Integrated metabolomics and transcriptomics analysis reveals the mechanism of Tangbi capsule for diabetic lower extremities arterial disease.

Objective: Tangbi capsule (TBC) is a traditional Chinese medicine prescription, which has the potential to improve the vascular insufficiency of lower extremities and limb numbness in diabetes. However, the potential mechanism remains unknown. This study aims to investigate the pharmacological effects and mechanism of TBC on rats with diabetic lower extremities arterial disease (LEAD). Methods: The mechanism of TBC on diabetic LEAD was investigated through metabolomics and transcriptomics analysis, and the main components of TBC were determined by mass spectrometry. The efficacy and mechanism of TBC on diabetic LEAD rats were investigated through in vitro experiments, histopathology, blood flow monitoring, western blot, and real-time polymerase chain reaction. Results: Mass spectrometry analysis identified 31 active chemical components in TBC including (2R)-2,3-Dihydroxypropanoic acid, catechin, citric acid, miquelianin, carminic acid, salicylic acid, formononetin, etc. In vitro analysis showed that TBC could reduce endothelial cell apoptosis and promote angiogenesis. Histopathological analysis showed that TBC led to an obvious improvement in diabetic LEAD as it improved fibrous tissue proliferation and reduced arterial wall thickening. In addition, TBC could significantly increase the expression levels of HIF-1α, eNOS, and VEGFA proteins and genes while reducing that of calpain-1 and TGF-ß, suggesting that TBC can repair vascular injury. Compared with the model group, there were 47 differentially expressed genes in the whole blood of TBC groups, with 25 genes upregulated and 22 downregulated. Eighty-seven altered metabolites were identified from the serum samples. Combining the changes in differentially expressed genes and metabolites, we found that TBC could regulate arginine biosynthesis, phenylalanine metabolism, pyrimidine metabolism, arachidonic acid metabolism, pyrimidine metabolism, arachidonic acid metabolism, nucleotide metabolism, vitamin B6 metabolism and other metabolic pathways related to angiogenesis, immune-inflammatory response, and cell growth to improve diabetic LEAD. Conclusion: TBC improved vascular endothelial injury, apoptosis, lipid accumulation, liver and kidney function, and restored blood flow in the lower extremities of diabetic LEAD rats. The mechanism of TBC in the treatment of diabetic LEAD may be related to the modulation of inflammatory immunity, lipid metabolism, and amino acid metabolism. This study presented preliminary evidence to guide the use of TBC as a therapy option for diabetic LEAD.

Milk-Derived Extracellular Vesicles Carrying ssc-let-7c Alleviate Early Intestinal Inflammation and Regulate Macrophage Polarization via Targeting the PTEN-Mediated PI3K/Akt Pathway.

Milk-derived extracellular vesicles (mEVs) are beneficial to the health of infants. However, the effect of mEVs on early intestinal inflammation is not well established. Herein, weaned colitic mice were used to explore the potential effects and underlying mechanisms of porcine mEVs (pmEVs) on intestinal inflammation during early life. We found that pmEVs administration attenuated early life intestinal inflammation and promoted colonic barrier integrity in mice. The anti-inflammatory effect of pmEVs was achieved by shifting a proinflammatory macrophage (M1) toward an anti-inflammatory macrophage (M2). Moreover, pmEVs can be absorbed by macrophages and reduce proinflammatory polarization (stimulated by LPS) in vitro. Noteworthily, ssc-let-7c was found to be highly expressed in pmEVs that can regulate the polarization of macrophages by targeting the tensin homologue deleted on chromosome ten (PTEN), thereby activating the PI3K/Akt pathway. Collectively, our findings revealed a crucial role of mEVs in early intestinal immunity and its underlying mechanism.

Fish oil supplementation in relation to the risk of chronic kidney disease among patients with diabetes.

AIM: To investigate the association between fish oil supplementation and subsequent risk of chronic kidney disease (CKD) among patients with diabetes, and further evaluate the mediation effect of typical glycolipid and inflammatory biomarkers. METHODS: In total, 24 497 patients with diabetes from the UK Biobank were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD risk, and the rate advancement period was calculated to quantify and communicate the impact of fish oil upon that risk. In addition, we also used mediation analysis to assess the mediating role of plasma biomarkers. RESULTS: Overall, 7122 patients reported taking fish oil supplements. During a mean of 11.3 years of follow-up, 3533 CKD cases occurred. In the fully adjusted model, fish oil use was inversely associated with the incidence of CKD (HR 0.90; 95% CI: 0.83, 0.97), which was mediated by serum levels of HbA1c (4.7%), C-reactive protein (CRP) (3.4%) and high-density lipoprotein cholesterol (HDL-C) (2.3%). Participants who took fish oil supplements displayed the same risk of CKD events, but that risk was delayed by approximately 2.79 years compared with non-users of fish oil. CONCLUSIONS: Our findings advocate the beneficial role of fish oil use in preventing CKD among patients with diabetes, which may be mediated by serum levels of HbA1c, CRP and HDL-C, and support public health policies aiming to promote fish oil supplementation for the prevention of diabetes complications.

Plant synthetic genomics: Big lessons from the little yeast.

Yeast has been extensively studied and engineered due to its genetic amenability. Projects like Sc2.0 and Sc3.0 have demonstrated the feasibility of constructing synthetic yeast genomes, yielding promising results in both research and industrial applications. In contrast, plant synthetic genomics has faced challenges due to the complexity of plant genomes. However, recent advancements of the project SynMoss, utilizing the model moss plant Physcomitrium patens, offer opportunities for plant synthetic genomics. The shared characteristics between P. patens and yeast, such as high homologous recombination rates and dominant haploid life cycle, enable researchers to manipulate P. patens genomes similarly, opening promising avenues for research and application in plant synthetic biology. In conclusion, harnessing insights from yeast synthetic genomics and applying them to plants, with P. patens as a breakthrough, shows great potential for revolutionizing plant synthetic genomics.

Effects of stannous fluoride dentifrice on gingival health and oxidative stress markers: a prospective clinical trial.

BACKGROUND: Periodontal disease results in oral dysbiosis, increasing plaque virulence and oxidative stress. Stannous fluoride (SnF2) binds lipopolysaccharides to reduce plaque virulence. This study prospectively assessed SnF2 effects on oxidative stress in adults with gingivitis. METHODS: This was a 2-month, single-center, single-treatment clinical trial. Twenty "disease" (> 20 bleeding sites with ≥ 3 pockets 3 mm-4 mm deep) and 20 "healthy" (≤ 3 bleeding sites with pockets ≤ 2 mm deep) adults were enrolled. All participants were instructed to use SnF2 dentifrice twice daily for 2 months. An oral examination, Modified Gingival Index (MGI) examination and Gingival Bleeding Index (GBI) examination were conducted at baseline, 1 month and 2 months. Gingival crevicular fluid (GCF), saliva, oral lavage and supragingival plaque were collected at each visit to evaluate: Endotoxins, Protein Carbonyls, L-lactate dehydrogenase (LDH), Ferric reducing antioxidant power (FRAP), Oxidized low density lipoproteins (oxi-LDL), IL-6 and C-reactive protein (CRP). A subset-analysis examined participants considered at higher risk of cardiovascular disease. Change-from-baseline analyses within each group were of primary interest. RESULTS: The disease group showed statistically significant reductions in GBI at Month 1 (67%) and Month 2 (85%) and in MGI at Month 1 (36%) and Month 2 (51%) versus baseline (p < 0.001). At baseline, the disease group showed greater LDH in GCF and oxi-LDL levels in saliva versus the healthy group (p ≤ 0.01). Total antioxidant capacity (FRAP) in saliva increased versus baseline for the disease group at Months 1 and 2 (p < 0.05), and levels for the disease group were greater than the healthy group at both timepoints (p < 0.05). SnF2 treatment reduced endotoxins (lavage) for both disease and healthy groups at Month 2 (p ≤ 0.021) versus baseline. There was a reduction in oxidative stress markers, namely protein carbonyl in saliva, at Months 1 and 2 (p < 0.001) for both groups and a reduction in cytokine IL-6 (lavage) in the disease group at Month 2 (p = 0.005). A subset analysis of participants at higher coronary disease risk showed reductions in endotoxins in lavage, oxi-LDL, and CRP in saliva at Month 2 (p ≤ 0.04). CONCLUSION: SnF2 dentifrice use reversed gingival inflammation, suppressed endotoxins and reduced some harmful oxidant products in saliva and gingiva. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT05326373, registered on 13/04/2022.

[Effects of cortical bone thickness and jaw bone density on pain during implant surgery].

PURPOSE: To investigate the effects of different cortical bone thickness and jaw bone density at implant sites on intraoperative pain during implant surgery. METHODS: One hundred and eighty-seven patients(263 implant sites) who underwent implant placement surgery at the Fourth Affiliated Hospital of Nanchang University from August 2021 to August 2022 were selected to investigate the effects of different cortical bone thickness and jaw bone density HU values at implant sites on the anesthetic effect under local infiltration anesthesia with epinephrine in articaine. SPSS 26.0 software package was used for data analysis. RESULTS: The mean cortical bone thickness at the painful sites[(3.90±1.36) mm] was significantly greater than that at the non-painful sites [(2.24±0.66) mm], and the difference was statistically significant(P＜0.05). The differences in cortical bone thickness in the mandibular anterior, premolar, and molar regions were statistically significant in the comparison of pain and non-pain sites. The mean HU value of bone density was (764.46±239.75) for the painful sites and (612.23±235.31) for the non-painful sites, with significant difference(P＜0.05). The difference was not significant(P＞0.05) when comparing the HU values of painful sites with non-painful sites in the mandibular anterior teeth and anterior molar region, while the difference was significant(P＜0.05) when comparing the HU values of painful sites with non-painful sites in the mandibular molar region. CONCLUSIONS: Sites with large cortical bone thickness have a greater effect on blocking infiltrative anesthetic penetration and are more prone to intraoperative pain during implantation. In the mandibular anterior and premolar regions, the HU value of the implant sites had less effect on infiltrative anesthetic penetration, and the effect was greater in the mandibular molar region, and the implant sites with high HU values in the mandibular molar region were more likely to have intraoperative pain. When the cortical bone thickness in the planned implant site is greater than 3.9 mm and the mean bone density in the mandibular molar region is greater than 665 HU. If there is sufficient safe distance for hole operation, it is recommended to apply mandibular nerve block anesthesia combined with articaine infiltration anesthesia to avoid intraoperative pain and bad surgical experience for the patients.

Association of soy intake and cooking methods with colorectal polyp and adenoma prevalence: findings from the extended Lanxi pre-colorectal cancer cohort (LP3C).

Background: Limited research has explored the association between dietary soy products and colorectal polyps and adenomas, with insufficient attention given to cooking methods and subtypes of polyps. This study aimed to comprehensively assess the relationship between soy intake, its cooking methods, and the risk of colorectal polyps and adenomas within a high-incidence population of colorectal cancer (CRC) in China. Methods: Data were derived from 14,903 participants aged 40-80 years, enrolled in the extended Lanxi Pre-colorectal Cancer Cohort (LP3C) between March 2018 and December 2022. This cross-sectional study is based on the participants' baseline information. Long-term dietary information was collected through a validated food frequency questionnaire (FFQ), and colorectal polyps and adenomas were identified through electronic colonoscopy. Employing multivariate logistic regression, results were expressed as odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs). Results: 4,942 cases of colorectal polyps and 2,678 cases of adenomas were ascertained. A significant positive association was found between total soy intake and the occurrence of polyps/adenomas. Considering cooking methods, a notable increase in polyp risk was associated with the consumption of fried soys while no association was detected for boiled or marinated soys. Furthermore, total soy intake demonstrated associations with large and multiple polyps, polyps Yamade-typed less than II, and polyps across all anatomical subsites. Conclusion: Within the high-risk CRC population in China, increased soy product intake was linked to a higher risk of polyps, primarily attributed to the consumption of fried soys. This suggests that modifying cooking methods to avoid fried soys may serve as a preventive strategy for colorectal polyps.

Seafood intake in childhood/adolescence and the risk of obesity: results from a Nationwide Cohort Study.

BACKGROUND & AIMS: Obesity has been linked to various detrimental health consequences. While there is established evidence of a negative correlation between seafood consumption and obesity in adults, the current research on the association between seafood intake in childhood/adolescence and the risk of obesity is lacking. Our aim was to evaluate the association between seafood intake in childhood/adolescence and the risk of obesity in a Chinese nationwide cohort. METHODS: We utilized data from the China Health and Nutrition Survey (CHNS) from the year of 1997 to 2015. Seafood consumption was evaluated through 3-day 24-hour recalls. In our study, overweight/obesity status was determined based on the Chinese Criteria of Overweight and Obesity in School-age Children and Adolescents (WS/T 586-2018), while abdominal obesity status was determined according to the Chinese Criteria of Waist Circumference Screening Threshold among Children and Adolescents (WS/T 611-2018). RESULTS: During an average follow-up of 7.9 years, 404 cases developed overweight/obesity among 2206 participants in the seafood-overweight/obesity analysis, while 381 cases developed abdominal obesity among 2256 participants in the seafood-abdominal-obesity analysis. The high-consumer group was associated with 35% lower risk of overweight/obesity risk and 26% lower risk of abdominal obesity after fully adjusting for sociodemographic and lifestyle factors, compared with the non-consumer group. Considering different cooking methods, boiled seafood consumption was associated with 43% lower risk of overweight/obesity and 23% lower risk of abdominal obesity in the fully adjusted model, while stir-fried seafood did not demonstrate a statistical significance. CONCLUSION: Higher intake of seafood in childhood/adolescents, particularly in a boiled way, was associated with lower obesity risk.

Analysis of the number of topological defects in active nematic fluids under applied shear flow.

The number of topological defects in the shear flow of active nematic fluids is numerically investigated in this study. The evolution of the flow state of extensile active nematic fluids is explored by increasing the activity of active nematic fluids. Evidently, medium-activity active nematic fluids exhibit a highly ordered vortex lattice fluid state. However, high-activity active nematic fluids exhibit a meso-scale turbulent flow accompanied by topological defects. The number of topological defects (Ndef) increases with increasing shear Reynolds number (Res). Fluid viscosity strongly influences Ndef, while the influence of fluid density is relatively weak. Ndef decreases with increasing activity length scale (lζ) value. A small Res value strongly influences Ndef, whereas a large lζ value only weakly influences Ndef. As the activity increases, Ndef in contractile active nematic fluids becomes larger than that of extensile active nematic fluids.

Designing a synthetic moss genome using GenoDesigner.

The de novo synthesis of genomes has made unprecedented progress and achieved milestones, particularly in bacteria and yeast. However, the process of synthesizing a multicellular plant genome has not progressed at the same pace, due to the complexity of multicellular plant genomes, technical difficulties associated with large genome size and structure, and the intricacies of gene regulation and expression in plants. Here we outline the bottom-up design principles for the de novo synthesis of the Physcomitrium patens (that is, earthmoss) genome. To facilitate international collaboration and accessibility, we have developed and launched a public online design platform called GenoDesigner. This platform offers an intuitive graphical interface enabling users to efficiently manipulate extensive genome sequences, even up to the gigabase level. This tool is poised to greatly expedite the synthesis of the P. patens genome, offering an essential reference and roadmap for the synthesis of plant genomes.

A Naturally Inspired Extrusion-Based Microfluidic Approach for Manufacturing Tailorable Magnetic Soft Continuum Microrobotic Devices.

Soft materials play a crucial role in small-scale robotic applications by closely mimicking the complex motion and morphing behavior of organisms. However, conventional fabrication methods face challenges in creating highly integrated small-scale soft devices. In this study, microfluidics is leveraged to precisely control reaction-diffusion (RD) processes to generate multifunctional and compartmentalized calcium-cross-linkable alginate-based microfibers. Under RD conditions, sophisticated alginate-based fibers are produced for magnetic soft continuum robotics applications with customizable features, such as geometry (compact or hollow), degree of cross-linking, and the precise localization of magnetic nanoparticles (inside the core, surrounding the fiber, or on one side). This fine control allows for tuning the stiffness and magnetic responsiveness of the microfibers. Additionally, chemically cleavable regions within the fibers enable disassembly into smaller robotic units or roll-up structures under a rotating magnetic field. These findings demonstrate the versatility of microfluidics in processing highly integrated small-scale devices.

Outcomes of patients in nasopharyngeal adenoid cystic carcinoma in the IMRT era: a single-center experience.

OBJECTIVE: Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with special biological features. Controversies exist regarding the treatment approach and prognostic factors in the IMRT era. This study aimed to evaluate the long-term outcomes and management approaches in NACC. METHODS: Fifty patients with NACC at our institution between 2010 and 2020 were reviewed. Sixteen patients received primary radiotherapy (RT), and 34 patients underwent primary surgery. RESULTS: Between January 2010 and October 2020, a total of 50 patients with pathologically proven NACC were included in our analysis. The median follow-up time was 58.5 months (range: 6.0-151.0 months). The 5-year overall survival rate (OS) and progression-free survival rate (PFS) were 83.9% and 67.5%, respectively. The 5-year OS rates of patients whose primary treatment was surgery and RT were 90.0% and 67.3%, respectively (log-rank P = 0.028). The 5-year PFS rates of patients whose primary treatment was surgery or RT were 80.8% and 40.7%, respectively (log-rank P = 0.024). Multivariate analyses showed that nerve invasion and the pattern of primary treatment were independent factors associated with PFS. CONCLUSIONS: Due to the relative insensitivity to radiation, primary surgery seemed to provide a better chance of disease control and improved survival in NACC. Meanwhile, postoperative radiotherapy should be performed for advanced stage or residual tumours. Cranial nerve invasion and treatment pattern might be important factors affecting the prognosis of patients with NACC.

Effect of Chinese Medicine in Patients with COVID-19: A Multi-center Retrospective Cohort Study.

OBJECTIVE: To evaluate the effectiveness and safety of Chinese medicine (CM) in the treatment of coronavirus disease 2019 (COVID-19) in China. METHODS: A multi-center retrospective cohort study was carried out, with cumulative CM treatment period of ⩾3 days during hospitalization as exposure. Data came from consecutive inpatients from December 19, 2019 to May 16, 2020 in 4 medical centers in Wuhan, China. After data extraction, verification and cleaning, confounding factors were adjusted by inverse probability of treatment weighting (IPTW), and the Cox proportional hazards regression model was used for statistical analysis. RESULTS: A total of 2,272 COVID-19 patients were included. There were 1,684 patients in the CM group and 588 patients in the control group. Compared with the control group, the hazard ratio (HR) for the deterioration rate in the CM group was 0.52 [95% confidence interval (CI): 0.41 to 0.64, P<0.001]. The results were consistent across patients of varying severity at admission, and the robustness of the results were confirmed by 3 sensitivity analyses. In addition, the HR for all-cause mortality in the CM group was 0.29 (95% CI: 0.19 to 0.44, P<0.001). Regarding of safety, the proportion of patients with abnormal liver function or renal function in the CM group was smaller. CONCLUSION: This real-world study indicates that the combination of a full-course CM therapy on the basic conventional treatment, may safely reduce the deterioration rate and all-cause mortality of COVID-19 patients. This result can provide the new evidence to support the current treatment of COVID-19. Additional prospective clinical trial is needed to evaluate the efficacy and safety of specific CM interventions. (Registration No. ChiCTR2200062917).

Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

Digital smart internal fixation surgery for coronal process basal fracture with normal joint spaces or radius-shortening: Occult factor of radius-ulna load sharing.

BACKGROUND: Reasonable postoperative humeroradial and humeroulnar joint spaces maybe an important indicator in biomechanical stability of smart internal fixation surgery for coronoid process basal fractures (CPBF). The aim of this study is to compare elbow articular stresses and elbow-forearm stability under smart internal fixations for the CPBF between normal elbow joint spaces and radius-shortening, and to determine the occult factor of radius-ulna load sharing. METHODS: CT images of 70 volunteers with intact elbow joints were retrospectively collected for accurate three-dimensional reconstruction to measure the longitudinal and transverse joint spaces. Two groups of ten finite element (FE) models were established prospectively between normal joint space and radius-shortening with 2.0 mm, including intact elbow joint and forearm, elbow-forearm with CPBF trauma, anterior or posterior double screws-cancellous bone fixation, mini-plate-cancellous bone fixation. Three sets of physiological loads (compression, valgus, varus) were used for FE intelligent calculation, FE model verification, and biomechanical and motion analysis. RESULTS: The stress distribution between coronoid process and radial head, compression displacements and valgus angles of elbow-forearm in the three smart fixation models of the normal joint spaces were close to those of corresponding intact elbow model, but were significantly different from those of preoperative CPBF models and fixed radius-shortening models. The maximum stresses of three smart fixation instrument models of normal joint spaces were significantly smaller than those of the corresponding fixed radius-shortening models. CONCLUSIONS: On the basis of the existing trauma of the elbow-forearm system in clinical practice, which is a dominant factor affecting radius-ulna load sharing, the elbow joint longitudinal space has been found to be the occult factor affecting radius-ulna load sharing. The stability and load sharing of radius and ulna after three kinds of smart fixations of the CPBF is not only related to the anatomical and biomechanical stability principles of smart internal fixations, but also closely related to postoperative elbow joint longitudinal space.

Identification of Transcriptomic Signatures of Pancreatic Ductal Adenocarcinoma-Derived Exosomes That Promote Macrophage M2 Polarization and Predict Prognosis: S100A9 Reveals Tumor Progression.

Background: Exosomes play a role in intercellular communication and participate in the interaction between pancreatic ductal adenocarcinoma (PDAC) cells and immune cells. Macrophages can receive tumor cell-derived exosomes to polarize into M2-type macrophages, which can enhance the invasion and metastasis of pancreatic cancer, leading to poor prognosis. However, the mechanism by which pancreatic cancer cell-derived exosomes promote M2-type macrophages is still unclear. Methods: M2 macrophage-associated exosome-derived key module genes were identified by differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) analysis using exoRbase 2.0, The Cancer Genome Atlas (TCGA), and The International Cancer Genome Consortium (ICGC) databases. Multivariate Cox regression analysis was used to identify key prognostic genes and obtain regression coefficients to establish prognostic signature. Immune infiltration, tumor mutations, and GSEA among different risk groups were compared. exoRbase 2.0, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), HPA, and TISCH2 databases were used to further analyze the expression pattern of S100A9 in pancreatic cancer. In vitro experiments, cell-derived exosome isolation, quantitative polymerase chain reaction (qPCR), western blot, flow cytometry analysis, cell transfection, transwell assay, and CCK-8 assay were applied to investigate the roles of S100A9 in macrophage M2 polarization and tumor progression. Results: The key genes of PDAC-derived exosomes promoting M2-type macrophage polarization were identified, and a risk score model was established. The risk score is related to the expression of common immune checkpoints, immune score, and stromal score, and the tumor mutational burden and biological function of high- and low-risk groups were also different. S100A9 was positively correlated with M2-type macrophage marker. In addition, scRNA-seq data from the TISCH2 database revealed that S100A9 is predominantly expressed in pancreatic cancer cells and mono/macrophage cells, suggesting that S100A9 in pancreatic cancer cells could be received by macrophages, thereby inducing macrophage polarization. In vitro, we used exosomes from BxPC-3 cell lines to coculture macrophages and found that macrophages were mainly polarized toward M2 type, which further promoted the proliferation and metastasis of PDAC. Conclusions: Our study established a reliable risk score model for PDAC-derived exosomes and M2 macrophages, identified the important role of S100A9 in macrophage M2 polarization, which provides a new strategy for the diagnosis and treatment of PDAC, and strengthened the understanding of the mechanism of tumor development and metastasis.