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Abstract Background Sialylation in uterine corpus endometrial carcinoma (UCEC) differs significantly from apoptotic and ferroptosis pathways. It plays a crucial role in cancer progression and immune response modulation. Exploring how sialylation affects tumor behavior and its link with long non-coding RNAs (lncRNAs) may provide new insights into UCEC prognosis and treatment. Methods We obtained RNA transcriptome, clinical, and mutation data of UCEC samples from the TCGA database. Our approach involved developing a risk model based on the co-expression patterns of sialylation genes and lncRNAs. Prognostic lncRNAs were identified through Cox regression and further refined using LASSO analysis. To understand the biological functions and pathways of model-associated differentially expressed genes (MADEGs), we conducted enrichment analyses. We also assessed the immune infiltration status of MADEGs using eight different algorithms, which helped in evaluating the potential for immunotherapy. Additionally, we validated the expression of these lncRNAs in UCEC using cell lines and clinical samples. Results We developed a UCEC risk model using five sialylation-related lncRNAs (AC004884.2, AC026202.2, LINC01579, LINC00942, SLC16A1-AS1). This model, confirmed through Cox analysis and clinical evaluation, effectively predicted patient outcomes. Survival data analysis across entire cohort, as well as within training and test groups, indicated better survival in low-risk UCEC patients. Enrichment analyses linked MADEGs to sialylation functions and cancer pathways. High-risk patients showed increased responsiveness to immune checkpoint inhibitors (ICIs), as indicated by immunological assessments. Subgroup C2 patients showed superior outcomes and a robust response to immunotherapy and chemotherapy. Notably, LINC01579, LINC00942, and SLC16A1-AS1 were significantly overexpressed in UCEC clinical tumor samples as well as in Ishikawa and HEC-1-B cell lines, compared to the normal groups. Conclusions This lncRNA signature associated with sialylation could guide prognosis, enhance the understanding of molecular mechanisms, and inform treatment strategies in UCEC. It highlights the potential for the use of ICIs and chemotherapy.

Abstract The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.

Abstract Background Neoadjuvant chemoradiotherapy (nCRT) followed by surgery remains a standard of care for resectable esophageal cancer (EC), and definitive chemoradiotherapy (dCRT) is an alternative for unresectable diseases. However, it is controversial for the use of the two aggressive regimens in elderly patients. Methods We systematically searched multiple databases for studies comparing overall survival (OS) and/or progression-free survival (PFS) between dCRT and surgery (nCRT + surgery or surgery alone) or between dCRT and radiotherapy (RT) alone in elderly patients (age ≥ 65 years) until March 28, 2024. Statistical analysis was performed using random-effects model. Results Fourty-five studies with 33,729 patients were included. dCRT significantly prolonged OS (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.58–0.70) and PFS (HR = 0.67, 95% CI: 0.60–0.76) compared to RT alone for unresectable EC, and resulted in a worse OS compared to surgery for resectable cases (HR = 1.34, 95% CI: 1.23–1.45). Similar results of OS were also observed when the multivariate-adjusted HRs were used as the measure of effect (dCRT vs. RT alone: HR = 0.65, 95% CI: 0.58–0.73; dCRT vs. surgery: HR = 1.49, 95% CI: 1.28–1.74). Subgroup analyses according to age group (≥ 70, ≥ 75, or ≥ 80 years), study design, study region, histological type, radiation field, chemotherapy regimen revealed comparable results. Conclusions nCRT + surgery is likely a preferred strategy for elderly patients with good physiological conditions; and dCRT is a better alternative for unresectable cases. Advanced age alone does not appear to be a key predictor for the tolerability of the two aggressive treatments.

Abstract Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.

At a global level, the supply of protein sources is insufficient to support the current magnitude of pig production. Moreover, given the exorbitant expense of conventional protein feed options like soybean meal and fish meal, it becomes imperative to promptly explore alternative sources of protein feed for the sustainable advancement of the pig industry. Cottonseed meal, a by-product from the extraction of cottonseed oil, exhibits significant potential as a protein source for pig feed owing to its high protein content, high yield, low cost, well-balanced amino acid composition, and sufficient accessibility. However, cottonseed meal possesses several anti-nutritional factors, especially gossypol, which adversely affect growth and reproductive performance, resulting in the limited utilization of cottonseed meal in pig feed. To maximize the benefits of cottonseed meal and promote its application in pig production, it is imperative to acquire comprehensive knowledge regarding its nutritional value and current utilization. In this review, we initially presented a summary of the nutritional values of cottonseed meal, primary anti-nutritional factors, and effective approaches for improving its utilization as a protein source feed. Subsequently, we comprehensively summarized the latest research progress of cottonseed meal application in pig nutrition over the past decade. The outcome of this review serves as a theoretical foundation and practical guidance for the research and application of cottonseed meal in pig nutrition and promotes the reduction of soybean meal utilization in the pig industry.

Abstract Background Most guidelines propose inducing labor within 24 h following term (37 or more weeks of gestation) prelabor rupture of membranes (PROM). However, the exact timing for initiating induction within the 24 h period remains unknown. This study aims to comparatively assess the efficacy and safety of the use of vaginal dinoprostone within 6 h versus within 6–24 h for singleton pregnancies with PROM and an unfavorable cervix (Bishop score

Abstract The transition from the swimming larval stage to the settlement stage represents a significant node in the marine sponge developmental process. Previous research has shown that the outer membrane vesicles (OMVs) from the bacterial species Tenacibaculum mesophilum associated with the sponge Tedania sp. influence larval settlement: low concentrations of OMVs increase the attachment rate, whereas high concentrations decrease the attachment rate. Here, by comparing the transcriptomes of sponge larvae in filtered seawater (FSW group) and in FSW supplemented with OMVs (FSW-OMV group), the results indicated that bacterial OMVs affected larval settlement by modulating the expression levels of apoptosis-inducing factor (AIF) in the host. Subsequently, quantitative real-time PCR revealed a decrease in aif expression near the time of settlement (SE) compared to that in the control group. RNA interference (RNAi) was used to target the aif gene, and the rate of larval settlement was significantly reduced, confirming the inhibitory effect of high concentrations of OMVs. Moreover, small RNA (sRNA) sequencing of OMVs revealed the existence of abundant AIF-sRNAs of 30 nt, further suggesting that one pathway for the involvement of sponge-associated bacteria in host development is the transport of OMVs and the direct function of cargo loading.

Abstract The increasing prevalence of myopia worldwide presents a significant public health challenge. A key strategy to combat myopia is with early detection and prediction in children as such examination allows for effective intervention using readily accessible imaging technique. To this end, we introduced DeepMyopia, an artificial intelligence (AI)-enabled decision support system to detect and predict myopia onset and facilitate targeted interventions for children at risk using routine retinal fundus images. Based on deep learning architecture, DeepMyopia had been trained and internally validated on a large cohort of retinal fundus images (n = 1,638,315) and then externally tested on datasets from seven sites in China (n = 22,060). Our results demonstrated robustness of DeepMyopia, with AUCs of 0.908, 0.813, and 0.810 for 1-, 2-, and 3-year myopia onset prediction with the internal test set, and AUCs of 0.796, 0.808, and 0.767 with the external test set. DeepMyopia also effectively stratified children into low- and high-risk groups (p

Objective: To assess the correlation between atmospheric pollutants, meteorological factors, and emergency department visits for respiratory diseases in Haikou City. Methods: Daily data on atmospheric pollutants, meteorological factors, and emergency department visits for respiratory diseases in Haikou City from 2018 to 2021 were collected. The Spearman rank correlation test was used to analyze the correlation, and a distributed lag non-linear model was employed to analyze the health effects and lag impacts of environmental factors. Subgroup analyses were conducted based on sex and age. Results: According to the criteria of International Classification of Diseases (ICD-10: J00-J99), a total of 221 913 cases were included, accounting for 21.3% of the total emergency department visits in Haikou City. For every 1 °C increase in temperature, the risk of emergency department visits increased by 1.029% (95% CI 1.016%-1.042%). Relative humidity greater than 80% reduced the risk of visits, while higher atmospheric pressure (>1 010 hpa) also decreased the likelihood of daily emergency department visits. Higher concentrations of PM25 (30-50 μg/m3), PM10 (>60 μg/m3), and O3 (75-125 μg/m3) were associated with increased visits. Higher temperatures (>25 °C) have a greater impact on females and children aged 0-14 years, while males are more sensitive to low atmospheric pressure. Individuals aged 65 and above exhibited increased sensitivity to O3 concentration, and the effects of PM2.5, PM10, and O3 are more pronounced in individuals over 14 years old. Conclusions: Short-term exposure to high temperatures, particulate matter pollutants (PM25 and PM10), and ozone (O3) is associated with increased emergency department visits for respiratory diseases.

Abstract Background Evidence on the association between serum vitamin C (sVC) levels and obesity is limited. This study aimed to explore the relationship between sVC and body mass index (BMI) in adolescents aged 12 to 19 years. Methods We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2003–2006, with 3952 participants. sVC and BMI were independent variables and dependent variables, respectively. The associations of sVC with BMI were examined using multivariable linear regression models. Age, sex, and race/ethnicity were analyzed as subgroups. Then, we devised smooth curve fittings and saturation threshold analysis to address the nonlinear relationship. Results sVC had a negative correlation with BMI after adjusting for all covariates (β: -1.020, 95% CI: -1.359, -0.680). In the subgroup analysis by age, sex, and race/ethnicity, there was still a negative correlation between sVC and BMI (p

Abstract Repositionable self-expanding valves allow for repositioning during deployment to achieve optimal valve placement. However, the risk of brain injury associated with repositioning, as detected by diffusion-weighted magnetic resonance imaging (DW-MRI), is unknown. Consecutive patients undergoing transcatheter aortic valve replacement (TAVR) with repositionable self-expanding valves and receiving DW-MRI before and within 7 days post-TAVR procedure were included. The primary outcomes were incidence, number, total volume, and volume per lesion of the cerebral ischemic lesion in DW-MRI after TAVR. Univariate and multivariate logistic regression assessed the association between repositioning and bigger total lesion volume (> 1 cm3 or > 0.5 cm3). Negative binomial regressions were performed to explore the association between repositioning and number of lesions. A propensity score matching was performed to adjust the potential confounders. Moreover, inverse probability of treatment weighted regression model with nonstabilized weights was used as sensitivity analysis. Among 243 included patients, repositioning was performed in 116 (47.7%) patients. The incidence of overt stroke (1.7% vs. 1.6%, p = 0.927) and silent stroke (86.2% vs. 85.8%, p = 0.932) were comparable between two groups. However, the number of new lesions (5.0 [2.0–9.0] vs. 3.0 [2.0–6.0], p = 0.048), and total lesion volume (275.0 [90.0–947.5] mm3 vs. 180.0 [50.0–440.0] mm3, p = 0.022) were significantly higher in the repositioned group. Moreover, the proportion of patients with lesion size greater than 0.5 cm3 was higher in the repositioned group (37.9% vs. 22.0%, p = 0.007). The similar results were observed after propensity score matching. In both multivariate regression model and sensitivity analysis, the repositioning was the independent predictor of number of lesions and bigger total lesion volume after TAVR. The utilization of the repositioning feature may increase the number and volume of silent brain infarcts in DW-MRI in patients who underwent TAVR. (Transcatheter Aortic Valve Replacement Single Center Registry in Chinese Population [TORCH]; NCT02803294)

Abstract With the widespread application of nuclear technology across various fields, ionizing radiation-induced injuries are becoming increasingly common. The bone marrow (BM) hematopoietic tissue is a primary target organ of radiation injury. Recent researches have confirmed that ionizing radiation-induced hematopoietic dysfunction mainly results from BM hematopoietic stem cells (HSCs) injury. Additionally, disrupting and reshaping BM microenvironment is a critical factor impacting both the injury and regeneration of HSCs post radiation. However, the regulatory mechanisms of ionizing radiation injury to BM HSCs and their microenvironment remain poorly understood, and prevention and treatment of radiation injury remain the focus and difficulty in radiation medicine research. In this review, we aim to summarize the effects and mechanisms of ionizing radiation-induced injury to BM HSCs and microenvironment, thereby enhancing our understanding of ionizing radiation-induced hematopoietic injury and providing insights for its prevention and treatment in the future.

Abstract BUB1 mitotic checkpoint serine/threonine kinase B (BUB1b) has been unequivocally identified as an oncogene in various cancers. However, the potential mechanism by which BUB1b orchestrates the progression of lung adenocarcinoma (LUAD) remains unclear. Here we found that both the transcript and protein levels of BUB1b were dramatically upregulated in tumor tissues and contributed to the dismal prognosis of LUAD patients. Moreover, gain- and loss-of-function assays, conducted both in vitro and in vivo, confirmed that BUB1b enhanced the viability of LUAD cells. Mechanistically, BUB1b forms a complex with OTUD3 and NRF2 and stabilizes the downstream NRF2 signaling pathway to facilitate insensitivity to ferroptosis and chemotherapy. In BALB/c nude mice bearing subcutaneous tumors that overexpress BUB1b, a combined strategy of ML385 targeting and chemotherapy achieved synergistic effects, inhibiting tumor growth and obviously improving survival. Taken together our study uncovered the underlying mechanism by which BUB1b promotes the progression of LUAD and proposed a novel strategy to enhance the efficacy of chemotherapy.

Abstract Background Painful diabetic neuropathy (PDN) is closely linked to inflammation, which has been demonstrated to be associated with pyroptosis. Emerging evidence has implicated TANK-binding kinase 1 (TBK1) in various inflammatory diseases. However, it remains unknown whether activated TBK1 causes hyperalgesia via pyroptosis. Methods PDN mice model of type 1 or type 2 diabetic was induced by C57BL/6J or BKS-DB mice with Lepr gene mutation. For type 2 diabetes PDN model, TBK1-siRNA, Caspase-1 inhibitor Ac-YVAD-cmk or TBK1 inhibitor amlexanox (AMX) were delivered by intrathecal injection or intragastric administration. The pain threshold and plantar skin blood perfusion were evaluated through animal experiments. The assessments of spinal cord, dorsal root ganglion, sciatic nerve, plantar skin and serum included western blotting, immunofluorescence, ELISA, and transmission electron microscopy. Results In the PDN mouse model, we found that TBK1 was significantly activated in the spinal dorsal horn (SDH) and mainly located in microglia, and intrathecal injection of chemically modified TBK1-siRNA could improve hyperalgesia. Herein, we described the mechanism that TBK1 could activate the noncanonical nuclear factor κB (NF-κB) pathway, mediate the activation of NLRP3 inflammasome, trigger microglia pyroptosis, and ultimately induce PDN, which could be reversed following TBK1-siRNA injection. We also found that systemic administration of AMX, a TBK1 inhibitor, could effectively improve peripheral nerve injury. These results revealed the key role of TBK1 in PDN and that TBK1 inhibitor AMX could be a potential strategy for treating PDN. Conclusions Our findings revealed a novel causal role of TBK1 in pathogenesis of PDN, which raises the possibility of applying amlexanox to selectively target TBK1 as a potential therapeutic strategy for PDN.

Abstract Background The epidemiological distribution of functional mitral regurgitation (FMR) in heart failure (HF) and mildly reduced ejection fraction (HFmrEF) patients and its impact on outcomes remains unclear. We attempt to investigate the prognosis of FMR in patients with HFmrEF. Methods The HF center registry study is a prospective, single, observational study conducted at the Second Affiliated Hospital of Shenzhen University, where 2330 patients with acute HF (AHF) were enrolled and 890 HFmrEF patients were included in the analysis. The patients were stratified into three categories based on the severity of FMR: none/mild, moderate, and moderate-to-severe/severe groups. Subsequently, a comparison of the clinical characteristics among these groups was conducted, along with an assessment of the incidence of the primary endpoint (comprising all-cause mortality and readmission for HF) during a one-year follow-up period. Results The one-year follow-up results indicated that the primary composite endpoint occurrence rates in the three groups were 23.5%, 32.9%, and 36.5%, respectively. The all-cause mortality rates in the three groups were 9.3%, 13.7%, and 16.4% respectively. Survival analysis demonstrated a statistically significant difference in the occurrence rates of the primary composite endpoint and all-cause mortality among the three groups (P

Abstract Lung cancer is a malignant tumor with highly heterogeneous characteristics. A classic Chinese medicine, Pinellia ternata (PT), was shown to exert therapeutic effects on lung cancer cells. However, its chemical and pharmacological profiles are not yet understood. In the present study, we aimed to reveal the mechanism of PT in treating lung cancer cells through metabolomics and network pharmacology. Metabolomic analysis of two strains of lung cancer cells treated with Pinellia ternata extracts (PTE) was used to identify differentially abundant metabolites, and the metabolic pathways associated with the DEGs were identified by MetaboAnalyst. Then, network pharmacology was applied to identify potential targets against PTE-induced lung cancer cells. The integrated network of metabolomics and network pharmacology was constructed based on Cytoscape. PTE obviously inhibited the proliferation, migration and invasion of A549 and NCI-H460 cells. The results of the cellular metabolomics analysis showed that 30 metabolites were differentially expressed in the lung cancer cells of the experimental and control groups. Through pathway enrichment analysis, 5 metabolites were found to be involved in purine metabolism, riboflavin metabolism and the pentose phosphate pathway, including D-ribose 5-phosphate, xanthosine, 5-amino-4-imidazolecarboxyamide, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Combined with network pharmacology, 11 bioactive compounds were found in PT, and networks of bioactive compound–target gene–metabolic enzyme–metabolite interactions were constructed. In conclusion, this study revealed the complicated mechanisms of PT against lung cancer. Our work provides a novel paradigm for identifying the potential mechanisms underlying the pharmacological effects of natural compounds.

Abstract O6-methylguanine-DNA methyltransferase (MGMT) has been demonstrated to be an important prognostic and predictive marker in glioblastoma (GBM). To establish a reliable radiomics model based on MRI data to predict the MGMT promoter methylation status of GBM. A total of 183 patients with glioblastoma were included in this retrospective study. The visually accessible Rembrandt images (VASARI) features were extracted for each patient, and a total of 14676 multi-region features were extracted from enhanced, necrotic, “non-enhanced, and edematous” areas on their multiparametric MRI. Twelve individual radiomics models were constructed based on the radiomics features from different subregions and different sequences. Four single-sequence models, three single-region models and the combined radiomics model combining all individual models were constructed. Finally, the predictive performance of adding clinical factors and VASARI characteristics was evaluated. The ComRad model combining all individual radiomics models exhibited the best performance in test set 1 and test set 2, with the area under the receiver operating characteristic curve (AUC) of 0.839 (0.709–0.963) and 0.739 (0.581–0.897), respectively. The results indicated that the radiomics model combining multi-region and multi-parametric MRI features has exhibited promising performance in predicting MGMT methylation status in GBM. The Modeling scheme that combining all individual radiomics models showed best performance among all constructed moels.

Abstract While protein aggregation’s association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.

Abstract Lung cancer is a leading cause of cancer-related mortality globally, with a dismal 5-year survival rate, particularly for Lung Adenocarcinoma (LUAD). Mechanical changes within the tumor microenvironment, such as extracellular matrix (ECM) remodeling and fibroblast activity, play pivotal roles in cancer progression and metastasis. However, the specific impact of the basement membrane (BM) on the mechanical characteristics of LUAD remains unclear. This study aims to identify BM genes influencing internal mechanical stress in tumors, elucidating their effects on LUAD metastasis and therapy resistance, and exploring strategies to counteract these effects. Using Matrigel overlay and Transwell assays, we found that mechanical stress, mimicked by matrix application, augmented LUAD cell migration and invasion, correlating with ECM alterations and activation of the epithelial-mesenchymal transition (EMT) pathway. Employing machine learning, we developed the SVM_Score model based on relevant BM genes, which accurately predicted LUAD patient prognosis and EMT propensity across multiple datasets. Lower SVM_Scores were associated with worse survival outcomes, elevated cancer-related pathways, increased Tumor Mutation Burden, and higher internal mechanical stress in LUAD tissues. Notably, the SVM_Score was closely linked to COL5A1 expression in myofibroblasts, a key marker of mechanical stress. High COL5A1 expression from myofibroblasts promoted tumor invasiveness and EMT pathway activation in LUAD cells. Additionally, treatment with Sorafenib, which targets COL5A1 secretion, attenuated the tumor-promoting effects of myofibroblast-derived COL5A1, inhibiting LUAD cell proliferation, migration, and enhancing chemosensitivity. In conclusion, this study elucidates the complex interplay between mechanical stress, ECM alterations, and LUAD progression. The SVM_Score emerges as a robust prognostic tool reflecting tumor mechanical characteristics, while Sorafenib intervention targeting COL5A1 secretion presents a promising therapeutic strategy to mitigate LUAD aggressiveness. These findings deepen our understanding of the biomechanical aspects of LUAD and offer insights for future research and clinical applications.

PURPOSE: The present study compares the diagnostic performance of unenhanced computed tomography (CT) radiomics-based machine learning (ML) classifiers and a radiologist in cystic renal masses (CRMs). METHODS: Patients with pathologically diagnosed CRMs from two hospitals were enrolled in the study. Unenhanced CT radiomic features were extracted for ML modeling in the training set (Guangzhou; 162 CRMs, 85 malignant). Total tumor segmentation was performed by two radiologists. Features with intraclass correlation coefficients of >0.75 were screened using univariate analysis, least absolute shrinkage and selection operator, and bidirectional elimination to construct random forest (RF), decision tree (DT), and k-nearest neighbor (KNN) models. External validation was performed in the Zhuhai set (45 CRMs, 30 malignant). All images were assessed by a radiologist. The ML models were evaluated using calibration curves, decision curves, and receiver operating characteristic (ROC) curves. RESULTS: Of the 207 patients (102 women; 59.1 ± 11.5 years), 92 (41 women; 58.0 ± 13.7 years) had benign CRMs, and 115 (61 women; 59.8 ± 11.4 years) had malignant CRMs. The accuracy, sensitivity, and specificity of the radiologist’s diagnoses were 85.5%, 84.2%, and 91.1%, respectively [area under the (ROC) curve (AUC), 0.87]. The ML classifiers showed similar sensitivity (94.2%–100%), specificity (94.7%–100%), and accuracy (94.3%–100%) in the training set. In the validation set, KNN showed better sensitivity, accuracy, and AUC than DT and RF but weaker specificity. Calibration and decision curves showed excellent and good results in the training and validation set, respectively. CONCLUSION: Unenhanced CT radiomics-based ML classifiers, especially KNN, may aid in screening CRMs.

Purpose: The poor retention and ambiguous differentiation of stem cells (SCs) within corpus cavernosum (CC) limit the cell application in erectile dysfunction (ED). Herein, the effects and mechanism of microRNA-145 (miR-145) gene modification on modulating the traits and fate of bone marrow-derived mesenchymal stem cells (BMSCs) were investigated. Materials and Methods: The effects of miR-145 on cell apoptosis, proliferation, migration, and differentiation were determined by flow cytometry, cell counting kit-8, transwell assays and myogenic induction. Then, the age-related ED rats were recruited to four groups including phosphate buffer saline, BMSC, vector-BMSC, overexpressed-miR-145-BMSC groups. After cell transplantation, the CC were harvested and prepared to demonstrate the retention and differentiation of BMSCs by immunofluorescent staining. Then, the target of miR-145 was verified by quantitative real-time polymerase chain reaction and immunohistochemical. After that, APTO-253, as an inducer of Krüppel-like factor 4 (KLF4), was introduced for rescue experiments in corpus cavernosum smooth muscle cells (CCSMCs) under the co-culture system. Results: In vitro, miR-145 inhibited the migration and apoptosis of BMSCs and promoted the differentiation of BMSCs into smooth muscle-like cells with stronger contractility. In vivo, the amount of 5-ethynyl-2'-deoxyuridine (EdU)+ cells within CC was significantly enhanced and maintained in the miR-145 gene modified BMSC group. The EdU/CD31 co-staning was detected, however, no co-staining of EdU/α-actin was observed. Furthermore, miR-145, which secreted from the gene modified BMSCs, dampened the expression of KLF4. However, the effects of miR-145 on CCSMCs could be rescued by APTO-253. Conclusions: Overall, miR-145 modification prolongs the retention of the transplanted BMSCs within the CC, and this effect might be attributed to the modulation of the miR-145/KLF4 axis. Consequently, our findings offer a promising and innovative strategy to enhance the local stem cell-based treatments.

The anti-detection capabilities of adversarial malware examples have drawn the attention of antivirus vendors and researchers. In black-box scenarios where internal information of the target model cannot be accessed, with the ability of the reinforcement learning (RL) agents to adjust strategies based on the feedback from the environment, existing RL-based methods enable evasion of Windows PE malware detectors. However, obtaining evasion rewards as positive feedback in the black-box setting proves challenging, resulting in low training efficiency. To address this issue, we introduce the intrinsic curiosity reward into the framework to motivate the agent to explore unknown state spaces and learn effective evasion strategies. Additionally, we employ the generative adversarial network (GAN) to obtain varying synthetic data, which replaces random or benign bytes as adversarial payloads for the agent's action content, improving attack capabilities and reducing the risk of hard-coded adversarial perturbations being anchored. We compare the attack performance with other RL-based baseline methods, and experimental results show that our framework is more flexible and effective, achieving a 63%-85% attack success rate against EMBER, FireEye and MalConv. Even if defensive measures are taken, the proposed method still has a certain attack capability, and the success rate remains between 48%-67%.

AbstractContext The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of guidelines that offer recommendations for its clinical use.Objective The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases.Methods We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence.Results Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment.Conclusions Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.

AbstractContext Hyperpigmentation, a common skin condition marked by excessive melanin production, currently has limited effective treatment options.Objective This study explores the effects of Tao-Hong-Si-Wu decoction (THSWD) on hyperpigmentation and to elucidate the underlying mechanisms.Materials and methods We employed network pharmacology, Mendelian randomization, and molecular docking to identify THSWD’s hub targets and mechanisms against hyperpigmentation. The Cell Counting Kit-8 (CCK-8) assay determined suitable THSWD treatment concentrations for PIG1 cells. These cells were exposed to graded concentrations of THSWD-containing serum (2.5%, 5%, 10%, 15%, 20%, 30%, 40%, and 50%) and treated with α-MSH (100 nM) to induce an in vitro hyperpigmentation model. Assessments included melanin content, tyrosinase activity, and Western blotting.Results ALB, IL6, and MAPK3 emerged as primary targets, while quercetin, apigenin, and luteolin were the core active ingredients. The CCK-8 assay indicated that concentrations between 2.5% and 20% were suitable for PIG1 cells, with a 50% cytotoxicity concentration (CC50) of 32.14%. THSWD treatment significantly reduced melanin content and tyrosinase activity in α-MSH-induced PIG1 cells, along with downregulating MC1R and MITF expression. THSWD increased ALB and p-MAPK3/MAPK3 levels and decreased IL6 expression in the model cells.Discussion and conclusion THSWD mitigates hyperpigmentation by targeting ALB, IL6, and MAPK3. This study paves the way for clinical applications of THSWD as a novel treatment for hyperpigmentation and offers new targeted therapeutic strategies.

Abstract Background Given the high cost of endoscopy in gastric cancer (GC) screening, there is an urgent need to explore cost-effective methods for the large-scale prediction of precancerous lesions of gastric cancer (PLGC). We aim to construct a hierarchical artificial intelligence-based multimodal non-invasive method for pre-endoscopic risk screening, to provide tailored recommendations for endoscopy. Methods From December 2022 to December 2023, a large-scale screening study was conducted in Fujian, China. Based on traditional Chinese medicine theory, we simultaneously collected tongue images and inquiry information from 1034 participants, considering the potential of these data for PLGC screening. Then, we introduced inquiry information for the first time, forming a multimodality artificial intelligence model to integrate tongue images and inquiry information for pre-endoscopic screening. Moreover, we validated this approach in another independent external validation cohort, comprising 143 participants from the China-Japan Friendship Hospital. Results A multimodality artificial intelligence-assisted pre-endoscopic screening model based on tongue images and inquiry information (AITonguequiry) was constructed, adopting a hierarchical prediction strategy, achieving tailored endoscopic recommendations. Validation analysis revealed that the area under the curve (AUC) values of AITonguequiry were 0.74 for overall PLGC (95% confidence interval (CI) 0.71–0.76, p

Abstract This study intends to inspect the effects of acute aerobic exercise (AE) on resting state functional connectivity (RSFC) in motor cortex of college students and the moderating effect of fitness level. Methods: 20 high fitness level college students and 20 ordinary college students were recruited in public. Subjects completed 25 min of moderate- and high-intensity acute aerobic exercise respectively by a bicycle ergometer, and the motor cortex’s blood oxygen signals in resting state were monitored by functional Near Infrared Spectroscopy (fNIRS, the Shimadzu portable Light NIRS, Japan) in pre- and post-test. Results: At the moderate intensity level, the total mean value of RSFC pre- and post-test was significantly different in the high fitness level group (pre-test 0.62 ± 0.18, post-test 0.51 ± 0.17, t (19) = 2.61, p = 0.02, d = 0.58), but no significant change was found in the low fitness level group. At the high-intensity level, there was no significant difference in the difference of total RSFC between pre- and post-test in the high and low fitness group. According to and change trend of 190 “edges”: at the moderate-intensity level, the number of difference edges in the high fitness group (d = 0.58, 23) were significantly higher than those in the low fitness group (d = 0.32, 15), while at high-intensity level, there was a reverse trend between the high fitness group (d = 0.25, 18) and the low fitness group (d = 0.39, 23). Conclusions: moderate-intensity AE can cause significant changes of RSFC in the motor cortex of college students with high fitness, while high fitness has a moderating effect on the relationship between exercise intensity and RSFC. RSFC of people with high fitness is more likely to be affected by AE and show a wider range of changes.

Abstract Background The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell transplantation, thus making exosomes promising candidates for large-scale clinical implementation and commercialization. However, exosome extraction and purification efficiencies are relatively low, and therapeutic heterogeneity is high due to differences in culture conditions and cell viability. Therefore, in this study, we investigated a priming procedure to enhance the production and therapeutic effects of exosomes from human umbilical cord mesenchymal stem cells (hucMSCs). After preconditioning hucMSCs with agonists/inhibitors that target the Wnt/β-catenin pathway, we assessed both the production of exosomes and the therapeutic efficacy of the optimized exosomes in the context of diabetic wound healing, hoping to provide a safer, more stable and more effective option for clinical application. Results The Wnt signalling pathway agonist CHIR99021 increased exosome production by 1.5-fold without causing obvious changes in the characteristics of the hucMSCs or the size of the exosome particles. Further studies showed that CHIR99021 promoted the production of exosomes by facilitating exocytosis. This process was partly mediated by SNAP25. To further explore whether CHIR99021 changed the cargo that was loaded into the exosomes and its therapeutic effects, we performed proteomic and transcriptomic analyses of exosomes from primed and control hucMSCs. The results showed that CHIR99021 significantly upregulated the expression of proteins that are associated with cell migration and wound healing. Animal experiments confirmed that, compared to control hucMSC-derived exosomes, CHIR99021-pretreated hucMSC-derived exosomes (CHIR-Exos) significantly accelerated wound healing in diabetic mice, enhanced local collagen deposition, promoted angiogenesis, and reduced chronic inflammation. Subsequent in vitro experiments confirmed that the CHIR-Exos promoted wound healing by facilitating cell migration, inhibiting oxidative stress-induced apoptosis, and preventing cell cycle arrest. Conclusions The Wnt agonist CHIR99021 significantly increased exosome secretion by hucMSCs, which was partly mediated by SNAP25. Notably, CHIR99021 treatment also significantly increased the exosomal levels of proteins that are associated with wound healing and cell migration, resulting in enhanced acceleration of wound healing. All of these results suggested that pretreatment of hucMSCs with CHIR99021 not only promoted exosome production but also improved the exosome therapeutic efficacy, thus providing a promising option for large-scale clinical implementation and commercialization. Graphical Abstract

Abstract Background Early-onset sepsis (EOS) is a serious illness that affects preterm newborns, and delayed antibiotic initiation may increase the risk of adverse outcomes. Purpose The objective of this study was to examine the present time of antibiotic administration in preterm infants with suspected EOS and the factors that contribute to delayed antibiotic initiation. Methods In this retrospective study in China, a total of 82 early preterm infants with suspected EOS between December 2021 and March 2023 were included. The study utilized a linear regression analytical approach to identify independent factors that contribute to delayed antibiotic administration. Results The mean gestational age and birth weight of the study population were 29.1 ± 1.4 weeks and 1265.7 ± 176.8 g, respectively. The median time of initial antibiotic administration was 3.8 (3.1-5.0) hours. Linear regression revealed that severe respiratory distress syndrome (RDS) (β = 0.07, P = 0.013), penicillin skin test (PST) timing (β = 0.06, P

Abstract Introduction To explore the diagnostic value of high-resolution ultrasound combined with multi-slice computer tomography (MSCT) for pediatric intra-abdominal hernias (IAHs), and to analyze the potential causes for missed diagnosis and misdiagnosis of IAHs in children. Methods A retrospective analysis was conducted on 45 children with surgically confirmed IAHs. The diagnostic rate of IAHs by preoperative high-resolution ultrasound combined with MSCT was compared with that of intraoperative examination, and the potential causes for missed diagnosis and misdiagnosis by the combination method were analyzed. Results Forty-five cases of pediatric IAHs were categorized into primary (25/45, 55.5%) and acquired secondary hernias (20/45, 44.5%). Among children with primary hernias, mesenteric defects were identified as the predominant subtype (40%). Acquired secondary hernias typically resulted from abnormal openings in the abdominal wall or band adhesions due to trauma, surgery, or inflammation. In particular, adhesive band hernias were the major type in children with acquired secondary hernias (40%). The diagnostic rate of high-resolution ultrasound was 77.8%, with “cross sign” as a characteristic ultrasonic feature. Among 10 cases of missed diagnosis or misdiagnosis, 5 were finally diagnosed as IAHs by multi-slice computer tomography (MSCT). Overall, the diagnostic rate of pediatric IAHs by preoperative ultrasound combined with radiological imaging reached 88.9%. Discussion IAHs in children, particularly mesenteric defects, are prone to strangulated intestinal obstruction and necrosis. High-resolution ultrasound combined with MSCT greatly enhances the diagnostic accuracy of pediatric IAHs.

Abstract Chronic obstructive pulmonary disease (COPD) is characterised by persistent airway inflammation even after cigarette smoking cessation. Neutrophil extracellular traps (NETs) have been implicated in COPD severity and acute airway inflammation induced by short-term cigarette smoke (CS). However, whether and how NETs contribute to sustained airway inflammation in COPD remain unclear. This study aimed to elucidate the immunoregulatory mechanism of NETs in COPD, employing human neutrophils, airway epithelial cells (AECs), dendritic cells (DCs), and a long-term CS-induced COPD mouse model, alongside cyclic guanosine monophosphate-adenosine monophosphate synthase and toll-like receptor 9 knockout mice (cGAS -−/− , TLR9 −/− ); Additionally, bronchoalveolar lavage fluid (BALF) of COPD patients was examined. Neutrophils from COPD patients released greater cigarette smoke extract (CSE)-induced NETs (CSE-NETs) due to mitochondrial respiratory chain dysfunction. These CSE-NETs, containing oxidatively-damaged DNA (NETs-DNA), promoted AECs proliferation, nuclear factor kappa B (NF-κB) activation, NF-κB-dependent cytokines and type-I interferons production, and DC maturation, which were ameliorated/reversed by silencing/inhibition of cGAS/TLR9. In the COPD mouse model, blocking NETs-DNA-sensing via cGAS −/− and TLR9 −/− mice, inhibiting NETosis using mitoTEMPO, and degrading NETs-DNA with DNase-I, respectively, reduced NETs infiltrations, airway inflammation, NF-κB activation and NF-κB-dependent cytokines, but not type-I interferons due to IFN-α/β receptor degradation. Elevated NETs components (myeloperoxidase and neutrophil elastase activity) in BALF of COPD smokers correlated with disease severity and NF-κB-dependent cytokine levels, but not type-I interferon levels. In conclusion, NETs-DNA promotes NF-κB-dependent autoimmunity via cGAS/TLR9 in long-term CS exposure-induced COPD. Therefore, targeting NETs-DNA and cGAS/TLR9 emerges as a potential strategy to alleviate persistent airway inflammation in COPD.

Abstract Background Esophageal cancer, a global health concern, impacts predominantly men, particularly in Eastern Asia. Lymph node metastasis (LNM) significantly influences prognosis, and current imaging methods exhibit limitations in accurate detection. The integration of radiomics, an artificial intelligence (AI) driven approach in medical imaging, offers a transformative potential. This meta-analysis evaluates existing evidence on the accuracy of radiomics models for predicting LNM in esophageal cancer. Methods We conducted a systematic review following PRISMA 2020 guidelines, searching Embase, PubMed, and Web of Science for English-language studies up to November 16, 2023. Inclusion criteria focused on preoperatively diagnosed esophageal cancer patients with radiomics predicting LNM before treatment. Exclusion criteria were applied, including non-English studies and those lacking sufficient data or separate validation cohorts. Data extraction encompassed study characteristics and radiomics technical details. Quality assessment employed modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and Radiomics Quality Score (RQS) tools. Statistical analysis involved random-effects models for pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC). Heterogeneity and publication bias were assessed using Deek’s test and funnel plots. Analysis was performed using Stata version 17.0 and meta-DiSc. Results Out of 426 initially identified citations, nine studies met inclusion criteria, encompassing 719 patients. These retrospective studies utilized CT, PET, and MRI imaging modalities, predominantly conducted in China. Two studies employed deep learning-based radiomics. Quality assessment revealed acceptable QUADAS-2 scores. RQS scores ranged from 9 to 14, averaging 12.78. The diagnostic meta-analysis yielded a pooled sensitivity, specificity, and AUC of 0.72, 0.76, and 0.74, respectively, representing fair diagnostic performance. Meta-regression identified the use of combined models as a significant contributor to heterogeneity (p-value = 0.05). Other factors, such as sample size (> 75) and least absolute shrinkage and selection operator (LASSO) usage for feature extraction, showed potential influence but lacked statistical significance (0.05

Abstract Background Advanced glycation end product-modified low-density lipoprotein (AGE-LDL) is related to inflammation and the development of atherosclerosis. Additionally, it has been demonstrated that receptor for advanced glycation end products (RAGE) has a role in the condition known as calcific aortic valve disease (CAVD). Here, we hypothesized that the AGE-LDL/RAGE axis could also be involved in the pathophysiological mechanism of CAVD. Methods Human aortic valve interstitial cells (HAVICs) were stimulated with AGE-LDL following pre-treatment with or without interleukin 37 (IL-37). Low-density lipoprotein receptor deletion (Ldlr −/− ) hamsters were randomly allocated to chow diet (CD) group and high carbohydrate and high fat diet (HCHFD) group. Results AGE-LDL levels were significantly elevated in patients with CAVD and in a hamster model of aortic valve calcification. Our in vitro data further demonstrated that AGE-LDL augmented the expression of intercellular cell adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and alkaline phosphatase (ALP) in a dose-dependent manner through NF-κB activation, which was attenuated by nuclear factor kappa-B (NF-κB) inhibitor Bay11-7082. The expression of RAGE was augmented in calcified aortic valves, and knockdown of RAGE in HAVICs attenuated the AGE-LDL-induced inflammatory and osteogenic responses as well as NF-κB activation. IL-37 suppressed inflammatory and osteogenic responses and NF-κB activation in HAVICs. The vivo experiment also demonstrate that supplementation with IL-37 inhibited valvular inflammatory response and thereby suppressed valvular osteogenic activities. Conclusions AGE-LDL promoted inflammatory responses and osteogenic differentiation through RAGE/NF-κB pathway in vitro and aortic valve lesions in vivo. IL-37 suppressed the AGE-LDL-induced inflammatory and osteogenic responses in vitro and attenuated aortic valve lesions in a hamster model of CAVD. Graphic Abstract

Cocoons have a direct impact on the quality of raw silk. Mulberry cocoons must be screened before silk reeling can begin in order to improve the quality of raw silk. For the silk product sector, the cocoons' level of categorization and sorting is crucial. Nonetheless, the majority of mulberry cocoon production facilities in use today choose the cocoons by hand. The accuracy and efficiency of mulberry cocoon plucking can be significantly improved by automatic methods. To increase efficiency, mulberry cocoons must be sorted automatically and intelligently using machine vision. We proposed an effective detection technique based on vision and terahertz spectrum characteristics data for distinguishing defective cocoons, including common and thin shelled defective cocoons. Each mulberry cocoon with a defect had its spatial coordinate and deflection angle computed so that grippers could grasp it. With 3762 photos in our dataset, our approach could detect mAP values up to 99.25% of the time. Furthermore, the GFLOPS of our suggested model was only 8.9 G, and its Parameters were only 5.3 M, making it appropriate for use in real-world application scenarios.

To improve the oxidation resistance of short carbon fiber (Csf)-reinforced mechanically alloyed SiBCN (MA-SiBCN) (Csf/MA-SiBCN) composites, dense amorphous Csf/SiBCN composites containing both MA-SiBCN and polymer-derived ceramics SiBCN (PDCs-SiBCN) were prepared by repeated polymer infiltration and pyrolysis (PIP) of layered Csf/MA-SiBCN composites at 1100 °C, and the oxidation behavior and damage mechanism of the as-prepared Csf/SiBCN at 1300–1600 °C were compared and discussed with those of Csf/MA-SiBCN. The Csf/MA-SiBCN composites resist oxidation attack up to 1400 °C but fail at 1500 °C due to the collapse of the porous framework, while the PIP-densified Csf/SiBCN composites are resistant to static air up to 1600 °C. During oxidation, oxygen diffuses through preexisting pores and the pores left by oxidation of carbon fibers and pyrolytic carbon (PyC) to the interior of the matrix. Owing to the oxidative coupling effect of the MA-SiBCN and PDCs-SiBCN matrices, a relatively continuous and dense oxide layer is formed on the sample surface, and the interfacial region between the oxide layer and the matrix of the as-prepared composite contains an amorphous glassy structure mainly consisting of Si and O and an incompletely oxidized but partially crystallized matrix, which is primarily responsible for improving the oxidation resistance.

To investigate the influence of carbonization process parameters on the characteristics of municipal sludge carbonization products, this study selected carbonization temperatures of 300–700 °C and carbonization times of 0.5–1.5 h to carbonize municipal sludge. The results showed that with an increase in temperature and carbonization time, the sludge was carbonized more completely, and the structure and performance characteristics of the sludge changed significantly. Organic matter was continuously cracked, the amorphous nature of the material was reduced, its morphology was transformed into an increasing number of regular crystalline structures, and the content of carbon continued to decrease, from the initial 52.85 to 38.77%, while the content of inorganic species consisting continued to increase. The conductivity was reduced by 87.8%, and the degree of conversion of salt ions into their residual and insoluble states was significant. Natural water absorption in the sludge decreased from 8.13 to 1.29%, and hydrophobicity increased. The dry-basis higher calorific value decreased from 8,703 to 3,574 kJ/kg. Heavy metals were concentrated by a factor of 2–3, but the content of the available state was very low. The results of this study provide important technological support for the selection of suitable carbonization process conditions and for resource utilization. HIGHLIGHTS Temperature and time are used to investigate the properties of carbonized sludge.; The structure and performance characteristics of the sludge changed significantly.; The EC, water absorption, particle size and calorific value tends to decrease.; Carbon content continues to decrease with the rising of temperature and time.; Heavy metals were concentrated, but the content of the soluble state was very low.;

Abstract Peroxyacetyl nitrate (PAN) is a hazardous secondary pollutant and a nitrogen reservoir in the troposphere, while comprehensive studies on its spatiotemporal distribution, chemical sources, and control strategies are limited. This study addressed these issues based on 1-year multi-site observations in the Pearl River Delta region, showing a pattern of higher PAN levels in the cold season, particularly in coastal areas. Moreover, in situ modeling indicated a net photochemical PAN formation in the warm season, while PAN was dominated by regional transport in the cold season (i.e., rural and coastal areas), releasing NO2 and PA radicals and promoting ozone (O3) formation. In addition, the feasibility of joint control of PAN and O3 was confirmed by their isopleth diagrams. C7–C9 aromatics and C4–C5 alkenes, largely from vehicle exhaust and solvent usage, were identified as the predominant contributors to PAN formation in this region. Overall, this study deepens our understanding of PAN chemistry and provides valuable insights into its control measures.

Abstract The identification of effective therapeutic targets plays a pivotal role in advancing cancer treatment outcomes. We employed a comprehensive pan-cancer analysis, complemented by experimental validation, to explore the potential of Nicotinamide N-methyltransferase (NNMT) as a promising therapeutic strategy for human cancers. By analyzing large-scale transcriptomic datasets across various cancer types, we consistently observed upregulated expression of NNMT. Furthermore, elevated NNMT expression correlated with inferior overall survival in multiple cancer cohorts, underscoring its significance as a prognostic biomarker. Additionally, we investigated the relationship between NNMT expression and the tumor immune microenvironment, which plays a crucial role in regulating anti-tumor immune responses. To confirm the malignant functions of NNMT in tumor cells, we conducted a series of cell-based experiments, revealing that NNMT promotes cancer cell proliferation and invasion, indicative of its oncogenic properties. The integration of computational analysis and experimental validation in our study firmly establishes NNMT as a potential therapeutic target for human cancers. Specifically, targeting NNMT holds promise for the development of innovative and effective cancer treatments. Further investigations into NNMT's role in cancer pathogenesis could potentially pave the way for groundbreaking advancements in cancer treatment.

Abstract Background Hematopoietic stem cell (HSC) regeneration underlies hematopoietic recovery from myelosuppression, which is a life-threatening side effect of cytotoxicity. HSC niche is profoundly disrupted after myelosuppressive injury, while if and how the niche is reshaped and regulates HSC regeneration are poorly understood. Methods A mouse model of radiation injury-induced myelosuppression was built by exposing mice to a sublethal dose of ionizing radiation. The dynamic changes in the number, distribution and functionality of HSCs and megakaryocytes were determined by flow cytometry, immunofluorescence, colony assay and bone marrow transplantation, in combination with transcriptomic analysis. The communication between HSCs and megakaryocytes was determined using a coculture system and adoptive transfer. The signaling mechanism was investigated both in vivo and in vitro, and was consolidated using megakaryocyte-specific knockout mice and transgenic mice. Results Megakaryocytes become a predominant component of HSC niche and localize closer to HSCs after radiation injury. Meanwhile, transient insulin-like growth factor 1 (IGF1) hypersecretion is predominantly provoked in megakaryocytes after radiation injury, whereas HSCs regenerate paralleling megakaryocytic IGF1 hypersecretion. Mechanistically, HSCs are particularly susceptible to megakaryocytic IGF1 hypersecretion, and mTOR downstream of IGF1 signaling not only promotes activation including proliferation and mitochondrial oxidative metabolism of HSCs, but also inhibits ferritinophagy to restrict HSC ferroptosis. Consequently, the delicate coordination between proliferation, mitochondrial oxidative metabolism and ferroptosis ensures functional HSC expansion after radiation injury. Importantly, punctual IGF1 administration simultaneously promotes HSC regeneration and hematopoietic recovery after radiation injury, representing a superior therapeutic approach for myelosuppression. Conclusions Our study identifies megakaryocytes as a last line of defense against myelosuppressive injury and megakaryocytic IGF1 as a novel niche signal safeguarding HSC regeneration.

Abstract Background The Chinese pig breed Bamei faces numerous challenges, such as antibiotic abuse, feed shortages, weaning stress, low immunity and disease resistance after weaning. Probiotic-fermented feed is an ideal profile that can improve the intestinal microbiota, promote the digestion and absorption of nutrients, and improve immunity. However, the combined effect of long-term intake of probiotic-fermented feeds on the intestinal microbiota, intestinal metabolic profiles, and immunity in pigs is not well understood. Here, we investigated the effects of feeding basal feed, Lactiplantibacillus-fermented feed, Bacillus subtilis-fermented feed, mixed-fermented feed, and antibiotic-added feed for 100 days on the gut microbiota, immunity, and metabolism of Bamei pigs after feeding five different fermented feeds by using 16S rDNA high-throughput sequencing, enzyme-linked immunoassay, and untargeted metabolomics, respectively. Results 16S rDNA sequencing revealed that after the piglets were fed five different feeds for 50 days, the structure of the intestinal microbiota of the Bamei pigs was significantly altered, and feeding the mixed Lactiplantibacillus (L.) plantarum and Bacillus (B.) subtilis-fermented feed not only increased the α-diversity of the intestinal microbiota and the relative abundance of Lactobacillus, but also suppressed the growth of the conditional pathogens, Clostridium and Streptococcus. The Sobs and Shannon indices were significantly lower (p

Abstract Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.

Abstract Background Patients with immunodeficiency virus-1 (HIV-1) infection are challenging to be cured completely due to the existence of HIV-1 latency reservoirs. However, the knowledge of the mechanisms and biomarkers associated with HIV-1 latency is limited. Therefore, identifying proteins related to HIV-1 latency could provide new insights into the underlying mechanisms of HIV-1 latency, and ultimately contribute to the eradication of HIV reservoirs. Methods An Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-labeled subcellular proteomic study was performed on an HIV-1 latently infected cell model (U1, a HIV-1-integrated U937 cell line) and its control (U937). Differentially expressed proteins (DEPs) were analyzed using STRING-DB. Selected DEPs were further evaluated by western blotting and multiple reaction monitoring technology in both cell model and patient-derived cluster of differentiation 4 (CD4)+ T cells. Finally, we investigated the relationship between a specific DEP lysosome-associated membrane glycoprotein 2 (LAMP2) and HIV-1 reactivation by panobinostat or lysosome regulation by a lysosomotropic agent hydroxychloroquine in U1 and U937 cells. Results In total, 110 DEPs were identified in U1 cells comparing to U937 control cells. Bioinformatics analysis suggested associations of the altered proteins with the immune response and endosomal/lysosomal pathway. LAMP2, leukocyte surface antigen CD47, CD55, and ITGA6 were downregulated in HIV-1 latent cells. Downregulated LAMP2 was further confirmed in resting CD4+ T cells from patients with latent HIV-1 infection. Furthermore, both HIV-1 reactivation by panobinostat and stimulation with hydroxychloroquine upregulated LAMP2 expression. Conclusions Our results indicated the involvement of the endosomal/lysosomal pathway in HIV-1 latency in macrophage cell model. The down-modulation of LAMP2 was associated with HIV latency, and the restoration of LAMP2 expression accompanied the transition of viral latency to active infection. This study provides new insights into the mechanism of HIV-1 latency and potential strategies for eradicating HIV-1 reservoirs by targeting LAMP2 expression.

Abstract Vitamin A plays a pivotal role in health, particularly in regulating fat metabolism. Despite its significance, research into the direct relationship between vitamin A levels and obesity, especially among adolescents, is sparse. This study aims to explore this association within the adolescent population in the United States. This cross-sectional study analyzed the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2006, with 8218 participants. The levels of vitamin A in the serum were determined based on utilizing high-performance liquid chromatography with photodiode array detection. The relationship between serum vitamin A concentrations and body mass index (BMI) was evaluated using weighted multiple linear regression models, incorporating subgroup analyses by sex and race/ethnicity to provide nuanced insights. A positive correlation was observed between serum vitamin A levels and BMI, with BMI increasing progressively across vitamin A quartiles (P

Abstract Background Lipid accumulation product (LAP) is an accessible and relatively comprehensive assessment of obesity that represents both anatomical and physiological lipid accumulation. Obesity and psoriasis are potentially related, according to previous research. Investigating the relationship between adult psoriasis and the LAP index was the goal of this study. Methods This is a cross-sectional study based on data from the National Health and Nutrition Examination Survey (NHANES) 2003–2006 and 2009–2014. The association between LAP and psoriasis was examined using multivariate logistic regression and smoothed curve fitting. To verify whether this relationship was stable across populations, subgroup analyses and interaction tests were performed. Results The LAP index showed a positive correlation with psoriasis in 9,781 adult participants who were 20 years of age or older. A 27% elevated probability of psoriasis was linked to every unit increase in ln LAP in the fully adjusted model (Model 3: OR 1.27, 95% CI 1.06–1.52). In comparison with participants in the lowest ln LAP quartile, those in the highest quartile had an 83% greater likelihood of psoriasis (Model 3: OR 1.83, 95% CI 1.08–3.11). This positive correlation was more pronounced for young males, participants who had never smoked, non-drinkers, participants who exercised little, as well as non-hypertensive and non-diabetic participants. Conclusions This study found that the LAP index and adult psoriasis were positively correlated, especially in young males without comorbidities. Therefore, it is proposed that LAP may serve as a biomarker for early diagnosis of psoriasis and tracking the effectiveness of treatment.

Abstract Aims Although central adiposity is a well-known risk factor for diabetes, the underlying mechanism remains unclear. The aim of this study was to explore the potential mediation role of circulating WBC counts in the association between central adiposity and the risk of diabetes. Materials and methods A cross-sectional study was conducted using data from the Fuqing cohort study, which included 6,613 participants aged 35–75 years. Logistic regression analysis and Spearman’s rank correlation analysis were used to examine the relationships between waist-to-hip ratio, WBC counts and glycemic status. Both simple and parallel multiple mediation models were used to explore the potential mediation effects of WBCs on the association of waist-to-hip ratio with diabetes. Results The study revealed a positive relationship between waist-to-hip ratio and risk of prediabetes (OR = 1.53; 95% CI, 1.35 to 1.74) and diabetes (OR = 2.89; 95% CI, 2.45 to 3.40). Moreover, elevated peripheral WBC counts were associated with both central adiposity and worsening glycemic status (P

The management of chronic wounds in diabetes remains challenging due to the complexity of impaired wound healing, delayed healing, susceptibility to infection, and elevated risk of reopening, highlighting the need for effective chronic wound management with innovative approaches such as multifunctional hydrogels. Here, we have produced HA-DA@rhCol hydrogels consisting of dopamine-modified hyaluronic acid and recombinant human collagen type-III (rhCol) by oxidative coupling of the catechol group using the H2O2/HRP catalytic system. The post-reactive hydrogel has a good porous structure, swelling rate, reasonable degradation, rheological and mechanical properties, and the catechol group and dopamine impart to the hydrogel tissue adhesiveness, antioxidant capacity, and excellent photothermal effects leading to superior in vitro antimicrobial activity. In addition, the ability of rhCol to confer hydrogels to promote angiogenesis and wound repair has also been investigated. Cytotoxicity and hemolysis tests demonstrated the good biocompatibility of the hydrogel. Wound closure, collagen deposition and immunohistochemical examination confirmed the ability of the hydrogel to promote diabetic wound healing. In summary, the adhesive hemostatic antioxidative hydrogel with rhCol to promote wound healing in diabetic rat is an excellent chronic wound dressing.

This study compared two different methods, the satellite altimetry-based and DEM (digital elevation model)-based, for estimating lake water volume changes. We focused on 34 lakes in China as the testing sites to compare the two methods for lake water volume changes from 2005 to 2020. The satellite altimetry-based method used water levels provided by the DAHITI (Database for Hydrological Time Series of Inland Waters) data and surface areas derived from Landsat imagery. The DEM-based method used the SRTM DEM data in combination with Landsat-derived lake extents. Our results showed a high degree of consistency in lake water volume changes estimated between the two methods (R2 > 0.90), but each method has its limitations. In terms of temporal coverage, the satellite altimetry-based method with the DAHITI data is limited by missing water level data in certain periods. The performance of the DEM-based method in extracting lake shore boundaries in regions with flat terrains (slope

Abstract To develop and validate a machine learning based algorithm to estimate physical activity (PA) intensity using the smartwatch with the capacity to record PA and determine outdoor state. Two groups of participants, including 24 adults (13 males) and 18 children (9 boys), completed a sequential activity trial. During each trial, participants wore a smartwatch, and energy expenditure was measured using indirect calorimetry as gold standard. The support vector machine algorithm and the least squares regression model were applied for the metabolic equivalent (MET) estimation using raw data derived from the smartwatch. Exercise intensity was categorized based on MET values into sedentary activity (SED), light activity (LPA), moderate activity (MPA), and vigorous activity (VPA). The classification accuracy was evaluated using area under the ROC curve (AUC). The METs estimation accuracy were assessed via the mean absolute error (MAE), the correlation coefficient, Bland–Altman plots, and intraclass correlation (ICC). A total of 24 adults aged 21–34 years and 18 children aged 9–13 years participated in the study, yielding 1790 and 1246 data points for adults and children respectively for model building and validation. For adults, the AUC for classifying SED, MVPA, and VPA were 0.96, 0.88, and 0.86, respectively. The MAE between true METs and estimated METs was 0.75 METs. The correlation coefficient and ICC were 0.87 (p

Abstract Although colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, the overall incidence and mortality from the disease have declined in recent decades. In contrast, there has been a steady increase in the incidence of CRC in individuals under 50 years of age. Hereditary syndromes contribute disproportionately to early onset CRC (EOCRC). These include microsatellite instability high (MSI+) tumors arising in patients with Lynch Syndrome. However, most EOCRCs are not associated with familial syndromes or MSI+ genotypes. Comprehensive genomic profiling has provided the basis of improved more personalized treatments for older CRC patients. However, less is known about the basis of sporadic EOCRC. To define the genomic landscape of EOCRC we used DNA content flow sorting to isolate diploid and aneuploid tumor fractions from 21 non-hereditary cases. We then generated whole exome mutational profiles for each case and whole genome copy number, telomere length, and EGFR immunohistochemistry (IHC) analyses on subsets of samples. These results discriminate the molecular features of diploid and aneuploid EOCRC and provide a basis for larger population-based studies and the development of effective strategies to monitor and treat this emerging disease.

Abstract Background Anti-synthetase syndrome (AS) is a rare autoimmune idiopathic inflammatory myopathy (IIM) with diverse manifestations, including arthritis, interstitial lung disease (ILD), Raynaud’s phenomenon, unexplained persistent fever, and mechanic’s hands. Case presentation We present the case of a 72-year-old woman, previously healthy, who was admitted to our hospital for treatment of cough and rapid breathing. The patient had elevated white blood cells and C-reactive protein, and tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). She was initially diagnosed with community-acquired pneumonia and received tamoxifen for anti-infection treatment, but her dystonia worsened. She eventually required non-invasive ventilator support, tested positive for SARS-Cov-2 again, and started antiviral therapy, corticosteroids to reduce alveolar effusion, anticoagulation, and other treatments. However, her condition continued to deteriorate, with the lowest oxygenation index reaching only 80mmHg. Ultimately, she underwent tracheal intubation and mechanical ventilation. Chest CT revealed rapid progressive interstitial changes in her lungs, and her hands showed noticeable fraternization changes. At this point, we suspected that the novel coronavirus infection might be associated with autoimmune diseases. The patient’s autoimmune antibody spectrum showed positive results for anti-recombinant RO-52 antibody and myositis-specific antibody anti-alanyl tRNA synthetase (anti-PL-12). The patient was treated with dexamethasone sodium phosphate for anti-inflammatory and anti-fibrotic effects. After successful extubation, the patient was discharged with only oral prednisone tablets at a dose of 30 mg. Conclusions This case presents an early diagnosis and successful treatment of anti-synthetase syndrome combined with SARS-Cov-2 infection, emphasizing the importance of comprehensive physical examination. Additionally, it highlights the rapid progression of interstitial lung disease under SARS-Cov-2 infection, which is often difficult to distinguish on imaging. In cases where treatment for SARS-Cov-2 infection is ineffective, early screening for autoimmune diseases is recommended. As there is currently no standardized method for treating AS-ILD, the successful treatment of this case provides a reference for clinical research on anti-synthetase syndrome in the later stage.