Systematic review and meta-analysis to predict mortality in heart failure with preserved ejection fraction: Development and validation of the HF-DANAS score.

AIMS: The morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) continue to increase with the accelerating global aging process. During the past decade, the pathophysiology, diagnostic methods, and prognostic prediction of HFpEF have been revolutionized, resulting in new and effective management strategies. Dynamic prognostic assessment facilitates systematic clinical management of patients, and the aim of this study was to investigate the risk factors for mortality in patients with HFpEF and to develop a risk prediction assessment model. METHODS AND REULTS: Data for the derivation cohort were obtained from three databases, PubMed, Embase, and Cochrane. The validation cohort was obtained from the Chinese Heart Failure Center database. The ß-coefficient was calculated based on the risk ratio (RR) and 95% confidence intervals (CI) corresponding to each risk factor to construct a mortality risk assessment model. A total of 30 studies were included in the meta-analysis: 22 prospective cohort studies and 8 retrospective cohort studies, including 34 196 HFpEF patients. Seven predictors of all-cause mortality in HFpEF patients were derived. Considering the need for feasibility in clinical practice, we performed subgroup and sensitivity analyses and determined the following cutoff values: age > 75 years (RR: 2.07, 95% CI: 1.83-2.35; P < 0.001), male sex (RR: 1.36, 95% CI: 1.17-1.59; P < 0.001), DM (RR: 1.23, 95% CI: 1.11-1.36; P < 0.001), anaemia (RR: 1.53, 95% CI: 1.41-1.67; P < 0.001), albumin concentration < 3.2 g/dL (RR: 1.29, 95% CI: 1.14-1.47; P < 0.001), AF (RR: 1.27, 95% CI: 1.12-1.43; P < 0.001), and NYHA class III/IV (RR: 1.63, 95% CI: 1.43-1.87; P < 0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for this model was 71.3% (95% CI: 0.696-0.736), with an optimal cut-off value of 10.75. The sensitivity and specificity were 0.778 and 0.566, respectively. According to this risk score, we divided patients into three risk classes (low, moderate, and high risk), the numbers of patients who died by the end of the 1-year follow-up were 23 (1.87%), 82 (5.62%), and 382 (15.52%) in these three groups, and the 5-year mortality rates were 9.82%, 20.68%, and 43.28%, respectively. CONCLUSIONS: This study developed an HF-DANAS scoring system for the HFpEF mortality risk containing seven predictors, providing clinicians with a simple assessment tool that can help improve clinical management.

Igniting hope: Harnessing NLRP3 inflammasome-GSDMD-mediated pyroptosis for cancer immunotherapy.

In the contemporary landscape of oncology, immunotherapy, represented by immune checkpoint blockade (ICB) therapy, stands out as a beacon of innovation in cancer treatment. Despite its promise, the therapy's progression is hindered by suboptimal clinical response rates. Addressing this challenge, the modulation of the NLRP3 inflammasome-GSDMD-mediated pyroptosis pathway holds promise as a means to augment the efficacy of immunotherapy. In the pathway, the NLRP3 inflammasome serves as a pivotal molecular sensor that responds to inflammatory stimuli within the organism. Its activation leads to the release of cytokines interleukin 1ß and interleukin 18 through the cleavage of GSDMD, thereby forming membrane pores and potentially resulting in pyroptosis. This cascade of processes exerts a profound impact on tumor development and progression, with its function and expression exhibiting variability across different tumor types and developmental stages. Consequently, understanding the specific roles of the NLRP3 inflammasome and GSDMD-mediated pyroptosis in diverse tumors is imperative for comprehending tumorigenesis and crafting precise therapeutic strategies. This review aims to elucidate the structure and activation mechanisms of the NLRP3 inflammasome, as well as the induction mechanisms of GSDMD-mediated pyroptosis. Additionally, we provide a comprehensive overview of the involvement of this pathway in various cancer types and its applications in tumor immunotherapy, nanotherapy, and other fields. Emphasis is placed on the feasibility of leveraging this approach to enhance ICB therapy within the field of immunotherapy. Furthermore, we discuss the potential applications of this pathway in other immunotherapy methods, such as chimeric antigen receptor T-cell (CAR-T) therapy and tumor vaccines.

Progress and trends in myocardial infarction-related long non-coding RNAs: a bibliometric analysis.

Background: Myocardial infarction (MI), a critical condition, substantially affects patient outcomes and mortality rates. Long non-coding RNAs (lncRNAs) play a critical role in the onset and progression of MI. This study aimed to explore the related research on MI-related lncRNAs from a bibliometric perspective, providing new clues and directions for researchers in the field. Methods: A comprehensive search was conducted on 7 August 2023, using the Web of Science Core Collection (WoSCC) database to compile a dataset of all English-language scientific journals. The search gathered all relevant publications from January 2000 to August 2023 that pertain to MI-related lncRNAs. Data on countries, institutions, journals, authors, and keywords were collected, sorted, statistically analyzed, and visualized using CiteSpace 6.2.R4, VOSviewer 1.6.19, an online bibliometric analysis platform (http://bibliometric.com), and the bibliometric package in R-Studio 4.3.1. Articles were screened by two independent reviewers. Results: Between January 2000 and August 2023, a total of 1,452 papers were published in the research field of MI-related lncRNAs. The year with the most publications was 2020, accounting for 256 papers. The publication volume displayed an exponential growth trend, fitting the equation y = 2.0215e0.2786x, R^2 = 0.97. In this domain, China leads in both the number of published papers (N = 1,034) and total citations, followed by the United States, Germany, Iran, and Italy. The most productive institution is Harbin Medical University (N = 144). The European Review for Medical and Pharmacological Sciences had the highest number of publications (N = 46), while Circulation Research had the most citations (TC = 4,537), indicating its irreplaceable standing in this field. Research mainly focuses on the cardiovascular system, cellular biology, physiology, etc. The most productive author is Zhang Y. Apart from "Myocardial Infarction" and "LncRNA," the most frequent keywords include "expression," "atherosclerosis," and "apoptosis." Cluster analysis suggests current research themes concentrate on cardiovascular diseases and gene expression, cardiac ischemia/reperfusion injury and protection, expression and proliferation, atherosclerosis and inflammatory response, among others. Keyword bursts indicate recent hot topics as targeting, autophagy, etc. Conclusion: This bibliometric analysis reveals that research on MI-related lncRNAs has rapidly expanded between January 2000 and August 2023, primarily led by China and the United States. Our study highlights the significant biological roles of lncRNAs in the pathogenesis and progression of MI, including their involvement in gene expression regulation, atherosclerosis development, and apoptosis. These findings underscore the potential of lncRNAs as therapeutic targets and biomarkers for MI. Additionally, our study provides insights into the features and quality of related publications, as well as the future directions in this research field. There is a long road ahead, highlighting the urgent need for enhanced global academic exchange.

Targeting erythroid progenitor cells for cancer immunotherapy.

Immunotherapy, especially immune checkpoint blockade therapy, represents a major milestone in the history of cancer therapy. However, the current response rate to immunotherapy among cancer patients must be improved; thus, new strategies for sensitizing patients to immunotherapy are urgently needed. Erythroid progenitor cells (EPCs), a population of immature erythroid cells, exert potent immunosuppressive functions. As a newly recognized immunosuppressive population, EPCs have not yet been effectively targeted. In this review, we summarize the immunoregulatory mechanisms of EPCs, especially for CD45+ EPCs. Moreover, in view of the regulatory effects of EPCs on the tumor microenvironment, we propose the concept of EPC-immunity, present existing strategies for targeting EPCs, and discuss the challenges encountered in both basic research and clinical applications. In particular, the impact of existing cancer treatments on EPCs is discussed, laying the foundation for combination therapies. The aim of this review is to provide new avenues for improving the efficacy of cancer immunotherapy by targeting EPCs.

Dual-Responsive Epigenetic Inhibitor Nanoprodrug Combined with Oncolytic Virus Synergistically Boost Cancer Immunotherapy by Igniting Gasdermin E-Mediated Pyroptosis.

Cancer immunotherapy has emerged as a promising approach for the treatment of various cancers. However, the immunosuppressive tumor microenvironment (TME) limits the efficacy of current immunotherapies. In this study, we designed a dual-responsive DNA methyltransferase inhibitor nanoprodrug ACNPs for combination therapy with oncolytic herpes simplex virus (oHSV). We found that the epigenetic inhibitor 5-Azacytidine (5-Aza) upregulated gasdermin E (GSDME) expression at the gene level, whereas the oHSV decreased the ubiquitination and degradation of GSDME to elevate its levels. Based on these observations, we further discovered that ACNPs and oHSV synergistically enhanced GSDME-mediated pyroptosis. Additionally, the combination therapy of ACNPs and oHSV effectively inhibited tumor growth, remodeled the immunosuppressive TME, and improved the efficacy of immune checkpoint blockade (ICB) therapy. These results demonstrate the potential to overcome immunosuppression through synergistic combinations, offering a promising approach for cancer immunotherapy.

Dysregulated Wnt/ß-catenin signaling confers resistance to cuproptosis in cancer cells.

Cuproptosis is characterized by the aggregation of lipoylated enzymes of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. As dysregulation of copper homeostasis can induce cuproptosis, there is emerging interest in exploiting cuproptosis for cancer therapy. However, the molecular drivers of cancer cell evasion of cuproptosis were previously undefined. Here, we found that cuproptosis activates the Wnt/ß-catenin pathway. Mechanistically, copper binds PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/ß-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/ß-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed the ß-catenin/TCF4 transcriptional complex directly binds the ATP7B promoter, inducing its expression. ATP7B effluxes copper ions, reducing intracellular copper and inhibiting cuproptosis. Knockdown of TCF4 or pharmacological Wnt/ß-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/ß-catenin pathway and cuproptosis sensitivity, and suggest a precision medicine strategy for cancer treatment through selective cuproptosis induction.

Harnessing cerium-based biomaterials for the treatment of bone diseases.

Bone, an actively metabolic organ, undergoes constant remodeling throughout life. Disturbances in the bone microenvironment can be responsible for pathologically bone diseases such as periodontitis, osteoarthritis, rheumatoid arthritis and osteoporosis. Conventional bone tissue biomaterials are not adequately adapted to complex bone microenvironment. Therefore, there is an urgent clinical need to find an effective strategy to improve the status quo. In recent years, nanotechnology has caused a revolution in biomedicine. Cerium(III, IV) oxide, as an important member of metal oxide nanomaterials, has dual redox properties through reversible binding with oxygen atoms, which continuously cycle between Ce(III) and Ce(IV). Due to its special physicochemical properties, cerium(III, IV) oxide has received widespread attention as a versatile nanomaterial, especially in bone diseases. This review describes the characteristics of bone microenvironment. The enzyme-like properties and biosafety of cerium(III, IV) oxide are also emphasized. Meanwhile, we summarizes controllable synthesis of cerium(III, IV) oxide with different nanostructural morphologies. Following resolution of synthetic principles of cerium(III, IV) oxide, a variety of tailored cerium-based biomaterials have been widely developed, including bioactive glasses, scaffolds, nanomembranes, coatings, and nanocomposites. Furthermore, we highlight the latest advances in cerium-based biomaterials for inflammatory and metabolic bone diseases and bone-related tumors. Tailored cerium-based biomaterials have already demonstrated their value in disease prevention, diagnosis (imaging and biosensors) and treatment. Therefore, it is important to assist in bone disease management by clarifying tailored properties of cerium(III, IV) oxide in order to promote the use of cerium-based biomaterials in the future clinical setting. STATEMENT OF SIGNIFICANCE: In this review, we focused on the promising of cerium-based biomaterials for bone diseases. We reviewed the key role of bone microenvironment in bone diseases and the main biological activities of cerium(III, IV) oxide. By setting different synthesis conditions, cerium(III, IV) oxide nanostructures with different morphologies can be controlled. Meanwhile, tailored cerium-based biomaterials can serve as a versatile toolbox (e.g., bioactive glasses, scaffolds, nanofibrous membranes, coatings, and nanocomposites). Then, the latest research advances based on cerium-based biomaterials for the treatment of bone diseases were also highlighted. Most importantly, we analyzed the perspectives and challenges of cerium-based biomaterials. In future perspectives, this insight has given rise to a cascade of cerium-based biomaterial strategies, including disease prevention, diagnosis (imaging and biosensors) and treatment.

Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity.

Oncolytic viruses (OVs) show promise as a cancer treatment by selectively replicating in tumor cells and promoting antitumor immunity. However, the current immunogenicity induced by OVs for tumor treatment is relatively weak, necessitating a thorough investigation of the mechanisms underlying its induction of antitumor immunity. Here, we show that HSV-1-based OVs (oHSVs) trigger ZBP1-mediated PANoptosis (a unique innate immune inflammatory cell death modality), resulting in augmented antitumor immune effects. Mechanistically, oHSV enhances the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA and subsequent activation of ZBP1. To further enhance the antitumor potential of oHSV, we conduct a screening and identify Fusobacterium nucleatum outer membrane vesicle (Fn-OMV) that can increase the expression of PANoptosis execution proteins. The combination of Fn-OMV and oHSV demonstrates potent antitumor immunogenicity. Taken together, our study provides a deeper understanding of oHSV-induced antitumor immunity, and demonstrates a promising strategy that combines oHSV with Fn-OMV.

Comparison between left bundle branch area pacing and right ventricular pacing: ventricular electromechanical synchrony and risk of atrial high-rate episodes.

Background: The electromechanical dyssynchrony associated with right ventricular pacing (RVP) has been found to have adverse impact on clinical outcomes. Several studies have shown that left bundle branch area pacing (LBBAP) has superior pacing parameters compared with RVP. We aimed to assess the difference in ventricular electromechanical synchrony and investigate the risk of atrial high-rate episodes (AHREs) in patients with LBBAP and RVP. Methods: We consecutively identified 40 patients with atrioventricular block and no prior atrial fibrillation. They were divided according to the ventricular pacing sites: the LBBAP group and the RVP group (including the right ventricular apical pacing (RVA) group and the right side ventricular septal pacing (RVS) group). Evaluation of ventricular electromechanical synchrony was implemented using electrocardiogram and two-dimensional speckle tracking echocardiography (2D-STE). AHRE was defined as event with an atrial frequency of ≥176 bpm lasting for ≥6 min recorded by pacemakers during follow-up. Results: The paced QRS duration of the LBBAP group was significantly shorter than that of the other two groups: LBBAP 113.56 ± 9.66 ms vs. RVA 164.73 ± 14.49 ms, p < 0.001; LBBAP 113.56 ± 9.66 ms vs. RVS 148.23 ± 17.3 ms, p < 0.001. The LBBAP group showed shorter maximum difference (TDmax), and standard deviation (SD) of the time to peak systolic strain among the 18 left ventricular segments, and time of septal-to-posterior wall motion delay (SPWMD) compared with the RVA group (TDmax, 87.56 ± 56.01 ms vs. 189.85 ± 91.88 ms, p = 0.001; SD, 25.40 ± 14.61 ms vs. 67.13 ± 27.40 ms, p < 0.001; SPWMD, 28.75 ± 21.89 ms vs. 99.09 ± 46.56 ms, p < 0.001) and the RVS group (TDmax, 87.56 ± 56.01 ms vs. 156.46 ± 55.54 ms, p = 0.003; SD, 25.40 ± 14.61 ms vs. 49.02 ± 17.85 ms, p = 0.001; SPWMD, 28.75 ± 21.89 ms vs. 91.54 ± 26.67 ms, p < 0.001). The interventricular mechanical delay (IVMD) was shorter in the LBBAP group compared with the RVA group (-5.38 ± 9.31 ms vs. 44.82 ± 16.42 ms, p < 0.001) and the RVS group (-5.38 ± 9.31 ms vs. 25.31 ± 21.36 ms, p < 0.001). Comparing the RVA group and the RVS group, the paced QRS duration and IVMD were significantly shorter in the RVS group (QRS duration, 164.73 ± 14.49 ms vs. 148.23 ± 17.3 ms, p = 0.02; IVMD, 44.82 ± 16.42 ms vs. 25.31 ± 21.36 ms, p = 0.022). During follow-up, 2/16 (12.5%) LBBAP patients, 4/11 (36.4%) RVA patients, and 8/13 (61.5%) RVS patients had recorded novel AHREs. LBBAP was proven to be independently associated with decreased risk of AHREs than RVP (log-rank p = 0.043). Conclusion: LBBAP generates narrower paced QRS and better intro-left ventricular and biventricular contraction synchronization compared with traditional RVP. LBBAP was associated with a decreased risk of AHREs compared with RVP.

m1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating MYC/PD-L1 signaling.

N1-methyladenosine (m1A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels. Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.

Development and validation of a nomogram model for all-cause mortality risk in patients with chronic heart failure and atrial fibrillation.

BACKGROUND: As the global aging process continues to accelerate, heart failure (HF) has become an important cause of increased morbidity and mortality in elderly patients. Chronic atrial fibrillation (AF) is a major risk factor for HF. Patients with HF combined with AF are more difficult to treat and have a worse prognosis. The aim of this study was to explore the risk factors for 1-year mortality in patients with HF combined with AF and to develop a risk prediction assessment model. METHODS: We recruited hospitalized patients with HF and AF who received standardized care in the Department of Cardiology at Shengjing Hospital of China Medical University from January 2013 to December 2018. The patients were randomly divided into modeling and internal validation groups using a random number generator at a 1:1 ratio. Multivariate Cox regression analysis was used to identify risk factors for all-cause mortality during a one-year follow-up period. Then, a nomogram was constructed based on the weights of each index and validated. Receiver operating characteristic curve, the area under the curve (AUC), decision curve, and calibration curve analyses for survival were used to evaluate the model's predictive and clinical validities and calibration. RESULTS: We included 3,406 patients who met the eligibility criteria; 1,703 cases each were included in the modeling and internal validation groups. Eight statistically significant predictors were identified: age, sex, New York Heart Association cardiac function class III or IV, a history of myocardial infarction, and the albumin, triglycerides, N-terminal pro-b-type natriuretic peptide, and blood urea nitrogen levels. The AUCs were 0.793 (95% confidence interval: 0.763-0.823) and 0.794 (95% confidence interval: 0.763-0.823) in the modeling and validation cohorts, respectively. CONCLUSIONS: We present a predictive model for all-cause mortality in patients with coexisting HF and AF comprising eight key factors. This model gives clinicians a simple assessment tool that may improve the clinical management of these patients.

T cell exhaustion initiates tertiary lymphoid structures and turbocharges cancer-immunity cycle.

Immune therapies represented by immune checkpoint blockade (ICB) have significantly transformed cancer treatment. However, the effectiveness of these treatments depends on the status of T cells. T cell exhaustion, characterized by diminished effector function, increased expression of co-inhibitory receptors, and clonal deletion, emerges as a hypofunctional state resulting from chronic exposure to antigens, posing an obstacle to ICB therapy. Several studies have deeply explored T cell exhaustion, providing innovative insights and correlating T cell exhaustion with tertiary lymphoid structures (TLS) formation. TLS, lymphocyte aggregates formed in non-lymphoid tissues amid chronic inflammation, serve as pivotal reservoirs for anti-tumour immunity. Here, we underscore the pivotal role of T cell exhaustion as a signalling mechanism in reinvigorating anti-tumour immunity by turbocharging cancer-immunity (CI) cycle, particularly when tumour becomes unmanageable. Building upon this concept, we summarize emerging immunotherapeutic strategies aimed at enhancing the response rate to ICB therapy and improving patient prognosis.

Tuning cellular metabolism for cancer virotherapy.

Oncolytic viruses (OVs) represent an emerging immunotherapeutic strategy owing to their capacity for direct tumor lysis and induction of antitumor immunity. However, hurdles like transient persistence and moderate efficacy necessitate innovative approaches. Metabolic remodeling has recently gained prominence as a strategic intervention, wherein OVs or combination regimens could reprogram tumor and immune cell metabolism to enhance viral replication and oncolysis. In this review, we summarize recent advances in strategic reprogramming of tumor and immune cell metabolism to enhance OV-based immunotherapies. Specific tactics include engineering viruses to target glycolytic, glutaminolytic, and nucleotide synthesis pathways in cancer cells, boosting viral replication and tumor cell death. Additionally, rewiring T cell and NK cell metabolism of lipids, amino acids, and carbohydrates shows promise to enhance antitumor effects. Further insights are discussed to pave the way for the clinical implementation of metabolically enhanced oncolytic platforms, including balancing metabolic modulation to limit antiviral responses while promoting viral persistence and tumor clearance.

Heterogeneity of myeloid cells in common cancers: Single cell insights and targeting strategies.

Tumor microenvironment (TME), is characterized by a complex and heterogenous composition involving a substantial population of immune cells. Myeloid cells comprising over half of the solid tumor mass, are undoubtedly one of the most prominent cell populations associated with tumors. Studies have unambiguously established that myeloid cells play a key role in tumor development, including immune suppression, pro-inflammation, promote tumor metastasis and angiogenesis, for example, tumor-associated macrophages promote tumor progression in a variety of common tumors, including lung cancer, through direct or indirect interactions with the TME. However, due to previous technological constraints, research on myeloid cells often tended to be conducted as studies with low throughput and limited resolution. For example, the conventional categorization of macrophages into M1-like and M2-like subsets based solely on their anti-tumor and pro-tumor roles has disregarded their continuum of states, resulting in an inadequate analysis of the high heterogeneity characterizing myeloid cells. The widespread adoption of single-cell RNA sequencing (scRNA-seq) in tumor immunology has propelled researchers into a new realm of understanding, leading to the establishment of novel subsets and targets. In this review, the origin of myeloid cells in high-incidence cancers, the functions of myeloid cell subsets examined through traditional and single-cell perspectives, as well as specific targeting strategies, are comprehensively outlined. As a result of this endeavor, we will gain a better understanding of myeloid cell heterogeneity, as well as contribute to the development of new therapeutic approaches.

A Tension Sensor Array for Cable-Driven Surgical Robots.

Tendon-sheath structures are commonly utilized to drive surgical robots due to their compact size, flexibility, and straightforward controllability. However, long-distance cable tension estimation poses a significant challenge due to its frictional characteristics affected by complicated factors. This paper proposes a miniature tension sensor array for an endoscopic cable-driven parallel robot, aiming to integrate sensors into the distal end of long and flexible surgical instruments to sense cable tension and alleviate friction between the tendon and sheath. The sensor array, mounted at the distal end of the robot, boasts the advantages of a small size (16 mm outer diameter) and reduced frictional impact. A force compensation strategy was presented and verified on a platform with a single cable and subsequently implemented on the robot. The robot demonstrated good performance in a series of palpation tests, exhibiting a 0.173 N average error in force estimation and a 0.213 N root-mean-square error. In blind tests, all ten participants were able to differentiate between silicone pads with varying hardness through force feedback provided by a haptic device.

Sex Differences in Clinical Outcomes Associated With Quantitative Flow Ratio-Guided Percutaneous Coronary Intervention.

Background: FAVOR III China (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease) reported improved clinical outcomes in quantitative flow ratio (QFR) relative to angiography-guided percutaneous coronary intervention (PCI), but the clinical impact of QFR-guided PCI according to sex remains unknown. Objectives: The authors sought to compare sex differences in the 2-year clinical benefits of a QFR-guided PCI strategy and to evaluate the differences in outcomes between men and women undergoing contemporary PCI. Methods: This study involved a prespecified subgroup analysis of the FAVOR III China trial, in which women and men were randomized to a QFR-guided strategy or a standard angiography-guided strategy. Sex differences in clinical benefit of the QFR guidance were analyzed for major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction, or ischemia-driven revascularization within 2 years. Results: A total of 1,126 women and 2,699 men were eligible and the occurrence of 2-year MACE was similar between women and men (10.3% vs 10.5%; P = 0.96). Compared with an angiography-guided strategy, a QFR-guided strategy resulted in a 7.9% and 9.7% reduction in PCI rates in men and women, respectively. A QFR-guided strategy resulted in similar relative risk reductions for 2-year MACE in women (8.0% vs 12.7%; HR: 0.62; 95% CI: 0.42-0.90) and men (8.7% vs 12.4%; HR: 0.69; 95% CI: 0.54-0.87) (Pinteraction = 0.61). Furthermore, QFR values were not significantly different between men and women with various angiographic stenosis categories. Conclusions: A QFR-guided PCI strategy resulted in improved MACE in both men and women at 2 years compared with an angiography-guided PCI strategy. The FAVOR III China Study [FAVOR III China]; (NCT03656848).

Establishment and verification of a nomogram that predicts the risk for coronary slow flow.

Background: Coronary slow flow (CSF) has gained significance as a chronic coronary artery disease, but few studies have integrated both biological and anatomical factors for CSF assessment. This study aimed to develop and validate a simple-to-use nomogram for predicting CSF risk by combining biological and anatomical factors. Methods: In this retrospective case-control study, 1042 patients (614 CSF cases and 428 controls) were randomly assigned to the development and validation cohorts at a 7:3 ratio. Potential predictive factors were identified using least absolute shrinkage and selection operator regression and subsequently utilized in multivariate logistic regression to construct the nomogram. Validation of the nomogram was assessed by discrimination and calibration. Results: N-terminal pro brain natriuretic peptide, high density lipoprotein cholesterol, hemoglobin, left anterior descending artery diameter, left circumflex artery diameter, and right coronary artery diameter were independent predictors of CSF. The model displayed high discrimination in the development and validation cohorts (C-index 0.771, 95% CI: 0.737-0.805 and 0.805, 95% CI: 0.757-0.853, respectively). The calibration curves for both cohorts showed close alignment between predicted and actual risk estimates, demonstrating improved model calibration. Decision curve analysis suggested high clinical utility for the predictive nomogram. Conclusion: The constructed nomogram accurately and individually predicts the risk of CSF for patients with suspected CSF and may be considered for use in clinical care.

Glutamine inhibition combined with CD47 blockade enhances radiotherapy-induced ferroptosis in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a formidable cancer type that poses significant treatment challenges, including radiotherapy (RT) resistance. The metabolic characteristics of tumors present substantial obstacles to cancer therapy, and the relationship between RT and tumor metabolism in HNSCC remains elusive. Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Here, we report that after RT, glutamine levels rise in HNSCC, and the glutamine transporter protein SLC1A5 is upregulated. Notably, blocking glutamine significantly enhances the therapeutic efficacy of RT in HNSCC. Furthermore, inhibition of glutamine combined with RT triggers immunogenic tumor ferroptosis, a form of nonapoptotic regulated cell death. Mechanistically, RT increases interferon regulatory factor (IRF) 1 expression by activating the interferon signaling pathway, and glutamine blockade augments this efficacy. IRF1 drives transferrin receptor expression, elevating intracellular Fe2+ concentration, disrupting iron homeostasis, and inducing cancer cell ferroptosis. Importantly, the combination treatment-induced ferroptosis is dependent on IRF1 expression. Additionally, blocking glutamine combined with RT boosts CD47 expression and hinders macrophage phagocytosis, attenuating the treatment effect. Dual-blocking glutamine and CD47 promote tumor remission and enhance RT-induced ferroptosis, thereby ameliorating the tumor microenvironment. Our work provides valuable insights into the metabolic and immunological mechanisms underlying RT-induced ferroptosis, highlighting a promising strategy to augment RT efficacy in HNSCC.

Nlrp3 inflammasome drives regulatory T cell depletion to accelerate periapical bone erosion.

AIM: Apical periodontitis is an inflammatory disorder triggered by an immune response to bacterial infection, leading to the periapical tissue damage and alveolar resorption. However, the underlying mechanisms driving this process remain elusive, due to the complex and interconnected immune microenvironment within the local lesion site. In this study, the influence of Nlrp3 inflammasome-mediated immune response on the apical periodontitis was investigated. METHODOLOGY: RNA sequencing, immunohistochemistry and ELISA assay were performed to investigate the activation of Nlrp3 inflammasome signalling pathways in the human periapical tissues, including radicular cysts, periapical granulomas and healthy oral mucosa. A mouse model of apical periodontitis was established to study the role of Nlrp3 knockout in periapical bone resorption and Treg cell stability, and the underlying mechanism was explored through in vitro experiments. In vivo Treg cell adoptive transfer was performed to investigate the effects of Treg cells on the progression of apical periodontitis. RESULTS: Our findings find that the hyperactivated Nlrp3 inflammasome is present in human periapical lesions and plays a vital role in the immune-related periapical bone loss. Using a mouse model of apical periodontitis, we observe that Nlrp3 deficiency is resistant to bone resorption. This protection was accompanied by elevated generation and infiltration of local Treg cells that displayed a notable ability to suppress RANKL-dependent osteoclast differentiation. In terms of the mechanism of action, Nlrp3 deficiency directly inhibits the osteoclast differentiation and bone loss through JNK/MAPK and NF-κB pathways. In addition, Nlrp3 induces pyroptosis in the stem cells from apical papilla (SCAPs), and the subsequent release of cytokines affects the stability of Treg cell in periapical lesions, leading indirectly to enhanced bone resorption. In turn, adoptive transfer of both Nlrp3-deficient and wild-type Treg cells effectively prevent the bone erosion during apical periodontitis. CONCLUSIONS: Together, our data identify that the Nlrp3 inflammasome modulates the Treg cell stability and osteoclastogenesis in the periapical inflammatory microenvironment, thus determining the progression of bone erosion.

Improved heart function and cardiac remodelling following sacubitril/valsartan in acute coronary syndrome with HF.

AIMS: This study sought to assess the effect of treatment of sacubitril/valsartan (S/V) on improving cardiac function and reversing cardiac remodelling in patients with acute coronary syndrome (ACS) complicated with heart failure with reduced ejection fraction after percutaneous coronary intervention (PCI). METHODS AND RESULTS: We enrolled 275 ACS patients with reduced left ventricular ejection fraction after PCI. The patients were divided into the routine and S/V groups according to the treatment drugs. The symptoms, N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, echocardiographic parameters [left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), left ventricular end-diastolic volume index (LVEDVI), and left ventricular end-systolic volume index (LVESVI)], major adverse cardiac events (MACEs), and adverse reactions were recorded at baseline and 6 months after treatment when a clinical follow-up was performed. The S/V group was further divided into prespecified subgroups including unstable angina (UA) group, non-ST-elevation myocardial infarction (NSTEMI) group, and ST-elevation myocardial infarction (STEMI) group according to the type of ACS. We analysed the changes in LVEF, LVMI, LVEDVI, LVESVI, and NT-proBNP in both groups and evaluated the correlation between the changes in the above variables (ΔLVEF, ΔLVMI, ΔLVEDVI, ΔLVESVI, and ΔNT-proBNP). Cox regression model was used to assess the independent risk factors of MACE. Prespecified subgroup analyses were also conducted. Compared with baseline, LVEF increased significantly (P < 0.05), NT-proBNP, LVMI, and LVESVI decreased significantly in both groups after 6 months (P < 0.05), and LVEDVI decreased significantly in the S/V group (P = 0.001). In the S/V group, ΔLVEF (t = -2.745, P = 0.006), ΔNT-proBNP (P = 0.009), ΔLVEDVI (t = 4.203, P = 0.001), and ΔLVESVI (t = 3.907, P = 0.001) were significantly improved than those in the routine group. In the S/V group, ΔLVEF was negatively correlated with ΔNT-proBNP (r = -0.244, P = 0.004), ΔLVMI (r = -0.190, P = 0.028), ΔLVEDVI (r = -0.173, P = 0.045), and ΔLVESVI (r = -0.261, P = 0.002). In Cox regression model analysis, ΔLVEF {hazard ratio [HR] = 0.87 [95% confidence interval (CI) 0.80-0.95], P = 0.003}, ΔLVEDVI [HR = 1.04 (95% CI 1.01-1.06), P = 0.013], and ΔLVESVI [HR = 1.04 (95% CI 1.01-1.08), P = 0.026] were independent risk factors for MACE. Subgroup analysis showed that ΔLVEF (t = 6.290, P = 0.001), ΔLVEDVI (t = 2.581, P = 0.011), and ΔNT-proBNP (P = 0.019) in the NSTEMI group were significantly improved than those in the UA group, ΔLVEDVI in the NSTEMI group was significantly better than that in the STEMI group (t = -3.365, P = 0.001), and ΔLVEF in the STEMI group was significantly better than that in the UA group (t = -3.928, P = 0.001). There was a significant difference in the survival probability without MACE among the three groups in the analysis of the Kaplan-Meier curve (P = 0.042). The incidence of MACE in the UA group was significantly higher than that in the NSTEMI group (32.4% vs. 6.3%, P = 0.004). CONCLUSIONS: The cardiac function is improved and cardiac remodelling is reversed significantly after treatment of S/V in ACS patients with reduced left ventricular ejection fraction after PCI, and the improvement is more obvious than the routine group. There is a significant negative correlation between the change in LVEF and the changes in NT-proBNP, LVMI, LVEDVI, and LVESVI. The increase of LVEF and the decrease of LVEDVI and LVESVI are protective factors to improve the prognosis. Patients with myocardial infarction and reduced left ventricular ejection fraction might benefit more from the initiation of S/V as first-line heart failure treatment after PCI.