ABSTRACT
Ovarian cancer (OC) was the fifth leading cause of cancer death and the deadliest gynecological cancer in women. This was largely attributed to its late diagnosis, high therapeutic resistance, and a dearth of effective treatments. Clinical and preclinical studies have revealed that tumor-infiltrating CD8+T cells often lost their effector function, the dysfunctional state of CD8+T cells was known as exhaustion. Our objective was to identify genes associated with exhausted CD8+T cells (CD8TEXGs) and their prognostic significance in OC. We downloaded the RNA-seq and clinical data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. CD8TEXGs were initially identified from single-cell RNA-seq (scRNA-seq) datasets, then univariate Cox regression, the least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression were utilized to calculate risk score and to develop the CD8TEXGs risk signature. Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, time-dependent receiver operating characteristics (ROC), nomogram, and calibration were conducted to verify and evaluate the risk signature. Gene set enrichment analyses (GSEA) in the risk groups were used to figure out the closely correlated pathways with the risk group. The role of risk score has been further explored in the homologous recombination repair deficiency (HRD), BRAC1/2 gene mutations and tumor mutation burden (TMB). A risk signature with 4 CD8TEXGs in OC was finally built in the TCGA database and further validated in large GEO cohorts. The signature also demonstrated broad applicability across various types of cancer in the pan-cancer analysis. The high-risk score was significantly associated with a worse prognosis and the risk score was proven to be an independent prognostic biomarker. The 1-, 3-, and 5-years ROC values, nomogram, calibration, and comparison with the previously published models confirmed the excellent prediction power of this model. The low-risk group patients tended to exhibit a higher HRD score, BRCA1/2 gene mutation ratio and TMB. The low-risk group patients were more sensitive to Poly-ADP-ribose polymerase inhibitors (PARPi). Our findings of the prognostic value of CD8TEXGs in prognosis and drug response provided valuable insights into the molecular mechanisms and clinical management of OC.
Subject(s)
CD8-Positive T-Lymphocytes , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/genetics , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Prognosis , RNA-Seq/methods , Biomarkers, Tumor/genetics , Single-Cell Analysis/methods , Gene Expression Regulation, Neoplastic , Single-Cell Gene Expression AnalysisABSTRACT
BACKGROUND: The aim of the study was to investigate the role of the genetic variation of glutathione S-transferase M1 (GSTM1) in the development of ovarian endometriosis and endometriosis-related primary infertility risk. METHODS: This case-control study included 564 women with ovarian endometriosis and 576 normal women in the control group in northern China. The polymorphism of GSTM1 was genotyped by polymerase chain reaction (PCR)/ligase detection reaction method. To assess the biological significance of polymorphisms, the level of GSTM1 mRNA expression in patients' endometrial tissues with different genotypes was detected by quantitative real-time PCR (qRT-PCR). RESULTS: Compared with the positive genotype, the null genotype of GSTM1 was associated with the risk of developing ovarian endometriosis (OR = 1.29, 95% CI = 1.02-1.62). Further analysis showed that patients with a null genotype also had a significantly higher risk of primary infertility than patients with positive genotypes (OR = 1.59, 95% CI = 1.01-2.49). In addition, we found that GSTM1 mRNA expression was present in the endometrial tissue of all patients, but the expression level of patients with a positive genotype was nearly 10 times higher than that of patients with a negative genotype. CONCLUSION: Our results suggest that the GSTM1 polymorphism is not only related to the genetic susceptibility to ovarian endometriosis but also a potential molecular marker of primary infertility in patients with ovarian endometriosis.
Subject(s)
Endometriosis , Case-Control Studies , Endometriosis/genetics , Female , Genetic Predisposition to Disease , Genotype , Glutathione Transferase/genetics , Humans , Infertility, Female , Polymorphism, GeneticABSTRACT
OBJECTIVE: Polymorphisms of T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) were reported to be associated with cancer risk and patients' survival. This study aims to investigate the correlation of TIM-3 polymorphisms with susceptibility to epithelial ovarian cancer (EOC) and patients' outcomes. METHODS: A total of 700 EOC patients and 710 healthy controls from North China were included. The polymorphisms (rs10053538, rs10515746 and rs1036199) were genotyped using the polymerase chain reaction/ligase detection reaction (PCR-LDR) method. Survival data were available for 339 patients after cytoreductive surgery. The expression level of TIM-3 was detected by real-time quantitative PCR (RT-qPCR). The prognostic value of TIM3 in EOC patients was assessed using the Kaplan-Meier plotter database. RESULTS: The results showed that none of the TIM3 polymorphisms were associated with the risk of developing EOC. Patients with the rs10053538 CA + AA genotype had worse PFS and OS than those with the CC genotype (HR = 1.49, 95% CI = 1.05-2.09, P = 0.024 and HR = 1.57, 95%CI = 1.09-2.26, P = 0.017, respectively). The RT-qPCR results showed that the expression levels of TIM-3 mRNA in EOC tissues with the rs10053538CA + AA genotypes were significantly higher than those with the CC genotype (P = 0.006). Analysis using the Kaplan-Meier plotter database showed that high expression of TIM-3 mRNA was significantly associated with shorter PFS and OS in EOC patients (HR = 1.57, 95%CI = 1.29-1.91, P < 0.001 and HR = 1.31, 95% CI = 1.06-1.63, P = 0.013, respectively). CONCLUSIONS: TIM-3 polymorphisms were not associated with risk of developing EOC. Both rs10053538 and the expression level of TIM-3 mRNA may be associated with its clinical outcome in EOC patients.
Subject(s)
Carcinoma, Ovarian Epithelial/genetics , Cytoreduction Surgical Procedures , Hepatitis A Virus Cellular Receptor 2/genetics , Neoplasm Recurrence, Local/epidemiology , Ovarian Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Carcinoma, Ovarian Epithelial/diagnosis , Carcinoma, Ovarian Epithelial/mortality , Carcinoma, Ovarian Epithelial/surgery , Case-Control Studies , China/epidemiology , Disease-Free Survival , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Recurrence, Local/genetics , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/mortality , Ovarian Neoplasms/surgery , Ovary/pathology , Ovary/surgery , Polymorphism, Single Nucleotide , Prognosis , Progression-Free Survival , Up-Regulation , Young AdultABSTRACT
OBJECTIVES: Glass fiber reinforced shape memory polyurethane (GFRSMPU) has great potential to be an alternative kind of material for orthodontic archwires for overcoming the disadvantages of metal wires in terms of esthetic and allergy and deficiency of pure shape memory polyurethane (SMPU) wires in mechanical properties. The objective of this study was to investigate the thermo-mechanical properties and shape recovery functions of GFRSMPU and evaluate the feasibility of using this composite for orthodontic archwires. MATERIAL AND METHODS: GFRSMPU were made from short cut glass fibers and SMPU by mixing extrusion. Scanning electron microscope (SEM) and differential scanning calorimetry (DSC) were performed to investigate the distribution of glass fibers in the mixture and glass transition temperature (Tg). Then the thermo-mechanical properties, including tensile modulus, flexural modulus and stress relaxation effects, were measured. Furthermore, shape recovery functions of GFRSMPU characterized by the shape recovery ratio and force were investigated through shape recovery tests, typodont models and finite element analysis (FEA). RESULTS: SEM images indicated that an excellent dispersity of glass fibers was obtained after double-extrusion. DSC experiments showed Tg was not enormously affected with the existence of glass fibers, but the mechanical properties of GFRSMPU were greatly improved. Shape recovery tests showed reduction of shape recovery ratio of the GFRSMPU material with the addition of glass fibers, but dentition aligning time was reduced by 50% in the simulation performed on identical typodont models with GFRSMPU archwires filled with 30 wt.% glass fibers. The FEA results illustrated that the reacting forces of GFRSMPU archwires with 30 wt.% glass fiber was increased by 96.36% compared with pure SMPU archwires. CONCLUSIONS: The mechanical properties of GFRSMPU can be considerably improved by adding glass fibers, and the shape memory function would be well preserved too. Enhanced SMPU owns a good application prospect in orthodontics for dentation aligning on the preliminary stage, as well as other medical fields.
Subject(s)
Biocompatible Materials , Glass , Materials Testing , Polyurethanes/chemistry , Dental Materials/chemistry , Pliability , Stress, Mechanical , Surface PropertiesABSTRACT
Excessive forces may cause root resorption and insufficient forces would introduce no effect in orthodontics. The objective of this study was to investigate the optimal orthodontic forces on a maxillary canine, using hydrostatic stress and logarithmic strain of the periodontal ligament (PDL) as indicators. Finite element models of a maxillary canine and surrounding tissues were developed. Distal translation/tipping forces, labial translation/tipping forces, and extrusion forces ranging from 0 to 300 g (100 g=0.98 N) were applied to the canine, as well as the force moment around the canine long axis ranging from 0 to 300 g·mm. The stress/strain of the PDL was quantified by nonlinear finite element analysis, and an absolute stress range between 0.47 kPa (capillary pressure) and 12.8 kPa (80% of human systolic blood pressure) was considered to be optimal, whereas an absolute strain exceeding 0.24% (80% of peak strain during canine maximal moving velocity) was considered optimal strain. The stress/strain distributions within the PDL were acquired for various canine movements, and the optimal orthodontic forces were calculated. As a result the optimal tipping forces (40-44 g for distal-direction and 28-32 g for labial-direction) were smaller than the translation forces (130-137 g for distal-direction and 110-124 g for labial-direction). In addition, the optimal forces for labial-direction motion (110-124 g for translation and 28-32 g for tipping) were smaller than those for distal-direction motion (130-137 g for translation and 40-44 g for tipping). Compared with previous results, the force interval was smaller than before and was therefore more conducive to the guidance of clinical treatment. The finite element analysis results provide new insights into orthodontic biomechanics and could help to optimize orthodontic treatment plans.
Subject(s)
Cuspid/physiology , Models, Dental , Biomechanical Phenomena , Computer Simulation , Cuspid/anatomy & histology , Finite Element Analysis , Humans , Imaging, Three-Dimensional , Maxilla , Orthodontic Friction/physiology , Periodontal Ligament/physiology , Rotation , Stress, Mechanical , Tooth Movement Techniques/statistics & numerical dataABSTRACT
PURPOSE: During dental implantation, if the temperature within the bone tissue exceeds a critical value, the thermal necrosis of bone cells may take place, inhibiting osseointegration. In contrast to conventional dental implant surgery, a surgery guided by a surgical template is a safer and more efficient technique; however, the temperature within the implant field is more difficult to control, because the surgical guide blocks irrigation water. The purpose of this study was to investigate the temperature distribution in the drilling site when preparing for dental implant placement with a surgical guide, and to derive suggestions for clinical operation. MATERIALS AND METHODS: Initially, the sources of heat during drilling were investigated, and theoretical equations were listed. Subsequently, a measurement system using thermocouples was constructed, with which the temperature increments at specific points in the simulated bone samples were recorded during guided drilling with different cooling methods. Based on the equations and data assessed, a thermal simulation model with a finite element method (FEM) was created, and the temperature change of the whole surgical field was calculated on the basis of the numerical simulation results. Consequently, the point experiencing the highest temperature within the bone was determined. RESULTS: From the experimental measurements, the highest temperature increment was located at a depth of 6 mm without irrigation and at 8 mm with cooling, rather than at the deepest point of the prepared hole. Because the surgical guide blocks the cooling water from entering the drilling site, the biggest increment of temperature using conventional irrigation with the surgical guide was 1.95 times that recorded when using a surgical guide consisting of cooling channels, and 3.6 times that recorded using a drill with an internal cooling hole. And from numerical analysis, during drilling for implant placement site with conventional irrigation, the highest temperature (45.6°C) was close to the critical point at which bone necrosis occurs. CONCLUSIONS: Based on theoretical analysis, experimentation, and FEM simulation, the temperature distribution of the drilling area in the placement of dental implants under surgical guide was determined. For clinical operation, improved cooling methods, such as using a drill with an internal cooling channel, should be used, and the drill should be regularly withdrawn during drilling.