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Abstract Background Individuals with diabetes have a significantly higher risk of developing various forms of cancer, and the potential biological links between these two diseases are not completely understood. Methods This was a longitudinal retrospective nationwide cohort study, a study design that allows us to examine the natural course of cancer development over an extended period of time with a large sample size. Initially, 3,111,975 and 22,208,395 eligible patients aged ≥ 20 years with and without diabetes, respectively, were matched by age, sex, and the Charlson comorbidity index. Ultimately, 1,751,457 patients were selected from each group. Stratified populations for diabetic retinopathy (DR) (n = 380,822) and without DR (n = 380,822) as well as proliferative DR (PDR) (n = 141,150) and non-proliferative DR (NPDR) (n = 141,150) were analyzed in this study. The main outcome measure was the first-time diagnosis of cancer during the follow-up period. Results We observed a 20% higher risk of total cancer incidence [hazard ratios (HR), 1.20; p

Abstract Background Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol. Methods The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a −/− and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers. Results We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells. Conclusions We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.

Abstract Background Cardiovascular disease (CVD) is one among the major causes of mortality all round the globe. Several anti-platelet regimens have been proposed following percutaneous coronary intervention (PCI). In this analysis, we aimed to show the adverse clinical outcomes associated with ticagrelor monotherapy after a short course of dual antiplatelet therapy (DAPT) with ticagrelor and aspirin following PCI in patients with versus without diabetes mellitus (DM). Methods Electronic databases were searched by four authors from September to November 2023. Cardiovascular outcomes and bleeding events were the endpoints of this analysis. Revman 5.4 software was used to conduct this meta-analysis. Risk ratio (RR) and 95% confidence intervals (CI) were used to represent the results which were generated. Results Three studies with a total number of 22,574 participants enrolled from years 2013 to 2019 were included in this analysis. Results of this analysis showed that DM was associated with significantly higher risks of major adverse cardiovascular events (RR: 1.73, 95% CI: 1.49 – 2.00; P = 0.00001), all-cause mortality (RR: 2.15, 95% CI: 1.73 – 2.66; P = 0.00001), cardiac death (RR: 2.82, 95% CI: 1.42 – 5.60; P = 0.003), stroke (RR: 1.78, 95% CI: 1.16 – 2.74; P = 0.009), myocardial infarction (RR: 1.63, 95% CI: 1.17 – 2.26; P = 0.004) and stent thrombosis (RR: 1.74, 95% CI: 1.03 – 2.94; P = 0.04) when compared to patients without DM. However, thrombolysis in myocardial infarction (TIMI) defined minor and major bleedings, bleeding defined according to the academic research consortium (BARC) type 3c (RR: 1.31, 95% CI: 0.14 – 11.90; P = 0.81) and BARC type 2, 3 or 5 (RR: 1.17, 95% CI: 0.85 – 1.62; P = 0.34) were not significantly different. Conclusion In patients who were treated with ticagrelor monotherapy after a short course of DAPT with ticagrelor and aspirin, DM was an independent risk factor for the significantly increased adverse cardiovascular outcomes. However, TIMI and BARC defined bleeding events were not significantly different in patients with versus without DM.

Abstract Background Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 probably cannot tolerate chemotherapy or other antitumor therapies. Some studies have reported that immunotherapy combined with antiangiogenic therapy is well‐tolerated and shows good antitumor activity. However, the efficacy of this combination as a later‐line therapy in patients with ECOG PS 2 is unclear. This study evaluated the effectiveness and safety of this combination strategy as third‐ or further‐line therapy in stage IV non‐small cell lung cancer (NSCLC) patients with ECOG PS 2. Methods In this retrospective study, patients treated with camrelizumab plus antiangiogenic therapy (bevacizumab, anlotinib, or recombinant human endostatin) were included. Objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), quality of life (QOL) assessed by ECOG PS, and safety were analyzed. Results Between January 10, 2019, and February 28, 2024, a total of 59 patients were included. The ORR was 35.6% (21/59) and the DCR was 86.4%. With a median follow‐up of 10.5 months (range: 0.7–23.7), the median PFS was 5.5 months (95% confidence interval [CI]: 3.8–7.3) and the median OS was 10.5 months (95% CI: 11.2–13.6). QOL was improved (≥1 reduction in ECOG PS) in 39 patients (66.1%). The most common Grade 3–4 treatment‐related adverse events were hepatic dysfunction (6 [10%]), hypertension (5 [8%]), and hypothyroidism (3 [5%]). There were no treatment‐related deaths. Conclusions Third‐ or further‐line immunotherapy combined with antiangiogenic therapy is well‐tolerated and shows good antitumor activity in stage IV NSCLC patients with ECOG PS 2. Future large‐scale prospective studies are required to confirm the clinical benefits of this combination therapy.

Microarray data is of great significance for cancer identification at the gene level. In the microarray dataset, only a small number of characteristic genomes have significant classification and identification rates for cancer. How to extract a small number of characteristic genes from a large number of microarray data is a classic NP-hard problem. This paper proposes a practical hybrid approach to implement the feature selection of gene expression from the microarray by combining the F-score algorithm and an improved artificial fish swarm algorithm with population variation (FSA-PV). Firstly, the F-score algorithm eliminates a large number of useless and redundant features in the dataset. Then, FSA-PV is discussed to obtain the ability to jump out of the local optimum while retaining the excellent feature of the subset as much as possible, and the adaptive step and visual are used to adjust the search space and to move the range of the algorithm in different environments to improve the local optimization and global optimization abilities. In addition, a naive Bayesian classifier is used to test the classification accuracy of subsets. Eight classical datasets are used to verify the performance of the proposed mechanism in the experiment part. The results reveal that the classification accuracy using the FSA-PV is significant superior to other algorithms in Breast dataset, and the classification accuracy is more than 90% in 8 cases. It further indicates the robustness and feasibility of the FSA-PV in the gene selection process.

AbstractContext Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.Objective To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan.Materials and methods In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses.Results In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Ki was 0.574 μM and the binding constant αKi was 2.77 μM. In vivo experiments revealed that the AUC(0-T) (15.05 vs. 90.95 μg/mL·h) and AUC(0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib.Conclusions Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.

Abstract Intestinal organoid transplantation is a promising therapy for the treatment of mucosal injury. However, how the transplanted organoids regulate the immune microenvironment of recipient mice and their role in treating intestinal ischemia-reperfusion (I/R) injury remains unclear. Here, we establish a method for transplanting intestinal organoids into intestinal I/R mice. We find that transplantation improve mouse survival, promote self-renewal of intestinal stem cells and regulate the immune microenvironment after intestinal I/R, depending on the enhanced ability of macrophages polarized to an anti-inflammatory M2 phenotype. Specifically, we report that L-Malic acid (MA) is highly expressed and enriched in the organoids-derived conditioned medium and cecal contents of transplanted mice, demonstrating that organoids secrete MA during engraftment. Both in vivo and in vitro experiments demonstrate that MA induces M2 macrophage polarization and restores interleukin-10 levels in a SOCS2-dependent manner. This study provides a therapeutic strategy for intestinal I/R injury.

Camellia oleifera is an important oilseed forest tree, but it is unknown whether and how inoculation with arbuscular mycorrhizal fungi, as well as spraying easily extractable glomalin-related soil protein (EG), regulates the fatty acid profile in seeds of this species. This study explored how inoculation with Rhizophagus intraradices (800 g inoculum/tree) and spraying EG (2.5 L/tree, four times in total, once a week) modulated the fatty acid profile for potential nutritional qualities in the seeds of 20-year-old C. oleifera. Spraying exogenous EG significantly increased fruit transverse diameter, longitudinal diameter, fruit weight, number of seeds, and seed weight but had no significant effect on the root mycorrhizal colonization rate. Inoculation with R. intraradices had no significant effect on these fruit traits but significantly boosted the root mycorrhizal colonization rate. A total of 11 saturated fatty acids and 12 unsaturated fatty acids were detected from the seeds, with the unsaturated fatty acids consisting primarily of C18:1N-12, C18:1N-9C, and C18:2-N6. Spraying exogenous EG significantly increased the levels of major unsaturated fatty acid components such as C18:1N-12, C18:1N-9C, C18:1N-7, and C18:2N-6 by 140.6%, 59.7%, 97.6%, and 60.6%, respectively, while decreasing the level of C16:0. Inoculation with R. intraradices only decreased the levels of C16:0 and C18:0, while increased the level of C18:2N-6. Both treatments increased the percentage of unsaturated fatty acids in total fatty acids, resulting in an increase in the unsaturation index of fatty acids. In addition, inoculation with R. intraradices significantly up-regulated the expression of CoFAD2, spraying exogenous EG significantly increased the expression of CoSAD, CoFAD2, and CoFAD3, and both treatments also significantly suppressed the expression of CoFAE. These findings suggested that exogenous EG as a biostimulant, is more suitable to regulate the nutritional values of fatty acids in seeds of 20-year-old C. oleifera.

The medicinal benefits of green seaweed Ulva have been documented in traditional Chinese medicine literatures. Sulfated polysaccharides found in Ulva are recognized as the primary bioactive compounds, known for their immunomodulatory and anti-inflammatory properties. Despite this knowledge, the available information regarding anti-allergic activities of Ulva remains limited. The objective of this study was to prepare and characterize Ulva-derived polysaccharides (UP), oligosaccharides (UO), and residues (UR), followed by assessing their potential in improving allergic enteritis and gut microbiota in a murine model of ovalbumin (OVA)-induced food allergy. The immunomodulatory activities of UP, UO, and UR were evaluated by measuring the expression of serum antibodies, splenic cytokines and duodenal transcript factors of T cell subsets. The impact of UP, UO, and UR on enteric microbiota was explored by 16S rRNA gene sequencing analysis of fresh fecal samples from treated mice. Oral treatment of UP, UO, and UR noticeably attenuated allergic diarrhea and enteritis. Additionally, Ulva samples treatment decreased serum levels of IgG1 and OVA-specific IgE while increased the level of OVA-specific IgG. Enhanced production of IFN-γ and reduced production of IL-4 and IL-10 by splenocytes were observed in the treated mice. In parallel, Ulva samples treatment led to a decreased number of GATA3+ cells and an increased number of T-bet+ cells in the duodenum. However, the population of Foxp3+ cells was not significantly altered. Moreover, treatment of Ulva samples improved enteric dysbiosis evidenced by an increased abundance of Lactobacillus murinus, L. johnsonii, and L. reuteri, and a decreased abundance of Kineothrix alysoides, Lacrimispora saccharolytica, L. aerotolerans, and Erysipelotrichaceae in feces. In conclusion, UP, UO, and UR, which could modulate the Th1/Th2 immune balance, alleviate allergic enteritis and improve enteric dysbiosis in varying degrees, are potential to be developed into therapeutic agents for food allergy.