Targeting of the IL-5 pathway in severe asthma reduces mast cell progenitors.

Background: Therapies targeting IL-5 or its receptor (IL-5Rα) are currently used to treat patients with severe eosinophilic asthma.

Objective: We sought to investigate the impact of anti-IL-5 and anti-IL-5Rα biological therapies on mast cells (MCs) and their progenitors.

Methods: Surface IL-5Rα expression was investigated on MCs and their progenitors in mouse lungs and bone marrow and in human lungs and blood.

Conduction Disturbances and Outcome After Surgical Aortic Valve Replacement in Patients With Bicuspid and Tricuspid Aortic Stenosis.

Background: This study aimed to compare the incidence and prognostic implications of new-onset conduction disturbances after surgical aortic valve replacement (SAVR) in patients with bicuspid aortic valve (BAV) aortic stenosis (AS) versus patients with tricuspid aortic valve (TAV) AS (ie, BAV-AS and TAV-AS, respectively). Additionally, the study included stratification of BAV patients according to subtype.

Methods: In this cohort study, the incidence of postoperative third-degree atrioventricular (AV) block with subsequent permanent pacemaker requirement and new-onset left bundle-branch block (LBBB) was investigated in 1147 consecutive patients without preoperative conduction disorder who underwent isolated SAVR (with or without ascending aortic surgery) between January 1, 2005, and December 31, 2022.

Left atrial dysfunction in bicuspid aortic valve patients with severe aortic stenosis is associated with post-operative atrial fibrillation following aortic valve replacement.

Aims: To investigate (i) the association between pre-operative left atrial (LA) reservoir strain and post-operative atrial fibrillation (AF) and (ii) the incidence of post-operative ischaemic stroke events separately in bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients after surgical aortic valve replacement for isolated severe aortic stenosis (AS).

Methods And Results: We prospectively enrolled 227 patients ( = 133 BAV and = 94 TAV) with isolated severe AS scheduled for aortic valve replacement. A comprehensive intra- and inter-observer validated pre-operative echocardiogram with an analysis of LA reservoir strain was performed.

Analysis of local extracellular matrix identifies different aetiologies behind bicuspid and tricuspid aortic valve degeneration and suggests therapies.

Aortic valve degeneration (AVD) is a life-threatening condition that has no medical treatment and lacks individual therapies. Although extensively studied with standard approaches, aetiologies behind AVD are unclear. We compared abundances of extracellular matrix (ECM) proteins from excised valve tissues of 88 patients with isolated AVD of normal tricuspid (TAV) and congenital bicuspid aortic valves (BAV), quantified more than 1400 proteins per ECM sample by mass spectrometry, and demonstrated that local ECM preserves molecular cues of the pathophysiological processes.

Next generation pan-cancer blood proteome profiling using proximity extension assay.

A comprehensive characterization of blood proteome profiles in cancer patients can contribute to a better understanding of the disease etiology, resulting in earlier diagnosis, risk stratification and better monitoring of the different cancer subtypes. Here, we describe the use of next generation protein profiling to explore the proteome signature in blood across patients representing many of the major cancer types. Plasma profiles of 1463 proteins from more than 1400 cancer patients are measured in minute amounts of blood collected at the time of diagnosis and before treatment.

Noninvasive detection of any-stage cancer using free glycosaminoglycans.

Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable.

Patients With Bicuspid Aortic Stenosis Demonstrate Adverse Left Ventricular Remodeling and Impaired Cardiac Function Before Surgery With Increased Risk of Postoperative Heart Failure.

Background: Differences in adverse cardiac remodeling between patients who have bicuspid (BAV) and tricuspid aortic valve (TAV) with severe isolated aortic stenosis (AS) and its prognostic impact after surgical aortic valve replacement remains unclear. We sought to investigate differences in preoperative diastolic and systolic function in patients with BAV and TAV who have severe isolated AS and the incidence of postoperative heart failure hospitalization and mortality.

Methods: Two hundred seventy-one patients with BAV (n=152) or TAV (n=119) and severe isolated AS without coronary artery disease or other valvular heart disease, scheduled for surgical aortic valve replacement, were prospectively included.

Diversity of respiratory parameters and metabolic adaptation to low oxygen tension in mesenchymal stromal cells.

Objective: Cell metabolism has been shown to play an active role in regulation of stemness and fate decision. In order to identify favorable culture conditions for mesenchymal stromal cells (MSCs) prior to transplantation, this study aimed to characterize the metabolic function of MSCs from different developmental stages in response to different oxygen tension during expansion.

Materials And Methods: We cultured human fetal cardiac MSCs and human adult bone-marrow MSCs for a week under hypoxia (3% O) and normoxia (20% O).

An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation.

Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny.

Mast cell-derived serotonin enhances methacholine-induced airway hyperresponsiveness in house dust mite-induced experimental asthma.

Background: Airway hyperresponsiveness (AHR) is a feature of asthma in which airways are hyperreactive to stimuli causing extensive airway narrowing. Methacholine provocations assess AHR in asthma patients mainly by direct stimulation of smooth muscle cells. Using in vivo mouse models, mast cells have been implicated in AHR, but the mechanism behind has remained unknown.

Synthetic tracheal grafts seeded with bone marrow cells fail to generate functional tracheae: First long-term follow-up study.

Objective: Synthetic tracheal grafts seeded with autologous bone marrow-mononuclear cells (BM-MNCs) have been described as becoming living and functional grafts representing a promising option for tracheal replacement for pathologies unamenable by segmental resection or autologous repair. This study aimed to present the first long-term follow-up of these procedures in humans.

Methods: We retrospectively analyzed 3 patients who received synthetic tracheal grafts seeded with BM-MNCs implanted.

Laminins and cancer stem cells: Partners in crime?

As one of the predominant protein families within the extracellular matrix both structurally and functionally, laminins have been shown to be heavily involved in tumor progression and drug resistance. Laminins participate in key cellular events for tumor angiogenesis, cell invasion and metastasis development, including the regulation of epithelial-mesenchymal transition and basement membrane remodeling, which are tightly associated with the phenotypic characteristics of stem-like cells, particularly in the context of cancer. In addition, a great deal of studies and reports has highlighted the critical roles of laminins in modulating stem cell phenotype and differentiation, as part of the stem cell niche.

Wnt/β-Catenin Stimulation and Laminins Support Cardiovascular Cell Progenitor Expansion from Human Fetal Cardiac Mesenchymal Stromal Cells.

The intrinsic regenerative capacity of human fetal cardiac mesenchymal stromal cells (MSCs) has not been fully characterized. Here we demonstrate that we can expand cells with characteristics of cardiovascular progenitor cells from the MSC population of human fetal hearts. Cells cultured on cardiac muscle laminin (LN)-based substrata in combination with stimulation of the canonical Wnt/β-catenin pathway showed increased gene expression of ISL1, OCT4, KDR, and NKX2.

In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome.

Unlabelled: Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions.

The safety of human pluripotent stem cells in clinical treatment.

Human pluripotent stem cells (hPSCs) have practically unlimited proliferation potential and a capability to differentiate into any cell type in the human body. Since the first derivation in 1998, they have been an attractive source of cells for regenerative medicine. Numerous ethical, technological, and regulatory complications have been hampering hPSC use in clinical applications.

A murine model of acute myeloid leukemia with Evi1 overexpression and autocrine stimulation by an intracellular form of GM-CSF in DA-3 cells.

The poor treatment response of acute myeloid leukemia (AML) overexpressing high-risk oncogenes such as EVI1, demands specific animal models for new treatment evaluations. Evi1 is a common site of activating integrations in murine leukemia virus (MLV)-induced AML and in retroviral and lentiviral gene-modified HCS. Still, a model of overt AML induced by Evi1 has not been generated.

Repeatable, Inducible Micro-RNA-Based Technology Tightly Controls Liver Transgene Expression.

Inducible systems for gene expression emerge as a new class of artificial vectors offering temporal and spatial exogenous control of gene expression. However, most inducible systems are less efficient in vivo and lack the target-organ specificity. In the present study, we have developed and optimized an oligonucleotide-based inducible system for the in vivo control of transgenes in the liver.

Clonal culturing of human embryonic stem cells on laminin-521/E-cadherin matrix in defined and xeno-free environment.

Lack of robust methods for establishment and expansion of pluripotent human embryonic stem (hES) cells still hampers development of cell therapy. Laminins (LN) are a family of highly cell-type specific basement membrane proteins important for cell adhesion, differentiation, migration and phenotype stability. Here we produce and isolate a human recombinant LN-521 isoform and develop a cell culture matrix containing LN-521 and E-cadherin, which both localize to stem cell niches in vivo.

Costimulation blockade induces foxp3(+) regulatory T cells to human embryonic stem cells.

Transplantation of human embryonic stem cells (hESCs), like other allogeneic cellular transplants, require immunomodulation or immunosuppression in order to be maintained in the recipient. Costimulation blockade applied at the time of transplantation inhibits costimulatory signals in the immunological synapse leading to a state of anergy in the donor reactive T-cell population and a state of immunological tolerance in the host. In models of solid organ transplantation, tolerance is maintained by the infiltration of Foxp3(+) regulatory T cells into the graft.

Verification of cell viability in bioengineered tissues and organs before clinical transplantation.

The clinical outcome of transplantations of bioartificial tissues and organs depends on the presence of living cells. There are still no standard operative protocols that are simple, fast and reliable for confirming the presence of viable cells on bioartificial scaffolds prior to transplantation. By using mathematical modeling, we have developed a colorimetric-based system (colorimetric scale bar) to predict the cell viability and density for sufficient surface coverage.

Diaminopropionic acid lipopeptides: characterization studies of polyplexes aimed at pDNA delivery.

Here we report a novel class of peptides-d-diaminopropionic acids (Dap)-for gene delivery. These peptides have attractive properties for gene delivery, and the advantage that they can be easily manipulated in relation to their composition, abiding with tailored-design. We characterized the toxicological and biophysical properties of DNA particles resulting from the interaction of the nucleic acid with a series of Dap(8) peptides conjugated to different alkyl groups.