Definitive chemoradiotherapy (dCRT) has become a cornerstone in the treatment of locally advanced esophageal cancer; however, local control remains suboptimal, and persistent lesions or locoregional recurrences after treatment are not uncommon. For patients without distant metastases but with local failure, whether surgical intervention can still offer curative potential remains a major clinical dilemma. Salvage esophagectomy (SE) offers potential long-term survival for selected patients, but this procedure is performed in the context of severe fibrosis, impaired local blood supply, and obscured anatomical planes following chemoradiotherapy, resulting in significantly higher perioperative risk compared to primary esophagectomy. Consequently, controversies exist regarding patient selection, preoperative restaging, choice of surgical approach, extent of lymphadenectomy, gastrointestinal reconstruction, and perioperative management. In recent years, with the refinement of restaging modalities such as PET/CT, the accumulation of experience in high-volume centers, and emerging evidence from clinical studies, the clinical role of SE has gradually shifted from a "high-risk salvage measure" to a "selective curative strategy aimed at achieving long-term survival in carefully selected patients". Nevertheless, standardized guidelines for patient selection, technical approaches, and perioperative management are still lacking. Based on current evidence and clinical experience, experts organized by the Integrated Esophageal Cancer Committee of Chinese Anti-Cancer Association systematically reviewed key issues regarding SE, including its definition, indications, preoperative evaluation, choice of surgical approach, lymphadenectomy, gastrointestinal reconstruction, and perioperative management, and formulated a Chinese expert consensus. This consensus aims to provide guidance for standardized assessment, appropriate referral, individualized surgical decision-making, and optimized perioperative management of patients with locoregional failure after dCRT. Ultimately, this will increase the likelihood of R0 resection, reduce the risk of severe complications, and promote the safer, more judicious, and standardized implementation of SE in high-risk scenarios.

Objective To explore the clinical features, diagnosis, treatment and prognosis of testicular Ewing sarcoma(ES), so as to enhance the understanding and differential diagnosis of this disease. Methods A retrospective analysis was conducted on the clinical manifestations, auxiliary examinations and pathological findings of a case of left-sided ES treated at our hospital, supplemented by a review of relevant literature. Results A 24-year-old male patient presented with left testicular enlargement with pain. Magnetic resonance imaging suggested a neoplastic lesion, with a high likelihood of testicular germ cell tumor. A radical left orchiectomy was performed. Postoperative pathology revealed testicular ES. The patient subsequently completed 8 cycles of VDC/IE chemotherapy and showed no evidence of recurrence at 10 months of follow-up. Analysis of literature on 5 previously reported cases of testicular ES had testicular enlargement as the primary presentation. All patients underwent surgery and 4 received adjuvant therapy. Follow-up revealed 1 death at 9 months postoperatively, with no recurrence or progression seen in the remainder. Conclusion ES occurring in the testis is extremely rare.Testicular ES is a poorly differentiated small round-cell malignant tumor that primarily presents as testicular enlargement. Current treatment mainly surgical resection combined with adjuvant chemotherapy.

Objective To explore the characteristics and temporal trends of renal cancer burden among Chinese adolescents and young adults(AYA), and predict its future epidemic situation, so as to provide evidence for formulating public health policies and reducing the disease burden.Methods Epidemiological data of renal cancer in Chinese AYA(15-39 years)from 1990 to 2021 were obtained from the Global Burden of Disease(GBD)2021 database. The current status and trends of renal cancer in this population were analyzed. The incidence and mortality trends of renal cancer in AYA over the next 15 years was predicted with ARIMA model. The impacts of smoking and body mass index(BMI)on the disease burden were evaluated. Results In 2021, the incidence(1.12/100000), prevalence(8.61/100000), mortality(0.19/100000), and disability-adjusted life years(DALYs)(11.37/100000 person-years)of renal cancer in Chinese AYA were significantly higher than those in 1990 and above the global average. All burden indicators and their increases were higher in males than in females, and the burden accelerated after 30 years of age. The incidence rose steadily from 2003 to 2021(APC=3.95), while the mortality increased significantly from 2013 to 2021(APC=2.40). The burden attributed to high BMI continued to rise, and the smoking-attributable fraction in males first increased then decreased. ARIMA predicted that the incidence of renal cancer in Chinese AYA males would accelerate, while the mortality in both genders would stabilize. Conclusion The burden of renal cancer in Chinese AYA shows a significant upward trend. Males and people over 30 years old are key targets for prevention and control. Strengthening the management of risk factors(smoking, high BMI)and promoting early diagnosis and treatment are essential to reduce the disease burden.

Objective To screen the aging-related genes associated with prognosis in clear cell renal cell carcinoma (ccRCC), construct a prognostic model to optimize risk stratification, explore the underlying mechanisms, and provide reference for individualized diagnosis and treatment of this disease.Methods RNA sequencing data, clinical data, and aging-related genes of ccRCC were obtained from databases.After differentially expressed genes were screened, a prognostic model was constructed using Cox regression.The performance of the model was evaluated with Kaplan-Meier curves and receiver operating characteristic (ROC) curves, and validated with clinical features.Key genes were verified with immunohistochemistry.Results A total of 70 differentially expressed genes were identified, including IFI16, PECAM1, and ABCB1 as key genes, and a model formula was constructed.Internal and external validations showed that the survival rate of the high-risk group was significantly lower, with the area under the ROC curve (AUC)＞0.6.The risk score was correlated with clinical features.IFI16 was highly expressed in cancer tissues and associated with poor prognosis.Conclusion The prognostic model constructed in this study has good performance.Integrating clinical features, it can improve the accuracy of prognosis assessment of ccRCC.

ObjectiveTo observe the clinical efficacy and safety of Shenshuai Guanchang prescription in improving the intestinal barrier function，reducing non-indole uremic toxins，ameliorating micro-inflammatory state，and delaying renal function progression in non-dialysis patients with chronic kidney disease （CKD） stage 4-5. MethodsA total of 80 patients with CKD stage 4-5 who did not receive dialysis replacement therapy and were diagnosed with the syndrome of spleen and kidney deficiency，blood stasis and dampness turbidity were randomly assigned into a control group and a treatment group，with 40 patients in each group. The control group received conventional basic treatment and Western medicine symptomatic treatment，while the treatment group received combined intervention with Shenshuai Guanchang prescription through retention enema in addition to the treatment of the control group. Both groups had a treatment course of 4 weeks. The two groups were compared regarding the changes in urine toxin indicators ［p-cresyl sulfate （PCS） and trimethylamine oxide （TMAO）］，intestinal barrier indicators ［D-lactic acid （D-LA），lipopolysaccharide （LPS），and intestinal fatty acid-binding protein （I-FABP）］，renal function indicators ［serum creatinine （SCr），blood urea nitrogen （BUN），and estimated glomerular filtration rate （eGFR）］，and micro-inflammatory state indicators ［interleukin-6 （IL-6），tumor necrosis factor-α （TNF-α），and neutrophil-to-lymphocyte ratio （NLR）］ before and after treatment. The therapeutic effects were evaluated from three aspects：The efficacy regarding traditional Chinese medicine （TCM） symptom scores，the efficacy regarding laboratory indicators，and comprehensive efficacy. The safety of the clinical research drugs used by both groups of patients was also observed. ResultsA total of 37 cases in the treatment group and 38 cases in the control group completed the observation. After treatment，the treatment group showed declined levels of PCS，TMAO，D-LA，SCr，TNF-α，and NLR，spleen and kidney deficiency symptom score，blood stasis and dampness symptom score，and total symptom score （P<0.05），and increased eGFR （P<0.05）. Moreover，the treatment group had lower levels of PCS，TMAO，D-LA，I-FABP，IL-6，and TNF-α，spleen and kidney deficiency symptom score，blood stasis and dampness symptom score，and total symptom score （P<0.05），higher response rate regarding TCM symptoms （χ²=6.68，P<0.05），and higher comprehensive efficacy （χ²=4.08，P<0.05） than the control group. No significant abnormalities were observed in the safety indicators of the two groups of patients. During the treatment period，adverse reactions were reduced after symptomatic treatment，and no serious adverse reactions occurred. ConclusionShenshuai Guanchang prescription can alleviate the clinical symptoms，improve the intestinal barrier function，reduce non-indole-type uremic toxins，alleviate the micro-inflammatory state，and has good clinical application safety of non-dialysis patients with CKD stage 4-5.

ObjectiveTo investigate the protective effect of Rehmanniae Radix iridoid glycosides （RIG） on the kidney tissue of streptozotocin （STZ）-induced diabetic mice and explore the underlying mechanism. MethodsTwelve of 72 male C57BL/6J mice were randomly selected as the normal group， and the remaining 60 mice were fed with a high-fat diet for six weeks combined with injection of 60 mg·kg^-1 STZ for 4 days to model type 2 diabetes mellitus. The successfully modeled mice were randomized into model， metformin （250 mg·kg^-1）， catalpol （100 mg·kg^-1）， low-dose RIG （RIG-L， 200 mg·kg^-1） and high-dose RIG （RIG-H， 400 mg·kg^-1） groups （n=11）. Mice in each group were administrated with corresponding drugs， while those in the normal group and model group were administrated with the same dose of distilled water by gavage once a day. After 8 weeks of intervention， an oral glucose tolerance test （OGTT） was performed， and the area under the curve （AUC） was calculated. After mice were sacrificed， both kidneys were collected. The body weight， kidney weight， and fasting blood glucose （FBG） were measured. Biochemical assays were performed to measure the serum levels of triglycerides （TG）， total cholesterol （TC）， serum creatinine （SCr）， and blood urea nitrogen （BUN）. Enzyme-linked immunosorbent assay （ELISA） was employed to determine the serum level of fasting insulin （FINS）， and the insulin sensitivity index （ISI） and homeostatic model assessment for insulin resistance （HOMA-IR） were calculated. The pathological changes in kidneys of mice were observed by hematoxylin-eosin staining and Masson staining. The immunohistochemical method （IHC） was employed to assess the expression of interleukin-1 （IL-1）， interleukin-6 （IL-6）， tumor necrosis factor-α（TNF-α）， transforming growth factor-β₁ （TGF-β₁）， and collagen-3 （ColⅢ） in the kidney tissue. The protein levels of TGF-β₁， cell signal transduction molecule 3 （Smad3）， matrix metalloproteinase-9 （MMP-9）， and ColⅢ in kidneys of mice were determined by Western blot. ResultsCompared with the normal group， the model group showcased decreased body weight and ISI （P<0.01）， increased kidney weight， FBG， AUC， FINS， HOMA-IR， TC， TG， SCr， and BUN （P<0.01）， glomerular hypertrophy， capsular space narrowing， and collagen deposition in the kidney， up-regulated protein levels of IL-1， IL-6， TNF-α， TGF-β₁， ColⅢ， and Smad3 （P<0.01）， and down-regulated protein level of MMP-9 （P<0.01） in the kidney tissue. Compared with the model group， the treatment groups had no significant difference in the body weight and decreased kidney weight （P<0.05， P<0.01）. The FBG level declined in the RIG-H group after treatment for 4-8 weeks and in the metformin， catalpol， and RIG-L groups after treatment for 6-8 weeks （P<0.01）. The AUC in the RIG-L， RIG-H， and metformin groups decreased （P<0.05， P<0.01）. The levels of TC， SCr， and BUN in the serum of mice in each treatment group became lowered （P<0.05， P<0.01）. The level of TG declined in the RIG-L， RIG-H， and metformin groups （P<0.05， P<0.01）. The serum level of FINS declined in the catalpol， RIG-L， and metformin groups （P<0.01）. Compared with the model group， the treatment groups showed decreased HOMA-IR （P<0.01）， increased ISI （P<0.01）， alleviated pathological changes in the kidney tissue， and down-regulated expression of IL-1 and TGF-β₁. In addition， the protein levels of IL-6， TNF-α， and ColⅢ in the RIG-H and metformin groups and IL-6 and TNF-α in the RIG-L group were down-regulated （P<0.05， P<0.01）， and the protein levels of IL-6， TNF-α， and ColⅢ in the catalpol group and ColⅢ in the RIG-L group showed a decreasing trend without statistical difference. The protein levels of TGF-β₁， Smad3， and ColⅢ in the RIG-H and metformin groups were down-regulated （P<0.01）. Compared with that in the model group， the protein level of MMP-9 was up-regulated in each treatment group （P<0.01）. ConclusionRIG can improve the renal structure and function of diabetic mice by regulating the TGF-β₁/Smads signaling pathway.

Objective:To identify proteins associated with the risk of gastric cancer (GC) and build a protein risk score for risk prediction of GC based on proteomic analysis.Methods:Gastric mucosal proteomics data were used to construct Dataset One, comprising 94 GC cases and 230 individuals with different stages of gastric mucosal lesions. The GC cases were recruited from the National Upper Gastrointestinal Cancer Early Detection (UGCED) Program in Linqu, Shandong Province, as well as clinical patients from the Fifth Medical Center, General Hospital of PLA, and Peking University Cancer Hospital. Non-cancer individuals were enrolled from the National UGCED Program in Linqu and community screening programs at the Dongfang Hospital. All participants were pathologically confirmed. Multivariate logistic regression analysis was employed to identify gastric mucosal proteins significantly associated with GC risk. Subsequently, plasma proteomics data from the UK Biobank Pharma Proteomics Project (UKB-PPP) were used to construct Dataset Two, including 40 baseline GC cases and 47 933 non-cancer individuals, and Dataset Three, comprising 138 incident GC cases and 47 933 non-cancer individuals during a prospective follow-up period. In Dataset Two, multivariate logistic regression analysis was conducted to assess associations between plasma protein levels and baseline GC risk. In Dataset Three, multivariate Cox regression analysis was used to examine associations with the risk of incident GC. A poly-protein risk score (PRS) was developed using a weighted summation method based on protein effect sizes from Dataset Two. Its associations with GC risk and the progression of gastric mucosal lesions were evaluated using linear regression trend tests.Results:A total of 324, 47 973 and 48 071 participants were included in Datasets One, Two, and Three, respectively. Across the three datasets, the proportions of males and individuals aged>60 years were higher in the GC group than in the non-GC group (all P values<0.05). The follow-up period in Dataset Three had a M ( P 25, P 75) of 14.47 (13.7, 15.2) years, with a median of 7.4 (4.6, 11.3) years for those who progressed to GC. Based on Dataset One, 2 524 tissue-differential proteins associated with GC risk were identified through multivariate logistic regression analysis adjusted for age and sex. Among these, seven proteins were consistently associated with GC risk across tissue and plasma levels in Datasets Two and Three, with consistent directions of association. Five proteins (MRC1, APOL1, BST2, PON2, and GGH) were positively associated with GC risk, while two (GSN and CLEC3B) were negatively associated. Analysis of the PRS based on these seven proteins showed that for each standard deviation increase in the tissue-derived PRS, the risk of GC increased by 6.26 times (95% CI: 4.02-9.75). In Dataset Two, each standard deviation increase in the plasma-derived PRS was associated with a 2.13-fold increase in GC risk (95% CI: 1.68-2.69). In the prospective cohort of Dataset Three, individuals in the high PRS group had a 2.27-fold higher risk of GC compared to the low PRS group (95% CI: 1.50-3.45). Moreover, each standard deviation increase in the plasma PRS was associated with a 57% higher risk of GC ( HR=1.57, 95% CI: 1.34-1.84). Additionally, the tissue-derived PRS showed an increasing trend with the progression of gastric mucosal lesions. Conclusion:The tissue and plasma proteomics identified seven individual proteins that may indicate the risk of developing gastric cancer, showing the potential as biomarkers for aiding in the screening of gastric cancer.

Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
Humans ; Parkinson Disease/drug therapy* ; Diabetes Mellitus, Type 2/pathology* ; Signal Transduction/physiology* ; Receptor, Insulin/metabolism* ; Animals ; Insulin Resistance/physiology* ; Insulin/metabolism*

Cardiotoxicity is a critical issue in drug development that poses serious health risks, including potentially fatal arrhythmias. The human ether-à-go-go related gene (hERG) potassium channel, as one of the primary targets of cardiotoxicity, has garnered widespread attention. Traditional cardiotoxicity testing methods are expensive and time-consuming, making computational virtual screening a suitable alternative. In this study, we employed machine learning techniques utilizing molecular fingerprints and descriptors to predict the cardiotoxicity of compounds, with the aim of improving prediction accuracy and efficiency. We used four types of molecular fingerprints and descriptors combined with machine learning and deep learning algorithms, including Gaussian naive Bayes (NB), random forest (RF), support vector machine (SVM), K-nearest neighbors (KNN), eXtreme gradient boosting (XGBoost), and Transformer models, to build predictive models. Our models demonstrated advanced predictive performance. The best machine learning model, XGBoost Morgan, achieved an accuracy (ACC) value of 0.84, and the deep learning model, Transformer_Morgan, achieved the best ACC value of 0.85, showing a high ability to distinguish between toxic and non-toxic compounds. On an external independent validation set, it achieved the best area under the curve (AUC) value of 0.93, surpassing ADMETlab3.0, Cardpred, and CardioDPi. In addition, we explored the integration of molecular descriptors and fingerprints to enhance model performance and found that ensemble methods, such as voting and stacking, provided slight improvements in model stability. Furthermore, the SHapley Additive exPlanations (SHAP) explanations revealed the relationship between benzene rings, fluorine-containing groups, NH groups, oxygen in ether groups, and cardiotoxicity, highlighting the importance of these features. This study not only improved the predictive accuracy of cardiotoxicity models but also promoted a more reliable and scientifically interpretable method for drug safety assessment. Using computational methods, this study facilitates a more efficient drug development process, reduces costs, and improves the safety of new drug candidates, ultimately benefiting medical and public health.

OBJECTIVE: To explore the feasibility of incorporating simple bedside indicators into death predictive model for elderly critically ill patients based on interpretability machine learning algorithms, providing a new scheme for clinical disease assessment. METHODS: Elderly critically ill patients aged ≥ 65 years who were hospitalized in the intensive care unit (ICU) of Tacheng People's Hospital of Ili Kazak Autonomous Prefecture from June 2017 to May 2020 were retrospectively selected. Basic parameters including demographic characteristics, basic vital signs and fluid intake and output within 24 hours after admission, as well acute physiology and chronic health evaluation II (APACHE II), Glasgow coma score (GCS) and sequential organ failure assessment (SOFA) were also collected. According to outcomes in hospital, patients were divided into survival group and death group. Four datasets were constructed respectively, namely baseline dataset (B), including age, body temperature, heart rate, pulse oxygen saturation, respiratory rate, mean arterial pressure, urine output volume, infusion volume, and crystal solution volume; B+APACHE II dataset (BA), B+GCS dataset (BG), and B+SOFA dataset (BS). Then three machine learning algorithms, Logistic regression (LR), extreme gradient boosting (XGboost) and gradient boosting decision tree (GBDT) were used to develop the corresponding mortality predictive models within four datasets. The feature importance histogram of each prediction model was drawn by SHapley additive explanation (SHAP) method. The area under curve (AUC), accuracy and F1 score of each model were compared to determine the optimal prediction model and then illuminate the nomogram. RESULTS: A total of 392 patients were collected, including 341 in the survival group and 51 in the death group. There were statistically significant differences in heart rate, pulse oxygen saturation, mean arterial pressure, infusion volume, crystal solution volume, and etiological distribution between the two groups. The top three causes of death were shock, cerebral hemorrhage, and chronic obstructive pulmonary disease. Among the 12 prognostic models trained by three machine learning algorithms, overall performance of prognostic models based on B dataset was behind, whereas the LR model trained by BA dataset achieved the best performance than others with AUC of 0.767 [95% confidence interval (95%CI) was 0.692-0.836], accuracy of 0.875 (95%CI was 0.837-0.903) and F1 score of 0.190. The top 3 variables in this model were crystal solution volume with first 24 hours, heart rate and mean arterial pressure. The nomogram of the model showed that the total score between 150 and 230 were advisable. CONCLUSION The interpretable machine learning model including simple bedside parameters combined with APACHE II score could effectively identify the risk of death in elderly patients with critically illness.
Humans ; Critical Illness ; Machine Learning ; Aged ; Algorithms ; Intensive Care Units ; Retrospective Studies ; APACHE ; Prognosis ; Organ Dysfunction Scores ; Hospital Mortality ; Male ; Female