Lipoprotein(a): Are we ready for large-scale clinical trials?

Cardiovascular diseases (CVD) are currently the most important disease threatening human health, which may be due to the high incidence of risk factors including hyperlipidemia. With the deepening of research on lipoprotein, lipoprotein (a) [Lp(a)] has been shown to be an independent risk factor for atherosclerotic cardiovascular diseases and calcified aortic valve stenosis and is now an unaddressed "residual risk" in current CVD management. Accurate measurement of Lp(a) concentration is the basis for diagnosis and treatment of high Lp(a). This review summarized the Lp(a) structure, discussed the current problems in clinical measurement of plasma Lp(a) concentration and the effects of existing lipid-lowering therapies on Lp(a).

Federated learning using model projection for multi-center disease diagnosis with non-IID data.

Multi-center disease diagnosis aims to build a global model for all involved medical centers. Due to privacy concerns, it is infeasible to collect data from multiple centers for training (i.e., centralized learning). Federated Learning (FL) is a decentralized framework that enables multiple clients (e.g., medical centers) to collaboratively train a global model while retaining patient data locally for privacy. However, in practice, the data across medical centers are not independently and identically distributed (Non-IID), causing two challenging issues: (1) catastrophic forgetting at clients, i.e., the local model at clients will forget the knowledge received from the global model after local training, causing reduced performance; and (2) invalid aggregation at the server, i.e., the global model at the server may not be favorable to some clients after model aggregation, resulting in a slow convergence rate. To mitigate these issues, an innovative Federated learning using Model Projection (FedMoP) is proposed, which guarantees: (1) the loss of local model on global data does not increase after local training without accessing the global data so that the performance will not be degenerated; and (2) the loss of global model on local data does not increase after aggregation without accessing local data so that convergence rate can be improved. Extensive experimental results show that our FedMoP outperforms state-of-the-art FL methods in terms of accuracy, convergence rate and communication cost. In particular, our FedMoP also achieves comparable or even higher accuracy than centralized learning. Thus, our FedMoP can ensure privacy protection while outperforming centralized learning in accuracy and communication cost.

Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti.

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD), especially advanced metabolic dysfunction-associated steatohepatitis (MASH), have an increased risk of cardiovascular diseases (CVDs). Whether CVD events will, in turn, influence the pathogenesis of MASLD remains unknown. Here, we show that myocardial infarction (MI) accelerates hepatic pathological progression of MASLD. Patients with MASLD who experience CVD events after their diagnosis exhibit accelerated liver fibrosis progression. MI promotes hepatic fibrosis in mice with MASH, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to damaged liver tissues. These adverse effects are significantly abrogated when deleting these cells. Meanwhile, MI substantially increases circulating and cardiac periostin levels, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of MASH. These preclinical and clinical results demonstrate that MI alters systemic homeostasis and upregulates pro-fibrotic factor production, triggering cross-disease communication that accelerates hepatic pathological progression of MASLD.

Corrigendum: Deep learning or radiomics based on CT for predicting the response of gastric cancer to neoadjuvant chemotherapy: a meta-analysis and systematic review.

[This corrects the article DOI: 10.3389/fonc.2024.1363812.].

Suppressing mitochondrial inner membrane protein (IMMT) inhibits the proliferation of breast cancer cells through mitochondrial remodeling and metabolic regulation.

Metabolic reprogramming is widely recognized as a hallmark of malignant tumors, and the targeting of metabolism has emerged as an appealing approach for cancer treatment. Mitochondria, as pivotal organelles, play a crucial role in the metabolic regulation of tumor cells, and their morphological and functional alterations are intricately linked to the biological characteristics of tumors. As a key regulatory subunit of mitochondria, mitochondrial inner membrane protein (IMMT), plays a vital role in degenerative diseases, but its role in tumor is almost unknown. The objective of this research was to investigate the roles that IMMT play in the development and progression of breast cancer (BC), as well as to elucidate the underlying biological mechanisms that drive these effects. In this study, it was confirmed that the expression of IMMT in BC tissues was significantly higher than that in normal tissues. The analysis of The Cancer Genome Atlas (TCGA) database revealed that IMMT can serve as an independent prognostic factor for BC patients. Additionally, verification in clinical specimens of BC demonstrated a positive association between high IMMT expression and larger tumor size (> 2 cm), Ki-67 expression (> 15%), and HER-2 status. Furthermore, in vitro experiments have substantiated that the suppression of IMMT expression resulted in a reduction in cell proliferation and alterations in mitochondrial cristae, concomitant with the liberation of cytochrome c, but it did not elicit mitochondrial apoptosis. Through Gene Set Enrichment Analysis (GSEA) analysis, we have predicted the associated metabolic genes and discovered that IMMT potentially modulates the advancement of BC through its interaction with 16 metabolic-related genes, and the changes in glycolysis related pathways have been validated in BC cell lines after IMMT inhibition. Consequently, this investigation furnishes compelling evidence supporting the classification of IMMT as prognostic marker in BC, and underscoring its prospective utility as a novel target for metabolic therapy.

Complementary multi-modality molecular self-supervised learning via non-overlapping masking for property prediction.

Self-supervised learning plays an important role in molecular representation learning because labeled molecular data are usually limited in many tasks, such as chemical property prediction and virtual screening. However, most existing molecular pre-training methods focus on one modality of molecular data, and the complementary information of two important modalities, SMILES and graph, is not fully explored. In this study, we propose an effective multi-modality self-supervised learning framework for molecular SMILES and graph. Specifically, SMILES data and graph data are first tokenized so that they can be processed by a unified Transformer-based backbone network, which is trained by a masked reconstruction strategy. In addition, we introduce a specialized non-overlapping masking strategy to encourage fine-grained interaction between these two modalities. Experimental results show that our framework achieves state-of-the-art performance in a series of molecular property prediction tasks, and a detailed ablation study demonstrates efficacy of the multi-modality framework and the masking strategy.

Inhibition of Glycyrrhiza Polysaccharide on Human Cytochrome P450 46A1 in vitro and in vivo: Implications in Treating Neurological Diseases.

BACKGROUND: Cytochrome P450 (CYP) 46A1, also known as cholesterol 24S-hydroxylase, is essential for maintaining the homeostasis of cholesterol in the brain and serves as a therapeutic target of neurodegenerative disorders and excitatory neurotoxicity. N-methyl-d-aspartate receptor (NMDAR) is a prototypical receptor for the excitatory neurotransmitter glutamate and can be specifically regulated by 24S-hydroxycholesterol (24S-HC). Glycyrrhiza is one of the most widely used herbs with broad clinical applications. It has several pharmacological activities, such as clearing heat and detoxifying, moistening the lung and relieving cough, analgesic, neuroprotective outcomes, and regulating a variety of drug activities. Glycyrrhiza is a commonly used herb for the treatment of epileptic encephalopathy. However, whether glycyrrhiza can interfere with the activity of CYP46A1 remains unknown. OBJECTIVE: This study aimed to investigate the regulating effects of glycyrrhiza polysaccharides (GP) on CYP46A1-mediated cholesterol conversion, as well as in the modulation of related proteins. MATERIALS AND METHODS: The effects of glycyrrhiza polysaccharide (GP) on the activity of CYP46A1 were investigated in vivo and in vitro. Moreover, the potential regulatory effects of GP on the expressions of CYP46A1, HMG-CoA reductase (HMGCR), and NMDAR were also detected. RESULTS: The in vitro results demonstrated that glycyrrhiza polysaccharide (GP), as the main water-soluble active component of glycyrrhiza, remarkably inhibited the activity of CYP46A1 in a non-competitive mode with a Ki value of 0.7003 mg/ml. Furthermore, the in vivo experiments verified that GP markedly decreased the contents of 24S-HC in rat plasma and brain tissues as compared to the control. More importantly, the protein expressions of CYP46A1, GluN2A, GluN2B, and HMG-CoA reductase (HMGCR) in rat brains were all downregulated, whereas the mRNA expressions of CYP46A1 and HMGCR were not significantly changed after treatment with GP. CONCLUSION: GP exhibits a significant inhibitory effect on CYP46A1 activity in vitro and in vivo, and the protein expressions of CYP46A1, HMGCR, and NMDAR are also inhibited by GP, which are of considerable clinical significance for GP's potential therapeutic role in treating neurological diseases.

A Study on the Preparation of a Vulcanizing Mixture and Its Application in Natural Rubber Latex.

The traditional preparation process of natural rubber latex requires tedious treatment of a variety of rubber additives. In this paper, a new process of wet mixed grinding was used to prepare a reinforced vulcanization mixture and a rapid vulcanization effect. The effect of different amounts of vulcanization mixtures on the mechanical properties of natural latex film was studied, and the pre-vulcanization process of latex and the vulcanization process of film were optimized. The results showed that with the increase in the amount of vulcanization mixture, the tensile strength increased from 5.96 MPa to 29.28 MPa, and the tear strength increased from 7.59 kN/m to 52.81 kN/m. When the vulcanization temperature of the latex film is heated from 80 °C to 100 °C, the vulcanization time is shortened by 5~6 times. The new vulcanization mixture prepared in this work has the characteristics of simple production and fast vulcanization speed, which provides a new solution for the development of the latex product industry.

Germline Cas9 promoters with improved performance for homing gene drive.

Gene drive systems could be a viable strategy to prevent pathogen transmission or suppress vector populations by propagating drive alleles with super-Mendelian inheritance. CRISPR-based homing gene drives convert wild type alleles into drive alleles in heterozygotes with Cas9 and gRNA. It is thus desirable to identify Cas9 promoters that yield high drive conversion rates, minimize the formation rate of resistance alleles in both the germline and the early embryo, and limit somatic Cas9 expression. In Drosophila, the nanos promoter avoids leaky somatic expression, but at the cost of high embryo resistance from maternally deposited Cas9. To improve drive efficiency, we test eleven Drosophila melanogaster germline promoters. Some achieve higher drive conversion efficiency with minimal embryo resistance, but none completely avoid somatic expression. However, such somatic expression often does not carry detectable fitness costs for a rescue homing drive targeting a haplolethal gene, suggesting somatic drive conversion. Supporting a 4-gRNA suppression drive, one promoter leads to a low drive equilibrium frequency due to fitness costs from somatic expression, but the other outperforms nanos, resulting in successful suppression of the cage population. Overall, these Cas9 promoters hold advantages for homing drives in Drosophila species and may possess valuable homologs in other organisms.

Efficacy and Safety of Neoadjuvant Subcutaneous Envafolimab in dMMR/MSI-H Locally Advanced Colon Cancer.

BACKGROUND: Neoadjuvant immunotherapy with programmed death-ligand 1 blockade for colon cancer, especially for mismatch repair-deficient (dMMR)/high microsatellite instability (MSI-H) colon cancer, has gained considerable attention recently. OBJECTIVE: This study aimed to assess the safety and efficacy of neoadjuvant subcutaneous envafolimab in patients with dMMR/MSI-H locally advanced colon cancer. METHODS: Patients with dMMR/MSI-H locally advanced colon cancer treated with envafolimab at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital from October 2021 to July 2023 were retrospectively reviewed and analyzed. The primary endpoint was the pathological complete response (CR) rate, and secondary endpoints were treatment-related adverse events and complete clinical response rate. RESULTS: Overall, 15 patients were analyzed. After neoadjuvant immunotherapy with envafolimab, six patients achieved a CR, with five partial responses, and four stable disease. Three patients achieving a complete clinical response chose to accept a "watch and wait" strategy, and surgery was performed in 12 patients. Postoperative pathology results revealed seven patients achieved pathological CRs, and five patients achieved tumor regression grade 2, with 66.7% of the total CR rate. The most common treatment-related adverse events were pruritus and rash (40%), with no severe cases. No recurrences occurred over a 7.9-month follow-up. CONCLUSIONS: Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.

Factors associated with clinical nurse's mental health: a qualitative study applying the social ecological model.

BACKGROUND: The prevalence of burnout, depression, and anxiety among Chinese nurses was 34%, 55.5%, and 41.8% respectively. Mental health problems have significant impacts on their personal well-being, work performance, patient care quality, and the overall healthcare system. Mental health is influenced by factors at multiple levels and their interactions. METHODS: This was a descriptive qualitative study using phenomenological approach. We recruited a total of 48 nurses from a tertiary hospital in Changsha, Hunan Province, China. Data were collected through focus group interviews. Audio-recorded data were transcribed and inductively analysed. RESULTS: Four major themes with 13 subthemes were identified according to the social ecological model: (1) individual-level factors, including personality traits, sleep quality, workplace adaptability, and years of work experience; (2) interpersonal-level factors, encompassing interpersonal support and role conflict; (3) organization-level factors, such as organizational climate, organizational support, career plateau, and job control; and (4) social-level factors, which included compensation packages, social status, and legislative provision and policy. CONCLUSIONS: Our study provides a nuanced understanding of the multifaceted factors influencing nurses' mental health. Recognizing the interconnectedness of individual, interpersonal, organizational, and social elements is essential for developing targeted interventions and comprehensive strategies to promote and safeguard the mental well-being of nurses in clinical settings. TRIAL AND PROTOCOL REGISTRATION: The larger study was registered with Chinese Clinical Trial Registry: ChiCTR2300072142 (05/06/2023) https://www.chictr.org.cn/showproj.html?proj=192676 . REPORTING METHOD: This study is reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ).

APEX-pHLA: A novel method for accurate prediction of the binding between exogenous short peptides and HLA class I molecules.

Human leukocyte antigen (HLA) molecules play critically significant role within the realm of immunotherapy due to their capacities to recognize and bind exogenous antigens such as peptides, subsequently delivering them to immune cells. Predicting the binding between peptides and HLA molecules (pHLA) can expedite the screening of immunogenic peptides and facilitate vaccine design. However, traditional experimental methods are time-consuming and inefficient. In this study, an efficient method based on deep learning was developed for predicting peptide-HLA binding, which treated peptide sequences as linguistic entities. It combined the architectures of textCNN and BiLSTM to create a deep neural network model called APEX-pHLA. This model operated without limitations related to HLA class I allele variants and peptide segment lengths, enabling efficient encoding of sequence features for both HLA and peptide segments. On the independent test set, the model achieved Accuracy, ROC_AUC, F1, and MCC is 0.9449, 0.9850, 0.9453, and 0.8899, respectively. Similarly, on an external test set, the results were 0.9803, 0.9574, 0.8835, and 0.7863, respectively. These findings outperformed fifteen methods previously reported in the literature. The accurate prediction capability of the APEX-pHLA model in peptide-HLA binding might provide valuable insights for future HLA vaccine design.

Early matrix softening contributes to vascular smooth muscle cell phenotype switching and aortic dissection through down-regulation of microRNA-143/145.

Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection.

Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models.

An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell- or fibroblast-specific knockout of Igf1r, the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl2-induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA.

Genetically determined blood pressure, antihypertensive drug classes, and frailty: A Mendelian randomization study.

Observational studies have suggested that the use of antihypertensive drugs was associated with the risk of frailty; however, these findings may be biased by confounding and reverse causality. This study aimed to explore the effect of genetically predicted lifelong lowering blood pressure (BP) through different antihypertensive medications on frailty. One-sample Mendelian randomization (MR) and summary data-based MR (SMR) were applied. We utilized two kinds of genetic instruments to proxy the antihypertensive medications, including genetic variants within or nearby drugs target genes associated with systolic/diastolic BP, and expression level of the corresponding gene. Among 298,618 UK Biobank participants, one-sample MR analysis observed that genetically proxied BB use (relative risk ratios, 0.76; 95% CI, 0.65-0.90; p = 0.001) and CCB use (0.83; 0.72-0.95; p = 0.007), equivalent to a 10-mm Hg reduction in systolic BP, was significantly associated with lower risk of pre-frailty. In addition, although not statistically significant, the effect directions of systolic BP through ACEi variants (0.72; 0.39-1.33; p = 0.296) or thiazides variants (0.74; 0.53-1.03; p = 0.072) on pre-frailty were also protective. Similar results were obtained in analyses for diastolic BP. SMR of expression in artery showed that decreased expression level of KCNH2, a target gene of BBs, was associated with lower frailty index (beta -0.02, p = 2.87 × 10-4). This MR analysis found evidence that the use of BBs and CCBs was potentially associated with reduced frailty risk in the general population, and identified KCNH2 as a promising target for further clinical trials to prevent manifestations of frailty.

Application of nursing intervention based on Snyder's hope theory in individuals with spinal cord injury.

OBJECTIVE: To study the effect of nursing intervention derived from Snyder's hope theory in individuals with spinal cord injury. METHODS: We retrospectively analyzed clinical data of 80 patients with spinal cord injury who were admitted to General Hospital of Pingxiang Mining Group Co., from August 2021 to October 2023. According to different nursing methods, they were assigned into a control group (n = 40, routine curative care) and an observation group (n = 40, routine curative care plus nursing intervention derived from Snyder's hope theory). The two groups were compared in terms of emotional state, level of hope, living standard, occurrence of complications, and nursing satisfaction. According to the occurrence of complications after nursing, the patients were divided into a good prognosis group and a poor prognosis group, and the influencing factors for prognosis were analyzed by univariate analysis and logistic multivariate analysis. RESULTS: After nursing, the anxiety and depression scores decreased in both groups when compared to their pre-nursing scores, with lower scores in the observation group than in the controls (P<0.05). Also, the observation group exhibited significantly higher score of hope, higher score of quality of life, and lower occurrence of complications when compared to the control group (P<0.05). The nursing satisfaction rate in the observation group was 95.00% (38/40), which was noticeably greater than 65.00% (26/40) in the control group (P<0.05). Multivariate analysis showed that nursing methods (P = 0.007, OR = 7.828, 95% CI: 1.766-34.688) and HB after intervention (P = 0.029, OR = 0.965, 95% CI: 0.935-0.996) were the influencing factors of complications after nursing intervention in patients with SCI. CONCLUSION: The implementation of nursing intervention derived from Snyder's hope theory can decrease the anxiety and depression levels, lower the occurrence of complications, enhance the hope level, increase the satisfaction rate, and improve the overall quality of life in patients with spinal cord injury.

KLF15 maintains contractile phenotype of vascular smooth muscle cells and prevents thoracic aortic dissection by interacting with MRTFB.

Thoracic aortic dissection (TAD) is a highly dangerous cardiovascular disorder caused by weakening of the aortic wall, resulting in a sudden tear of the internal face. Progressive loss of the contractile apparatus in vascular smooth muscle cells (VSMCs) is a major event in TAD. Exploring the endogenous regulators essential for the contractile phenotype of VSMCs may aid the development of strategies to prevent TAD. Krüppel-like factor 15 (KLF15) overexpression was reported to inhibit TAD formation; however, the mechanisms by which KLF15 prevents TAD formation and whether KLF15 regulates the contractile phenotype of VSMCs in TAD are not well understood. Therefore, we investigated these unknown aspects of KLF15 function. We found that KLF15 expression was reduced in human TAD samples and ß-aminopropionitrile monofumarate-induced TAD mouse model. Klf15KO mice are susceptible to both ß-aminopropionitrile monofumarate- and angiotensin II-induced TAD. KLF15 deficiency results in reduced VSMC contractility and exacerbated vascular inflammation and extracellular matrix degradation. Mechanistically, KLF15 interacts with myocardin-related transcription factor B (MRTFB), a potent serum response factor coactivator that drives contractile gene expression. KLF15 silencing represses the MRTFB-induced activation of contractile genes in VSMCs. Thus, KLF15 cooperates with MRTFB to promote the expression of contractile genes in VSMCs, and its dysfunction may exacerbate TAD. These findings indicate that KLF15 may be a novel therapeutic target for the treatment of TAD.

Identification of Circulating Inflammatory Proteins Associated with Calcific Aortic Valve Stenosis by Multiplex Analysis.

Calcific aortic valve stenosis (CAVS) is characterized by increasing inflammation and progressive calcification in the aortic valve leaflets and is a major cause of death in the aging population. This study aimed to identify the inflammatory proteins involved in CAVS and provide potential therapeutic targets. We investigated the observational and causal associations of 92 inflammatory proteins, which were measured using affinity-based proteomic assays. Firstly, the case-control cohort identified differential proteins associated with the occurrence and progression of CAVS. Subsequently, we delved into exploring the causal impacts of these associated proteins through Mendelian randomization. This involved utilizing genetic instruments derived from cis-protein quantitative loci identified in genome-wide association studies, encompassing a cohort of over 400,000 individuals. Finally, we investigated the gene transcription and protein expression levels of inflammatory proteins by single-cell and immunohistochemistry analysis. Multivariate logistic regression and spearman's correlation analysis showed that five proteins showed a significant positive correlation with disease severity. Mendelian randomization showed that elevated levels of two proteins, namely, matrix metallopeptidase-1 (MMP1) and sirtuin 2 (SIRT2), were associated with an increased risk of CAVS. Immunohistochemistry and single-cell transcriptomes showed that expression levels of MMP1 and SIRT2 at the tissue and cell levels were significantly higher in calcified valves than in non-calcified control valves. These findings indicate that MMP1 and SIRT2 are causally related to CAVS and open up the possibility for identifying novel therapeutic targets.