The variants in PTPRB, TRAF3IP3, and DISC1 genes were associated with Graves' disease in the Chinese population.

Previously, a case series study was conducted on our part in which 5 patients with Graves' disease (GD) were collected from a 3-generation family to screen for susceptibility genes responsible for GD. The single nucleotide variants of Microtubule-associated protein 7 domain containing 2 c. 452C > T, p. Ala151Val, Solute carrier family 1 member 7 c. 1204C > T, p. Arg402Cys, tumor necrosis factor receptor-associated factor 3 interacting protein 3 (TRAF3IP3) c. 209A > T, p. Asn70Ile, protein tyrosine phosphatase receptor type B (PTPRB) c. 3472A > G, p. Ser1158Gly, Phosphoinositide-3-kinase regulatory subunit 3 c. 121C > T, p. Pro41Ser, disrupted in schizophrenia 1 (DISC1), c. 1591G > C p. Gly531Arg were associated with the familial GD. We then further confirmed these variants and investigated whether other mutations render susceptibility to GD. The case-control study collected patients with sporadic GD or no GD family history. A snapshot program was used for genotyping the selected SNPs in 235 GD patients (GD group 1) and 284 healthy patients (control group). Furthermore, another 184 GD patients were recruited (GD group 2) to sequence the specified exons of these genes. The sequenced data was compared with Chinese Millionome Database (CMDB). Several variants of PTPRB, phosphoinositide-3-kinase regulatory subunit 3, TRAF3IP3, and DISC1 were found in GD group 2 but not in CMDB. Moreover, the allele frequency of SNP rs2076150 (TRAF3IP3) and rs2492367 DISC1 in GD group 2 was significantly higher than that of in CMDB (all P < .05). When the control group or CMDB was set as a reference group, a significantly higher frequency in alter allele C of SNP rs186466118 PTPRB was observed in GD group 1 and GD group (constituted by GD group 1 and GD group 2). Equally importantly, there was a correlation between the allele C of SNP rs186466118 and the increased risk of GD susceptibility (all P < .05). PTPRB, TRAF3IP3, and DISC1 may be susceptibility genes for GD, and more variants of PTPRB, TRAF3IP3, and DISC1 were found in GD patients.

Downregulation of miR-224-5p Promotes Migration and Proliferation in Human Dental Pulp Stem Cells.

INTRODUCTION: Pulp regeneration, as a treatment for pulp necrosis, has significant advantages over root canal therapy for the preservation of living pulp. To date, research on pulp regeneration has mainly focused on the transplantation of pulp stem cells into the root canal, but there is still a lack of research on the migration of pulp cells into the root canal via cell homing. Stem cells from the apical tooth papilla (SCAP) are recognized as multidirectional stem cells, but these cells are difficult to obtain. MicroRNAs are small noncoding RNAs that play crucial roles in regulating normal and pathologic functions. We hypothesized that some types of microRNAs might improve the migration and proliferation function of dental pulp stem cells (DPSCs), which are easily obtained in clinical practice, and as a result, DPSCs might replace SCAP and provide valuable information for regenerative endodontics. METHODS: Magnetic activated cell sorting of DPSCs and SCAP was performed. Next-generation sequencing was performed to examine DPSCs and SCAP miRNAs expression and to identify the most significant differentially expressed miRNA. CCK-8 and transwell assays were used to determine the impact of this miRNA on DPSCs proliferation and migration. RESULTS: The most significant differentially expressed miRNA between DPSCs and SCAP was miR-224-5p. Downregulating miR-224-5p promoted DPSCs proliferation and migration; the opposite results were observed when miR-224-5p was upregulated. CONCLUSION: MiR-224-5p promotes proliferation and migration in DPSCs, a finding that is of great significance for further exploring the role of dental pulp stem cells in regenerative endodontics.

ERBB2-modulated ATG4B and autophagic cell death in human ARPE19 during oxidative stress.

Age-related macular degeneration (AMD) is an ocular disease with retinal degeneration. Retinal pigment epithelium (RPE) degeneration is mainly caused by long-term oxidative stress. Kinase activity could be either protective or detrimental to cells during oxidative stress; however, few reports have described the role of kinases in oxidative stress. In this study, high-throughput screening of kinome siRNA library revealed that erb-b2 receptor tyrosine-protein kinase 2 (ERBB2) knockdown reduced reactive oxygen species (ROS) production in ARPE-19 cells during oxidative stress. Silencing ERBB2 caused an elevation in microtubule associated protein light chain C3-II (MAP1LC3B-II/I) conversion and sequesterone (SQSTM)1 protein level. ERBB2 deprivation largely caused an increase in autophagy-regulating protease (ATG4B) expression, a protease that negatively recycles MAP1LC3-II at the fusion step between the autophagosome and lysosome, suggesting ERBB2 might modulate ATG4B for autophagy induction in oxidative stress-stimulated ARPE-19 cells. ERBB2 knockdown also caused an accumulation of nuclear factor erythroid 2-related factor 2 (NRF2) and enhanced its transcriptional activity. In addition, ERBB2 ablation or treatment with autophagy inhibitors reduced oxidative-induced cytotoxic effects in ARPE-19 cells. Furthermore, ERBB2 silencing had little or no additive effects in ATG5/7-deficient cells. Taken together, our results suggest that ERBB2 may play an important role in modulating autophagic RPE cell death during oxidative stress, and ERBB2 may be a potential target in AMD prevention.

Concurrent preoperative chemotherapy and three-dimensional conformal radiotherapy followed by surgery for oral squamous cell carcinoma: a retrospective analysis of 104 cases.

OBJECTIVES: The objectives of this study were to assess the clinical effects of an integrated program consisting of concurrent preoperative combined paclitaxel and nedaplatin chemotherapy and three-dimensional conformal radiotherapy followed by surgery intended to cure oral squamous cell carcinoma and to determine whether this integrated program is feasible and effective with respect to the treatment of oral squamous cell carcinoma. METHODS: A total of 104 biopsy-confirmed patients who presented with oral squamous cell carcinoma for the first time were included in this study. Concurrent preoperative combined paclitaxel and nedaplatin chemotherapy and three-dimensional conformal radiotherapy were administered to these patients. The most common treatment regimen consisted of infusions of paclitaxel (135-175 mg/m2/day), infusions of nedaplatin (150 mg; 80-100 mg/m2/day), and irradiation at doses ranging from 1.5 Gy twice daily to 30-40 Gy over 3-4 weeks. The clinical variables evaluated herein included the local recurrence rate, distant metastasis rate, postoperative survival rate, and degree of mouth opening restriction. RESULTS: The median follow-up time for surviving patients was 60 months, and the median time to progression for all patients was 57.69 months (95% confidence interval, 56.09 to 59.29 months, and the 3-year disease-free survival probability was 97.11%). The effectiveness rate of the integrated program was 98.08%, and the surgery resection rate was 100%. Only a few postoperative adverse reactions were observed. The local recurrence and distant metastasis rates were 1.92% (2 patients) and 2.88% (3 patients), respectively. The titanium rejection and infection reaction rate that led to restriction of mouth opening was only 2.88% (3 patients). Finally, the 5-year post-surgery survival rate was 91.35% (95 patients). CONCLUSION: Preoperative combined paclitaxel and nedaplatin chemotherapy and three-dimensional conformal radiotherapy have significant clinical effects leading to positive anti-tumor results in patients with oral squamous cell carcinoma. These treatments also increase the likelihood that patients will undergo successful surgical treatment. The integrated program described herein can increase long-term survival and surgery resection rates and is associated with only a limited number of adverse reactions.

Differential autophagic effects of vital dyes in retinal pigment epithelial ARPE-19 and photoreceptor 661W cells.

Indocyanine green (ICG) and brilliant blue G (BBG) are commonly used vital dyes to remove internal limiting membrane (ILM) in vitreoretinal surgery. The vital dyes have shown cytotoxic effects in ocular cells. Autophagy is a stress responsive pathway for either protecting cells or promoting cell death. However, the role of autophagy in ocular cells in response to the vital dyes remains unknown. In this study, we found that ICG and BBG reduced cell viability in both human retinal pigment epithelial ARPE-19 and mouse photoreceptor 661W cells. ICG and BBG induced lipidated GFP-LC3-II and LC3-II in ARPE-19 and 661W cells. Combination treatment with the autophagy inhibitor chloroquine indicated that ICG and BBG reduced autophagic flux in ARPE-19 cells, whereas the vital dyes induced autophagic flux in 661W cells. Moreover, genetic and pharmacological ablation of autophagy enhanced vital dyes-induced cytotoxicity in ocular cells. Dietary supplements, including resveratrol, lutein, and CoQ10, induced autophagy and diminished the cytotoxic effects of ICG and BBG in ocular cells. These results suggest that autophagy may protect ARPE-19 and 661W cells from vital dyes-induced damage.