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Abstract This multicohort phase II trial (ALTER-G-001; NCT05262335) aimed to assess the efficacy of first-line anlotinib plus chemotherapy for gastrointestinal (GI) cancer patients with unresectable liver metastases. Eligible patients with colorectal cancer (Cohort A) or noncolorectal and nonesophageal GI cancer (Cohort C) received six cycles of anlotinib plus standard chemotherapeutic regimens followed by anlotinib plus metronomic capecitabine as a maintenance therapy. Liver metastasectomy can be performed when liver metastases are converted to resectable lesions. The primary outcome was the investigator-confirmed objective response rate (ORR) in the intention-to-treat population. Among the 47 patients in Cohort A, the ORR was 40.4% (95% CI 26.4–55.7), including 1 with a complete response (CR) and 18 who achieved a partial response (PR). The median progression-free survival (PFS) was 8.7 months (95% CI 7.3-NE), and the median overall survival (OS) was not reached. In Cohort C, 14 of 44 patients achieved a PR, with an ORR of 31.8% (95% CI 18.6–47.6). The PFS and OS were 5.8 months (95% CI 4.8–6.5) and 11.4 months (95% CI 5.8–19.3), respectively. The liver metastasectomy rate in patients with liver-limited disease was 22.7% (5/22) in Cohort A and 6.7% (2/30) in Cohort C. For pancreatic cancer patients, the ORR of the efficacy-evaluable population was 36.0% (9/25), and those with liver-limited metastasis had better survival. Moreover, no new safety concerns emerged. In conclusion, an anlotinib-based first-line regimen demonstrated promising antitumor activity among GI cancer patients with unresectable liver metastases and led to liver metastasectomy in selected patients.

Abstract Colorectal cancer is the most common type of cancer in the digestive system and poses a major threat to human health. The gut microbiota has been found to be a key factor influencing the development of colorectal cancer. Extracellular vesicles are important mediators of intercellular communication. Not only do they regulate life activities within the same individual, but they have also been found in recent years to be important mediators of communication between different species, such as the gut microbiota and the host. Their preventive, diagnostic, and therapeutic value in colorectal cancer is being explored. The aim of this review is to provide insights into the complex interactions between host and gut microbiota, particularly those mediated through extracellular vesicles, and how these interactions affect colorectal cancer development. In addition, the potential of extracellular vesicles from various body fluids as biomarkers was evaluated. Finally, we discuss the potential, challenges, and future research directions of extracellular vesicles in their application to colorectal cancer. Overall, extracellular vesicles have great potential for application in medical processes related to colorectal cancer, but their isolation and characterization techniques, intercellular communication mechanisms, and the effectiveness of their clinical application require further research and exploration.

Abstract Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.

Introduction: Morphological abnormalities of erythrocytes/red blood cells (RBCs), e.g., increased acanthocytes, in Parkinson’s disease (PD) have been reported previously, although the underlying mechanisms remain to be characterized. In this study, the potential roles of α-synuclein (α-syn), a protein critically involved in PD and highly abundant in RBCs, were studied in PD patients as well as in a PD mouse model. Methods: Transgenic [PAC-Tg (SNCAA53T), A53T] mice overexpressing A53T mutant α-syn and SNCA knockout mice were employed to characterize the effect of α-syn on RBC morphology. In addition to A53T and SNCA knockout mice, the morphology of RBCs of PD patients was also examined using scanning electron microscopy. The potential roles of α-syn were further investigated in cultured RBCs and mice. Results: Morphological abnormalities of RBCs and increased accumulation of aggregated α-syn on the RBC membrane were observed in PD patients. A similar phenomenon was also observed in A53T mice. Furthermore, while mice lacking α-syn expression showed a lower proportion of acanthocytes, treating RBCs derived from SNCA knockout mice with aggregated α-syn resulted in a higher percentage of acanthocytes. In a follow-up proteomic investigation, several major classes of proteins were identified as α-syn-associated proteins on the RBC membrane, seven of which were calcium-binding proteins. Applying aggregated α-syn to the RBC membrane directly induced extracellular calcium influx along with morphological changes; both observations were adequately reversed by blocking calcium influx. Conclusions: This study demonstrated that α-syn plays a critical role in PD-associated morphological abnormalities of RBCs, at least partially via a process mediated by extracellular calcium influx.

Abstract Background An increasing number of clinical studies have begun to explore combination strategies with immune checkpoint inhibitors, aiming to present new opportunities for overcoming anti-PD-1 treatment resistance in gastric cancer. Unfortunately, the exploration of certain immune checkpoint inhibitor combination strategies has yielded suboptimal results. Therefore, it is necessary to comprehensively analyze the expression patterns of immune checkpoints and identify optimal combination regimens of anti-PD-1 inhibitors with other immune checkpoint inhibitors. Methods Leveraging single-cell RNA sequencing (scRNA-seq) and multivariate linear regression interaction models, we dissected the immune checkpoint expression characteristics of CD8+ T cells in gastric cancer and the immune checkpoint expression pattern (ICEP) mediating anti-PD-1 treatment resistance. Furthermore, we employed transcription factor analysis and CellOracle to explore the transcriptional regulatory mechanisms governing CD8+ T cell differentiation fates. Finally, we utilized Nichenet and spatial transcriptomic analysis to investigate the spatial expression patterns of immune checkpoints. Results Interaction analysis indicated that, among the known immune checkpoints, co-expression of NKG2A and PD-1 might exert a more profound inhibitory effect on the proliferative capacity of CD8+ T cells. The co-expression analysis revealed differential co-expression pattern of PD-1 and NKG2A, defined as ICEP1 (CD8+ T cells co-expressing PD-1, CTLA-4, TIGIT, LAG-3 or CD38) and ICEP2 (CD8+ T cells solely expressing NKG2A or co-expressing with other immune checkpoints), reflecting the co-occurrence pattern of PD-1 and the mutual exclusivity of NKG2A. Further, these two ICEP CD8+ T cell subsets represented distinct CD8+ T cell differentiation fates governed by MSC and RUNX3. Notably, ICEP2 CD8+ T cells were associated with anti-PD-1 therapy resistance in gastric cancer. This phenomenon may be attributed to the recruitment of LGMN+ macrophages mediated by the CXCL16-CXCR6 signaling pathway. Conclusion This study unveiled two distinct ICEPs and the mutually exclusivity and co-occurrence characteristics of CD8+ T cells in gastric cancer. The ICEP2 CD8+ T cell subset, highly expressed in gastric cancer patients resistant to anti-PD-1 therapy, may be recruited by LGMN+ macrophages through CXCL16-CXCR6 axis. These findings provide evidence for NKG2A as a novel immunotherapeutic target in gastric cancer and offer new insights into combination strategies for immune checkpoint inhibitors in gastric cancer. Graphical Abstract

ObjectiveThis study aimed to clarify the subgroups of career calling among Chinese nurses, explore the factors correlated with the subgroups, and investigate the relationship between nurse safety behavior and different profiles of career calling.MethodsA cross-sectional study of 2,567 nurses from 25 hospitals in China was conducted from February to September 2023. A latent profile model of nurses’ career calling was analyzed using Mplus 7.4. The influencing factors of each profile were analyzed by multinomial logistic regression analysis. The hierarchical regression analysis was used to examine the relationship between nurse safety behavior and different profiles of career calling. The STROBE guidelines were followed in this research.ResultsThree distinct latent profiles were identified: “low-calling” type (12.4%), “medium-calling” type (54.4%), and “high-calling” type (33.2%) groups, respectively. Gender and number of night shifts per month were identified as factors influencing the latent profiles of nurses’ career calling. The different categories of career calling significantly predicted the nurse safety behavior (ΔR2 = 0.307, p

Summary: Immunotherapy has significantly altered the treatment paradigm of non-small cell lung cancer (NSCLC), but not all patients experience durable benefits. Predictive biomarkers are needed to identify patients who may benefit from immunotherapy. We retrospectively collected tumor tissues from 65 patients with advanced NSCLC before treatment, and performed transcriptomic and genomic analysis. By performing single-sample gene set enrichment analysis, we constructed a predictor named IKCscore based on the tumor microenvironment characteristics. IKCscore is a robust biomarker predicting response to immunotherapy, and its predictive capacity was confirmed from public datasets across different cancer types (N = 892), including OAK, POPLAR, IMvigor210, GSE135222, GSE126044, and Kim cohorts. High IKCscore was characterized by inflammatory tumor microenvironment phenotype and higher T cell receptor diversity. The IKCscore exhibits promise as a bioindicator that can predict the efficacy of both immunotherapy and immunotherapy-based combination therapies, while providing guidance for personalized therapeutic strategies for advanced NSCLC patients.

The South-to-North Water Diversion Project Middle Route (SNWD-MR) annually diverts hundreds of millions of cubic meters of water from the Danjiangkou Reservoir to Beijing, significantly impacting the regional groundwater cycle. To conserve water resources, the government has implemented ecological water replenishment (EWR) in some water systems. This study aimed to study the coupled process of groundwater dynamics and land subsidence (LS) in Yongding River (YDR) basin (Beijing section) following the implementation of the SNWD-MR and EWR. First, an Interferometric Synthetic Aperture Radar (InSAR) time series technique was used to detect spatial and temporal distributions of surface displacement between 2015 and 2020 based on satellite images from Sentinel-1A/B. The results indicated a predominant LS deceleration trend during the InSAR observation period. The area with subsidence velocity below 20 mm/yr decreased significantly by 18.6% after SNWD-MR and EWR (from 2016 to 2020). Then, groundwater level fluctuations during the InSAR observation period were analyzed using groundwater measurement well data. Over 60% of these wells showed a rebound in groundwater levels after the implementation of SNWD-MR and EWR. The polynomial distribution lag model (PDL) revealed the association between LS and groundwater level changes, depicting both short- and long-term lag effect. The results showed significant spatial and temporal heterogeneity on the short- and long-term response between groundwater level change and regional subsidence. In addition, we calculated the differential subsidence slope based on the InSAR-derived LS and analyzed its impact on the river slope after SNWD-MR and EWR. The results show that two sections with significant severe differential subsidence slope occur between 0 and 14,000 m and between 54,000 and 78,000 m along the YDR. The slope change caused by LS may reduce the conveyance capacity of surface canals, and more attention should be paid in those two sections. These findings have an important scientific significance for management strategy for LS control against the background of SNWD-MR and EWR.

ABSTRACT Backgrounds Severe asthma is a significant health burden because children with severe asthma are vulnerable to medication‐related side effects, life‐threatening deterioration, and impaired quality of life. However, there is a lack of data to elucidate the role of inflammatory variables in asthma. This study aimed to compare the levels of inflammatory factors in serum and sputum in children with acute and stable asthma to those in healthy children and the ability to predict clinical response to azithromycin therapy. Methods This study recruited 95 individuals aged 1−3 years old and collected data from January 2018 to 2020. We examined serum and sputum inflammatory factors and constructed the least absolute shrinkage and selection operator (LASSO) model. Predictive models were constructed through multifactor logistic regression and presented in the form of column‐line plots. The performance of the column‐line diagrams was measured by subject work characteristics (ROC) curves, calibration plots, and decision curve analysis (DCA). Then, filter‐paper samples were collected from 45 children with acute asthma who were randomly assigned to receive either azithromycin (10 mg/kg, n = 22) or placebo (n = 23). Pretreatment levels of immune mediators were then analyzed and compared with clinical response to azithromycin therapy. Results Of the 95 eligible participants, 21 (22.11%) were healthy controls, 29 (30.53%) had stable asthma, and 45 (47.37%) had acute asthma. The levels of interferon‐γ (IFN‐γ), tumor necrosis factor‐a (TNF‐α), chemokine CCL22 (CCL22), interleukin 12 (IL‐12), chemokine CCL4 (CCL4), chemokine CCL2 (CCL2), and chemokine CCL13 (CCL13）were significantly higher in the acute asthma group than in the stable asthma group. A logistic regression analysis was performed using CCL22 and IL‐1 as independent variables. Additionally, IFN‐γ, TNF‐α, IL‐1, IL‐13, and CCL22 were identified in the LASSO model. Finally, we found that CCL22 and IL‐1 were more responsive in predicting the response to azithromycin treatment. Conclusion Our results show that CCL22 and IL‐1 are both representative markers during asthma symptom exacerbations and an immune mediator that can predict response to azithromycin therapy.

The onset of drug resistance in advanced cancer patients markedly diminishes their prognosis. Recently, disulfidptosis, a novel form of cell death, has been identified, triggered by excessive disulfide formation leading to cell shrinkage and F-actin contraction. Previous studies have identified 15 essential genes (FLNA, FLNB, MYH9, TLN1, ACTB, MYL6, MYH10, CAPZB, DSTN, IQGAP1, ACTN4, PDLIM1, CD2AP, INF2, SLC7A11) associated with disulfidptosis. This study sourced pan-cancer mRNA expression data from Xena to thoroughly evaluate the molecular and clinical characteristics of disulfidptosis-related genes. Through unsupervised clustering, mRNA expression data identified the expression levels of disulfidptosis-related genes and potential clusters related to this form of cell death. Kaplan-Meier survival curves illustrated the correlation between different clusters and overall survival. The findings reveal that high expression of disulfidptosis-related genes is linked to poor survival in liver cancer. The GDSC database was utilized to analyze the relationship between disulfidptosis-related genes and the AUC of 198 drugs. The results demonstrate that 12 disulfidptosis-related genes influence sorafenib resistance, as revealed by the intersection of differential genes related to sorafenib resistance from the GSE109211 dataset. Among them, the MYH9 gene was found to play a crucial role in both. Finally, experimental evidence confirmed that MYH9 mitigates sorafenib resistance in hepatocellular carcinoma through disulfidptosis-like changes. This study identifies disulfidptosis as a promising avenue for enhancing the sensitivity of tumor cells to drugs, offering new therapeutic perspectives for future research on disulfidptosis and drug resistance in cancer patients.

Five kinds of commercially available sour fish sauce were taken as the research object to clarify their quality and flavor characteristics. The physicochemical and nutritional indexes, free amino acids, and volatile components were analyzed. The results showed that the moisture, ash, total acid, amino acid nitrogen, reducing sugar, protein, vitamin C and fat contents in the five kinds of sour fish sauce were significantly different (P

Abstract Background The tetraspanin family plays a pivotal role in the genesis of migrasomes, and Tetraspanin CD151 is also implicated in neovascularization within tumorous contexts. Nevertheless, research pertaining to the involvement of CD151 in hepatocellular carcinoma (HCC) neovascularization and its association with migrasomes remains inadequate. Methods To investigate the correlation between CD151 and migrasome marker TSPAN4 in liver cancer, we conducted database analysis using clinical data from HCC patients. Expression levels of CD151 were assessed in HCC tissues and correlated with patient survival outcomes. In vitro experiments were performed using HCC cell lines to evaluate the impact of CD151 expression on migrasome formation and cellular invasiveness. Cell lines with altered CD151 expression levels were utilized to study migrasome generation and in vitro invasion capabilities. Additionally, migrasome function was explored through cellular aggregation assays and phagocytosis studies. Subsequent VEGF level analysis and tissue chip experiments further confirmed the role of CD151 in mediating migrasome involvement in angiogenesis and cellular signal transduction. Results Our study revealed a significant correlation between CD151 expression and migrasome marker TSPAN4 in liver cancer, based on database analysis of clinical samples. High expression levels of CD151 were closely associated with poor survival outcomes in HCC patients. Experimentally, decreased CD151 expression led to reduced migrasome generation and diminished in vitro invasion capabilities, resulting in attenuated in vivo metastatic potential. Migrasomes were demonstrated to facilitate cellular aggregation and phagocytosis, thereby promoting cellular invasiveness. Furthermore, VEGF-enriched migrasomes were implicated in signaling and angiogenesis, accelerating HCC progression. Conclusions In summary, our findings support the notion that elevated CD151 expression promotes migrasome formation, and migrasomes play a pivotal role in the invasiveness and angiogenesis of liver cancer cells, thereby facilitating HCC progression. This finding implies that migrasomes generated by elevated CD151 expression may constitute a promising high-priority target for anti-angiogenic therapy in HCC, offering crucial insights for the in-depth exploration of migrasome function and a renewed comprehension of the mechanism underlying liver cancer metastasis.

Abstract Background Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. Methods Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. Results Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-β-muricholic acid (Tβ-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. Conclusions Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism. Graphical Abstract Schematic model depicting the proposed mechanism of cholestasis-mediated progression of colorectal liver metastasis. As cholestasis progresses, excessive primary bile acids that accumulate in the liver intoxicates hepatocytes, which lead to exacerbated release of chemokines, particularly CXCL2 and CXCL5. Neutrophils are then accumulated by CXCL2 and CXCL5 and undergo an immunosuppressive-phenotypic alteration induced by direct stimulation of BAs via activating the p38 MAPK signaling pathway, which eventually led to the dysfunction of T cells and progression of LM. Targeting bile acid anabolism can effectively restore the immune-activated microenvironment and prevent the progression of LM.

In recent years, the use of chimeric antigen receptor (CAR)-T cells has emerged as a promising immunotherapy in multiple diseases. CAR-T cells are T cells genetically modified to express a surface receptor, known as CAR, for the targeting of cognate antigens on specific cells. The effectiveness of CAR-T cell therapy in hematologic malignancies including leukemia, myeloma, and non-Hodgkin’s lymphoma has led to consider its use as a potential avenue of treatment for autoimmune diseases. However, broadening the use of CAR-T cell therapy to a large spectrum of autoimmune conditions is challenging particularly because of the possible development of side effects including cytokine release syndrome and neurotoxicity. The design of CAR therapy that include additional immune cells such as double-negative T cells, γδ T cells, T regulatory cells and natural killer cells has shown promising results in preclinical studies and clinical trials in oncology, suggesting a similar potential utility in the treatment of autoimmune diseases. This review examines the mechanisms, efficacy, and safety of CAR approaches with a focus on their use in autoimmune diseases including systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, multiple sclerosis, myasthenia gravis, lupus nephritis and other autoimmune diseases. Advantages and disadvantages as compared to CAR-T cell therapy will also be discussed.

Abstract Radiofrequency ablation (RFA), a form of thermal ablation, employs localized heat to induce protein denaturation in tissue cells, resulting in cell death. It has emerged as a viable treatment option for patients who are ineligible for surgery in various diseases, particularly liver cancer and other tumor‐related conditions. In addition to directly eliminating tumor cells, RFA also induces alterations in the infiltrating cells within the tumor microenvironment (TME), which can significantly impact treatment outcomes. Moreover, incomplete RFA (iRFA) may lead to tumor recurrence and metastasis. The current challenge is to enhance the efficacy of RFA by elucidating its underlying mechanisms. This review discusses the clinical applications of RFA in treating various diseases and the mechanisms that contribute to the survival and invasion of tumor cells following iRFA, including the roles of heat shock proteins, hypoxia, and autophagy. Additionally, we analyze‌ the changes occurring in infiltrating cells within the TME after iRFA. Finally, we provide a comprehensive summary of clinical trials involving RFA in conjunction with other treatment modalities in the field of cancer therapy, aiming to offer novel insights and references for improving the effectiveness of RFA.

A better understanding of the factors contributing to systemic concentrations of carotenoids is necessary given the weak correlations between circulating levels and dietary intake of carotenoids. Although genetic variation may play a key role in the interindividual variability in carotenoid concentrations, few genome-wide association studies (GWAS) have focused on carotenoids. We used a random sample (n = 519) of postmenopausal participants in the Sister Study with data on genotypes and plasma carotenoid levels to conduct GWAS for each of five carotenoids (mcg/mL): alpha-carotene, beta- carotene, cryptoxanthin, lycopene, and lutein/zeaxanthin. We used linear regression models and an additive genetic model to evaluate associations between 371,532 variants and inverse normal transformed carotenoid concentrations. We found evidence for one genome-wide statistically significant association with the combined carotenoids of lutein and zeaxanthin for rs6564851-C (beta = −0.377, se = 0.059, p = 4.6×10−10) and rs6420424-A (beta = −0.334, se = 0.059, p = 2.2×10−8), upstream of beta-carotene oxygenase 1 (BCO1) gene on chromosome 16. No other variant was associated with any of the remaining four carotenoids. Our results for the common rs6564851 and rs6420424 variants correspond to previous findings. Although biologic mechanisms explain the association between beta-carotene and the variants, the inverse association with lutein/zeaxanthin will require further investigation.

IntroductionRecent studies have emphasized the intricate connection between exercise and cognition, focusing on specific cognitive processes and their correlations with specific motor skills. However, research on the impact of the qualitative aspects of movement on both short- and long-term cognitive performance is limited. In this quasi-experimental study, we investigate the impact of a 10-week fancy rope-skipping intervention on motor coordination and selective attention of 7–9-year-old children.MethodsA total of 60 primary school students from Changbin School in Haikou participated and completed the study from October to December 2022. The 60 participants were divided into a fancy rope-skipping group and a control group. Children's motor coordination was assessed using the Körperkoordinations Test für Kinder (KTK), while selective attention was evaluated using the d2 Test of Attention. Children were assessed at baseline and after the 10-week intervention.ResultsCompared with the control group, the scores for the total KTK and for the hopping for height, jumping sideways, and moving sideways sub-items were significantly higher in the rope-skipping group after the intervention, with a significant interaction effect between time and intervention. Attention concentration improved in the rope-skipping group and had a significant interaction effect between time and intervention compared with the control group; the effects of the intervention on other aspects of selective attention were unclear.ConclusionsOur study suggests that a 10-week fancy rope-skipping intervention may potentially enhance motor coordination and selective attention accuracy in children aged 7–9 years.

Abstract High‐sensitivity flow cytometers have been developed for multi‐parameter characterization of single extracellular vesicles (EVs), but performance varies among instruments and calibration methods. Here we compare the characterization of identical (split) EV samples derived from human colorectal cancer (DiFi) cells by three high‐sensitivity flow cytometers, two commercial instruments, CytoFLEX/CellStream, and a custom single‐molecule flow cytometer (SMFC). DiFi EVs were stained with the membrane dye di‐8‐ANEPPS and with PE‐conjugated anti‐EGFR or anti‐tetraspanin (CD9/CD63/CD81) antibodies for estimation of EV size and surface protein copy numbers. The limits of detection (LODs) for immunofluorescence and vesicle size based on calibration using cross‐calibrated, hard‐dyed beads were ∼10 PE/∼80 nm EV diameter for CytoFLEX and ∼10 PEs/∼67 nm for CellStream. For the SMFC, the LOD for immunofluorescence was 1 PE and ≤ 35 nm for size. The population of EVs detected by each system (di‐8‐ANEPPS+/PE+ particles) differed widely depending on the LOD of the system; for example, CellStream/CytoFLEX detected only 5.7% and 1.5% of the tetraspanin‐labelled EVs detected by SMFC, respectively, and median EV diameter and antibody copy numbers were much larger for CellStream/CytoFLEX than for SMFC as measured and validated using super‐resolution/single‐molecule TIRF microscopy. To obtain a dataset representing a common EV population analysed by all three platforms, we filtered out SMFC and CellStream measurements for EVs below the CytoFLEX LODs as determined by bead calibration (10 PE/80 nm). The inter‐platform agreement using this filtered dataset was significantly better than for the unfiltered dataset, but even better concordance between results was obtained by applying higher cutoffs (21 PE/120 nm) determined by threshold analysis using the SMFC data. The results demonstrate the impact of specifying LODs to define the EV population analysed on inter‐instrument reproducibility in EV flow cytometry studies, and the utility of threshold analysis of SMFC data for providing semi‐quantitative LOD values for other flow cytometers.

Abstract Background Creativity is an essential cognitive ability that plays a crucial role in advanced thinking. While previous research has demonstrated the impact of insomnia on cognitive function, its effects on creativity in Chinese adolescents remain unclear. This study explored the relationship between insomnia (specifically, daytime and nighttime disturbances) and creativity in adolescents. Additionally, it examined the potential mediating effect of the need for cognition on this relationship. Methods Questionnaires were administered to 302 adolescents to measure their creativity, need for cognition, and insomnia levels using the Williams Creative Tendencies Scale, Need for Cognition Scale, and Bergen Insomnia Scale, respectively. Regression analysis was conducted to examine the direct impact of insomnia on creativity. Furthermore, a mediation model was constructed to investigate the role of the need for cognition in mediating the relationship between insomnia and creativity. Results The findings of the present study indicated that insomnia had a direct impact on the creativity of adolescents, demonstrating a time-of-day effect. Daytime disturbances were found to have a positive correlation with overall creativity and imagination, whereas no significant direct effect was found between nighttime disturbances and creativity. Further analysis revealed that insomnia, specifically daytime disturbances, might influence creativity by affecting the individual’s need for cognition. However, no similar indirect effects were observed for the relationship between nighttime disturbances and creativity. Conclusions Our findings indicate that adolescents might experience improved creativity as a result of daytime disruptions, and the level of need for cognition could play a crucial role in understanding the link between insomnia and creativity in adolescents.

Abstract The diagnosis of leukemic T-cell malignancies is often challenging, due to overlapping features with reactive T-cells and limitations of currently available T-cell clonality assays. Recently developed therapeutic antibodies specific for the mutually exclusive T-cell receptor constant β chain (TRBC)1 and TRBC2 isoforms provide a unique opportunity to assess for TRBC-restriction as a surrogate of clonality in the flow cytometric analysis of T-cell neoplasms. To demonstrate the diagnostic utility of this approach, we studied 164 clinical specimens with (60) or without (104) T-cell neoplasia, in addition to 39 blood samples from healthy donors. Dual TRBC1 and TRBC2 expression was studied within a comprehensive T-cell panel, in a fashion similar to the routine evaluation of kappa and lambda immunoglobulin light chains for the detection of clonal B-cells. Polytypic TRBC expression was demonstrated on total, CD4+ and CD8+ T-cells from all healthy donors; and by intracellular staining on benign T-cell precursors. All neoplastic T-cells were TRBC-restricted, except for 8 cases (13%) lacking TRBC expression. T-cell clones of uncertain significance were identified in 17 samples without T-cell malignancy (13%) and accounted for smaller subsets than neoplastic clones (median: 4.7 vs. 69% of lymphocytes, p

Abstract T-cell lymphoma is a highly invasive tumor with significant heterogeneity. Invasive tissue biopsy is the gold standard for acquiring molecular data and categorizing lymphoma patients into genetic subtypes. However, surgical intervention is unfeasible for patients who are critically ill, have unresectable tumors, or demonstrate low compliance, making tissue biopsies inaccessible to these patients. A critical need for a minimally invasive approach in T-cell lymphoma is evident, particularly in the areas of early diagnosis, prognostic monitoring, treatment response, and drug resistance. Therefore, the clinical application of liquid biopsy techniques has gained significant attention in T-cell lymphoma. Moreover, liquid biopsy requires fewer samples, exhibits good reproducibility, and enables real-time monitoring at molecular levels, thereby facilitating personalized health care. In this review, we provide a comprehensive overview of the current liquid biopsy biomarkers used for T-cell lymphoma, focusing on circulating cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), Epstein-Barr virus (EBV) DNA, antibodies, and cytokines. Additionally, we discuss their clinical application, detection methodologies, ongoing clinical trials, and the challenges faced in the field of liquid biopsy.

Abstract Baccaurea ramiflora Lour., an evergreen tree of the Baccaurea genus of the Phyllanthaceae family, is primarily distributed in South Asia, Southeast Asia, and southern China, including southern Yunnan Province. It is a wild or semi-cultivated tree species with ornamental, edible, and medicinal value, exhibiting significant development potential. In this study, we present the whole-genome sequencing of B. ramiflora, employing a combination of PacBio SMRT and Illumina HiSeq 2500 sequencing techniques. The assembled genome size was 975.8 Mb, with a contig N50 of 509.33 kb and the longest contig measuring 7.74 Mb. The genome comprises approximately 73.47% highly repetitive sequences, of which 52.1% are long terminal repeat–retrotransposon sequences. A total of 29,172 protein-coding genes were predicted, of which 25,980 (89.06%) have been annotated, Additionally, 3452 non-coding RNAs were identified. Comparative genomic analysis revealed a close relationship between B. ramiflora and the Euphorbiaceae family, with both being sister groups that diverged approximately 59.9 million years ago. During the evolutionary process, B. ramiflora exhibited positive selection in 278 candidate genes. Synonymous substitution rate and collinearity analysis demonstrated that B. ramiflora underwent a single ancient genome-wide triploidization event, without recent genome-wide duplication events. This high-quality B. ramiflora genome provides a valuable resource for basic research and tree improvement programs focusing on the Phyllanthaceae family.

This paper proposes a novel distributed control strategy for DC microgrids using a convex relaxation method to ensure the system operates at the optimal power flow solution. Initially, a suitable convex relaxation technique is applied to transform the non-convex optimal power flow problem into a convex form, with the accuracy of this method being rigorously demonstrated. Next, the Karush–Kuhn–Tucker (KKT) optimality conditions of the relaxed problem are equivalently transformed, and a synchronization term is derived to facilitate the distributed control, thereby ensuring operation under optimal power flow. This paper also analyzes the impacts of communication delay and network structure on the performance of the proposed control strategy. Finally, simulations and numerical experiments are presented to validate the effectiveness of the proposed method.

Zwitterionic π-allenyl palladium species are newly developed intermediates. A substrate-controlled step existed in the cycloaddition of zwitterionic π-allenyl palladium species with tropsulfimides or tropones. With the assistance of previously experimental studies, zwitterionic allenyl/propargyl palladium species was provenly found by HRMS. Further DFT calculation studies show that zwitterionic π-allenyl palladium species are generated through the oxidative addition of Pd(0), which can be promoted by Lewis acid like Yb(OTf)3, and the cycloaddition more likely undergoes through an outer sphere nucleophilic attack. The isomerization is caused by the difference of dissociation energy between the cycloaddition intermediation of tropsulfimides and tropones, forming the substrate-controlled specificity.

Exosomes, also termed extracellular vesicles (EVs), are an important component of the tumor microenvironment (TME) and exert versatile effects on the molecular communications in the TME of hepatocellular carcinoma (HCC). Exosome-mediated intercellular communication is closely associated with the tumorigenesis and development of HCC. Exosomes can be extracted through ultracentrifugation and size exclusion, followed by molecular analysis through sequencing. Increasing studies have confirmed the important roles of exosome-derived ncRNAs in HCC, including tumorigenesis, progression, immune escape, and treatment resistance. Due to the protective membrane structure of exosomes, the ncRNAs carried by exosomes can evade degradation by enzymes in body fluids and maintain good expression stability. Thus, exosome-derived ncRNAs are highly suitable as biomarkers for the diagnosis and prognostic prediction of HCC, such as exosomal miR-21-5p, miR-221-3p and lncRNA-ATB. In addition, substantial studies revealed that the up-or down-regulation of exosome-derived ncRNAs had an important impact on HCC progression and response to treatment. Exosomal biomarkers, such as miR-23a, lncRNA DLX6-AS1, miR-21-5p, lncRNA TUC339, lncRNA HMMR-AS1 and hsa_circ_0004658, can reshape immune microenvironment by regulating M2-type macrophage polarization and then promote HCC development. Therefore, by controlling exosome biogenesis and modulating exosomal ncRNA levels, HCC may be inhibited or eliminated. In this current review, we summarized the recent findings on the role of exosomes in HCC progression and analyzed the relationship between exosome-derived ncRNAs and HCC diagnosis and treatment.

Background This study aims to examine the relationship between functional movements and golf performance using the Golf Specific Functional Movement Screen (GSFMS). Methods This cross-sectional study included a total of 56 collegiate golfers (aged 20.89 ± 0.99 years, height of 174.55 ± 7.76 cm, and weight 68.48 ± 9.30 kg) who met the criteria, and were recruited from Hainan Normal University in June 2022. The participants’ golf motor skills (1-yard putt, 10-yard putt, 25-yard chip, 130/100-yard set shot, driver, and 9-hole stroke play) were tested and the GSFMS (e.g., pelvic tilt, pelvic rotation, and torso rotation) was used. Results There were significant weak or moderate correlations between the variables. Furthermore, a multiple linear regression analysis found that pelvic rotation and lower-body rotation abilities can significantly predict golf skill levels, which collectively explain 31.2% of the variance in golf skill levels among collegiate golfers (Adjusted R2 = 0.312, F = 2.663, p < 0.05). Standardised β values indicate that pelvic rotation (β = 0.398) has a more substantial impact on golf skill levels than lower-body rotation (β = 0.315). Conclusions This study found the weak to moderate correlations between the GSFMS and golf performance, and pelvic rotation and lower-body rotation abilities, thus predicting golf skills. Our findings provide novel insights into the relationship between functional abilities and comprehensive skill performance within the context of the Gray Cook’s Movement Pyramid model, and provide theoretical support and practical reference for collegiate golf motor-skill learning and sports injury prevention.

Objective This study aimed to investigate the caregiving behaviours and supportive needs of caregivers of patients with HIV/AIDS and provide a basis for healthcare institutions to carry out caregiver interventions.Design A purposive sampling method was used to select 11 caregivers of patients with HIV/AIDS in the Infectious Disease Department of a tertiary hospital in Nanjing, China, to conduct semistructured interviews. Colaizzi analysis was used to collate and analyse the interview data.Setting All interviews were conducted at a tertiary hospital specialising in infectious diseases in Nanjing, Jiangsu Province.Participants We purposively sampled 11 caregivers of people with HIV/AIDS, including nine women and two men.Results Analysing the results from the perspective of iceberg theory, three thematic layers were identified: behavioural, value and belief. The behavioural layer includes a lack of awareness of the disease, physical and mental coping disorders, and an increased sense of stigma; the values layer includes a heightened sense of responsibility, the constraints of traditional gender norms, the influence of strong family values and the oppression of public opinion and morality and the belief layer includes the faith of standing together through storms and stress.Conclusion Healthcare professionals should value the experiences of caregivers of patients with HIV/AIDS and provide professional support to improve their quality of life.

Objective The efficacy of sirolimus in treating severe or refractory systemic lupus erythematosus (SLE) has been confirmed by small-scale clinical trials. However, few studies focused on mild or moderate SLE. Therefore, in this study we elucidated clinical efficacy of add-on sirolimus in patients with mild or moderate SLE.Methods Data of 17 consecutive patients with SLE were retrospectively collected. SLE Disease Activity Index-2000 (SLEDAI-2K), clinical manifestation, laboratory data and peripheral T lymphocyte subsets with cytokines were collected before and 6 months after sirolimus add-on treatment. T cell subsets were detected by flow cytometry and cytokines were determined by multiplex bead-based flow fluorescent immunoassay simultaneously. Twenty healthy controls matched with age and sex were also included in our study.Results (1) The numbers of peripheral blood lymphocytes, T cells, T helper (Th) cells, regulatory T (Treg) cells, Th1 cells, Th2 cells and Treg/Th17 ratios in patients with SLE were significantly lower, while the numbers of Th17 cells were evidently higher than those of healthy control (p

Abstract Data-driven garment animation is a current topic of interest in the computer graphics industry. Existing approaches generally establish the mapping between a single human pose or a temporal pose sequence, and garment deformation, but it is difficult to quickly generate diverse clothed human animations. We address this problem with a method to automatically synthesize dressed human animations with temporal consistency from a specified human motion label. At the heart of our method is a two-stage strategy. Specifically, we first learn a latent space encoding the sequence-level distribution of human motions utilizing a transformer-based conditional variational autoencoder (Transformer-CVAE). Then a garment simulator synthesizes dynamic garment shapes using a transformer encoder–decoder architecture. Since the learned latent space comes from varied human motions, our method can generate a variety of styles of motions given a specific motion label. By means of a novel beginning of sequence (BOS) learning strategy and a self-supervised refinement procedure, our garment simulator is capable of efficiently synthesizing garment deformation sequences corresponding to the generated human motions while maintaining temporal and spatial consistency. We verify our ideas experimentally. This is the first generative model that directly dresses human animation.

Photovoltaic (PV) power forecasting is essential for secure operation of a power system. Effective prediction of PV power can improve new energy consumption capacity, help power system planning, promote development of smart grids, and ultimately support construction of smart energy cities. However, different from centralized PV power forecasts, three critical challenges are encountered in distributed PV power forecasting: 1) lack of on-site meteorological observation, 2) leveraging extraneous data to enhance forecasting performance, 3) spatial-temporal modelling methods of meteorological information around the distributed PV stations. To address these issues, we propose a Graph Spatial-Temporal Attention Neural Network (GSTANN) to predict the very short-term power of distributed PV. First, we use satellite remote sensing data covering a specific geographical area to supplement meteorological information for all PV stations. Then, we apply the graph convolution block to model the non-Euclidean local and global spatial dependence and design an attention mechanism to simultaneously derive temporal and spatial correlations. Subsequently, we propose a data fusion module to solve the time misalignment between satellite remote sensing data and surrounding measured on-site data and design a power approximation block to map the conversion from solar irradiance to PV power. Experiments conducted with real-world case study datasets demonstrate that the prediction performance of GSTANN outperforms five state-of-the-art baselines.

Abstract Background Recent case studies indicate that the 2014-2016 Ebola outbreak, one of the worst pre-2020 global biological catastrophes in modern history, helped some nations to better prepared their responses for the COVID-19 pandemic. While such national case studies explore how specific nations applied EVD-related policies in their domestic battle against the COVID-19 pandemic, there is no known study that assesses how many WHO nations learned from the West African crisis and to what scale. Objective Applying the policy legacies analytical framework and a systematized literature review, this research examines how prior policy experiences with the 2014-16 EVD crisis as a large-scale emergent outbreak helped to inform and to condition WHO nations to proactively prepare their national policies and health systems for future threats, including ultimately COVID-19. Methods A systematized literature review of 803 evaluated sources assesses to what extent Ebola-affected and non-affected nations directly modified governmental health systems in relation to this warning. The study further evaluates how nations with documented Ebola-related changes fared during COVID-19 compared to nations that did not. We present a categorical theoretical framework that allows for classifying different types of national response activities (termed conditioned learning). Results Ten (90.9%) of 11 nations that were affected by 2014-16 Ebola crisis have documented evidence of repurposing their EVD-related policies to fight COVID-19. 164 (70.0%) of 234 non-EVD-affected nations had documented evidence of specifically adapting national systems to incorporate policy recommendations developed from the 2014-16 crisis, which informed their COVID-19 responses in 2020. Conclusions The shock of 2014-16 EVD outbreak affected most nations around the world, whether they experienced Ebola cases. We further develop a categorical framework that helps characterised nations previous experiences with this biological catastrophe, providing a means to analyse to what extent that individual nations learned and how these EVD-related changes helped inform their COVID-19 response. Nations that demonstrated EVD-related conditioned learning nations tended to have more stringent COVID-19 responses before April 2020 and utilized documented response mechanisms developed out of the West African crisis.

Abstract Background Studies exploring whether metastatic organotropism and risk in gastric cancer (GC) differ by primary anatomical site are scarce. Methods This study included 15,260 and 1623 patients diagnosed with GC from the Surveillance, Epidemiology, and End Results (SEER) registry database and the Nanfang Hospital in China, respectively. Patients were stratified according to primary site of GC, and the incidence of metastasis to different organs was used to determine the metastatic organotropism for each GC subsite. Finally, the metastatic organotropism and risk were compared among the different subsite groups. Results Liver metastasis was the most common metastasis site in cardia GC, whereas other‐site metastases were more common in the body, antrum, overlapping lesions, and unspecified GCs. Liver and other‐site metastases were also frequently observed in the fundus, pylorus, lesser curvature, and greater curvature GCs. Patients with GC with definite primary tumor sites in the SEER and validation Nanfang hospital cohorts were compared by grouping as proximal and distal GCs for further analysis. In the SEER cohort, the top three metastatic sites of proximal GC were liver (21.4%), distant lymph node (LN) (14.6%), and other‐site (mainly peritoneum, 11.9%), whereas those of distal GC were other‐site (mainly peritoneum, 19.5%), liver (11.8%), and distant LN (9.5%). The incidence of metastasis to the liver, distant LN, lung, and brain was significantly higher in patients with proximal GC than in those with distal GC in both the SEER and Nanfang cohorts (p

Abstract Aims To investigate loneliness, depression and sleep quality in patients with Type 2 Diabetes (T2DM) and to examine the mediating role of depression between loneliness and sleep quality among this group of patients with T2DM. Design A cross‐sectional study. Methods A group of T2DM patients was recruited from a tertiary hospital affiliated with a university in Wuhu City, Anhui Province from May to October 2021 by convenient sampling. Pearson correlation analysis and structural equation modelling were used for data analysis in this study. Results The direct effect of loneliness on sleep quality was not statistically significant, but the indirect effect of depression on sleep quality was statistically significant. Depression mediated the relationship between loneliness and sleep quality. Depression can affect emotional health and reduce sleep quality. We should reduce the loneliness of patients, prevent the occurrence of depression and improve the quality of sleep.

Abstract Background Trastuzumab is a first‐line targeted therapy for human epidermal growth factor receptor‐2 (HER2)‐positive gastric cancer. However, the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit, and there is currently no effective reversal measure. Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves, while the understanding of the mechanisms of environment‐mediated drug resistance is relatively lacking. This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients. Methods Trastuzumab‐sensitive and trastuzumab‐resistant HER2‐positive tumor tissues and cells were collected for transcriptome sequencing. Bioinformatics were used to analyze cell subtypes, metabolic pathways, and molecular signaling pathways. Changes in microenvironmental indicators (such as macrophage, angiogenesis, and metabolism) were verified by immunofluorescence (IF) and immunohistochemical (IHC) analyses. Finally, a multi‐scale agent‐based model (ABM) was constructed. The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM. Results Based on transcriptome sequencing, molecular biology, and in vivo experiments, we found that the level of glutamine metabolism in trastuzumab‐resistant HER2‐positive cells was increased, and glutaminase 1 (GLS1) was significantly overexpressed. Meanwhile, tumor‐derived GLS1 microvesicles drove M2 macrophage polarization. Furthermore, angiogenesis promoted trastuzumab resistance. IHC showed high glutamine metabolism, M2 macrophage polarization, and angiogenesis in trastuzumab‐resistant HER2‐positive tumor tissues from patients and nude mice. Mechanistically, the cell division cycle 42 (CDC42) promoted GLS1 expression in tumor cells by activating nuclear factor kappa‐B (NF‐κB) p65 and drove GLS1 microvesicle secretion through IQ motif‐containing GTPase‐activating protein 1 (IQGAP1). Based on the ABM and in vivo experiments, we confirmed that the combination of anti‐glutamine metabolism, anti‐angiogenesis, and pro‐M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2‐positive gastric cancer. Conclusions This study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism, M2 macrophage polarization, and pro‐angiogenic function of macrophages, leading to acquired trastuzumab resistance in HER2‐positive gastric cancer. A combination of anti‐glutamine metabolism, anti‐angiogenesis, and pro‐M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.

Ensuring national food security is crucial for strengthening the agriculture sector of China, and it holds both theoretical and practical significance in the context of the “dual circulation” (i. e., domestic and international economic circulations) strategy. This study explores the resilience of China’s food security and its capacity for risk management under the “dual circulation” framework, providing an analysis of the current status, characteristics, influencing factors, and feasible pathways for enhancing food security resilience and risk management capabilities. The study identifies key factors influencing food security resilience and risk management, including the agricultural production base, the level of agricultural technology, food production methods, support policies for food production, and the international trade environment. Feasible pathways for enhancing food security resilience and risk management capabilities include improving the stability of food supply, enhancing the adaptability of food production, promoting the sustainability of food production, maintaining the continuity of policy systems, and strengthening the coordination between domestic and international markets. To achieve these goals, it is recommended to solidify the foundation of grain production capacity, improve technological support for grain production, strengthen intelligent monitoring and management, accelerate the establishment of guarantee systems, and optimize grain import and export trade. These measures will enhance China’s food security resilience and risk management capabilities in the context of “dual circulation”.

Abstract Immunity-related GTPase family M (IRGM), located on human chromosome 5q33.1, encodes a protein that promotes autophagy and suppresses the innate immune response. The minor allele of rs13361189 (−4299T>C), a single nucleotide polymorphism in the IRGM promoter, has been associated with several diseases, including Crohn’s disease and tuberculosis. Although patterns of linkage disequilibrium and minor allele frequency for this polymorphism differ dramatically between subjects of European and African descent, studies of rs13361189 have predominantly been conducted in Europeans and the mechanism of association is poorly understood. We recruited a cohort of 68 individuals (30 White, 34 African American, 4 other race) with varying rs13361189 genotypes and assessed a panel of immune response measures including whole blood cytokine induction following ex vivo stimulation with Toll-like Receptor ligands. Minor allele carriers were found to have increased serum immunoglobulin M, C-reactive protein, and circulating CD8+ T cells. No differences in whole blood cytokines were observed between minor allele carriers and non-carriers in the overall study population; however, minor allele status was associated with increased induction of a subset of cytokines among African American subjects, and decreased induction among White subjects. These findings underline the importance of broad racial inclusion in genetic studies of immunity.

Diabetes mellitus (DM) refers to a group of chronic diseases with global prevalence, characterized by persistent hyperglycemia resulting from various etiologies. DM can harm various organ systems and lead to acute or chronic complications, which severely endanger human well-being. Traditional treatment mainly involves controlling blood sugar levels through replacement therapy with drugs and insulin; however, some patients still find a satisfactory curative effect difficult to achieve. Extensive research has demonstrated a close correlation between enteric dysbacteriosis and the pathogenesis of various types of DM, paving the way for novel therapeutic approaches targeting the gut microbiota to manage DM. Fecal microbiota transplantation (FMT), a method for re-establishing the intestinal microbiome balance, offers new possibilities for treating diabetes. This article provides a comprehensive review of the correlation between DM and the gut microbiota, as well as the current advancements in FMT treatment for DM, using FMT as an illustrative example. This study aims to offer novel perspectives and establish a theoretical foundation for the clinical diagnosis and management of DM.

Neoadjuvant chemoimmunotherapy has revolutionized the therapeutic strategy for non-small cell lung cancer (NSCLC), and identifying candidates likely responding to this advanced treatment is of important clinical significance. The current multi-institutional study aims to develop a deep learning model to predict pathologic complete response (pCR) to neoadjuvant immunotherapy in NSCLC based on computed tomography (CT) imaging and further prob the biologic foundation of the proposed deep learning signature. A total of 248 participants administrated with neoadjuvant immunotherapy followed by surgery for NSCLC at Ruijin Hospital, Ningbo Hwamei Hospital, and Affiliated Hospital of Zunyi Medical University from January 2019 to September 2023 were enrolled. The imaging data within 2 weeks prior to neoadjuvant chemoimmunotherapy were retrospectively extracted. Patients from Ruijin Hospital were grouped as the training set (n = 104) and the validation set (n = 69) at the 6:4 ratio, and other participants from Ningbo Hwamei Hospital and Affiliated Hospital of Zunyi Medical University served as an external cohort (n = 75). For the entire population, pCR was obtained in 29.4% (n = 73) of cases. The areas under the curve (AUCs) of our deep learning signature for pCR prediction were 0.775 (95% confidence interval [CI]: 0.649 - 0.901) and 0.743 (95% CI: 0.618 - 0.869) in the validation set and the external cohort, significantly superior than 0.579 (95% CI: 0.468 - 0.689) and 0.569 (95% CI: 0.454 - 0.683) of the clinical model. Furthermore, higher deep learning scores correlated to the upregulation for pathways of cell metabolism and more antitumor immune infiltration in microenvironment. Our developed deep learning model is capable of predicting pCR to neoadjuvant chemoimmunotherapy in patients with NSCLC.

Introduction:Crocus sativus L. has an important medicinal and economic value in traditional perennial Chinese medicine. However, due to its unique growth characteristics, during cultivation it is highly susceptible to disease. The absence of effective resistance genes restricts us to breed new resistant varieties of C. sativus.Methods: In present study, comprehensive transcriptome sequencing was introduced to explore the disease resistance of the candidate gene in healthy and corm rot-infected C. sativus.Results and discussion: Totally, 43.72 Gb of clean data was obtained from the assembly to generate 65,337 unigenes. By comparing the gene expression levels, 7,575 differentially expressed genes (DEGs) were primarily screened. A majority of the DEGs were completely in charge of defense and metabolism, and 152 of them were annotated as pathogen recognition genes (PRGs) based on the PGRdb dataset. The expression of some transcription factors including NAC, MYB, and WRKY members, changed significantly based on the dataset of transcriptome sequencing. Therefore, this study provides us some valuable information for exploring candidate genes involved in the disease resistance in C. sativus.

Abstract Background Hepatic masses are relatively common findings, and the diagnostic approach often begins by identifying patient and mass characteristics that are risk factors for malignancy. Chronic immunosuppression is a known risk factor for various malignancies, and azathioprine in particular has been reported in association with solid and hematologic malignancies, including diffuse large B-cell lymphoma. Case presentation A 46-year-old white woman presented to clinic with several weeks of gastrointestinal symptoms and was found to have a hepatic mass on imaging. Her history was notable for neuromyelitis optica spectrum disorder on chronic immunosuppression with azathioprine. It was initially thought to be an inflammatory adenoma. On 6-month follow-up imaging, the mass had grown rapidly in size and was surgically resected. Further workup determined the mass to be an iatrogenic immunodeficiency-associated Epstein–Barr virus-positive diffuse large B-cell lymphoma confined to the liver. Azathioprine was discontinued and the patient underwent treatment with rituximab with no evidence of recurrence 2 years after the initiation of treatment. Conclusions This case report describes the first time hepatic Epstein–Barr virus-positive diffuse large B-cell lymphoma has been reported with azathioprine, which highlights the unique sequelae of chronic immunosuppression, including atypical hematologic malignancies, and the importance of considering chronic immunosuppression in the diagnostic evaluation of a hepatic mass.

Abstract Background Several clinical studies have uncovered a negative correlation between baseline tumor burden and the efficacy of immune checkpoint inhibitor (ICI) treatment. This study aimed to uncover the specific mechanisms underlying the difference in sensitivity to ICI treatment between tumors with high (HTB) and low (LTB) tumor burden. Methods For in vivo studies, several mouse models of subcutaneous tumors were established, and transcriptome sequencing, immunohistochemistry, and flow cytometry assays were used to detect the immune status in these subcutaneous tumors. For in vitro experiments, co‐culture models, cytokine antibody arrays, western blotting, flow cytometry, and enzyme‐linked immunosorbent assays were used to explore the underlying molecular mechanisms Results We found that MC38 or B16 subcutaneous tumors from the HTB group did not show any response to anti‐programmed cell death protein‐1 (PD‐1) therapy. Through flow cytometry assays, we found that the infiltration with CD8+ T cells was significantly decreased whereas M2‐like macrophages were enriched in subcutaneous tumors of HTB groups compared with those of LTB group. These changes were not affected by the initial number of injected tumor cells or tumor age, nor could they be reversed by surgical tumor reduction. Intraperitoneal colony‐stimulating factor 1 receptor (CSF‐1R) inhibitor PLX3397 injection at different time points of tumor growth only had an effect when administered in the early tumor stage to maintain the “heat” of the tumor microenvironment during the process of tumor growth, thereby achieving a response to ICI treatment when the tumor grew to a large size. Mechanistically, we found that insulin‐like growth factor binding protein 2 (IGFBP2) expression levels were significantly elevated in HTB tumor tissues. IGFBP2 promoted the programmed death‐ligand 1 (PD‐L1) expression in M2‐like macrophages by activating signal transducer and activator of transcription 3 (STAT3), and PD‐L1+ M2‐like macrophages exerted an immunosuppressive effect by inhibiting the proliferation and activation of CD8+ T cells in a PD‐L1‐dependent fashion. Conclusions This study suggested that the low efficacy of ICI treatment in HTB tumors is mainly attributed to the intratumoral accumulation of PD‐L1+ M2‐like macrophages via the IGFBP2‐STAT3‐PD‐L1 signaling pathway and their substantial inhibitory effects on T cell proliferation and activation.

Abstract Purpose Acute postoperative hypertension (APH) is a common complication during the anesthesia recovery period that can lead to adverse outcomes, including cardiovascular and cerebrovascular accidents. Identification of risk factors for APH will allow for preoperative optimization and appropriate perioperative management. This study aimed to identify risk factors for APH. Patients and methods In this retrospective single-center study, 1,178 cases were included. Data was entered by two investigators, and consistency analysis was performed by another. Patients were divided into APH and non-APH groups. A predictive model was built by multivariate stepwise logistic regression. The predictive ability of the logistic regression model was tested by drawing the receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC). Hosmer and Lemeshow goodness-of-fit (GOF) test was performed to reflect the goodness of fit of the model. Calibration curve was created to represent the relationship between predicted risk and observed frequency. Sensitivity analysis was performed to evaluate the robustness of the results. Results Multivariate logistic regression analysis showed that age over 65 years (OR = 3.07, 95% CI: 2.14 ~ 4.42, P

In this paper, by replacing the exponential memory kernel function of a tabu learning single-neuron model with the power-law memory kernel function, a novel Caputo’s fractional-order tabu learning single-neuron model and a network of two interacting fractional-order tabu learning neurons are constructed firstly. Different from the integer-order tabu learning model, the order of the fractional-order derivative is used to measure the neuron’s memory decay rate and then the stabilities of the models are evaluated by the eigenvalues of the Jacobian matrix at the equilibrium point of the fractional-order models. By choosing the memory decay rate (or the order of the fractional-order derivative) as the bifurcation parameter, it is proved that Hopf bifurcation occurs in the fractional-order tabu learning single-neuron model where the value of bifurcation point in the fractional-order model is smaller than the integer-order model’s. By numerical simulations, it is shown that the fractional-order network with a lower memory decay rate is capable of producing tangent bifurcation as the learning rate increases from 0 to 0.4. When the learning rate is fixed and the memory decay increases, the fractional-order network enters into frequency synchronization firstly and then enters into amplitude synchronization. During the synchronization process, the oscillation frequency of the fractional-order tabu learning two-neuron network increases with an increase in the memory decay rate. This implies that the higher the memory decay rate of neurons, the higher the learning frequency will be.

Conclusions: The method for measuring the experimental resolution, minimum detection limit, and accuracy based on linear models is simple and reasonable. The experimental performance is evaluated from multiple perspectives, which simplifies and improves the process and effect of the evaluation in order to suggest improvement strategies for analysis experiments and related equipment.

Purpose: Thyroid eye disease (TED) is an autoimmune condition with an array of clinical manifestations, which can be complicated by compressive optic neuropathy. It is important to identify patients with TED early to ensure close monitoring and treatment to prevent potential permanent disability or vision loss. Deep learning artificial intelligence (AI) algorithms have been utilized in ophthalmology and in other fields of medicine to detect disease. This study aims to introduce a deep learning model to evaluate orbital computed tomography (CT) images for the presence of TED and potential compressive optic neuropathy. Design: Retrospective review and deep learning algorithm modeling. Subjects: Patients with TED with dedicated orbital CT scans and with an examination by an oculoplastic surgeon over a 10-year period at a single academic institution. Patients with no TED and normal CTs were used as normal controls. Those with other diagnoses, such as tumors or other inflammatory processes, were excluded. Methods: Orbital CTs were preprocessed and adopted for the Visual Geometry Group-16 network to distinguish patients with no TED, mild TED, and severe TED with compressive optic neuropathy. The primary model included training and testing of all 3 conditions. Binary model performance was also evaluated. An oculoplastic surgeon was also similarly tested with single and serial images for comparison. Main Outcome Measures: Accuracy of deep learning model discernment of region of interest for CT scans to distinguish TED versus normal control, as well as TED with clinical signs of optic neuropathy. Results: A total of 1187 photos from 141 patients were used to develop the AI model. The primary model trained on patients with no TED, mild TED, and severe TED had 89.5% accuracy (area under the curve: range, 0.96–0.99) in distinguishing patients with these clinical categories. In comparison, testing of an oculoplastic surgeon in these 3 categories showed decreased accuracy (70.0% accuracy in serial image testing). Conclusions: The deep learning model developed in the study can accurately detect TED and further detect TED with clinical signs of optic neuropathy based on orbital CT. The model proved superior compared with human expert grading. With further optimization and validation, this TED deep learning model could help guide frontline health care providers in the detection of TED and help stratify the urgency of a referral to an oculoplastic surgeon and endocrinologist. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

To understand the mechanism of the dynamic accumulation of active ingredients in Cinnamomum cassia Presl, metabolomic and transcriptomic analyses of 5~8 years old C. cassia were performed. A total of 72 phenylpropanoids, 146 flavonoids, and 130 terpenoids showed marked changes. Most phenylpropanoids and flavonoids showed markedly higher abundances in 6-year-old C. cassia than in others, which was related to the higher expression of genes that synthesize and regulate phenylpropanoids and flavonoid. We identified transcription factors (TFs) and genes involved in phenylpropanoids and flavonoids synthesis and regulation through co-expression network analyses. Furthermore, most of the terpenoids in 5-year-old C. cassia showed markedly higher abundances than in others, which was due to the differentially expressed genes upstream of the terpenoids pathway. The results of our study provide new insights into the synthesis and accumulation of phenylpropanoid, flavonoids and terpenoids in C. cassia at four growth stages.

Background: Circulating tumor DNA (ctDNA) is a promising technique for predicting curative effects and monitoring tumor recurrence. The utility of ctDNA for gastric cancer with peritoneal dissemination remains elusive. Objectives: To assess the feasibility of ctDNA in predicting tumor response to chemotherapy in gastric cancer with peritoneal dissemination. Design: This was a prospective study. Methods: We enrolled 30 patients with gastric cancer peritoneal metastasis, treated with intraperitoneal and intravenous paclitaxel plus S-1. Peripheral blood samples of patients were prospectively collected at baseline, after treatment initiation accompanied by computed tomography scan and disease progression. Mutational profiles from ctDNA were analyzed to evaluate its association with chemotherapeutic response. Results: Tumor protein 53 ( TP53 ) was the most frequently altered gene at baseline blood samples. Although baseline TP53 mutation was not related to therapeutic response, patients with TP53 mutation had worse progression-free survival (PFS) and overall survival (OS). Additionally, baseline ctDNA content fraction (CCF) was found to be significantly lower in responders than non-responders. Meanwhile, patients with high CCF had a trend of worse PFS and OS. Combining TP53 alteration and CCF, the prognosis of TP53 -wt patients could be further stratified. Patients with CCF-low_ TP53 -wt had markedly longer survival than those with CCF-high_ TP53 -wt. Conclusion: Our study highlighted the significance of ctDNA in predicting potential clinical outcomes in gastric cancer patients during chemotherapy. Trial registration: ChiCTR-IIR-16009802 (Chinese Clinical Trial Registry).