Gastrointestinal (GI) cancers are a leading cause of cancer morbidity and mortality worldwide. Despite advances in treatment, cancer relapse remains a significant challenge, necessitating novel therapeutic strategies. In this study, we engineered nanobody-based chimeric antigen receptor (CAR) natural killer (NK) cells targeting cadherin 17 (CDH17) for the treatment of GI tumors. In addition, to enhance the efficacy of CAR-NK cells, we also incorporated CV1, a CD47-SIRPα axis inhibitor, to evaluate the anti-tumor effect of this combination. We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner. CDH17-CAR-NK cells also exhibit potent in vivo anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47-signal regulatory protein α (SIRPα) axis inhibitor CV1, likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment. Collectively, our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers. The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy. Further investigations are warranted to speed up the clinical translation of these findings.

Objective:To deconstruct the overall medical expense and analyze systemic characteristics of cost structure dynamics in China from the perspective of optimizing healthcare resource allocation.Methods:Utilizing hospitalization records in a sample city from 2022-2023 as the research literature,the linear regression models for different cost components was established over the two-year period within each DRG-based case group to identify statistically significant temporal trends and directional changes in cost structures.Results:Most DRG groups exhibited significant trends in at least one cost component.Notable concentration patterns emerged in medication,comprehensive care and therapeutic service costs.When evaluating structure improvement,most achieved optimized allocation in at least one major cost component.Conclusion:The sample city demonstrates continuous optimization in healthcare cost structures,yet specific cost categories and DRG groups deviated from resource allocation optimization goals.Policy interventions should prioritize granular,DRG-specific adjustments to address heterogeneous structural dynamics.

Objective: To investigate the effects of Zuogui Jiangtang Jieyu Formula (ZGJTJYF) on histone H3 lysine 18 lactylation (H3K18la) in the hippocampus of rats with diabetes mellitus complicated with depression (DD) and predict the regulatory genes of H3K18la. Methods: Male Sprague-Dawley rats were divided into control, model, and positive drug (metformin [0.18 g/kg] and fluoxetine [1.8 mg/kg]) groups, and the three groups were treated with high, medium, and low ZGJTJYF doses (20.52, 10.26, and 5.13 g/kg, respectively), with 10 rats per group. After treatment, the forced swimming and water maze tests were performed to assess depressive-like behaviors and cognitive function. An enzyme-linked immunosorbent assay was used to measure blood insulin, glycosylated hemoglobin, lactate levels, and lactate content in the hippocampus. Western blotting was used to detect H3K18la expression in the hippocampus. Cleavage Under Targets and lagmentation(CUT&Tag) experiments targeted hippocampal H3K18la epigenetic modification regions to analyze the transcription factors bound by H3K18la. Kyoto Encyclopedia of Genes and Genomes and Protein-Protein Interaction networks were constructed to identify key pathways and target genes regulated by H3K18la. Results: Compared with the normal group, the model group rats showed prolonged immobility time in the forced swim test, increased escape latency in the water maze experiment, decreased target quadrant distance ratio (P<0.01), increased serum lactate content, and decreased lactate content in hippocampal homogenate (P<0.01), as well as decreased H3K18la protein expression in the hippocampus (P<0.01). Compared with the model group, ZGJTJYF reduced the immobility time in the forced swim test and the escape latency in the water maze test (P<0.01), while the distance ratio in the target quadrant increased (P<0.01) in model rats. Lowered fasting blood glucose, insulin, and glycosylated hemoglobin levels (P<0.05, P<0.01) were also observed. ZGJTJYF also increased the lactate content and H3K18la protein expression in hippocampal homogenate (P<0.05, P<0.01). The DNA sequences bound by H3K18la were predominantly enriched at the transcription start sites. ZGJTJYF modulated H3K18la-associated pathways, including cell adhesion junctions, tumor growth factor-beta (TGF-β) signaling, stem cell pluripotency regulation, mitogen-activated protein kinase(MAPK) signaling pathway, and insulin resistance, leading to the identification of 12 target genes. Conclusion ZGJTJYF enhances hippocampal lactate levels and H3K18la modification in DD rats, which may regulate neural cell interactions, neurogenic stem cell function, TGF-β signaling, MAPK signaling, and insulin resistance pathways.

Objective:To deconstruct the overall medical expense and analyze systemic characteristics of cost structure dynamics in China from the perspective of optimizing healthcare resource allocation.Methods:Utilizing hospitalization records in a sample city from 2022-2023 as the research literature,the linear regression models for different cost components was established over the two-year period within each DRG-based case group to identify statistically significant temporal trends and directional changes in cost structures.Results:Most DRG groups exhibited significant trends in at least one cost component.Notable concentration patterns emerged in medication,comprehensive care and therapeutic service costs.When evaluating structure improvement,most achieved optimized allocation in at least one major cost component.Conclusion:The sample city demonstrates continuous optimization in healthcare cost structures,yet specific cost categories and DRG groups deviated from resource allocation optimization goals.Policy interventions should prioritize granular,DRG-specific adjustments to address heterogeneous structural dynamics.

ObjectiveTo explore and verify the key pathway of Zuogui Jiangtang Jieyu prescription in the treatment of diabetes with depression by means of gene set enrichment analysis （GSEA） and short time-series expression miner （STEM）. MethodSD rats were randomly divided into six groups， including a normal group， a model group， high， medium， and low dose groups of Zuogui Jiangtang Jieyu prescription， and a positive drug group. The model of diabetes with depression was established by high-fat feeding， streptozotocin （STZ） injection， and chronic mild unpredictable stress. The high， medium， and low dose groups of Zuogui Jiangtang Jieyu prescription were orally administered at 20.52， 10.26， and 5.13 g·kg^-1 respectively. The positive drug group was orally administered 0.18 g·kg^-1 metformin and 1.8 g·kg^-1 fluoxetine. The rats in the normal group and model group were administered with an equal volume of distilled water. After 28 days， the animals were tested for depressive-like behaviors and cognitive function using the forced swimming test and Morris water maze. Fasting blood glucose was measured using blood glucose test strips. Cholesterol and triglyceride levels were measured using enzyme-linked immunosorbent assay （ELISA）. Three hippocampus samples were randomly selected from the normal group， the model group， the high dose group of Zuogui Jiangtang Jieyu prescription for high-throughput transcriptome sequencing. Differential gene analysis， GSEA analysis， and STEM analysis were used to screen the key pathways and target genes of Zuogui Jiangtang Jieyu prescription in the treatment of diabetes with depression. Key target genes were validated using real-time fluorescence quantitative PCR （Real-time PCR）. The expression of the signal protein mediated by the target genes was detected by Western blot. ResultCompared with the results in the normal group， the fasting blood glucose， cholesterol， and triglyceride levels in the model group were significantly increased （P<0.01）. Moreover， the immobility time in the forced swimming test was significantly increased， while the time to climb the platform was significantly prolonged， and the search distance in the target quadrant was significantly reduced in the Morris water maze test （P<0.05，P<0.01）. Compared with the model group， the high dose of Zuogui Jiangtang Jieyu prescription significantly reduced the levels of blood glucose， cholesterol， and triglycerides in rats with diabetes with depression （P<0.05，P<0.01）， reduced the immobility time in the forced swimming test， shortened the stage time in the Morris water maze test， and increased the search distance ratio in the target area （P<0.05，P<0.01）. Transcriptome sequencing differential analysis showed that the normal group had 1 366 differentially expressed genes compared to the model group， while the model group had 1 149 differentially expressed genes compared to the high dose group of Zuogui Jiangtang Jieyu prescription， with 581 intersecting genes. The GSEA results showed that there were 9 sets of differentially expressed genes between the normal group and the model group， and 43 sets of differentially expressed genes between the model group and the high dose group of Zuogui Jiangtang Jieyu prescription， with 7 intersecting gene sets. STEM analysis showed that according to the analysis order of the normal group， model group， and high dose group of Zuogui Jiangtang Jieyu prescription， two significantly different trend clustering groups were obtained. One key gene set for axonal guidance， as well as key target signal elements Sema3c， Sema7a， Robo3， Epha8， and Epha7， were identified through synthesizing the three analysis results. Real-time PCR validated that compared with the results in the normal group， the mRNA expression of Robo3， Sema7a， and Epha7 in the hippocampus of the model rats was significantly reduced （P<0.05， P<0.01）. Compared with the model group， the high dose of Zuogui Jiangtang Jieyu prescription significantly increased the mRNA expression of Robo3， Sema7a， and Epha7 （P<0.05， P<0.01）. Western blot results showed that compared with the results in the normal group， the Sema7a， ITGB1， and FAK protein expression in the hippocampus of the model group was significantly reduced （P<0.01）. Compared with the model group， the high dose of Zuogui Jiangtang Jieyu prescription significantly increased the protein expression of Sema7a， ITGB1， and FAK in the hippocampus （P<0.05，P<0.01）. ConclusionZuogui Jiangtang Jieyu prescription may treat diabetes with depression by regulating axonal guidance based on the Sema7a/ITGB1 signaling pathway.

Stomach exuberance and spleen deficiency are common pathogenesis of many metabolic diseases. Through analyzing the pathogenesis of stomach exuberance and spleen deficiency， it is believed that its essence is stomach heat and spleen deficiency. Stomach heat includes gastrointestinal heat， spleen and stomach damp-heat， and spleen deficiency is divided into deficiency of spleen yin， deficiency of spleen qi ， and deficiency of spleen yang. It is suggested that the metabolic diseases of stomach-exuberance and spleen-deficiency syndrome can be divided into three categories，i.e. stomach-heat and spleen yin-deficiency， stomach-heat and spleen qi-deficiency， and stomach-heat and spleen yang-deficiency， and the main treatment methods are clearing and draining heat， nourishing yin and moistening intestine， clearing dampness and heat， strengthening spleen and qi， clearing dampness and heat， strengthening spleen and warming yang， respectively， with prescriptions as Maziren Pills （麻子仁丸）， Qinlian Pingwei Powder （芩连平胃散）， and Jiawei Lianli Decoction （加味连理汤） accordingly.

Objective We aimed to investigate(i)the preventive and therapeutic effects of Huogu Muli Prescription(HGMLP),a Chinese medical compound consisting of epimedii folium,drynariae rhizoma,and ostreae concha,on postmenopausal osteoporosis(PMOP)rats and(ii)whether it exerts its effects by regulating the osteoclast-osteogenesis balance.Methods Forty-eight female Sprague-Dawley rats were randomly divided into the following six groups:(i)the sham-operated group,(ii)the model group,(iii)the Qianggu Capsule group,(iv)the calcium carbonate group,and(v,vi)the HGMLP low-dose and high-dose groups(n = 8 rats per group).After adaptive feeding,rats in all groups except the sham-operated group were treated with bilateral ovarian castration to establish the PMOP model.Each day,rats in the Qianggu Capsule group received 0.054 g/kg Qianggu Capsule suspension intragastrically,rats in the calcium carbonate group received 1.670 g/kg calcium carbonate suspension intragastrically,and rats in the HGMLP low-dose and high-dose groups received 0.188 g/kg and 0.375 g/kg HGMLP intragastrically.Rats in the sham-operated group and the model group received an equal volume of normal saline intragastrically.After 90 consecutive days,serum estradiol(E2),estrogen receptor α(ERα),procollagen typeⅠN propeptide(PINP),and tartrate-resistant acid phosphatase 5b(TRACP-5b)were detected by ELISA.Total antioxidant capacity(T-AOC),superoxide dismutase(SOD),catalase(CAT),and malondialdehyde(MDA)levels were measured by colorimetry.Bone mineral density(BMD),trabecular number(Tb.N),trabecular separation/spacing(Tb.Sp),trabecular thickness(Tb.Th),and structure model index(SMI)were measured by Micro-CT,and the microstructure of cancellous bone was observed.The expressions of osteoprotegerin(OPG),receptor activator of nuclear factor-κB(RANK),RANK ligand(RANKL),phosphorylation of forkhead box O3(FoxO3α),Wnt2,β-catenin,and peroxisome proliferator-activated receptor γ(PPARγ)in rat femur tissue were detected by Western blotting.Results(i)The serum levels of E2 and ERα increased in the Qianggu Capsule group and HGMLP groups,compared with the model group(all P<0.05).(ii)Compared with the model group,the serum levels of PINP,TRACP-5b decreased and PINP/TRACP-5b increased in both the Qianggu Capsule group and HGMLP high-dose group(all P<0.05).(iii)The activities of T-AOC,AOD,and CAT in the Qianggu Capsule group and HGMLP groups were higher than those in the model group,while the content of MDA lower(all P<0.05).(iv)Compared with the model group,the femoral BMD,Tb.Th,and Tb.N increased in the Qianggu Capsule group and HGMLP groups,while the femoral Tb.Sp and SMI decreased(all P<0.05);the femoral BMD increased and the Tb.Sp decreased in the calcium carbonate group(all P<0.05).(v)The protein expressions of RANKL,RANK,FoxO3α,and PPARγ in the Qianggu Capsule group and HGMLP groups were lower than those in the model group,while the protein expressions of OPG,Wnt2,and β-catenin were higher(all P<0.05).Conclusion HGMLP can significantly increase estrogen levels,inhibit osteoclast differentiation,and inhibit bone resorption in the PMOP rats.It also alleviates oxidative stress,promotes osteogenic differentiation,inhibits lipogenic differentiation,improves bone formation,and recovers the balance between osteoclasts and osteoblasts,thus achieving prevention and treatment of PMOP.The potential mechanism of HGMLP may be related to regulation via the OPG/RANKL/RANK or FoxO3α/Wnt2/β-catenin/PPARγ pathways.

ObjectiveTo explore the potential mechanism of Zuogui Jiangtang Jieyu Formula （左归降糖解郁方， ZJJF） for diabetic rats with depression. MethodsSixty rats were randomly divided into normal group， model group， wingless MMTV integration site family member 5a （Wnt5a） agonist group， ZJJF group， and ZJJF plus Wnt5a inhibitor group， with 12 rats in each group. Except for the normal group， the rats were fed with high-fat chow， streptozotocin injection， and chronic mild unpredictable stress combination， to establish model of diabetes mellitus complicated with depression. After successful modelling， rats in the Wnt5a agonist group were given bilateral hippocampal stereotactic injections of Wnt5a agonist Foxy-5 with 5 μl each for 7 consecutive days； rats in ZJJF group were given 20.52 g/（kg·d） of ZJJF by gavage； rats in ZJJF plus Wnt5a inhibitor group were given the drug by gavage， and bilateral hippocampal stereotactic injections of Wnt5a inhibitors Box5， with the same dosage and injection method as above. The normal group and model group were given 10 ml/（kg·d） of normal saline by gavage. All groups were gavaged for 4 consecutive weeks. At the end of the intervention， the depression-like behaviour of rats was evaluated using the forced swimming experiment （immobility time） and the absent field experiment （number of activities）； the blood glucose and insulin levels of rats were measured and the insulin resistance index was calculated； the dendritic morphology of dentate gyrus neurons in the hippocampus was observed using Golgi staining； the level of dentate gyrus neuron proliferation was measured using 5-bromodeoxyuracil nucleoside （Brdu） injection and immunofluorescence； RT-qPCR and Western blot were used to detect the mRNA and protein expression of Wnt5a， Ras homologue genomic member A （RhoA） and Rho homologue-associated coiled-coil protein kinase 1 （ROCK1） in the dentate gyrus. ResultsCompared with the normal group， rats in the model group had significantly higher blood glucose， insulin and insulin resistance indices， longer immobility time， fewer activities， lower Brdu integral optical density values and Wnt5a， RhoA， ROCK1 protein and mRNA expression in the dentate gyrus of the hippocampus （P＜0.05 or P＜ 0.01）； the dendritic branches of rat hippocampal dentate gyrus neurons could be seen to be significantly reduced or broken， and their length shortened. Compared with the model group， the blood glucose， insulin and insulin resistance indices of rats in ZJJF group and the ZJJF plus Wnt5a inhibitor group significantly reduced （P＜0.05 or P＜0.01）； the immobility time of rats in the Wnt5a agonist group and ZJJF group was significantly shortened， the number of activities increased， the Brdu integral optical density values elevated， and the Wnt5a， RhoA， ROCK1 protein and mRNA expression elevated （P＜0.05 or P＜0.01）， and the number of dendritic branches of hippocampal dentate gyrus neurons significantly increased， the length lengthened， and the complexity of dendrites increased. Compared with the Wnt5a agonist group， rats in the ZJJF group showed significant decrease in blood glucose， insulin and insulin resistance indices， prolongation of immobilisation time， reduction in the number of activities， and reduction in the Brdu integral optical density value； except for the Wnt5a mRNA in ZJJF group， Wnt5a， RhoA， ROCK1 protein and mRNA expression reduced in both ZJJF group and ZJJF plus Wnt5a inhibitor group （P＜0.05 or P＜0.01）. Compared with ZJJF group， Wnt5a， RhoA， ROCK1 protein and mRNA expression were reduced in ZJJF plus Wnt5a inhibitor group （P＜0.05 or P＜0.01）. ConclusionZJJF can improve hyperglycemia and depressive-like behaviours in rat models of diabetes with depression， and its antidepressant effects may be related to the activation of hippocampal Wnt5a/RhoA signaling and promotion of dentate gyrus neuron dendritic growth.

Objective Th is aim of this review was to clarify the role of neutrophils in diabetes by summarizing the characterization studies,potential trends,and research hotspots relating to neutrophils in the diabetes research field.Methods 2998 relevant studies on neutrophils in the diabetes research field indexed in Web of Science from 2010 to 2023 were retrieved,and a visual analysis of the relevant literature was conducted using CiteSpace 6.1.R6.Results Since 2012,the number of publications on this topic has grown rapidly.Bayat Mohammad,Liu Tong,Amini Abdollah,and Zhang Rui are high-yield authors,with seven related articles published.China and Shanghai Jiao Tong University are the country and institution with the most published papers.The most influential journal in this field is"Nature Medicine".Literature co-citation analysis of topics related to diabetes showed that the greatest focus is currently on"extracellular trap"and"COVID-19 patient".Co-occurrence analysis,clustering analysis,and keyword burst analysis indicated that"lymphocyte ratio"(13.08)and"neutrophil extracellular trap"(7.2)are the most researched topics in the field of neutrophils and diabetes.Literature in this field mainly focuses on"myocardial infarction","endothelial","oxidative stress",and"apoptosis".Conclusions This article highlights the evolving trends in research into neutrophils in the diabetes field using CiteSpace,providing new insights for researchers aiming to conduct research in this area.

In China,the cost weight of Diagnosis Related Group (DRG) payment generally adopts the historical data method. In order to adapt to medical costs at different levels of hospitals,medical insurance departments often set a grade coefficient to adjust the payment standard. However,the grade coefficient could solidify the"siphon effect"of high-level hospitals to some extent. In order to promote hierarchical diagnosis and treatment,some region select certain basic group which is suitable for treatment in primary hospitals,and cancel grade coefficient to achieve"same disease same price". It discusses the background and principle of same-disease-same-price policy,sorts out the current implementation status,analyzes the selection criteria and characteristics of basic DRG group and evaluates whether the selected groups coordinate policy principle,so as to provide references for improving the reform of DRG payment and promoting the hierarchical diagnosis and treatment system in China.