Objectives:To explore whether short-course radiotherapy (SCRT)-based total neoadjuvant therapy (TNT) combined with PD-1 inhibitors could further promote tumor regression and improve the prognosis.Methods:This is a prospective, multicenter, two-arm randomized controlled, seamless phase Ⅱ/Ⅲ trial for proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). Eligible patients were randomly assigned to the iTNT (TNT+PD-1) group or the TNT group. Patients in the TNT group received SCRT (5 Gy×5) followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX chemotherapy, with the iTNT group receiving SCRT followed by the same regime in combination with 4 cycles of Sintilimab. Total mesorectal excision (TME) surgery or watch and wait (W&W) was performed after neoadjuvant therapy and then 2 cycles of same regimen as before were recommended. The primary endpoints are the complete response (CR) rate for phase Ⅱ trial and 3-year disease-free survival (DFS) for phase Ⅲ trial. A total of 588 patients will be enrolled for the phase Ⅱ/Ⅲ trial. Short-term efficacy and safety data from the initial 100 treated patients were analyzed as planned.Results:From 2022-8-31 to 2023-5-24 the initial 100 patients were enrolled from 10 hospitals in China, 76.0%(76/100) patients were male, and the median age was 61 years (21-74 years). More patients had tumors located in the lower rectum (78.0%, 78/100), staged T3-4 (97.0%, 97/100) and N1-2 (93.0%, 93/100), and about half of the tumors invaded the mesorectal fascia (52.0%, 52/100) and with extramural vascular invasion (51.0%, 51/100). Analyses were performed according to the per-protocal (PP) set. All patients in the iTNT group ( n=52) and the TNT group ( n=48) completed SCRT; The 4-cycle chemotherapy±Sintilimab completion rates were 86.5% and 100.0% in the iTNT and TNT groups, respectively. In the iTNT group, 82.7% (43/52), 11.5% (6/52), and 5.8% (3/52) of the patients received 4, 3, and 2 cycles of PD-1 inhibitor. After TNT, 68 patients underwent radical surgery and 15 patients achieved cCR and adopted W&W. The pathological complete response (pCR) rates were 48.5% (16/33) and 17.1% (6/35) in the iTNT and TNT groups, with CR rates of 50.0% (25/50) and 26.1% (12/46), respectively. The incidence of treatment-related grade 3-4 adverse events was 26.9% (14/52, iTNT group) and 18.8% (9/48, TNT group), with thrombocytopenia and leukopenia being the most common. Among patients receiving immunotherapy, grade 3 immunotherapy-related adverse events occurred in 2 (3.8%, 2/52) patients: one case was pancreatitis, another case was hepatitis combined with myositis and myocarditis. Conclusion:The preliminary results show that SCRT-based TNT combined with PD-1 inhibitors could further improve the CR rate for LARC without unexpected serious adverse events.

BACKGROUND:Lijin manipulation can promote skeletal muscle repair and treat skeletal muscle injury.However,the formation of fibrosis and scar tissue hyperplasia are closely related to the quality of skeletal muscle repair.To study the regulatory effect of Lijin manipulation on the formation of fibrosis and scar tissue hyperplasia is helpful to explain the related mechanism of Lijin manipulation to improve the repair quality of skeletal muscle injury. OBJECTIVE:To explore the mechanism of Lijin manipulation to improve the repair quality of skeletal muscle injury in rabbits,thereby providing a scientific basis for clinical treatment. METHODS:Forty-five healthy adult Japanese large-ear white rabbits were randomly divided into blank group,model group and Lijin group,with 15 rats in each group.Gastrocnemius strike modeling was performed in both model group and Lijin group.The Lijin group began to intervene with tendon manipulation on the 3rd day after modeling,once a day,and 15 minutes at a time.Five animals in each group were killed on the 7th,14th and 21st days after modeling.The morphology and inflammatory cell count of gastrocnemius were observed by hematoxylin-eosin staining,the collagen fiber amount was observed by Masson staining,the expression of interleukin-6 and interleukin-10 in gastrocnemius was detected by ELISA.The protein and mRNA expressions of paired cassette gene 7,myogenic differentiation factor,myoblastogenin,alpha-actin,transforming growth factor beta 1,and type Ⅰ collagen were detected by western blot and RT-PCR,respectively,and the expression of type Ⅰ collagen protein was detected by immunohistochemistry. RESULTS AND CONCLUSION:Hematoxylin-eosin staining and Masson staining showed that compared with the model group,inflammatory cell infiltration and collagen fiber content decreased in the Lijin group(P<0.01),and the muscle fibers gradually healed.ELISA results showed that compared with the model group,the expression of interleukin-6 in the Lijin group continued to decrease(P<0.05),and the expression of interleukin-10 increased on the 7th day after modeling(P<0.05)and then showed a decreasing trend(P<0.05).Western blot and RT-PCR results showed that compared with the model group,the protein and mRNA expressions of paired cassette gene 7,myogenic differentiation factor,myoblastogenin in the Lijin group were significantly increased on the 14th day after modeling(P<0.05),but decreased on the 21st day(P<0.05);the protein and mRNA expressions of alpha-actin,transforming growth factor beta 1,and type Ⅰ collagen in the Lijin group were significantly decreased compared with those in the model group(P<0.05).Immunohistochemical results showed that the expression of type Ⅰ collagen in the Lijin group was significantly lower than that in the model group(P<0.05).To conclude,Lijin manipulation could improve the repair quality of skeletal muscle injury by inhibiting inflammation,promoting the proliferation and differentiation of muscle satellite cells,and reducing fibrosis.

Objective To investigate the influencing factors for stroke-associated pneumonia(SAP)in acute ischemic stroke(AIS)patients after endovascular treatment(EVT).Methods A retrospective case-control trial was conducted on 426 AIS patients with large vessel occlusion(LVO)in anterior circulation admitted in the neurological departments from First Affiliated Hospital of Army Medical University and Zigong Third People's Hospital during January 2017 and April 2021.Based on SAP occurrence or not,they were divided into an SAP group and a non-SAP group.Demographic information(gender and age),TOAST stroke subtypes(large artery atherosclerosis type,cardiac embolism type,others),vascular risk factors(hypertension,hyperlipidemia,diabetes,atrial fibrillation,smoking,prior stroke history,smoking),and post-onset clinical data[dysphagia,LDL cholesterol,white blood cells,neutrophils,baseline and postoperative NIHSS scores,endovascular outcomes(mTICI grade 2b or 3),90-day good prognosis(mRS 0-1)]were collected and compared between the 2 groups.Multivariate logistic regression analysis was performed using the parameters with P<0.1 in univariate analysis as independent variables to investigate factors influencing SAP occurrence after EVT in AIS patients.Results Among the 426 participants,SAP occurred in 194 cases(45.5%).Multivariate logistic regression analysis revealed that admission white blood cell count(OR=1.125,95%CI:1.043～1.213,P=0.000 2),postoperative NIHSS score(OR=1.019,95%CI:1.001～1.037,P=0.041),and male(OR=1.687,95%CI:1.078～2.638,P=0.022)were associated with SAP occurrence after EVT in AIS patients.Conclusion Higher admission white blood cell count,elevated postoperative NIHSS score,and male gender are risk factors for SAP in AIS patients after EVT.These risk factors should be focused on clinical practice to control SAP incidence.

Abstract Ferroptosis , a novel , non-apoptotic form of cell death discovered in 2012 , has garnered significant at- tention. It is implicated in the pathogenesis and progression of various intestinal diseases , including colorectal canc- er, intestinal ischemia-reperfusion injury , functional gastrointestinal disorders , and inflammatory bowel disease. These processes involve multiple pathological mechanisms such as inflammation , immune dysregulation , and intesti- nal epithelial dysfunction. By reviewing and summarizing recent literature on ferroptosis-related mechanisms in in- testinal diseases , this article explores the roles and effects of ferroptosis in different intestinal pathologies.

Objective:To evaluate the effects of sequential immunotherapy with radiotherapy on survival time and immune function in patients with unresectable stage III non-small cell lung cancer (NSCLC) in a real-world study.Methods:Data of 84 patients with unresectable stage III NSCLC who were treated at the Affiliated Hospital of Inner Mongolia Medical University from January 2021 to December 2022 (retrospective cohort) and from January 2023 to December 2023 (prospective cohort) were collected. The patients were divided into the combination group ( n=40) and radiotherapy group ( n=44) based on whether they received sequential immunotherapy or not. The progression-free survival (PFS) and overall survival (OS) between two groups were compared using standardized mortality ratio weighting (SMRW). Univariate Cox proportional hazards model, multivariate regression analysis, multi-model comparison of propensity score matching and subgroup analysis were emploed to analyze the robustness of clinical efficacy between two groups. E-value analysis was used to analyze the sensitivity of unmeasured confounding factors in observational studies. Additionally, the percentage of CD4 +T cells, CD8 +T cells and natural killer (NK) cells, and CD4 +/CD8 + T cell ratio before and after treatment between two groups were compared using analysis of covariance. Results:Among 84 patients, 77 (92%) cases were male and 7 (8%) were female. Among them, 42 (50%) were aged 65 years or older. The variables showed high homogeneity after SMRW, with a standardized mean difference of less than 0.1. In the combination group, the median PFS [17.0 months vs. 7.0 months, HR=0.260, 95% CI: 0.130-0.490, P<0.001] and OS [not reached vs. 24.0 months, HR=0.210, 95% CI: 0.070-0.590, P=0.002] were significantly longer compared to that in the radiotherapy group, with statistically significant differences. The study results were confirmed by robustness and sensitivity analyses. After treatment, patients in the combination group showed a statistically significant increase in the percentage of CD4 + T cells and NK cells, and CD4 +/CD8 + T cell ratio, as well as a decrease in the percentage of CD8 + T cells compared to those in the radiotherapy group (all P<0.05). Conclusions:Sequential immunotherapy following radiotherapy can significantly improve survival and prognosis of unresectable stage III NSCLC patients. The survival benefit is even greater when combined with chemotherapy. The main mechanism of the survival benefit may be the improvement of anti-tumor immune function.

BACKGROUND:Lijin manipulation can reduce fibrosis scar hyperplasia and promote skeletal muscle repair.However,improper activation of the Wnt/β-catenin signaling pathway can aggravate the fibrosis of injured skeletal muscle and adversely affect the repair process of skeletal muscle.To study the regulatory effect of Lijin manipulation on the Wnt/β-catenin signaling pathway is conducive to elucidate the related mechanisms of Lijin manipulation in reducing fibrosis scar hyperplasia and promoting skeletal muscle injury repair.OBJECTIVE:To explore the mechanism of Lijin manipulation in promoting the repair of skeletal muscle injury in rabbits.METHODS:Forty-five healthy adult Japanese white rabbits were randomly divided into blank group,model group and Lijin group with 15 rabbits in each group.Gastrocnemius muscle percussion modeling was performed in both model group and Lijin group.Lijin manipulation was performed in the Lijin group on the 3rd day after modeling,once a day,15 minutes once.Five animals in each group were selected and killed on the 7th,14th and 21st days after modeling.The general morphological structure of gastrocnemius was observed by hematoxylin-eosin staining and the content of collagen fiber was observed by Masson staining.Western blot was used to detect the protein expression of Wnt3a,β-catenin,GSK3β,p-GSK3β,TCF,type I collagen and type III collagen in gastrocnemius muscle,and RT-PCR was used to detect the mRNA expression of Wnt3a,β-catenin and TCF.The expression of β-catenin was detected by immunofluorescence,and the expression of type I collagen and type III collagen was detected by immunohistochemistry.RESULTS AND CONCLUSION:The results of hematoxylin-eosin staining and Masson staining showed that compared with the model group,inflammatory cell infiltration and collagen fiber amount decreased in the Lijin group(P<0.001),and muscle fibers gradually healed.Western blot results showed that compared with the model group,the protein expression levels of Wnt3a,β-catenin,TCF,type I collagen and type III collagen were significantly decreased in the Lijin group at all observation time points(P<0.05),while the ratio of P-GSK3β/GSK3β was significantly increased in the Lijin group at all observation time points compared with the model group(P<0.05).RT-PCR results showed that compared with the model group,the mRNA expression levels of Wnt3a,β-catenin and TCF were significantly decreased in the Lijin group at all observation time points(P<0.001).Immunofluorescence results showed that compared with the model group,the fluorescence intensity of β-catenin expression in the Lijin group was significantly decreased at each observation time point and gradually became similar to that in the blank group(P<0.001).Immunohistochemical results showed that the expression levels of type I collagen and type III collagen in the Lijin group were significantly lower than those in the model group(P<0.01).To conclude,Lijin manipulation could inhibit the abnormal activation of the Wnt/β-catenin signaling pathway,reduce fibrotic scar hyperplasia,and promote the repair of injured skeletal muscle.

BACKGROUND:Excessive apoptosis in skeletal muscle cells will destroy the dynamic balance of the number of myocytes,leading to pathological injury of skeletal muscle.Lijin manipulation is effective in treating skeletal muscle injury,but whether it can inhibit apoptosis and promote the repair of skeletal muscle injury is unknown.OBJECTIVE:To explore the mechanism by which Lijin manipulation reduces inflammation and apoptosis during the repair of skeletal muscle injury in rabbits.METHODS:Forty-five healthy adult Japanese white rabbits were randomly divided into blank group,model group and Lijin group(n=15 per group).No intervention was performed in the blank group.Gastrocnemius muscle percussion molding was performed in both the model group and Lijin group.After modeling,the model group was not treated,while the Lijin manipulation(Stroking,kneading,and rubbing)was performed in the Lijin group on the 3rd day,once a day,15 min/time.Sampling in each group was performed on the 7th,14th and 21st days after modeling.The general morphological structure of gastrocnemius was observed by hematoxylin-eosin staining.The ultrastructure of gastrocnemius muscle was observed by transmission electron microscopy.Apoptosis of gastrocnemius cells was observed by TUNEL staining.The expressions of interleukin-1β,interleukin-6 and interleukin-10 in gastrocnemius muscle were detected by ELISA.The protein expressions of BAX,BCL-2 and Caspase3 in gastrocnemius muscle were detected by western blot.The mRNA expression of BAX and BCL-2 was detected by RT-PCR.RESULTS AND CONCLUSION:(1)Hematoxylin-eosin staining results showed that compared with the model group,inflammatory cells decreased in number,myocyte amount increased,and muscle tissue gradually healed in the Lijin group at each observation point.(2)The results of transmission electron microscopy showed that compared with the model group,the arrangement of muscle fibers at each observation point in the Lijin group was gradually orderly,mitochondria were gradually complete,Z-line arrangement was gradually regular,and free ribosomes were gathered.(3)TUNEL staining results showed that compared with the model group,apoptosis rate in the Lijin group was gradually decreased at all observation points(P<0.05).(4)ELISA results showed that compared with the model group,the expression of interleukin-1β and interleukin-6 in the Lijin group continued to decrease(P<0.05),while the expression of interleukin-10 increased on the 7th day after modeling,and then showed a downward trend(P<0.05).(5)Western blot results showed that compared with the model group,the expression of BCL-2 protein/BAX protein in the Lijin group was significantly increased at each observational point(P<0.05).The protein expression of Caspase3 decreased significantly(P<0.001),and was gradually similar to that of the blank group.(6)RT-PCR results showed that compared with the model group,the mRNA expression level of BCL-2/BAX in the Lijin group was significantly higher at each observational point(P<0.05).To conclude,Lijin manipulation can inhibit inflammation,reduce apoptosis,and promote the repair of injured skeletal muscle.

Objective:To explore the diagnostic value of serum soluble semaphorin 4D (sSema4D) and soluble CD40 ligand (sCD40L) in left ventricular hypertrophy (LVH) in patients with primary hypertension (EH).Methods:Eighty-four patients with EH combined with LVH admitted to Qingdao Hospital of Shandong First Medical University from December 2022 to December 2023 were prospectively selected as the study group, and 84 patients with EH and without LVH admitted to Qingdao Hospital of Shandong First Medical University during the same period were regarded as the control group. Enzyme linked immunosorbent assay was applied to detect the levels of sSema4D and sCD40L. Employing Pearson correlation coefficient, the study assessed the association between concentrations of sSema4D and sCD40L in serum and various echocardiographic measurements. A multivariate Logistic regression model was engaged to probe into the contributing factors for the development of LVH. ROC curve was plotted to analyze the diagnostic value of serum sSema4D and sCD40L for EH combined with LVH.Results:Serum sSema4D and sCD40L levels were significantly higher in the study group than in the control group: (8.56 ± 2.19) μg/L vs. (5.12 ± 1.43) μg/L, (4.02 ± 1.03) μg/L vs. (3.22 ± 0.98) μg/L, and the differences were statistically significant ( P<0.05). The duration of hypertension, LVEDD, IVSTD, LVPWT, and LVMI were significantly higher in the study group than in the control group: (7.33 ± 1.53) years vs. (4.26 ± 1.35) years, (50.28 ± 3.33) mm vs. (44.45 ± 3.76) mm, (11.64 ± 3.21) mm vs. (9.53 ± 2.89) mm, (12.45 ± 1.52) mm vs. (9.13 ± 0.98) mm, (126.11 ± 15.28) g/m 2 vs. (81.15 ± 11.31) g/m 2, and the differences were statistically significant ( P<0.05). According to Pearson correlation analysis, it was known that both serum sSema4D and sCD40L were positively correlated with LVEDD, IVSTD, LVPWT and LVMI ( r = 0.425 and 0.533, 0.612 and 0.436, 0.513 and 0.628, 0.589 and 0.618; P<0.05). Multivariate Logistic regression analysis showed that hypertension duration, LVEDD, IVSTD, LVPWT, LVMI, sSema4D, sCD40L were risk factors for LVH in EH patients ( P<0.05). According to the ROC curve, the AUC for diagnosing EH combined with LVH with serum sSema4D was 0.848, the AUC for diagnosing EH combined with LVH with serum sCD40L was 0.725, and the AUC for diagnosing EH combined with LVH with serum sCD40L was 0.888, the combination of sCD40L and sCD40L was superior to their respective individual diagnoses ( Z = 2.651 and 2.526, P<0.05). Conclusions:The serum levels of sSema4D and sCD40L in patients with EH combined with LVH are obviously elevated, which are influencing factors for the occurrence of EH combined with LVH. Combined testing of the two has high diagnostic value for EH combined with LVH.

Objectives:To explore whether short-course radiotherapy (SCRT)-based total neoadjuvant therapy (TNT) combined with PD-1 inhibitors could further promote tumor regression and improve the prognosis.Methods:This is a prospective, multicenter, two-arm randomized controlled, seamless phase Ⅱ/Ⅲ trial for proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). Eligible patients were randomly assigned to the iTNT (TNT+PD-1) group or the TNT group. Patients in the TNT group received SCRT (5 Gy×5) followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX chemotherapy, with the iTNT group receiving SCRT followed by the same regime in combination with 4 cycles of Sintilimab. Total mesorectal excision (TME) surgery or watch and wait (W&W) was performed after neoadjuvant therapy and then 2 cycles of same regimen as before were recommended. The primary endpoints are the complete response (CR) rate for phase Ⅱ trial and 3-year disease-free survival (DFS) for phase Ⅲ trial. A total of 588 patients will be enrolled for the phase Ⅱ/Ⅲ trial. Short-term efficacy and safety data from the initial 100 treated patients were analyzed as planned.Results:From 2022-8-31 to 2023-5-24 the initial 100 patients were enrolled from 10 hospitals in China, 76.0%(76/100) patients were male, and the median age was 61 years (21-74 years). More patients had tumors located in the lower rectum (78.0%, 78/100), staged T3-4 (97.0%, 97/100) and N1-2 (93.0%, 93/100), and about half of the tumors invaded the mesorectal fascia (52.0%, 52/100) and with extramural vascular invasion (51.0%, 51/100). Analyses were performed according to the per-protocal (PP) set. All patients in the iTNT group ( n=52) and the TNT group ( n=48) completed SCRT; The 4-cycle chemotherapy±Sintilimab completion rates were 86.5% and 100.0% in the iTNT and TNT groups, respectively. In the iTNT group, 82.7% (43/52), 11.5% (6/52), and 5.8% (3/52) of the patients received 4, 3, and 2 cycles of PD-1 inhibitor. After TNT, 68 patients underwent radical surgery and 15 patients achieved cCR and adopted W&W. The pathological complete response (pCR) rates were 48.5% (16/33) and 17.1% (6/35) in the iTNT and TNT groups, with CR rates of 50.0% (25/50) and 26.1% (12/46), respectively. The incidence of treatment-related grade 3-4 adverse events was 26.9% (14/52, iTNT group) and 18.8% (9/48, TNT group), with thrombocytopenia and leukopenia being the most common. Among patients receiving immunotherapy, grade 3 immunotherapy-related adverse events occurred in 2 (3.8%, 2/52) patients: one case was pancreatitis, another case was hepatitis combined with myositis and myocarditis. Conclusion:The preliminary results show that SCRT-based TNT combined with PD-1 inhibitors could further improve the CR rate for LARC without unexpected serious adverse events.

Objective:To explore the diagnostic value of serum soluble semaphorin 4D (sSema4D) and soluble CD40 ligand (sCD40L) in left ventricular hypertrophy (LVH) in patients with primary hypertension (EH).Methods:Eighty-four patients with EH combined with LVH admitted to Qingdao Hospital of Shandong First Medical University from December 2022 to December 2023 were prospectively selected as the study group, and 84 patients with EH and without LVH admitted to Qingdao Hospital of Shandong First Medical University during the same period were regarded as the control group. Enzyme linked immunosorbent assay was applied to detect the levels of sSema4D and sCD40L. Employing Pearson correlation coefficient, the study assessed the association between concentrations of sSema4D and sCD40L in serum and various echocardiographic measurements. A multivariate Logistic regression model was engaged to probe into the contributing factors for the development of LVH. ROC curve was plotted to analyze the diagnostic value of serum sSema4D and sCD40L for EH combined with LVH.Results:Serum sSema4D and sCD40L levels were significantly higher in the study group than in the control group: (8.56 ± 2.19) μg/L vs. (5.12 ± 1.43) μg/L, (4.02 ± 1.03) μg/L vs. (3.22 ± 0.98) μg/L, and the differences were statistically significant ( P<0.05). The duration of hypertension, LVEDD, IVSTD, LVPWT, and LVMI were significantly higher in the study group than in the control group: (7.33 ± 1.53) years vs. (4.26 ± 1.35) years, (50.28 ± 3.33) mm vs. (44.45 ± 3.76) mm, (11.64 ± 3.21) mm vs. (9.53 ± 2.89) mm, (12.45 ± 1.52) mm vs. (9.13 ± 0.98) mm, (126.11 ± 15.28) g/m 2 vs. (81.15 ± 11.31) g/m 2, and the differences were statistically significant ( P<0.05). According to Pearson correlation analysis, it was known that both serum sSema4D and sCD40L were positively correlated with LVEDD, IVSTD, LVPWT and LVMI ( r = 0.425 and 0.533, 0.612 and 0.436, 0.513 and 0.628, 0.589 and 0.618; P<0.05). Multivariate Logistic regression analysis showed that hypertension duration, LVEDD, IVSTD, LVPWT, LVMI, sSema4D, sCD40L were risk factors for LVH in EH patients ( P<0.05). According to the ROC curve, the AUC for diagnosing EH combined with LVH with serum sSema4D was 0.848, the AUC for diagnosing EH combined with LVH with serum sCD40L was 0.725, and the AUC for diagnosing EH combined with LVH with serum sCD40L was 0.888, the combination of sCD40L and sCD40L was superior to their respective individual diagnoses ( Z = 2.651 and 2.526, P<0.05). Conclusions:The serum levels of sSema4D and sCD40L in patients with EH combined with LVH are obviously elevated, which are influencing factors for the occurrence of EH combined with LVH. Combined testing of the two has high diagnostic value for EH combined with LVH.