Gastric cancer (GC) is one of the most common malignancies and a prominent cause of cancer mortality worldwide. H. pylori infection promotes atrophy, IM and GC. Nevertheless, the identification and characterization of non-H. pylori driver bacteria associated with gastric carcinogenesis remain unexplored. In our study, we characterized the fecal microbial composition and mucosal metabolites in patients with progressive histological stages along gastric tumorigenesis—from SG through AG to GC. Interestingly, the abundance of S. anginosus was increased in the GC group when compared to both SG and AG groups. In the while, the GC group harbored a higher level of P. merdae and B. bifidum compared to the AG group. The abundance of P. merdae distinguished the GC and SG group, the area under the curve (AUC) was 0.6963. Furthermore, non-targeted metabolomics found the lyso family including lysoPC, lysoPS and lysoPE increased in the tumor tissue. The PldA enzyme was the key enzyme combination the phospholipids, and we found P. merdae held the genome of PldA enzyme. This study suggests the level of P. merdae might be a biomarker in monitoring the progression of GC.

4093 Background: Early detection of gastric cancer (GC) is limited by invasive endoscopy and the low sensitivity of current blood-based biomarkers for early-stage disease. Emerging evidence indicates that GC engages in complex crosstalk with the bone marrow microenvironment, imposing stress on hematopoiesis. Tumor-derived exosomal and inflammatory mediators reprogram transcriptional and epigenetic profiles in hematopoietic progenitors, driving abnormal hematopoiesis and inducing genomic instability. Here, we report a noninvasive strategy for GC detection based on genome-wide profiling of DNA remnants in mature red blood cells (rbcDNA) and validate its performance for early-stage disease across independent multicenter cohorts. Methods: We analyzed rbcDNA from 1–2 mL peripheral blood of 865 individuals, including 434 treatment-naive patients with stage I–III GC (~60% stage I) and 431 non-GC controls with benign gastric conditions. Shallow whole-genome sequencing revealed reproducible rbcDNA read-depth features that distinguished GC from non-cancer states. A machine-learning classifier was trained on dimensionally reduced rbcDNA features in a discovery cohort (n = 435), with a cutoff fixed at 90% specificity. The locked model was then evaluated in a test cohort (n = 109) and three independent validation cohorts from distinct medical centers (n = 321). Results: In a discovery cohort, we identified GC-associated rbcDNA features that were significantly enriched in hematopoietic regulation and cell-cycle pathways, reflecting systemic hematopoietic stress rather than tumor-derived copy-number alterations. The resulting classifier achieved AUCs of 93% in the discovery cohort and 95% in the test cohort. At the predefined cutoff, the classifier yielded 83% overall sensitivity and 79% sensitivity for stage I GC in the test cohort. Across three independent medical center cohorts, the model achieved sensitivities of 83%, 90%, and 86%, with specificities ranging from 89% to 94%, consistent with the discovery and test cohorts. The assay effectively distinguished early-stage GC from precancerous lesions, including atrophic gastritis and intestinal metaplasia, while showing limited detection in non-gastric solid tumors. Importantly, rbcDNA identified ~80% of GC cases that were negative for conventional serum tumor markers. Conclusions: These findings establish rbcDNA as an effective biomarker for accurate, noninvasive detection of early-stage GC.

Perioperative hypothermia (PHT) and shivering represent significant clinical challenges in geriatric surgical populations. This network meta-analysis (NMA) systematically evaluates the comparative efficacy of various warming interventions in preventing PHT and shivering among elderly patients undergoing abdominal or pelvic surgery. We conducted a comprehensive literature search across PubMed, EMBASE, Cochrane library, and China Wanfang databases for randomized controlled trials (RCTs) published up to April 2024. Inclusion criteria encompassed RCTs comparing warming strategies in patients aged ≥ 60 years undergoing abdominal or pelvic surgery. Methodological quality was assessed using the Cochrane Risk of Bias tool 2.0. Primary outcomes included incidence rates of PHT and shivering. A frequentist approach to NMA was performed using random-effects models, with surface under the cumulative ranking curve (SUCRA) values calculated for treatment ranking. The analysis incorporated 18 RCTs (n = 2161) evaluating eight distinct warming strategies. Network meta-analysis revealed that forced-air warming with blankets at ≥ 40 °C (FABWH) demonstrated superior efficacy for PHT prevention, while forced-air warming at ≥ 40 °C (FAWH) showed optimal performance for shivering reduction. Compared to standard care, FABWH significantly reduced PHT risk (RR = 0.14, 95% CI 0.04-0.46; P = 0.0012) and shivering incidence (RR = 0.21, 95% CI 0.07-0.69; P = 0.008). FAWH exhibited comparable effectiveness, with risk reductions of 72% for PHT (RR = 0.28, 95% CI 0.13-0.58; P = 0.0006) and 84% for shivering (RR = 0.16, 95% CI 0.07-0.39; P < 0.001). This NMA provides robust evidence that active warming strategies, particularly FABWH and FAWH, significantly mitigate PHT and shivering risks in elderly surgical patients. Future research should focus on long-term outcomes and cost-effectiveness analyses to optimize clinical decision-making.

The secreted isochorismatases derived from certain filamentous pathogens play vital roles in the infection of host plants by lowering salicylic acid (SA) levels and suppressing SA-mediated defense pathway. However, it remains unclear whether the fungus Fusarium oxysporum f. sp. cubense tropical race 4 (FocTR4), which causes vascular wilt in bananas, utilizes isochorismatases to modulate SA levels in the host and subvert the banana defense system for successful infection. In the current study, we selected and functionally characterized the foisc1 gene, one of 10 putative isochorismatase-encoding genes in FocTR4 that showed significant upregulation during early stages of infection. Deletion of foisc1 resulted in enhanced vegetative growth and conidiation, increased sensitivity to SA, reduced colonization within host plants, as well as impaired pathogenicity. Conversely, complementation restored phenotypes similar to those observed in the wild-type strain. Furthermore, deletion of foisc1 led to a notable rise in activities of defense-related enzymes such as catalase, peroxidase, and phenylalnine ammonialyase; along with an upregulated expression of several defense-related genes including PR genes and NPR1 genes within hosts' tissues. The non-secretory nature of Foisc1 protein was confirmed and its absence did not affect SA levels within host plants. Transcriptome analysis revealed that deletion of foisc1 resulted in decreased expression levels for numerous genes associated with pathogenicity including those involved in fusaric acid biosynthesis and effector genes as well as a catechol 1,2-dioxygenase gene essential for SA degradation; while increasing expression levels for numerous genes associated with hyphal growth and conidiation were observed instead. Therefore, our findings suggest that Foisc1 may influence hyphal growth, conidiation, sensitivity to SA, and pathogenicity of FocTR4 through modulation of various genes implicated in these processes. These findings provide valuable insights into the pathogenesis of FocTR4, and create a groundwork for the future development of innovative control strategies targeting vascular wilt disease of banana.

Internet-based health education has been increasingly integrated into perioperative and postoperative management for patients with colorectal cancer (CRC). However, the overall effectiveness of such interventions on psychological well-being and recovery outcomes remains uncertain. A systematic search was conducted in PubMed, Embase, Cochrane Library, Web of Science, CNKI, and Wanfang databases from inception to December 2024. Eligible studies included randomized controlled trials (RCTs) or cohort studies evaluating Internet-based health education interventions in CRC patients, with control groups receiving conventional care or standard education. Primary outcomes were SAS (Self-Rating Anxiety Scale) and SDS (Self-Rating Depression Scale), and 36-Item Short Form Health Survey quality of life (QOL); secondary outcomes included postoperative recovery indicators such as time to first flatus and length of hospital stay. Data were pooled using random-effects meta-analyses, and heterogeneity was assessed using the I² statistic. A total of 20 studies (19 RCTs and 1 cohort study) involving 1540 participants were included. Meta-analysis showed that Internet-based health education methods can significantly improve self-care skills (SMD = 2.62, 95

The human oral microbiome plays a significant role in systemic health, including potential links to digestive tract cancers. However, few studies have examined the causal relationship between the oral microbiota and digestive tract cancers using robust methodologies. This study aimed to investigate the causal associations between specific oral microbiota and the risk of gastric, esophageal, colorectal, liver, and pancreatic cancers using a Mendelian randomization (MR) approach. We employed a two-sample MR analysis using genome-wide association study (GWAS) data from 2,948 individuals from the CNGBdb for the oral microbiome and over 150,000 individuals from BioBank Japan for digestive cancers. Single nucleotide polymorphisms (SNPs) associated with the oral microbiota were selected as instrumental variables, and the inverse-variance weighted (IVW) method was used for causal estimates. Sensitivity analyses, including MR‒Egger regression and leave-one-out tests, were performed to assess pleiotropy and robustness. Linkage disequilibrium score regression (LDSC) was applied to explore genetic correlations. Our MR analysis revealed several suggestive associations between the oral microbiota and digestive tract cancers. For esophageal cancer, both Fusobacterium periodonticum (OR = 1.36, 95

Sialylation significantly influences tumor progression, invasion, and metastasis. Accurately characterizing sialylated N-glycopeptides (SGPs), particularly the linkage-specific analysis of α2,3,α2,6 sialic acids, remains a challenging yet crucial task in glycoproteomics. Notably, to date, there is a notable lack of detailed studies on α2,3/α2,6 sialylation in serum. Here, we present SiaQuant, an integrated strategy that employs liquid chromatography-ion mobility-tandem mass spectrometry (LC-IM-MS/MS), capitalizing on the distinctive separation of characteristic isomeric glycan fragments in ion mobility to accurately analyze serum α2,3/α2,6 sialylation patterns. It first provides proteome-wide insights into α2,3/α2,6 sialylation in serum, revealing three-dimensional heterogeneities across N-glycans, N-glycosites, and N-glycoproteins. Additionally, SiaQuant identifies potential candidate biomarkers for neoadjuvant chemotherapy (NACT) response in locally advanced cervical cancer (LACC), where the elevated level of α2,3/α2,6 sialylation was found to be associated with NACT resistance. In summary, SiaQuant offers the most comprehensive site- and linkage-specific N-glycosylation profiling of serum and shows great potential in clinical usage.

Background Preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) has been widely utilized to select euploid embryos in patients carrying balanced chromosomal rearrangements (BCRs) by chromosome copy number analysis. However, reliable and extensively validated PGT-SR methods for selecting embryos without BCRs in large-cohort studies are lacking. Methods In this prospective, multicenter, cohort study, carriers with BCRs undergoing PGT-SR were recruited across 12 academic fertility centers within China. PGT-SR was performed using genome-wide SNP genotyping and haplotyping approach. Parental haplotypes were phased by available genotypes from a close relative or an unbalanced embryo. The karyotypes of embryos were inferred from the haplotypes. Only a single embryo was transferred in each cycle. Findings Between April 2018 and March 2023, 1298 carriers we randomly enrolled. A total of 7867 blastocysts from 1603 PGT-SR cycles were biopsied, in which 7750 (98.51%) were successfully genotyped and analyzed. Overall, 75.98% (1218/1603) of cycles obtained euploid embryos and 53.15% (852/1603) generated non-carrier embryos. The proportion of carrier and non-carrier embryos was similar in different subgroups. A total of 1030 non-carrier and 439 carrier embryos were transferred, 817 healthy babies were delivered cumulatively. Our results demonstrate that SNP-haplotyping method is highly accurate (sensitivity 95% CI: 98.34%-100%, specificity 95% CI: 96.63%-100%, respectively), and can be applied universally to different BCR types. Moreover, the clinical outcomes were comparable between the carrier and non-carrier embryo groups. Interpretation This study demonstrates the effectiveness of preimplantation genetic genome-wide SNP-genotyping and haplotyping method, resulting in the delivery of more babies with a normal karyotype. Funding This study was funded by the National Key Research and Development Program of China (2022YFC2703200, 2021YFC2700600, 2021YFC2700500), National Natural Science Foundation of China (82201807, 82171639, 82071717). Shanghai Science and Technology Innovation Action Plan Program (18411953800), and the Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2022YQ075). Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Letrozole, an aromatase inhibitor, is commonly used for ovulation induction in patients with polycystic ovary syndrome (PCOS). However, the effect of different doses of letrozole on pregnancy outcomes remains controversial. This systematic review and network meta‑analysis aims to compare the effects of different doses of letrozole on pregnancy outcomes in PCOS patients. A systematic search was performed in databases such as PubMed, WOS, and Wanfang for randomized clinical trials (RCTs) assessing different doses of letrozole in PCOS patients. The primary outcome was pregnancy outcome. A network meta‑analysis was conducted using Stata 17's network package and the 'netmeta' and 'gemtc' packages in R software. A total of 30 RCTs involving 3663 patients were included, comparing 11 intervention strategies. Compared with 2.5 mg letrozole, 5 mg letrozole (OR = 1.99, 95% CI: 1.47-2.68; p > 0.05), 7.5 mg letrozole (OR = 1.89, 95% CI: 1.17-3.06; p > 0.05), and 7.5 mg letrozole combined with clomiphene (OR = 7.60, 95% CI: 1.33-43.35; p > 0.05) all significantly improved pregnancy outcomes. Additionally, compared with 2.5 mg letrozole combined with human gonadotropin (HMG), 5 mg (OR = 1.12), 7.5 mg (OR = 1.19), and 20 mg (OR = 1.72) letrozole combined with HMG showed improvements in pregnancy rates, though the differences were not statistically significant (p > 0.05). The lack of unpublished studies and non‑English publications may have introduced publication bias. Letrozole treatment significantly improves pregnancy outcomes in PCOS patients. Moderate‑dose letrozole is recommended as the most effective strategy for improving pregnancy outcomes. Further clinical studies are required to confirm these findings.

Objective: This study aimed to compare the effects of Internet-based health education methods on post-treatment recovery and quality of life in patients with colorectal cancer through meta-analysis. Methods: PubMed, Embase, Cochrane Library, Wanfang database and other databases were systematically searched to screen clinical studies that met the inclusion criteria. The Cochrane bias risk tool was used to assess study quality, and RevMan 5.4 and STATA 17 software were used for data merging and statistical analysis, heterogeneity assessment, sensitivity analysis and publication bias test. Results: A total of 20 studies involving 1540 patients with colorectal cancer were included. Meta-analysis showed that Internet-based health education methods can significantly improve self-care skills (SMD = 2.62, 95%CI: 0.25 ~ 4.99, P = 0.03), significantly reduce SAS (SMD=-0.97, 95%CI: -1.11~-0.83, P < 0.01) and SDS scores (SMD=-2.08, 95%CI: -3.54~-0.63, P = 0.01), reduce the incidence of postoperative complications (Log(OR)=-1.08, 95%CI: -1.45~-0.72, P < 0.01), and significantly improve QOL scores (SMD = 0.51, 95%CI: 0.29 ~ 0.72, P < 0.01). Subgroup analysis showed that the intervention method based on the WeChat platform was more effective in improving SAS (SMD=-1.06, P < 0.01). Conclusion: Internet-based health education methods have significant positive effects in colorectal cancer patients, effectively reducing the incidence of postoperative complications, improving self-care ability, alleviating anxiety and depression symptoms, and improving quality of life. Further research is necessary to explore the long-term effects of different Internet education models.

The present study aimed to explore how semaglutide can help protect the heart from injury caused by hypoxia/reoxygenation (H/R) and to reveal the underlying mechanism. Briefly, AC16 cardiomyocytes were subjected to 8 h of hypoxia followed by 12 h of reoxygenation to simulate H/R. The cells were divided into the following five groups: Normoxia, H/R, H/R + semaglutide, H/R + semaglutide + rapamycin (autophagy inducer), and H/R + semaglutide + 3‑methyladenine (3‑MA; autophagy inhibitor) groups. Cell viability was examined using a Cell Counting Kit‑8 assay, ATP levels were examined using a bioluminescent detection kit, reactive oxygen species (ROS) production was detected using a ROS Assay Kit, and monomeric red fluorescent protein (mRFP)‑green fluorescent protein (GFP)‑LC3 was assessed using tandem mRFP‑GFP fluorescence microscopy, while autophagosomes were observed using transmission electron microscopy. Furthermore, the protein expression levels of autophagy markers (LC3, p62 and Beclin1) and regulators of mitochondrial autophagy [PTEN‑induced putative kinase protein‑1 (PINK1) and Parkin] were examined using western blot analysis. In AC16 cells, exposure to hypoxia followed by reoxygenation led to an increase in oxidative stress. This condition also induced an increase in autophagy activity, as evidenced by an increase in the number of autophagosomes, elevated LC3‑II/LC3‑I ratio, and upregulation of p62, Beclin1, PINK1 and Parkin expression compared with those in cells cultured under normoxia. Notably, treatment with semaglutide or rapamycin effectively reversed the H/R‑induced oxidative stress, enhanced the changes in autophagy activity, autophagosome levels and elevated LC3BII/LC3BI ratio, and increased the expression levels of Beclin1, PINK1, Parkin and p62 expression. Notably, the use of 3‑MA exhibited distinct effects under the same conditions; it exacerbated oxidative stress, decreased autophagy activity and reduced the LC3BII/LC3BI ratio. In conclusion, semaglutide was found to reduce oxidative stress caused by H/R and to increase autophagy via the ROS/PINK1/Parkin/p62 pathway. The present study offers a novel understanding of how semaglutide may protect the heart, and suggests its potential use in the treatment of myocardial ischemia/reperfusion injury.

Ferroptosis is an important mechanism underlying cardiac ischemia/reperfusion (I/R) injury. However, the specific molecular mechanisms by which aerobic exercise alleviates cardiac I/R injury and inhibits ferroptosis remain unclear. In this study, we investigated the effects of IGFBP2 on aerobic exercise-mediated protection of cardiac function following I/R and its influence on ferroptosis in cardiomyocytes and SIRT1 activation. Wild-type (WT) or IGFBP2 knockout (IGFBP2_KO) C57BL/6J mice with I/R injury were subjected to aerobic exercise intervention, and cardiomyocytes exposed to hypoxia/reoxygenation (H/R) were treated with IGFBP2. We explored the role of IGF-1R in IGFBP2-mediated cardiac protection using IGF-1R conditional knockout (IGF-1R_CKO) mice subjected to aerobic exercise intervention and cardiomyocytes exposed to H/R and incubated with IGFBP2 and IGF-1R silenced via adenoviral vector (ADV) transfection. The effects of SIRT1 and TXNIP/TRX on ferroptosis in cardiomyocytes exposed to H/R were also examined using SIRT1 inhibitors, SIRT1 agonists, and adenovirus transfection to modulate TXNIP expression levels. Aerobic exercise increased circulating IGFBP2 levels in mice, inhibited ferroptosis in cardiomyocytes, and protected cardiac function following I/R (p < 0.001). IGFBP2 suppressed ferroptosis in cardiomyocytes subjected to H/R and enhanced SIRT1 activation (p < 0.001). IGF-1R_CKO abrogated the inhibitory effects of IGFBP2 and aerobic exercise on cardiomyocyte ferroptosis (p < 0.001). SIRT1 activation inhibited ferroptosis in cardiomyocytes exposed to H/R by downregulating TXNIP expression, upregulating TRX expression, and increasing TXNIP/TRX binding (p < 0.001). Inhibition of TXNIP suppressed ferroptosis following H/R (p < 0.001). Aerobic exercise-induced circulating IGFBP2 directly interacts with IGF-1R, leading to increased activation of SIRT1 and reduced levels of free TXNIP, thus inhibiting cardiomyocyte ferroptosis in cardiac I/R injury.

Abstract Postoperative venous thromboembolic events (VTEs), such as lower extremity deep vein thrombosis (DVT), are major risk factors for gastric cancer (GC) patients following radical gastrectomy. Accurately predicting and managing these risks is crucial for optimal patient care. This retrospective case‒control study involved 693 GC patients from our hospital who underwent radical gastrectomy. We collected plentiful and comprehensive clinical indicators including a total of 49 baseline, preoperative, surgical and pathological clinical data. Using univariate logistic regression, we identified potential risk factors, followed by feature selection through the Boruta algorithm. We then constructed the final predictive model using multivariate logistic regression and evaluated it using receiver operating characteristic (ROC) curve analysis, calibration plots, decision curve analysis, and other methods. Additionally, we applied various machine learning techniques, including decision trees and random forests, to assess our model’s predictive strength. This retrospective case‒control study involved 693 GC patients from our hospital who underwent radical gastrectomy. We collected plentiful and comprehensive clinical indicators including a total of 49 baseline, preoperative, surgical and pathological clinical data. Using univariate logistic regression, we identified potential risk factors, followed by feature selection through the Boruta algorithm. We then constructed the final predictive model using multivariate logistic regression and evaluated it using receiver operating characteristic (ROC) curve analysis, calibration plots, decision curve analysis, and other methods. Additionally, we applied various machine learning techniques, including decision trees and random forests, to assess our model’s predictive strength. Univariate logistic analysis revealed 14 risk factors associated with postoperative lower limb DVT. Based on the Boruta algorithm, six significant clinical factors were selected, namely, age, D-dimer (D-D) level, low-density lipoprotein, CA125, and calcium and chloride ion levels. A nomogram was developed using the outcomes from the multivariate logistic regression analysis. The predictive model showed high accuracy, with an area under the curve of 0.936 in the training set and 0.875 in the validation set. Various machine learning algorithms confirmed its strong predictive capacity. MR analysis revealed meaningful causal relationships between key clinical factors and DVT risk. Based on various machine learning methods, we developed an effective predictive diagnostic model for postoperative lower extremity DVT in GC patients. This model demonstrated excellent predictive value in both the training and validation sets. This novel model is a valuable tool for clinicians to use in identifying and managing thrombotic risks in this patient population.

Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1). STING activation enhanced lysosome biogenesis through inducing the nuclear translocation of transcription factor EB (TFEB) as well as its paralogs transcription factor E3 (TFE3) and microphthalmia-associated transcription factor (MITF). STING-induced lipidation of GABA type A receptor-associated protein (GABARAP), an autophagy-related protein, on STING vesicles was responsible for TFEB activation. Membrane-bound GABARAP sequestered the GTPase-activating protein folliculin (FLCN) and FLCN-interacting protein (FNIP) complex to block its function toward the Rag GTPases Ras-related GTP-binding C and D (RagC and RagD), abolishing mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent phosphorylation and inactivation of TFEB. Functionally, STING-induced lysosome biogenesis within cells facilitated the clearance of cytoplasmic DNA and invading pathogens. Thus, our findings reveal that induction of lysosome biogenesis is another important function of the cGAS-STING pathway.

Objective: This study (CRD42023464989) aimed to explore the effects of pre-operation immunonutrition on safety and immune related factors in colorectal cancer patients undergoing surgery. Methods: We systematically searched PubMed, Embase, and Wanfang databases to collect all clinical randomized controlled trials of the application of pre-operation immunonutrition for patients with colorectal cancer, published until July 2023. The primary outcomes were safety and immune related factors. Results: A total of 16 studies were finally included. Preoperative immunonutrition could reduce the postoperative infection rate (risk ratio (RR) = 0.56, 95% confidence interval (CI): 0.36, 0.88; p = .01), and wound infection rate (RR = 0.44, 95% CI: 0.27, 0.70; p < .001) in patients with colorectal cancer. For length of stay (mean difference (MD) = -1.10, 95% CI: -2.70, 0.49; p = .17), it was similar between groups. Meanwhile, patients in the pre-operation immune nutrition group also had significantly increased infiltrative lymphocytes CD16+ (MD = 0.04, 95% CI: 0.02, 0.06; p < .001), and CD56+ (MD = 0.05, 95% CI: 0.03, 0.06; p < .001) cells in the tumor tissues, compared to the control group. Conclusion: Immunonutrition intervention has the potential to reduce postoperative infectious complications and improve tumor infiltrative lymphocytes in patients with colorectal cancer undergoing surgery.

Abstract Background Digestive system cancers represent a significant global health challenge and are attributed to a combination of demographic and lifestyle changes. Lipidomics has emerged as a pivotal area in cancer research, suggesting that alterations in lipid metabolism are closely linked to cancer development. However, the causal relationship between specific lipid profiles and digestive system cancer risk remains unclear. Methods Using a two-sample Mendelian randomization (MR) approach, we elucidated the causal relationships between lipidomic profiles and the risk of five types of digestive system cancer: stomach, liver, esophageal, pancreatic, and colorectal cancers. The aim of this study was to investigate the effect impact of developing lipid profiles on the risk of digestive system cancers utilizing data from public databases such as the GWAS Catalog and the UK Biobank. The inverse‒variance weighted (IVW) method and other strict MR methods were used to evaluate the potential causal links. In addition, we performed sensitivity analyses and reverse MR analyses to ensure the robustness of the results. Results Significant causal relationships were identified between certain lipidomic traits and the risk of developing digestive system cancers. Elevated sphingomyelin (d40:1) levels were associated with a reduced risk of developing gastric cancer (odds ratio (OR) = 0.68, P < 0.001), while elevated levels of phosphatidylcholine (16:1_20:4) increased the risk of developing esophageal cancer (OR = 1.31, P = 0.02). Conversely, phosphatidylcholine (18:2_0:0) had a protective effect against colorectal cancer (OR = 0.86, P = 0.036). The bidirectional analysis did not suggest reverse causality between cancer risk and lipid levels. Strict MR methods demonstrated the robustness of the above causal relationships. Conclusion Our findings underscore the significant causal relationships between specific lipidomic traits and the risk of developing various digestive system cancers, highlighting the potential of lipid profiles in informing cancer prevention and treatment strategies. These results reinforce the value of MR in unraveling complex lipid-cancer interactions, offering new avenues for research and clinical application.

Abstract Background Acute myocardial infarction (AMI) remains a significant cause of global mortality, exacerbated by ischemia-reperfusion (IR) injury. Myocardial cell pyroptosis has emerged as a critical pathway influencing IR injury severity. Methods We aimed to investigate the cardioprotective effects of aerobic exercise on IR injury by examining the modulation of IGFBP2 and its impact on GSDME-dependent myocardial cell pyroptosis. Mechanistic pathways were explored using western blot analysis, ELISA, immunofluorescence, and echocardiography. Results Our findings demonstrate that aerobic exercise leads to increased circulating levels of IGFBP2, which effectively suppresses GSDME-dependent myocardial cell pyroptosis. This regulation occurs via the AKT-GSK3β signaling pathway, involving VDAC1 phosphorylation, thereby enhancing mitochondrial function and reducing oxidative stress. Conclusion In conclusion, our study highlights the role of IGFBP2 in mitigating GSDME-dependent pyroptosis as a mechanism through which aerobic exercise exerts cardioprotective effects against IR injury. These insights suggest potential therapeutic targets for managing acute myocardial infarction.

Although the significance of the curative effect has been recognized, ideal nanocarriers with the properties of lysosomal escape and biocompatibility are still lacking for the development of siRNA-based cancer gene therapy. In this work, a lysosomal escaped and redox-responsive polyacrylamide nanohydrogel (cRGD-9R-PA(ss)) was constructed for STAT3 siRNA delivery. The functional groups, including tumor-targeting peptide cRGD, cell-penetrating and lysosome-escaping peptide 9R, and a redox-responsive disulfide bond, were introduced to the polyacrylamide nanohydrogel to attain enhanced transfection efficiency and biocompatibility. The synthesized cRGD-9R-PA(ss)(siRNA) was dispersed as core-shell nanoparticles in water with an average size of 48 nm. cRGD-9R-PA(ss)(siRNA) could prevent lysosomal phagocytosis and responsive release STAT3 siRNA into C26 tumor cells, thus promoting STAT3 gene silencing and inhibiting the proliferation of cancer cells in vitro and in vivo. Our results demonstrate that cRGD-9R-PA(ss) hydrogel nanospheres constitute a potential candidate vector for siRNA-based colon cancer gene therapy.

Hepatocellular carcinoma is the most common form of liver tumor. m6A modification and noncoding RNA show indispensable roles in HCC. We sought to establish and verify an appropriate m6A-related long noncoding RNA prognostic tool for predicting hepatocellular carcinoma progression. We extracted the RNA expression levels and the clinicopathologic data from GTEx and TCGA databases. Multivariate Cox regression analysis and receiver operating characteristic curves were performed to test the model's predictive ability. We further built a nomogram for overall survival according to the risk score and clinical features. A competing endogenous RNA network and Gene Ontology assessment were implemented to identify related biological mechanisms and processes. By bioinformatics analysis, a risk model comprising GABPB1-AS1, AC025580.1, LINC01358, AC026356.1, AC009005.1, HCG15, and AC026368.1 was built to offer a prognostic prediction for hepatocellular carcinoma independently. The prognostic tool could better prognosticate hepatocellular carcinoma patients' survival than other clinical characteristics. Then, a nomogram with risk score and clinical characteristics was created, which had strong power to calculate the survival probability in hepatocellular carcinoma. The immune-associated processes involving the differentially expressed genes between the two subgroups were displayed. Analyses of prognosis, clinicopathological characteristics, tumor mutation burden, immune checkpoint molecules, and drug response showed significant differences among the two risk subtypes, hinting that the model could appraise the efficacy of immunotherapy and chemotherapy. The tool can independently predict the prognosis in patients with hepatocellular carcinoma, which benefits drug selection in hepatocellular carcinoma patients.

Development of resistance to therapy-induced cell death is a major hurdle in the effective treatment of advanced solid tumors. Erastin and RSL3 were originally found to induce synthetic lethality by induction of a novel form of cell death termed ferroptosis. Emerging evidence suggests that ferroptosis inducers enhance chemosensitivity of classic therapeutic agents by triggering ferroptotic cell death. In this study we evaluated the effects of erastin and RSL3 on the resistance of docetaxel, doxorubicin, and cisplatin, and revealed a mechanism whereby these ferroptosis inducers augment docetaxel efficacy in non-small cell lung cancer by regulating redox signaling to promote ferroptosis. Transcriptome analysis revealed that combination treatment modulated not only p53 signaling pathway but also immune responses and several signaling pathways including MAPK, NF-κB and PI3K/Akt. Considering that glutathione peroxidase 4 (GPX4) serves as the main effector to protect cells from ferroptosis, this study identified three novel non-covalent GPX4 inhibitors with the aid of pharmacophore-based virtual screening. The new ferroptosis-inducing compounds synergized with docetaxel to increase the cytotoxicity by promoting ferroptotic cell death in docetaxel-resistant A549/DTX cells. Collectively, the induction of ferroptosis contributed to docetaxel-induced cytotoxic effects and overcame drug resistance in A549/DTX cells. Ferroptosis has a great potential to become a new approach to attenuate resistance to some classic therapeutic drugs in cancer patients.