Myocardial geometric remodeling is a response to increased stress which includes increased afterload situations during clinical conditions. In this review, we have focused on early and late geometric features in aorti...Myocardial geometric remodeling is a response to increased stress which includes increased afterload situations during clinical conditions. In this review, we have focused on early and late geometric features in aortic stenosis, importance of recognition of these findings and consequences due to progression of valve disease. We have also pointed out the similarities in early focal and global myocardial geometric remodeling in acute and chronic conditions as hypertension and acute stress cardiomypathy which are associated with myocardial functional and geometric response to acute or chronic stress exposure and relevant increased afterload. In aortic stenosis, target organ involvement in disease progression has been evaluated and discussed in the report. In addition to quantitative evaluation of valve disease, importance of myocardial involvement and global assessment of patients with aortic stenosis also have been mentioned in the report. Finally, we have discussed the importance of global myocardial geometric changes and timing for surgery before development of heart failure in this specific group of patients.展开更多
Glioblastoma(GBM,WHO grade IV glioma)is the most common and lethal malignant brain tumor in aduts with a dismal prognosis.The extracellular matrix(ECM)supports GBM progression by promoting tumor cell proliferation,mig...Glioblastoma(GBM,WHO grade IV glioma)is the most common and lethal malignant brain tumor in aduts with a dismal prognosis.The extracellular matrix(ECM)supports GBM progression by promoting tumor cell proliferation,migration,and immune escape.Uridine diphosphate(UDP)-glucose 6-dehydrogenase(UGDH)is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM.We investigated how targeting UGDH in GBM infuence$the GBM immune microenvironment,including tumor-associated microglia/macrophages(TAMs)and T cells.TAMs are the main im-mune effector cells in GBM and can directly target tumor cells if properly activated.In co-cultures of GBM cells and human primary macrophages,UGDH knockdown in GBM cells pro-moted macrophage phagocytosis and M-like polarization.In orthotropic human GBM xeno-grafts and syngeneic mouse glioma models,targeting UGDH decreased ECM deposition,increased TAM phagocytosis marker expression,reduced M2-like TAMS and inhibited tumor growth.UGDH knockdown in GBM cells also promoted cytotoxic T cell ifltration and activa-tion in orthotopic syngeneic mouse glioma models.The potent and in-human-use small mole-cule GAG synthesis inhibitor 4-methylumbelliferone(4-MU)was found to inhibit GBM cell proliferation and migration in vitro,mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM.Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvi-ronment.展开更多
文摘Myocardial geometric remodeling is a response to increased stress which includes increased afterload situations during clinical conditions. In this review, we have focused on early and late geometric features in aortic stenosis, importance of recognition of these findings and consequences due to progression of valve disease. We have also pointed out the similarities in early focal and global myocardial geometric remodeling in acute and chronic conditions as hypertension and acute stress cardiomypathy which are associated with myocardial functional and geometric response to acute or chronic stress exposure and relevant increased afterload. In aortic stenosis, target organ involvement in disease progression has been evaluated and discussed in the report. In addition to quantitative evaluation of valve disease, importance of myocardial involvement and global assessment of patients with aortic stenosis also have been mentioned in the report. Finally, we have discussed the importance of global myocardial geometric changes and timing for surgery before development of heart failure in this specific group of patients.
基金This work was supported by grants from NIH R01NS091165(S.X.),R01 NS099460(M Ying),R01 NS096754(J Laterra),and R01 NS076759(J Laterra)。
文摘Glioblastoma(GBM,WHO grade IV glioma)is the most common and lethal malignant brain tumor in aduts with a dismal prognosis.The extracellular matrix(ECM)supports GBM progression by promoting tumor cell proliferation,migration,and immune escape.Uridine diphosphate(UDP)-glucose 6-dehydrogenase(UGDH)is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM.We investigated how targeting UGDH in GBM infuence$the GBM immune microenvironment,including tumor-associated microglia/macrophages(TAMs)and T cells.TAMs are the main im-mune effector cells in GBM and can directly target tumor cells if properly activated.In co-cultures of GBM cells and human primary macrophages,UGDH knockdown in GBM cells pro-moted macrophage phagocytosis and M-like polarization.In orthotropic human GBM xeno-grafts and syngeneic mouse glioma models,targeting UGDH decreased ECM deposition,increased TAM phagocytosis marker expression,reduced M2-like TAMS and inhibited tumor growth.UGDH knockdown in GBM cells also promoted cytotoxic T cell ifltration and activa-tion in orthotopic syngeneic mouse glioma models.The potent and in-human-use small mole-cule GAG synthesis inhibitor 4-methylumbelliferone(4-MU)was found to inhibit GBM cell proliferation and migration in vitro,mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM.Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvi-ronment.