AIM:To explore the relationship be-tween the level of myeloid-derived suppressor cell(MDSC)infiltration in tumor tissues and the clinical efficacy and prognosis of combined PD-1 inhibitor and chemotherapy in the treatment of advanced non-small cell lung cancer(NSCLC).METHODS:A retrospective analysis was conducted on 92 NSCLC patients who received PD-1 inhibitor combined with chemotherapy at the First Affiliated Hospital of Anhui Medical University from June 2019 to June 2024.Tumor tissue samples were examined using immunohistochemistry to detect the level of MDSC infiltration,dividing the patients into high-in-filtration group(MDSC≥2)and low-infiltration group(MDSC＜2).The objective response rate(iORR),disease control rate(iDCR),progression-free survival(PFS),and overall survival(OS)were compared between the two groups.Kaplan-Meier survival analysis and Log-rank test were used to plot PFS and OS survival curves,and Cox regression analysis was applied to identify factors influencing prognosis.RESULTS:Among the 92 patients,53 were in the low MDSC infiltration group,and 39 were in the high MDSC infiltration group.The low MDSC infiltration group showed significantly better treatment responses compared to the high MDSC infiltration group.The objective response rate(iORR)was 77.3％in the low MDSC infiltration group,higher than the 56.4％in the high MDSC in-filtration group(P=0.033).The disease control rate(iDCR)was 94.3％,also significantly higher than the 66.7％in the high MDSC infiltration group(P=0.001).Moreover,the median progression-free sur-vival(PFS)and overall survival(OS)in the low MD-SC infiltration group were 16.9 months and 27.6 months,respectively,which were significantly lon-ger than those in the high MDSC infiltration group(PFS 12.6 months,OS 22.3 months).Kaplan-Meier analysis revealed that both PFS and OS in the low MDSC infiltration group were significantly longer than those in the high MDSC infiltration group.Cox univariate analysis showed that smoking,PD-L1 ex-pression levels,tumor stage,and MDSC infiltration level were closely associated with PFS and OS.Mul-tivariate Cox regression analysis further indicated that high MDSC infiltration was an independent risk factor for both PFS(HR=2.678,P=0.013)and OS(HR=2.254,P=0.022).CONCLUSION:The level of MDSC infiltration in tumor tissues is closely related to the efficacy and prognosis of PD-1 inhibitor com-bined with chemotherapy in NSCLC patients.High MDSC infiltration suggests reduced treatment sen-sitivity and poor prognosis.MDSC infiltration level may serve as a predictive biomarker for the effica-cy and prognosis of PD-1 inhibitor combined with chemotherapy in advanced NSCLC.

Objective:To explore the impacts of carnosic acid(CA)on learning and cognitive function in epileptic rats and the mechanism of regulating PKA-CREB signaling pathway in this process.Methods:Epilepsy rat models were prepared by intraperi-toneal injection of 50 mg/kg PTZ.After successful modeling,the rats were randomly grouped into control group,model group,CA low-dose group,CA high-dose group,CA high+PKA inhibitor group(CA high+H-89 group),with 15 rats in each group.The epileptic be-havior of rats in each group was evaluated;Morris water maze experiment was applied to test the cognitive ability of rats;HE staining and Nissl staining were applied to detect the morphology of hippocampal tissue and neurons of rats in each group;ELISA was applied to detect the contents of IL-1β,TNF-α,MDA,and the SOD activity in the hippocampus of rats in each group;and Western blot was applied to detect the protein expressions of PKA,p-PKA,CREB,p-CREB and BDNF in the hippocampus of rats in each group.Results:Compared with control group,the hippocampal neurons of rats in model group were irregularly arranged,with pyknosis of the nuclei,and the number of neurons decreased,the epilepsy frequency,Racine grading,escape latency,time of first platform crossing,and levels of IL-1β,TNF-α and MDA all increased,the frequency of crossing the platform,SOD activity,p-PKA/PKA,p-CREB/CREB,and the expression of BDNF protein all reduced(P<0.05);compared with model group,the arrangement of neuronal cells in hippocampal tissue of rats in CA group gradually became orderly,nuclear pyknosis gradually decreased,and the number of neurons increased,the epilepsy frequency,Racine grading,escape latency,time of first platform crossing,and levels of IL-1β,TNF-α and MDA all reduced,the frequency of crossing the platform,SOD activity,p-PKA/PKA,p-CREB/CREB,and the expression of BDNF protein all increased(P<0.05);further injection of PKA inhibitors on the basis of high-dose CA treatment showed that the improvement effects of high-dose CA on cognitive dysfunction,neuronal damage,inflammation,and oxidative stress in epileptic rats were reversed(P<0.05).Conclusion:CA can improve the learning and cognitive function of epileptic rats by activating the PKA-CREB signaling pathway.

AIM:To explore the relationship be-tween the level of myeloid-derived suppressor cell(MDSC)infiltration in tumor tissues and the clinical efficacy and prognosis of combined PD-1 inhibitor and chemotherapy in the treatment of advanced non-small cell lung cancer(NSCLC).METHODS:A retrospective analysis was conducted on 92 NSCLC patients who received PD-1 inhibitor combined with chemotherapy at the First Affiliated Hospital of Anhui Medical University from June 2019 to June 2024.Tumor tissue samples were examined using immunohistochemistry to detect the level of MDSC infiltration,dividing the patients into high-in-filtration group(MDSC≥2)and low-infiltration group(MDSC＜2).The objective response rate(iORR),disease control rate(iDCR),progression-free survival(PFS),and overall survival(OS)were compared between the two groups.Kaplan-Meier survival analysis and Log-rank test were used to plot PFS and OS survival curves,and Cox regression analysis was applied to identify factors influencing prognosis.RESULTS:Among the 92 patients,53 were in the low MDSC infiltration group,and 39 were in the high MDSC infiltration group.The low MDSC infiltration group showed significantly better treatment responses compared to the high MDSC infiltration group.The objective response rate(iORR)was 77.3％in the low MDSC infiltration group,higher than the 56.4％in the high MDSC in-filtration group(P=0.033).The disease control rate(iDCR)was 94.3％,also significantly higher than the 66.7％in the high MDSC infiltration group(P=0.001).Moreover,the median progression-free sur-vival(PFS)and overall survival(OS)in the low MD-SC infiltration group were 16.9 months and 27.6 months,respectively,which were significantly lon-ger than those in the high MDSC infiltration group(PFS 12.6 months,OS 22.3 months).Kaplan-Meier analysis revealed that both PFS and OS in the low MDSC infiltration group were significantly longer than those in the high MDSC infiltration group.Cox univariate analysis showed that smoking,PD-L1 ex-pression levels,tumor stage,and MDSC infiltration level were closely associated with PFS and OS.Mul-tivariate Cox regression analysis further indicated that high MDSC infiltration was an independent risk factor for both PFS(HR=2.678,P=0.013)and OS(HR=2.254,P=0.022).CONCLUSION:The level of MDSC infiltration in tumor tissues is closely related to the efficacy and prognosis of PD-1 inhibitor com-bined with chemotherapy in NSCLC patients.High MDSC infiltration suggests reduced treatment sen-sitivity and poor prognosis.MDSC infiltration level may serve as a predictive biomarker for the effica-cy and prognosis of PD-1 inhibitor combined with chemotherapy in advanced NSCLC.

Objective:To explore the impacts of carnosic acid(CA)on learning and cognitive function in epileptic rats and the mechanism of regulating PKA-CREB signaling pathway in this process.Methods:Epilepsy rat models were prepared by intraperi-toneal injection of 50 mg/kg PTZ.After successful modeling,the rats were randomly grouped into control group,model group,CA low-dose group,CA high-dose group,CA high+PKA inhibitor group(CA high+H-89 group),with 15 rats in each group.The epileptic be-havior of rats in each group was evaluated;Morris water maze experiment was applied to test the cognitive ability of rats;HE staining and Nissl staining were applied to detect the morphology of hippocampal tissue and neurons of rats in each group;ELISA was applied to detect the contents of IL-1β,TNF-α,MDA,and the SOD activity in the hippocampus of rats in each group;and Western blot was applied to detect the protein expressions of PKA,p-PKA,CREB,p-CREB and BDNF in the hippocampus of rats in each group.Results:Compared with control group,the hippocampal neurons of rats in model group were irregularly arranged,with pyknosis of the nuclei,and the number of neurons decreased,the epilepsy frequency,Racine grading,escape latency,time of first platform crossing,and levels of IL-1β,TNF-α and MDA all increased,the frequency of crossing the platform,SOD activity,p-PKA/PKA,p-CREB/CREB,and the expression of BDNF protein all reduced(P<0.05);compared with model group,the arrangement of neuronal cells in hippocampal tissue of rats in CA group gradually became orderly,nuclear pyknosis gradually decreased,and the number of neurons increased,the epilepsy frequency,Racine grading,escape latency,time of first platform crossing,and levels of IL-1β,TNF-α and MDA all reduced,the frequency of crossing the platform,SOD activity,p-PKA/PKA,p-CREB/CREB,and the expression of BDNF protein all increased(P<0.05);further injection of PKA inhibitors on the basis of high-dose CA treatment showed that the improvement effects of high-dose CA on cognitive dysfunction,neuronal damage,inflammation,and oxidative stress in epileptic rats were reversed(P<0.05).Conclusion:CA can improve the learning and cognitive function of epileptic rats by activating the PKA-CREB signaling pathway.

AIM:To investigate the relationship between the dynamic changes of Lymphocyte-to-monocytes ratios(LMR)before PD-1 inhibitor treat-ment and the efficacy and prognosis of PD-1 inhibi-tor treatment in patients with advanced non-small cell lung cancer(NSCLC).METHODS:The clinical case data of 83 patients with advanced non-small cell lung cancer admitted to the Cancer Hospital of Wuhu Second People's Hospital from June 2019 to July 2022 were retrospectively analyzed.The rou-tine blood LMR values of all patients before and af-ter treatment were collected,the cut-off value was calculated according to the ROC curve,and the LMR was divided into two groups:high and low be-fore treatment and after treatment.The differenc-es of ORR,DCR,PFS and OS among the patients in each group were analyzed and compared,and the value of LMR value and dynamic changes after treatment on the efficacy and prognosis of patients with PD-1 inhibitors in the treatment of NSCLC pa-tients was analyzed.RESULTS:According to the ROC curve,the critical value of LMR was 1.8,and the LMR was divided into the low LMR group at baseline(LMRB/S<1.8),the high LMR group at base-line(LMRB/S≥1.8)and the low LMR group after treatment(LMRafter<1.8)and the high LMR group af-ter treatment(LMRafter≥1.8).The ORR and DCR after immunotherapy in the high LMRB/S group were high-er than those in the low LMRB/S group(P=0.037;P= 0.0025).Among the patients with low LMRB/S be-fore treatment,the DCR of the LMRafter≥1.8 group was better than that of the LMRafter<1.8 group after treatment(P=0.005).Among the patients with high LMR before treatment,the DCR of the LMRafter≥1.8 group was better than that of the LMRafter<1.8 group(P=0.034).Kaplan-Meier analysis showed that PFS and OS were longer in the high LMRB/S group than in the low LMRB/S group before treat-ment.In the low LMRB/S group before treatment,PFS and OS were longer in patients with LMRafter≥1.8 than those with LMRafter<1.8(P=0.047;P=0.007).Multivariate Cox regression model analysis showed that high LMRB/S value before treatment was an in-dependent risk factor for PFS and OS in NSCLC pa-tients(P=0.006;P=0.033).CONCLUSION:High LMR value of patients before immunotherapy may im-prove the efficacy of PD-1 inhibitors,improve the prognosis of patients,and prolong the survival time.Moreover,the increase of LMR value after treatment may increase the efficacy of patients with low LMR before treatment and improve the prognosis of patients.

Objective To investigate the mechanism of RNF7 for regulating myeloid-derived suppressor cells(MDSCs)in non-small cell lung cancer(NSCLC).Methods TIMER2.0 database and immunohistochemistry were used to analyze RNF7 expression level and its correlation with immune cell infiltration in non-small cell lung cancer.The impact of RNF7 expression levels on prognosis of lung cancer patients was analyzed using Kaplan-Meier survival analysis.CMT-167 cells with RNF7 overexpression or knockdown were inoculated subcutaneously in C57BL/6 mice,and the mice in RNF7 knockdown group were treated with anti-PD-1 or IgG isotype control 7 days after the inoculation.The tumor tissues were harvested after 30 days for tumor volume measurement,detection of S100A8+A9 and Gr-1 expressions with immunohistochemistry,and analysis of MDSC infiltration.Gene set enrichment analysis(GSEA)was performed to identify the potential pathways regulated by RNF7 in NSCLC.Western blotting and luciferase assays were used to assess the impact of RNF7 on the NF-κB signaling pathway.ELISA and RT-qPCR were used to measure chemokine(C-X-C motif)ligand 1(CXCL1)expression.Results RNF7 expression was significantly upregulated in NSCLC,and high RNF7 expression levels were associated with poor prognosis of the patients(P<0.001).TIMER2.0 analysis revealed a positive correlation between RNF7 expression and MDSC infiltration(P<0.001).GSEA suggested that RNF7 was enriched in the NF-κB signaling pathway.In NSCLC cells,RNF7 knockdown significantly inhibited NF-κB activation and reduced CXCL1 expression.In the tumor-bearing mice,RNF7 overexpression significantly increased MDSC infiltration in the tumor tissue,and RNF7 knockdown obviously reduced MDSC infiltration and enhanced the efficacy of anti-PD-1 therapy.Conclusion High expression of RNF7 in NSCLC cells promotes CXCL1 expression by activating the NF-κB signaling pathway,thus leading to the chemotactic recruitment of MDSCs,which contributes to tumor resistance to anti-PD-1 therapy.

Osteoporotic proximal humeral fracture (OPHF) is one of the common osteoporotic fractures in the aged, with an incidence only lower than vertebral compression fracture, hip fracture, and distal radius fracture. OPHF, secondary to osteoporosis and characterized by poor bone quality, comminuted fracture pattern, slow healing, and severely impaired shoulder joint function, poses a big challenge to the current clinical diagnosis and treatment. In the field of diagnosis, treatment, and rehabilitation of OPHF, traditional Chinese and Western medicine have accumulated rich experience and evidence from evidence-based medicine and achieved favorable outcomes. However, there is still a lack of guidance from a relevant consensus as to how to integrate the advantages of the two medical systems and achieve the integrated diagnosis and treatment. To promote the diagnosis and treatment of OPHF with integrated traditional Chinese and Western medicine, relevant experts from Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine have been organized to formulate Expert consensus on the diagnosis and treatment of osteoporotic proximal humeral fracture with integrated traditional Chinese and Western medicine ( version 2024) by searching related literatures and based on the evidences from evidence-based medicine. This consensus consists of 13 recommendations about the diagnosis, treatment and rehabilitation of OPHF with integrated traditional Chinese medicine and Western medicine, aimed at standardizing, systematizing, and personalizing the diagnosis and treatment of OPHF with integrated traditional Chinse and Western medicine to improve the patients ′ function.

Objective To investigate the mechanism of RNF7 for regulating myeloid-derived suppressor cells(MDSCs)in non-small cell lung cancer(NSCLC).Methods TIMER2.0 database and immunohistochemistry were used to analyze RNF7 expression level and its correlation with immune cell infiltration in non-small cell lung cancer.The impact of RNF7 expression levels on prognosis of lung cancer patients was analyzed using Kaplan-Meier survival analysis.CMT-167 cells with RNF7 overexpression or knockdown were inoculated subcutaneously in C57BL/6 mice,and the mice in RNF7 knockdown group were treated with anti-PD-1 or IgG isotype control 7 days after the inoculation.The tumor tissues were harvested after 30 days for tumor volume measurement,detection of S100A8+A9 and Gr-1 expressions with immunohistochemistry,and analysis of MDSC infiltration.Gene set enrichment analysis(GSEA)was performed to identify the potential pathways regulated by RNF7 in NSCLC.Western blotting and luciferase assays were used to assess the impact of RNF7 on the NF-κB signaling pathway.ELISA and RT-qPCR were used to measure chemokine(C-X-C motif)ligand 1(CXCL1)expression.Results RNF7 expression was significantly upregulated in NSCLC,and high RNF7 expression levels were associated with poor prognosis of the patients(P<0.001).TIMER2.0 analysis revealed a positive correlation between RNF7 expression and MDSC infiltration(P<0.001).GSEA suggested that RNF7 was enriched in the NF-κB signaling pathway.In NSCLC cells,RNF7 knockdown significantly inhibited NF-κB activation and reduced CXCL1 expression.In the tumor-bearing mice,RNF7 overexpression significantly increased MDSC infiltration in the tumor tissue,and RNF7 knockdown obviously reduced MDSC infiltration and enhanced the efficacy of anti-PD-1 therapy.Conclusion High expression of RNF7 in NSCLC cells promotes CXCL1 expression by activating the NF-κB signaling pathway,thus leading to the chemotactic recruitment of MDSCs,which contributes to tumor resistance to anti-PD-1 therapy.