Computational Sensitivity Investigation of Hydrogel Injection Characteristics for Myocardial Support

Biomaterial injection is a potential new therapy for augmenting ventricular mechanics after myocardial infarction (MI). Recent in vivo studies have demonstrated that hydrogel injections can mitigate the adverse remodeling due to MI. More importantly, the material properties of these injections influence the efficacy of the therapy. The goal of the current study is to explore the interrelated effects of injection stiffness and injection volume on diastolic ventricular wall stress and thickness. To achieve this, finite element models were constructed with different hydrogel injection volumes (150 µL and 300 µL), where the modulus was assessed over a range of 0.1 kPa to 100 kPa (based on experimental measurements). The results indicate that a larger injection volume and higher stiffness reduce diastolic myofiber stress the most, by maintaining the wall thickness during loading. Interestingly, the efficacy begins to taper after the hydrogel injection stiffness reaches a value of 50 kPa. This computational approach could be used in the future to evaluate the optimal properties of the hydrogel

Students as Community Vaccinators: Implementation of A Service-Learning COVID-19 Vaccination Program

While the COVID-19 pandemic has caused major educational disruptions, it has also catalyzed innovation in service-learning as a real-time response to pandemic-related problems. The limited number of qualified providers was primed to restrict SARS-CoV-2 vaccination efforts. Thus, New York State temporarily allowed healthcare professional trainees to vaccinate, enabling medical students to support an overwhelmed healthcare system and contribute to the public health crisis. Here, we describe a service-learning vaccination program directed towards underserved communities. A faculty-led curriculum prepared medical students to communicate with patients about COVID-19 vaccines and to administer intramuscular injections. Qualified students were deployed to public vaccination clinics located in under-served neighborhoods in collaboration with an established community partner. Throughout the program, 128 students worked at 103 local events, helping to administer 26,889 vaccine doses. Analysis of a retrospective survey administered to participants revealed the program taught fundamental clinical skills and was a transformative service-learning experience. As new virus variants emerge and nations battle recurrent waves of infection, the need for effective vaccination plans continues to grow. The program described here offers a novel framework that academic medical centers could adapt to increase vaccine access in their local community and provide students with a uniquely meaningful educational experience

Effects of hydrogel injection on borderzone contractility post-myocardial infarction.

Injectable hydrogels are a potential therapy for mitigating adverse left ventricular (LV) remodeling after myocardial infarction (MI). Previous studies using magnetic resonance imaging (MRI) have shown that hydrogel treatment improves systolic strain in the borderzone (BZ) region surrounding the infarct. However, the corresponding contractile properties of the BZ myocardium are still unknown. The goal of the current study was to quantify the in vivo contractile properties of the BZ myocardium post-MI in an ovine model treated with an injectable hydrogel. Contractile properties were determined 8 weeks following posterolateral MI by minimizing the difference between in vivo strains and volume calculated from MRI and finite element model predicted strains and volume. This was accomplished by using a combination of MRI, catheterization, finite element modeling, and numerical optimization. Results show contractility in the BZ of animals treated with hydrogel injection was significantly higher than untreated controls. End-systolic (ES) fiber stress was also greatly reduced in the BZ of treated animals. The passive stiffness of the treated infarct region was found to be greater than the untreated control. Additionally, the wall thickness in the infarct and BZ regions was found to be significantly higher in the treated animals. Treatment with hydrogel injection significantly improved BZ function and reduced LV remodeling, via altered MI properties. These changes are linked to a reduction in the ES fiber stress in the BZ myocardium surrounding the infarct. The current results imply that injectable hydrogels could be a viable therapy for maintaining LV function post-MI

Acute Myeloid Leukemia iPSCs Reveal a Role for RUNX1 in the Maintenance of Human Leukemia Stem Cells

Leukemia stem cells (LSCs) are believed to have more distinct vulnerabilities than the bulk acute myeloid leukemia (AML) cells, but their rarity and the lack of universal markers for their prospective isolation hamper their study. We report that genetically clonal induced pluripotent stem cells (iPSCs) derived from an AML patient and characterized by exceptionally high engraftment potential give rise, upon hematopoietic differentiation, to a phenotypic hierarchy. Through fate-tracking experiments, xenotransplantation, and single-cell transcriptomics, we identify a cell fraction (iLSC) that can be isolated prospectively by means of adherent in vitro growth that resides on the apex of this hierarchy and fulfills the hallmark features of LSCs. Through integrative genomic studies of the iLSC transcriptome and chromatin landscape, we derive an LSC gene signature that predicts patient survival and uncovers a dependency of LSCs, across AML genotypes, on the RUNX1 transcription factor. These findings can empower efforts to therapeutically target AML LSCs. [Display omitted] •AML-iPSC-derived hematopoietic cells recapitulate a LSC hierarchy•iLSCs can be easily prospectively isolated•A LSC 16-gene set correlates with AML patient survival•The RUNX1 TF is critical for the maintenance of LSCs across AML genetic subgroups Wesely et al. report that AML-iPSC-derived hematopoietic cells are hierarchically organized and contain cells with hallmark features of LSCs (iLSCs). Through integrative genomic studies of bulk and single-cell transcriptomes and chromatin accessibility, they derive a LSC gene signature and identify RUNX1 as an AML LSC dependency with therapeutic implications

Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths

RNA splicing factors are recurrently mutated in clonal blood disorders, but the impact of dysregulated splicing in hematopoiesis remains unclear. To overcome technical limitations, we integrated genotyping of transcriptomes (GoT) with long-read single-cell transcriptomics and proteogenomics for single-cell profiling of transcriptomes, surface proteins, somatic mutations, and RNA splicing (GoT-Splice). We applied GoT-Splice to hematopoietic progenitors from myelodysplastic syndrome (MDS) patients with mutations in the core splicing factor SF3B1. SF3B1mut cells were enriched in the megakaryocytic-erythroid lineage, with expansion of SF3B1mut erythroid progenitor cells. We uncovered distinct cryptic 3' splice site usage in different progenitor populations and stage-specific aberrant splicing during erythroid differentiation. Profiling SF3B1-mutated clonal hematopoiesis samples revealed that erythroid bias and cell-type-specific cryptic 3' splice site usage in SF3B1mut cells precede overt MDS. Collectively, GoT-Splice defines the cell-type-specific impact of somatic mutations on RNA splicing, from early clonal outgrowths to overt neoplasia, directly in human samples.</p