Comparison of Magnetic Resonance Imaging and Serum Biomarkers for Detection of Human Pluripotent Stem Cell-Derived Teratomas.

The use of cells derived from pluripotent stem cells (PSCs) for regenerative therapies confers a considerable risk for neoplastic growth and teratoma formation. Preclinical and clinical assessment of such therapies will require suitable monitoring strategies to understand and mitigate these risks. Here we generated human-induced pluripotent stem cells (iPSCs), selected clones that continued to express reprogramming factors after differentiation into cardiomyocytes, and transplanted these cardiomyocytes into immunocompromised rat hearts post-myocardial infarction. We compared magnetic resonance imaging (MRI), cardiac ultrasound, and serum biomarkers for their ability to delineate teratoma formation and growth. MRI enabled the detection of teratomas with a volume >8 mm(3). A combination of three plasma biomarkers (CEA, AFP, and HCG) was able to detect teratomas with a volume >17 mm(3) and with a sensitivity of more than 87%. Based on our findings, a combination of serum biomarkers with MRI screening may offer the highest sensitivity for teratoma detection and tracking

Online insomnia treatment-a review

Spiegelhalder K, Acker J, Baumeister H, et al. Digitale Behandlungsangebote für Insomnie – eine Übersichtsarbeit. SOMNOLOGIE. 2020;24(4):106-114.Zusammenfassung Digital angebotene psychologische Interventionen gegen Schlafstörungen sind aktuell ein sehr intensiv bearbeitetes Forschungsthema. In dieser Übersichtsarbeit werden Originalarbeiten und Metaanalysen zu diesem Thema zusammengefasst. Hierbei zeigt sich, dass die internetbasierte kognitive Verhaltenstherapie für Insomnie (KVT-I) bei Erwachsenen durchweg sehr effektiv ist mit allenfalls leicht geringeren Effektstärken als die gleiche Behandlung mit physischer Präsenz von Therapeuten und Patienten. Behandlungseffekte zeigen sich dabei auch für sekundäre Outcome-Parameter wie Depressivität, Angst, Fatigue und Lebensqualität. Hingegen lassen die Forschung zur Wirksamkeit der internetbasierten KVT‑I bei Erwachsenen mit komorbiden psychischen Störungen oder körperlichen Erkrankungen sowie die Forschung zur Frage, wieviel Therapeutenkontakt in die Behandlung integriert werden sollte, anscheinend noch keine abschließenden Antworten zu. In diesen Bereichen scheint weitere Forschung notwendig zu sein scheint.Digitally provided psychological interventions for sleep disorders are currently a very intensively researched topic. In this review, original work and meta-analyses are summarized. Thus, it was shown that internet-based cognitive behavioral therapy for insomnia (CBT-I) in adults is consistently very effective, with only slightly reduced effects compared with the same treatment with the physical presence of therapists and patients. Treatment effects are also shown for secondary outcome parameters such as depression, anxiety, fatigue, and quality of life. On the other hand, research on the effectiveness of internet-based CGT-I in adults with comorbid mental disorders or physical illnesses, and on the issue of how much contact with therapists should be integrated into treatment, does not seem to provide any conclusive answers. Further research seems to be needed in these areas

A direct role for phosphatidylinositol-4,5-bisphosphate in unconventional secretion of fibroblast growth factor 2

Fibroblast growth factor 2 (FGF-2) is a mitogen that is exported from cells by an endoplasmic reticulum/Golgi-independent secretory pathway. Recent findings have shown that FGF-2 export occurs by direct translocation from the cytoplasm across the plasma membrane into the extracellular space. Here, we report that FGF-2 contains a binding site for phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2)], the principal phosphoinositide species associated with plasma membranes. Intriguingly, in the context of a lipid bilayer, the interaction between FGF-2 and PI(4,5)P(2) is shown to depend on a lipid background that resembles plasma membranes. We show that the interaction with PI(4,5)P(2) is critically important for FGF-2 secretion as experimental conditions reducing cellular levels of PI(4,5)P(2) resulted in a substantial drop in FGF-2 export efficiency. Likewise, we have identified FGF-2 variant forms deficient for binding to PI(4,5)P(2) that were found to be severely impaired with regard to export efficiency. These data show that a transient interaction with PI(4,5)P(2) associated with the inner leaflet of plasma membranes represents the initial step of the unconventional secretory pathway of FGF-2

Comparison of Magnetic Resonance Imaging and Serum Biomarkers for Detection of Human Pluripotent Stem Cell-Derived Teratomas

The use of cells derived from pluripotent stem cells (PSCs) for regenerative therapies confers a considerable risk for neoplastic growth and teratoma formation. Preclinical and clinical assessment of such therapies will require suitable monitoring strategies to understand and mitigate these risks. Here we generated human-induced pluripotent stem cells (iPSCs), selected clones that continued to express reprogramming factors after differentiation into cardiomyocytes, and transplanted these cardiomyocytes into immunocompromised rat hearts post-myocardial infarction. We compared magnetic resonance imaging (MRI), cardiac ultrasound, and serum biomarkers for their ability to delineate teratoma formation and growth. MRI enabled the detection of teratomas with a volume >8 mm3. A combination of three plasma biomarkers (CEA, AFP, and HCG) was able to detect teratomas with a volume >17 mm3 and with a sensitivity of more than 87%. Based on our findings, a combination of serum biomarkers with MRI screening may offer the highest sensitivity for teratoma detection and tracking

Costimulation‐adhesion blockade is superior to Cyclosporine A and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation

RationaleHuman embryonic stem cell (hESC) derivatives are attractive candidates for therapeutic use. The engraftment and survival of hESC derivatives as xenografts or allografts require effective immunosuppression to prevent immune cell infiltration and graft destruction.ObjectiveTo test the hypothesis that a short-course, dual-agent regimen of two costimulation-adhesion blockade agents can induce better engraftment of hESC derivatives compared to current immunosuppressive agents.Methods and resultsWe transduced hESCs with a double fusion reporter gene construct expressing firefly luciferase (Fluc) and enhanced green fluorescent protein, and differentiated these cells to endothelial cells (hESC-ECs). Reporter gene expression enabled longitudinal assessment of cell engraftment by bioluminescence imaging. Costimulation-adhesion therapy resulted in superior hESC-EC and mouse EC engraftment compared to cyclosporine therapy in a hind limb model. Costimulation-adhesion therapy also promoted robust hESC-EC and hESC-derived cardiomyocyte survival in an ischemic myocardial injury model. Improved hESC-EC engraftment had a cardioprotective effect after myocardial injury, as assessed by magnetic resonance imaging. Mechanistically, costimulation-adhesion therapy is associated with systemic and intragraft upregulation of T-cell immunoglobulin and mucin domain 3 (TIM3) and a reduced proinflammatory cytokine profile.ConclusionsCostimulation-adhesion therapy is a superior alternative to current clinical immunosuppressive strategies for preventing the post-transplant rejection of hESC derivatives. By extending the window for cellular engraftment, costimulation-adhesion therapy enhances functional preservation following ischemic injury. This regimen may function through a TIM3-dependent mechanism

Human Engineered Heart Muscles Engraft and Survive Long Term in a Rodent Myocardial Infarction Model

RATIONAL: Tissue engineering approaches may improve survival and functional benefits from human embryonic stem cell-derived cardiomyocte (ESC-CM) transplantation, thereby potentially preventing dilative remodelling and progression to heart failure. OBJECTIVE: Assessment of transport stability, long term survival, structural organisation, functional benefits, and teratoma risk of engineered heart muscle (EHM) in a chronic myocardial infarction (MI) model. METHODS AND RESULTS: We constructed EHMs from ESC-CMs and released them for transatlantic shipping following predefined quality control criteria. Two days of shipment did not lead to adverse effects on cell viability or contractile performance of EHMs (n=3, P=0.83, P=0.87). After ischemia/reperfusion (I/R) injury, EHMs were implanted onto immunocompromised rat hearts at 1 month to simulate chronic ischemia. Bioluminescence imaging (BLI) showed stable engraftment with no significant cell loss between week 2 and 12 (n=6, P=0.67), preserving up to 25% of the transplanted cells. Despite high engraftment rates and attenuated disease progression (change in ejection fraction for EHMs −6.7±1.4% vs control −10.9±1.5%, n>12, P=0.05), we observed no difference between EHMs containing viable or non-viable human cardiomyocytes in this chronic xenotransplantation model (n>12, P=0.41). Grafted cardiomyocytes showed enhanced sarcomere alignment and increased connexin 43 expression at 220 days after transplantation. No teratomas or tumors were found in any of the animals (n=14) used for long-term monitoring. CONCLUSIONS: EHM transplantation led to high engraftment rates, long term survival, and progressive maturation of human cardiomyocytes. However, cell engraftment was not correlated with functional improvements in this chronic MI model. Most importantly, the safety of this approach was demonstrated by the lack of tumor or teratoma formation