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Rotator cuff tear is the most common tendon injury. Currently, arthroscopic rotator cuff repair (ARCR) is the primary method for diagnosing and treating rotator cuff tear. One of the major complications following ARCR is retear. This study aims to evaluate the correlation between systemic lipid metabolism and retear occurrence after ARCR through a retrospective analysis of postoperative patients. This retrospective study reviewed consecutive patients of a single surgeon who underwent ARCR from January 2021 to January 2022. Eligibility for inclusion required complete sequential follow-up data, encompassing preoperative laboratory tests and a series of postoperative magnetic resonance imaging (MRI) evaluations at 1, 2, 3, and 6 months. Exclusion criteria included patients with incomplete laboratory tests, a history of tumors, prior shoulder surgeries, isolated subscapularis tendon tears, the rotator cuff related muscles are not clearly or completely displayed in MRI, absence of follow-up MRI, or those under treatment with lipid-lowering medications. Logistic regression analysis was employed to identify preoperative factors associated with retear, with statistical significance adjudged at P < .05. From the initial cohort of 400 patients who underwent ARCR during the study period, 202 met both inclusion and exclusion criteria. These patients were subsequently divided into a training group (n = 122) and a test group (n = 80), maintaining a ratio of 6:4. Statistical analysis revealed significant risk factors for post-ARCR retear including high body mass index (>27.1; odds ratio (OR): 5.994, 95% confidential interval (CI): 1.762-13.980; P = .042), subscapularis muscle fatty infiltration of Grades 3 and 4 (OR: 8.509, 95%CI: 3.811-17.702; P = .009), serum apolipoprotein B (ApoB) levels exceeding 1.4 g/L (OR: 9.658, 95%CI: 3.520-21.753; P = .028), and an ApoB/A1 ratio greater than 1.8 (OR: 5.098, 95%CI: 1.787-10.496; P = .016). Conversely, the serum high-density lipoprotein level above 1.2 mmol/L (OR: -3.342, 95%CI: -7.466 to 0.659; P = .039) served as a protective factor. The model incorporating these 5 factors predicted retear with a sensitivity of 78.3% and specificity of 98.0% (area under the curve = 0.924, accuracy = 90.3%). Moreover, a new model comprising 3 lipid metabolism-related factors including high-density lipoprotein, ApoB and the ApoB/A1 ratio showed a sensitivity of 80.5% and specificity of 83.2% (area under the curve = 0.866, accuracy = 85.8%) for predicting retear after ARCR. A predictive model utilizing key systemic lipid metabolism markers including HDL, ApoB, and the ApoB/A1 ratio, demonstrates effective forecasting of retear incidence following ARCR. Show less

Cognitive decline is a common aspect of aging, and identifying modifiable lifestyle factors, such as physical activity and sleep, is crucial for promoting healthy brain aging. While both are individually linked to cognition, few studies have simultaneously assessed their independent and combined effects using objective wearable-based data, particularly in older Asian populations. This study aimed to examine the independent and interactive effects of wearable-assessed sleep and physical activity parameters on memory performance in healthy older adults. We also explored whether age and hippocampal volume moderated these associations. This prospective cross-sectional analysis included 88 cognitively healthy community-dwelling adults (≥60 years of age) from the Integrating Systematic Data of Geriatric Medicine to Explore the Solution for Healthy Aging cohort in Taiwan. Participants underwent 12-day wrist-worn actigraphy, brain magnetic resonance imaging, and neuropsychological assessments. Light-intensity physical activity (LPA) and wake after sleep onset (WASO) were selected based on age-adjusted partial correlations with Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery memory scores. Multivariate regressions, age-stratified models (cutoff=72 years), and PROCESS moderation and mediation analyses were conducted, adjusting for age, education, daytime sleepiness, and hippocampal volume. Partial correlation analyses adjusting for age showed that higher LPA (r=0.260; P=.02) and lower WASO (r=-0.251; P=.02) were significantly associated with better memory scores. Age significantly moderated both effects: LPA was beneficial beyond 73.8 years of age, and WASO was detrimental beyond 71.1 years of age. Multivariate regression models confirmed that both WASO (β=-.044; P=.04) and LPA (β=.042; P=.01) were significant predictors of memory. In subgroup analyses (age ≥72 years), both LPA (β=.054; P=.04) and WASO (β=-.111; P=.01) remained significant predictors. Moderated mediation analyses showed that WASO was associated with reduced LPA (β=-.325; P=.03), but the indirect effect on memory via LPA was not significant. Instead, WASO exerted a direct and age-moderated effect on memory performance. Hippocampal volume moderated both associations, supporting the brain reserve hypothesis. Our findings highlight WASO and LPA, as measured by wearable devices, as modifiable behavioral factors linked to memory function in older adults. The impact of these factors intensifies with advancing age and may be influenced by hippocampal reserve. Promoting daily light physical activity and maintaining sleep continuity may serve as accessible, age-tailored strategies for preserving cognitive health in aging populations. ClinicalTrials.gov NCT04207502; https://classic.clinicaltrials.gov/ct2/show/NCT04207502. Show less

Hyperlipidemia and its associated hepatic steatosis pose significant global health burdens, necessitating novel therapeutic strategies. High-fat diet (HFD)-fed C57BL/6 mice received TAC (2.5, 5.0, 10.0 g/L) or simvastatin for 2 weeks. Metabolic parameters, serum lipid profiles, hepatic function markers, and histopathology were systematically analyzed. Molecular pathways were interrogated through qPCR, Western blot, and pharmacological inhibition of AMPK (Compound C) and PPARα (GW6471). TAC treatment demonstrated significant dose-dependent improvements across multiple parameters. Compared to HFD controls, TAC reduced body weight by 21.3% and liver index by 18.7%, while lowering fasting blood glucose levels by 32.4%. Serum analyses showed substantial reductions in total cholesterol (46.2%), triglycerides (38.5%), and LDL-cholesterol (52.1%), accompanied by a 29.8% increase in HDL-cholesterol. Hepatic function improved markedly, with ALT and AST levels decreasing by 57.3% and 49.6% respectively. Histopathological examination revealed a 68.4% reduction in hepatic lipid accumulation. At the molecular level, TAC treatment resulted in a 2.7-fold increase in AMPK phosphorylation while significantly reducing HMGCR expression by 63.1% and nuclear SREBP-1c levels by 71.5%. Concurrently, TAC upregulated PPARα and LXRα expression by 3.1-fold and 2.4-fold respectively, leading to enhanced expression of lipolytic enzymes LPL and HL by 2.8-fold and 2.1-fold. These beneficial effects were completely abolished by co-treatment with pathway-specific inhibitors. TAC ameliorates hyperlipidemia and hepatic steatosis through dual modulation of AMPK/SREBP-1c-mediated lipid synthesis and PPARα/LXRα-driven lipolysis, presenting a multifaceted therapeutic approach for metabolic disorders. Show less

Macroautophagy/autophagy is a stress-responsive lysosomal catabolic pathway that promotes cellular homeostasis and tumor cell survival, but its role in breast cancer progression and metastasis remains unclear. Here, we show that a brain-specific serine/threonine protein kinase, BRSK2, a marker of aggressive metastatic disease in breast cancer patients, is crucial in regulating autophagy. BRSK2 is overexpressed in aggressive cancer and is associated with reduced disease-specific survival. BRSK2 also regulates basal autophagy and activates AKT, STAT3, and NF-κB-mediated cancer cell survival pathways. In addition, BRSK2 overexpression increases the levels of inflammatory cytokines and chemokines in breast cancer cells. Downregulation of BRSK2 using specific siRNAs or the BRSK2 kinase small-molecule inhibitor GW296115 markedly reduced nutrient-deprivation stress-mediated autophagy, cell growth, and metastatic potential, and enhanced breast cancer cell apoptosis. Endogenous BRSK2 is associated with the Vps34-class III PI3K-Beclin-1-ATG14 autophagy signaling complexes that could protect cancer cells from nutrient-deprivation stress. Our findings demonstrate the key role of the BRSK2-mediated protective autophagy and cell growth and survival under nutrient deprivation stress via survival signals, e.g., PI3K/AKT or STAT3-NF-kB, in aggressive breast cancer cells. Show less

The cytoplasmic fate of mRNAs is dictated by the balance of translation and mRNA degradation, governed in part by the 3' poly-adenosine tail and cytoplasmic poly(A)-binding proteins (PABPCs). Deadenylases remove poly(A) to initiate mRNA decay, while sequence-specific RNA-binding factors, including Pumilio proteins (PUM1 and PUM2), modulate these processes. We investigated how human PUM1&2 repress target mRNAs by accelerating their degradation. We found that the poly(A) tail plays a central role in PUM repression, dependent on the interplay of deadenylases and PABPCs. PUM-mediated repression requires the CCR4-NOT deadenylase but not the poly(A) nuclease (PAN). PUMs associate with and require PABPC1 and PABPC4 to repress. In the absence of PABPCs, both PUM targets and non-targets become unstable, bypassing PUM control. Increasing PABPC inhibits PUM activity in a concentration-dependent manner by stabilizing poly(A) mRNAs. Our results establish a Goldilocks principle wherein PABPC abundance tunes the response of mRNAs to regulatory factors through protection of poly(A) from deadenylation. Variation of PABPC levels across tissues and development suggests physiological relevance for this mechanism. Show less

Assessing white matter hyperintensity (WMH) is essential for the diagnosis, treatment, and prognosis of multiple sclerosis (MS) and neuromyelitis optical spectrum disorder (NMOSD). MS and NMOSD present dispersed small lesions alongside larger aggregated lesions that are irregularly shaped, posing challenges for the automatic segmentation of WMH on magnetic resonance images. Furthermore, research on NMOSD brain WMH segmentation is limited due to the rare nature of the disease. This study aims to propose a deep learning method for MS and NMOSD brain WMH segmentation. In this study, we propose a 2.5D Fourier Convolutional ResUnet (FrC-ResUnet). It utilizes a spectral encoder to extract global information, enabling accurate segmentation of scattered lesions. Additionally, the model incorporates the selective features module (SFM) and the convolutional block attention module (CBAM) to enhance lesion-background differentiation and outline the lesions distinctly. We evaluated our approach on the MS public and local datasets of MS and NMOSD. Compared to U-Net, ResUNet, FC-DenseNet, AttentionUNet, lesion prediction algorithm (LPA) and Sequence Adaptive Multimodal SEGmentation (SAMSEG), the 2.5D FrC-ResUnet achieved the highest Dice similarity coefficient (DSC) on three different datasets, with values of 0.710, 0.667, and 0.822, respectively. The 2.5D FrC-ResUnet demonstrates accurate and robust segmentation of NMOSD brain WMH. Meanwhile, the model excels in segmenting MS brain WMH, particularly when confronted with irregularly shaped and dispersed lesions. Show less

Dipeptidyl peptidase-4 inhibitors (DPP-4i) serve as an incretin-based hypoglycemic class for the treatment of type 2 diabetes (T2D). DPP-4i have been reported to produce a pleiotropic effect on lipid profiles in addition to regulation of glucose homeostasis. The aim of this systematic review and meta-analysis was to quantitatively evaluate the impact of DPP-4i on lipid parameters in patients with T2D. PubMed, Embase, and The Cochrane Library were systematically searched for randomized controlled trials. Trials were identified if changes in lipid parameters, including low-density-lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), high-density-lipoprotein cholesterol (HDL-C), non-HDL-C, and apolipoprotein B (ApoB) were reported. A total of 95 publications were identified. DPP-4i significantly reduced levels of LDL-C (-3.48 mg/dL; 95% CI, -4.77 to -2.20; I2 = 70%, P < .00001), TC (-2.59 mg/dL; 95% CI, -3.88 to -1.29; I2 = 73%, P < .0001), TG (-5.39 mg/dL; 95% CI, -8.04 to -2.75; I2 = 77%, P < .0001), and non-HDL-C (-6.27 mg/dL; 95% CI, -10.94 to -1.60; I2 = 53%, P = .008). No significant effect was found on HDL-C (-0.32 mg/dL; 95% CI, -1.19 to 0.55; I2 = 97%, P = .47) and ApoB (-0.88 mg/dL; 95% CI, -3.36 to 1.60; I2 = 36%, P = .49) during DPP-4i treatment. DDP-4i significantly improved lipid parameters including LDL-C, TC, TG, and non-HDL-C in patients with T2D. This underscores the potential cardiovascular benefits of DPP-4i and their role in improving diabetes-related outcomes. PROSPERO registration no. CRD42020175999. Show less

Lipoprotein(a) [Lp(a)] is established as an independent risk factor for atheromatous cardiovascular disease and aortic valve stenosis. Currently available lipid-lowering pharmacotherapies have limited effects on elevated levels of Lp(a), and several new therapies are in development to lower Lp(a). This article reviews the novel therapies in development to reduce Lp(a) in patients with elevated levels. These were identified by a PubMed search and mainly focus on the drugs that are at an advanced stage of development. The N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) pelacarsen and the small-interfering RNA (siRNA) agents olpasiran, lepodisiran, and zerlasiran have all been shown to be safe and effective in lowering Lp(a) levels between 80% and almost 100%. Pelacarsen, olpasiran, and lepodisiran are being tested in phase 3 cardiovascular outcome studies, and the first results may be available in 2026. Muvalaplin is a small molecule given orally once daily and reduces Lp(a) by up to 65%. It is also being assessed in a cardiovascular outcome study. It will be essential to identify what baseline level of Lp(a) is needed, and what degree of Lp(a) lowering is required to produce a cardiovascular benefit and whether aggressive lowering of Lp(a) has any adverse effects. Show less

FGFR3 mutations are among the most frequent genomic alterations in urothelial cancer (UC) being mainly associated with the luminal papillary (LumP) subtype. With the establishment of fibroblast growth factor receptor (FGFR) inhibitors, the treatment of UC is now shifting more and more towards personalized medicine. A systematic review using Medline and scientific meeting records was carried out according to the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines to assess the potential role of FGFR inhibitors in combination with additional therapies for the management of UC. Ongoing trials were identified via a systematic search on ClinicalTrials.gov. A total of eleven full-text papers, ten congress abstracts, and 5 trials on ClinicalTrials.gov were identified. Following the BLC2001 and THOR study, erdafitinib is the only approved FGFR1-4 inhibitor for metastatic UC with susceptible FGFR2/3 alterations following platinum-based chemotherapy. According to the THOR data of cohort 2, erdafitinib should not be recommended in patients who are eligible for and have not received prior immune checkpoint inhibitors (ICIs). One phase 3 trial is currently evaluating the intravesical device system (TAR210) in FGFR-altered intermediate non-muscle invasive bladder cancer (MoonRISe-1). Preclinical evidence suggests that combination-based approaches could be considered to improve the efficacy of FGFR inhibitors in patients with UC. Nine phase 1b/2 trials are focusing on the combination of FGFR inhibitors with ICIs, chemotherapy, or enfortumab vedotin. In metastatic disease, some preliminary analyses have reported promising results from these combinations (e.g. NORSE and FORT-2 trial). However, no phase 3 trial is terminated, so there is currently no level 1 evidence with long-term outcomes to support the combination of FGFR inhibitors with ICIs, chemotherapy, or targeted therapies. A better understanding of the different mechanisms of action to inhibit FGFR signaling pathways, optimal patient selection and treatment approaches is still needed. Show less

Excessive adipose tissue accumulation adversely impacts the health of both humans and livestock. Adenylyl cyclase 3 (ADCY3) is a promising anti-obesity target, yet its regulatory role in adipogenesis remains incompletely understood. Our findings revealed a dynamic pattern of ADCY3 expression during adipogenesis and lipid droplet (LDs) accumulation. Functional analyses demonstrated that ADCY3 overexpression impaired adipogenesis by downregulating adipogenic transcription factors CEBPα and PPARγ. Furthermore, it reduced both the number and size of LDs through suppressing triglyceride synthesis and fatty acid metabolism, concomitantly downregulating key genes involved in LDs formation (PLIN1, CIDEC, FIT2, and Seipin), as well as factors mediating glycerol ester synthesis and fatty acid metabolism (DGAT1, DGAT2, ACC, SCD, FASN, and ACSL1). Transcriptomic profiling revealed that ADCY3 overexpression suppressed PPARγ signaling, leading to the downregulation of oxidative phosphorylation genes encoded by both the nuclear and mitochondrial genomes. Our results implicate ADCY3 in the regulation of lipid metabolism, with the speculative involvement of mitochondrial metabolic remodeling. This perspective offers a framework for developing future interventions against excessive lipid deposition. Show less

Gout is a chronic inflammatory condition increasingly recognized as a risk factor for cardiovascular events (CVE). Early identification of high-risk individuals is crucial for targeted prevention and management. However, conventional risk stratification approaches often fall short in accuracy and clinical utility. This study aimed to develop and validate a robust, interpretable machine learning (ML)-based model for predicting CVE in patients with gout. This retrospective cohort study included 686 hospitalized gout patients at Xiyuan Hospital (Beijing, China) between January 1, 2013, and December 31, 2023. We applied Synthetic Minority Oversampling Technique (SMOTE) combined with random undersampling of the majority class. Then, patients were randomly divided into training (70%) and testing (30%) sets. A comprehensive set of clinical and biochemical variables (n = 39) was collected. Feature selection was performed using Boruta algorithms and Lasso to identify the most predictive variables. Multiple ML algorithms-including Decision Tree Learner, LightGBM Learner, K Nearest Neighbors Learner, CatBoost Learner, Gradient Boosting Desicion Tree Learner-were implemented to construct predictive models. SHAP values were used to assess model interpretability, and robustness was evaluated through 10-fold bootstrap resampling with enhanced standard error estimation. Of the 686 patients, 263 experienced cardiovascular events during follow-up (incidence rate: 38.3%). A logistic regression model was constructed based on eight variables selected using the Boruta feature selection algorithm: sex, age, PLT, EOS, LYM, CO2, GLU and APO-B. Among the five models evaluated, the CatBoost classifier achieved the best performance, with the highest area under the ROC curve (AUC) of 0.976 and the recall of 0.971. Furthermore, SHAP (SHapley Additive exPlanations) values were employed to provide both global and individual-level interpretability of the CatBoost model. To assess the model's generalization performance, bootstrap resampling was performed 10 times. Based on these results, the standard error was improved using machine learning-based enhancement methods, thereby optimizing the model's robustness and predictive stability. The logistic regression analysis revealed that age (OR=1.351, p<0.001), CO2 (OR=0.603, p=0.004), eosinophil count (OR=2.128, p=0.001), and platelet count (OR=0.961, p<0.001) were significantly associated with the outcome, indicating their potential roles as independent predictors. Notably, while APO_B (p=0.138) and sex (p=0.132) showed no significant association, glucose levels (OR=2.1, p=0.066) exhibited a marginal trend toward significance, warranting further investigation. This tool may support clinicians in identifying high-risk individuals, enabling early interventions and optimized management strategies. This study has several limitations. First, the analysis was based on a single-center dataset, which may limit the generalizability of the findings. External validation in multi-center and prospective cohorts, along with an expanded sample size, is warranted to confirm these results. Second, key confounding factors such as medication use, lifestyle habits, and gout flare frequency were not included in the analysis; future studies should incorporate these variables to provide a more comprehensive assessment. Show less

Emerging lipid-modifying agents show potential but lack evidence for the management of uric acid and gout. We aimed to explore the causal effects of lipid traits, lipid-modifying drugs on uric acid levels and risk of gout. Two-sample MR analyses were performed to investigate the associations of genetically predicted lipid traits (LDL-C, HDL-C and TG) and lipid-modifying drug targets (PCSK9, HMGCR, NPC1L1, CETP, ABCG5/G8, APOB, LDLR, LPL, ANGPTL3, and APOC3) with uric acid levels and gout risk. Validation analyses were performed using the independent cohort of the UK Biobank. Summary-data-based MR was further conducted to estimate the associations of the expression of drug target genes with the outcomes. Genetically predicted lower HDL-C and higher TG were significantly associated with elevated uric acid levels ( The online version contains supplementary material available at 10.1007/s43657-024-00212-7. Show less

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. Show less

Atherosclerosis has an auto-immune component driven by self-reactive T and B cells. Identifying their antigenic drivers may lead to new diagnosis and treatment approaches. Here, we aim to identify immunogenic T cell epitopes derived from atherosclerosis-relevant proteins such as ApoB100 by studying the repertoire of peptides presented by HLA in human plaques. We used immunopeptidomics to identify peptides presented by HLA-DR molecules from plaques of patients that underwent endarterectomy surgery. We selected a set of 20 peptides derived from ApoB100 and studied the presence and cytokine profile of ApoB100-specific CD4 revealed significant CD4 We show that immunopeptidomics can be a valid approach to new discover antigens in atherosclerosis. Show less

To quantify international variations in lipid-lowering therapies (LLT) use among patients with coronary heart disease (CHD) and attainment of European guideline-recommended lipid goals. INTERASPIRE is an observational study (2020-23) covering 14 countries from all WHO regions. Patients (18-79 years) hospitalized in the preceding 6-36 months with CHD were invited for standardized interviews and examination, with central laboratory analyses for low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and apolipoprotein B (apoB). Valid lipid data meeting quality control standards were available from 13 countries. Lipid goals followed the 2019 guidelines of the European Atherosclerosis Society and the European Society of Cardiology: LDL-C < 1.4 mmol/L, non-HDL-C < 2.2 mmol/L, and apoB <65 mg/dL.Among 4061 patients (78.8% male, mean age 60.3 years), between index event and interview, 66.3% had no change in treatment intensity. LLT use at interview was largely statin monotherapy: 49.6% high-intensity (inter-country range 5.3%-77.3%) and 24.1% low/moderate-intensity (inter-country range 5.1%-70.1%). Otherwise, 12.2% (inter-country range 0.2%-41.1%) were on combination therapy, and 12.7% on no LLT (inter-country range 3.5%-36.7%). Goal attainment for LDL-C was 17.5%. Corresponding non-HDL-C and apoB goals were achieved by 29.9% and 29.2%, respectively. Higher-income countries (defined by the World Bank's 2024-25 classification of income levels) did better in goal attainment than lower-middle-income countries. In this international study, contemporary lipid goals were not achieved in most CHD patients, with lower-middle-income countries having the worst goal attainment. Contributory factors include absence of any LLT use, low use of combinations and a failure to up-titrate LLT to achieve guideline targets. Show less

In Traditional Chinese Medicine (TCM), dampness is a pathogenic factor arising from impaired production and transportation of bodily fluids. While Fuling Zexie decoction (FLZXD) has demonstrated therapeutic efficacy in dampness constitution (DC) treatment, the material basis underlying its constitutional modulatory effects remains unclear. This study proposes objective indicators for the differentiation and therapeutic evaluation of DC and elucidates the material basis of FLZXD in DC treatment. Serum exosome proteomic profiling was conducted across two independent cohorts to identify DC-related indicators and assess the therapeutic efficacy of FLZXD in DC-associated hyperlipidemia (DC-hyperlipidemia). The bioactive compounds of FLZXD were prioritized through a comprehensive analysis of patent documentation and network pharmacology, with subsequent validation of DC-related targets using enzyme-linked immunosorbent assay (ELISA). Proteomic analysis of serum exosomes revealed signatures that differentiate individuals with a balanced constitution (BC) from those with DC. The differentially expressed proteins (DEPs) were enriched predominantly in pathways related to the complement cascade and cardiovascular diseases. FLZXD demonstrated therapeutic efficacy against DC-hyperlipidemia, as evidenced by the reversal of DEPs expression following treatment, which was supported by the patentable findings and network pharmacology analysis. Through experimental validation and pharmacological evidence, the active herbs of FLZXD (Fuling, Zexie and Baizhu, collectively referred to as FZB) were identified, and a total of 73 putative therapeutic targets involved in the dampness-resolving effects of FZB were revealed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment further confirmed that FLZXD exerts its anti-dampness effects primarily through regulation of the complement and coagulation cascades. Among eight candidate indicators specifically associated with DC, four proteins were validated via ELISA, indicating potential utility for the differentiation of DC. The sensitivity (%), specificity (%), fold change (FC), p-value, and area under the curve (AUC) for each indicator were as follows: apolipoprotein B-100 (APOB) (100.00, 80.00, 0.63, 0.0051, 0.94), complement factor H-related protein 1 (CFHR1) (90.00, 100.00, 0.55, 0.0001, 0.98), alpha-1-acid glycoprotein 1 (ORM1) (100.00, 80.00, 0.71, 0.0043, 0.92), and pigment epithelium-derived factor (SERPINF1) (90.00, 70.00, 0.66, 0.0002, 0.87). The integrative approach, combining proteomic profiling, network pharmacology analysis, and clinical validation, establishes an integrative approach for research on TCM constitutions. This approach provides (1) molecular insights into the differentiation of DC, (2) a foundation for mechanism-based, targeted therapeutic strategies, and (3) enhanced patient stratification to support personalized treatment approaches. Show less

Lipoprotein(a) (Lp[a]) is an apolipoprotein B100 (apoB)-containing lipoprotein with a single apolipoprotein(a) (apo[a]) covalently bound to apoB via a disulfide bond and oxidized phospholipids linked to apoB and apo(a), which is associated with proinflammatory, prothrombotic, and proatherogenic mechanisms. Elevated Lp(a) (≥125 nmol/L [≥50 mg/dL]) is an independent, causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD), affecting >1.4 billion individuals worldwide. There are no pharmacological Lp(a)-lowering therapies approved in the United States; however, lipoprotein apheresis may be considered under certain circumstances. Germany is the only country where apheresis is approved for patients with elevated Lp(a) and progressing ASCVD. Existing lipid-lowering therapies including proprotein convertase subtilisin/kexin type 9 inhibitors have shown modest effects on Lp(a) levels but fallen short of clinically meaningful reductions of >50 to 100 mg/dL. Several Lp(a)-lowering, RNA-targeted agents are in development, including antisense oligonucleotides (ASOs) and small interfering RNAs. Pelacarsen is a second-generation ASO that targets the production of apo(a) and includes chemical modifications such as triantennary N-acetylgalactosamine that improve biostability, decrease off-target toxicity compared with unmodified ASOs, and allow rapid, specific uptake by hepatocytes, the site of apo(a) synthesis. A phase 2b study of pelacarsen showed ≥80% reduction in Lp(a) concentration with a favorable safety profile in patients with established ASCVD. The ongoing phase 3 Lp(a)HORIZON study is evaluating whether the Lp(a)-lowering effects of pelacarsen translate into reductions in the incidence of major cardiovascular events, also in patients with established ASCVD. Herein, we review the mechanism of action of pelacarsen and evidence for its Lp(a)-lowering effects. Show less

This study aims to identify oxidative stress-related genes (OSGs) in papillary thyroid carcinoma (PTC) and their common targets with resveratrol. Oxidative stress-related differentially expressed genes (OS-DEGs) were identified by intersecting datasets. The screened core genes were utilized to construct a prognostic model, and their prognostic value, along with their associations with clinical pathological characteristics and immune infiltration, was assessed. Subsequently, the core targets at the intersection of resveratrol and oxidative stress (OS) in PTC were screened, and their binding properties with resveratrol were analyzed. By conducting cross-database analysis, 38 OS-DEGs were identified, and 3 core genes APOE、CDKN2A、APOD were determined. The prognostic model based on core genes exhibited robust prognostic capabilities. The core genes displayed significant correlations with various clinical pathological parameters and a range of immune cells. Additionally, 13 targets of resveratrol for antioxidative stress were screened from databases. 6 high-performing targets, JUN, TGFB1, BCL2, CDKN1A, FOS, ICAM1, were revealed by topological analysis, all exhibiting binding energies lower than - 5.0 kcal/mol. Our study is the pioneering research to provide new insights into the diagnosis, prognosis, and treatment of PTC through the analysis of OSGs, presenting potential clinical implications. Furthermore, this research reveals the molecular functions associated with resveratrol and its pharmacological targets regulating OS in PTC for the first time. Show less

Inflammation and hyperlipidaemia contribute with similar magnitude to the risk of future atherothrombotic events. However, the relative importance of high-sensitivity CRP (hsCRP) and lipoprotein(a) (Lp[a]) as determinants of risk of major adverse cardiovascular events (MACE) are not well defined among patients aged 75 years or older with established atherosclerotic cardiovascular disease (ASCVD). The present study prospectively enrolled 2,333 patients aged 75 years or older diagnosed with ASCVD with measurement of hsCRP and Lp(a) at Fuwai Hospital. The primary endpoint was MACE, defined as a composite of all-cause death, myocardial infarction (MI), stroke or ischaemia-driven coronary revascularisation. The median follow-up time was 3.0 years (interquartile range [IQR]: 2.5-3.2 years). hsCRP was significantly associated with an increased risk of MACE (adjusted hazard ratio [aHR]: 1.05, 95% confidence interval [CI]: 1.03-1.08 per 1 mg/l increment, P < 0.001; highest versus lowest quartile: aHR: 1.70 [1.22-2.38]), whereas there was no significant association between Lp(a) and MACE risk (aHR: 1.02 [0.98-1.06] per 10 mg/dl increment, P = 0.341; highest versus lowest quartile: aHR: 1.06 [0.77-1.47]). Risks of MACE were significantly higher in participants with hsCRP ≥2 mg/l than in those with hsCRP <2 mg/l, irrespective of Lp(a) strata (aHR: 1.41 [1.12-1.79]; P = 0.004). Concomitant elevation of hsCRP (≥2 mg/l) and Lp(a) (≥30 mg/dl) was associated with the greatest risk of MACE (aHR, 1.54 [1.13-2.12]; P = 0.007). Inflammation assessed by hsCRP predicted risk of future cardiovascular events more strongly than Lp(a) in patients aged 75 years or older with established ASCVD. These results provided real-world evidence on older patients potentially benefit by targeted anti-inflammatory strategies for secondary ASCVD prevention. Show less

Insulin resistance (IR) contributes to atherogenic dyslipidemia and elevated ASCVD risk. Apolipoprotein A1 (ApoA1)-associated lipoproteins have diverse anti-atherogenic functions, but it is unclear whether IR drives adverse changes in their proteomic composition. We hypothesized that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions would improve its composition. We studied 861 participants without diabetes (age 47 ± 12 years, 65.5% female). IR was directly measured using the steady-state plasma glucose (SSPG) concentration via the insulin suppression test. ApoA1-associated proteins were quantified by mass spectrometry. A subset underwent interventions for 3 months (N total 108): pioglitazone, PIO Show less

The revalorization of animal by-products, such as porcine blood, is a key strategy for sustainable aquaculture and circular economy practices. This study aimed to fill the existing knowledge gap on the effects of spray-dried porcine blood hydrolysate (PBSH), assessing its potential as a functional feed ingredient for gilthead sea bream. Two practical diets were formulated: a control diet containing 5% blood meal, and a PBSH diet including 5% PBSH previously characterized in vitro. The results indicated that the PBSH diet promoted lower hepatosomatic index, a down-regulation of key hepatic lipogenic enzymes ( Show less