Neuromuscular Regeneration of Volumetric Muscle Loss Injury in Response to Agrin-Functionalized Tissue Engineered Muscle Grafts and Rehabilitative Exercise.

Neuromuscular deficits compound the loss of contractile tissue in volumetric muscle loss (VML). Two avenues for promoting recovery are neuromuscular junction (NMJ)-promoting substrates (e.g.

Mechanism-Driven Design of Multispecific Antibodies for Targeted Disease Treatment.

Antibody-based therapeutics constitute a rapidly growing class of pharmaceutical compounds. However, monoclonal antibodies, which specifically engage only one target, often lack the mechanistic intricacy to treat complex diseases. To expand the utility of antibody therapies, significant efforts have been invested in designing multispecific antibodies, which engage multiple targets using a single molecule.

Brain Frontal-Lobe Misery Perfusion in COVID-19 ICU Survivors: An MRI Pilot Study.

Post-acute COVID-19 syndrome (PCS) is highly prevalent. Critically ill patients requiring intensive care unit (ICU) admission are at a higher risk of developing PCS. The mechanisms underlying PCS are still under investigation and may involve microvascular damage in the brain.

Engineering Anticytokine Antibodies for Immune Modulation.

The delicate balance of immune homeostasis is regulated by the interactions between cytokines and their cognate cell surface signaling receptors. There is intensive interest in harnessing cytokines as drugs for diseases such as cancer and autoimmune disorders. However, the multifarious and often contradictory activities of cytokines, coupled with their short serum half-lives, limit clinical performance and result in dangerous toxicities.

The use of weakly supervised machine learning for necrosis assessment in patients with osteosarcoma: A pilot study.

Percent necrosis (PN) following chemotherapy is a prognostic factor for survival in osteosarcoma. Pathologists estimate PN by calculating tumor viability over an average of whole-slide images (WSIs). This non-standardized, labor-intensive process requires specialized training and has high interobserver variability.

Hippocampal synaptic alterations associated with tau pathology in primary age-related tauopathy.

Primary age-related tauopathy (PART) is characterized by aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology has been associated with cognitive impairment in PART. However, the potential underlying mechanisms are not well understood.

Engineered cytokine/antibody fusion proteins improve delivery of IL-2 to pro-inflammatory cells and promote antitumor activity.

Progress in cytokine engineering is driving therapeutic translation by overcoming the inherent limitations of these proteins as drugs. The interleukin-2 (IL-2) cytokine harbors great promise as an immune stimulant for cancer treatment. However, the cytokine's concurrent activation of both pro-inflammatory immune effector cells and anti-inflammatory regulatory T cells, its toxicity at high doses, and its short serum half-life have limited clinical application.

Hippocampal Synaptic Alterations Associated with Tau Pathology in Primary Age-Related Tauopathy.

Primary Age-Related Tauopathy (PART) is characterized by the aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology have been associated with cognitive impairment in PART. However, the underlying mechanisms of cognitive impairment in PART are not well understood.

Engineering Skeletal Muscle Grafts with PAX7::GFP-Sorted Human Pluripotent Stem Cell-Derived Myogenic Progenitors on Fibrin Microfiber Bundles for Tissue Regeneration.

Tissue engineering strategies that combine human pluripotent stem cell-derived myogenic progenitors (hPDMs) with advanced biomaterials provide promising tools for engineering 3D skeletal muscle grafts to model tissue development in vitro and promote muscle regeneration in vivo. We recently demonstrated (i) the potential for obtaining large numbers of hPDMs using a combination of two small molecules without the overexpression of transgenes and (ii) the application of electrospun fibrin microfiber bundles for functional skeletal muscle restoration following volumetric muscle loss. In this study, we aimed to demonstrate that the biophysical cues provided by the fibrin microfiber bundles induce hPDMs to form engineered human skeletal muscle grafts containing multinucleated myotubes that express desmin and myosin heavy chains and that these grafts could promote regeneration following skeletal muscle injuries.

Systematic study of the iodinated rectal hydrogel spacer material discrepancy on accuracy of proton dosimetry.

Purpose: Iodination of rectal hydrogel spacer increases the computed tomography (CT) visibility. The effect of iodinated hydrogel spacer material on the accuracy of proton dosimetry has not been fully studied yet. We presented a systematic study to determine the effect of iodination on proton dosimetry accuracy during proton therapy (PT).

Pediatric Otoscopy Video Screening With Shift Contrastive Anomaly Detection.

Ear related concerns and symptoms represent the leading indication for seeking pediatric healthcare attention. Despite the high incidence of such encounters, the diagnostic process of commonly encountered diseases of the middle and external presents a significant challenge. Much of this challenge stems from the lack of cost effective diagnostic testing, which necessitates the presence or absence of ear pathology to be determined clinically.

Visualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors.

Elucidating how synaptic molecules such as AMPA receptors mediate neuronal communication and tracking their dynamic expression during behavior is crucial to understand cognition and disease, but current technological barriers preclude large-scale exploration of molecular dynamics in vivo. We have developed a suite of innovative methodologies that break through these barriers: a new knockin mouse line with fluorescently tagged endogenous AMPA receptors, two-photon imaging of hundreds of thousands of labeled synapses in behaving mice, and computer vision-based automatic synapse detection. Using these tools, we can longitudinally track how the strength of populations of synapses changes during behavior.

Engineering skeletal muscle: Building complexity to achieve functionality.

Volumetric muscle loss (VML) VML is defined as the loss of a critical mass of skeletal muscle that overwhelms the muscle's natural healing mechanisms, leaving patients with permanent functional deficits and deformity. The treatment of these defects is complex, as skeletal muscle is a composite structure that relies closely on the action of supporting tissues such as tendons, vasculature, nerves, and bone. The gold standard of treatment for VML injuries, an autologous muscle flap transfer, suffers from many shortcomings but nevertheless remains the best clinically available avenue to restore function.

Protocol for the Use of a Novel Bioreactor System for Hydrated Mechanical Testing, Strained Sterile Culture, and Force of Contraction Measurement of Tissue Engineered Muscle Constructs.

Bioreactor systems are built as controlled environments for biological processes and utilized in the field of tissue engineering to apply mechanical, spatial, and chemical cues to developing tissue grafts. Often the systems are applied to instruct differentiation and maturation of the cells grown inside. Perhaps the most obvious targets for strain and compression-based bioreactors are mechanically active tissues, as it is hypothesized that biomimetic mechanical environments instruct immature cells to form differentiated tissues.

Engineering 3D skeletal muscle primed for neuromuscular regeneration following volumetric muscle loss.

Volumetric muscle loss (VML) overwhelms the native regenerative capabilities of skeletal muscle and has few effective treatments to regain lost muscle mass and function. Tissue engineered muscle constructs designed to promote neuromuscular regeneration are a promising therapeutic avenue. To date, there has been no engineered muscle construct for VML treatment that has incorporated a pharmacologic agent to promote neuromuscular regeneration.

Biomimetic Model of Contractile Cardiac Tissue with Endothelial Networks Stabilized by Adipose-Derived Stromal/Stem Cells.

Cardiac tissue engineering strategies have the potential to regenerate functional myocardium following myocardial infarction. In this study, we utilized novel electrospun fibrin microfiber sheets of different stiffnesses (50.0 ± 11.

Vascularized and Innervated Skeletal Muscle Tissue Engineering.

Volumetric muscle loss (VML) is a devastating loss of muscle tissue that overwhelms the native regenerative properties of skeletal muscle and results in lifelong functional deficits. There are currently no treatments for VML that fully recover the lost muscle tissue and function. Tissue engineering presents a promising solution for VML treatment and significant research has been performed using tissue engineered muscle constructs in preclinical models of VML with a broad range of defect locations and sizes, tissue engineered construct characteristics, and outcome measures.

Myoblast maturity on aligned microfiber bundles at the onset of strain application impacts myogenic outcomes.

Engineered skeletal muscle grafts may be employed in various applications including the treatment of volumetric muscle loss (VML) and pharmacological drug screening. To recapitulate the well-defined structure of native muscle, tensile strains have been applied to the grafts. In this study, we cultured C2C12 murine myoblasts on electrospun fibrin microfiber bundles for 7 days in custom-built bioreactor units and investigated the impact of strain regimen and delayed onset of tensile straining on myogenic outcomes.

Engineering functional and histological regeneration of vascularized skeletal muscle.

Tissue engineering strategies to treat patients with volumetric muscle loss (VML) aim to recover the structure and contractile function of lost muscle tissue. Here, we assessed the capacity of novel electrospun fibrin hydrogel scaffolds seeded with murine myoblasts to regenerate the structure and function of damaged muscle within VML defects to the mouse tibialis anterior muscle. The electrospun fibrin scaffolds provide pro-myogenic alignment and stiffness cues, myomimetic hierarchical structure, suturability, and scale-up capabilities.

Adipose-derived perivascular mesenchymal stromal/stem cells promote functional vascular tissue engineering for cardiac regenerative purposes.

Cardiac tissue engineering approaches have the potential to regenerate functional myocardium with intrinsic vascular networks. This study compared the relative effects of human adipose-derived stem/stromal cells (hASCs) and human dermal fibroblasts (hDFs) in cocultures with neonatal rat ventricular cardiomyocytes (NRVCMs) and human umbilical vein endothelial cells (HUVECs). At the same ratios of NRVCM:hASC and NRVCM:hDF, the hASC cocultures displayed shorter action potentials and maintained capture at faster pacing rates.

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer.

Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES.