ObjectiveTo investigate the associations of multiple glycolipid metabolic indicators and their cumulative abnormality burden with incident colorectal cancer risk in a general population-based prospective cohort, and to examine the mediating role of glycolipid metabolic abnormalities in the relationships between smoking, alcohol consumption, physical activity, and colorectal cancer incidence. MethodsA total of 17 897 eligible participants recruited from the Taizhou Cohort between 2011 and 2014 were included. Cox proportional hazards regression models were used to assess the associations of conventional and derived glycolipid indicators, as well as a glycolipid abnormality index constructed from total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and insulin, with incident colorectal cancer risk. Restricted cubic spline models were applied to evaluate dose-response relationships for major indicators. Receiver operating characteristic curves were generated to compare predictive performance across indicators. Mediation analyses were conducted to assess the mediating effects of the glycolipid abnormality index on the associations of smoking, alcohol consumption, and physical activity with colorectal cancer incidence. ResultsDuring a median follow-up of 11.2 years, 102 incident colorectal cancer cases were identified, with an incidence density of 51.2 per 100 000 person-years. After adjustment for potential confounders, Cox proportional hazards regression analyses showed that decreased high-density lipoprotein cholesterol was associated with a 1.74-fold higher risk of colorectal cancer (HR=1.74, 95%CI: 1.03‒2.95), elevated low-density lipoprotein cholesterol was associated with a 1.78-fold higher risk (HR=1.78, 95%CI: 1.05‒3.02), and abnormal fasting plasma glucose was associated with a 1.86-fold higher risk (HR=1.86, 95%CI: 1.15‒3.02). Triglycerides and fasting plasma glucose showed an approximately linear increasing association with colorectal cancer risk in multivariable restricted cubic spline models. The glycolipid abnormality index showed a clear gradient association with colorectal cancer risk; participants with three or more abnormal indicators had a 3.08-fold higher risk than those without abnormalities (HR=3.08, 95%CI: 1.60‒5.92). The area under the curve was 0.795, higher than that of individual glycolipid indicators and other combined indices, and gender-stratified analyses showed generally consistent patterns. Glycolipid metabolic abnormalities partially mediated the associations of smoking, alcohol consumption, and physical activity with colorectal cancer incidence, with mediation proportions of 8.33%, 9.45%, and 9.04%, respectively. ConclusionGlycolipid metabolic abnormalities are associated with an increased risk of incident colorectal cancer. The glycolipid abnormality index shows an increasing relationship with colorectal cancer risk and demonstrates better discrimination, and it partially mediates the associations of smoking, alcohol consumption, and physical activity with colorectal cancer incidence in the overall population.

Anchored in the realities of contemporary medical education,this study dissects the persistent bottlenecks that impede the seamless embedding of Red Medical Culture-China's revolutionary medical ethos underpinned by humanitarian com-mitment and public-health dedication-into medical students' ideological-and-political education(IPE).Key impediments include shallow integration,misalignment with modern pedagogical paradigms,paucity of tailored resources,and a dearth of qualified fac-ulty.To counter these constraints,we articulate a multi-pronged praxis that simultaneously preserves and reinvigorates Red Medi-cal Culture.Pilot programs indicated that systematic incorporation of this heritage cultivated socially accountable professionals who internalized historical mission,upheld ethical standards,and embraced humanistic patient-centered care,while concurrently sharpening critical innovation and consolidating comprehensive professional competence.

Objective To discuss the preliminary application of CRISPR-Cas9 gene editing technology in repair of antithrombin gene(SERPINC1)c.318_319insT mutation.Methods The single guide RNA(sgRNA)was designed by CRISPR online design website,and AT c.318_319 insT mutant and CRISPR-Cas9 repairsome were constructed.The gene fragments from the wild-type gene,AT c.318_319 insT mutant and CRISPR-Cas9 repairsome were transferred into lentiviral expression vectors,and then PCR sequencing was performed for verification.The successfully constructed lentiviral recombinant plasmids were transfected into the human embryonic kid-ney cells(HEK293T).After cell culture,HEK293T cells were lysed.The AT:Ag levels in the cell lysing reagents from wild-type gene,CRISPR-Cas9 repairsome and mutant were compared by ELISA and Western blot,respectively.The recombinant AT protein was characterized in vitro by cellular immunofluorescence assay.Results Both the AT c.318_319insT mutant and CRISPR-Cas9 repair-some were successfully constructed.The results of experiments with HEK293T cells in vitro showed that the wild-type AT:Ag in the cell lysing reagents was set as 100％,the AT:Ag of CRISPR-Cas9 repairsome was 47％,and the AT:Ag of AT c.318_319insT was 22％,which were consistent with the results of western blot and cellular immunofluorescence assay.Conclusion The cellular experiments in vitro verified that CRISPR-Cas9 gene editing technology could effectively repair the SERPINC1 c.318_319 insT mutation in situ,which might provide the experimental support for the application of CRISPR-Cas9 gene editing technology in the gene therapy of hereditary thrombotic diseases.

Objective To discuss the preliminary application of CRISPR-Cas9 gene editing technology in repair of antithrombin gene(SERPINC1)c.318_319insT mutation.Methods The single guide RNA(sgRNA)was designed by CRISPR online design website,and AT c.318_319 insT mutant and CRISPR-Cas9 repairsome were constructed.The gene fragments from the wild-type gene,AT c.318_319 insT mutant and CRISPR-Cas9 repairsome were transferred into lentiviral expression vectors,and then PCR sequencing was performed for verification.The successfully constructed lentiviral recombinant plasmids were transfected into the human embryonic kid-ney cells(HEK293T).After cell culture,HEK293T cells were lysed.The AT:Ag levels in the cell lysing reagents from wild-type gene,CRISPR-Cas9 repairsome and mutant were compared by ELISA and Western blot,respectively.The recombinant AT protein was characterized in vitro by cellular immunofluorescence assay.Results Both the AT c.318_319insT mutant and CRISPR-Cas9 repair-some were successfully constructed.The results of experiments with HEK293T cells in vitro showed that the wild-type AT:Ag in the cell lysing reagents was set as 100％,the AT:Ag of CRISPR-Cas9 repairsome was 47％,and the AT:Ag of AT c.318_319insT was 22％,which were consistent with the results of western blot and cellular immunofluorescence assay.Conclusion The cellular experiments in vitro verified that CRISPR-Cas9 gene editing technology could effectively repair the SERPINC1 c.318_319 insT mutation in situ,which might provide the experimental support for the application of CRISPR-Cas9 gene editing technology in the gene therapy of hereditary thrombotic diseases.

Objective To explore the biological mechanism of radiation resistance in esophageal squamous cell carcinoma(ESCC)and search for effective sensitization targets.Methods We retrieved 186 signaling pathways and related gene information from the MSigDB database.We also obtained RNA transcriptome data of ESCC patients using the Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.We collected clinical pathological characteristics and tissue samples of 97 ESCC patients in our hospital from 2013 to 2020.Gene set variation analysis(GSVA)was made to calculate KEGG signaling pathway score,radiotherapy resistance related signaling pathways were screened through random forest algorithm,key genes in the pathway were screened using DESeq2,and a radiotherapy efficacy prediction model was constructed based on support vector machine-recursive feature elimination(SVM-RFE).The results were validated through experiments such as Western blotting and clonogenic assay.Results Based on the KEGG signaling pathway and GSVA enrichment score,random forest analysis showed that in the TCGA and GSE45670 cohorts,the contribution of tryptophan metabolism pathway enrichment values to radiation resistance in ESCC was significantly better than that of the other pathways.DESeq2 analysis revealed that key molecules in the tryptophan metabolism pathway,namely,IDO1,ALDH1B1,AOC1,INMT,AFMID and ALDH7A1,were significantly differentially expressed in the resistant and sensitive groups of ESCC.Based on the SVM-RFE algorithm,the AUC was 0.77,which could accurately predict the radiotherapy efficacy of ESCC.Western blotting experiments showed that IDO1 was highly expressed in ESCC cells,and IDO1 inhibitor treatment significantly inhibited the survival ability and radiosensitivity of KYSE-410 cells.In the enrolled patients of our hospital,immunohistochemical studies showed that IDO1 was highly expressed in the radiotherapy resistant group of ESCC and was associated with poor radiotherapy prognosis in ESCC patients.In addition,further testing showed that the expression of IDO1 in patient samples from our hospital was positively correlated with its PD-L1 expression,but negatively correlated with the infiltration ratio of CD3/CD8 immune cells.Conclusion Tryptophan catabolism is associated with radiation resistance in ESCC,and the key enzyme IDO1 in tryptophan metabolism can be used as a therapeutic target for radiosensitization in ESCC.

Anchored in the realities of contemporary medical education,this study dissects the persistent bottlenecks that impede the seamless embedding of Red Medical Culture-China's revolutionary medical ethos underpinned by humanitarian com-mitment and public-health dedication-into medical students' ideological-and-political education(IPE).Key impediments include shallow integration,misalignment with modern pedagogical paradigms,paucity of tailored resources,and a dearth of qualified fac-ulty.To counter these constraints,we articulate a multi-pronged praxis that simultaneously preserves and reinvigorates Red Medi-cal Culture.Pilot programs indicated that systematic incorporation of this heritage cultivated socially accountable professionals who internalized historical mission,upheld ethical standards,and embraced humanistic patient-centered care,while concurrently sharpening critical innovation and consolidating comprehensive professional competence.

Objective To explore the efficacy and safety of side-to-side anastomosis(SS)and end-to-side anastomosis(ES)of the ileocolon in laparoscopic right hemicolectomy of colon cancer,so as to provide evidence-based evidence for surgical selection.Methods PubMed,Embase,Web of Science,Cochrane Library,China National Knowledge Infrastructure,Wanfang Data,VIP database,Chinese BioMedical Literature database were searched from inception to November 2024 to collect relevant clinical studies of SS versus ES.The Newcastle-Ottawa Scale(NOS)was used to evaluate the literature quality of retrospective studies,and the Cochrane system was used to evaluate the literature quality of randomized controlled trials(RCT).Rev Man 5.3 software was used for Meta-analysis,sensitivity analysis,and publication bias analysis.Results 9 retrospective studies and 4 RCTs with a total of 2 632 patients were included.The Meta-analysis results of the retrospective study show that:Compared with SS,ES has a shorter tolerance time for liquid diet(MD=-0.20,95%CI:-0.40～0.00,P<0.05),fewer daily episodes of diarrhea(MD=-1.06,95%CI:-1.79～0.23,P<0.05),but a higher pain score at 12 hours post-surgery(MD=0.95,95%CI:0.50～1.40,P<0.05).Comparison of the overall complication rates of the two anastomosis methods showed no statistically significant difference((OR)=1.05,95%CI:0.22～5.14,P>0.05).Sensitivity analysis of the retrospective study shows:the incidence of ES bowel obstruction was higher than that of SS,with a statistically significant difference((OR)=2.18,95%CI:1.15～4.14,P<0.05);The sensitivity analysis of the RCT shows:the overall incidence of complications at the anastomotic site of SS was significantly higher than that of ES,with a statistically significant difference((OR)=5.26,95%CI:1.91～14.48,P<0.05),and the results of other outcome indicators did not show reversal.The analysis of publication bias risk showed no significant publication bias.Conclusion Ileocolonic ES has a slight advantage over SS in laparoscopic right hemicolectomy of colon cancer,both anastomoses are safe and effective,and the surgeon can choose the appropriate anastomosis technique according to the patient's specific situation,in order to improve the postoperative recovery.

Objective To explore the biological mechanism of radiation resistance in esophageal squamous cell carcinoma(ESCC)and search for effective sensitization targets.Methods We retrieved 186 signaling pathways and related gene information from the MSigDB database.We also obtained RNA transcriptome data of ESCC patients using the Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.We collected clinical pathological characteristics and tissue samples of 97 ESCC patients in our hospital from 2013 to 2020.Gene set variation analysis(GSVA)was made to calculate KEGG signaling pathway score,radiotherapy resistance related signaling pathways were screened through random forest algorithm,key genes in the pathway were screened using DESeq2,and a radiotherapy efficacy prediction model was constructed based on support vector machine-recursive feature elimination(SVM-RFE).The results were validated through experiments such as Western blotting and clonogenic assay.Results Based on the KEGG signaling pathway and GSVA enrichment score,random forest analysis showed that in the TCGA and GSE45670 cohorts,the contribution of tryptophan metabolism pathway enrichment values to radiation resistance in ESCC was significantly better than that of the other pathways.DESeq2 analysis revealed that key molecules in the tryptophan metabolism pathway,namely,IDO1,ALDH1B1,AOC1,INMT,AFMID and ALDH7A1,were significantly differentially expressed in the resistant and sensitive groups of ESCC.Based on the SVM-RFE algorithm,the AUC was 0.77,which could accurately predict the radiotherapy efficacy of ESCC.Western blotting experiments showed that IDO1 was highly expressed in ESCC cells,and IDO1 inhibitor treatment significantly inhibited the survival ability and radiosensitivity of KYSE-410 cells.In the enrolled patients of our hospital,immunohistochemical studies showed that IDO1 was highly expressed in the radiotherapy resistant group of ESCC and was associated with poor radiotherapy prognosis in ESCC patients.In addition,further testing showed that the expression of IDO1 in patient samples from our hospital was positively correlated with its PD-L1 expression,but negatively correlated with the infiltration ratio of CD3/CD8 immune cells.Conclusion Tryptophan catabolism is associated with radiation resistance in ESCC,and the key enzyme IDO1 in tryptophan metabolism can be used as a therapeutic target for radiosensitization in ESCC.

Objective:To construct a general deep learning dose prediction model applicable to radiotherapy for head and neck tumors, establish design methods for artificial intelligence (AI)-assisted radiotherapy plan and evaluate the accuracy of prediction.Methods:Radiotherapy plans of 818 patients who received radiotherapy for head and neck cancers from January 2018 to June 2021 in Cancer Hospital of Chinese Academy of Medical Sciences were enrolled. Patients involved 17 types of common head and neck cancers, and the prescribed dose covered 5 kinds of dose gradients ranging from 54 Gy to 73.92 Gy. And 1-2 cases per each cancer type (31 cases in total) were randomly selected as the validation set, and the remaining 787 cases were used as the training set to build a deep learning head and neck radiotherapy generalized dose prediction model. Then based on the dose prediction results of this model, a program was written to automatically generate inverse optimization condition scripts, which were sent back to the treatment planning system to achieve AI-assisted radiotherapy plan design. Among the patients who received radiotherapy in our hospital from June 2021 to January 2022, 1 patient for each disease type (17 cases in total) was selected to evaluate the AI-assisted plan design program and evaluate its clinical feasibility using paired t-test. Results:Dose prediction model accuracy evaluation revealed that in the 31-case validation set, there was no statistical difference in the evaluation metrics of clinical concern for organs at risks, except for the D 1 cm3 prediction for spinal cord planning risk volume, which was statistically different compared with the clinical reference plan. The AI-assisted plan design program had higher plan quality metric scores (37.88±6.42) than manual plans (35.00±7.63) in 17 test cases ( t=-1.00, P=0.166). The number of manual adjustments to the inverse optimization conditions was reduced from (5.47±2.97) times to (2.76±1.00) times for the AI-assisted plan compared to the manual-only plan ( t=4.12, P<0.001). And the number of outlined dose shaping structures was reduced from 7.35±3.98 to 3.12±1.18 ( t=5.61, P<0.001). Conclusions:The unified universal model of dose prediction established for different head and neck cancers has high accuracy in dose prediction for all types of head and neck tumor plans. The AI-assisted planning method established in this pattern can reduce the clinical workload of physicists and improve the efficiency of their work.

Peptide-based radiopharmaceuticals targeting integrin α5β1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target α5β1 demonstrate inadequate in vivo performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an α5β1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for α5β1-overexpressing tumors.