Exercise-induced β2-adrenergic receptor activation enhances the anti-leukemic activity of expanded γδ T-Cells via DNAM-1 upregulation and PVR/Nectin-2 recognition

Exercise mobilizes cytotoxic lymphocytes to blood which may allow superior cell products to be manufactured for cancer therapy. Gamma-Delta (γδ) T-cells have shown promise for treating solid tumors, but there is a need to increase their potency against hematologic malignancies. Here, we show that human γδ T-cells mobilized to blood in response to just 20-minutes of graded exercise have surface phenotypes and transcriptomic profiles associated with cytotoxicity, adhesion, migration and cytokine signaling. Following 14-days ex vivo expansion with zoledronic acid and interleukin (IL)-2, exercise mobilized γδ T-cells had surface phenotypes and transcriptomic profiles associated with enhanced effector functions, and demonstrated superior cytotoxic activity against multiple hematologic tumors in vitro, and in vivo in leukemia bearing xenogeneic mice. Infusing humans with the β1+β2-agonist isoproterenol and administering β1 or β1+β2 antagonists prior to exercise revealed these effects to be β2-adrenergic receptor (AR) dependent. Antibody blocking of DNAM-1 on expanded γδ T-cells, as well as the DNAM-1 ligands PVR and Nectin-2 on leukemic targets, abolished the enhanced anti-leukemic effects of exercise. These findings provide a mechanistic link between exercise, β2-AR activation, and the manufacture of superior γδ T-cell products for adoptive cell therapy against hematological malignancies

Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice

BackgroundEvery bout of exercise mobilizes and redistributes large numbers of effector lymphocytes with a cytotoxic and tissue migration phenotype. The frequent redistribution of these cells is purported to increase immune surveillance and play a mechanistic role in reducing cancer risk and slowing tumor progression in physically active cancer survivors. Our aim was to provide the first detailed single cell transcriptomic analysis of exercise-mobilized lymphocytes and test their effectiveness as a donor lymphocyte infusion (DLI) in xenogeneic mice engrafted with human leukemia.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from healthy volunteers at rest and at the end of an acute bout of cycling exercise. Flow cytometry and single-cell RNA sequencing was performed to identify phenotypic and transcriptomic differences between resting and exercise-mobilized cells using a targeted gene expression panel curated for human immunology. PBMCs were injected into the tail vein of xenogeneic NSG-IL-15 mice and subsequently challenged with a luciferase tagged chronic myelogenous leukemia cell line (K562). Tumor growth (bioluminescence) and xenogeneic graft-versus-host disease (GvHD) were monitored bi-weekly for 40-days.ResultsExercise preferentially mobilized NK-cell, CD8+ T-cell and monocyte subtypes with a differentiated and effector phenotype, without significantly mobilizing CD4+ regulatory T-cells. Mobilized effector lymphocytes, particularly effector-memory CD8+ T-cells and NK-cells, displayed differentially expressed genes and enriched gene sets associated with anti-tumor activity, including cytotoxicity, migration/chemotaxis, antigen binding, cytokine responsiveness and alloreactivity (e.g. graft-versus-host/leukemia). Mice receiving exercise-mobilized PBMCs had lower tumor burden and higher overall survival (4.14E+08 photons/s and 47%, respectively) at day 40 compared to mice receiving resting PBMCs (12.1E+08 photons/s and 22%, respectively) from the same donors (p<0.05). Human immune cell engraftment was similar for resting and exercise-mobilized DLI. However, when compared to non-tumor bearing mice, K562 increased the expansion of NK-cell and CD3+/CD4-/CD8- T-cells in mice receiving exercise-mobilized but not resting lymphocytes, 1-2 weeks after DLI. No differences in GvHD or GvHD-free survival was observed between groups either with or without K562 challenge.ConclusionExercise in humans mobilizes effector lymphocytes with an anti-tumor transcriptomic profile and their use as DLI extends survival and enhances the graft-versus-leukemia (GvL) effect without exacerbating GvHD in human leukemia bearing xenogeneic mice. Exercise may serve as an effective and economical adjuvant to increase the GvL effects of allogeneic cell therapies without intensifying GvHD

Successful Percutaneous Recanalization of a Chronically Occluded Inferior Vena Cava in a Young Child

Young children with congenital heart disease are undergoing an increasing number of catheter-based interventions. These procedures can lead to obstruction of large central veins, making future interventions more challenging or even impossible. We present a young child with a chronically occluded inferior vena cava (IVC) secondary to prior catheterization-based interventions for congenital heart disease. The IVC was recanalized with serial angioplasty and stent placement with continued patency for over two years. Despite the long duration of obstruction, the IVC was successfully recanalized, eliminating the potential consequences of long-term IVC obstruction and making it easier for future catheter-based interventions, if needed.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

RSV prophylaxis guideline changes and outcomes in children with congenital heart disease

ObjectiveThe aim of this study was to compare inpatient outcomes and costs for children with respiratory syncytial virus and congenital heart disease before and after the change in management guidelines for respiratory syncytial virus prophylaxis.DesignHospital discharge data from the Vizient (formerly University HealthSystem Consortium) were queried from October 2012 to June 2014 (Era 1) and July 2014 to April 2016 (Era 2) for patients aged <24 months with an any International Classification of Disease (ICD)‐9 or ICD‐10 code for congenital heart disease (745‐747.49, Q20.0‐Q26.4) and a primary or secondary admitting diagnosis of respiratory syncytial virus infection (079.6, J20.5), acute bronchiolitis due to respiratory syncytial virus (466.11, J21.0) or respiratory syncytial virus pneumonia (480.1, J12.1).SettingThis study is a review of a national administrative discharge database.Patients: Respiratory syncytial virus admissions were identified in 1269 patients aged <24 months with congenital heart disease, with 644 patients in Era 1 and 625 in Era 2. Patients 0–12 months old represented 83% of admissions.InterventionsPrior to 2014, children aged 0–24 months with congenital heart disease were eligible to receive respiratory syncytial virus prophylaxis. Updated guidelines, published in 2014, restricted the recommendation to administer palivizumab respiratory syncytial virus prophylaxis to children with congenital heart disease only if they are ≤12 months old.Outcome measuresThe outcome measures are hospital length of stay, ICU admission rate, mortality, and direct costs.ResultsThere was no change in length of stay, ICU admission rate, in‐hospital mortality, or direct costs for children 13–24 months old with congenital heart disease after the change in guidelines. There were no deaths in 13–24 month olds, regardless of era.ConclusionsOur findings provide additional support for the new guideline recommendations to provide respiratory syncytial virus prophylaxis only for children ≤12 months old with congenital heart disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144272/1/chd12590_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144272/2/chd12590.pd

Successful Transcatheter Recanalization of a Chronically Occluded Left Pulmonary Artery Due to Fibrosing Mediastinitis

12 month embargo; published online 16 June 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Novel use of the double kissing crush technique to stent complex pulmonary artery stenosis in a child with Alagille syndrome

Coronary bifurcation lesions and treatment with two-stent techniques have been developed, including the double kissing (DK) crush technique. The use of this technique in children or noncoronary vessels, including pulmonary arteries, has not been described. We present a 12-year-old girl with Alagille syndrome, a ventricular septal defect (VSD), and complex bilateral pulmonary artery (PA) stenoses who is status post six catheterizations for PA angioplasty and stenting to improve her marked right ventricular hypertension. With collaboration between the congenital and structural teams, she successfully underwent the DK crush technique for a complex lesion in her PA. This improved pulmonary flow and allowed for successful surgical VSD closure

Anxiety reduction after pre-procedure meetings in patients with CHD

Background: Cardiac catheterisations for CHD produce anxiety for patients and families. Current strategies to mitigate anxiety and explain complex anatomy include pre-procedure meetings and educational tools (cardiac diagrams, echocardiograms, imaging, and angiography). More recently, three-dimensionally printed patient-specific models can be added to the armamentarium. The purpose of this study was to evaluate the efficacy of pre-procedure meetings and of different educational tools to reduce patient and parent anxiety before a catheterisation. Methods: Prospective study of patients >= 18 and parents of patients <18 scheduled for clinically indicated catheterisations. Patients completed online surveys before and after meeting with the interventional cardiologist, who was blinded to study participation. Both the pre- and post-meeting surveys measured anxiety using the State-Trait Anxiety Inventory. In addition, the post-meeting survey evaluated the subjective value (from 1 to 4) of individual educational tools: physician discussion, cardiac diagrams, echocardiograms, prior imaging, angiograms and three-dimensionally printed cardiac models. Data were compared using paired t-tests. Results: Twenty-three patients consented to participate, 16 had complete data for evaluation. Mean State-Trait Anxiety Inventory scores were abnormally elevated at baseline and decreased into the normal range after the pre-procedure meeting (39.8 versus 31, p = 0.008). Physician discussion, angiograms, and three-dimensional models were reported to be most effective at increasing understanding and reducing anxiety. Conclusion: In this pilot study, we have found that pre-catheterisation meetings produce a measurable decrease in patient and family anxiety before a procedure. Discussions of the procedure, angiograms, and three-dimensionally printed cardiac models were the most effective educational tools.6 month embargo; published online: 05 June 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Iliocaval Occlusion Treated with Angioplasty in a 1,500-g Infant

12 month embargo; first published: 01 October 2023This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]