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Abstract Cancer immunotherapy using anti‐programmed death‐ligand 1 (PD‐L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, and overall low patient response rate impede its further clinical application. Mounting evidence has revealed that PD‐L1 is not only present in tumor cell membrane but also in cytoplasm, exosome, or even nucleus. Among these, the dynamic and spatial heterogeneous expression of PD‐L1 in tumors is mainly responsible for the unsatisfactory efficacy of PD‐L1 antibodies. Hence, numerous studies focus on inhibiting or degrading PD‐L1 to improve immune response, while a comprehensive understanding of the molecular mechanisms underlying spatial heterogeneity of PD‐L1 can fundamentally transform the current status of PD‐L1 antibodies in clinical development. Herein, the concept of spatial heterogeneous expression of PD‐L1 is creatively introduced, encompassing the structure and biological functions of various kinds of PD‐L1 (including mPD‐L1, cPD‐L1, nPD‐L1, and exoPD‐L1). Then an in‐depth analysis of the regulatory mechanisms and potential therapeutic targets of PD‐L1 is provided, seeking to offer a solid basis for future investigation. Moreover, the current status of agents is summarized, especially small molecular modulators development directed at these new targets, offering a novel perspective on potential PD‐L1 therapeutics strategies.

AbstractTraditional landslide susceptibility assessment methods often rely on single models, which can be biased and less accurate. In this article, we introduce a two-tiered strategy to enhance landslide susceptibility predictions. Initially, we employ an ensemble stacking technique that combines the strengths of three machine learning classifiers. This combination leverages the support vector classifier (SVC) as the key meta-classifier to optimize and refine predictions. Subsequently, we integrate the extreme gradient boosting (XGB), random forest (RF) and gradient boosting decision tree (GBDT) models with SVC to create hybrid approaches. In this study, we evaluate and compare the effectiveness of six machine learning algorithms for predicting landslide susceptibility in Anhua County, Hunan Province, China. The results demonstrated that the stacking ensemble model outperforms traditional models. The XBG+SVC model achieves the highest AUC value (0.9468), which is followed by the GBDT+SVC (0.9316), RF+SVC (0.9162), XGB (0.9393), GBDT (0.9009), and RF (0.8693). These findings indicate that stacking machine learning approaches hold promise for landslide susceptibility mapping.

ObjectiveType 2 diabetes mellitus (T2DM) remains a major and widespread public health concern throughout the world. The prevalence of T2DM in the elderly has risen to the top of the list of public health concerns. In this study, obesity- and lipid-related indices were used to predict T2DM in middle-aged and elderly Chinese adults.MethodsThe data came from the China Health and Retirement Longitudinal Study (CHARLS), including 7902 middle-aged and elderly participants aged 45 years or above. The study assessed the association of obesity- and lipid-related indices and T2DM by measuring 13 indicators, including body mass index (BMI), waist circumference(WC), waist-height ratio (WHtR), conicity index(CI), visceral adiposity index (VAI), Chinese visceral adiposity index (CVAI), lipid accumulation product (LAP), a body shape index (ABSI), body roundness index (BRI), triglyceride glucose index (TyG-index) and its correlation index (TyG-BMI, TyG-WC, TyG-WHtR). The association of 13 obesity- and lipid-related indices with T2DM was investigated by binary logistic regression. Additionally, the predictive anthropometric index was evaluated, and the ideal cut-off value was established using the receiver operating characteristic (ROC) curve analysis and area under the curve (AUC).ResultsThe study included 7902 participants, of whom 3638(46.04) and 4264(53.96) were male and female. The prevalence of T2DM in mid-aged and old adults in China was 9.02% in males and 9.15% in females. All the above 13 indicators show a modest predictive power (AUC>0.5), which was significant for predicting T2DM in adults (middle-aged and elderly people) in China (P

Dendrobium huoshanense is an edible medicinal herb. Its stem polysaccharide (DHP) can alleviate hepatic injury, but the underlying mechanism is not fully understood. Receptor-interacting protein 2 (RIP2) is an important regulator in metabolic diseases. Here, we found that high fructose decreased RIP2 expression, and increased inositol-requiring enzyme-1α (IRE1α) and spliced X-box binding protein 1 (XBP1s) expression in cultured hepatocytes along with lipid accumulation, which were attenuated by DHP. RIP2 overexpression blocked high fructose-induced upregulation of IRE1α and XBP1s as well as hepatocyte lipid accumulation. RIP2 knockdown reversed amelioration effect of DHP on hepatocyte lipid accumulation. Furthermore, high fructose increased hepatocyte miR-429 expression targeting RIP2. MiR-429 inhibitor reversed high fructose-induced downregulation of RIP2 and lipid accumulation. Notably, DHP reduced miR-429 expression and increased RIP2 expression in its amelioration of lipid accumulation in this cell model. These results suggested that DHP protected against high fructose-induced hepatocyte lipid accumulation through downregulating miR-429 to upregulate RIP2 expression.

Background: The objective of the present study was to identify patients with pathologic stage I lung adenocarcinoma (LUAD) who are at high risk of recurrence and assess the efficacy of adjuvant chemotherapy (ACT) in these individuals. Methods: A retrospective study was conducted on 1504 patients with pathologic stage I LUAD who underwent surgical resection at Shanghai Pulmonary Hospital and Sun Yat-sen University Cancer Center. Cox proportional hazard regression analyses were performed to identify indicators associated with a high risk of recurrence, while the Kaplan-Meier method and Log-rank test were employed to compare recurrence-free survival (RFS) and overall survival (OS) between patients with ACT and those without it. Results: Four independent indicators, including age (≥62 years), visceral pleural invasion (VPI), predominant pattern (micropapillary/solid), and lymphovascular invasion (LVI), were identified to be significantly related with RFS. Subsequently, patients were classified into high-risk and low-risk groups by LVI, VPI, and predominant pattern. The administration of ACT significantly increased both RFS (P

AbstractBackground Liver cirrhosis is a significant yet largely preventable and underappreciated cause of global health loss. This study aimed to profile the global and regional burdens of liver cirrhosis between 2010 and 2019 and the contributions of various aetiologies.Method Data on the incidence, mortality, and disability-adjusted life years (DALYs) of cirrhosis were obtained from the Global Burden of Disease 2019 study. The burden of cirrhosis was estimated by age, sex, region, aetiology, and socio-demographic index (SDI). The temporal trend was quantified using the annual percentage changes (APC.)Results Globally, there were 2.05 million new cases and 1.47 million deaths due to cirrhosis in 2019. From 2010 to 2019, the age-standardized incidence rate (ASIR) for cirrhosis increased slightly from 25.19 to 25.35 worldwide, while the age-standardized death rate (ASDR) and age-standardized DALYs (ASDALYs) decreased from 20.37 to 18.00 and 639.86 to 560.43, respectively. Cirrhosis incidence, mortality and DALYs were consistently higher in males than females. Stratification according to the socio-demographic index (SDI) revealed that low SDI countries had the highest ASDR and ASDALYs in 2019, while middle SDI countries had the highest ASIR. Regarding the aetiology of cirrhosis, hepatitis C accounted for the largest proportion of cirrhosis-related incidence (26.9%), death (26.8%) and DALYs (26.3%); however, non-alcoholic fatty liver disease (NAFLD) exhibited a rapidly growing cause of incident cirrhosis (+26.7%), cirrhosis-related death (+25.1%), and DALYs (+21.0%) worldwide during this period. The ASIR for NAFLD also significantly increased with APC 1.080 over the study period.Conclusions Albeit the global burden of cirrhosis incidence increased from 2010 to 2019, cirrhosis-associated deaths and DALYs declined significantly. Notably, NAFLD exhibited the most significant increase as a contributor to cirrhosis worldwide.

PurposeThis study aimed to investigate the association between increased C-reactive protein (CRP) and cardiovascular disease (CVD) in individuals with rectal cancer, as well as to understand the effect of chemotherapy for cancer on increasing CRP and its underlying mechanisms.Patients and methodsFrom January 1, 2010 to December 31, 2020, individuals with rectal cancer were evaluated at the First Affiliated Hospital of Gannan Medical University. Then, in patients with rectal cancer, the relationship between increased CRP and CVD attributes was summarized, and the impact of chemotherapy on CRP levels was qualitatively assessed. For further investigation into potential regulatory mechanisms of CRP, differentially expressed genes (DEGs), GO and KEGG enrichment analyses were conducted.ResultsA total of 827 individuals were included in the study, including 175 with CVD (21.16%) and 652 without CVD. A significant association between increased CRP and CVD events was observed in rectal cancer patients (p < 0.01), and it significantly improved the classification performance of the CVD predictive model in the AUC (0.724 vs 0.707) and NRI (0.069, 95% CI 0.05-0.14). Furthermore, a comparison of CRP levels before and after chemotherapy revealed a significant increase among rectal cancers post-treatment (p < 0.001). Analysis of differentially expressed genes and co-expression indicated that 96 DEGs were involved in the pathophysiology of increased CRP after chemotherapy, and three hub genes were implicated in atherosclerotic susceptibility.ConclusionIn conclusion, our findings indicated that increased CRP levels following chemotherapy profoundly impacted CVD events in individuals with rectal cancer, and may be beneficial in promoting CVD prediction in clinical practice.

Abstract Background Pyruvate kinase deficiency (PKD) is a rare congenital hemolytic anemia. Here, we summarized the clinical features and laboratory examinations of four Chinese children with PKD and analyze genomic mutations. Method Collected and analyzed the clinical data of all children and their parents and completed the relevant laboratory examinations of all children. Analyzed the sequences of related genes in children by second‐generation sequencing technology and verified the suspected mutations in children's family by Sanger sequencing method or second‐generation sequencing technology. Results A total of six mutations in gene PKLR were detected in four cases. Except for c.1510C>T (P1) and c.941T>C (P2 and P4), which had been reported in previous studies, the other four novel gene mutations were reported for the first time, including a rare homozygous mutation with large fragment deletion. All those gene mutations cause changes in the amino acids encoded by the gene, as well as subsequent changes in protein structure or loss of function. Conclusion Compound heterozygous or homozygous mutations in the coding region of PKLR gene are the causes of PKD in these four Chinese children. The second‐generation sequencing technology is an effective means to diagnose PKD. The mutations of c.457‐c.462delATCGCC, c.1297T>C, c.1096C>T and Exon4‐10del of PKLR reported in this article have not been included in the Thousand Genome Database, dbSNP(v138) and ExAC Database. The PKLR gene mutations found in these children with PKD can provide references for further research of the genetic characteristics of PKD and subsequent gene therapy.

BackgroundPatients with atrial septal defect (ASD) exhibit distinctive electrocardiogram (ECG) patterns. However, ASD cannot be diagnosed solely based on these differences. Artificial intelligence (AI) has been widely used for specifically diagnosing cardiovascular diseases other than arrhythmia. Our study aimed to develop an artificial intelligence-enabled 8-lead ECG to detect ASD among adults.MethodIn this study, our AI model was trained and validated using 526 ECGs from patients with ASD and 2,124 ECGs from a control group with a normal cardiac structure in our hospital. External testing was conducted at Wuhan Central Hospital, involving 50 ECGs from the ASD group and 46 ECGs from the normal group. The model was based on a convolutional neural network (CNN) with a residual network to classify 8-lead ECG data into either the ASD or normal group. We employed a 10-fold cross-validation approach.ResultsStatistically significant differences (p

The Quercus variabilis, a deciduous broadleaved tree species, holds significant ecological and economical value. While a chromosome-level genome for this species has been made available, it remains riddled with unanchored sequences and gaps. In this study, we present a nearly complete comprehensive telomere-to-telomere (T2T) and haplotype-resolved reference genome for Q. variabilis. This was achieved through the integration of ONT ultra-long reads, PacBio HiFi long reads, and Hi-C data. The resultant two haplotype genomes measure 789 Mb and 768 Mb in length, with a contig N50 of 65 Mb and 56 Mb, and were anchored to 12 allelic chromosomes. Within this T2T haplotype-resolved assembly, we predicted 36,830 and 36,370 protein-coding genes, with 95.9% and 96.0% functional annotation for each haplotype genome. The availability of the T2T and haplotype-resolved reference genome lays a solid foundation, not only for illustrating genome structure and functional genomics studies but also to inform and facilitate genetic breeding and improvement of cultivated Quercus species.

Background Both IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephropathy (HSPN) are characterized by glomerular mesangial IgA deposition. Several large studies on adults have suggested that glomerular C4d deposition has prognostic value in IgAN. However, there are few relevant studies on the clinical value of C4d deposition in children with IgAN or HSPN. Methods We performed a retrospective cohort study in pediatric patients with IgAN or HSPN. Clinicopathological data were collected at the time of kidney biopsy. Kidney C4d deposition was analyzed by immunohistochemistry. The end point was defined as a [greater than or equal to] 20% decrease in estimated glomerular filtration from baseline. Results We enrolled 75 children, including 36 children with IgAN and 39 with HSPN. The prevalence of C4d deposition was 36% (27/75). C4d deposition was more abundant in children with proteinuria [greater than or equal to] 50 mg/kg/day (51.9% versus 20.8%, P = 0.006) or nephrotic syndrome (37.0% versus 10.4%, P = 0.006). Mesangial hypercellularity (hazard ratio [HR], 5.745, 95% confidence interval [CI], 1.670-19.761, P = 0.006) and IgM deposition (HR, 4.522, 95% CI, 1.321-15.478, P = 0.016) were associated with C4d deposition. After a median follow-up of 22 months, seven (19.4%) IgAN patients and one (2.6%) HSPN patient had decreased kidney function. In children with IgAN, positive C4d was associated with decreased kidney function (P = 0.047). Conclusion Glomerular C4d deposition was associated with mesangial hypercellularity and glomerular IgM deposition in IgAN and HSPN. Glomerular C4d deposition may be a risk factor for eGFR decline in children with IgAN. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information., Author(s): Dan Wu [sup.1] , Lei Lei [sup.1] , Hejia Zhang [sup.1] , Xingfeng Yao [sup.2] , Zhi Chen [sup.1] , Nan Zhang [sup.2] , Jie Ni [sup.1] , Chen [...]