG2 and were chemoresistant to Bortezomib and etoposide. Importantly, we found that SP cells in HNSCC had abnormal activation of Wnt/β-catenin signaling as compared to non-SP cells. Together, these findings indicate that SP cells might be a major driving force of head and neck tumor formation and metastasis. The Wnt/β-catenin signaling pathway may be an important target for eliminating cancer stem cells in HNSCC

Epigenetic Regulation of Head and Neck Squamous Cell Carcinoma Chemoresistance, Invasion, and Metastasis

Development of chemoresistance, invasive growth, and metastasis remain key challenges in head and neck squamous cell carcinoma (HNSCC) therapy. Recent studies revealed that an activated hepatocyte growth factor receptor (MET) is frequently overexpressed and highly associated with HNSCC invasion and metastasis. Also, autophagy, a highly conservative intracellular recycling system, has shown to play a primary role in cancer cells to attenuate cytotoxicity of chemoreagents in many hematopoietic and solid cancers. However, little is known about the epigenetic regulation of the MET signaling pathway or autophagy induction and whether it plays a role in promoting HNSCC invasion and metastasis or development of resistance to therapy. In our study, we found that histone deacetylase 6 (HDAC6) is a key epigenetic regulator of autophagy that promotes chemoresistance in HNSCC against the proteasome inhibitor, Bortezomib. The depletion of HDAC6 inhibited autophagy activation and enhanced Bortezomib-induced apoptosis in HNSCC cells. Mechanistically, we revealed that HDAC6 mediated activation of autophagy by modulating activation of protein kinases such as unc-51 like autophagy activating kinase 1 (ULK1) to promote clearing of large quantities of cytotoxic, unfolded protein aggregates induced by the Bortezomib. In addition, we found histone demethylases KDM6B plays an important role in acquiring cisplatin resistance in HNSCC and in unraveling the mechanism associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Interestingly, we also identified KDM6B as an essential epigenetic regulator of MET-driven HNSCC metastasis. KDM6B was highly expressed in both the growth factor-induced HNSCC cells and in cells overexpressing the oncogenic translocated promoter region MET (TPR-MET). KDM6B knockdown significantly decreased the HNSCC invasion and metastasis by regulating the expression of ETS proto-oncogene 1 (ETS1) and the high mobility group AT-Hook 2 (HMGA2) genes, known as the drivers of metastasis. Mechanistically, KDM6B facilitated the binding of the transcription factor ELK1, a downstream target of c-MET signaling pathway, to the promoters of ETS1 and HMGA2. In conclusion, our study provides insight into the epigenetic regulation of HNSCC chemoresistance, invasion, and metastasis and suggests that HDAC6 and KDM6B could be an important therapeutic target to improve chemotherapeutic efficacy and to decrease the tumor burden of HNSCC patients

Endodontic treatment of maxillary incisor with dens invaginatus and dens exvaginatus: Case report

Dens Invaginatus (DI) and talon cusp are rare dental malformations involving complicated clinical and anatomical features and pose many approaches to managing the case. In this case, lingual caries led to pulp necrosis on tooth #10 with two Type II Oehler's DI chambers with talon cusp. Nonsurgical endodontic treatment was achieved using modern endodontic techniques and material. On the other hand, tooth #7 with Type I Oehler’s DI with lingual caries was not associated with pulp pathosis and indicated with a preventative treatment approach.&nbsp;</p

Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy.

Chemoresistance is a major barrier to effective chemotherapy of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Recently, autophagy, a highly conservative intracellular recycling system, has shown to be associated with chemoresistance in cancer cells. However, little is known about how autophagy plays a role in the development of chemoresistance in HNSCC and how autophagy is initiated when HNSCC cells undergo cytotoxic stress. Here, we report that autophagy was activated when HNSCC cells are treated with the proteasome inhibitor bortezomib, proposed as an alternative chemotherapeutic agent for both primary and cisplatin-resistant HNSCC cells. Ablation of histone deacetylase 6 (HDAC6) expression and its activity in HNSCC cells significantly inhibited autophagy induction by altering the phosphorylation status of mammalian target of rapamycin and enhanced the bortezomib cytotoxicity. Similarly, a combination regimen of bortezomib and the histone deacetylase inhibitor trichostatin A abolished HDAC6 activity and decreased autophagy induction while significantly enhancing bortezomib-induced apoptosis in HNSCC cells. These data uncover a novel molecular mechanism indicating that HDAC6 may serve as a critical causal link between autophagy, apoptosis, and the cell survival response in HNSCC. A combination regimen resulting in regression of autophagy improves chemotherapeutic efficacy, thereby providing a new strategy to overcome chemoresistance and to improve the treatment and survival of HNSCC patients

Loss of KDM4B impairs osteogenic differentiation of OMSCs and promotes oral bone aging

Aging of craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects, and complicates dental treatment outcomes. Age-related alveolar bone loss could be attributed to decreased progenitor pool through senescence, imbalance in bone metabolism and bone-fat ratio. Mesenchymal stem cells isolated from oral bones (OMSCs) have distinct lineage propensities and characteristics compared to MSCs from long bones, and are more suited for craniofacial regeneration. However, the effect of epigenetic modifications regulating OMSC differentiation and senescence in aging has not yet been investigated. In this study, we found that the histone demethylase KDM4B plays an essential role in regulating the osteogenesis of OMSCs and oral bone aging. Loss of KDM4B in OMSCs leads to inhibition of osteogenesis. Moreover, KDM4B loss promoted adipogenesis and OMSC senescence which further impairs bone-fat balance in the mandible. Together, our data suggest that KDM4B may underpin the molecular mechanisms of OMSC fate determination and alveolar bone homeostasis in skeletal aging, and present as a promising therapeutic target for addressing craniofacial skeletal defects associated with age-related deteriorations

Mycoplasma hyorhinis infection promotes TNF-α signaling and SMAC mimetic-mediated apoptosis in human prostate cancer

Growing evidence suggests an association between Mycoplasma infections and the development and progression of prostate cancer (PCa). In this study, we report that chronic and persistent M. hyorhinis infection induced robust TNF-α secretion from PCa cells. TNF-α secreted from M. hyorhinis-infected PCa cells subsequently led to activation of the NF-κB pathway. Chronic M. hyorhinis infection induced gene expression of pro-inflammatory cytokines and chemokines in a NF-κB-dependent manner and promoted cell proliferation, migration, and invasion in PCa cells. The elimination of M. hyorhinis in PCa cells significantly blocked TNF-α secretion, gene expression of cytokines and chemokines, migration, and invasion in PCa cells, suggesting M. hyorhinis-induced TNF-α plays an important role to promote malignant transformation of PCa. Furthermore, second mitochondria-derived activator of caspases (SMAC) mimetics potentiated caspase activation and cell death in M. hyorhinis-infected PCa by antagonizing inhibitor of apoptosis proteins (IAPs) activity. Tissue microarray analysis indicated that TNF-α is co-expressed in M. hyorhinis-infected human patient tissues. Findings from this study advance our understanding of the mycoplasma-oncogenesis process and suggest the potential for new approaches for preventions, diagnosis, and therapeutic approaches against prostate cancers

Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress

Developing strategies to activate tumor-cell-intrinsic immune response is critical for improving tumor immunotherapy by exploiting tumor vulnerability. KDM4A, as a histone H3 lysine 9 trimethylation (H3K9me3) demethylase, has been found to play a critical role in squamous cell carcinoma (SCC) growth and metastasis. Here we report that KDM4A inhibition promoted heterochromatin compaction and induced DNA replication stress, which elicited antitumor immunity in SCC. Mechanistically, KDM4A inhibition promoted the formation of liquid-like HP1γ puncta on heterochromatin and stall DNA replication, which activated tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation. Moreover, KDM4A inhibition collaborated with PD1 blockade to inhibit SCC growth and metastasis by recruiting and activating CD8+ T&nbsp;cells. In&nbsp;vivo lineage tracing demonstrated that KDM4A inhibition plus PD1 blockade efficiently eliminated cancer stem cells. Altogether, our results demonstrate that targeting KDM4A can activate anti-tumor immunity and enable PD1 blockade immunotherapy by aggravating replication stress in SCC cells