The role of residual inflammatory risk and LDL cholesterol in patients with in-stent restenosis undergoing percutaneous coronary intervention.

BACKGROUND: To evaluate the relationships between residual inflammatory risk [assessed by high-sensitivity C-reactive protein (hsCRP)], residual cholesterol risk [assessed by low-density lipoprotein cholesterol (LDL-C)] and clinical outcomes among patients who underwent percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) lesions. METHODS: Between January 2017 and December 2018, a total of 2079 patients who underwent PCI for ISR were consecutively enrolled. The primary outcome was the rate of major adverse cardiac events (MACE), defined as a composite endpoint of all-cause death, spontaneous myocardial infarction (MI), or repeat revascularization. RESULTS: During a median follow-up of 36 months, 436 MACEs occurred. Baseline hsCRP was significantly associated with MACE (highest versus lowest quartile, adjusted hazard ratio [aHR] 1.90 [95 % CI, 1.39-2.59]; P < 0.001). By contrast, the baseline LDL-C quartile was not associated with MACE (highest versus lowest quartile, aHR 0.93 [95 % CI, 0.71- 1.22]; P = 0.59). Compared with patients without residual risk (hsCRP <2 mg/L and LDL-C < 70 mg/dL), participants with both residual inflammatory and LDL-C risk (hsCRP ≥2 mg/L and LDL-C ≥ 70 mg/dL) (aHR, 1.39 [95 % CI, 1.06-1.83]; P = 0.02) and those with residual inflammatory risk only (hsCRP ≥2 mg/L and LDL-C < 70 mg/dL) (aHR, 1.34 [95 % CI, 1.01-1.72]; P = 0.04) had significantly higher risks of MACE. CONCLUSIONS: In the current cohort of patients after ISR PCI, inflammation assessed by hsCRP predicted higher risk of adverse clinical outcomes, whereas the level of LDL-C was not associated with adverse prognosis.

miR-155 enhances apoptosis of macrophage through suppressing PI3K-AKT activation in Pseudomonas aeruginosa keratitis.

Keratitis induced by Pseudomonas aeruginosa (P. aeruginosa) is an acute and serious corneal inflammation. As a family of gene regulators, miRNAs play a crucial role in modulating host response after microbial invasion. However, their functions in P. aeruginosa keratitis remain largely unclear. In the present study, we demonstrated that miR-155 expression was significantly increased in macrophages and corneal tissue after P. aeruginosa infection. In vivo studies demonstrated that mice with miR-155 knockdown displayed more resistance to P. aeruginosa keratitis, with a lower bacterial burden. In addition, in vitro and in vivo studies indicated that miR-155 enhanced apoptosis of macrophages after P. aeruginosa infection, and resulted in a susceptible phenotype of P. aeruginosa keratitis. Moreover, miR-155 induced apoptosis through reducing activation of PI3K-Akt signaling pathway. Our data provided evidence of miR-155 mediated apoptosis of macrophage in P. aeruginosa keratitis, which may be an underlying target for the therapy of P. aeruginosa keratitis and other infectious diseases.

LncRNA-mRNA co-expression analysis reveals aquaporin-9-promoted neutrophil extracellular trap formation and inflammatory activation in sepsis.

Sepsis is a life-threatening condition caused by an excessive inflammatory response to an infection. However, the precise regulatory mechanism of sepsis remains unclear. Using a strand-specific RNA-sequencing, we identified 115 hub differentially expressed long noncoding RNAs (lncRNAs) and 443 mRNAs in septic patients, primarily participated in crucial pathways including neutrophil extracellular trap (NET) formation and toll-like receptor signaling. Notably, NETs related gene aquaporin-9 (AQP9) and its associated lncRNAs exhibited significant upregulation in septic neutrophils. Functional experiments revealed AQP9 interacts with its lncRNAs to augment the formation of neutrophil NETs. In murine sepsis models, AQP9 inhibition with phloretin reduced proinflammatory cytokine production and lung damage. These findings provide crucial insights into the regulatory role of AQP9 in sepsis, unraveling its interaction with associated lncRNAs in transmitting downstream signals, holding promise in informing the development of novel therapeutic strategies aimed at ameliorating the debilitating effects of sepsis.

Prognostic Value of Plasma Endothelin-1 in Predicting Worse Outcomes in Patients with Prediabetes and Diabetes and Stable Coronary Artery Diseases.

BACKGRUOUND: Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in coronary artery disease (CAD) and diabetes. This study aimed to determine the prognostic value of ET-1 in the patients with stable CAD under different glucose metabolism states. METHODS: In this prospective, large-cohort study, we consecutively enrolled 7,947 participants with angiography-diagnosed stable CAD from April 2011 to April 2017. Patients were categorized by baseline glycemic status into three groups (normoglycemia, prediabetes, and diabetes) and further divided into nine groups by circulating ET-1 levels. Patients were followed for the occurrence of cardiovascular events (CVEs), including nonfatal myocardial infarction, stroke, and cardiovascular mortality. RESULTS: Of the 7,947 subjects, 3,352, 1,653, and 2,942 had normoglycemia, prediabetes, and diabetes, respectively. Over a median follow-up of 37.5 months, 381 (5.1%) CVEs occurred. The risk for CVEs was significantly higher in patients with elevated ET-1 levels after adjustment for potential confounders. When patients were categorized by both status of glucose metabolism and plasma ET-1 levels, the high ET-1 levels were associated with higher risk of CVEs in prediabetes (adjusted hazard ratio [HR], 2.089; 95% confidence interval [CI], 1.151 to 3.793) and diabetes (adjusted HR, 2.729; 95% CI, 1.623 to 4.588; both P<0.05). CONCLUSION: The present study indicated that baseline plasma ET-1 levels were associated with the prognosis in prediabetic and diabetic patients with stable CAD, suggesting that ET-1 may be a valuable predictor in CAD patients with impaired glucose metabolism.

Galectin-3 induces pathogenic immunosuppressive macrophages through interaction with TREM2 in lung cancer.

BACKGROUND: High infiltration of tumor-associated macrophages (TAMs) is associated with tumor promotion and immunosuppression. The triggering receptor expressed on myeloid cells 2 (TREM2) is emerged as a key immunosuppressive regulator for TAMs, however, how TREM2-expressing TAMs are recruited and what ligands TREM2 interacts with to mediate immunosuppression is unknown. METHODS: Flow cytometry and single-cell RNA sequencing were used to analyze TREM2 expression. Mechanistically, mass spectrometry and immunoprecipitation were employed to identify proteins binding to TREM2. Phagocytosis and co-culture experiments were used to explore the in vitro functions of galectin3-TREM2 pair. Establishment of TREM2f/f-Lyz2-cre mice to validate the role of TREM2 signaling pathway in lung carcinogenesis. GB1107 were further supplemented to validate the therapeutic effect of Galectin3 based on TREM2 signaling regulation. RESULTS: This study identified that abundant TREM2+ macrophages were recruited at the intra-tumor site through the CCL2-CCR2 chemotactic axis. Galectin-3 impaired TREM2-mediated phagocytosis and promoted the conversion of TREM2+ macrophages to immunosuppressive TAMs with attenuated antigen presentation and co-stimulatory functions both in vitro both in vivo, and galectin-3 is a potential ligand for TREM2. Genetic and pharmacological blockade of TREM2 and galectin-3 significantly inhibited lung cancer progression in subcutaneous and orthotopic cancer models by remodeling the tumor immune microenvironment. CONCLUSION: Our findings revealed a previously unknown association between galectin-3 and TREM2 in TAMs of lung cancer, and suggested simultaneous inhibition of galectin3 and TREM2 as potent therapeutic approach for lung cancer therapy.

Oxygen-doped Carbon Nitrides with Visible Room-temperature Phosphorescence and Invisible Thermal-Stimuli-Responsive Ultraviolet Delayed Fluorescence for Security Applications.

Multi-mode emissive materials with stimuli-responsive producing invisible signals are very attractive for advanced security applications, but development of such materials remains highly challenging. In this work, oxygen-doped carbon nitrides (O-CNs) are prepared via microwave-assisted heating of urea, which exhibit ultraviolet (UV) solid-state fluorescence (SSFL), visible room temperature phosphorescence (RTP) and thermal-stimuli production of invisible UV delayed fluorescence (DF) properties. Further studies confirmed that the SSFL and RTP could be attributed to the introduction of oxygen functional group (e.g., C=O) in the skeleton of O-CNs, thus minimizing the aggregation caused quenching effect, facilitating intersystem crossing, and stabilizing the excited triplet states. The specific thermal-stimuli production of UV DF is deemed to be the relatively large energy gap between ground and excited singlet states as well as an effective triplet-triplet annihilation. Notably, the emission maximum of UV DF locates at ~310 nm with an ultra-narrow full width at half maximum (FWHM) down to 19 nm, so it is completely invisible to the naked eyes, but detectable by a UV camera. To employ the unique characteristics of O-CNs, security protection strategies with superior concealment by virtue of the thermal-stimuli quenching visible RTP and meanwhile producing invisible UV DF are demonstrated.

Physical Frailty and the Risk of Degenerative Valvular Heart Disease.

Background and Objectives: The relationship between physical frailty, age-related conditions, and the incidence of degenerative valvular heart disease (VHD) remains unclear. This study aimed to investigate the potential association between physical frailty and the development of degenerative VHD. Research Design and Methods: Participants from the UK Biobank who were initially free of VHD and heart failure were categorized into 3 groups based on the frailty phenotype: non-frailty, pre-frailty, and frailty. The frailty phenotype was determined by evaluating the following 5 components: weight loss, exhaustion, reduced physical activity, slow gait speed, and low grip strength. The incidence of degenerative VHD, including mitral valve regurgitation (MR), aortic valve regurgitation (AR), and aortic valve stenosis (AS), was assessed using hospital admission or death registries. Results: Among the 331 642 participants, 11 885 (3.6%) exhibited frailty and 143 379 (43.2%) were categorized as pre-frailty. During a median follow-up of 13.8 years, there were 3 684 MR, 1 205 AR, and 3 166 AS events. Compared to non-frailty participants, those with pre-frailty and frailty showed significantly increased risks for MR (hazard ratio [HR], HRpre-frailty:1.19, 95% confidence interval [CI]: 1.11-1.28; HRfrailty: 1.50, 95% CI: 1.30-1.74), AR (HRpre-frailty:1.19, 95% CI: 1.05-1.34; HRfrailty: 1.58, 95% CI: 1.22-2.04), and AS (HRpre-frailty:1.19, 95% CI: 1.11-1.29; HRfrailty: 1.74, 95% CI: 1.51-2.00). Among the 5 components, slow gait speed showed the strongest association with the risk of various types of VHD (HRMR: 1.50, 95% CI: 1.34-1.65; HRAR: 1.50, 95% CI: 1.24-1.80; HRAS: 1.46, 95% CI: 1.32-1.62), followed by exhaustion, low grip strength, and weight loss. Discussion and Implications: Pre-frailty and frailty were associated with a higher risk of all 3 types of degenerative VHD. Early detection and intervention for pre-frailty and frailty in middle-aged and older individuals may assist in preventing or delaying the onset of degenerative VHD.

HSP70 contributes to pathogenesis of fulminant hepatitis induced by coronavirus.

Fulminant viral hepatitis (FH) represents a significant clinical challenge, with its pathogenesis not yet fully elucidated. Heat shock protein (HSP)70, a molecular chaperone protein with a broad range of cytoprotective functions, is upregulated in response to stress. However, the role of HSP70 in FH remains to be investigated. Notably, HSP70 expression is upregulated in the livers of coronavirus-infected mice and patients. Therefore, we investigated the mechanistic role of HSP70 in coronavirus-associated FH pathogenesis. FH was induced in HSP70-deficient (HSP70 KO) mice or in WT mice treated with the HSP70 inhibitor VER155008 when infected with the mouse hepatitis virus strain A59 (MHV-A59). MHV-A59-infected HSP70 KO mice exhibited significantly reduced liver damage and mortality. This effect was attributed to decreased infiltration of monocyte-macrophages and neutrophils in the liver of HSP70 KO mice, resulting in lower levels of inflammatory cytokines such as IL-1ß, TNFα, and IL-6, and a reduced viral load. Moreover, treatment with the HSP70 inhibitor VER155008 protected mice from MHV-A59-induced liver damage and FH mortality. In summary, HSP70 promotes coronavirus-induced FH pathogenesis by enhancing the infiltration of monocyte-macrophages and neutrophils and promoting the secretion of inflammatory cytokines. Therefore, HSP70 is a potential therapeutic target in viral FH intervention.

The impacts of percutaneous coronary intervention to treat chronic total occlusion of right coronary artery on the 5-year prognosis: A single-centered retrospective study.

BACKGROUND: Chronic total occlusions (CTO) occur in about 20% of patients referred for coronary angiography, and right coronary artery (RCA) CTO has been reported in 38-50% of the entire CTO population. Limited data on angiographic and procedural characteristics of RCA-CTO and the risk of adverse cardiac events asks for a detailed study. METHODS: From 2010 to 2013, patients with attempted revascularization of at least one CTO lesion were included and followed up to 5 years after PCI. Eligible patients are assigned to RCA-CTO and non-RCA-CTO groups based on their target vessels. The primary endpoint was major adverse cardiovascular events (MACEs; a composite of all-cause death, myocardial infarction (MI) or rehospitalization for heart failure), and secondary endpoints were cardiac death, target lesion revascularization (TLR) and target vessel revascularization (TVR). RESULTS: The present study included 2659 eligible patients, among which 1285 patients were assigned to the RCA-CTO group, whereas 1374 patients were assigned to the non-RCA-CTO group. Lesions in RCA had longer lesion length, higher J-CTO score, higher rates of severe vessel tortuosity, a higher percentage of Rentrop grade 2-3, and more likely to be re-try lesion than those in LAD or LCX (all P < 0.01). CTO lesions in RCA reached less successful recanalization and post-procedural TIMI 3 flow (all <0.01). Multivariate Cox analysis revealed that RCA-CTO was not associated with primary outcome MACEs. Besides MACEs, RCA-CTO was also not associated with cardiac death, but was significantly associated with TLR and TVR (adjusted HR: 1.37 [95% CI:1.07-1.76], P = 0.01; adjusted HR: 1.43 [95% CI:1.13-1.82], P = 0.003). CONCLUSION: RCA-CTO lesions, which had more complex angiographic features, independently contributed to TLR and TVR but not to MACEs or cardiac death in the 5 years of follow-up.

Wearable device-measured moderate to vigorous physical activity and risk of degenerative aortic valve stenosis.

BACKGROUND AND AIMS: Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS: A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS: In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS: Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.

Comprehensive analysis of the association between triglyceride-glucose index and coronary artery disease severity across different glucose metabolism states: a large-scale cross-sectional study from an Asian cohort.

BACKGROUND: The triglyceride-glucose (TyG) index is associated with the development and prognosis of coronary artery disease (CAD). However, the impact of the TyG index on CAD severity across different glucose metabolism states exhibits significant disparities in previous research. METHODS: This cross-sectional study comprised 10,433 participants from a prospective cohort. Participants were categorized into four groups based on glucose metabolism state: normal glucose regulation (NGR), prediabetes (pre-DM), diabetes mellitus (DM) without insulin prescribed (Rx), and DM with insulin Rx. The TyG index was determined by the following formula: Ln [TG (mg/dL) × FPG (mg/dL) / 2], where TG is triglycerides and FPG is fasting plasm glucose. Statistical methods such as binary logistic regression, interaction analysis, restricted cubic spline (RCS), and receiver operating characteristic (ROC) were employed to analyze the relationship between the TyG index and CAD severity across the entire population and glucose metabolism subgroups. Mediation analysis was conducted to examine the mediating effects of glycated hemoglobin (HbA1c) on these relationships. Sensitivity analysis was performed to ensure the robustness of the findings. RESULTS: Multivariable logistic regression analysis revealed a significant positive association between the TyG index and multi-vessel CAD in the entire population (OR: 1.34; 95% CI: 1.22-1.47 per 1-unit increment). Subgroup analysis demonstrated consistent positive associations in the NGR, pre-DM, and DM non-insulin Rx groups, with the highest OR observed in the NGR group (OR: 1.67; 95% CI: 1.3-2.14 per 1-unit increment). No correlation was found in the DM with insulin Rx subgroup. RCS analyses indicated the distinct dose-response relationships across different glucose metabolism subgroups. Including the TyG index in the established model slightly improved the predictive accuracy, particularly in the NGR group. Mediation analyses showed varying mediating effects of HbA1c among different glucose metabolism subgroups. Sensitivity analysis confirmed the robustness of the aforementioned relationships in the new-onset CAD population and in individuals not using antilipidemic medications. CONCLUSIONS: The TyG index positively associated with CAD severity across all glucose metabolism states, except for individuals receiving insulin treatment. Moreover, it might serve as a supplementary noninvasive predictor of CAD severity in addition to established factors, especially in NGR patients.

Pushing Trap-Controlled Persistent Luminescence Materials toward Multi-Responsive Smart Platforms: Recent Advances, Mechanism, and Frontier Applications.

Smart stimuli-responsive persistent luminescence materials, combining the various advantages and frontier applications prospects, have gained booming progress in recent years. The trap-controlled property and energy storage capability to respond to external multi-stimulations through diverse luminescence pathways make them attractive in emerging multi-responsive smart platforms. This review aims at the recent advances in trap-controlled luminescence materials for advanced multi-stimuli-responsive smart platforms. The design principles, luminescence mechanisms, and representative stimulations, i.e., thermo-, photo-, mechano-, and X-rays responsiveness, are comprehensively summarized. Various emerging multi-responsive hybrid systems containing trap-controlled luminescence materials are highlighted. Specifically, temperature dependent trapping and de-trapping performance is discussed, from extreme-low temperature to ultra-high temperature conditions. Emerging applications and future perspectives are briefly presented. It is hoped that this review would provide new insights and guidelines for the rational design and performance manipulation of multi-responsive materials for advanced smart platforms.

Image Captioning via Dynamic Path Customization.

This article explores a novel dynamic network for vision and language (V&L) tasks, where the inferring structure is customized on the fly for different inputs. Most previous state-of-the-art (SOTA) approaches are static and handcrafted networks, which not only heavily rely on expert knowledge but also ignore the semantic diversity of input samples, therefore resulting in suboptimal performance. To address these issues, we propose a novel Dynamic Transformer Network (DTNet) for image captioning, which dynamically assigns customized paths to different samples, leading to discriminative yet accurate captions. Specifically, to build a rich routing space and improve routing efficiency, we introduce five types of basic cells and group them into two separate routing spaces according to their operating domains, i.e., spatial and channel. Then, we design a Spatial-Channel Joint Router (SCJR), which endows the model with the capability of path customization based on both spatial and channel information of the input sample. To validate the effectiveness of our proposed DTNet, we conduct extensive experiments on the MS-COCO dataset and achieve new SOTA performance on both the Karpathy split and the online test server. The source code is publicly available at https://github.com/xmu-xiaoma666/DTNet.

Artificial Intelligence in the Screening, Diagnosis, and Management of Aortic Stenosis.

The integration of artificial intelligence (AI) into clinical management of aortic stenosis (AS) has redefined our approach to the assessment and management of this heterogenous valvular heart disease (VHD). While the large-scale early detection of valvular conditions is limited by socioeconomic constraints, AI offers a cost-effective alternative solution for screening by utilizing conventional tools, including electrocardiograms and community-level auscultations, thereby facilitating early detection, prevention, and treatment of AS. Furthermore, AI sheds light on the varied nature of AS, once considered a uniform condition, allowing for more nuanced, data-driven risk assessments and treatment plans. This presents an opportunity to re-evaluate the complexity of AS and to refine treatment using data-driven risk stratification beyond traditional guidelines. AI can be used to support treatment decisions including device selection, procedural techniques, and follow-up surveillance of transcatheter aortic valve replacement (TAVR) in a reproducible manner. While recognizing notable AI achievements, it is important to remember that AI applications in AS still require collaboration with human expertise due to potential limitations such as its susceptibility to bias, and the critical nature of healthcare. This synergy underpins our optimistic view of AI's promising role in the AS clinical pathway.

Association of the stress hyperglycemia ratio with coronary artery disease complexity as assessed by the SYNTAX score in patients with acute coronary syndrome.

BACKGROUND: Mounting evidence supports a significant correlation between the stress hyperglycemia ratio (SHR) and both short- and long-term prognoses in patients with acute coronary syndrome (ACS). Nevertheless, research examining the association between the SHR and the complexity of coronary artery disease (CAD) is scarce. Therefore, this study aimed to explore the association between the SHR and CAD complexity, as assessed by the SYNTAX score, in patients with ACS. METHODS: A total of 4715 patients diagnosed with ACS were enrolled and divided into five groups according to the quintiles of the SHR. CAD complexity was assessed using the SYNTAX score and categorized as low (≤ 22) or mid/high (> 22) levels. Logistic regression was utilized to examine the association between the SHR and CAD severity (mid-/high SYNTAX score). Restricted cubic spline (RCS) curves were generated to assess the association between the SHR and CAD severity. Subgroup analyses were conducted to stratify outcomes based on age, sex, diabetes mellitus (DM) status, and clinical presentation. RESULTS: Among the total ACS population, 503 (10.7%) patients had mid/high SYNTAX scores. Logistic regression analysis revealed that the SHR was an independent risk factor for mid/high SYNTAX scores in a U-shaped pattern. After adjusting for confounding variables, Q1 and Q5 demonstrated elevated odds ratios (ORs) relative to the reference category Q3, with ORs of 1.61 (95% CI: 1.19 ∼ 2.19) and 1.68 (95% CI: 1.24 ∼ 2.29), respectively. Moreover, the ORs for Q2 (1.02, 95% CI: 0.73 ∼ 1.42) and Q4 (1.18, 95% CI: 0.85 ∼ 1.63) resembled that of Q3. Compared with the merged Q2-4 group, the ORs were 1.52 (95% CI: 1.21 ∼ 1.92) for Q1 group and 1.58 (95% CI: 1.25 ∼ 2) for the Q5 group. Subgroup analysis revealed that the U-shaped association between the SHR and mid/high SYNTAX score was attenuated in DM patients (P for interaction = 0.045). CONCLUSIONS: There were U-shaped associations between the SHR and CAD complexity in ACS patients, with an SHR ranging from 0.68 to 0.875 indicating a relatively lower OR for mid/high SYNTAX scores. Further studies are necessary to both evaluate the predictive value of the SHR in ACS patients and explore the underlying mechanisms of the observed U-shaped associations.

Multifunctional Bispecific Nanovesicles Targeting SLAMF7 Trigger Potent Antitumor Immunity.

The effectiveness of immune checkpoint inhibitor (ICI) therapy is hindered by the ineffective infiltration and functioning of cytotoxic T cells and the immunosuppressive tumor microenvironment (TME). Signaling lymphocytic activation molecule family member 7 (SLAMF7) is a pivotal co-stimulatory receptor thought to simultaneously trigger NK-cell, T-cell, and macrophage antitumor cytotoxicity. However, the potential of this collaborative immune stimulation in antitumor immunity for solid tumors is underexplored due to the exclusive expression of SLAMF7 by hematopoietic cells. Here, we report the development and characterization of multifunctional bispecific nanovesicles (NVs) targeting SLAMF7 and glypican-3-a hepatocellular carcinoma (HCC)-specific tumor antigen. We found that by effectively "decorating" the surfaces of solid tumors with SLAMF7, these NVs directly induced potent and specific antitumor immunity and remodeled the immunosuppressive TME, sensitizing the tumors to programmed cell death protein 1 (PD1) blockade. Our findings highlight the potential of SLAMF7-targeted multifunctional bispecific NVs as an anticancer strategy with implications for designing next-generation targeted cancer therapies.

Prediction of hypoattenuating leaflet thickening in patients undergoing transcatheter aortic valves replacement based on clinical factors and 4D-computed tomography morphological characteristics: A retrospective cross-sectional study.

BACKGROUND: The rapid increase in the number of transcatheter aortic valve replacement (TAVR) procedures in China and worldwide has led to growing attention to hypoattenuating leaflet thickening (HALT) detected during follow-up by 4D-CT. It's reported that HALT may impact the durability of prosthetic valve. Early identification of these patients and timely deployment of anticoagulant therapy are therefore particularly important. METHODS: We retrospectively recruited 234 consecutive patients who underwent TAVR procedure in Fuwai Hospital. We collected clinical information and extracted morphological characteristics parameters of the transcatheter heart valve (THV) post TAVR procedure from 4D-CT. LASSO analysis was conducted to select important features. Three models were constructed, encapsulating clinical factors (Model 1), morphological characteristics parameters (Model 2), and all together (Model 3), to identify patients with HALT. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were plotted to evaluate the discriminatory ability of models. A nomogram for HALT was developed and verified by bootstrap resampling. RESULTS: In our study patients, Model 3 (AUC = 0.738) showed higher recognition effectiveness compared to Model 1 (AUC = 0.674, p = 0.032) and Model 2 (AUC = 0.675, p = 0.021). Internal bootstrap validation also showed that Model 3 had a statistical power similar to that of the initial stepwise model (AUC = 0.723 95%CI: 0.661-0.786). Overall, Model 3 was rated best for the identification of HALT in TAVR patients. CONCLUSION: A comprehensive predictive model combining patient clinical factors with CT-based morphology parameters has superior efficacy in predicting the occurrence of HALT in TAVR patients.

Fish swim bladders as valve leaflets enhance the durability of transcatheter aortic valve replacement devices.

Transcatheter aortic valve replacement (TAVR) has emerged as an effective therapy for inoperable patients with severe aortic stenosis (AS). However, calcification-induced limited durability restricts its application. Fish swim bladders (FSB), which are resistant to calcific degeneration, offer a viable solution to this challenge. In this study, we developed a new TAVR device using FSB as the valve leaflet. Furthermore, the in vitro durability, in vivo performance, and size selection of this TAVR device were assessed by an experimental study and finite element analysis. A self-expandable TAVR device was fabricated by suturing the FSB films into a 23 mm nitinol alloy frame. Further, hemodynamic performance, such as effective orifice area, transvalvular pressure difference and regurgitant fraction, the durability was tested by the pulsatile flow test and accelerated fatigue test, according to the ISO 5840-3. The effect of release size on hydrodynamic performance was also investigated. Finally, the in vivo performance of the TAVR device were examined using a porcine implantation model. The results showed that the strength of the FSB films satisfied the requirements for valve leaflets. The hemodynamic performance of the FSB TAVR device met the requirements of ISO 5840-3 standards. After 400 million cycles, the FSB showed no fiber loss, torn, perforation, or other valve failure phenomena. In porcine models, the devices were well-positioned, functioned well with no stenosis immediately after the operation. Collectively, we successfully developed a TAVR device with FSB as valve leaflets that exhibited good fatigue resistance. STATEMENT OF SIGNIFICANCE: The source of material for the leaflets of commercialized biological heart valves (BHVs) is mainly bovine pericardium, but this material suffers the following problems: large and uneven thickness of the material, the presence of α-Gal and Neu5Gc antigens, and the susceptibility to structural valve degradation (SVD). New material for BHVs leaflets is rarely reported. In this study, we prepared a transcatheter aortic valve (TAV) and performed long-term in vitro and short-term in vivo studies using fish swim bladder (FSB) as the leaflets. The study confirmed that FSB TAV device can complete 400 million fatigue tests and maintain the good morphology of the leaflets, and that it still maintains good functionality after a certain amount of compression, indicating that FSB is a promising material for leaflets.