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Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with challenges in diagnosis and treatment due to tumor heterogeneity. This study identifies palmitoylation-related signature genes as potential diagnostic and therapeutic targets. Integrating GEO datasets, six differentially expressed genes (DEGs) linked to palmitoylation were identified. Machine learning algorithms (LASSO, RF, SVM) selected three core genes: TRPM4, LAMB3, and APOE. A diagnostic model based on these genes achieved an AUC of 0.929, demonstrating robust accuracy in distinguishing PCa from normal tissues. Functional analysis revealed roles in lipid metabolism and immune modulation, with ssGSEA highlighting correlations between key genes and immune cell infiltration. Experimental validation showed that LAMB3 overexpression suppressed PCa cell proliferation, migration, and invasion, while knockdown enhanced these processes. Molecular docking identified diethylstilbestrol as a potential therapeutic agent targeting LAMB3 and APOE. These findings emphasize the clinical relevance of palmitoylation-related genes in PCa diagnosis and therapy, offering novel biomarkers and insights for personalized treatment strategies. Show less

Here, we identified a type of hypothetical T7SS effector in This alternative strategy facilitates effectors' delivery, even for fragmented substrates, highlighting its importance in ensuring the functionality of T7SS. Show less

Non-small cell lung carcinoma (NSCLC) with co-expression of thyroid transcription factor-1 and p40 is an extremely rare and diagnostically challenging subtype. These tumors exhibit both glandular and squamous features, which reflect a dual-lineage differentiation pattern. A 78-year-old male with a history of smoking and alcohol consumption was found to have a solid nodule in the right peripheral lung on CT. Postoperative pathology confirmed that the solid nodule was poorly differentiated NSCLC with diffused and strong positivity for both thyroid transcription factor-1 and p40 by immunohistochemistry. Next-generation sequencing identified somatic mutations of LRP1B and TP53, along with copy number amplification of TP63 and SOX2 as well as copy number loss of CDKN2A/B. NSCLC with co-expression of Thyroid Transcription Factor-1 and p40 is a rare and diagnostically challenging subtype, most frequently observed in older male patients with a history of smoking and predominantly arising in peripheral lung regions. The morphological, immunophenotypic and molecular features of these tumors suggest that they may originate from stem-like basal cells with dual-lineage differentiation. Literature review identified high-frequency alterations in TP53, FGFR1, CDKN2A, EGFR, KRAS, MYC, NF1 and AKT1. Next-generation sequencing-based genomic profiling facilitate the diagnosis and treatment of such cases. Show less

To develop and evaluate a predictive model for myocardial injury in patients with advanced gastric cancer treated with fluorouracil plus platinum-based chemotherapy, incorporating baseline characteristics and inflammatory, nutritional, and atherosclerotic factors. A total of 268 patients with advanced gastric cancer who received this treatment between April 2020 and September 2024 were selected and divided into a training set ( In the training set, 56 patients (29.79%) developed myocardial injury, while 23 patients (28.75%) in the validation set developed myocardial injury, with no statistically significant difference in the incidence or clinical characteristics between the two sets ( This predictive model aids in the early identification of myocardial injury, guiding clinical decision-making and improving prognosis. Show less

Emerging evidence suggests that ApoB outperforms LDL-C in predicting cardiovascular risk, especially in cases of discordance with the two. However, the specific type and composition of lipoprotein particles in this situation remain unclear. 375,544 individuals were enrolled from the UK Biobank without baseline cardiovascular disease, not on lipid-lowering therapy, and with available lipid nuclear magnetic resonance (NMR) data. Based on whether the absolute difference in baseline percentile of LDL-C and ApoB level was over 10 units, participants were categorized into concordant, discordantly high ApoB, and discordantly low ApoB group. The primary endpoint was major adverse cardiovascular events (MACE). Cox regression analysis showed the risk of MACE was increased in the discordantly high ApoB group (HR, 1.11; 95% CI, 1.06-1.15) and reduced in the discordantly low ApoB group (HR, 0.87; 95% CI, 0.83-0.93). Similar trends were observed in the NMR data. Compared to the other two groups, the discordantly high ApoB group exhibited the highest concentrations of VLDL-C, VLDL-CE, and VLDL particles. However, the CE content per LDL, IDL, and VLDL particle was lower in this group. Mediation analysis showed that VLDL particles and triglycerides mediated 25.5% and 26.6% of the MACE risk, respectively, in the discordantly high ApoB group (both P < 0.001). ApoB is a more comprehensive marker of cardiovascular risk than LDL-C. The higher cardiovascular risk in discordantly high ApoB individuals was partly mediated by VLDL; however, no conclusive evidence indicated that VLDL provides additional prognostic value beyond triglyceride measurements alone. Show less

Sarcopenic obesity (SO) is characterized by the presence of both obesity and sarcopenia and is related to disability and loss of independence in older adults. The extent to which time spent in light physical activity (LPA), or moderate-to-vigorous physical activity (MVPA) is associated with SO risk in older adults remains unclear. The aim of this study was (a) to examine the association between the level of adherence to recommended amounts of MVPA and the risk of SO in older adults and (b) to determine whether time spent in LPA is associated with SO risk independently of time spent in MVPA. This cross-sectional study involved 862 community-dwelling older adults (58% women; aged 65-79 years) from four European countries. Accelerometer-determined time in MVPA was categorized as follows: inactive (< 75 min/week), moderately active (75-149 min/week), active (150-299 min/week) and highly active (≥ 300 min/week). Time in LPA was expressed in tertiles. The outcome measure SO risk was determined based on appendicular lean mass, waist circumference, handgrip strength and the 5-times sit-to-stand test. Odds ratios (OR) with a 95% confidence interval (95% CI) of high SO risk across levels of MVPA and LPA were determined by binary logistic regression adjusted for the level of systemic inflammation (high-sensitivity C-reactive protein) and dietary protein intake. Compared to the inactive group, ORs of having a high SO risk were about 50%-80% lower, depending on the MVPA level, with the largest risk reduction in the highly active group (OR: 0.23, 95% CI: 0.13-0.39; p < 0.05). The likelihood of having a high SO risk was significantly lower among the highly active group compared to the active group (OR: 0.50; 95% CI: 0.33-0.77; p < 0.05). More time in LPA was associated with a significantly lower likelihood of having high SO risk (highest vs. lowest tertile: OR: 0.52, 95% CI: 0.30-0.89; p < 0.05) only in participants with low amounts of MVPA. In contrast, LPA was not associated with SO risk among participants meeting the MVPA recommendation. MVPA is strongly associated with a lower likelihood of having a high SO risk in older adults, independently of the level of systemic inflammation and intakes of dietary proteins. LPA is related to SO risk in sedentary older adults, which supports the promotion of physical activity regardless of intensity for mitigating SO. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder driven by dysregulated lipid metabolism and remains a leading cause of cardiovascular morbidity. The Shen-Hong-Tong-Luo (SHTL) preparation has demonstrated clinical benefit in stabilizing atherosclerotic plaques, yet its molecular mechanisms are not fully defined. This research sought to elucidate the protective effects exerted by SHTL on AS progression. To investigate the impact of SHTL on macrophage function and plaque stability, we utilized ApoE SHTL markedly attenuated the progression of AS, demonstrated by reduced plaque formation within both the aortic root and aorta, diminished plasma lipid concentrations, and suppressed inflammatory responses. SHTL demonstrates significant anti-inflammatory and lipid-regulatory effects, attenuating AS progression through the PPARγ/Mfge8 pathway, thereby enhancing macrophage efferocytosis. These findings highlight a novel mechanism by which SHTL may contribute to preventing and treating atherosclerotic diseases. Show less

Long-persistent luminescent (LPL) materials store photon energy as charges and emit light over extended periods via charge recombination. LPL decay typically follows a power law rather than an exponential decay, enabling confirmation of charge accumulation from emission decay characteristics. While charge generation in organic materials has been widely studied at donor-acceptor (D/A) interfaces, it remains underexplored in single-component luminescent materials. Here, we investigate charge generation in organic solids by dispersing a luminescent molecule in various hosts and performing slow transient emission analyses. This approach enables the evaluation of ionization through accumulated triplet excited states and the detection of weak charge accumulation, which are difficult to capture using conventional transient techniques. Our results show that ionization in single-component materials proceeds through resonance-enhanced multiphoton ionization, although it is less efficient than at D/A interfaces. This approach provides insight into long-term photophysical and photochemical processes such as photodegradation. Show less

Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the pathogenesis of cardiovascular diseases. However, the relationship between mitochondrial calcium homeostasis in vascular smooth muscle cells (VSMCs) and atherosclerosis remains poorly understood. Here, we demonstrate that cholesterol induces mitochondrial calcium overload and lipid accumulation in VSMCs, which is resulted from dysregulation of mitochondrial calcium uniporter (MCU), as evidenced by genetic and pharmacologic inhibition of MCU. Furthermore, MCU inhibitors alleviate Western diet-induced atherosclerosis in ApoE-/- mice. Mechanistically, high-fat and high-cholesterol diets induce the contact between mitochondria and the endoplasmic reticulum (ER) in VSMCs as indicated by transmission electron microscopy, proximity ligation assay and immunofluorescence staining, which increases the formation of mitochondria-associated membranes (MAMs), leading to Ca2 + release from the ER into the mitochondria and thus elevating Ca2 + in the mitochondria. Using mitochondrial calcium uptake 1 (MICU1) mutant and Ca2 + detection assay, we confirmed that this increased Ca2 + binds to MICU1, a blocker of MCU, to impair its ability to block MCU, thus enabling the MCU to remain open and resulting in mitochondrial calcium overload. Further, mitochondrial calcium overload dysregulates fatty acid β-oxidation by modulating medium-chain acyl-CoA dehydrogenase (ACADM), thereby leading to lipid deposition. The inhibition of MCU alleviates the pathological changes elecited by cholesterol. Our findings unveil the previously unrecognized role of MAM-MICU1-MCU axis in cholesterol-induced mitochondrial calcium overload and atherosclerosis, indicating that MCU represents a promising therapeutic target for the treatment of atherosclerosis. Show less

The active ingredients of Traditional Chinese Medicine with diverse structures exhibited anti-inflammatory and lipid lowering functions, demonstrating significant therapeutic effects in inflammatory diseases of atherosclerosis. We incorporate Astaxanthin (AST) and Dihydroartemisinin (DHA) into PLGA NPs to synthesized HA@PLGA@AST/DHA NPs (HPAD NPs) for alleviating atherosclerosis. In vitro assay indicated that the designed HPAD NPs promoted cholesterol efflux of macrophages by enhancing selective lipophagy, which is benefit to lipid antigen degradation. Meanwhile, HPAD NPs regulated T-cell differentiation and crucially induced macrophages from pro-inflammatory M1 type to anti-inflammatory M2 type. In vivo study demonstrated that HPAD NPs decreased the necrotic core dimension and improved plaque stability in ApoE Show less

Aortic dissection (AD) involves complex interactions among amino acid, glucose, and lipid metabolism, exacerbating aortic inflammation and extracellular matrix (ECM) degradation, coupled with smooth muscle cell (SMC) dysfunction (phenotypic alteration, aging, apoptosis). To explore AD pathogenesis, we integrated single-cell RNA sequencing (scRNA-seq), metabolomics, machine learning, and Mendelian randomization to investigate SMC changes and gene-metabolite interactions. ScRNA-seq data (GSE213740, GSE155468) were analyzed for cell clustering and pseudo-time trajectories via Seurat and Monocle2. Metabolomics (9 samples: 6 AD, 3 controls) and machine learning validated key genes/metabolites, with Mendelian randomization assessing causal links. Nine cell subsets and 2000 variable genes were identified, with SMCs central to AD via cholesterol metabolism. APOE and PLTP were key genes; metabolomics highlighted cholesterol esters (CEs) and triglycerides (TGs) as critical metabolites. Machine learning confirmed APOE/PLTP's high predictive accuracy (AUC: 0.796-0.989). Mendelian randomization linked elevated CEs and TGs to increased AD risk (IVW: P = .04 and P = .02, respectively). This study establishes a gene-metabolite network where APOE and PLTP regulate CEs/TGs, influencing SMC function and AD progression, offering potential therapeutic targets. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti-inflammatory activities, its clinical application is limited by a narrow therapeutic window. In the present study, we developed phosphatidylserine-exposing nanovesicles (Col@PSVs) that leverage the innate phagocytic capacity of macrophage-derived foam cells by presenting surface "eat-me" signals, thereby enabling targeted immune modulation. The synergistic collaboration between Col and PSVs allows low-dose Col to retain robust anti-inflammatory efficacy while mitigating dose-dependent toxicity. Mechanistically, Col@PSVs potently suppress CCR7-mediated NF-κB signaling activation in foam cells, leading to a marked downregulation of pro-inflammatory cytokine and disruption of inflammatory cascades. In ApoE Show less

Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital neurocutaneous disorder characterized by ocular, skin, and central nervous system manifestations. Despite its recognizable clinical features, such as nevus psiloliparus, histopathologic characterization of ECCL remains limited in the dermatopathology literature, and diagnosis is often clinical. This scarcity of published histopathological descriptions makes diagnostic confirmation challenging and underscores the value of synthesizing the available evidence. This comprehensive review synthesizes reported histopathological findings across cutaneous manifestations highlighting key tissue-level features that may aid diagnostic confirmation. Additionally, we review the emerging role of molecular diagnostics, particularly the identification of mosaic activating mutations in Show less

Axin1 plays a critical role in regulating the Wnt/β-catenin signaling pathway and cancer progression, and its polymerization is indispensable for the assembly of the β-catenin destruction complex. However, the mechanisms that control Axin1 polymerization are limited. Here, we reveal that TRIM15 interferes with the polymerization of Axin1, thereby promoting Wnt activation and colorectal cancer growth. Mechanistically, TRIM15 strongly interacts with Axin1 through its coiled-coil domain to disrupt the polymerization among Axin1 molecules. Manipulation of TRIM15 expression dramatically weakens Wnt signaling, cell proliferation, and tumor growth. Furthermore, conditional genetic ablation of Trim15 in mice inhibits tumor formation in both AOM/DSS-induced and Apc Show less

Myasthenia gravis (MG) lacks disease-specific biomarkers that can support monitoring of disease activity or guide treatment decisions. This study aimed to validate serum inflammatory proteins as MG-specific biomarkers by comparing their specificity to controls and individuals with other autoimmune neurological disorders, including multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). In this multicentre cross-sectional study, serum from 200 acetylcholine receptor antibody seropositive (AChR+) MG patients, 192 matched controls, 93 MS patients, and 51 CIDP patients was analyzed using a 92-plex inflammation panel (Olink PEA). Logistic regression, principal component analysis, and Boruta machine learning algorithms identified differentially expressed proteins. MG subgroups were defined by age at onset, disease severity, and immunosuppressive treatment. Fourteen proteins significantly distinguished MG from controls, including AXIN1 (OR: 0.24), IL7 (OR: 9.38), ST1A1 (OR:0.42), IL10 (OR:3.62), CASP-8 (OR:1.61), and TNFSF14 (OR:0.50) (Bonferroni-corrected p < 0.00135). AXIN1, ST1A1, STAMBP, CDCP1, and SIRT2 were specific for MG, separating it from MS and CIDP. Shared markers across disorders included IL6, IL8, STAMBP, and TNFSF14. A 15-protein profile, including FGF-23 and CXCL9, correlated with MG severity. Subgroup analyses revealed distinct protein patterns by age and treatment. TRANCE and CD6 were reduced in immunosuppressed patients, whereas EN-RAGE, IL10, and TNFRSF9 varied in those receiving biologicals. This study validates the MG-specific serum proteomic biomarkers AXIN1, STAMBP, ST1A1, CDCP1, and SIRT2 and identifies signatures associated with severity, onset, and treatment. These findings support the use of blood-based biomarkers for monitoring and stratification in MG clinical trials and care. Show less

Neuroinflammation represents a central pathological mechanism in Alzheimer's disease (AD). Lipopolysaccharide (LPS) is a potent inducer of neuroinflammation and demonstrates elevated circulating levels in AD patients. This study aims to investigate the genetic association between serum LPS activity level, inflammatory proteins and AD. A two-sample mendelian randomization (MR) analysis was performed to explore the causal effect of serum LPS activity level and 91 inflammatory proteins on AD, including 1, 260, 136 sporadic AD and 2, 838, 825 familial AD patients, respectively. Meta-analysis was conducted on multiple datasets to determine statistically significant results that was initially observed in one dataset. Serum LPS activity level is a risk factor for early onset sporadic AD with OR = 1.392, 95% CI: 1.038-1.869. In most other sporadic AD datasets, LPS shows a trend of increasing the risk of AD onset. After meta-analysis in 10 independent datasets, no association between LPS and sporadic AD was observed. In most familial AD datasets, LPS level demonstrated a trend of decreasing AD risk in MR analysis, however, meta-analysis of the combined 8 datasets showed no statistically significant difference. Two inflammatory proteins, AXIN1 and IL-1 alpha, were identified as significant risk factors for sporadic AD. This study suggested that serum LPS activity level may present a risk effect in early onset sporadic AD. Two inflammatory proteins AXIN1 and IL-1 alpha were associated with the risk of sporadic AD. These findings provide a new perspective for the early diagnosis and treatment of sporadic and familial AD. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction and neuronal loss, with glutamate excitotoxicity playing a central role in its pathology. The astrocytic glutamate transporter EAAT2, responsible for maintaining synaptic glutamate homeostasis, is significantly downregulated in AD. Restoration of EAAT2 expression presents a promising therapeutic strategy. This study explores the potential of modulating the Wnt/β-catenin signaling pathway to enhance EAAT2 levels by targeting the Axin-1/β-catenin interaction. Through virtual screening of 120,993 compounds from the Asinex-CNS database, five lead candidates were identified based on molecular docking, MMGBSA scores, and drug-likeness parameters. Advanced in-silico analyses-including Principal Component Analysis, Dynamic Cross-Correlation Mapping, molecular dynamics simulations, and MM/PBSA binding free energy calculations-highlighted BAS 04937103 as the most promising compound for disrupting β-catenin degradation. In vitro validation using C6 glioma cells and primary astrocytic cultures demonstrated that BAS 04937103 enhanced β-catenin stabilization and nuclear translocation, reduced Axin-1 expression, and significantly upregulated EAAT2 levels. These molecular effects corresponded with decreased extracellular glutamate concentrations, improved glutamate uptake, and reduced oxidative stress. Collectively, these findings establish BAS 04937103 as a novel modulator of the Axin/β-catenin interaction with therapeutic potential in mitigating glutamate-mediated neurotoxicity in Alzheimer's disease. Show less

Adolescent idiopathic scoliosis (AIS) is a multifactorial disease with environmental and genetic components. AIS clinical management is complicated by the lack of reliable predictive markers of progression. Recent studies have highlighted a potential role for epigenetic mechanisms in disease progression. However, most findings derive from peripheral blood analyses, with little data available on musculoskeletal tissues directly affected by AIS. Given the tissue-specific nature of epigenetic regulation, validating blood-based biomarkers in disease-relevant tissues is essential. We performed a comparative multi-gene RT-qPCR analysis, arranged in a custom array format, to assess the local expression of candidate epigenetically regulated genes associated with AIS progression across bone, paravertebral muscle, spinal ligament, and peripheral blood, all collected from the same patients. Tissue- and gene-specific expression patterns were observed, supporting the presence of local regulatory mechanisms. Peripheral blood expression of Show less

Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether causal relationships exist among these associations remains unclear, as traditional observational studies are susceptible to confounding factors. To evaluate causal relationships between kidney cancer, kidney fibrosis, and inflammatory factors using Mendelian randomization, and explore tumor microenvironment heterogeneity through single-cell analysis. Based on large-scale GWAS data, bidirectional Mendelian randomization analysis was performed to assess causal relationships between kidney cancer and kidney fibrosis, using MR Egger, inverse variance weighted (IVW), and weighted mode methods. Causal associations between kidney cancer and inflammatory factors including Axin-1, C-C motif chemokine 28, and interleukin-10 receptor subunit were analyzed. Single-cell RNA sequencing data from the GEO database (GSM4819725) was integrated for tumor microenvironment analysis. Bidirectional Mendelian randomization analysis revealed no significant causal relationship between kidney cancer and kidney fibrosis [kidney cancer→kidney fibrosis: IVW OR=0.992(95%CI: 0.913-1.077, P=0.842); kidney fibrosis→kidney cancer: IVW OR=0.922(95%CI: 0.824-1.030, P=0.151)]. However, significant positive causal associations were identified between kidney cancer and multiple inflammatory factors: Axin-1 levels [OR=1.448(95%CI: 1.107-1.894, P=0.007)], C-C motif chemokine 28 [OR=1.287(95%CI: 1.076-1.540, P=0.006)], and interleukin-10 receptor subunit [OR=1.135(95%CI: 1.032-1.248, P=0.009)]. Sensitivity analyses confirmed the robustness of results. Single-cell analysis revealed cellular heterogeneity in the tumor microenvironment, including various cell types such as immune cells, T cells, and NK cells, with pseudotime analysis demonstrating cell differentiation trajectories and dynamic gene expression changes. Mendelian randomization analysis provides genetic evidence for causal relationships between kidney cancer and inflammatory factors, while excluding direct causal associations between kidney cancer and kidney fibrosis. Show less

This study aimed to investigate the anti-tumour effect and the possible molecular mechanism of Tianma granules on colorectal cancer (CRC). The therapeutic effect of Tianma granules on CRC cell lines (HT116 and SW480) and AOM/DSS-induced CRC mouse models was evaluated. Tianma granules can attenuate weight loss and increase the survival rate of CRC mice, restore reduced colon length, reduce tumour numbers and increase goblet cell numbers in CRC mice. Tianma granules also downregulated the level of CRC-specific markers (COX2 and MUC2), inhibited the inflammation (decreased TNF-α, IL-1β, IL-6 levels and increased INF-γ level), and promoted apoptosis (decreased TUNEL positive cell rate; decreased Bax and Cleaved caspase3 protein levels and increased Bcl2 level) in CRC mice. In vitro, Tianma granules can inhibit the viability, proliferation, migration and invasion of CRC cells, while promoting cell apoptosis, cell cycle arrest and cell senescence. Tianma granules promoted AXIN1 protein levels and inhibited p-GSK-3β, β-catenin, Wnt5a and Cyclin D1 and c-Myc protein levels. Moreover, the network pharmacology analysis and in vitro validation revealed berberine might be the key compound responsible for Tianma granules' pharmacological actions. In conclusion, Tianma granules can inhibit inflammation and tumour progression in AOM/DSS-induced CRC mice, as well as inhibit CRC cell malignant phenotype. The protection of Tianma granules against CRC may be achieved by inhibiting the Wnt signalling pathway. Show less

Thyroid cancer pathogenesis involves complex interactions between genetic predisposition and alterations in the tumor microenvironment. The causal relationships between inflammatory gene variants and thyroid cancer risk remain poorly understood, as does the cellular heterogeneity within the tumor ecosystem. This study aimed to investigate the causal associations between inflammatory protein genes and thyroid cancer risk, and to characterize the cellular composition and differentiation trajectories within the thyroid cancer microenvironment. We employed a two-pronged approach combining Mendelian randomization (MR) analysis and single-cell RNA sequencing (scRNA-seq). MR analyses were conducted using genetic variants associated with the expression of inflammatory proteins (4EBP1_EIF4EBP1, ADA_ADA, ARTN_ARTN, AXIN1_AXIN1, and Beta-NGF_NGF) as instrumental variables to assess their causal effects on thyroid cancer risk. Multiple MR methods (MR Egger, weighted median, inverse variance weighted, simple mode, and weighted mode) were used to enhance robustness. For the cellular characterization, scRNA-seq was performed on thyroid cancer samples, followed by dimensionality reduction, clustering analysis, cell type annotation, and pseudotime trajectory inference. MR analyses revealed a significant positive causal association between AXIN1_AXIN1 expression and thyroid cancer risk (weighted median: OR = 1.396, p < 0.05; inverse variance weighted: OR = 1.291, p < 0.05), while ADA_ADA showed protective effects (simple mode: OR = 0.731, p < 0.05). The scRNA-seq analysis identified six major cell populations within the thyroid cancer microenvironment: epithelial cells, T cells, natural killer cells, fibroblasts, stromal cells, and macrophages. Pseudotime analysis revealed distinct differentiation trajectories with natural killer cells and macrophages appearing in early pseudotime, while epithelial cells and fibroblasts demonstrated multiple developmental states. Gene expression profiling identified four distinct cellular states with unique molecular signatures, including immune/inflammatory, stromal, and vascular components. Our findings suggest that inflammatory protein genes, particularly AXIN1, have causal effects on thyroid cancer risk, providing potential targets for risk prediction and intervention. Show less

Endometrial cancer (EC) is a common gynecologic malignancy with limited treatment options. This study aimed to evaluate the potential of itraconazole (ITZ), a widely used antifungal drug, as an anti-tumor agent and an adjuvant to immunotherapy for EC. The effects of ITZ on Ishikawa cells were assessed using proliferation assays, apoptosis assays, and invasion assays. The combination of ITZ and immune checkpoint inhibitors (ICIs) was evaluated to determine their synergistic effects on tumor invasion. Tumor-associated macrophages (TAMs) polarization and cytokine levels were analyzed by flow cytometry and enzyme linked immunosorbent assay (ELISA). Western blotting and Real-time reverse transcription polymerase chain reaction (RT-PCR) were used to investigate the impact of ITZ on the Wnt/β-catenin signaling pathway. Finally, ITZ inhibits Ishikawa cells proliferation and invasion through apoptosis induction. When combined with ICIs, ITZ significantly enhanced the inhibition of tumor invasion, an effect associated with TAMs polarization. ITZ increased IFN-γ secretion, reduced IL-10 levels, and promoted TAMs polarization from the M2 to the M1 phenotype. Mechanistically, ITZ downregulated Wnt-3a and β-catenin expression while upregulating Axin-1, thereby suppressing Wnt/β-catenin signaling in TAMs. ITZ demonstrated robust anti-tumor activity against EC by inhibiting Ishikawa cells proliferation, invasion, and enhancing the efficacy of ICIs. Through its dual role in directly targeting tumor cells and modulating the tumor microenvironment, ITZ shows promise as a multitargeted therapeutic agent and a valuable adjuvant to immunotherapy for EC. Show less

Early life air pollution exposure may play a role in development of respiratory infections, but underlying mechanisms are still not understood. We utilized data from two independent prospective birth cohorts to investigate the influence of prenatal and postnatal ambient air pollution exposure of PM Show less

AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are crucial kinase signalling hubs that regulate the balance between catabolism and anabolism in skeletal muscle. The scaffold protein AXIN1 has been proposed to regulate the switch between these pathways and be required for GLUT4 translocation in skeletal muscle and adipocyte cell lines. Muscle-specific AXIN1 knockout (KO) mice exhibit no discernable phenotype, possibly due to compensation by AXIN2 upon AXIN1 loss. Thus we generated and characterized muscle-specific inducible AXIN1 and AXIN2 double knockout (dKO) mice. Surprisingly AXIN1/2 dKO mice displayed normal AMPK and mTORC1 signalling and glucose uptake in response to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), insulin and in situ muscle contraction. These findings suggest that AXIN proteins are not essential for the regulation of AMPK and mTORC1 signalling or glucose uptake in skeletal muscle. This study challenges the previously indicated critical roles of AXIN1 in exercise-stimulated AMPK activation and GLUT4-mediated glucose uptake in skeletal muscle. KEY POINTS: Phenotyping of tamoxifen-inducible muscle-specific AXIN1/2 double knockout (dKO) mice. We find no evidence for AXIN-dependent AMPK or mTORC1 regulation in skeletal muscle by insulin, AMPK activation or contraction. Glucose uptake regulation by insulin and AMPK activation is normal in AXIN1/2 dKO mice. Show less

Innate immunity, the primary defence mechanism, encompasses a range of protective processes like anatomical barriers, cytokine secretion, and the action of various immune cells. Cattle breeds might differ in these processes because of their genetic differences such as copy number variations (CNVs). Therefore, the present investigation employed an array comparative genomic hybridisation (aCGH) approach on breed representative pooled DNA samples to evaluate CNVs across six cattle breeds: four indigenous Indian breeds, Kangayam (KNG), Tharparkar (TP), Sahiwal (SW), Gir (GIR), one crossbred Karan Fries (KF), and one exotic breed, Holstein Friesian (HF). In aCGH, HF DNA was used as control, while test DNA was from the other breeds. Each pooled test DNA sample was a representative of 18 animals belonging to three distinct geographical locations of India. The study using Aberration Detection Method 2 (ADM-2) of Agilent Genomic Workbench revealed the highest number of duplications in KNG (1189 genes), followed by TP (534 genes), and the greatest number of deletions in SW (774 genes). Among these genes, 183 and 76 innate immune genes with hub genes TGF-β1, CD79A, and IL4 showed duplications in KNG and TP, respectively. In SW, 113 innate immune genes with hub genes PSMC5, MAPK1, and AXIN1 showed deletions. In contrast, KF and HF showed no genes with deletions and fewer duplicated innate immunity genes, reflecting either lower genetic variability in their immune gene repertoire or a potential bias due to HF DNA as a control in aCGH. Functional enrichment of innate immune genes revealed duplications in KNG enriched in interleukin-1 receptor (IL1R) activity (p = 9.9 × 10 Show less

WNT/β-catenin signaling is mediated by the transcriptional coactivator β-catenin (CTNNB1). CTNNB1 abundance is regulated by phosphorylation and proteasomal degradation, promoted by a destruction complex composed of the scaffold proteins APC and AXIN1 or AXIN2, and the kinases casein kinase 1α (CSNK1A1) and GSK3A or GSK3B. Loss of CSNK1A1 increases CTNNB1 abundance, resulting in hyperactive WNT signaling. Previously, we demonstrated that the HECT domain E3 ubiquitin ligase HUWE1 is necessary for hyperactive WNT signaling in HAP1 haploid human cells lacking CSNK1A1. Here, we investigated the mechanism underlying this requirement. In HAP1 cells lacking CSNK1A1, GSK3A/GSK3B still phosphorylated a fraction of CTNNB1, promoting its degradation. HUWE1 loss enhanced GSK3A/GSK3B-dependent CTNNB1 phosphorylation, further reducing CTNNB1 abundance. However, the reduction in CTNNB1 caused by HUWE1 loss was smaller than the reduction in WNT target gene transcription. To test whether the reduction in WNT signaling caused by HUWE1 loss resulted from reduced CTNNB1 alone, we engineered the endogenous CTNNB1 locus in HAP1 cells to encode a CTNNB1 variant insensitive to destruction complex-mediated phosphorylation and degradation. HUWE1 loss in these cells did not change CTNNB1 abundance but still reduced WNT signaling, demonstrating that another mechanism was at play. Genetic interaction and overexpression analyses revealed that the reduction in WNT signaling caused by HUWE1 loss required not only GSK3A or GSK3B, but also APC and AXIN1. Therefore, in HAP1 cells lacking CSNK1A1, a residual destruction complex containing APC, AXIN1 and GSK3A or GSK3B downregulates WNT signaling by phosphorylating and targeting CTNNB1 for degradation, and HUWE1 enhances WNT signaling by antagonizing this activity. Regulation of WNT signaling by HUWE1 also requires its ubiquitin ligase activity. We conclude that HUWE1 enhances WNT/CTNNB1 signaling through two mechanisms, one that antagonizes destruction complex-mediated CTNNB1 degradation and another that is independent of changes in CTNNB1 abundance. Coordinated regulation of CTNNB1 abundance and a second signaling step by HUWE1 would be an efficient way to control WNT signaling output, enabling sensitive and robust activation of the pathway. Show less

Effective solutions to obesity remain elusive, partly owing to its root in a positive energy balance (EB), which stems from the interplay of numerous traits spanning body size and composition, diet, physical activity, and metabolic profile. Nevertheless, EB-contributing traits are typically studied in isolation. We integrate numerous EB-related traits measured in the UK Biobank to uncover the underlying patterns of EB and associated genes in study participants. We used sparse factor analysis to integrate traits and performed genome-wide association analyses on the integrated phenotypes to elucidate EB-related genes and metabolic pathways. We performed pleiotropy analyses on candidate single-nucleotide polymorphisms to uncover the genetic basis of EB. We identified multiple genes and genomic regions associated with EB, including many that have previously not been directly associated with obesity measures (e.g., MIR5591, FNDC3B, ANAPC10, SULT1A1, AXIN1, SKIDA1, ERLIN1, DOCK7), which we validated using an independent subset of the UK Biobank dataset along with data from the Atherosclerosis Risk in Communities cohort. We found that the covariances in EB traits are primarily driven by genome-wide pleiotropic associations. We offer new insight into EB patterns and the genetic basis of EB. Show less

Mongolia has the highest incidence of liver cancer worldwide, largely driven by a high prevalence of hepatitis virus infections. Mutations in oncogenes and tumor suppressor genes provide valuable insights into the molecular mechanisms of hepatocellular carcinoma (HCC). This study aimed to investigate the prevalence of mutations in key oncogenes and tumor suppressor genes in Mongolian HCC patients and to explore their molecular mechanisms, particularly in relation to hepatitis virus infections. We analyzed 55 tumor tissue samples from Mongolian HCC patients (2019-2021), identifying mutations in TP53, CTNNB1, AXIN1, KRAS, and JAK1 through sequencing. Western blotting was used to assess β-catenin and p53 protein levels. Our findings showed p53 overexpression in tumors with TP53 mutations (F270I and S362S), while mutations such as R213* and a short-sequence deletion upstream of intron 7 produced premature stop codons, resulting in truncated p53 and loss of tumor suppressor function. β-catenin accumulation was observed in tumors with CTNNB1 mutations (D32N/Y, S33C/Y, S34V, S37P, T41A, and S45P). CCND1 expression, a key target of the Wnt/β-catenin pathway, was significantly upregulated in tumors harboring CTNNB1 and AXIN1 mutations (p = 0.02213). Statistical analysis revealed a positive correlation between β-catenin and CCND1 expression levels (r = 0.42703). Hepatitis virus infections were significantly associated with these mutations (p < 0.01), suggesting a link between viral infection and genetic alterations in HCC development. Compared to TCGA data, our cohort displayed a significantly higher mutation frequency (p < 0.001 and p < 0.05), indicating potential regional genetic and environmental influences. This study provides insights into the molecular mechanisms of HCC in Mongolia, highlighting distinct mutational patterns in TP53, CTNNB1, AXIN1, and KRAS. The association between hepatitis virus infections and these mutations underscores their potential oncogenic impact and may inform future therapeutic strategies for HCC in this population. Show less

This paper aims to investigate m6A modification during DKD progression. We evaluated m6A regulators expression in peripheral blood mononuclear cells, whole kidney tissue, glomerular, and tubulointerstitial samples. CIBERSORT and single-sample gene set enrichment analysis analyzed glomerular immune characteristics. Logistic-LASSO regression were used to develop the m6A regulators model that can identify early DKD. Consensus clustering algorithms were used to classify DKD in glomerular samples into m6A modified subtypes based on the expression of m6A regulators. Gene set variation analysis algorithm was used to evaluate the functional pathway enrichment of m6A modified subtypes. Weighted gene co-expression network analysis and protein-protein interaction networks identified m6A modified subtype marker genes. The Nephroseq V5 tool was used to evaluate the correlation between m6A modified subtypes marker genes and renal function. DKD patients' m6A regulators expression differed from the control group in various tissue types. DKD stages have various immune characteristics. The m6A regulators model with YTHDC1, METTL3, and ALKBH5 better identified early DKD. DKD was divided into two subtypes based on the expression of 26 m6A regulators. Subtype 1 was enriched in myogenesis, collagen components, and cytokine receptor interaction, while subtype 2 was enriched in protein secretion, proliferation, apoptosis, and various signaling pathways (e.g., TGFβ signaling pathway, PI3K/AKT/mTOR pathway, and etc.). Finally, AXIN1 and GOLGA4 were identified as possible biomarkers associated with glomerular filtration rate. From the viewpoint of m6A modification, the immune characteristics and molecular mechanisms of DKD at various stages are different, and targeted treatment would improve efficacy. Show less