Causal effects and metabolites mediators between immune cell and risk of breast cancer: a Mendelian randomization study.

Introduction: The incidence and mortality of female breast cancer remain high, and the immune microenvironment of breast cancer has undergone significant alterations. However, the impact of blood immune cell levels on the risk of breast cancer is not fully understood. Therefor this study aims to investigate the causal relationship between blood immune cell levels and the risk of breast cancer. Methods: A Mendelian randomization (MR) analysis was employed to assess the causal relationship between immune cells and the risk of breast cancer, as along with their potential mediating factors. Genetic statistics of metabolites breast cancer and immune cells were obtained from the GWAS Catalog, while the genome-wide association study (GWAS) statistics of breast cancer were extracted from the UK biobank. Two-sample MR analysis were performed using inverse-variance weighted (IVW) to ascertain the causal association between immune cells and the risk of breast cancer. Furthermore, 1,400 metabolites were analyzed for their mediating role between immune cells and the risk of breast cancer. Results: MR analysis through IVW method revealed that genetically predicted CD24+ CD27+ B cells were associated with a decreased risk of breast cancer (OR = 0.9978, 95% CI: 0.996-0.999, p = 0.001), while IgD- CD38+ B cells were linked to an increased risk of breast cancer (OR = 1.002, 95% CI: 1.001-1.004, p = 0.005). Additional CD14+ CD16+ monocytes were associated with an increased risk of breast cancer (OR = 1.000, 95% CI: 1.000-1.001, p = 0.005). Mediation analysis revealed a positive causal relationship between IgD- CD38+ B cells and Glycerate levels, with the latter also exhibiting a positive causal relationship with the risk of breast cancer (p < 0.05). Conversely, IgD- CD38+ B cells displayed a negative causal relationship with Succinoyltaurine levels, and the latter also demonstrated a negative causal relationship with the risk of breast cancer (p < 0.05). Conclusion: This MR study provides novel genetic evidence supporting a causal relationship between IgD- CD38+ B cells and the risk of BC. Moreover, it is identified that IgD- CD38+ B cells contribute to an increased risk of BC through both positive and negative mediation effects involving Glycerate and Succinoyltaurine.

METTL3 Reduces Oxidative Stress-induced Apoptosis in Presbycusis by Regulating the N6-methyladenosine Level of SIRT1 mRNA.

N6-methyl adenosine (m6A) modification is known to play a crucial role in various aging-related diseases. However, its involvement in presbycusis, a type of age-related hearing loss, is not yet clear. We examined the changes in oxidative stress levels in both plasma of presbycusis patients and mice. To determine the expression of m6A and its functional enzymes, we used liquid chromatography tandem-mass spectrometry (LC-MS/MS), enzyme-linked immunosorbent assay (ELISA), and RT-PCR to analyze the total RNA of presbycusis patients blood cells (n = 8). Additionally, we detected the expression of m6A functional enzymes in the cochlea of presbycusis mice using immunohistochemistry. We assessed the effects of m6A methyltransferase METTL3 on SIRT1 protein expression, reactive oxygen species (ROS) levels, and apoptosis in an oxidative stress model of organ of Corti 1 (OC1) cells. To observe the effect on SIRT1 protein expression, we interfered with the m6A recognition protein IGF2BP3 using siRNA. In both presbycusis patients and mice, there was an increased level of oxidative stress in plasma.There was a decrease in the expression of m6A, METTL3, and IGF2BP3 in presbycusis patients blood cells. The expression of METTL3 and IGF2BP3 was also reduced in the cochlea of presbycusis mice. In OC1 cells, METTL3 positively regulated SIRT1 protein levels, while reversely regulated the level of ROS and apoptosis. IGF2BP3 was found to be involved in the regulation of SIRT1 protein expression. In addition, METTL3 may play a protective role in oxidative stress-induced injury of OC1 cells, while both METTL3 and IGF2BP3 cooperatively regulate the level of m6A and the fate of SIRT1 mRNA in OC1 cells.

Cochlear Marginal Cell Pyroptosis Is Induced by Cisplatin via NLRP3 Inflammasome Activation.

Better understanding the mechanism of cisplatin-induced ototoxicity is of great significance for clinical prevention and treatment of cisplatin-related hearing loss. However, the mechanism of cisplatin-induced inflammatory response in cochlear stria vascularis and the mechanism of marginal cell (MC) damage have not been fully clarified. In this study, a stable model of cisplatin-induced MC damage was established in vitro, and the results of PCR and Western blotting showed increased expressions of NLRP3, Caspase-1, IL-1ß, and GSDMD in MCs. Incomplete cell membranes including many small pores appearing on the membrane were also observed under transmission electron microscopy and scanning electron microscopy. In addition, downregulation of NLRP3 by small interfering RNA can alleviate cisplatin-induced MC pyroptosis, and reducing the expression level of TXNIP possesses the inhibition effect on NLRP3 inflammasome activation and its mediated pyroptosis. Taken together, our results suggest that NLRP3 inflammasome activation may mediate cisplatin-induced MC pyroptosis in cochlear stria vascularis, and TXNIP is a possible upstream regulator, which may be a promising therapeutic target for alleviating cisplatin-induced hearing loss.

The Prognostic Signature of Head and Neck Squamous Cell Carcinoma Constructed by Immune-Related RNA-Binding Proteins.

Purpose: This study aimed to construct a prognostic signature consisting of immune-related RNA-binding proteins (RBPs) to predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) effectively. Methods: The transcriptome and clinical data of HNSCC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. First, we ascertained the immunological differences in HNSCC, through single-sample gene set enrichment analysis, stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE), and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) deconvolution algorithm. Then we used univariate proportional hazards (Cox) regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to screen immune-related RBPs and acquire the risk score of each sample. Subsequently, we further investigated the difference in prognosis, immune status, and tumor mutation burden in high- and low-risk groups. Finally, the efficacy of immunotherapy was measured by the tumor immune dysfunction and exclusion (TIDE) score. Results: We derived 15 immune-related RBPs, including FRMD4A, ASNS, RAB11FIP1, FAM120C, CFLAR, CTTN, PLEKHO1, SELENBP1, CHCHD2, NPM3, ATP2A3, CFDP1, IGF2BP2, NQO1, and DENND2D. There were significant differences in the prognoses of patients in the high- and low-risk groups in the training set (p < 0.001) and the validation set (p < 0.01). Furthermore, there were statistical differences between the high-risk group and low-risk group in immune cell infiltration and pathway and tumor mutation load (p < 0.001). In the end, we found that patients in the low-risk group were more sensitive to immunotherapy (p < 0.001), and then we screened 14 small-molecule chemotherapeutics with higher sensitivity to the high-risk group (p < 0.001). Conclusion: The study constructed a prognostic signature of HNSCC, which might guide clinical immunotherapy in the future.

The Prognostic Value and Immune Landscapes of a m6A/m5C/m1A-Related LncRNAs Signature in Head and Neck Squamous Cell Carcinoma.

Background: N6-methyladenosine (m6A), 5-methylcytosine (m5C) and N1-methyladenosine (m1A) are the main RNA methylation modifications involved in the progression of cancer. However, it is still unclear whether m6A/m5C/m1A-related long non-coding RNAs (lncRNAs) affect the prognosis of head and neck squamous cell carcinoma (HNSCC). Methods: We summarized 52 m6A/m5C/m1A-related genes, downloaded 44 normal samples and 501 HNSCC tumor samples with RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) database, and then searched for m6A/m5C/m1A-related genes co-expressed lncRNAs. We adopt the least absolute shrinkage and selection operator (LASSO) Cox regression to obtain m6A/m5C/m1A-related lncRNAs to construct a prognostic signature of HNSCC. Results: This prognostic signature is based on six m6A/m5C/m1A-related lncRNAs (AL035587.1, AC009121.3, AF131215.5, FMR1-IT1, AC106820.5, PTOV1-AS2). It was found that the high-risk subgroup has worse overall survival (OS) than the low-risk subgroup. Moreover, the results showed that most immune checkpoint genes were significantly different between the two risk groups (p < 0.05). Immunity microenvironment analysis showed that the contents of NK cell resting, macrophages M2, and neutrophils in samples of low-risk group were significantly lower than those of high-risk group (p < 0.05), while the contents of B cells navie, plasma cells, and T cells regulatory (Tregs) were on the contrary (p < 0.05). In addition, patients with high tumor mutational burden (TMB) had the worse overall survival than those with low tumor mutational burden. Conclusion: Our study elucidated how m6A/m5C/m1A-related lncRNAs are related to the prognosis, immune microenvironment, and TMB of HNSCC. In the future, these m6A/m5C/m1A-related lncRNAs may become a new choice for immunotherapy of HNSCC.

The Prognostic Value of the DNA Repair Gene Signature in Head and Neck Squamous Cell Carcinoma.

PURPOSE: To construct a prognostic signature composed of DNA repair genes to effectively predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: After downloading the transcriptome and clinical data of HNSCC from the Cancer Genome Atlas (TCGA), 499 patients with HNSCC were equally divided into training and testing sets. In the training set, 13 DNA repair genes were screened using univariate proportional hazard (Cox) regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct a risk model, which was validated in the testing set. RESULTS: In the training and testing sets, there were significant differences in the clinical outcomes of patients in the high- and low-risk groups showed by Kaplan-Meier survival curves (P < 0.001). Univariate and multivariate Cox regression analyses showed that the risk score had independent prognostic predictive ability (P < 0.001). At the same time, the immune cell infiltration, immune score, immune-related gene expression, and tumor mutation burden (TMB) of patients with HNSCC were also different between the high- and low-risk groups (P < 0.05). Finally, we screened several chemotherapeutics for HNSCC, which showed significant differences in drug sensitivity between the high- and low-risk groups (P < 0.05). CONCLUSION: This study constructed a 13-DNA-repair-gene signature for the prognosis of HNSCC, which could accurately and independently predict the clinical outcome of the patient. We then revealed the immune landscape, TMB, and sensitivity to chemotherapy drugs in different risk groups, which might be used to guide clinical treatment decisions.

Two Well-Compatible Acceptors with Efficient Energy Transfer Enable Ternary Organic Photovoltaics Exhibiting a 13.36% Efficiency.

Organic photovoltaics (OPVs) are fabricated with PM6 as donor and T6Me, IT-2F, or their mixture as acceptor. A 13.36% power conversion efficiency (PCE) is achieved from the optimized ternary OPVs with 50 wt% IT-2F in acceptors, which is attributed to the enhanced photon harvesting of ternary active layers and improved exciton utilization efficiency through energy transfer from IT-2F to T6Me. The efficient energy transfer from IT-2F to T6Me can be confirmed from the photoluminescence spectra of neat and blend films, which may provide additional channels to enhance exciton utilization efficiency for achieving short-circuit current density (JSC ) improvement of ternary OPVs. It should be highlighted that the fill factor (FF) of ternary OPVs can be monotonously increased along with the incorporation of IT-2F, indicating the gradually optimized phase separation degree of ternary active layers. The third component IT-2F plays a key role in optimizing phase separation as a morphology regulator. Over 8% PCE improvement is achieved in the optimized ternary OPVs compared with the over 12% PCEs of the corresponding binary OPVs, respectively. This work indicates that the performance of ternary OPVs can be well optimized by carefully picking materials with good compatibility and complementary absorption spectra, as well as the appropriate energy levels.

Designing an asymmetrical isomer to promote the LUMO energy level and molecular packing of a non-fullerene acceptor for polymer solar cells with 12.6% efficiency.

Isomers with small structural changes usually exhibit different properties. Rationally designing isomers of some high-performance SMAs can further enhance their function. In this work, an asymmetrical small molecule acceptor (SMA) MeIC1 isomerized from MeIC is reported. Compared with the symmetrical MeIC, the asymmetrical isomer showed almost the same absorption range but an elevated LUMO energy level and simultaneously enhanced π-π stacking and electron mobility by replacing the thieno[3,2-b]thiophene unit with a larger sized dithieno[3,2-b:2',3'-d]thiophene unit in the ladder-type core of MeIC. As a result, the MeIC1-based PSCs achieved a higher PCE up to 12.58% with a promoted V oc and J sc and an unchanged FF compared with those of MeIC-based PSCs when blended with PBDB-T. This work reveals that asymmetrical isomerization is effective for PCE promotion.

Asymmetrical Ladder-Type Donor-Induced Polar Small Molecule Acceptor to Promote Fill Factors Approaching 77% for High-Performance Nonfullerene Polymer Solar Cells.

In this work, an effectual strategy of constructing polar small molecule acceptors (SMAs) to promote fill factor (FF) of nonfullerene polymer solar cells (PSCs) is first reported. Three asymmetrical SMAs of IDT6CN, IDT6CN-Th, and IDT6CN-M, which own large dipole moments, are designed and synthesized. The PSCs based on three polar SMAs exhibit apparently higher FFs compared with their symmetrical analogues. The asymmetrical design strategy accompanied with side chain and end group engineering makes IDT6CN-Th- and IDT6CN-M-based nonfullerene PSCs achieve high power conversion efficiency with FFs approaching 77%.