Background Platelet parameters are important indicators of cardiovascular risk, and environmental pollutants such as polychlorinated biphenyls (PCBs) may impair platelet function through oxidative stress. Objective To investigate the differential effects of single and mixed exposure to PCBs on platelet parameters among individuals with normal glucose tolerance (NGT), impaired fasting glucose (IFG), and type 2 diabetes mellitus (T2DM), and to evaluate the potential modifying role of a healthy lifestyle. Methods This study included 2249 participants (including 707 with NGT, 759 with IFG, and 783 with T2DM). Plasma PCB concentrations were measured using triple quadrupole gaschromatography-tandem mass spectrometry. Generalized linear regression was used to assess the associations between individual PCB congeners and platelet parameters. Quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR) models were used to evaluate the overall effects of PCBs mixture exposure on platelet parameters across different glycemic states, as well as its interaction with healthy lifestyle score (HLS). Results Generalized linear regression analyses showed significant differences in the effects of PCBs on platelet parameters across different glycemic states (P<0.05). After adjusting for confounders, PCBs mixture exposure was significantly associated with lower platelet counts (PLT) in individuals with NGT (b=−10.60, 95%CI: −16.48, −4.71) and IFG (b=−12.91, 95%CI: −18.90, −6.92), whereas no significant association was observed in individuals with T2DM (P=0.051). Mean platelet volume (MPV) and platelet-large cell ratio (P-LCR) increased significantly with higher PCBs exposure levels across all three groups (P<0.05). BKMR analysis showed a positive association between PCBs mixture exposure and P-LCR, with the strongest association observed in the NGT group. Furthermore, a significant interaction was observed between HLS and PCBs mixture exposure, and a higher HLS attenuated the effects of PCBs on P-LCR. Conclusion Glycemic glycemic states may modify the effects of PCBs on platelets. Individuals with NGT appear more sensitive to PCBs exposure, whereas the T2DM state may attenuate this effect. Moreover, healthy lifestyles, including not smoking, moderate alcohol consumption, maintaining moderate-to-high physical activity, a healthy diet, and an appropriate body mass index (BMI), may mitigate the adverse effects of most PCBs on platelet parameters.

Background Platelet parameters are important indicators of cardiovascular risk, and environmental pollutants such as polychlorinated biphenyls (PCBs) may impair platelet function through oxidative stress. Objective To investigate the differential effects of single and mixed exposure to PCBs on platelet parameters among individuals with normal glucose tolerance (NGT), impaired fasting glucose (IFG), and type 2 diabetes mellitus (T2DM), and to evaluate the potential modifying role of a healthy lifestyle. Methods This study included 2249 participants (including 707 with NGT, 759 with IFG, and 783 with T2DM). Plasma PCB concentrations were measured using triple quadrupole gaschromatography-tandem mass spectrometry. Generalized linear regression was used to assess the associations between individual PCB congeners and platelet parameters. Quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR) models were used to evaluate the overall effects of PCBs mixture exposure on platelet parameters across different glycemic states, as well as its interaction with healthy lifestyle score (HLS). Results Generalized linear regression analyses showed significant differences in the effects of PCBs on platelet parameters across different glycemic states (P<0.05). After adjusting for confounders, PCBs mixture exposure was significantly associated with lower platelet counts (PLT) in individuals with NGT (b=−10.60, 95%CI: −16.48, −4.71) and IFG (b=−12.91, 95%CI: −18.90, −6.92), whereas no significant association was observed in individuals with T2DM (P=0.051). Mean platelet volume (MPV) and platelet-large cell ratio (P-LCR) increased significantly with higher PCBs exposure levels across all three groups (P<0.05). BKMR analysis showed a positive association between PCBs mixture exposure and P-LCR, with the strongest association observed in the NGT group. Furthermore, a significant interaction was observed between HLS and PCBs mixture exposure, and a higher HLS attenuated the effects of PCBs on P-LCR. Conclusion Glycemic glycemic states may modify the effects of PCBs on platelets. Individuals with NGT appear more sensitive to PCBs exposure, whereas the T2DM state may attenuate this effect. Moreover, healthy lifestyles, including not smoking, moderate alcohol consumption, maintaining moderate-to-high physical activity, a healthy diet, and an appropriate body mass index (BMI), may mitigate the adverse effects of most PCBs on platelet parameters.

End-stage liver disease (ESLD) covers the end-stage of acute and chronic liver diseases, mainly involving decompensated cirrhosis, various types of liver failure, and advanced liver cancer. Hepatocyte transplantation has shown promise in treating ESLD, but its clinical application is hampered by the shortage of donor hepatocytes. Cell therapy, an emerging effective treatment for ESLD, faces the same limitation due to scarce hepatocyte availability. Hepatocyte-like cells (HLCs), which are terminally differentiated cells, can be induced from both stem cells and somatic cells. As HLCs exhibit the morphology and function of primary hepatocytes, they offer a promising supplementary source of hepatocytes for cell therapy. First, we provide a background for the differentiation and maturation of primary hepatocytes. Subsequently, based on the current insights into the molecular pathways that regulate hepatocyte differentiation in vivo, we describe a strategy for establishing HLC derived from either stem cells or somatic cells. The key characteristics of these HLCs are also detailed. Furthermore, HLC offers therapeutic potential for liver failure, and HLC-based liver organoids and bioartificial liver systems have demonstrated the ability to provide liver functions, offering an innovative approach to treating various types of ESLD. Despite their promise, challenges such as efficiency in differentiation and functional maturation need to be addressed to improve the clinical application of HLCs. This review discusses these advancements and outlines the therapeutic potential and current challenges of HLC therapy for ESLD.

Objective To establish a method for acquisition, perfusion, preservation and transportation of the genetically modified pig kidneys. Methods An eight genetically modified pig was utilized as experimental subject. Prior to kidneys procurement, the health status of the pig was assessed through hematology examination, and the vascular structure of the kidneys was examined using imaging techniques. Following kidneys acquisition, the pig kidneys were perfused and subsequently packaged into the cryogenic storage container labeled "For Organ Transportation Only" for interprovincial transport after communicating the transportation process with transportation department. To evaluate pathological damage to the pig kidneys, a serious of methods were employed such as hematoxylin-eosin (HE) staining, real-time fluorescent quantitative polymerase chain reaction (RT-qPCR), terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) fluorescence staining and enzyme-linked immune absorbent assay (ELISA). Results The preoperative examination of the eight genetically modified pig showed that the serum creatinine was 73.2 μmol/L, blood urea nitrogen was 2.8 mmol/L and hemoglobin was 116 g/L, all within the normal range, indicating normal renal function. CT angiography revealed no lesions in the pig kidneys, and no dilation, stenosis or premature branching of the blood vessels. The total time of obtaining the left and right kidneys from the eight genetically modified pig was (125 ± 10) min, with a blood loss of (20 ± 2) mL. The warm ischemia times were 3 min and 7 min, respectively. The perfusion and trimming times of the left and right kidneys were 36 min and 41 min, respectively. After perfusion, both kidneys were white and moist. The cold preservation and transportation time was 8 h. HE staining showed that some glomeruli were shrunk, and the lumens of the surrounding renal tubules were slightly depressed and swollen with partial inner membrane shedding and microvacuoles formed when the kidneys were preserved for 8 h. The level of cysteinyl aspartate-specific proteinase-3 messenger RNA in the kidneys tissue gradually increased with the extension of cold preservation time after 2 h (P<0.05). TUNEL fluorescence staining showed that only a small number of cells underwent apoptosis after 8 h of cold preservation, which was not significantly different from that at 0 h (P>0.05). ELISA results showed that the contents of lactate dehydrogenase (LDH) and creatinine in the preservation solution remained relatively stable, but the content of kidney injury molecule 1 (KIM-1) gradually increased with the extension of preservation time, suggesting that the pig kidneys had mild injury. Conclusions By establishing methods for acquisition, perfusion, preservation and transportation of the kidneys from genetically modified donor pig, it is possible to effectively and reliably use genetically modified pig kidneys for xenotransplantation.

ObjectiveThe central symptom of Parkinson’s disease (PD) is impaired motor function. Beta-band electrical activity in the motor network of the basal ganglia is closely related to motor function. In this study, we combined scalp electroencephalography (EEG), brain functional network, and clinical scales to investigate the effects of beta burst-period neural electrical activity on brain functional network characteristics, which may serve as a reference for clinical diagnosis and treatment. MethodsThirteen PD patients were included in the PD group, and 13 healthy subjects were included in the healthy control group. Resting-state EEG data were collected from both groups, and beta burst and non-burst periods were extracted. A phase synchronization network was constructed using weighted phase lag indices, and the topological feature parameters of phase synchronization network were compared between the two groups across different periods and four frequency bands. Additionally, the correlation between changes in network characteristics and clinical symptoms was analyzed. ResultsDuring the beta burst period, the topological characteristic parameters of phase synchronization network in all four frequency bands were significantly higher in PD patients compared to healthy controls. The average clustering coefficient of the phase synchronization network in the beta band during the beta burst period was negatively correlated with UPDRS-III scores. In the low gamma band during the non-burst period, the average clustering coefficient of phase synchronization network was positively correlated with UPDRS and UPDRS-III scores, while UPDRS-III scores were positively correlated with global efficiency and average degree. ConclusionThe brain functional network features of PD patients were significantly enhanced during the beta burst period. Moreover, the beta-band brain functional network characteristics during the beta burst period were negatively correlated with clinical scale scores, whereas low gamma-band functional network features during the non-burst period were positively correlated with clinical scale scores. These findings indicate that motor function impairment in PD patients is associated with the beta burst period. This study provides valuable insights for the diagnosis of PD.

ObjectiveTo explore the effect of respiratory training based on core stabilization training on lumbar disc herniation. MethodsFrom January, 2023 to October, 2024, 96 patients with lumbar disc herniation admitted to the First Affiliated Hospital of Bengbu Medical University were divided into control group (n = 32), core group (n = 32) and respiratory group (n = 32). All the groups underwent conventional rehabilitation therapy, with core stabilization training in the core group and respiratory training combined with core stabilization training in the respiratory group, additionally, for four weeks. Before and after training, the scores of Visual Analogue Scale, Japanese Orthopaedic Association (JOA) and Oswestry Dysfunction Index (ODI) were compared, the average electromyographic value (AEMG) and root mean square (RMS) value of the multifidus and transversus abdominis were detected by surface electromyography (sEMG); and the thickness of the multifidus and transversus abdominis were measured by musculoskeletal ultrasonography bilaterally. ResultsThe intra-group effect (F > 597.796, P < 0.001), inter-group effect (F > 16.535, P < 0.001) and interaction effect (F > 49.622, P < 0.001) were significant in the scores of VAS, JOA and ODI; which were better in the respiratory group than in the control group and the core group (P < 0.05), and were better in the core group than in the control group (P < 0.001). The intra-group effect (F > 7971.631, P < 0.001), inter-group effect (F > 177.760, P < 0.001) and interaction effect (F > 478.771, P < 0.001) were significant in the thickness of the transversus abdominis and multifidus; which were better in the respiratory group than in the control group and the core group (P < 0.001), and were better in the core group than in the control group (P < 0.001). The intra-group effect (F > 144303.007, P < 0.001), inter-group effect (F > 1495.458, P < 0.001) and interaction effect (F > 3121.361, P < 0.001) were significant in the RMS of the multifidus and transversus abdominis; which were better in the respiratory group than in the control group and the core group (P < 0.001), and were better in the core group than in the control group (P < 0.001). The intra-group effect (F > 1890.532, P < 0.001), inter-group effect (F > 607.132, P < 0.001) and interaction effect (F > 824.923, P < 0.001) were significant in the AEMG of the multifidus and transversus abdominis; which were better in the respiratory group than in the control group and core group (P < 0.001), and were better in the core group than in the control group (P < 0.001). ConclusionCore training combined with respiratory training can more effectively reduce pain and improve dysfunction by enhancing the strength and control of the core muscles， thus improving the quality of life of patients with lumbar disc herniation.

Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.
Female ; Mice ; Demethylation/drug effects* ; Embryonic Stem Cells ; Estrogens/administration & dosage* ; Gene Expression/drug effects* ; Histones/metabolism* ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Mice, Inbred C57BL ; Oocytes ; Ovary/drug effects* ; Reproductive Techniques, Assisted ; Animals

Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Objective To explore the predictive value of radiomics for postoperative pancreatic fistula, infection, and long-term survival in patients with pancreatic ductal adenocarcinoma (PDAC). Methods 206 patients who received radical resection of pancreatic cancer in Zhongshan Hospital, Fudan University from January 2014 to December 2020 and were pathologically confirmed as PDAC after surgery were retrospectively selected, all of whom had complete surgical data and long-term follow-up data. Pyradiomics was used to analyze the enhanced CT images of all patients and extract radiomics features. LASSO dimensionality reduction combined with logistic regression analysis was used to construct a predictive model for pancreatic fistula and abdominal infection after PDAC surgery, and evaluating the model’s effectiveness using ROC curves. A long-term survival prediction model for PDAC patients was constructed using LASSO dimensionality reduction combined with Cox regression analysis, and patient risk scores were calculated. The patients were divided into high-risk and low-risk groups based on the median, and the survival curves were compared to evaluate the effectiveness of the model. The imaging omics features with the highest weight were divided into high expression group and low expression group according to the median, and the prognostic differences and clinical features were compared. Radiomics and clinical features were combined to analyze the influencing factors of long-term prognosis and construct a clinical imaging comprehensive model. Results A total of 1 595 radiomics features were extracted. A predictive model for pancreatic fistula and infection after PDAC surgery was constructed, with AUC values of 0.81 and 0.79, respectively. The PDAC long-term survival prediction model was successfully constructed, and the prognosis of the high-risk group was worse than that of the low-risk group (P<0.001). The weight of the radiomics feature “log-sigma-5-mm-3D_glszm_ZonePercentage” was 59.557. The CA19-9 level in the high expression group is higher than that in the low expression group (P=0.017), and there is a statistically significant difference in survival curves between the two groups (P=0.021). The comprehensive clinical imaging model suggested that age, AJCC stage, lymph infiltration, CA19-9 level and imaging characteristics were risk factors for long-term prognosis of PDAC patients (HR=1.028, 4.084, 2.566, 1.232 and 2.536). Conclusions The predictive model based on radiomics has good predictive performance for pancreatic fistula, infection, and long-term prognosis after PDAC surgery. Patients with high expression of the radiomics feature “log-sigma-5-mm-3D_glszm_ZonePercentage” face poorer prognosis.

Objective To construct a predictive model for high-grade pathological components of early invasive lung adenocarcinoma(ILAC)based on radiomics.Methods Collecting information on total 495 patients who underwent radical operation and were pathologically diagnosed as stage Ⅰ in the cardiothoracic surgery of Zhoushan Hospital from January 2015 to December 2019,including gender,age,pathological findings,tumor markers and preoperative chest CT images.The micropapillary and solid components in postoperative pathology were defined as"high-grade pathological components",while those without high-grade pathological components were classified into the low-grade group and those with high-grade pathological components were classified into the high-grade group.And patients were randomly divided into the training set(343 cases)and the validation set(152 cases)with a ratio of 7∶3 using the simple randomization grouping method.The region of interest of nodules on CT images were delineated layer by layer by scientific research platform and 1950 radiomics features were extracted.And then those features were filtrated by F-test,Pearson correlation coefficient,and L1 based feature selection.A model was built by using Logistic regression machine learning classifier,named mod 2,and radscore was also obtained.Differences between general information and CT features were analyzed.Binary Logistic regression analysis was used to construct a model for statistically significant variables,named mod 1.At the same time,Radscore was added to build the mod and named comb mod.The area under the curve(AUC),sensitivity and specificity of the three models were calculated.A nomogram was also drawn.Results A total of 495 patients were divided into the training set(n=343)and the validation set(n=152).Gender,carcinoma embryonic antigen(CEA),nodule,and maximum diameter were screened out in clinical features and involved in constructing the mod 1.Twelve features were selected from the radiomics features to build mod 2.Comb mod performed best,training set AUC:0.887,validation set AUC:0.875,and had good clinical practicability.Conclusion The model composed of general feature,CT feature and radiomics features could accurately predict high-grade pathological components in early ILAC,and provide references for clinicians to choose surgical method for patients.