Surface functionalization of exosomes for chondrocyte-targeted siRNA delivery and cartilage regeneration.

Osteoarthritis (OA) is the most prevalent degenerative cartilage disease, but no effective treatment is currently available to ameliorate the dysregulation of cartilage catabolism. Cartilage degeneration is closely related to the change in the physiology of chondrocytes: for example, chondrocytes of the OA patients overexpress matrix metallopeptidase 13 (MMP13), a.k.a. collagenase 3, which damages the extracellular matrix (ECM) of the cartilage and deteriorate the disease progression. Inhibiting MMP13 has shown to be beneficial for OA treatments, but delivering therapeutics to the chondrocytes embedded in the dense cartilage is a challenge. Here, we engineered the exosome surface with the cartilage affinity peptide (CAP) through lipid insertion to give chondrocyte-targeting exosomes, CAP-Exo, which was then loaded with siRNA against MMP13 (siMMP13) in the interior to give CAP-Exo/siMMP13. Intra-articular administration of CAP-Exo/siMMP13 reduced the MMP13 level and increased collagen COL2A1 and proteoglycan in cartilage in a rat model of anterior cruciate ligament transection (ACLT)-induced OA. Proteomic analysis showed that CAP-Exo/siMMP13 treatment restored the altered protein levels in the IL-1ß-treated chondrocytes. Taken together, a facile exosome engineering method enabled targeted delivery of siRNA to chondrocytes and chondrocyte-specific silencing of MMP13 to attenuate cartilage degeneration.

Chondrocyte-Targeted Delivery System of Sortase A-Engineered Extracellular Vesicles Silencing MMP13 for Osteoarthritis Therapy.

Targeted drug delivery and the reduction of off-target effects are crucial for the promising clinical application of nucleic acid drugs. To address this challenge, a new approach for treating osteoarthritis (OA) that accurately delivers antisense oligonucleotides (ASO) targeting matrix metalloproteinase-13 (ASO-MMP13) to chondrocytes, is developed. Small extracellular vesicles (exos) are ligated with chondrocyte affinity peptide (CAP) using Sortase A and subsequently incubated with cholesterol-modified ASO-MMP13 to construct a chondrocyte-targeted drug delivery exo (CAP-exoASO). Compared with exos without CAP (ExoASO), CAP-exoASOs attenuate IL-1ß-induced chondrocyte damage and prolong the retention time of ASO-MMP13 in the joint without distribution in major organs following intra-articular injection. Notably, CAP-exoASOs decrease MMP13 expression (P < 0.001) and upregulate COL2A1 expression (P = 0.006), resulting in reorganization of the cartilage matrix and alleviation of progression in the OA model. Furthermore, the Osteoarthritis Research Society International (OARSI) score of articular cartilage tissues treated with CAP-exoASO is comparable with that of healthy rats (P = 0.148). A mechanistic study demonstrates that CAP-exoASO may reduce inflammation by suppressing the IL-17 and TNF signaling pathways. Based on the targeted delivery effect, CAP-exoASOs successfully accomplish cartilage repair and have considerable potential for development as a promising therapeutic modality for satisfactory OA therapy.

LINC00426, a novel m6A-regulated long non-coding RNA, induces EMT in cervical cancer by binding to ZEB1.

PURPOSE: To explore the function and molecular mechanism of LINC00426 in Cervical Cancer (CC), and to explore the clinical treatment strategy of LINC00426 for CC. METHODS: Bioinformatics analysis was used to explore the expression of LINC00426 and patient prognosis of CC. Cell function experiments were conducted to explore the potential effect of LINC00426 on CC malignant phenotypes. The difference in m6A modification level between the high and low expression groups of LINC00426 was analyzed by detecting the total m6A level. The luciferase reporter assay was used to confirm the binding of miR-200a-3p to LINC00426. The RIP assay was used to confirm the binding of LINC00426 to ZEB1. Cell viability assay was performed to detect the effect of LINC00426 on cellular drug resistance. RESULTS: LINC00426 is up-regulated in CC, which can enhance the proliferation, migration and invasion of CC cells. METTL3 promotes the expression of LINC00426 by m6A methylation modification. In addition, the LINC00426/miR-200a-3p/ZEB1 axis affects the proliferation, migration, and invasion of CC by regulating the expression of EMT markers. Through the detection of cell viability, we observed that overexpression LINC00426 in cells resulted in resistance to cisplatin and bleomycin, and more sensitive to imatinib. CONCLUSION: LINC00426 is a cancer-promoting lncRNA related to m6A modification. The process of EMT in CC is regulated by the LINC00426/miR-200a/3p/ZEB1 axis. LINC00426 can affect the sensitivity of CC cells to chemotherapy drugs, and is expected to become a therapeutic target for CC.

Post-transcriptional regulation of tumor suppressor gene lncRNA CARMN via m6A modification and miRNA regulation in cervical cancer.

PURPOSE: The abnormal regulation of lncRNA CARMN has been proved to be a tumor suppressor gene of cervical cancer (CC). However, its role in CC is still elusive. The regulation of CARMN post-transcriptional level by m6A modification and miRNA has not been studied. This study aims to analyze the molecular mechanism of m6A modification and miRNA on the abnormal expression of CARMN in CC cells, so as to provide a new theoretical basis for the diagnosis and treatment of CC. METHODS: MeRIP-seq was used to identify the differential m6A-modified genes between tumor and normal cervical tissues. RT-qPCR assay was used to detect gene expression levels in tissues or cells. The m6A modification sites of CARMN was predicted by bioinformatics, and the modification of m6A and its regulatory effect on CARMN were analyzed by MeRIP-qPCR, Actinomycin D assay and RIP assay. RIP-microarray combined with bioinformatics methods to screen miRNAs that may target CARMN. The regulation mechanism between miRNA and CARMN was verified by RT-qPCR, nucleo-plasmic separation assay, mRNA stability assay, dual-luciferase reporter assay, and in vivo experiments. RESULTS: MeRIP-seq found that CARMN is a significant different gene in the abundance of m6A in CC, and the modification level of m6A in CC tissues was higher than that in normal cervical tissues. Further, this study verified that m6A reader YTHDF2 could recognize m6A-modified CARMN and promote its degradation in CC cells. miR-21-5p was proved to be the downstream target gene of CARMN, and miR-21-5p could negatively regulate the expression of CARMN. Further experiments showed that miR-21-5p could directly bind to CARMN and lead to the degradation of CARMN. The in vivo experimental results indicated that the level of miR-21-5p in the overexpressed CARMN group was significantly lower than that in the control group. CONCLUSION: m6A modification and miR-21-5p play important roles in promoting the occurrence and development of tumors by regulating CARMN, provide new potential targets for the treatment of CC.

An improved UAV target detection algorithm based on ASFF-YOLOv5s.

Object detection in drone-captured scenarios is a recent popular task. Due to the high flight altitude of unmanned aerial vehicle (UAV), the large variation of target scales, and the existence of dense occlusion of targets, in addition to the high requirements for real-time detection. To solve the above problems, we propose a real-time UAV small target detection algorithm based on improved ASFF-YOLOv5s. Based on the original YOLOv5s algorithm, the new shallow feature map is passed into the feature fusion network through multi-scale feature fusion to improve the extraction capability for small target features, and the Adaptively Spatial Feature Fusion (ASFF) is improved to improve the multi-scale information fusion capability. To obtain anchor frames for the VisDrone2021 dataset, we improve the K-means algorithm to obtain four different scales of anchor frames on each prediction layer. The Convolutional Block Attention Module (CBAM) is added in front of the backbone network and each prediction network layer to improve the capture capability of important features and suppress redundant features. Finally, to address the shortcomings of the original GIoU loss function, the SIoU loss function is used to accelerate the convergence of the model and improve accuracy. Extensive experiments conducted on the dataset VisDrone2021 show that the proposed model can detect a wide range of small targets in various challenging environments. At a detection rate of 70.4 FPS, the proposed model obtained a precision value of 32.55%, F1-score of 39.62%, and a mAP value of 38.03%, which improved 2.77, 3.98, and 5.1%, respectively, compared with the original algorithm, for the detection performance of small targets and to meet the task of real-time detection of UAV aerial images. The current work provides an effective method for real-time detection of small targets in UAV aerial photography in complex scenes, and can be extended to detect pedestrians, cars, etc. in urban security surveillance.

Engineering the highly efficient heterogeneous catalyst based on PdCu nanoalloy and nitrogen-doped Ti3C2Tx MXene for ethanol electrooxidation.

Improving the electrocatalytic performance by modulating the surface and interface electronic structure of noble metals is still a research hotspot in electrocatalysis. Herein, we prepared the heterogeneous catalyst based on the well-dispersed PdCu nanoalloy and the N-doped Ti3C2Tx MXene support (PdCu/N-Ti3C2Tx) via in situ growth of PdCu nanoparticles on the fantastic N-Ti3C2Tx sheets. By exploring the electrocatalytic properties of ethanol oxidation reaction (EOR), the composition optimized Pd1Cu1/N-Ti3C2Tx delivers higher mass activity/specific activity/intrinsic activity (2200.7 mA mgPd-1/13.1 mA cm-2/2.2 s-1), anti-poisoning ability and stability than those of Pd/N-Ti3C2Tx, Pd1Cu1/Ti3C2Tx and commercial Pd/C, which can be attributed to the modified surface electronic features of Pd by the participation of Cu atoms and N-Ti3C2Tx MXene, as well as the "metal-carrier" effect between the PdCu nanoalloy and N-Ti3C2Tx heterogeneous interface. Furthermore, the conductivity of N-Ti3C2Tx MXene can be improved by N-doping, and the abundant terminal groups (-O, -OH, -F and N) on the N-Ti3C2Tx surface can promote the electron exchange between PdCu and N-Ti3C2Tx. This work provides an effective strategy for engineering heterogeneous electrocatalysts for enhanced electrocatalytic EOR by adjusting the interfacial electronic structure of noble metals.

Gene signature of m6A RNA regulators in diagnosis, prognosis, treatment, and immune microenvironment for cervical cancer.

Continuing studies imply that m6A RNA modification is involved in the development of cervical cancer (CC), but lack strong support on recurrence and diagnosis prediction. In this research, a comprehensive analysis of 33 m6A regulators was performed to fulfill them. Here, we performed diagnostic and prognosis models and identified key regulators, respectively. Then the CC patients were separated into two clusters in accordance with 33 regulators, and participants in the cluster 1 had a worse prognosis. Subsequently, the m6AScore was calculated to quantify the m6A modification pattern based on regulators and we found that patients in cluster 1 had higher m6AScore. Afterwards, immune microenvironment, cell infiltration, escape analyses and tumor burden mutation analyses were executed, and results showed that m6AScore was correlated with them, but to a limited extent. Interestingly, HLAs and immune checkpoint expression, and immunophenoscore in patients with high-m6AScores were significantly lower than those in the low-m6AScore group. These suggested the m6AScores might be used to predict the feasibility of immunotherapy in patients. Results provided a distinctive perspective on m6A modification and theoretical basis for CC diagnosis, prognosis, clinical treatment strategies, and potential mechanism exploration.

Preparation of Mn/Zn@PG Catalyst for Catalytic Oxidation Treatment of Coal Chemical Wastewater.

In this study, Mn/Zn@palygorskite (PG) catalysts with developed pores and good salt tolerance were prepared and applied to the treatment of coal chemical wastewater. A doping ratio of metal elements, calcination temperature, and calcination time was used to optimize the preparation conditions and determine the optimal preparation conditions of the Mn/Zn@PG catalysts. The catalysts, obtained under various preparation conditions, were characterized and analyzed by XRD, SEM, EDS, BET, XRF, XPS, and other techniques. Results showed that the Zn and Mn elements in the Mn/Zn@PG catalyst existed as ZnO and MnO2, respectively. The optimal working conditions of the Mn/Zn@PG catalyst for catalytic oxidation treatment of coal chemical wastewater, obtained through the optimization of working conditions, are the following: reaction time 60 min, wastewater pH = 9.28, ozone ventilation rate 0.2 L/min, catalyst filling ratio 20%. The height-to-diameter ratio of the tower was 6:1. The abrasion resistance and catalytic performance of the Mn/Zn@PG catalyst after repeated use were investigated, and the mechanism of the loss of active components of the Mn/Zn@PG catalyst was explored. The coal chemical wastewater, before and after treatment, was analyzed by UV-vis spectroscopy and 3D fluorescence spectroscopy. The hierarchical-principal component comprehensive evaluation system (AHP-PCA) was established to evaluate the catalytic ozonation process of coal chemical wastewater, so that the overall evaluation of the process performance can be achieved.

Comprehensive analysis of prognosis-related alternative splicing events in ovarian cancer.

Ovarian cancer (OV) is characterized by high incidence and poor prognosis. Increasing evidence indicates that aberrant alternative splicing (AS) events are associated with the pathogenesis of cancer. We examined prognosis-related alternative splicing events and constructed a clinically applicable model to predict patients' outcomes. Public database including The Cancer Genome Atlas (TCGA), TCGA SpliceSeq, and the Genomics of Drug Sensitivity in Cancer databases were used to detect the AS expression, immune cell infiltration and IC50. The prognosis-related AS model was constructed and validated by using Cox regression, LASSO regression, C-index, calibration plots, and ROC curves. A total of eight AS events (including FLT3LG|50942|AP) were selected to establish the prognosis-related AS model. Compared with high-risk group, low-risk group had a better outcome (P = 1.794e-06), was more sensitive to paclitaxel (P = 0.022), and higher proportions of plasma cells. We explored the upstream regulatory mechanisms of prognosis-related AS and found that two splicing factor and 156 tag single nucleotide polymorphisms may be involved in the regulation of prognosis-related AS. In order to assess patient prognosis more comprehensively, we constructed a clinically applicable model combining risk score and clinicopathological features, and the 1 -, and 3-year AUCs of the clinically applicable model were 0.812, and 0.726, which were 7.5% and 3.3% higher than that of the risk score. We constructed a prognostic signature for OV patients and comprehensively analysed the regulatory characteristics of the prognostic AS events in OV.

Sandwich-structured PEDOT:PSS/MXene-PdAu/PEDOT:PSS film for highly sensitive detection of shikonin in lithospermum erythrorhizon.

Promising electrochemical sensing platforms can be constructed by two-dimensional (2D) inorganic materials, metal nanoparticles and conducting polymers (CPs) via suitable and effective composite-structural fabrication. Herein, a sandwich-structured composite film was fabricated with MXene (Ti3C2Tx), PdAu nanoparticles and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). In the fabrication, PdAu nanoparticles were first loaded on the surface of MXene nanosheets by one-pot method, preventing self-stacking and improving the dispersion of MXene nanosheets. And then, the PEDOT:PSS/MXene-PdAu/PEDOT:PSS sandwich structure was obtained with PEDOT:PSS as the upper and lower layers and MXene-PdAu as the interlayer. Indeed, the upper PEDOT:PSS film can permeate between MXene-PdAu particles and contribute to the continuity of MXene nanosheets, forming a complete conducting three-dimensional framework. The formed PEDOT:PSS/MXene-PdAu/PEDOT:PSS framework exhibits promising electrochemical sensing properties towards shikonin detection with a wide range of 0.001-35 µM, a low detection limit of 0.33 nM and a high sensitivity of 5.685 µA µM-1 cm-2. Furthermore, this sensing platform performs favorable selectivity and stability. In the actual sample testing, the sensing platform was used for shikonin detection in Lithospermum erythrorhizon and performed comparable results with high-performance liquid chromatography (HPLC), indicating the promising application prospect of PEDOT:PSS/MXene-PdAu/PEDOT:PSS film for the qualitative and quantitative analysis of shikonin.

Robust poly(3,4-ethylenedioxythiophene) granules loaded Cu/Ni-doped Pd catalysts for high-efficiency electrooxidation of ethylene glycol.

In our work, poly(3,4-ethylenedioxythiophene) (PEDOT) granules supported Cu/Ni-doped Pd electrocatalysts (PdCu/PEDOT and PdNi/PEDOT) were synthesized for ethylene glycol (EG) oxidation in alkaline medium. The amorphous PEDOT granules as the catalyst supports provide plenty of attachment sites for PdCu and PdNi nanoparticles. The optimized Pd1Cu3/PEDOT and Pd7Ni3/PEDOT catalysts both perform superior mass-based activity, area-based activity and intrinsic activity for EG oxidation as compared to other control samples. Moreover, chronoamperometry and long-term cyclic voltammetry tests demonstrate that the Pd1Cu3/PEDOT catalyst performs optimal anti-poisoning capability and catalytic durability. The outstanding electrocatalytic performance can be attributed to the favourable dispersion of Pd1Cu3 and Pd7Ni3 nanoparticles on the PEDOT granules and the synergistic effects between Pd, Cu/Ni atoms and the electron-rich conjugated structure of PEDOT. In summary, this work synthesized two Pd/PEDOT-based electrocatalysts with promising catalytic application prospect in direct ethylene glycol fuel cell (DEGFC), which may provide some theoretical support for the design and synthesis of competent electrocatalysts for DEGFC.

Construction of a hypoxia-immune-related prognostic model and targeted therapeutic strategies for cervical cancer.

Emerging evidence indicates that hypoxia and immunity play important roles in tumorigenesis and development. However, the hypoxia-immune-related prognostic risk model has not been established in cervical cancer (CC). We aimed to construct a hypoxia-immune-related prognostic risk model, which has potential application in predicting the prognosis of CC patients and the response to targeted therapy. The RNA-seq data and corresponding clinical information were retrieved from The Cancer Genome Atlas (TCGA) database. The hypoxia status and immune status of CC patients were evaluated using the Consensus Clustering method and single-sample gene set enrichment analysis (ssGSEA), respectively. The univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression were applied to establish the prognostic risk model of CC. The chemotherapy response for six chemotherapeutic agents of each CC patient was calculated according to the Genomics of Drug Sensitivity in Cancer (GDSC). And the Connectivity Map (CMap) database was performed to screen candidate small-molecule drugs. In this study, we identified seven gene signatures (P4HA2, MSMO1, EGLN1, ZNF316, IKZF3, ISCU and MYO1B) with prognostic values. And the survival time of patients with low risk was significantly longer than those with high risk. Meanwhile, CC patients in the high-risk group yielded higher sensitivity to five chemotherapeutic agents. And we listed 10 candidate small-molecule drugs that exhibited a high correlation with the prognosis of CC. Thus, the prognostic model can accurately predict the prognosis of patients with CC and may be helpful for the development of new hypoxia-immune prognostic markers and therapeutic strategies for CC.

Fabrication of rGO/MXene-Pd/rGO hierarchical framework as high-performance electrochemical sensing platform for luteolin detection.

A  nanocomposite of rGO/MXene-Pd/rGO with hierarchical structure based on Ti3C2Tx MXene, Pd nanoparticles, and reduced graphene oxide (rGO) was synthesized by a green approach. Ti3C2Tx MXene decorated with Pd nanoparticles (MXene-Pd) was prepared first. Then, graphene oxide (GO), MXene-Pd, and GO were coated on the surface of the glassy carbon electrode (GCE) in sequence. After each coating of the GO layer, the GO nanosheets were reduced to rGO electrochemically. The fabricated rGO/MXene-Pd/rGO hierarchical framework performs a pie structure with MXene-Pd as the stuffing and rGO nanosheets as the crust, which will be beneficial to the enhancement of its electrochemical sensing performance. As compared with other electrodes, the rGO/MXene-Pd/rGO/GCE exhibited higher electrocatalytic activity and better sensing performance for luteolin detection, with a wide linear range of 6.0 × 10-10 to 8 × 10-7 M and 1.0 × 10-6 to 1.0 × 10-5 M (oxidation peak potential Epa = 0.34 V vs. SCE), a low detection limit of 2.0 × 10-10 M, and a high sensitivity of 112.72 µA µM-1 cm-2. Moreover, the fabricated sensor also showed high selectivity, reproducibility, and repeatability toward the detection of luteolin. The real sample analysis for luteolin in honeysuckle was successfully carried out by rGO/MXene-Pd/rGO and verified with high-performance liquid chromatography (HPLC) analysis techniques with acceptable results. All the above tests indicate the promising application prospect of the rGO/MXene-Pd/rGO framework for luteolin detection in honeysuckle and other herbs containing luteolin.

One-pot synthesis of porous Pd-polypyrrole/nitrogen-doped graphene nanocomposite as highly efficient catalyst for electrooxidation of alcohols.

Herein, a ternary-nanocomposite Pd-polypyrrole/nitrogen-doped graphene (Pd-PPy/NGE) has been prepared facilely by the one-pot method. In simple terms, PPy was in-situ polymerized on the surface of NGE with PdCl42- as the oxidant, and simultaneously Pd nanopaticles were loaded on the surface of PPy or embedded in PPy particles. The obtained Pd-PPy/NGE nanocomposite exhibits promising electrocatalytic properties toward the oxidation reaction of alcohols in alkaline medium. Especially, the optimized Pd-PPy/NGE (1:50) catalyst possesses mass activity of 2176.7, 1192.7 and 498.9 mA mgPd-1 toward ethylene glycol, methanol and ethanol electrooxidation, respectively, which are 4.3, 6.7 and 2.9 times of those for commercial Pd/C catalyst. Moreover, the Pd-PPy/NGE (1:50) also shows higher anti-poisoning ability and operating stability than the Pd/C catalyst. The promising electrocatalytic performance of the Pd-PPy/NGE (1:50) for alcohols oxidation can be ascribed to the well dispersion of Pd nanoparticles, the porous and stable three dimentional structure of the composite, and the synergistic effect between different components. The structural randomness of the conducting polymer and the potential synergistic effect between the metal nanoparticles and various supports would provide broad development space for these composites as electrocatalysts in direct alcohol fuel cell.

Fabrication of hierarchical Ru/PEDOT:PSS/Ti3C2Tx nanocomposites as electrochemical sensing platforms for highly sensitive Sudan I detection in food.

In our paper, a promising electrochemical sensing platform was fabricated with titanium carbide (Ti3C2Tx), poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), and ruthenium nanoparticles (RuNPs). First, the Shandong pancake structural PEDOT:PSS/Ti3C2Tx was prepared by physical stirring. PEDOT:PSS as the dispersant was embedded into the Ti3C2Tx nanosheets, increasing the degree of dispersion of the Ti3C2Tx nanosheets and further improving the specific surface area of the composite material. Then, RuNPs were supported on the surface of PEDOT:PSS/Ti3C2Tx to form the hierarchical ternary nanocomposite of Ru/PEDOT:PSS/Ti3C2Tx. The prepared Ru/PEDOT:PSS/Ti3C2Tx nanocomposite exhibited promising electrochemical sensing properties toward Sudan I detection with a wide detection range of 0.01 âˆ¼ 100 µM and a high sensitivity of 482.43 µA mM-1 cm-2. Moreover, the Ru/PEDOT:PSS/Ti3C2Tx sensing platform has been successfully applied for Sudan I detection in ketchup and chili paste, implying the promising application prospect of Ru/PEDOT:PSS/Ti3C2Tx in food safety testing.

Fanconi Anemia Pathway Genes Advance Cervical Cancer via Immune Regulation and Cell Adhesion.

Fanconi anemia (FA) pathway is a typical and multienzyme-regulated DNA damage repairer that influences the occurrence and development of disease including cancers. Few comprehensive analyses were reported about the role of FA-related genes (FARGs) and their prognostic values in cancers. In this study, a comprehensive pan-cancer analysis on 79 FARGs was performed. According to the correlation analyses between HPV integration sites and FARGs, we found that FARGs played specific and critical roles in HPV-related cancers, especially in cervical cancer (CC). Based on this, a FARGs-associated prognostic risk score (FPS) model was constructed, and subsequently a nomogram model containing the FPS was developed with a good accuracy for CC overall survival (OS) and recurrence-free survival (RFS) outcome prediction. We also used the similar expression pattern of FARGs by consensus clustering analysis to separate the patients into three subgroups that exhibited significant differential OS but not RFS. Moreover, differential expressed genes (DEGs) between the two risk groups or three clusters were identified and immune pathways as well as cell adhesion processes were determined by functional enrichment analysis. Results indicated that FARGs might promote occurrence and development of CC by regulating the immune cells' infiltration and cell adhesion. In addition, through the machine learning models containing decision tree, random forest, naïve bayes, and support vector machine models, screening of important variables on CC prognosis, we finally determined that ZBTB32 and CENPS were the main elements affecting CC OS, while PALB2 and BRCA2 were for RFS. Kaplan-Meier analysis revealed that bivariate prediction of CC outcome was reliable. Our study systematically analyzed the prognostic prediction values of FARGs and demonstrated their potential mechanism in CC aggressiveness. Results provided perspective in FA pathway-associated modification and theoretical basis for CC clinical treatments.

Esophageal Cancer Associated Immune Genes as Biomarkers for Predicting Outcome in Upper Gastrointestinal Tumors.

Esophageal cancer (EC) is the seventh most common tumor in the world, ranking the sixth leading cause of cancer death, with a 5-year survival rate of 15-25%. Therefore, reliable prognostic biomarkers are needed to effectively predict the prognosis of EC. In this study, the gene profile information of the EC cohort served as a training set, which was derived from TCGA and Immport databases. GO and KEGG enrichment analysis was performed on the differential genes in normal and tumor groups of EC. The immune genes in differentially expressed genes (DEGs) were further obtained for univariate and multivariate Cox and Lasso regression analysis, and 6 independent immune genes (S100A3, STC2, HSPA6, CCL25, GPER1, and OSM) associated with prognosis were obtained to establish an immune risk score signature (IRSS). The signature was validated using head and neck cancers (HNSC) and gastric cancer (GC)in upper gastrointestinal malignancies as validation sets. The Kaplan-Meier results showed that the prognosis of the high-risk group was significantly favorable than that of the low-risk group in both the training set (P < 0.001; HR = 3.68, 95% CI = 2.14-6.35) and the validation set (P = 0.010; HR = 1.43, 95% CI = 1.09-1.88). A nomogram combining multiple clinical information and IRSS was more effective than a single independent prognostic factor in predicting outcome. This study explored the potential link between immunity and EC, and established and validated prognostic biomarkers that can effectively predict the prognosis of EC, HNSC and GC based on six immune genes.

Identification of autophagy-related risk signatures for the prognosis, diagnosis, and targeted therapy in cervical cancer.

BACKGROUND: To rummage autophagy-related prognostic, diagnostic, and therapeutic biomarkers in cervical cancer (CC). METHODS: The RNA-sequence and clinical information were from the TCGA and GTEx databases. We operated Cox regression to determine signatures related to overall survival (OS) and recurrence-free survival (RFS) respectively. The diagnostic and therapeutic effectiveness of prognostic biomarkers were further explored. RESULTS: We identified nine (VAMP7, MTMR14, ATG4D, KLHL24, TP73, NAMPT, CD46, HGS, ATG4C) and three risk signatures (SERPINA1, HSPB8, SUPT20H) with prognostic values for OS and RFS respectively. Six risk signatures (ATG4C, ATG4D, CD46, TP73, SERPINA1, HSPB8) were selected for qPCR. We screened five prognostic signatures(ATG4C, CD46, HSPB8, MTMR14, NAMPT) with diagnostic function through the GEO database. Correlation between our models and treatment targets certificated the prognostic score provided a reference for precision medicine. CONCLUSIONS: We constructed OS and RFS prognostic models in CC. Autophagy-related risk signatures might serve as diagnostic and therapeutic biomarkers.

Development and Validation of a Tumor Mutation Burden-Related Immune Prognostic Signature for Ovarian Cancers.

Ovarian cancer (OC), one of the most common malignancies of the female reproductive system, is characterized by high incidence and poor prognosis. Tumor mutation burden (TMB), as an important biomarker that can represent the degree of tumor mutation, is emerging as a key indicator for predicting the efficacy of tumor immunotherapy. In our study, the gene expression profiles of OC were downloaded from TCGA and GEO databases. Subsequently, we analyzed the prognostic value of TMB in OC and found that a higher TMB score was significantly associated with a better prognosis (p = 0.004). According to the median score of TMB, 9 key TMB related immune prognostic genes were selected by LASSO regression for constructing a TMB associated immune risk score (TMB-IRS) signature, which can effectively predict the prognosis of OC patients (HR = 2.32, 95% CI = 1.68-3.32; AUC = 0.754). Interestingly, TMB-IRS is also closely related to the level of immune cell infiltration and immune checkpoint molecules (PD1, PD-L1, CTLA4, PD-L2) in OC. Furthermore, the nomogram combined with TMB-IRS and a variety of clinicopathological features can more comprehensively evaluate the prognosis of patients. In conclusion, we explored the relationship between TMB and prognosis and validated the TMB-IRS signature based on TMB score in an independent database (HR = 1.60, 95% CI = 1.13-2.27; AUC = 0.639), which may serve as a novel biomarker for predicting OC prognosis as well as possible therapeutic targets.