Neovascularization characterizes diabetic retinopathy and choroidal neovascularization associated with age-related macular degeneration, the most common causes of severe visual loss in the developed world. Gene transfer to the eye using adeno-associated viral (AAV) vectors is a promising new treatment for inherited and acquired ocular diseases. We used an AAV vector with rapid onset and high levels of gene expression in the retina to deliver three anti-angiogenic factors (pigment epithelium-derived factor, tissue inhibitor of metalloproteinase-3, and endostatin) to the eyes of mice in a mouse model of retinopathy of prematurity. All three vectors inhibited ischemia-induced neovascularization.
Cellular therapy with ASCs, EC/ASCs, and topical CM accelerated diabetic wound healing in the swine model. Enhanced angiogenesis and immunomodulation might be key contributors to this process.
Summary
Chemotherapy resistance from imbalanced apoptosis regulation may contribute to poor outcome in leukaemias with t(4;11). Anti‐apoptotic BCL‐2 expression and target modulation were characterized in cell lines with t(4;11) and BCL‐2 expression was examined in MLL and non‐MLL infant/paediatric leukaemia cases by Western blot analysis and/or real‐time polymerase chain reaction. Cytotoxicity of Genasense™ (Oblimersen Sodium, G3139) alone or combined with cytotoxic drugs was assessed by MTT [(3‐4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide] assays of the cell lines, applying pharmacostatistical response surface modelling of drug interactions. Apoptosis and cell cycle were evaluated by flow cytometry in RS4:11 cells. Primary leukaemias and cell lines with t(4;11) expressed abundant BCL2 mRNA and protein. Variable, sometimes substantial BCL2 mRNA was detected in other leukaemia subtypes. G3139 reduced BCL2 mRNA and protein in RS4:11 cells. The most sensitive cell line to single‐agent G3139 was RS4:11. Low G3139 concentrations sensitized RS4:11 and MV4‐11 cells to select anti‐leukaemia cytotoxic drugs. In RS4:11 cells, combining G3139 with doxorubicin (ADR) increased active caspase 3 and TUNEL staining compared to ADR alone, indicating greater apoptosis, and G3139 increased S‐phase progression. The abundant BCL‐2 affords a molecular target in leukaemias with t(4;11). G3139 exhibits preclinical activity and synergy with select cytotoxic agents in RS4:11 and MV4‐11 cells, and these effects occur through apoptosis.
Our results suggest that assessments of medical knowledge during active learning exercises could supplement non-cognitive assessments and could be good predictors of performance on summative examinations.
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