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Background CD8 + T cells play a critical role in the innate antitumour immune response. Recently, CD8 + T cell dysfunction has been verified in various malignant cancers, including non-small cell lung cancer (NSCLC). However, the molecular biological mechanisms of CD8 + T cell dysfunction in human NSCLC are still unclear. Methods The expression of circular ubiquitin-specific protease-7 (circUSP7) in NSCLC tissues, exosomes, and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Exosomes were isolated from the culture medium of NSCLC cells and the plasma of NSCLC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit. The exosomes were then characterized by transmission electronic microscopy (TEM), NanoSight and western blotting. The role of circUSP7 in CD8 + T cell dysfunction was assessed by enzyme-linked immunosorbent assay (ELISA). In vivo circular RNA (circRNA) precipitation (circRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays were performed to explore the molecular mechanisms of circUSP7 in CD8 + T cells. In a retrospective study, the clinical characteristics and prognostic significance of circUSP7 in NSCLC tissues were determined. Results The expression levels of circUSP7 were higher in human NSCLC tissues than in matched adjacent nontumour tissues. Increased levels of circUSP7 indicate poor clinical prognosis and CD8 + T cell dysfunction in patients with NSCLC. The circUSP7 found in NSCLC patient plasma is predominantly secreted by NSCLC cells in an exosomal manner, and circUSP7 inhibits IFN-γ, TNF-α, Granzyme-B and Perforin secretion by CD8 + T cells. Furthermore, circUSP7 inhibits CD8 + T cell function by upregulating the expression of Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) via sponging miR-934. Finally, we show that circUSP7 may promote resistance to anti-PD1 immunotherapy in NSCLC patients. Conclusions Exosomal circUSP7 is predominantly secreted by NSCLC cells and contributes to immunosuppression by promoting CD8 + T cell dysfunction in NSCLC. CircUSP7 induces resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for NSCLC patients.

The quality of treatment and prognosis after pediatric congenital heart surgery remains unsatisfactory. A reliable prediction model for postoperative complications of congenital heart surgery patients is essential to enable prompt initiation of therapy and improve the quality of prognosis. Here, we develop an interpretable machine-learning-based model that integrates patient demographics, surgery-specific features and intraoperative blood pressure data for accurately predicting complications after pediatric congenital heart surgery. We used blood pressure variability and the k-means algorithm combined with a smoothed formulation of dynamic time wrapping to extract features from time-series data. In addition, SHAP framework was used to provide explanations of the prediction. Our model achieved the best performance both in binary and multi-label classification compared with other consensus-based risk models. In addition, this explainable model explains why a prediction was made to help improve the clinical understanding of complication risk and generate actionable knowledge in practice. The combination of model performance and interpretability is easy for clinicians to trust and provide insight into how they should respond before the condition worsens after pediatric congenital heart surgery.

Image enhancement is a widely used technique in digital image processing that aims to improve image aesthetics and visual quality. However, traditional methods of enhancement based on pixel-level or global-level modifications have limited effectiveness. Recently, as learning-based techniques gain popularity, various studies are now focusing on utilizing networks for image enhancement. However, these techniques often fail to optimize image frequency domains. This study addresses this gap by introducing a transformer-based model for improving images in the wavelet domain. The proposed model refines various frequency bands of an image and prioritizes local details and high-level features. Consequently, the proposed technique produces superior enhancement results. The proposed model’s performance was assessed through comprehensive benchmark evaluations, and the results suggest it outperforms the state-of-the-art techniques.

Recently, many new diagnostic biomarkers have been developed for colorectal cancer. We chose 2 methods with high diagnostic efficiency, the detection of serum microRNA and metabolomics based on gas chromatography/mass spectrometry (GC/MS), and aimed to establish appropriate models. We reviewed the diagnostic value of all microRNA identified by previous diagnostic tests. We selected appropriate microRNA to validate their diagnostic efficiency, and determined the optimal combination. We included 85 patients with colorectal cancer (CRC) and 78 healthy controls (HC) and detected the expression of the microRNA. GC/MS analysis was conducted, and we used 3 multivariate statistical methods to establish diagnostic models. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19‐9 (CA19‐9) were detected for comparison with the novel models. Ultimately, 62 published studies and 63 microRNA were included in this review. MiR‐21, miR‐29a, miR‐92a, miR‐125b and miR‐223 were selected to further validate their diagnostic value. The serum levels of the 5 microRNA in CRC patients were significantly higher than those in the HC. The combination of miR‐21, miR‐29a, miR‐92a and miR‐125b had the highest area under the curve (AUC) at 0.952, with a sensitivity of 84.7% and a specificity of 98.7%. The GC/MS analysis exhibited an excellent diagnostic value and the AUC reached 1.0. With regard to traditional biomarkers, the AUC of CEA and CA19‐9 were 0.808 and 0.705, respectively. The application prospects are good for microRNA and metabolomics as new diagnostic methods because of their high diagnostic value compared with traditional biomarkers. The combination of miR‐21, miR‐29a, miR‐92a and miR‐125b had the highest area under the curve (AUC) at 0.952 with a sensitivity of 84.7% and a specificity of 98.7%. The GC/MS analysis exhibited an excellent diagnostic value and the AUC reached 1.0. There is a good application prospect for microRNAs and metabolomics as new diagnostic methods because of their high diagnostic value compared with traditional biomarkers.

The role of TELO2‐interacting protein 1 (TTI1) in the progression of several types of cancer has been reported recently. The aim of this study was to estimate the expression and potential value of TTI1 in non‐small‐cell lung cancer (NSCLC) patients. The expression of TTI1 and its prognostic value in NSCLC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. To verify the bioinformatics findings, a tissue microarray containing 160 NSCLC and paired peritumoral tissues from NSCLC patients was analyzed by immunohistochemistry for TTI1. Subsequently, the roles of TTI1 in NSCLC cells were investigated in vivo by establishing xenograft models in nude mice and in vitro by transwell, CCK‐8, wound healing, and colony formation assays. In addition, quantitative real‐time polymerase chain reaction and western blot were applied to explore the underlying mechanism by which TTI1 promotes tumor progression. Finally, the relationship between TTI1 and Ki67 expression level in NSCLC was probed, and Kaplan–Meier and Cox analyses were performed to assess the prognostic merit of TTI1 and Ki67 in NSCLC patients. We found that the expression of TTI1 was significantly upregulated in NSCLC tissues compared to paired peritumoral tissues, which coincides with the bioinformatics findings from the TCGA and GEO databases. TTI1 was highly expressed in NSCLC patients with large tumors, advanced tumor stage, and lymphatic metastasis. In addition, the prognostic analysis identified TTI1 as an independent indication for poor prognosis of NSCLC patients. In vitro, upregulation of TTI1 in NSCLC cells could facilitate cell invasion, metastasis, viability, and proliferation. Mechanistically, our study verified that TTI1 could regulate mTOR activity, which has a pivotal role in human cancer. Consistently, the expressions of TTI1 and Ki67 had a positive relationship in NSCLC cells and tissues. Notably, patients with overexpression of TTI1 or Ki67 had a shorter overall survival rate and a higher disease‐free survival rate compared to patients with low expression of TTI1 or Ki67, and the combination of TTI1 and Ki67 was an independent parameter predicting the prognosis and recurrence of NSCLC patients. We conclude that TTI1 promotes NSCLC cell proliferation, metastasis, and invasion by regulating mTOR activity, and the combination of TTI1 and Ki67 is a valuable molecular biomarker for the survival and recurrence of NSCLC patients. Our study demonstrated for the first time that TTI1 could promote NSCLC cell proliferation, invasion and metastasis in vitro, and boost NSCLC cell progression in vivo. The study also demonstrated an independent prognostic role of TTI1 in NSCLC. In terms of mechanism, TTI1 could regulate the mTOR signaling pathway. The expression of TTI1 and KI67 had a positive correlation in NSCLC and combination of TTI1 and KI67 is a valuable biomarker for predicting the survival and recurrence of patients with NSCLC.

Background Previous studies have confirmed the oncogenic role of HMGB2 in various cancers, but the biological functions of HMGB2-derived circRNAs remain unknown. Thus, we intended to investigate the potential role of HMGB2-derived circRNAs in lung adenocarcinomas (LUAD) and squamous cell carcinomas (LUSC). Methods The expression profiles of HMGB2-derived circRNAs in LUAD and LUSC tissues and matched normal tissues were assessed using qRT–PCR. The role of circHMGB2 in the progression of the LUAD and LUSC was determined in vitro by Transwell, CCK-8, flow cytometry and immunohistochemistry assays, as well as in vivo in an immunocompetent mouse model and a humanized mouse model. In addition, in vivo circRNA precipitation assays, luciferase reporter assays and RNA pulldown assays were performed to explore the underlying mechanism by which circHMGB2 promotes anti-PD-1 resistance in the LUAD and LUSC. Results The expression of circHMGB2 (hsa_circ_0071452) was significantly upregulated in NSCLC tissues, and survival analysis identified circHMGB2 as an independent indicator of poor prognosis in the LUAD and LUSC patients. We found that circHMGB2 exerted a mild effect on the proliferation of the LUAD and LUSC cells, but circHMGB2 substantially reshaped the tumor microenvironment by contributing to the exhaustion of antitumor immunity in an immunocompetent mouse model and a humanized mouse model. Mechanistically, circHMGB2 relieves the inhibition of downstream CARM1 by sponging miR-181a-5p, thus inactivating the type 1 interferon response in the LUAD and LUSC. Moreover, we found that the upregulation of circHMGB2 expression decreased the efficacy of anti-PD-1 therapy, and we revealed that the combination of the CARM1 inhibitor EZM2302 and an anti-PD-1 antibody exerted promising synergistic effects in a preclinical model. Conclusion circHMGB2 overexpression promotes the LUAD and LUSC progression mainly by reshaping the tumor microenvironment and regulating anti-PD-1 resistance in the LUAD and LUSC patients. This study provides a new strategy for the LUAD and LUSC treatment.

Mesenchymal stem cells (MSCs) are adult stromal cells with the capacity to differentiate into multiple types of cells. MSCs represent an attractive option in regenerative medicine due to their multifaceted abilities for tissue repair, immunosuppression, and anti-inflammation. Recent studies demonstrate that MSCs exert their effects via paracrine activity, which is at least partially mediated by extracellular vesicles (EVs). MSC-derived EVs (MSC-EVs) could mimic the function of parental MSCs by transferring their components such as DNA, proteins/peptides, mRNA, microRNA (miRNA), lipids, and organelles to recipient cells. In this review, we aim to summarize the mechanism and role of miRNA transfer in mediating the effects of MSC-EVs in the models of human diseases. The first three sections of the review discuss the sorting of miRNAs into EVs, uptake of EVs by target cells, and functional transfer of miRNAs via EVs. Then, we describe the composition of miRNAs in MSC-EVs. Next, we provide the existing evidence that MSC-EVs affect the outcomes of renal, liver, heart, and brain diseases by transferring their miRNA contents. In conclusion, EV-mediated miRNA transfer plays an important role in disease-modulating capacity of MSCs.

Background Mountain uplift has been recognized as a critical driver of adaptive evolution and species diversification. Hypochilidae, an ancient and relict spider family, is predominantly found in montane regions. However, the factors promoting speciation within this family remain poorly understood. Results We utilized multi-locus data from 97% of Hypochilidae species, including 27 mitochondrial genomes, to construct a robust phylogenetic tree. Time-calibrated analyses reveal that Hypochilidae originated in the Late Jurassic period. In North America, the genus Hypochilus diversified in association with relatively ancient orogenic events, particularly the uplift of the Rocky Mountains, California Mountains, and southern Appalachians, which mainly occurred prior to the Oligocene. In contrast, the Asian genus Ectatosticta exhibited a rapid diversification pattern, spreading from the southern to the northeastern regions of the Qinghai-Tibet Plateau (QTP) after the Miocene. The species accumulation and net diversification rates of Asian Ectatosticta were significantly higher than those of North American Hypochilus , with a notable acceleration in diversification rates observed in BAMM software. Conclusion Mountain orogeny has profoundly influenced the speciation of the ancient and relict spider family Hypochilidae, with the stepwise uplift of the QTP driving the diversification and radiation of Asian lineages.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n  = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n  = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%–58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%–33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%–39.6%; P  = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%–35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%–17.9%); P  = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3–4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 . In the phase 2 trial NEOSUMMIT-01, perioperative treatment of patients with locally advanced gastric or gastro-esophageal junction adenocarcinoma with anti-PD-1 and SOX/XELOX versus SOX/XELOX alone improved pathological complete response or near-complete response rate.

Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.