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Ivonescimab is a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor, yielding promising clinical outcomes for patients with advanced non-small cell lung cancer in early-phase studies. We compared the efficacy and safety of ivonescimab with pembrolizumab in patients with programmed cell death ligand-1 (PD-L1)-positive advanced non-small cell lung cancer. HARMONi-2 is a randomised, double-blind, phase 3 trial across 55 hospitals in China. Eligible patients were aged 18 years or older and had locally advanced or metastatic PD-L1-positive non-small cell lung cancer without sensitising epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations and an Eastern Cooperative Oncology Group performance-status of 0 or 1. Patients were randomly assigned (1:1) to receive 20 mg/kg ivonescimab or 200 mg pembrolizumab intravenously every 3 weeks. Randomisation was stratified by histology, clinical stage, and PD-L1 expression. The primary endpoint was progression-free survival (PFS) assessed by a masked independent radiographic review committee per RECIST v1.1 in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05499390; recruitment is complete, with the trial ongoing and final analysis to be reported later. Between Nov 9, 2022, and Aug 26, 2023, 398 (45%) of 879 screened patients were randomly assigned to receive ivonescimab (n=198) or pembrolizumab (n=200). At the preplanned interim analysis, median PFS was significantly longer with ivonescimab than with pembrolizumab (11·1 vs 5·8 months; stratified hazard ratio [HR] 0·51 [95% CI 0·38–0·69]; one-sided p<0·0001). The PFS benefit of ivonescimab over pembrolizumab was broadly consistent within prespecified subgroups, including patients with PD-L1 tumour proportion score (TPS) 1–49% (HR 0·54 [95% CI 0·37–0·78]) and PD-L1 TPS of 50% of higher (HR 0·48 [0·29–0·79]). Grade 3 or higher treatment-related adverse events occurred in 58 (29%) patients with ivonescimab and 31 (16%) patients with pembrolizumab. Immune-related adverse events of grade 3 or higher were observed in 14 (7%) of 197 patients on ivonescimab and 16 (8%) of 199 patients on pembrolizumab. Ivonescimab demonstrated a manageable safety profile in patients with both squamous and non-squamous non-small cell lung cancer. In patients with squamous cell carcinoma, grade 3 or higher treatment-related adverse events were comparable between the two groups. Ivonescimab significantly improved PFS compared with pembrolizumab in previously untreated patients with advanced PD-L1 positive non-small cell lung cancer. Therefore, ivonescimab might represent another treatment option in the first-line setting for PD-L1-positive advanced non-small cell lung cancer. Akeso Biopharma.

Temporal knowledge graph reasoning(TKGR) has attracted widespread attention due to its ability to handle dynamic temporal features. However, existing methods face three major challenges: (1) the difficulty of capturing long-distance dependencies in information sparse environments; (2) the problem of noise interference; (3) the complexity of modeling temporal relationships. These seriously impact the accuracy and robustness of reasoning. To address these challenges, we proposes a framework based on Dual-gate and Noise-aware Contrastive Learning (DNCL) to improve the performance of TKGR. The framework consists of three core modules: (1) We employ a multi-dimensional gated update module, which flexibly selects key information and suppresses redundant information through a dual-gate mechanism, thereby alleviating the long-distance dependencies problem; (2) We construct a noise-aware adversarial modeling module, which improves robustness and reduces the impact of noise through adversarial training; (3) We design a multi-layer embedding contrastive learning module, which enhances the representation ability through intra-layer and inter-layer contrastive learning strategies to better capture the latent relationships in the temporal dimension. Experimental results on four benchmark datasets show that the DNCL model is better than the current methods, especially for ICEWS14, ICEWS05-15 and ICEWS18 datasets, Hit@1 has improved by 6.91%, 4.31% and 5.30% respectively.

Homologous recombination deficiency (HRD) causes faulty double-strand break repair and is a prevalent cause of tumorigenesis. However, the incidence of HRD and its clinical significance in pan-cancer patients remain unknown. Using computational analysis of Single-nucleotide polymorphism array data from 10,619 cancer patients, we demonstrate that HRD frequently occurs across multiple cancer types. Analysis of the pan-cancer cohort revealed that HRD is not only a biomarker for ovarian cancer and triple-negative breast cancer, but also has clinical prognostic value in numerous cancer types, including adrenocortical cancer and thymoma. We discovered that homologous recombination–related genes have a high mutation or deletion frequency. Pathway analysis shows HRD is positively correlated with the DNA damage response and the immune-related signaling pathways. Single cell RNA sequencing of tumor-infiltrating lymphocytes reveals a significantly higher proportion of exhausted T cells in HRD patients, indicating pre-existing immunity. Finally, HRD could be utilized to predict pan-cancer patients’ responses to Programmed cell death protein 1 immunotherapy. In summary, our work establishes a comprehensive map of HRD in pan-cancer. The findings have significant implications for expanding the scope of Poly ADP-ribose polymerase inhibitor therapy and, possibly, immunotherapy.

Background Intestinal tuberculosis is a chronic and specific infection caused by Mycobacterium tuberculosis invading the intestine. Due to the nonspecific clinical presentation, it is stressed that intestinal perforation complicates umbilical intestinal fistula and bladder ileal fistula is very rare and extremely difficult to be diagnosed. It is significant to identify the disease and take urgent intervene in the early stage. Case presentation An 18-month-old boy patient presented with abdominal pain. Abdominal CT suggested abscess formation in the right lower abdomen and pelvis. The patient underwent resection of necrotic and stenotic intestinal segments with the creation of an ileostomy, cystostomy and vesicoureteral fistula repair for the presence of intestinal perforation complicated by vesicoureteral fistula and umbilical enterocutaneous fistula. Histopathology confirmed the intestinal tuberculosis. The patient was discharged successfully after 11 days post anti-tuberculosis treatment. Conclusion Our case report here is a rare case of umbilical intestinal fistula with bladder ileal fistula secondary to intestinal perforation from intestinal tuberculosis. The purpose of this report is to make the surgical community aware of atypical presentations of intestinal tuberculosis. If our peers encounter the similar situation, they can be prepared for corresponding diagnosis and treatment.

Background Children with obstructive sleep apnea (OSA) can develop cognitive impairments. Urinary adrenaline (EPI), norepinephrine (NE) and gamma-aminobutyric acid (GABA) are elevated, and taurine is decreased in children with OSA. The purpose of this study was to investigate the above-mentioned neurotransmitter levels in children with and without OSA, and explore their association with OSA-related cognitive impairments. Methods Children underwent overnight polysomnography (PSG) for habitual snoring or mouth breathing in the pediatric sleep center from February 2023 to February 2024, as well as a group of healthy controls were enrolled in this study. Pediatric Quality of Life Inventory (PedsQL) and Child Behavior Checklist (CBCL) were used to evaluate the cognitive function of these children. Morning urine samples were collected to measure the urinary neurotransmitter levels. Results This study recruited 74 children with OSA, 30 children with primary snoring (PS) and 16 healthy controls. In the comparison of PedsQL scores, social function (85(75, 100)), school function (65.88 ± 18.52), and total scores (74.15 ± 12.74) of OSA group were significantly lower than that of non-OSA group ( P  < 0.05); OSA group also exhibited increased withdrawn (1 (0, 2)) and attention problems (2 (1, 5)) scores in CBCL than non-OSA group ( P  < 0.05). A total of 39 cases in the OSA group (PedsQL total score below 77.42) were considered to have mild cognitive impairment (MCI), who had higher urinary EPI (190.68 ± 38.77 ng/ml) and lower taurine (432.20 ± 53.52 ng/ml) levels than both PS and OSA without MCI groups ( P  < 0.001). Logistic regression analysis showed that high levels of urinary NE ( OR  = 1.027, 95% CI : 1.002 ~ 1.052) and low levels of taurine ( OR  = 0.982, 95% CI : 0.969 ~ 0.995) are significantly associated with cognitive impairment in children with OSA, and their combination has a larger area under the curve (0.695) for prediction, with a sensitivity of 64.1% and specificity of 68.6% ( P  = 0.004). Conclusions Children with OSA presented impaired cognitive functions such as school, social function deficits and attention problems. Measuring urinary EPI and taurine levels may contribute to the prediction of OSA-related cognitive impairments.

Background Enhancer RNAs (eRNAs) are demonstrated to be closely associated with tumourigenesis and cancer progression. However, the role of eRNAs in lung adenocarcinoma (LUAD) remains largely unclear. Thus, a comprehensive analysis was constructed to identify the key eRNAs, and to explore the clinical utility of the identified eRNAs in LUAD. Methods First, LUAD expression profile data from the Cancer Genome Atlas (TCGA) dataset and eRNA-relevant information were integrated for Kaplan-Meier survival analysis and Spearman’s correlation analysis to filtered the key candidate eRNAs that was associated with survival rate and their target genes in LUAD. Then, the key eRNA was selected for subsequent clinical correlation analysis. KEGG pathway enrichment analyses were undertaken to explore the potential signaling pathways of the key eRNA. Data from the human protein atlas (HPA) database were used to validate the outcomes and the quantitative real time-polymerase chain reaction (qRT-PCR) analysis was conducted to measure eRNA expression levels in tumor tissues and paired normal adjacent tissues from LUAD patients. Finally, the eRNAs were validated in pan-cancer. Results As a result, TBX5-AS1 was identified as the key eRNA, which has T-box transcription factor 5 (TBX5) as its regulatory target. KEGG analysis indicated that TBX5-AS1 may exert a vital role via the PI3K/AKT pathway, Ras signaling pathway, etc. Additionally, the qRT-PCR results and the HPA database indicated that TBX5-AS1 and TBX5 were significantly downregulated in tumour samples compared to matched-adjacent pairs. The pan-cancer validation results showed that TBX5-AS1 was associated with survival in four tumors, namely, adrenocortical carcinoma (ACC), LUAD, lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). Correlations were found between TBX5-AS1 and its target gene, TBX5, in 26 tumor types. Conclusion Collectively, our results indicated that TBX5-AS1 may be a potential prognostic biomarker for LUAD patients and promote the targeted therapy of LUAD.

Background In diabetic retinopathy (DR), hypoxia-inducible factor (HIF-1α) induces oxidative stress by upregulating glycolysis. This process leads to neurodegeneration, particularly photoreceptor cell damage, which further contributes to retinal microvascular deterioration. Further, the regulation of Wnt-inhibitory factor 1 (WIF1), a secreted Wnt signaling antagonist, has not been fully characterized in neurodegenerative eye diseases. We aimed to explore the impact of WIF1 on photoreceptor function within the context of DR. Method Twelve-week-old C57BL/KsJ-db/db mice were intravitreally injected with WIF1 overexpression lentivirus. After 4 weeks, optical coherence tomography (OCT), transmission electron microscopy (TEM), H&E staining, and electroretinography (ERG) were used to assess the retinal tissue and function. The potential mechanism of action of WIF1 in photoreceptor cells was explored using single-cell RNA sequencing. Under high-glucose conditions, 661 W cells were used as an in vitro DR model. WIF1-mediated signaling pathway components were assessed using quantitative real-time PCR, immunostaining, and western blotting. Result Typical diabetic manifestations were observed in db/db mice. Notably, the expression of WIF1 was decreased at the mRNA and protein levels. These pathological manifestations and visual function improved after WIF1 overexpression in db/db mice. TEM demonstrated that WIF1 restored damaged mitochondria, the Golgi apparatus, and photoreceptor outer segments. Moreover, ERG indicated the recovery of a-wave potential amplitude. Single-cell RNA sequencing and in vitro experiments suggested that WIF1 overexpression prevented the expression of glycolytic enzymes and lactate production by inhibiting the canonical Wnt signaling pathway, HIF-1α, and Glut1, thereby reducing retinal and cellular reactive oxygen species levels and maintaining 661 W cell viability. Conclusions WIF1 exerts an inhibitory effect on the Wnt/β-catenin-HIF-1α-Glut1 glycolytic pathway, thereby alleviating oxidative stress levels and mitigating pathological structural characteristics in retinal photoreceptor cells. This mechanism helps preserve the function of photoreceptor cells in DR and indicates that WIF1 holds promise as a potential therapeutic candidate for DR and other neurodegenerative ocular disorders. Graphical Abstract Highlights WIF1 inhibits HIF-1α-Glut1 glycolytic pathway in photoreceptor cells Improves oxidative stress and ameliorates pathological structural characteristics. Helps preserve the function of photoreceptor cells in diabetic retinopathy WIF1 is an excellent candidate for targeted therapy against diabetic retinopathy.

Background The identification of differentially expressed genes (DEGs) is an important task in many biological studies. The currently widely used methods often calculate a score for each gene by estimating the significance level in terms of the differential expression. However, biological experiments often have only three duplications, plus plenty of noises contain in gene expression datasets, which brings a great challenge to statistical analysis methods. Moreover, the abundance of gene expression levels are not evenly distributed. Thus, those low expressed genes are more easily to be detected by fold-change based methods, which may results in high false positives among the DEG list. Since phenotypical changes result from DEGs should be strongly related to several distinct cellular functions, a more robust method should be designed to increase the true positive rate of the functional related DEGs. Results In this study, we propose a two-way rectification method for identifying DEGs by maximizing the co-function relationships between genes and their enriched cellular pathways. An iteration strategy is employed to sequentially narrow down the group of identified DEGs and their associated biological functions. Functional analyses reveal that the identified DEGs are well organized in the form of functional modules, and the enriched pathways are very significant with lower p -value and larger gene count. Conclusions An integrative rectification method was proposed to identify key DEGs and their related functions simultaneously. The experimental validations demonstrate that the method has high interpretability and feasibility. It performs very well in terms of the identification of remarkable functional related genes.

Tool wear state recognition is a challenging problem because the various types of signals corresponding to different wear states have similar features, making classification difficult. Convolutional neural networks are widely used in the field of tool wear state recognition. To address this problem, this study proposes a milling cutter wear state monitoring model that combines KANS and deep residual networks (ResNet). The traditional ResNet-34’s top linear classifier was replaced with a nonlinear convolutional classifier including _top_kan, and the data were preprocessed using continuous wavelet transform (CWT) to enhance the model’s immunity to interference and feature characterization. The experimental results based on the PHM dataset show that the improved KANS-ResNet-34 model improves accuracy by 1.07% compared to ResNet-34, making it comparable to ResNet-50, while its computation time is only 1/33.68 of the latter. This significantly improves computational efficiency, reduces the pressure on hardware resources, and provides an effective tool wear state recognition solution.

Background The mechanism of many complex diseases has not been detected accurately in terms of their stage evolution. Previous studies mainly focus on the identification of associations between genes and individual diseases, but less is known about their associations with specific disease stages. Exploring biological modules through different disease stages could provide valuable knowledge to genomic and clinical research. Results In this study, we proposed a powerful and versatile framework to identify stage-specific cancer related genes and their dynamic modules by integrating multiple datasets. The discovered modules and their specific-signature genes were significantly enriched in many relevant known pathways. To further illustrate the dynamic evolution of these clinical-stages, a pathway network was built by taking individual pathways as vertices and the overlapping relationship between their annotated genes as edges. Conclusions The identified pathway network not only help us to understand the functional evolution of complex diseases, but also useful for clinical management to select the optimum treatment regimens and the appropriate drugs for patients.