CD28-expressing δ T cells are increased in perivascular adipose tissue of hypertensive mice and in subcutaneous adipose tissue of obese humans.

OBJECTIVES: γδ T-lymphocytes play a role in angiotensin II (AngII)-induced hypertension, vascular injury and T-cell infiltration in perivascular adipose tissue (PVAT) in mice. Mesenteric arteries of hypertensive mice and subcutaneous arteries from obese humans present similar remodeling. We hypothesized that γδ T-cell subtypes in mesenteric vessels with PVAT (MV/PVAT) from hypertensive mice and subcutaneous adipose tissue (SAT) from obese humans, who are prone to develop hypertension, would be similar. METHODS: Mice were infused with AngII for 14 days. MV/PVAT T-cells were used for single-cell RNA-sequencing (scRNA-seq). scRNA-seq data (GSE155960) of SAT CD45+ cells from three lean and three obese women were downloaded from the Gene Expression Omnibus database. RESULTS: δ T-cell subclustering identified six δ T-cell subtypes. AngII increased T-cell receptor δ variable 4 (Trdv4)+ γδ T-effector memory cells and Cd28high δ TEM-cells, changes confirmed by flow cytometry. δ T-cell subclustering identified nine δ T-cell subtypes in human SAT. CD28 expressing δ T-cell subclustering demonstrated similar δ T-cell subpopulations in murine MV/PVAT and human SAT. Cd28+ γδ NKTEM and Cd28high δ TEM-cells increased in MV/PVAT from hypertensive mice and CD28high δ TEM-cells in SAT from obese women compared to the lean women. CONCLUSION: Similar CD28+ δ T-cells were identified in murine MV/PVAT and human SAT. CD28high δ TEM-cells increased in MV/PVAT in hypertensive mice and in SAT from humans with obesity, a prehypertensive condition. CD28+ δ T-lymphocytes could have a pathogenic role in human hypertension associated with obesity, and could be a potential target for therapy.

Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to improve the early graft-versus-leukemia effect mediated by natural killer (NK) cells. Our approach is based on the adoptive transfer of Therapeutic Inducers of Natural Killer cell Killing (ThINKK). ThINKK are expanded and differentiated from HSC, and exhibit blood plasmacytoid dendritic cell (pDC) features. We previously demonstrated that ThINKK stimulate NK cells and control acute lymphoblastic leukemia (ALL) development in a preclinical mouse model of HSCT for ALL. Here, we assessed the cellular identity of ThINKK and investigated their potential to activate allogeneic T cells. We finally evaluated the effect of immunosuppressive drugs on ThINKK-NK cell interaction. METHODS: ThINKK cellular identity was explored using single-cell RNA sequencing and flow cytometry. Their T-cell activating potential was investigated by coculture of allogeneic T cells and antigen-presenting cells in the presence or the absence of ThINKK. A preclinical human-to-mouse xenograft model was used to evaluate the impact of ThINKK injections on graft-versus-host disease (GvHD). Finally, the effect of immunosuppressive drugs on ThINKK-induced NK cell cytotoxicity against ALL cells was tested. RESULTS: The large majority of ThINKK shared the key characteristics of canonical blood pDC, including potent type-I interferon (IFN) production following Toll-like receptor stimulation. A minor subset expressed some, although not all, markers of other dendritic cell populations. Importantly, while ThINKK were not killed by allogeneic T or NK cells, they did not increase T cell proliferation induced by antigen-presenting cells nor worsened GvHD in vivo. Finally, tacrolimus, sirolimus or mycophenolate did not decrease ThINKK-induced NK cell activation and cytotoxicity. CONCLUSION: Our results indicate that ThINKK are type I IFN producing cells with low T cell activation capacity. Therefore, ThINKK adoptive immunotherapy is not expected to increase the risk of GvHD after allogeneic HSCT. Furthermore, our data predict that the use of tacrolimus, sirolimus or mycophenolate as anti-GvHD prophylaxis regimen will not decrease ThINKK therapeutic efficacy. Collectively, these preclinical data support the testing of ThINKK immunotherapy in a phase I clinical trial.

MEK Inhibition for RASopathy-Associated Hypertrophic Cardiomyopathy: Clinical Application of a Basic Concept.

The term "RASopathies" designates a group of developmental syndromes that are caused by activating variants of the rat sarcoma virus protein (RAS)/mitogen-activated protein kinase (MAPK) cascade. The most prevalent clinical diagnosis is Noonan syndrome, and other, less prevalent conditions include Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and others. Hypertrophic cardiomyopathy occurs in 10% of these patients and can be severe and life-threating. Recently, repurposing of medications inhibiting the RAS/MAPK on a compassionate use basis has emerged as a promising concept to improve the outcome of these patients. Herein, we specifically review the role of the RAS/MAPK pathway in RASopathy-associated cardiomyopathy, and discuss the role of small-molecule inhibition in the treatment of this condition. We describe how drug repurposing of trametinib (mitogen-activated protein/extracellular signal-regulated kinase inhibition) and sirolimus/everolimus (mammalian target of rapamycin inhibition) was performed, how genotype-specific therapies are chosen and followed, as well as initial outcomes from early case series. Finally, we lay out the challenges and opportunities for trials that aim to quantify the benefits of this approach.

QTc intervals at rest and during exercise assessed by group correction formulas in survivors of childhood acute lymphoblastic leukemia.

INTRODUCTION: Early signs of subclinical cardiac damage must be identified before they turn into clinical manifestations. Tailoring a formula is relevant for precise QTc evaluation in childhood acute lymphoblastic leukemia (ALL) survivors considering they are at risk of long-term cardiac problems. Therefore, we aim to develop group heart rate correction formulas for QT intervals in childhood ALL survivors at rest and during exercise, and to assess the applicability of these methods across a variety of risk groups exposed to diverse chemotherapy dosages. METHODS: Two hundred and fifty childhood ALL survivors in the PETALE study were classified into 3 groups depending on their prognostic risk group. ECG measurements (QT and RR intervals) were made at rest and during a cardiopulmonary exercise test. QT correction for heart rate was applied using 5 different formulas, which included 2 previously published formulas and 3 group-specific formulas for each sex. RESULTS: The QT/RR relation showed 2 different curves between rest and during exercise, which was worse for females. Group-specific QTc formulas allowed adequate heart rate-corrected QT interval, independently of the cumulative dose of doxorubicin received during treatment. Group-specific formulas showed significantly shorter QTc intervals than QTc from Bazett's formula. QTc (Bazett's formula) values surpassed the established clinical norm in 22 males (11%) and 22 females (11%), with a majority occurring during exercise, affecting 15 males (7.5%) and 10 females (5%). CONCLUSION: This study shows the applicability of personalized group correction of QT/RR data in childhood ALL survivors. Our comprehensive assessments (spanning rest, exercise, and recovery) is an effective approach for risk stratification of cardiac complications in childhood ALL survivors.

The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.

Developmental role of macrophages modeled in human pluripotent stem cell-derived intestinal tissue.

Macrophages populate the embryo early in gestation, but their role in development is not well defined. In particular, specification and function of macrophages in intestinal development remain little explored. To study this event in the human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrate into the organoid, proliferate, and occupy the emerging microanatomical niches of epithelial crypts and ganglia. They also acquire a transcriptomic profile similar to that of fetal intestinal macrophages and display tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to the regulation of metabolism and growth of the developing intestine.

Echocardiographic Parameters Associated With Cardiorespiratory Fitness and Physical Activity in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: Children's exposure to chemotherapeutic agents causes several long-term adverse effects but physical activity has been evidenced to be an effective strategy to improve cardiac function. This cross-sectional study aimed to explore the association between physical activity levels, cardiorespiratory fitness, and cardiac parameters measured by echocardiography. METHODS: Participants were 216n childhood acute lymphoblastic leukemia survivors who underwent a maximal cardiopulmonary exercise test and self-reported their daily minutes of moderate to vigorous physical activity. They underwent a complete transthoracic echocardiographic assessment. Systolic and diastolic function analysis and strain images analysis were performed. The associations were studied through the preventive fraction (examined with univariate crude and adjusted logistic regression models) of regular physical activity (≥150 min·wk-1) and adequate cardiorespiratory fitness levels (above the median ≥ 32.0 mL·kg-1·min-1) on cardiac parameters. RESULTS: Crude analysis shows that regular physical activity was associated with a significant preventive fraction in mitral E/A ratio (56%; P = .013), while adjusted analyses highlighted a nonsignificant reduction of 74% to 37% in the prevalence of cardiac parameters associated with physical activity. Similar associations of adequate cardiorespiratory fitness on cardiac parameters were observed. Adjusted analyses revealed a nonsignificant reduction of 7% to 86% in the prevalence of cardiac parameters associated with cardiorespiratory fitness. CONCLUSION: This study reports that regular physical activity and adequate cardiorespiratory fitness were associated with a higher preventive fraction. Thus, engaging in physical activity prevents childhood acute lymphoblastic leukemia survivors' cardiac dysfunctions. These findings are novel and clinically relevant in pediatric cardiooncology and provide additional evidence to strengthen the benefits of exercise as long-term care in childhood cancer survivors.

Relationship between cardiac mechanical properties and cardiac magnetic resonance imaging at rest in childhood acute lymphoblastic leukemia survivors.

The characterization of cardiac mechanical properties may contribute to better understanding of doxorubicin-induced cardiotoxicity. Our study aims to investigate the relationship between cardiac mechanical properties, T1 and T2 relaxation times and partition coefficient. Fifty childhood acute lymphoblastic leukemia survivors underwent a cardiac magnetic resonance (CMR) at rest on a 3T MRI system and included a standard ECG-gated 3(3)3(3)5 MOLLI sequence for T1 mapping and an ECG-gated T2-prepared TrueFISP sequence for T2 mapping. Partition coefficient, ejection fraction, end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. CircAdapt model was used to study cardiac mechanical performance (left ventricle stiffness (LVS), contractility (LVC) and pressure (Pmin and Pmax), cardiac work efficiency (CWE) and ventricular arterial coupling). In the whole cohort, our results showed that LVC (R2 = 69.2%, r = 0.83), Pmin (R2 = 62.9%, r = 0.79) and Pmax can be predicted by significant CMR parameters, while T1 (R2 = 23.2%, r = 0.48) and partition coefficient (R2 = 13.8%, r = 0.37) can be predicted by significant cardiac mechanical properties. In SR group LVS (R2 = 94.8%, r = 0.97), LVC (R2 = 93.7%, r = 0.96) and Pmin (R2 = 90.6%, r = 0.95) can be predicted by significant cardiac mechanical properties, while in HR + DEX group CWE (R2 = 49.8%, r = 0.70) can be predicted by significant cardiac mechanical properties. Partition coefficient (R2 = 72.6%, r = 0.85) can be predicted by significant CMR parameters in SR group. Early characterization of cardiac mechanical properties from CMR parameters has the potential to early detect doxorubicin-induced cardiotoxicity.

Treatment of Refractory Epilepsy With MEK Inhibitor in Patients With RASopathy.

BACKGROUND: Several specific syndromes within the RASopathies spectrum lead to an increased risk of seizures up to developing refractory epileptic encephalopathy. Management remains symptomatic. METHODS: Here we report two patients treated with trametinib, a MEK1-2 inhibitor, as a precision strategy for drug-resistant epilepsy. Patient 1 is a six-year-old girl with cardiofaciocutaneous syndrome (BRAF p.F595L, germline mutation), and Patient 2 is a 14-month-old boy with Schimmelpenning syndrome (KRAS p.G12D, postzygotic somatic mutation). Trametinib was initiated at a dosage of 0.025 mg/kg/day. RESULTS: Patient 1 had multiple seizures per day, multifocal motor to bilateral tonic-clonic. Electroencephalography (EEG) showed a dramatic reduction in EEG discharges three months after trametinib onset, while a marked clinical improvement occurred after about five months, at the same dosage, and the girl is currently seizure-free for more than six months. Patient 2 had left cerebral hemiatrophy leading to right focal motor seizures, multiple per week to multiple per day, since the age of three months. On trametinib, he experienced an early benefit, remaining seizure-free for more than three months. However, after six months we observed recurrence of seizures. After 22 months of treatment, trametinib was discontinued because of a suspected drug-induced inflammatory colitis. After discontinuation, we observed a significant clinical and EEG "rebound effect." CONCLUSIONS: We provide proof of concept that MEK inhibition is a promising approach for the treatment of patients with refractory epilepsy with selected germline and mosaic RASopathies. Future trials are encouraged to better investigate their potentials and limitations.

Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.

Importance: Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. Objective: To identify a new gene for nsBAV. Design, Setting, and Participants: This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. Main Outcomes and Measures: To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. Results: A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. Conclusions and Relevance: This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.

Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1.

Muscle stem cells, the engine of muscle repair, are affected in myotonic dystrophy type 1 (DM1); however, the underlying molecular mechanism and the impact on the disease severity are still elusive. Here, we show using patients' samples that muscle stem cells/myoblasts exhibit signs of cellular senescence in vitro and in situ. Single cell RNAseq uncovers a subset of senescent myoblasts expressing high levels of genes related to the senescence-associated secretory phenotype (SASP). We show that the levels of interleukin-6, a prominent SASP cytokine, in the serum of DM1 patients correlate with muscle weakness and functional capacity limitations. Drug screening revealed that the senolytic BCL-XL inhibitor (A1155463) can specifically remove senescent DM1 myoblasts by inducing their apoptosis. Clearance of senescent cells reduced the expression of SASP, which rescued the proliferation and differentiation capacity of DM1 myoblasts in vitro and enhanced their engraftment following transplantation in vivo. Altogether, this study identifies the pathogenic mechanism associated with muscle stem cell defects in DM1 and opens a therapeutic avenue that targets these defective cells to restore myogenesis.

Cardiac Mechanical Performance Assessment at Different Levels of Exercise in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: There is a shortage of relevant studies interested in cardiac mechanical performance. Thus, it is clinically relevant to study the impact of cancer treatments on survivors' cardiac mechanical performance to improve our knowledge. The first objective of this study is to assess survivors' cardiac mechanical performance during a cardiopulmonary exercise test (CPET) using both ventricular-arterial coupling (VAC) and cardiac work efficiency (CWE) from cardiac magnetic resonance (CMR) acquisitions. The second objective is to assess the impact of doxorubicin and dexrazoxane (DEX) treatments. METHODS: A total of 63 childhood acute lymphoblastic leukemia survivors underwent a CMR at rest on a 3T magnetic resonance imaging system, followed by a CPET on ergocycle. The CircAdapt model was used to study cardiac mechanical performance. At different levels of exercise, arterial elastance, end-systolic elastance, VAC, and CWE were estimated. RESULTS: We observed significant differences between the different levels of exercise for both VAC ( P <0.0001) and CWE parameters ( P =0.001). No significant differences were reported between prognostic risk groups at rest and during the CPET. Nevertheless, we observed that survivors in the SR group had a VAC value slightly lower than heart rate (HR)+DEX and HR groups throughout the CPET. Moreover, survivors in the SR group had a CWE parameter slightly higher than HR+DEX and HR groups throughout the CPET. CONCLUSIONS: This study reveals that the combination of CPET, CMR acquisitions and CircAdapt model was sensitive enough to observe slight changes in the assessment of VAC and CWE parameters. Our study contributes to improving survivors' follow-up and detection of cardiac problems induced by doxorubicin-related cardiotoxicity.

N-acetylneuraminate pyruvate lyase controls sialylation of muscle glycoproteins essential for muscle regeneration and function.

Deleterious variants in N-acetylneuraminate pyruvate lyase (NPL) cause skeletal myopathy and cardiac edema in humans and zebrafish, but its physiological role remains unknown. We report generation of mouse models of the disease: NplR63C, carrying the human p.Arg63Cys variant, and Npldel116 with a 116-bp exonic deletion. In both strains, NPL deficiency causes drastic increase in free sialic acid levels, reduction of skeletal muscle force and endurance, slower healing and smaller size of newly formed myofibers after cardiotoxin-induced muscle injury, increased glycolysis, partially impaired mitochondrial function, and aberrant sialylation of dystroglycan and mitochondrial LRP130 protein. NPL-catalyzed degradation of sialic acid in the muscle increases after fasting and injury and in human patient and mouse models with genetic muscle dystrophy, demonstrating that NPL is essential for muscle function and regeneration and serves as a general marker of muscle damage. Oral administration of N-acetylmannosamine rescues skeletal myopathy, as well as mitochondrial and structural abnormalities in NplR63C mice, suggesting a potential treatment for human patients.

Acan downregulation in parvalbumin GABAergic cells reduces spontaneous recovery of fear memories.

While persistence of fear memories is essential for survival, a failure to inhibit fear in response to harmless stimuli is a feature of anxiety disorders. Extinction training only temporarily suppresses fear memory recovery in adults, but it is highly effective in juvenile rodents. Maturation of GABAergic circuits, in particular of parvalbumin-positive (PV+) cells, restricts plasticity in the adult brain, thus reducing PV+ cell maturation could promote the suppression of fear memories following extinction training in adults. Epigenetic modifications such as histone acetylation control gene accessibility for transcription and help couple synaptic activity to changes in gene expression. Histone deacetylase 2 (Hdac2), in particular, restrains both structural and functional synaptic plasticity. However, whether and how Hdac2 controls the maturation of postnatal PV+ cells is not well understood. Here, we show that PV+- cell specific Hdac2 deletion limits spontaneous fear memory recovery in adult mice, while enhancing PV+ cell bouton remodeling and reducing perineuronal net aggregation around PV+ cells in prefrontal cortex and basolateral amygdala. Prefrontal cortex PV+ cells lacking Hdac2, show reduced expression of Acan, a critical perineuronal net component, which is rescued by Hdac2 re-expression. Pharmacological inhibition of Hdac2 before extinction training is sufficient to reduce both spontaneous fear memory recovery and Acan expression in wild-type adult mice, while these effects are occluded in PV+-cell specific Hdac2 conditional knockout mice. Finally, a brief knock-down of Acan expression mediated by intravenous siRNA delivery before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear recovery in wild-type mice. Altogether, these data suggest that controlled manipulation of PV+ cells by targeting Hdac2 activity, or the expression of its downstream effector Acan, promotes the long-term efficacy of extinction training in adults.

Cardiorespiratory Fitness and Cardiac Magnetic Resonance Imaging in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: Childhood acute lymphoblastic leukemia survivors' anthracycline-induced cardiotoxicity could be prevented with good cardiorespiratory fitness levels and regular physical activity. This cross-sectional study aimed to assess the association between cardiorespiratory fitness and physical activity with cardiac magnetic resonance parameters. METHODS: A total of 96 childhood acute lymphoblastic leukemia survivors underwent a maximal cardiopulmonary exercise test and answered physical activity questionnaires. We calculated the odds ratio of the preventive fraction of regular physical activity (≥150 min/wk) and adequate cardiorespiratory fitness levels (above the median ≥31.4 mL·kg-1·min-1) on cardiac magnetic resonance parameters (left ventricular [LV] and right ventricular [RV] morphological and functional parameters). RESULTS: An adequate cardiorespiratory fitness was associated with a significant preventive fraction for LV (up to 84% for LV end-diastolic volume) and RV volumes (up to 88% for RV end-systolic volume). The adjusted analyses highlighted a preventive fraction of 36% to 91% between an adequate cardiorespiratory fitness and LV and RV parameters, late gadolinium enhancement fibrosis, and cardiac magnetic resonance relaxation times. No associations were reported with regular physical activity. CONCLUSIONS: This study provides additional evidence regarding the benefits of an adequate cardiorespiratory fitness level for childhood cancer survivors' cardiac health.

Dexrazoxane Treatments Limits Subclinical Cardiac Dysfunction in Childhood Acute Lymphoblastic Leukemia Survivors Exposed to Doxorubicin Treatments.

INTRODUCTION: Doxorubicin leads to dose dependent cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors. We investigated survivors' heart health using echocardiography and evaluated doxorubicin and dexrazoxane treatments on cardiac function. METHODS: A total of 196 childhood ALL survivors were stratified (standard risk [SR], high risk with and without dexrazoxane (HR+DEX and HR). We performed a complete transthoracic echocardiographic assessment with M-mode echocardiography, Doppler, and Tissue Doppler. We used 2-dimensional and 3-dimensional echocardiography to measure the left ventricular ejection fraction, whereas myocardial strain imaging was used to obtain global strain indices. RESULTS: Although most cardiac and arterial dimension parameters were not different between groups, a difference was observed in posterior intima of the right carotid ( P =0.017). Diastolic functions analyses reported that LV shortening fraction and left and right ventricular lateral S' wave amplitudes were lower in HR than in SR and HR+DEX groups ( P =0.028, P =0.048, and P =0.005, respectively). The LV lateral E' in diastolic function was lower in the HR than in SR and HR+DEX groups ( P =0.036). The LV end-systolic wall stress was higher in HR than in SR and HR+DEX groups ( P =0.009). A decrease contractility was observed, while the effect was not group specific. Strain rate was not different between groups, as opposed to tissue Doppler measurements. CONCLUSIONS: This study showed that dexrazoxane treatments could limit subclinical cardiac dysfunction in childhood ALL survivors, whereas survivors in HR group who did not receive dexrazoxane had potential subclinical cardiac damage observable in heart failure patients. Echocardiographic screening for survivors must be part of the follow-up routine in cardio-oncology.

New prospectives on treatment opportunities in RASopathies.

The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.

Endocardial Regulation of Cardiac Development.

The endocardium is a specialized form of endothelium that lines the inner side of the heart chambers and plays a crucial role in cardiac development. While comparatively less studied than other cardiac cell types, much progress has been made in understanding the regulation of and by the endocardium over the past two decades. In this review, we will summarize what is currently known regarding endocardial origin and development, the relationship between endocardium and other cardiac cell types, and the various lineages that endocardial cells derive from and contribute to. These processes are driven by key molecular mechanisms such as Notch and BMP signaling. These pathways in particular have been well studied, but other signaling pathways and mechanical cues also play important roles. Finally, we will touch on the contribution of stem cell modeling in combination with single cell sequencing and its potential translational impact for congenital heart defects such as bicuspid aortic valves and hypoplastic left heart syndrome. The detailed understanding of cellular and molecular processes in the endocardium will be vital to further develop representative stem cell-derived models for disease modeling and regenerative medicine in the future.

The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery.

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.