Diabetic kidney disease（DKD） is a chronic kidney structural and functional disorder caused by diabetes. With the global prevalence of diabetes continuing to rise， DKD has gradually become a major cause of chronic kidney disease and end-stage renal disease（ESRD）， posing a serious threat to patients' quality of life and long-term health outcomes. Studies have shown that apoptosis plays a pivotal role in the development and progression of DKD， with its mechanisms involving abnormal activation of multiple signaling pathways such as Toll-like receptor 4（TLR4）/nuclear transcription factor-κB（NF-κB）/B-cell lymphoma-2（Bcl-2）/cysteinyl aspartate-specific proteinase（Caspase）-3， protein kinase R-like endoplasmic reticulum kinase（PERK）/eukaryotic initiation factor 2α（eIF2α）/activating transcript factor 4（ATF4）/CCAAT enhancer-binding protein homologous protein（CHOP）， phosphatidylinositol 3-kinase（PI3K）/protein kinase B（Akt）/glycogen synthase kinase-3β（GSK-3β）， Janus kinase 2（JAK2）/signal transducer and activator of transcription 3（STAT3）， adenosine monophosphate-activated protein kinase（AMPK）/mammalian target of rapamycin（mTOR） and silent information regulator 1（SIRT1）/tumor suppressor protein 53（p53）， thereby accelerating renal pathological damage in DKD. Extensive evidence-based medical studies have confirmed that traditional Chinese medicine（TCM）， leveraging its unique therapeutic advantages of multi-target， multi-component and multi-pathway approaches， has demonstrated remarkable efficacy and favorable safety profiles in treating DKD. Recent studies have demonstrated that active components of TCM can specifically target and modulate key effectors in apoptotic signaling pathways. Meanwhile， traditional compound formulations exert synergistic effects through multiple approaches such as replenishing deficiency and activating blood circulation， detoxifying and dredging collaterals， tonifying kidney essence， and removing stasis and purging turbidity， thereby comprehensively regulating critical pathological processes including endoplasmic reticulum stress and mitochondrial apoptosis pathways. This combined therapeutic approach of molecular targeting and holistic regulation provides novel strategies for delaying the progression of DKD. Based on this， this paper provides an in-depth analysis of key apoptotic signaling pathways and their regulatory mechanisms， while systematically summarizing recent research advances regarding the therapeutic effects of TCM active components， compound formulations， and proprietary Chinese medicines on DKD through modulation of these pathways， with particular emphasis on their underlying molecular mechanisms. These findings not only elucidate the modern scientific connotation and theoretical basis of TCM in treating DKD but also establish a solid theoretical and practical foundation for promoting the wider clinical application and further research of TCM in the field of DKD treatment.

Objective To investigate the exposure-response relationships and lag effects between air pollutants (PM_2.5, PM₁₀, O₃, and NO₂) and mortality in Jiading District, Shanghai, and to provide a scientific basis for the formulation of environmental health policies. Methods Using an individual-level time-stratified case-crossover design, conditional logistic regression models in conjunction with a distributed lag nonlinear model (DLNM) were employed to analyze the exposure-response relationship and temporal lag patterns of ambient air pollution on resident mortality in Jiading District (1994–2024). Results A total of 59 048 death cases were collected, including 18,701 deaths from cardiovascular diseases and 11 731 deaths from respiratory diseases. PM_2.5 and NO₂ had a significant impact on all-cause mortality, cardiovascular disease mortality, and respiratory disease mortality, with the most significant effects observed within a lag of 0–3 days. PM₁₀ also had some impact on these three types of mortality, but its effect was generally weaker than that of PM_2.5 and NO₂. The exposure-response curves showed that the risk of death increased rapidly with increasing concentrations of PM_2.5 and PM₁₀, while the effect of NO₂ plateaued at higher levels. No significant differences were found across age or gender subgroups. Conclusion Short-term exposure to PM_2.5, PM₁₀, and NO₂ significantly increases all-cause mortality risk in Jiading District, with effects persisting up to 7 days, highlighting the need for enhanced air pollution control measures, particularly targeting fine particulate matter.

With the rapid development of artificial intelligence, computational pathology has been seamlessly integrated into the entire clinical workflow, which encompasses diagnosis, treatment, prognosis, and biomarker discovery. This integration has significantly enhanced clinical accuracy and efficiency while reducing the workload for clinicians. Traditionally, research in this field has depended on the collection and labeling of large datasets for specific tasks, followed by the development of task-specific computational pathology models. However, this approach is labor intensive and does not scale efficiently for open-set identification or rare diseases. Given the diversity of clinical tasks, training individual models from scratch to address the whole spectrum of clinical tasks in the pathology workflow is impractical, which highlights the urgent need to transition from task-specific models to foundation models (FMs). In recent years, pathological FMs have proliferated. These FMs can be classified into three categories, namely, pathology image FMs, pathology image-text FMs, and pathology image-gene FMs, each of which results in distinct functionalities and application scenarios. This review provides an overview of the latest research advancements in pathological FMs, with a particular emphasis on their applications in oncology. The key challenges and opportunities presented by pathological FMs in precision oncology are also explored.
Humans ; Precision Medicine/methods* ; Medical Oncology/methods* ; Artificial Intelligence ; Neoplasms/pathology* ; Computational Biology/methods*

Objective To explore the clinical efficacy of the regimen based on sacubitril/valsartan and empagliflozin in the treatment of elderly hypertension patients with type 2 diabetes(T2DM)and determine the impact on left ventricular remodeling.Methods A prospective randomized trial was conducted on 100 elderly patients with essential hypertension combined with T2DM admitted in our hospital from January 2022 to January 2023.All of them had left ventricular hypertrophy(LVH).They were randomly divided into an observation group(n=50,empagliflozin combined with sacubitril/valsartan)and a control group(n=50,empagliflozin combined with valsartan).Baseline data,and SBP,DBP,left ventricular ejection fraction,left ventricular mass(LVM),interventricular septal thickness(IVST),left ventricular posterior wall thickness(LVPWT),and LVM index(LVMI)before and at 3 and 6 months after treatment were recorded and compared between the two groups.The incidence of adverse events was also compared between them.Results Repeated measures ANOVA showed that the values of SBP,DBP,IVST,LVPWT,LVM and LVMI were gradually reduced in the two groups with the extension of treatment time,and reached the lowest levels at 6 months of treatment(Ftime=4.829,10.037,121.202,65.784,214.796,162.801,P＜0.05,P＜0.01).With the elapse of treatment time,the observation group obtained more significant declines in terms of SBP,DBP,IVST,LVPWT,LVM and LVMI(Ftreatment×time=5.252,5.685,4.574,6.239,8.292,11.660,P＜0.05,P＜0.01).The inter-group effect was statistically significant.After 6 months of treatment,the values of above indicators were notably lower in the observation group than the control group(Ftreatment=79.151,97.673,4.250,8.080,9.598,20.091,P＜0.05,P＜0.01).SBP(129.80±7.67 mm Hg vs 138.48±12.35 mm Hg.P＜0.01),DBP(79.76±5.96 mm Hg vs 87.46±9.57 mm Hg,P＜0.01),IVST,LVPWT,LVM and LVMI were obviously lower in the observation group than the control group.Both valsartan+empagliflozin and sacubitril/valsartan+empagliflozin showed good safety.Conclusion Sacubitril/valsartan can effectively improve blood pressure,cardiac function,and left ventricular remodeling in elderly hypertensive patients with T2DM and LVH,with good safety.

Objective:To investigate the association between SPAG17 gene variant and Familial severe asthenozoospermia, and to assess its impact on the outcome of intracytoplasmic sperm injection (ICSI). Methods:Two siblings (Probands 1 and 2) with severe asthenozoospermia from a Chinese family who presented at the Reproductive Medicine Center Ⅱ of Gansu Maternity and Child Health Care Hospital (Gansu Provincial Central Hospital) in May 2023 were selected as study subjects. Clinical data were collected, and sperm morphology and ultrastructure (assessed by transmission electron microscopy) were analyzed. Pathogenic variants were screened using whole exome sequencing (WES) and verified by Sanger sequencing. This study was approved by the Medical Ethics Committee of Gansu Maternity and Child Health Care Hospital (Ethics No.: 2023GSFYLS78).Results:Probands 1 and 2 had primary infertility for 10 and 3 years, respectively, and both exhibited normal semen concentration, but the percentage of progressive motile sperm (PR) was significantly lower than the normal reference value (>32.00%), measuring 2.33%±0.58% and 0.80%±0.45%, respectively. Additionally, the percentage of sperms with normal morphology was slightly below the reference range (>4.00%), with the values of 3.36%±0.35% and 2.93%±1.36%. Both probands were found to harbor homozygous c. 2188C>T (p.Q730*) nonsense variant of the SPAG17 gene (NM_206996.4), for which their mother was a heterozygous carrier (their father had already deceased). Both sibs underwent ICSI treatment using a long gonadotropin-releasing hormone agonist protocol during the follicular phase combined with assisted oocyte activation (AOA). The wife of Proband 1 ultimately gave birth to a healthy girl, whilst the wife of Proband 2 delivered two healthy girls.Conclusion:The homozygous c. 2188C>T (p.Q730*) nonsense variant of the SPAG17 gene is closely related with the severe asthenozoospermia phenotype. Live births can be achieved through ICSI combined with AOA technology, though the overall utilizable embryo rate may be relatively low.

Objective:To evalaute the prevalence and determinants of thyroid nodules in children and adolescents in Jiangsu Province.Methods:This study included in-school students aged 8-17 years and selected through stratified cluster random sampling in Jiangsu. Thyroid nodule was diagnosed when its diameter was ≥3 mm. Random urine samples were collected for the detection of urinary iodine concentration with arsenic-cerium catalytic spectrophotometry. Data were analyzed by using χ2 test and logistic regression model. Results:In the 8 201 children and adolescents selected, the thyroid nodule detection rate was 16.10%. Multivariate logistic regression analysis revealed that, compared with those with urinary iodine levels of 100-299 μg/L, boys, those with normal body weight, those who were satisfied with their school performance, urinary iodine concentration ≥300 μg/L ( OR=1.15, 95% CI: 1.01-1.31), being girls ( OR=1.42, 95% CI: 1.26-1.60), being overweight ( OR=1.27, 95% CI: 1.07-1.50), being obese ( OR=1.23, 95% CI: 1.03-1.47), and dissatisfied with school performance ( OR=1.22, 95% CI: 1.04-1.43) were associated with higher likelihood of thyroid nodule detection. Children and adolescents who had solid snacks 2 times per week to 2 times per month ( OR=0.86, 95% CI: 0.74-0.99) or less than 2 times per month ( OR=0.80, 95% CI: 0.68-0.93) were more likely to have lower detection rate compared with those who had solid snacks more than 2 times per week. The detection rate of thyroid nodule increased with age ( OR=1.09, 95% CI: 1.06-1.11). Conclusion:The main factors influencing the detection rate of thyroid nodule in children and adolescents aged 8-17 years in Jiangsu included gender, age, urinary iodine concentration, BMI, self-assessed school performance and dietary habit.

Objective:To explore the impact of Epstein-Barr Virus(EBV) infection on treatment response and survival in newly diagnosed multiple myeloma(MM).Methods:The clinical data of 196 patients with newly diagnosed MM admitted to Zhongshan Hospital of Fudan University from June 1st, 2019 to February 25th,2021 were analyzed retrospectively and divided into EBV-positive group (106 cases) and negative group (90 cases) according to the primary EBV DNA results in peripheral blood mononuclear cells.To analyse the distribution of EBV positive rates in each type and in each stage of the Revised International Staging System (R-ISS), and to compare EBV DNA loads in EBV-positive patients among R-ISS stages.Rank sum test, 2×2 chi-square test and independent sample t-test were used to compare laboratory findings, such as liver and kidney function, immunohistochemistry and cytogenetics, treatment efficacy and survival prognosis between the two groups.The clinical prognosis of EBV-positive patients was summarized through survival analysis and Cox regression.Results:The EBV positive rate in patients with newly diagnosed MM was 54% (106/196), with the highest rate in patients with κ light chain type (9/12).Patients with R-ISS stage Ⅲ had a significantly higher positive rate than with stage Ⅰ ( χ2=4.68, P=0.031) and stage Ⅱ ( χ2=6.04, P=0.014), but there was no significant difference in EBV DNA loads between EBV-positive MM patients by stage ( Z=3.27, P=0.195).Serum creatinine (Scr) and β 2-microglobulin (β 2-MG) levels were higher in the EBV-positive group than in the EBV-negative group ( Z=1.98, P=0.048 and Z=2.08, P=0.038), and the occurrence of t(4;14) was also higher in the EBV-positive group ( χ2=3.93, P=0.047).The proportion of complete response (CR)/stringent complete response(sCR) and very good partial response(VGPR) after completion of the fourth chemotherapy were significantly lower in the EBV-positive group than in the EBV-negative group ( χ2=12.82, P=0.001 and χ2=8.30, P=0.004), and a higher rate of progressive disease (PD) occurred in the EBV-positive group ( χ2=4.48, P=0.046).The 2-year progression-free survival (PFS) of MM patients was shorter in the EBV-positive group compared to that in the EBV-negative group ( Z=-4.50, P0.01).Cox regression analysis showed that R-ISS stage Ⅲ ( HR=5.38, 95% CI 1.28-22.56, P=0.021), failure to achieve VGPR after the fourth chemotherapy ( HR=3.02, 95% CI 1.42-6.46, P=0.004), EBV-positive ( HR=1.98, 95% CI 1.02-3.87, P=0.045), with 1q21 amplification ( HR=2.35, 95% CI 1.16-4.75, P=0.017) and 13q14 deletion ( HR=1.93, 95% CI 1.01-3.67, P=0.046) were independent risk factors for PFS in newly diagnosed MM. Conclusions:EBV infection is an independent risk factor for poor prognosis, which has important clinical implications for the outcome and prognosis of patients with newly diagnosed MM, and may become a novel clinical assessment indicator.

Objective:To investigate the value of targeted three-dimensional contrast-enhanced ultrasound（3D-tCEUS）in efficacy evaluation of non-surgical treatments for renal cell carcinoma（RCC）.Methods:Forty nude mice with subcutaneous xenograft tumor model of human RCC（786-O cells）were divided into four groups based on different treatment methods：control，thermal ablation（TA），sunitinib（Suni），and TA+Suni. 3D-tCEUS were performed on days 1，3，7，and 14 post-treatment using self-developed vascular endothelial growth factor receptor 2（VEGFR2）targeted microbubbles. Tumor overall volume（V T）and non-enhanced volume（V N）were measured，from which the volume of the active（enhanced）region was calculated as V A = V T - V N. The tumor total and active area volume was standardized as V T st and V A st（standardized tumor volume = tumor volume after treatment / tumor volume at the beginning of treatment）. Tumor growth curves were plotted and tumor inhibition rates calculated for V T and V A respectively. Quantitative parameters，including the area under the curve（AUC）and the difference in peak intensity before and after burst（dTE），were obtained from the viable tumor enhanced region，and the standardized targeted quantitative parameters were derived by calculating the ratios of parameters at various time points post-treatment to those pre-treatment. The differences in V T st，V A st，AUC and dTE between different treatment groups at different time points were compared. At the end of the experiment，tumor tissues were obtained for immunohistochemical staining to observe the expression of VEGFR2 and CD31 antigens. Results:During the treatment period，no statistically significant differences in weight changes were observed among groups（all P > 0.05）. When V T was taken as the research object，V T st increased across all groups during the treatment period，with the TA group showing the most significant growth，while the TA + Suni group exhibited the smoothest increase in growth curve. When analyzing the tumor enhanced region，tumor growth trend of V A st was different with V T st for all groups；the Suni group showed a slow upward trend，whereas the TA + Suni group showed a continuous decline. Significant differences in tumor inhibition rate originated from V T and V A were noted within the same experimental group（ P < 0.05 for all experimental groups）. One day post-treatment，the AUC and dTE of the TA group were higher than that of the Control group，while the dTE of the TA + Suni group was lower than that of the Control group（all P < 0.05）. By day 3，statistically significant differences in AUC and dTE were observed between each experimental group and Control groups（all P < 0.05）. At day 14，the TA group showed increased AUC and dTE compared with those before treatment，while all other groups，particularly Suni group and TA + Suni group，demonstrated significant reductions（all P < 0.05）. Immunohistochemical results revealed the highest VEGFR2 and CD31 positivity in the TA group，followed by the Control group，while the Suni and TA + Suni groups exhibited lower rates. Conclusions:The combination of TA and targeted therapy effectively induces RCC cells death，demonstrating superior efficacy compared to monotherapy. 3D-tCEUS serves as a accurate and reliable tool for early evaluating the efficacy of non-surgical RCC treatments.

OBJECTIVE: To investigate the association between SPAG17 gene variant and Familial severe asthenozoospermia, and to assess its impact on the outcome of intracytoplasmic sperm injection (ICSI). METHODS: Two siblings (Probands 1 and 2) with severe asthenozoospermia from a Chinese family who presented at the Reproductive Medicine Center II of Gansu Maternity and Child Health Care Hospital (Gansu Provincial Central Hospital) in May 2023 were selected as study subjects. Clinical data were collected, and sperm morphology and ultrastructure (assessed by transmission electron microscopy) were analyzed. Pathogenic variants were screened using whole exome sequencing (WES) and verified by Sanger sequencing. This study was approved by the Medical Ethics Committee of Gansu Maternity and Child Health Care Hospital (Ethics No.: 2023GSFYLS78). RESULTS: Probands 1 and 2 had primary infertility for 10 and 3 years, respectively, and both exhibited normal semen concentration, but the percentage of progressive motile sperm (PR) was significantly lower than the normal reference value (> 32.00%), measuring 2.33% ± 0.58% and 0.80% ± 0.45%, respectively. Additionally, the percentage of sperms with normal morphology was slightly below the reference range (> 4.00%), with the values of 3.36% ± 0.35% and 2.93% ± 1.36%. Both probands were found to harbor homozygous c.2188C>T (p.Q730*) nonsense variant of the SPAG17 gene (NM_206996.4), for which their mother was a heterozygous carrier (their father had already deceased). Both sibs underwent ICSI treatment using a long gonadotropin-releasing hormone agonist protocol during the follicular phase combined with assisted oocyte activation (AOA). The wife of Proband 1 ultimately gave birth to a healthy girl, whilst the wife of Proband 2 delivered two healthy girls. CONCLUSION The homozygous c.2188C>T (p.Q730*) nonsense variant of the SPAG17 gene is closely related with the severe asthenozoospermia phenotype. Live births can be achieved through ICSI combined with AOA technology, though the overall utilizable embryo rate may be relatively low.
Humans ; Male ; Asthenozoospermia/genetics* ; Adult ; Sperm Injections, Intracytoplasmic ; Pedigree ; Spermatozoa ; Female ; Exome Sequencing

Objective The causal relationship between immune cells and hepatocellular carcinoma(HCC)risk was investigated using a two-sample Mendelian randomization method.Methods The datasets including 731 immune cells and HCC were obtained from the GWAS database and Finngen database,respectively.The stability and reliability of Mendelian randomization studies were evaluated by the MR-Egger regression,MR PRESSO,Cochran's Q test,and leave one out test.The inverse variance weighting,MR-Egger,weigh-ted median,simple mode and weighted mode were used to investigate the causal relationship between immune cells and HCC.Results A total of 4 immune cells were found to have a potential causal relationship with HCC,and the results were stable.The CD3+CD39+Treg,CD80+granulocyte and CD4+Treg were protective factors for HCC(OR=0.910,95%CI:0.852-0.972;OR=0.919,95%CI:0.865-0.975;OR=0.924,95%CI:0.873-0.978),while CD45+CD33+HLA-DR+CD14+marrow cells were a risk factor for HCC(OR=1.116,95%CI:1.033-1.204).Conclusion The CD3+CD39+Treg,CD80+granulocytes,and CD4+Treg are negatively associated with the risk of HCC,while CD45+CD33+HLA-DR+CD14+marrow cells are positively associated with the risk of HCC.