Identification and characterization of stem cell secretome-based recombinant proteins for wound healing applications

Stem cells have been introduced as a promising therapy for acute and chronic wounds, including burn injuries. The effects of stem cell-based wound therapies are believed to result from the secreted bioactive molecules produced by stem cells. Therefore, treatments using stem cell-derived conditioned medium (CM) (referred to as secretome) have been proposed as an alternative option for wound care. However, safety and regulatory concerns exist due to the uncharacterized biochemical content and variability across different batches of CM samples. This study presents an alternative treatment strategy to mitigate these concerns by using fully characterized recombinant proteins identified by the CM analysis to promote pro-regenerative healing. This study analyzed the secretome profile generated from human placental stem cell (hPSC) cultures and identified nine predominantly expressed proteins (ANG-1, FGF-7, Follistatin, HGF, IL-6, Insulin, TGFβ-1, uPAR, and VEGF) that are known to contribute to wound healing and angiogenesis. These proteins, referred to as s (CMFs), were used in combination to test the effects on human dermal fibroblasts (HDFs). Our results showed that CMF treatment increased the HDF growth and accelerated cell migration and wound closure, similar to stem cell and CM treatments. In addition, the CMF treatment promoted angiogenesis by enhancing new vessel formation. These findings suggest that the defined CMF identified by the CM proteomic analysis could be an effective therapeutic solution for wound healing applications. Our strategy eliminates the regulatory concerns present with stem cell-derived secretomes and could be developed as an off-the-shelf product for immediate wound care and accelerating healing

Social Deprivation, Inequality, and the Neighborhood-Level Incidence of Psychotic Syndromes in East London

licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Modulating Neuromuscular Junction Density Changes in Botulinum Toxin–Treated Orbicularis Oculi Muscle

While botulinum toxin injections are effective in reducing muscle spasms in blepharospasm and hemifacial spasm patients, they have a relatively short duration of action due to formation of new functional neuromuscular junctions. Co-injection of botulinum toxin–treated eyelids with corticotrophin-releasing factor or antibody to insulin growth factor–receptor prevented neuromuscular junction increases. The long-term goal is to increase the duration of effectiveness of botulinum toxin and reduce the lifetime exposure in patients

Microenvironmental stiffness induces metabolic reprogramming in glioblastoma

The mechanical properties of solid tumors influence tumor cell phenotype and the ability to invade surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state, which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peritumoral brain tissues, but tumor stiffness is heterogeneous where tumor edges are softer than the tumor core. We then developed 3D scaffolds with μ-compressive moduli resembling either stiffer tumor core or softer peritumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis, which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells

Glioblastoma Spheroid Invasion through Soft, Brain-Like Matrices Depends on Hyaluronic Acid-CD44 Interactions.

Increased secretion of hyaluronic acid (HA), a glycosaminoglycan abundant in the brain extracellular matrix (ECM), correlates with worse clinical outcomes for glioblastoma (GBM) patients. GBM cells aggressively invade the brain parenchyma while encountering spatiotemporal changes in their local ECM, including HA concentration. To investigate how varying HA concentrations affect GBM invasion, patient-derived GBM cells are cultured within a soft, 3D matrix in which HA concentration is precisely varied and cell migration observed. Data demonstrate that HA concentration can determine the invasive activity of patient-derived GBM cells in a biphasic and highly sensitive manner, where the absolute concentration of HA at which cell migration peaked is specific to each patient-derived line. Furthermore, evidence that this response relies on phosphorylated ezrin, which interacts with the intracellular domain of HA-engaged CD44 to effectively link the actin cytoskeleton to the local ECM is provided. Overall, this study highlights CD44-HA binding as a major mediator of GBM cell migration that acts independently of integrins and focal adhesion complexes and suggests that targeting HA-CD44-ezrin interactions represents a promising therapeutic strategy to prevent tumor cell invasion in the brain