Increased co-expression of 4-1BB with PD-1 on CD8+ tumor-infiltrating lymphocytes is associated with improved prognosis and immunotherapy response in cervical cancer

BackgroundThe combination of agonistic antibodies with immune checkpoint inhibitors presents a promising avenue for cancer immunotherapy. Our objective is to explore the co-expression of 4-1BB, ICOS, CD28, with PD-1 on CD8+ T cells in the peripheral blood and tumor tissue of cervical cancer(CC) patients, with a specific focus on the association between the co-expression levels of 4-1BB with PD-1 and clinical features, prognosis as well as immunotherapy response. The goal is to offer valuable insights into cervical cancer immunotherapy.MethodsIn this study, 50 treatment-naive patients diagnosed with CC were enrolled. Flow cytometry was used to detect PD-1/4-1BB, PD-1/ICOS and PD-1/CD28 co-expression on CD8+ T cells. Subsequent analysis aimed to investigate the differential co-expression between peripheral blood and cancer tissue, and also the correlation between co-expression and clinical features in these patients. Gene Expression Omnibus (GEO) datasets, The Cancer Genome Atlas (TCGA) cohort, The IMvigor210 cohort, The BMS038cohort and Immunophenoscores were utilized to investigate the correlation between PD-1/4-1BB and the immune microenvironment, prognosis, immunotherapy, and drug sensitivity in cervical cancer.ResultsThe co-expression levels of PD-1/4-1BB, PD-1/ICOS, and PD-1/CD28 on CD8+ tumor-infiltrating lymphocytes (TILs) were significantly higher in cervical cancer patients compared to those in peripheral blood. Clinical feature analysis reveals that on CD8+ TILs, the co-expression of PD-1/4-1BB is more closely correlated with clinical characteristics compared to PD-1/ICOS, PD-1/CD28, PD-1, and 4-1BB. Pseudo-time analysis and cell communication profiling reveal close associations between the subgroups harboring 4-1BB and PD-1. The prognosis, tumor mutation burden, immune landscape, and immunotherapy response exhibit statistically significant variations between the high and low co-expression groups of PD-1/4-1BB. The high co-expression group of PD-1/4-1BB is more likely to benefit from immunotherapy.ConclusionPD-1/4-1BB, PD-1/ICOS, and PD-1/CD28 exhibit elevated co-expression on CD8+TILs of cervical cancer, while demonstrating lower expression in circulating T cells. The co-expression patterns of PD-1/4-1BB significantly contributed to the prediction of immune cell infiltration characteristics, prognosis, and tailored immunotherapy tactics. PD-1/4-1BB exhibits potential as a target for combination immunotherapy in cervical cancer

Increased co-expression of TIM-3 with TIGIT or 2B4 on CD8+ T cells is associated with poor prognosis in locally advanced nasopharyngeal carcinoma

The use of immune checkpoint inhibitors in malignant tumors improves patient outcomes. Because single-agent immune checkpoint blockade has a low objective response rate, it is meaningful to explore combined blockade of immune checkpoint receptors. We aimed to investigate the co-expression of TIM-3 with TIGIT or 2B4 on peripheral blood CD8+ T cells from patients with locally advanced nasopharyngeal carcinoma. The correlation between co-expression level and clinical characteristics and prognosis was studied to provide a basis for immunotherapy for nasopharyngeal carcinoma. Flow cytometry was used to detect TIM-3/TIGIT and TIM-3/2B4 co-expression on CD8+ T cells. The differences in co-expression between patients and healthy controls were analyzed. The correlation between co-expression of TIM-3/TIGIT or TIM-3/2B4 and the patient clinical characteristics and prognosis was examined. Also, the correlation between the TIM-3/TIGIT or 2B4 co-expression and other common inhibitory receptors was analyzed. We further validated our results using mRNA data from the Gene Expression Omnibus (GEO) database. TIM-3/TIGIT and TIM-3/2B4 co-expression was upregulated on peripheral blood CD8+ T cells from patients with nasopharyngeal carcinoma. They were both correlated with poor prognosis. There was a correlation between TIM-3/TIGIT co-expression and patient age and pathological stage, whereas TIM-3/2B4 co-expression correlated with age and sex. CD8+ T cells with elevated mRNA levels of TIM3/TIGIT and TIM3/2B4 also showed increased expression of multiple inhibitory receptors, indicating T cell exhaustion in locally advanced nasopharyngeal carcinoma. TIM-3/TIGIT or TIM-3/2B4 can be used as potential targets for combination immunotherapy in locally advanced nasopharyngeal carcinoma

Experimental Research on Enhanced Denitrification by Biological Agents

Biological agents play a significant role in sewage treatment, with good removal effect, low sludge yield, good performance, and shorten the system start-up time, impact load resistance and stability enhancement.This paper describes the characteristics ofbiological agents and the effect of biological agents on wastewater denitrification was investigated through experiments, so as to provide effective basis support for the wide application of biological agents in the field of urban sewage treatment.The experiment showed that through reasonable addition of biological agents,the removal rates of COD,NH3-N and TNinlowpollutantsewage treatmentwere increased by 41%, 15% and 62% respectively

Thickness Impact on the Morphology, Strain Relaxation and Defects of Diamond Heteroepitaxially Grown on Ir/Al2O3 Substrates

This paper investigates the formation and propagation of defects in the heteroepitaxial growth of single-crystal diamond with a thick film achieving 500 µm on Ir (001)/Al2O3 substrate. The growth of diamond follows the Volmer–Weber mode, i.e., initially shows the islands and subsequently coalesces to closed films. The films’ strain imposed by the substrate gradually relaxed as the film thickness increased. It was found that defects are mainly located at the diamond/Ir interface and are then mainly propagated along the [001] direction from the nucleation region. Etching pits along the [001] direction formed by H2/O2 plasma treatment were used to show defect distribution at the diamond/Ir/Al2O3 interface and in the diamond bulk, which revealed the reduction of etching pit density in diamond thick-film surface. These results show the evident impact of the thickness on the heteroepitaxially grown diamond films, which is of importance for various device applications

Genomic profiles and their relationships with clinical characteristics and immune features in cervical cancer

Objective: This study aimed to investigate the genomic alteration profiles of cervical cancer patients, examine the correlation between mutation patterns and clinical and immune attributes, and discover novel targets for treatment of individuals with cervical cancer. Methods: We performed targeted next-generation sequencing of tumor tissues and blood samples obtained from 45 cervical cancer patients to analyze somatic alterations, mutation patterns, and HLA alleles comprehensively. Additionally, we used flow cytometry to assess expression levels of immune checkpoint genes. Results: Notably, genes such as AR (78%), KMT2D (76%), and NOTCH1 (62%) exhibited higher mutation frequencies. Moreover, the tumor mutation burden (TMB) was significantly greater in HPV-positive cervical cancer patients than in HPV-negative patients (P=0.029). BMI (P=0.047) and mutations in BARD1 (P=0.034), CEP290 (P=4E-04), and SLX4 (P=0.0128) were identified as predictors of shorter overall survival in cervical cancer patients. Furthermore, the present study revealed significant upregulation of PD-1 (P=0.027) and Tim-3 (P=0.048) in the high mutant-allele tumor heterogeneity (MATH) cohort. In the elderly cervical cancer patient population, HLA-A03:01 emerged as a high-risk allele (OR=3.2, P<0.0001); HLA-C07:02 (OR=0.073, P=0.02) and HLA-B*07:02 (OR=0.257, P=0.037) were associated with a reduced risk among patients with low TMB. Conclusions: This study offers insights into the mutation characteristics of cervical cancer patients and identifies potential therapeutic

Fabrication of a Micron-Scale Three-Dimensional Single Crystal Diamond Channel Using a Micro-Jet Water-Assisted Laser

Two types of a trench with conventional vertical and new reverse-V-shaped cross-sections were fabricated on single crystal diamond (SCD) substrate using a micro-jet water-assisted laser. In addition, a microwave plasma chemical vapor deposition device was used to produce multiple micrometer-sized channels using the epitaxial lateral overgrowth technique. Raman and SEM methods were applied to analyze both types of growth layer characterization. The hollowness of the microchannels was measured using an optical microscope. According to the findings, the epitaxial lateral overgrowth layer of the novel reverse-V-shaped trench produced improved SCD surface morphology and crystal quality

Normally-off Hydrogen-Terminated Diamond Field-Effect Transistor with SnO_x Dielectric Layer Formed by Thermal Oxidation of Sn

SnOx films were deposited on a hydrogen-terminated diamond by thermal oxidation of Sn. The X-ray photoelectron spectroscopy result implies partial oxidation of Sn film on the diamond surface. The leakage current and capacitance–voltage properties of Al/SnOx/H-diamond metal-oxide-semiconductor diodes were investigated. The maximum leakage current density value at −8.0 V is 1.6 × 10−4 A/cm2, and the maximum capacitance value is measured to be 0.207 μF/cm2. According to the C–V results, trapped charge density and fixed charge density are determined to be 2.39 × 1012 and 4.5 × 1011 cm−2, respectively. Finally, an enhancement-mode H-diamond field effect transistor was obtained with a VTH of −0.5 V. Its IDMAX is −21.9 mA/mm when VGS is −5, VDS is −10 V. The effective mobility and transconductance are 92.5 cm2V−1 s−1 and 5.6 mS/mm, respectively. We suspect that the normally-off characteristic is caused by unoxidized Sn, whose outermost electron could deplete the hole in the channel