Predicting short-term major postoperative complications in intestinal resection for Crohn's disease: A machine learning-based study.

BACKGROUND: Due to the complexity and numerous comorbidities associated with Crohn's disease (CD), the incidence of postoperative complications is high, significantly impacting the recovery and prognosis of patients. Consequently, additional studies are required to precisely predict short-term major complications following intestinal resection (IR), aiding surgical decision-making and optimizing patient care. AIM: To construct novel models based on machine learning (ML) to predict short-term major postoperative complications in patients with CD following IR. METHODS: A retrospective analysis was performed on clinical data derived from a patient cohort that underwent IR for CD from January 2017 to December 2022. The study participants were randomly allocated to either a training cohort or a validation cohort. The logistic regression and random forest (RF) were applied to construct models in the training cohort, with model discrimination evaluated using the area under the curves (AUC). The validation cohort assessed the performance of the constructed models. RESULTS: Out of the 259 patients encompassed in the study, 5.0% encountered major postoperative complications (Clavien-Dindo ≥ III) within 30 d following IR for CD. The AUC for the logistic model was 0.916, significantly lower than the AUC of 0.965 for the RF model. The logistic model incorporated a preoperative CD activity index (CDAI) of ≥ 220, a diminished preoperative serum albumin level, conversion to laparotomy surgery, and an extended operation time. A nomogram for the logistic model was plotted. Except for the surgical approach, the other three variables ranked among the top four important variables in the novel ML model. CONCLUSION: Both the nomogram and RF exhibited good performance in predicting short-term major postoperative complications in patients with CD, with the RF model showing more superiority. A preoperative CDAI of ≥ 220, a diminished preoperative serum albumin level, and an extended operation time might be the most crucial variables. The findings of this study can assist clinicians in identifying patients at a higher risk for complications and offering personalized perioperative management to enhance patient outcomes.

Integration analysis of cell division cycle-associated family genes revealed potential mechanisms of gliomagenesis and constructed an artificial intelligence-driven prognostic signature.

Cell division cycle-associated (CDCA) gene family members are essential cell proliferation regulators and play critical roles in various cancers. However, the function of the CDCA family genes in gliomas remains unclear. This study aims to elucidate the role of CDCA family members in gliomas using in vitro and in vivo experiments and bioinformatic analyses. We included eight glioma cohorts in this study. An unsupervised clustering algorithm was used to identify novel CDCA gene family clusters. Then, we utilized multi-omics data to elucidate the prognostic disparities, biological functionalities, genomic alterations, and immune microenvironment among glioma patients. Subsequently, the scRNA-seq analysis and spatial transcriptomic sequencing analysis were carried out to explore the expression distribution of CDCA2 in glioma samples. In vivo and in vitro experiments were used to investigate the effects of CDCA2 on the viability, migration, and invasion of glioma cells. Finally, based on ten machine-learning algorithms, we constructed an artificial intelligence-driven CDCA gene family signature called the machine learning-based CDCA gene family score (MLCS). Our results suggested that patients with the higher expression levels of CDCA family genes had a worse prognosis, more activated RAS signaling pathways, and more activated immunosuppressive microenvironments. CDCA2 knockdown inhibited the proliferation, migration, and invasion of glioma cells. In addition, the MLCS had robust and favorable prognostic predictive ability and could predict the response to immunotherapy and chemotherapy drug sensitivity.

The role of the CXCR6/CXCL16 axis in the pathogenesis of fibrotic disease.

CXC chemokine receptor 6 (CXCR6), a seven-transmembrane domain G-protein-coupled receptor, plays a pivotal regulatory role in inflammation and tissue damage through its interaction with CXC chemokine ligand 16 (CXCL16). This axis is implicated in the pathogenesis of various fibrotic diseases and correlates with clinical parameters that indicate disease severity, activity, and prognosis in organ fibrosis, including afflictions of the liver, kidney, lung, cardiovascular system, skin, and intestines. Soluble CXCL16 (sCXCL16) serves as a chemokine, facilitating the migration and recruitment of CXCR6-expressing cells, while membrane-bound CXCL16 (mCXCL16) functions as a transmembrane protein with adhesion properties, facilitating intercellular interactions by binding to CXCR6. The CXCR6/CXCL16 axis is established to regulate the cycle of damage and repair during chronic inflammation, either through modulating immune cell-mediated intercellular communication or by independently influencing fibroblast homing, proliferation, and activation, with each pathway potentially culminating in the onset and progression of fibrotic diseases. However, clinically exploiting the targeting of the CXCR6/CXCL16 axis requires further elucidation of the intricate chemokine interactions within fibrosis pathogenesis. This review explores the biology of CXCR6/CXCL16, its multifaceted effects contributing to fibrosis in various organs, and the prospective clinical implications of these insights.

Diverse animal models for Chlamydia infections: unraveling pathogenesis through the genital and gastrointestinal tracts.

Chlamydia trachomatis is responsible for infections in various mucosal tissues, including the eyes, urogenital, respiratory, and gastrointestinal tracts. Chronic infections can result in severe consequences such as blindness, ectopic pregnancy, and infertility. The underlying mechanisms leading to these diseases involve sustained inflammatory responses, yet thorough comprehension of the underlying mechanisms remains elusive. Chlamydial biologists employ in multiple methods, integrating biochemistry, cell biology, and genetic tools to identify bacterial factors crucial for host cell interactions. While numerous animal models exist to study chlamydial pathogenesis and assess vaccine efficacy, selecting appropriate models for biologically and clinically relevant insights remains a challenge. Genital infection models in animals have been pivotal in unraveling host-microbe dynamics, identifying potential chlamydial virulence factors influencing genital pathogenicity. However, the transferability of this knowledge to human pathogenic mechanisms remains uncertain. Many putative virulence factors lack assessment in optimal animal tissue microenvironments, despite the diverse chlamydial infection models available. Given the propensity of genital Chlamydia to spread to the gastrointestinal tract, investigations into the pathogenicity and immunological impact of gut Chlamydia become imperative. Notably, the gut emerges as a promising site for both chlamydial infection vaccination and pathogenesis. This review elucidates the pathogenesis of Chlamydia infections and delineates unique features of prevalent animal model systems. The primary focus of this review is to consolidate and summarize current animal models utilized in Chlamydia researches, presenting findings, discussions on their contributions, and suggesting potential directions for further studies.

An effective strategy for assembling the sex-limited chromosome.

BACKGROUND: Most currently available reference genomes lack the sequence map of sex-limited (such as Y and W) chromosomes, which results in incomplete assemblies that hinder further research on sex chromosomes. Recent advancements in long-read sequencing and population sequencing have provided the opportunity to assemble sex-limited chromosomes without the traditional complicated experimental efforts. FINDINGS: We introduce the first computational method, Sorting long Reads of Y or other sex-limited chromosome (SRY), which achieves improved assembly results compared to flow sorting. Specifically, SRY outperforms in the heterochromatic region and demonstrates comparable performance in other regions. Furthermore, SRY enhances the capabilities of the hybrid assembly software, resulting in improved continuity and accuracy. CONCLUSIONS: Our method enables true complete genome assembly and facilitates downstream research of sex-limited chromosomes.

Intergenic sequences harboring potential enhancer elements contribute to Axenfeld-Rieger syndrome by regulating PITX2.

Recent studies have uncovered that non-coding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese ARS family and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between PITX2 and FAM241A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-seq and RT-qPCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while Foxc1 expression remained unchanged. ChIP-seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a significant downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) which is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence which is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent. 2.

Gold Catalysis, Asymmetric Friedel-Crafts Alkylation Cascade for One-Pot Synthesis of Chiral Dihydrocarbazoles and Dihydrodibenzofurans.

A one-pot gold-catalyzed acyl migration followed by ytterbium-catalyzed asymmetric Friedel-Crafts alkylation is disclosed, leading to the rapid synthesis of chiral dihydrocarbazoles and dihydrodibenzofuran in generally moderate to good overall yields with good to excellent enantioselectivities. The gold-catalyzed acyl migration of propargyl acetates generates α-ylidene-ß-diketones with high E/Z ratios, which are then subjected to the ytterbium-catalyzed asymmetric Friedel-Crafts alkylation without any purification. Importantly, this protocol provides a new type of substrate for asymmetric Friedel-Crafts alkylation.

Urban and agricultural land use led to niche differentiation of AOA, AOB and comammox along the Beiyun River continuum.

River ecological health has been severely threatened by anthropogenic land-use pressures. Here, by combining remote sensing and molecular biology methods, we evaluated the impact of land-use activities on nitrification, a fundamental ecological process in rivers, which is conducted by ammonia-oxidising archaea (AOA) and ammonia-oxidising bacteria (AOB), or the newly discovered complete ammonia oxidisers (comammox). We explored the relationships of the abundance, activity, and diversity of AOA, AOB, and comammox in river sediments with land-use pressure by proposing a quantitative land use pattern index (LPI) over a 184 km continuum along the Beiyun River in North China. We found that comammox dominated nitrification in the forestry upstream (67.07 % in summer, 56.40 % in winter), while AOB became the major player in the urban middle (56.51 % in summer, 53.08 % in winter) and agricultural downstream reaches (62.98 % in summer, 50.74 % in winter). In addition, urban and agricultural land use lowered the α diversity of AOA and comammox, as well as simplified their co-occurrence networks, but promoted AOB diversity and complicated their networks. The structural equation model illustrated that the key drivers affecting the key taxa and activities were ammonia, and C/N for AOB, and total organic matter, and pH for comammox. We thus conclude that watershed urban and agricultural land use drive the niche differentiation of AOA, AOB, and comammox, specifically leading to a robust AOB community but weakened AOA and comammox communities. Our study connects the macro and micro worlds and provides a new paradigm for studying the variation in microbial communities as well as the potential ecological consequences under the increased anthropogenic land-use pressures in the Anthropocene.

Association of composite dietary antioxidant index with prevalence of stroke: insights from NHANES 1999-2018.

Background: There is a growing acknowledgment of the potential influence of antioxidative effects resulting from dietary decisions on the occurrence of stroke. The objective of this study was to elucidate the correlation between the composite dietary antioxidant index (CDAI) and the incidence of stroke in the general population of the United States. Methods: We gathered cross-sectional data encompassing 40,320 participants from the National Health and Nutrition Examination Survey (NHANES) spanning the years 1999 to 2018. Employing weighted multivariate logistic regression, we assessed the correlation between CDAI and stroke, while also investigating potential nonlinear relationships through restricted cubic spline (RCS) regression. Further, the intake of CDAI components were then incorporated into a predictive nomogram model, subsequently evaluated for its discriminatory prowess in stroke risk assessment using the receiver operating characteristic (ROC) curve. Results: Post-adjustment for confounding variables, we found that higher CDAI score were associated with a decreased risk of stroke, the odds ratio (OR) [95% CI] of CDAI associating with prevalence was 0.96 [0.94-0.98] (P< 0.001). Moreover, the adjusted OR [95% CI] for stroke across ascending CDAI quartiles stood at 0.90 [0.74-1.09], 0.74 [0.60-0.91], and 0.61 [0.50-0.76] compared to the reference quartile, respectively. The RCS analysis indicated a nonlinear yet negative correlation between CDAI and stroke. The nomogram model, constructed based the intake of antioxidants, exhibited a significant predictive capacity for stroke risk, boasting an area under the curve (AUC) of 77.4% (76.3%-78.5%). Conclusion: Our investigation ascertained a nonlinear negative relationship between CDAI and stroke within the broader American population. However, given the inherent limitations of the cross-sectional design, further comprehensive research is imperative to establish the causative nature of this association.

Potential effects of nutrition-induced alteration of gut microbiota on inflammatory bowel disease: A review.

Inflammatory bowel disease (IBD), mainly comprising ulcerative colitis and Crohn's disease, is a group of gradually progressive diseases bringing significant mental anguish and imposes serious economic burdens. Interplay of genetic, environmental, and immunological factors have been implicated in its pathogenesis. Nutrients, as crucial environmental determinants, mainly encompassing carbohydrates, fats, proteins, and micronutrients, are closely related to the pathogenesis and development of IBD. Nutrition is essential for maintaining the dynamic balance of intestinal eco-environments to ensure intestinal barrier and immune homeostasis, while this balance can be disrupted easily by maladjusted nutrition. Research has firmly established that nutrition has the potential to shape the composition and function of gut microbiota to affect the disease course. Unhealthy diet and eating disorders lead to gut microbiota dysbiosis and further destroy the function of intestinal barrier such as the disruption of membrane integrity and increased permeability, thereby triggering intestinal inflammation. Notably, appropriate nutritional interventions, such as the Mediterranean diet, can positively modulate intestinal microecology, which may provide a promising strategy for future IBD prevention. In this review, we provide insights into the interplay between nutrition and gut microbiota and its effects on IBD and present some previously overlooked lines of evidence regarding the role of derived metabolites in IBD processes, such as trimethylamine N-oxide and imidazole propionate. Furthermore, we provide some insights into reducing the risk of onset and exacerbation of IBD by modifying nutrition and discuss several outstanding challenges and opportunities for future study.

Identification and functional study of a novel variant of PAX9 causing tooth agenesis.

OBJECTIVES: To search for pathogenic gene of a family with non-syndromic tooth agenesis, and explore the possible pathogenesis. MATERIALS AND METHODS: A Chinese family with non-syndromic tooth agenesis was recruited and screened for the pathogenic variants by whole exome sequencing technology and co-segregation analysis. The subcellular localization of wild-type and mutant protein was detected by immunofluorescence assay. Cycloheximide chase assay was performed to examine the difference in degradation rate between mutant protein and wild-type one. Dual-luciferase reporter assays were conducted to explore the alterations of mutant protein in the regulation of downstream target genes. RESULTS: A novel missense variant of PAX9 (c.296C>A:p.A99D) was found in this family. Bioinformatics software showed ß-return and the random coil were shortened in the p.A99D. The variant did not affect the subcellular localization of PAX9, but the degradation rate of p.A99D was accelerated (p < 0.05). p.A99D inhibited the activation of downstream target gene BMP4 (p < 0.05). CONCLUSIONS: This novel variant expands the pathogenic gene spectrum. The variant impaired the protein structure, accelerated the degradation of protein, and inhibited the activation of the downstream target gene BMP4, an upstream molecule in the TGF-ß/BMP pathway, which may contribute to tooth agenesis in this family.

Safety and Efficacy of LVIS Jr Stent-assisted Coiling of Intracranial Aneurysms in Small-diameter Parent Arteries : A Single-center Experience.

OBJECTIVE: To investigate the safety and efficacy of LVIS Jr stent-assisted coiling (SAC) of intracranial aneurysms (IAs) in small-diameter parent arteries and determine the factors influencing incomplete aneurysm occlusion. MATERIAL AND METHODS: Clinical and imaging data of 130 patients with IAs in small-diameter parent arteries that were treated with LVIS Jr SAC were retrospectively analyzed. Stent apposition was evaluated by high-resolution flat detector CT, and aneurysm embolization density was evaluated using 2D-DSA. Perioperative complications were recorded. Multivariate logistic regression analyses were performed to determine possible factors for incomplete aneurysm occlusion. RESULTS: In this study, 130 patients (60 and 70 patients with ruptured and unruptured aneurysms, respectively) were successfully treated with LVIS Jr SAC. Immediate digital subtraction angiography (DSA) showed that the aneurysm occlusion was Raymond-Roy class I, II, IIIa, and IIIb in 93 (71.5%), 24 (18.5%), 8 (6.2%), and 5 (3.8%) cases, respectively. There were three cases of acute in-stent thrombosis and two cases of severe vasospasm observed during the perioperative period. The 6­month follow-up angiograms indicated that complete aneurysm occlusion in 122 patients was 79.5% (97/122). Multivariate logistic regression analyses showed that an aneurysm size > 10.0 mm, parent artery mean diameter < 2.0 mm, and incomplete stent apposition at the aneurysm neck were possible risk factors for incomplete aneurysm occlusion. CONCLUSION: The LVIS Jr SAC is effective for managing IAs in small-diameter parent arteries. An aneurysm size > 10.0 mm, parent artery mean diameter < 2.0 mm, and incomplete stent apposition at the aneurysm neck are possible risk factors for incomplete aneurysm occlusion.

Polychlorinated Biphenyl Concentrations and Estimated Intakes in Fish Oil Supplements on the Japanese Market.

Polychlorinated biphenyls (PCBs) are synthetic organic contaminants that are widespread in the environment. There are 209 PCB congeners. Fish oil produced from marine fish is widely used as a health supplement. PCB contamination of fish oil is of concern. We determined the concentrations of all 209 PCB congeners in commercially available fish oil supplements from Japan and estimated PCB intakes for humans consuming the supplements. We determined the concentrations of non-dioxin-like PCBs separately. The total PCB concentrations in 37 fish oil supplements purchased in Japan were 0.024-19 ng/g whole weight, and the non-dioxin-like PCB concentration range was also 0.024-19 ng/g whole weight. The total PCB intakes calculated for a 50 kg human consuming the supplements were 0.039-51 ng/day (0.00078-1.0 ng/(kg body weight per day)) and the non-dioxin-like PCB intake range was also 0.039-51 ng/day (0.00078-1.0 ng/(kg body weight per day)). The total PCB intakes were much lower than the tolerable daily intake of 20 ng/(kg body weight per day) recommended by the WHO. The results indicated that PCBs in the fish oil supplements pose acceptable risks to humans consuming the fish oil supplements daily.

Antiviral Effect of Extracellular Matrix Protein ABI3BP on Vesicular Stomatitis Virus and Its Mechanism: A Preliminary Study In Vitro.

Objective To explore the influence of extracellular matrix protein ABI-interactor 3-binding protein (ABI3BP) on vesicular stomatitis virus (VSV) genome replication and innate immune signaling pathway.Methods The small interfering RNA (siRNA) was transfected to knock down ABI3BP gene in human skin fibroblast BJ-5ta cells. VSV-green fluorescent protein (VSV-GFP)-infected cell model was established. The morphological changes and F-actin stress fiber formation were detected on ABI3BP knockdown cells by phalloidin immunofluorescence staining. The mRNA level of virus replication was detected by RT-qPCR in BJ-5ta cells after VSV-GFP infection; western blotting was performed to detect the changes in interferon regulatory factor 3 (IRF3) and TANK-binding kinase 1 (TBK1) phosphorylation levels.Results The VSV-GFP-infected BJ-5ta cell model was successfully established. Efficient knockdown of ABI3BP in BJ-5ta cells was achieved. Phalloidin immunofluorescence staining revealed structural rearrangement of intracellular F-actin after ABI3BP gene knockdown. Compared with the control group, the gene copy number of VSV-GFP in ABI3BP knockdown cells increased by 2.2 - 3.5 times (P<0.01) and 2.2 - 4.0 times (P<0.01) respectively when infected with VSV of multiplicity of infection 0.1 and 1. The expression of viral protein significantly increased in ABI3BP knockdown cells after virus infection. The activation of type-I interferon pathway, as determined by phosphorylated IRF3 and phosphorylated TBK1, was significantly decreased in ABI3BP knockdown cells after VSV-GFP infection.Conclusions Extracellular matrix protein ABI3BP plays an important role in maintaining the formation and rearrangement of actin structure. ABI3BP gene deletion promotes RNA virus replication, and ABI3BP is an important molecule that maintains the integrity of type I interferon pathway.

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma (uHCC). HAIC-based treatment showed great potential for treating uHCC. However, large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking. AIM: To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors, programmed cell death of protein 1 (PD-1) and its ligand (PD-L1) blockers (triple therapy) under real-world conditions. METHODS: Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis. Study-level pooled analyses of hazard ratios (HRs) and odds ratios (ORs) were performed. This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades (AIPB) at Sun Yat-sen University Cancer Center from January 2018 to April 2023. Propensity score matching (PSM) was performed to balance the bias between the groups. The Kaplan-Meier method and cox regression were used to analyse the survival data, and the log-rank test was used to compare the suvival time between the groups. RESULTS: A total of 13 randomized controlled trials were included. HAIC alone and in combination with sorafenib were found to be effective treatments (P values for ORs: HAIC, 0.95; for HRs: HAIC + sorafenib, 0.04). After PSM, 176 HCC patients were included in the analysis. The triple therapy group (n = 88) had a longer median overall survival than the AIPB group (n = 88) (31.6 months vs 14.6 months, P < 0.001) and a greater incidence of adverse events (94.3% vs 75.4%, P < 0.001). CONCLUSION: This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC. Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

Isolated spinal artery aneurysm: etiology, clinical characteristics, and outcomes.

OBJECTIVE: Isolated spinal aneurysms (ISAs) are rare causes of subarachnoid hemorrhage (SAH), which encompass a highly heterogeneous group of clinical entities with multifarious pathogeneses, clinical characteristics, and treatment strategies. Therefore, knowledge about the ISAs remains inadequate. In this study, the authors present a comprehensive analysis of clinical data associated with ISAs at their institutions to enhance the understanding of this disease. METHODS: Patients with ISAs confirmed by spinal angiography or surgery at the authors' institutions between 2015 and 2022 were included. Data regarding clinical presentation, lesion location, aneurysm morphology, comorbidities, treatment results, and clinical outcomes were reviewed. RESULTS: Seven patients with ISAs were included in the study. Among them, 4 patients (57.1%) experienced severe headache, and 3 patients (42.9%) reported sudden-onset back pain. Additionally, lower-extremity weakness and urinary retention were observed in 2 of these patients (28.6%). Four of the aneurysms exhibited fusiform morphology, whereas the remaining were saccular. All saccular aneurysms in this series were attributed to hemodynamic factors. Conservative treatment was administered to 3 patients, 2 of whom underwent follow-up digital subtraction angiography, which showed spontaneous occlusion of both aneurysms. Four patients ultimately underwent invasive treatments, including 2 who underwent microsurgery and 2 who received endovascular embolization. One patient died of recurrent SAH, while the remaining 6 patients had a favorable prognosis at the latest follow-up assessment. CONCLUSIONS: The morphology of aneurysms may be associated with their etiology. Saccular ISAs are usually caused by pressure due to abnormally increased blood flow, whereas fusiform lesions may be more likely to be secondary to vessel wall damage. The authors found that a saccular spinal aneurysm in young patients with a significant dilated parent artery may be a vestige of spinal cord arteriovenous shunts. ISAs can be managed by surgical, endovascular, or conservative procedures, and the clinical outcome is generally favorable. However, the heterogeneous nature of the disease necessitates personalized treatment decision-making based on specific clinical features of each patient.

Low shear stress induces macrophage infiltration and aggravates aneurysm wall inflammation via CCL7/CCR1/TAK1/ NF-κB axis.

BACKGROUND: This study aimed to elucidate the mechanism by which wall shear stress (WSS) influences vascular walls, accounting for the susceptibility of intracranial aneurysms (IAs) to rupture. METHOD: We collected blood samples from the sacs of 24 ruptured and 28 unruptured IAs and analyzed the expression of chemokine CCL7 using enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression analyses were employed to assess clinical data, aneurysm morphology, and hemodynamics in both groups. Pearson correlation analysis investigated the relationship between CCL7 expression in aneurysm sac blood and WSS. Additionally, we established a bionic cell parallel plate co-culture shear stress model and a mouse low shear stress (LSS) model. The model was modulated using CCL7 recombinant protein, CCR1 inhibitor, and TAK1 inhibitor. We further evaluated CCL7 expression in endothelial cells and the levels of TAK1, NF-κB, IL-1ß, and TNF-α in macrophages. Subsequently, the intergroup differences in expression were calculated. RESULTS: CCL7 expression was significantly higher in the ruptured group compared to the unruptured group. Hemodynamic analysis indicated that WSS was an independent predictor of the risk of aneurysm rupture. A negative linear correlation was observed between CCL7 expression and WSS. Upon addition of CCL7 recombinant protein, upregulation of CCR1 expression and increased levels of p-TAK1 and p-p65 were observed. Treatment with CCR1 and TAK1 inhibitors reduced inflammatory cytokine expression in macrophages under LSS conditions. Overexpression of TAK1 significantly alleviated the inhibitory effects of CCR1 inhibitors on p-p65 and inflammatory cytokines. CONCLUSION: LSS prompts endothelial cells to secrete CCL7, which, upon binding to the macrophage surface receptor CCR1, stimulates the release of macrophage inflammatory factors via the TAK1/NF-κB signaling pathway. This process exacerbates aneurysm wall inflammation and increases the risk of aneurysm rupture.

VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.

The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.