ObjectiveThe exacerbating trend of global population aging poses profound socioeconomic and public health challenges, making the comprehensive elucidation of biological aging mechanisms and the discovery of effective anti-aging interventions an urgent priority in the life sciences. Based on our previous serum metabolomics findings that dimethylglycine, an intermediate metabolite of amino acid metabolism naturally present in the human body, was significantly enriched in the serum of longevity families, this study aimed to systematically investigate the anti-aging effects of dimethylglycine both in living organisms and in controlled laboratory environments, and to preliminarily elucidate its underlying molecular mechanisms. While existing literature indicates that dimethylglycine possesses antioxidant and immunomodulatory properties, its direct anti-aging efficacy and the specific molecular pathways through which it operates remain largely unexplored. MethodsTo comprehensively evaluate the anti-aging properties of dimethylglycine, we utilized replicative senescent human embryonic lung fibroblasts, specifically the WI-38 cell line, as an experimental model in a controlled laboratory environment. Cell viability and safety were thoroughly assessed using Cell Counting Kit-8 and lactate dehydrogenase release assays across various concentrations of dimethylglycine. The impact of dimethylglycine on cellular senescence phenotypes, oxidative stress, and proliferative capacity was evaluated via senescence-associated beta-galactosidase staining, reactive oxygen species fluorescence detection, and 5-ethynyl-2'-deoxyuridine incorporation assays. Furthermore, the molecular alterations of senescence-associated secretory phenotype factors and core senescence signaling pathways were quantified using quantitative reverse transcription polymerase chain reaction for the messenger RNA levels of interleukin-6, interleukin-8, p21, and matrix metalloproteinase-1, and enzyme-linked immunosorbent assay for the measurement of p16 and p21 protein expression levels. For the living organism model, the wild-type nematode Caenorhabditis elegans was used to evaluate systemic physiological effects. We conducted a comprehensive lifespan analysis at 20°C, heat stress resistance survival assays at 35℃, senescence-associated beta-galactosidase staining, lipofuscin accumulation tracking, intracellular reactive oxygen species measurement, and Oil Red O staining to ascertain systemic lipid accumulation. Additionally, network pharmacology bioinformatics tools, including PharmMapper and STRING databases, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were utilized to predict target pathways, alongside highly detailed molecular docking simulations utilizing SwissDock and Protein-Ligand Interaction Profiler to examine interactions with the cytochrome P450 family 2 subfamily C member 9 protein. ResultsThe experimental outcomes robustly demonstrate the potent anti-aging capabilities of dimethylglycine. At the cellular level, toxicity analyses firmly confirmed that dimethylglycine is highly safe; continuous treatment with 50 mol/L and 70 mol/L of dimethylglycine for 5 d did not induce any cellular membrane damage or cytotoxicity, but rather actively promoted cellular proliferation. Utilizing the optimal standardized concentration of 50 mol/L, dimethylglycine treatment significantly ameliorated senescent phenotypic markers in human embryonic lung fibroblasts, which was evidenced by a drastic and highly significant reduction in the senescence-associated beta-galactosidase positive cell percentage (P<0.000 1) and intracellular reactive oxygen species levels (P<0.000 1), alongside a marked increase in the 5-ethynyl-2'-deoxyuridine-positive proliferation rate (P=0.003 5). On a molecular expression scale, dimethylglycine significantly downregulated the messenger RNA expression of multiple core senescence-associated secretory phenotype inflammatory factors, including interleukin-6, interleukin-8, p21, and matrix metalloproteinase-1. Concurrently, it effectively suppressed the protein expression of critical cell cycle arrest markers, diminishing p16 protein levels by 57.3% (P=0.000 4) and p21 protein levels by 27.2% (P=0.000 7). In the nematode Caenorhabditis elegans animal model, dimethylglycine significantly extended the mean lifespan from 20.402 d to an impressive 23.066 d (P<0.000 1) and notably enhanced overall survival rates under severe heat stress environmental conditions (P=0.017). Furthermore, systemic dimethylglycine intervention significantly mitigated age-related physiological decline by decreasing bodily lipofuscin accumulation (P<0.000 1), significantly reducing senescence-associated beta-galactosidase activity, lowering systemic reactive oxygen species fluorescence (P=0.008), and effectively alleviating overall fat accumulation (P<0.000 1). Mechanistically, extensive network pharmacology and Kyoto Encyclopedia of Genes and Genomes analyses strongly revealed that the potential targets of dimethylglycine are significantly enriched in fundamental drug metabolism and oxidative stress response pathways. Precision molecular docking simulations conclusively demonstrated that dimethylglycine forms highly stable structural interactions with the cytochrome P450 family 2 subfamily C member 9 protein, specifically highlighting the definitive formation of 5 stable hydrogen bonds involving serine 365, leucine 366, and serine 429 residues, as well as two critical salt bridge formations with arginine 97 and histidine 368 residues. It is additionally predicted to interact favorably with glutathione S-transferase family proteins. ConclusionDimethylglycine exhibits a profoundly significant and multifaceted anti-aging activity at both the cellular and entire living animal levels. By powerfully alleviating oxidative stress, heavily suppressing the core p16 and p21-dependent cellular senescence signaling pathways, and substantially mitigating the detrimental senescence-associated secretory phenotype, dimethylglycine effectively delays fundamental cellular senescence processes and drastically extends whole-organism lifespan. The biological mechanisms driving these robust protective effects are highly likely closely associated with its direct stable interactions with crucial metabolic and detoxifying enzyme systems, such as cytochrome P450 family 2 subfamily C member 9 and glutathione S-transferase family proteins, thereby systemically improving metabolic dysregulation and restoring critical redox homeostasis. This comprehensive study provides highly solid experimental evidence supporting dimethylglycine as a highly potent and safe potential anti-aging intervention agent, while simultaneously offering a clear molecular mechanistic explanation for the previously documented high abundance of dimethylglycine observed within exceptionally long-lived human populations.

Objective To discuss the efficacy of transcatheter arterial chemoembolization(TACE)in combination with targeted therapy and immune checkpoint inhibitors for advanced hepatocellular carcinoma(HCC),and to identify the influencing factors.Methods A total of 60 patients with advanced HCC,who were admitted to the Air Force Medical Center of China from January 2016 to December 2022,were enrolled in this study.Thirty patients received TACE combined with targeted therapy and immune checkpoint inhibitors(TACE-L-P group),and the other 30 patients received TACE combined with targeted therapy(TACE-L group).The progression-free survival(PFS),overall survival(OS),disease control rate(DCR),and objective response rate(ORR)were compared between the two groups.Results In the TACE-L group and TACE-L-P group,the median PFS(mPFS)was 7 months and 10 months respectively(P=0.011),the median OS(mOS)was 15.5 months and 29 months respectively(P=0.014).Child-Pugh class B(HR=3.89,95％CI:1.27-11.94,P=0.018)and Barcelona Clinic Liver Cancer(BCLC)stage C(HR=2.83,95％CI:1.32-6.03,P=0.007)were the independent risk factors for OS,while micro wave ablation(HR=0.21,95％CI:0.07-0.63,P=0.005)and TACE-L-P(HR=0.09,95％CI:0.03-0.3,P=0.001)were the independent protection factors for OS.Besides,elevated bilirubin level(HR=1.03,95％CI:1-1.06,P=0.032)and elevated gamma-glutamyl transferase(GGT)level(HR=1.01,95％CI:1-1.01,P=0.002)were the independent risk factors for disease progression,and TACE-L-P(HR=0.27,95％CI:0.09-0.79,P=0.017)was the independent protection factor for disease progression.The ORR and DCR in TACE-L-P group were remarkably higher than those in TACE-L group,which were 43.4％vs 13.3％and 63.4％vs 23.3％respectively,the differences between the two groups were statistically significant(both P＜0.05).Conclusion In treating advanced HCC,TACE combined with targeted therapy and immune checkpoint inhibitors is superior to TACE combined with targeted therapy in therapeutic efficacy.

Objective·To explore the correlation between body compositions and cardiovascular fitness(CRF)in patients with coronary heart disease(CHD).Methods·The CHD patients(CHD group)who underwent elective percutaneous coronary intervention treatment at Renji Hospital,Shanghai Jiao Tong University School of Medicine from October 2022 to June 2023 as well as healthy people(control group)were selected.All the participants completed cardiopulmonary exercise testing(CPET)to determine CRF and bioelectrical impedance analysis(BIA)to determine body compositions on the same day.Results·A total of 191 patients with coronary heart disease and 188 healthy individuals were included.There was no statistically significant difference in baseline characteristics between the two groups.Compared with the control group,the CRF indicators of the CHD group were significantly reduced(all P<0.05).In terms of body composition indicators,the trunk muscle mass(TMM)of the CHD group was significantly lower than that of the control group(P<0.01),and the trunk fat mass(TFM)was significantly higher than that of the control group(P<0.01).Correlation analysis showed that TMM(R=0.538),lower limbs muscle mass(LMM)(R=0.754),and lower limbs fat mass(LFM)(R=0.593)were positively correlated with peak oxygen uptake per kilogram of bodyweight(VO2peak/kg)in the CHD group(all P<0.01),while TFM(R=-0.563)was negatively correlated with VO2peak/kg(P<0.01).There was no statistically significant correlation between other body composition indicators and VO2peak/kg.According to VO2peak/kg,the CHD patients were divided into low CRF group,medium CRF group,and high CRF group.The results showed that there were statistically significant differences in LMM,TMM,LFM,and TFM among the three groups of patients(all P<0.05).Multiple linear regression analysis suggested that age,gender,TMM,TFM,LMM,and LFM were related factors of VO2peak/kg in the patients with CHD.The VO2peak/kg of CHD patients increased with the increase of TMM,LMM,and LFM and the decrease of age and TFM;the female patients had lower VO2peak/kg compared to the males.Conclusion·The CRF of CHD patients is significantly lower than that of the healthy population,with higher TFM and lower TMM;in the CHD patients,CRF is negatively correlated with TFM and positively correlated with TMM,LMM,and LFM.

Objective·To analyze the differences and classify hypertrophic cardiomyopathy(HCM)patients and healthy controls(HC)using short-axis cine cardiac magnetic resonance(CMR)images-derived radiomics features.Methods·One hundred HCM subjects were included,and fifty HC were randomly selected at 2∶1 ratio during January 2018 to December 2021 in the Department of Cardiology,Renji Hospital,Shanghai Jiao Tong University School of Medicine.The CMR examinations were performed by experienced radiologists on these subjects.CVI 42 post-processing software was used to obtain left ventricular morphology and function measurements,including left ventricular ejection fraction(LVEF),left ventricular end-diastolic volume(LVEDV)and left ventricular end-diastolic mass(LVEDM).The 3D radiomic features of the end-diastolic myocardial region were extracted from short-axis images CMR cine.The distribution of the radiomic features in the two groups was analysed and machine learning models were constructed to classify the two groups.Results·One hundred and seven 3D radiomic features were selected and extracted.After exclusion of highly correlated features,least absolute shrinkage and selection operator(LASSO)was used,and a 5-fold cross-validation was performed.There were still 11 characteristics with non-zero coefficients.The K-best method was used to decide the top 8 features for subsequent analysis.Among them,four features were significantly different between the two groups(all P<0.05).Support vector machine(SVM)and random forest(RF)models were constructed to discriminate the two groups.The results showed that the maximum area under the curve(AUC)for the single-feature model(first order grayscale:entropy)was 0.833(95%CI 0.685?0.968)and the maximum accuracy for the multi-feature model was 83.3%with an AUC of 0.882(95%CI 0.705?0.980).Conclusion·There are significant differences in both left ventricular function and left ventricular morphology between HCM and HC.The 3D myocardial radiomic features of the two groups are also significantly different.Although single feature is able to distinguish the two groups,the combination of multi-features show better classification performance.

Objective·To develop a machine learning approach for early identification of metabolic syndromes associated with inflammatory metabolic state changes in breast cancer patients after neoadjuvant therapy,using common laboratory and transthoracic echocardiography indices.Methods·Female patients with primary invasive breast cancer diagnosed at the Department of Breast Surgery,Renji Hospital,Shanghai Jiao Tong University School of Medicine,between September 2020 and September 2022,were included.General patient information,laboratory test results,and transthoracic echocardiography data were collected.After feature extraction,five machine learning algorithms,including random forest(RF),gradient boosting(GB),support vector machine(SVM),K-nearest neighbor(KNN),and decision tree(DT),were applied to construct a prediction model for the changes of the patients' metabolic state after neoadjuvant therapy,and the prediction performances of the five models were compared.Results·A total of 232 cases with valid clinical data were included,comprising 135 cases before neoadjuvant therapy and 97 cases after completing 4 cycles of neoadjuvant therapy.Feature extraction identified five key features:white blood cell count,hemoglobin,high-density lipoprotein(HDL),interleukin-2 receptor,and interleukin-8.In the multi-feature analysis,the area under the receiver operating characferistic curve(AUC)was higher in the combination of white blood cell count,hemoglobin and HDL compared to the combination of interleukin-2 receptor and interleukin-8(RF:0.928 vs 0.772,GB:0.900 vs 0.792,SVM:0.941 vs 0.764,KNN:0.907 vs 0.762,DT:0.799 vs 0.714).The RF,SVM,and GB models showed higher AUC(0.928,0.941,0.900)and accuracy(0.914,0.897,0.776).The SVM model exhibited superior accuracy in the training data compared to the RF and GB models(P=0.394,0.122 and 0.097,respectively).Conclusion·The SVM model can be used to establish a prediction model for identifying breast cancer patients at high risk of developing inflammatory metabolic state-related metabolic syndrome after neoadjuvant therapy by incorporating five common clinical indicators,namely,white blood cell count,hemoglobin,high-density lipoprotein,interleukin-2 receptor,and interleukin-8.SVM modeling may be useful for clinicians to establish individualized screening protocols based on a patient's inflammatory metabolic state.

Child ; Humans ; East Asian People ; Quality of Life ; Students ; Child Abuse, Sexual ; Young Adult ; Resilience, Psychological

Objective:To investigate the safety and effectiveness of the laparoscopic hepatectomy guided by three-dimensional visualization technology for treating hepatolithiasis in military flying personnel and to discuss the aeromedical assessment.Methods:The diagnosis and treatment of a military flying personnel with hepatolithiasis admitted to the Air Force Medical Center in December of 2021 and the conclusions of aeromedical assessment were analyzed. The literature was reviewed in combination with the progress of new technologies.Results:This case, a 40-year-old male helicopter aerial machinist, had been found gallbladder stones for 12 years, hepatolithiasis for 8 years, and intermittent right upper abdominal pain for more than 3 months. Ultrasound and CT examination showed multiple gallbladder stones, intrahepatic bile duct stones in the right posterior lobe of the liver with bile duct dilatation. Under the guidance of three-dimensional visualization technology, laparoscopic liver segment 6 precise resection, cholecystectomy, common bile duct exploration and stone removal, and T-tube drainage were performed. The patient was well recovered and waivered to flight after 6 months of the operation. As of the submission date, he has safely flown for 50 h.Conclusions:Laparoscopic anatomical hepatectomy guided by three-dimensional visualization technology in the military flying personnel with hepatolithiasis shows good safety and effect, and those who recover well after surgery can be waivered to flight.

Objective:To investigate the safety and effectiveness of the laparoscopic hepatectomy guided by three-dimensional visualization technology for treating hepatolithiasis in military flying personnel and to discuss the aeromedical assessment.Methods:The diagnosis and treatment of a military flying personnel with hepatolithiasis admitted to the Air Force Medical Center in December of 2021 and the conclusions of aeromedical assessment were analyzed. The literature was reviewed in combination with the progress of new technologies.Results:This case, a 40-year-old male helicopter aerial machinist, had been found gallbladder stones for 12 years, hepatolithiasis for 8 years, and intermittent right upper abdominal pain for more than 3 months. Ultrasound and CT examination showed multiple gallbladder stones, intrahepatic bile duct stones in the right posterior lobe of the liver with bile duct dilatation. Under the guidance of three-dimensional visualization technology, laparoscopic liver segment 6 precise resection, cholecystectomy, common bile duct exploration and stone removal, and T-tube drainage were performed. The patient was well recovered and waivered to flight after 6 months of the operation. As of the submission date, he has safely flown for 50 h.Conclusions:Laparoscopic anatomical hepatectomy guided by three-dimensional visualization technology in the military flying personnel with hepatolithiasis shows good safety and effect, and those who recover well after surgery can be waivered to flight.

Objective:To develop an evaluation index system for community screening and referral procedure of patients with chronic heart failure.Methods:Experts in fields of medical education, health administration and various clinical specialties were selected from Shanghai through the purpose sampling method. Two rounds of expert consultation with Delphi method were conducted during October 2020 to February 2021, the contents of consultation included the importance and availability of the index system. According to the consultation results, the index system for community screening and referral procedure of patients with chronic heart failure was developed.Results:A total of 16 experts participated in the consultation, among whom 15 held senior or associate senior titles and 14 had worked for 20 years. The recovery rates of valid questionnaires of two rounds expert of consultation were 16/16. The familiarity and judgment coefficient were 0.82 and 0.90 in the first round of expert consultation, and 0.86 and 0.90 in the second round. The expert consultation coordination coefficient of the importance in the community screening and referral procedure were 0.652 and 0.462 for the first consultation; 0.741 and 0.525 for the second consultation. In the final version of the evaluation index system there were 7 first-level indicators, 15 secondary indicators and 3 conditions for screening; and 2 first-level indicators, 5 secondary indicators and 1 condition for referral.Conclusion:In this study the positivity coefficient and authority degree of experts are high; the opinions are relatively concentrated. The consultation results have a high rationality and feasibility, which would be applicable for assessment of community screening and referral procedure of patients with chronic heart failure.

Objective: Systematically summarize the research progress of clinical trials of gastric cancer oncology drugs and the overview of marketed drugs in China from 2012 to 2021, providing data and decision-making evidence for relevant departments. Methods: Based on the registration database of the drug clinical trial registration and information disclosure platform of Food and Drug Administration of China and the data query system of domestic and imported drugs, the information on gastric cancer drug clinical trials, investigational drugs and marketed drugs from January 1, 2012 to December 31, 2021 was analyzed, and the differences between Chinese and foreign enterprises in terms of trial scope, trial phase, treatment lines and drug type, effect and mechanism studies were compared. Results: A total of 114 drug clinical trials related to gastric tumor were registered in China from 2012 to 2021, accounting for 3.7% (114/3 041) of all anticancer drug clinical trials in the same period, the registration number showed a significant growth rate after 2016 and reached its peak with 32 trials in 2020. Among them, 85 (74.6%, 85/114) trials were initiated by Chinese pharmaceutical enterprise. Compared with foreign pharmaceutical enterprise, Chinese pharmaceutical enterprise had higher rates of phase I trials (35.3% vs 6.9%, P=0.001), but the rate of international multicenter trials (11.9% vs 67.9%, P<0.001) was relatively low. There were 76 different drugs involved in relevant clinical trials, of which 65 (85.5%) were targeted drugs. For targeted drugs, HER2 is the most common one (14 types), followed by PD-1 and multi-target VEGER. In the past ten years, 3 of 4 marketed drugs for gastric cancer treatment were domestic and included in the national medical insurance directory. Conclusions: From 2012 to 2021, China has made some progress in drug research and development for gastric carcinoma. However, compared with the serious disease burden, it is still insufficient. Targeted strengthening of research and development of investment in many aspects of gastric cancer drugs, such as new target discovery, matured target excavating, combination drug development and early line therapy promotion, is the key work in the future, especially for domestic companies.
China ; Gastrointestinal Agents/therapeutic use* ; Gastrointestinal Neoplasms ; Humans ; Pharmaceutical Preparations ; United States ; United States Food and Drug Administration