The incidence and prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) continue to rise, yet evidence-based therapy remains limited. Due to the complexity of HFpEF pathology, traditional HF medication has shown inconsistent efficacy in improving clinical outcomes and reducing morbidity. Therefore, highlighting the urgent need for novel interventions. The αlpha-7 nicotinic acetylcholine receptor (α7nAChR) is a central mediator of the cholinergic anti-inflammatory pathway and has emerged as a promising therapeutic target in various conditions, such as sepsis, arthritis, metabolic dysfunction, and atherosclerosis. This review aims to examine the emerging therapeutic potential of α7nAChR in HF and HFpEF pathology, focusing on its protective role in modulating the complex interplay between systemic and cardiovascular inflammation, renin-angiotensin-aldosterone system activation, neurocardiac signaling and metabolic dysfunction.

Rapid hematopoietic adaptations are important for building and sustaining the biological response to β-glucan. The signals involved in these early events have not yet been fully explored. Given that type I interferons are produced in response to β-glucan and can profoundly impact hematopoietic stem cell (HSC) function, we hypothesized that this pathway may be involved in the early bone marrow response to β-glucan. In vivo administration of β-glucan led to local interferon-α production in the peritoneal cavity and bone marrow, upregulation of its receptor, IFNAR1, specifically on long-term hematopoietic stem cells (LT-HSCs), and broad expansion of downstream progenitor subpopulations. We demonstrate that intact type I interferon signaling is critical for β-glucan-mediated LT-HSC proliferation, mitochondrial activity, and glycolytic commitment. By determining that type I interferon signaling is important for LT-HSCs, which sit at the apex of the hematopoietic hierarchy, we uncover an important component of the early inflammatory response to β-glucan.

Importance:Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with increased risk of cardiovascular disease (CVD) events and mortality. However, there are no approved therapies for preventing or treating CHIP. Objective:To investigate whether low-dose aspirin might benefit older adults with CHIP for the primary prevention of CVD. Design, Setting, and Participants:This was a prespecified substudy of the Aspirin in Reducing Events in the Elderly (ASPREE) double-blind, randomized clinical trial of daily low-dose aspirin vs placebo evaluating disability-free survival, which took place at primary and community care facilities in the US and Australia. Enrollment was from March 2010 to December 2014, and the randomized trial ended in June 2017. Community-dwelling Australian adults aged 70 years and older without a diagnosed cardiovascular event, atrial fibrillation, a serious intercurrent illness likely to cause death within the next 5 years, anemia, or a current or recurrent condition with a high risk of bleeding were included in the original study. Of 19 114 in the original trial, 11 402 were included in the substudy, and 9434 were included in the analysis. Follow-up for this substudy went through June 2022, with data analysis in February 2025. In-trial median (IQR) follow-up time was 4.6 (3.5-5.6) years, and posttrial observational follow-up was 8.7 (7.5-10.1) years from randomization. Interventions:Participants were randomized to aspirin, 100 mg, daily or placebo. Main Outcomes and Measures:CHIP was measured in blood specimens collected at trial entry. Major adverse cardiovascular events (MACEs), including fatal and nonfatal ischemic stroke, nonfatal myocardial infarction and coronary heart disease death, and clinically significant bleeding were adjudicated by independent expert committees blinded to trial-group assignments. Results:A total of 9434 participants (median [IQR] age, 73.7 [71.6-77.1] years; 5067 [54%] female) provided a sample at baseline for analysis, 2124 of whom (23%) had CHIP at variant allele fraction (VAF) ≥2%, with 532 (5.6%) at ≥10% VAF. CHIP was not associated with increased risk of MACEs at 2% to 10% VAF (adjusted hazard ratio [aHR], 0.84, 95% CI, 0.68-1.03; P = .09) or ≥10% VAF (aHR, 0.80, 95% CI, 0.57-1.12; P = .19). However, CHIP was associated with increased risk of clinically significant bleeding (2%-10% VAF: aHR, 1.24; 95% CI 1.02-1.51; P = .03; ≥10% VAF: aHR, 1.21; 95% CI, 0.85-1.73; P = .28). There was no evidence of a differential effect of aspirin according to presence of CHIP on MACEs (without CHIP: HR, 0.91; 95% CI, 0.72-1.16; 2%-10% VAF: HR, 1.40; 95% CI, 0.77-2.53; ≥10% VAF: HR, 1.33; 95% CI, 0.52-3.37; heterogeneity P = .35) or clinically significant bleeding (without CHIP: HR, 1.64; 95% CI, 1.22-2.30; 2%-10% VAF: HR, 1.45; 95% CI, 0.82-2.57; ≥10% VAF: HR, 1.41; 95% CI, 0.49-4.07; heterogeneity P = .91). Conclusion and Relevance:In this secondary analysis of a randomized clinical trial of daily low-dose aspirin in healthy adults 70 years and older, CHIP was not associated with higher CVD risk. However, participants with CHIP had a greater risk of clinically significant bleeding. There was no evidence that participants with CHIP were more likely than those without CHIP to benefit or experience more harm from aspirin when used for primary prevention of CVD events. Trial Registration:ClinicalTrials.gov Identifier: NCT01038583.

Atherosclerosis is a lipid disorder where modified lipids (especially oxidized LDL) induce macrophage foam cell formation in the aorta. Its pathogenesis involves a continuum of persistent inflammation accompanied by dysregulated anti-inflammatory responses. Changes in the immune cell status due to differences in the lesional microenvironment are crucial in terms of plaque development, its progression, and plaque rupture. Ly6Chi monocytes generated through both medullary and extramedullary cascades act as one of the major sources of plaque macrophages and thereby foam cells. Both monocytes and monocyte-derived macrophages also participate in pathological events in atherosclerosis-associated multiple organ systems through inter-organ communications. For years, macrophage phenotypes M1 and M2 have been shown to perpetuate inflammatory and resolution responses; nevertheless, such a dualistic classification is too simplistic and contains severe drawbacks. As the lesion microenvironment is enriched with multiple mediators that possess the ability to activate macrophages to diverse phenotypes, it is obvious that such cells should demonstrate substantial heterogeneity. Considerable research in this regard has indicated the presence of additional macrophage phenotypes that are exclusive to atherosclerotic plaques, namely Mox, M4, Mhem, and M(Hb) type. Furthermore, although the concept of macrophage clusters has come to the fore in recent years with the evolution of high-dimensional techniques, classifications based on such 'OMICS' approaches require extensive functional validation as well as metabolic phenotyping. Bearing this in mind, the current review provides an overview of the status of different macrophage populations and their role during atherosclerosis and also outlines possible therapeutic implications.

Oxidation of lipids, excessive cell death, and iron deposition are prominent features of human atherosclerotic plaques. While extensive research has established the detrimental roles of lipid oxidation and apoptosis in atherosclerosis development, the involvement of iron in atherogenesis is not yet fully understood. With the emergence of an iron-dependent form of cell death termed ferroptosis, new attention has been brought to the complex inter-play among iron, ferroptosis, and atherosclerosis. Mechanistically, ferroptosis is caused by the lethal accumulation of iron-mediated lipid peroxides. Emerging studies have underscored ferroptosis as a contributor to worsened atherosclerosis. Herein, we review the evidence that oxidative damage and iron overload in the context of atherosclerosis may promote ferroptosis within plaques. Furthermore, we summarize recent findings of lipid peroxidation, thereby potentially ferroptosis, in various plaque cell types-such as endothelial cells, macrophages, dendritic cells, T cells, and vascular smooth muscle cells-across different stages of atherosclerosis. Understanding how these processes influence atherosclerotic plaque progression may permit targeting stage-dependent ferroptosis in each cell population and could provide a rationale for developing cell type-specific intervention strategies to mitigate atherogenic ferroptosis effectively.

Hepatoblastoma is the most common primary liver cancer in children, with an incidence of approximately 1.5 cases per million children per year. Most cases are sporadic, typically presenting at a median age of 18 months, with only 5% occurring after 4 years of age. Clinical presentation often includes an abdominal mass and, less commonly, abdominal pain, weight loss, jaundice and precocious puberty. Low birth weight is a significant risk factor, along with genetic conditions such as Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18. Screening protocols for hepatoblastoma are recommended for children with predisposing conditions. Medical imaging is crucial for hepatoblastoma diagnosis and staging, with abdominal ultrasonography being the initial modality of choice, followed by abdominal contrast MRI for detailed evaluation and monitoring. Chest computer tomography is indicated to evaluate potential lung metastases. The Pretreatment Extent of Disease (PRETEXT) system is employed for hepatoblastoma staging and for guiding treatment strategies such as surgical resection and chemotherapy. Patients with advanced hepatoblastoma may require liver transplantation. Advancements in surgery and chemotherapy have improved survival rates, with 5-year survival rates exceeding 80-90% in localized disease. However, challenges remain in treating individuals with high-risk and metastatic hepatoblastoma. Ongoing research into treatment stratification, the introduction of novel therapies, including targeted and immune therapies, and the application of otoprotectants are essential to address refractory or recurrent hepatoblastoma and to increase the overall survival of patients. Long-term quality of life and the management of treatment-related sequelae are becoming increasingly important as survival rates improve.

Plasmalogens are a distinct subclass of glycerophospholipids that exhibit unique structural features, notably possessing a vinyl ether linkage at the sn1 position of the glycerol backbone. These specialized lipids play crucial roles in various biological functions. Although the biosynthetic pathway of plasmalogens has been well-characterized, their catabolism remains less studied. In this study, we investigated the impact of global and tissue-specific loss-of-function of a plasmalogen catabolizing enzyme, lysoplasmalogenase (TMEM86B), on circulatory and tissue lipidomes. We generated both global and hepatocyte-specific Tmem86b knockout mice using cre-loxP technology. Mice with homozygous global inactivation of Tmem86b (Tmem86b KO mice) were viable and did not display any marked phenotypic abnormalities. Tmem86b KO mice demonstrated significantly elevated levels of the plasmalogens, alkenylphosphatidylethanolamine (PE(P)), and alkenylphosphatidylcholine (PC(P)), as well as lysoplasmalogens, in the plasma, liver, and natural killer cells compared to their wild-type counterparts. The endogenous alkenyl chain composition of plasmalogens remained unaltered in Tmem86b KO mice. Consistent with the global knockout findings, hepatocyte-specific Tmem86b knockout mice also exhibited increased plasmalogen levels in the plasma and liver compared to their floxed control counterparts. Overall, our findings shed light on the role of Tmem86b in plasmalogen catabolism, demonstrating how its ablation leads to elevated plasmalogen levels in select tissues and cells. This study enhances our understanding of the regulatory mechanisms governing plasmalogen metabolism and highlights the potential of targeting Tmem86b to therapeutically raise plasmalogen levels.

Wilms tumor (WT) is the most common pediatric renal tumor, and with multidisciplinary treatment overall outcomes are excellent. However, a small subset of patients with WT will relapse. The ideal treatment of relapsed WT is yet to be defined. Ongoing studies through the Children's Oncology Group Renal Tumors Committee (COG-RTC) and the International Society of Paediatric Oncology Renal Tumor Study Group (SIOP-RTSG) aim to improve risk stratification and treatment strategies. Members met at the SIOP 55th Annual Congress 2023 to outline available data and knowledge gaps and develop future research priorities.

β-Thalassemia is a genetic disorder arising from mutations in the β-globin gene, leading to ineffective erythropoiesis and iron overload. Ineffective erythropoiesis, a hallmark of β-thalassemia, is an important driver of iron overload, which contributes to liver fibrosis, diabetes, and cardiac disease. Iron homeostasis is regulated by the hormone hepcidin; BMP6/hemojuvelin-mediated (BMP6/HJV-mediated) signaling induces hepatic hepcidin expression via SMAD1/5, with transmembrane serine protease 6 (TMPRSS6) being a negative regulator of HJV. Individuals with loss-of-function mutations in the TMPRSS6 gene show increased circulating hepcidin and iron-refractory iron-deficiency anemia, suggesting that blocking TMPRSS6 may be a viable strategy to elevate hepcidin levels in β-thalassemia. We generated a human mAb (REGN7999) that inhibits TMPRSS6. In an Hbbth3/+ mouse model of β-thalassemia, REGN7999 treatment led to significant reductions in liver iron, reduced ineffective erythropoiesis, and showed improvements in RBC health, running distance during forced exercise, and bone density. In a phase I, doubleblind, randomized, placebo-controlled study in healthy human volunteers (NCT05481333), REGN7999 increased serum hepcidin and reduced serum iron with an acceptable tolerability profile. Our results suggest that, by both reducing iron and improving RBC function, inhibition of TMPRSS6 by REGN7999 may offer a therapy for iron overload and impaired erythropoiesis in β-thalassemia.

Monoclonal antibody therapies have transformed the lives of patients across a diverse range of diseases. However, antibodies can usually only access extracellular proteins, including the extracellular portions of membrane proteins that are expressed on the cell surface. In contrast, T cell receptors (TCRs) survey the entire cellular proteome when processed and presented as peptides in association with human leukocyte antigen (pHLA complexes). Antibodies that mimic TCRs by recognizing pHLA complexes have the potential to extend the reach of antibodies to this larger pool of targets and provide increased binding affinity and specificity. A major challenge in developing TCR mimetic (TCRm) antibodies is the limited sequence differences between the target pHLA complex relative to the large global repertoire of pHLA complexes. Here, we provide a comprehensive strategy for generating fully human TCRm antibodies across multiple HLA alleles, beginning with pHLA target discovery and validation and culminating in the engineering of TCRm-based chimeric antigen receptor T cells with potent antitumor activity. By incorporating mass spectrometry, bioinformatic predictions, HLA-humanized mice, antibody screening, and cryo-electron microscopy, we have established a pipeline to identify additional pHLA complex-specific antibodies with therapeutic potential.

Background Patients with diffuse anaplastic Wilms tumor (DAWT) experience relatively poor oncologic outcomes. Previous work has described mechanisms of telomerase upregulation in DAWT, posing a potential therapeutic target. Methods We assessed in vitro sensitivity to vincristine, irinotecan, and telomerase-targeting drug 6-thio-2’-deoxyguanosine (6dG) in DAWT cell lines WiT49 and PDM115 and in spheroids derived from cell lines and four DAWT patient-derived xenografts (PDX). We also tested in vivo response to vincristine/irinotecan (VI), 6dG, or combination in WTPDX. Results Sensitivity to vincristine varied with EC50 between 0.13 and 44.92 nM in spheroids, with EC50 for SN-38 (irinotecan active metabolite) from 3.06 to 70.96 nM. All were resistant to 6dG monotherapy with EC50 from 3.06 to 50+ μM. In KT-51, 10 μM 6dG significantly slowed spheroid growth. 6dG treatment increased DNA damage response markers pChk1 S345, p53 and γH2AX levels in KT-51, KT-53 and KT-60 spheroids. In WiT49 2D culture, treatment of sub-toxic doses of 6dG did not induce apoptosis or cell cycle arrest and exhibited minimal synergistic capacity with VI; TERT overexpression did not increase 6dG sensitivity. In vivo treatment of KT-51, KT-53, and KT-60 with VI exhibited variable responses from progressive disease to complete clinical responses, but 6dG monotherapy resulted in no tumor responses and 6dG addition to VI conferred no increased tumor suppression. Conclusions DAWT models are variably sensitive to VI but are resistant to 6dG monotherapy or combination with VI. Future research will address limitations of preclinical WT model systems and assess additional targeted therapies for high-risk WT subtypes.

Background: Enhanced recovery after surgery (ERAS) protocols are multi-disciplinary approaches to standardize perioperative care. This is the first prospective, multi-institutional study to evaluate ERAS in pediatric patients undergoing abdominal tumor resections. Methods: All patients >1-month-old undergoing abdominal tumor resection at one of three children's hospitals between 2020 and 2022 were eligible. ERAS counseling was performed, and informed consent obtained. The ERAS protocol was standardized across institutions. We compared the prospective cohort to a propensity-matched historical cohort (2014-2020) from each institution utilizing 16 variables. Categorical variables were compared using McNemar's and/or Stuart-Maxwell testing. Continuous data was compared using logistic regression. Results: Ninety-five patients enrolled in the prospective cohort and were compared to 95 well-matched historic patients. Median LOS was 5.3 (4.1-7.2) days in the historic cohort, and 4.3 (3.3-6.2) days in the ERAS cohort (p = 0.053). Post-operative opioid consumption was lower in ERAS patients at 0.08 (0.03 -0.16) MME mg/kg/day versus 0.23 (0.12-0.52) in historic patients (p = 0.013). ERAS patients received clear (POD#0, 0-0) and regular (POD#1, 1.0-1.0) diets two days sooner (both p < 0.001). ERAS patients ambulated two days sooner (1.0, 1.0-2.0 versus 3.0, 2.0-5.0). The number of patients who experienced any complication was significantly lower in the ERAS cohort (44, 44.2 %) compared to historic (82, 86.3 %, p < 0.001). This reduction was seen across each Clavien-Dindo grade 1-3 category (all p < 0.05). Conclusion: ERAS protocols are feasible in pediatric patients undergoing abdominal tumor resections. Use of an ERAS protocol significantly reduced complications, opioid consumption, time to mobility, and time to diets. Level of Evidence: II. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic and mesenchymal, which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown, and how to eradicate neuroblastoma regardless of its cell state is a clinical challenge. To better understand the cellular plasticity of neuroblastoma in chemoresistance, we define the transcriptomic and epigenetic map of adrenergic and mesenchymal types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We show that cancer cells not only undergo a bidirectional switch between adrenergic and mesenchymal states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. These cell state alterations are coupled with epigenetic reprogramming and dependency switching of cell state-specific transcription factors, epigenetic modifiers, and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances the anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

Ferroptosis is an iron-dependent form of cell death driven by the excessive peroxidation of poly-unsaturated fatty acids (PUFAs) within membrane phospholipids. Ferroptosis is a hallmark of many diseases and preventing or inducing ferroptosis has considerable therapeutic potential. Like other forms of cell death, the pathological importance and therapeutic potential of ferroptosis is well appreciated. However, while cell death modalities such as apoptosis and necroptosis have critical physiological roles, such as in development and tissue homeostasis, whether ferroptosis has important physiological roles is largely unknown. In this regard, key questions for field are as follows: Is ferroptosis used for physiological processes? Are certain cell-types purposely adapted to be either resistant or sensitive to ferroptosis to be able to function optimally? Do physiological perturbations such as aging and diet impact ferroptosis susceptibility? Herein, we have reviewed emerging evidence that supports the idea that being able to selectively and controllably induce or resist ferroptosis is essential for development and cell function. While several factors regulate ferroptosis, it appears that the ability of cells and tissues to control their lipid composition, specifically the abundance of phospholipids containing PUFAs, is crucial for cells to be able to either resist or be sensitized to ferroptosis. Finally, aging and diets enriched in specific PUFAs lead to an increase in cellular PUFA levels which may sensitize cells to ferroptosis. Therefore, changes in dietary PUFAs or againg may impact the pathogenesis of diseases where ferroptosis is involved.

Impaired cholesterol homeostasis is a major factor contributing to the development and progression of atherosclerosis. Previous studies have shown that metformin, the first-line antidiabetic therapy, has cardioprotective effects in patients with diabetes. However, the antiatherogenic effect of metformin in nondiabetic individuals remains unclear. The aim of this study was to determine the antiatherosclerotic effects of metformin under normoglycemic conditions and, mechanistically, to assess its impact on hematopoietic stem and progenitor cell (HSPC) biology and extramedullary myelopoiesis. Here, we demonstrated that metformin decreased atherosclerotic lesion size, reduced plaque macrophages, and lowered circulating atherogenic Ly6-Chi monocytes and neutrophil levels in Apoe-/- mice, independent of blood glucose regulation. Mechanistically, metformin-treated Apoe-/- mice exhibited increased HSPC retention in the bone marrow and decreased numbers of circulating hematopoietic stem and progenitor cells (HSPCs), along with reduced levels of Ly6-Chi monocytes and neutrophils in the spleen. Our results indicate that decreased circulating cholesterol and increased expression of the ATP-binding cassette transporter gene Abca1 in HSPCs, thereby promoting cholesterol efflux in these cells, are critical factors leading to the suppressed mobilization of HSPCs and myelopoiesis in metformin-treated mice. Collectively, our findings support the use of metformin as an antiatherosclerotic agent under euglycemic conditions. We reveal that this effect is achieved by dampening HSPC mobilization and extramedullary myelopoiesis, providing molecular evidence for metformin's role in reducing macrophage-driven inflammation and, consequently, attenuating atherosclerotic progression.NEW & NOTEWORTHY This study uncovers a novel role for metformin in reducing inflammatory and atherogenic monocytes by dampening extramedullary myelopoiesis, thereby delaying atherosclerosis development under normoglycemic conditions. We demonstrate that metformin suppresses hematopoietic stem and progenitor cell mobilization and reduces macrophage-driven inflammation, providing mechanistic evidence for its antiatherosclerotic potential beyond diabetes management. These findings highlight new therapeutic opportunities for metformin in cardiovascular disease, extending its clinical utility to the prevention of atherosclerosis in nondiabetic individuals.

Despite the advent of advanced molecular prognostic tools, it is still difficult to predict the course of disease for cancer patients at the individual level. This lack of predictability is also reflected in many experimental cancer model systems, begging the question of whether certain biological aspects of cancer (eg. growth, evolution etc.) can ever be anticipated or if there remains an inherent unpredictability to cancer, similar to other complex biological systems. We demonstrate by a combination of agent-based mathematical modelling, analysis of patient-derived xenograft model systems from multiple cancer types, and in-vitro culture that certain conditions increase stochasticity of the clonal landscape of cancer growth. Our findings indicate that under those conditions, the cancer genome may behave as a complex dynamic system, making its long-term evolution inherently unpredictable.

Hepatoblastoma is the most common primary liver cancer in children, with an incidence of approximately 1.5 cases per million children per year. Most cases are sporadic, typically presenting at a median age of 18 months, with only 5