rhNRG-1 improved the cardiac function of CHF patients by increasing the LVEF% and showed the capability of antiremodeling by decreasing ESV and EDV compared with pre-treatment. (A Randomized, Double-Blind, Multi-Center, Placebo Parallel controlled, Standard Therapy Based Phase II Clinical Trial to Evaluate the Efficacy and Safety of Recombinant Human Neuregulin-1 for Injection in Patients with Chronic Heart Failure; ChiCTR-TRC-00000414).

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Our results suggest that cMLCK is a downstream effector of rhNRG-1 involved in rhNRG-1-induced cardiac function improvement, and that myocardial cMLCK up-regulation can improve cardiac function in rats with MI.

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We showed previously that mild real hypoxia and hypoxia-mimetic agents induced in vitro cell differentiation of acute myeloid leukemia (AML). We here investigate the in vivo effects of intermittent hypoxia on syngenic grafts of leukemic blasts in a PML-RAR␣ transgenic mouse model of AML. For intermittent hypoxia, leukemic mice were housed in a hypoxia chamber equivalent to an altitude of 6000 m for 18 hours every consecutive day. The results show that intermittent hypoxia significantly prolongs the survival of the leukemic mice that received transplants, although it fails to cure the disease. By histologic and cytologic analyses, intermittent hypoxia is shown to inhibit the infiltration of leukemic blasts in peripheral blood, bone marrow, spleen, and liver without apoptosis induction. More intriguingly, intermittent hypoxia also induces leukemic cells to undergo differentiation with progressive increase of hypoxia-inducible factor-1␣ protein, as evidenced by morphologic criteria of maturating myeloid cells and increased expression of mouse myeloid cell differentiation-related antigens Gr-1 and Mac-1. Taken together, this study represents the first attempt to characterize the in vivo effects of hypoxia on an AML mouse model. Additional investigations may uncover ways to mimic the differentiative effects of hypoxia in a manner that will benefit human patients with AML. IntroductionAngiogenesis is an essential phenotype in growth and development, wound healing, and reproduction. 1,2 An inadequate amount of vessel growth contributes to ulcer formation, whereas excessive angiogenesis is relevant to a number of pathologic conditions including arthritis, psoriasis, and cancers. [3][4][5][6] Leukemia, a common hematopoietic malignancy, has traditionally been regarded as a "liquid tumor" with the appearance of leukemic cells freely floating in the peripheral circulation. Accordingly, leukemia was assumed not to require angiogenesis for its growth. However, recent evidence suggests that angiogenesis is also important in the pathogenesis of numerous different hematologic malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), as well as multiple myeloma. [7][8][9][10][11][12] For example, bone marrow (BM) from patients with acute promyelocytic leukemia (APL; a unique subtype of AML with a specific chromosomal translocation t(15;17) that causes the expression of a fusion protein, PML-RAR␣ [promyelocytic leukemia retinoic acid receptor ␣] 13,14 ) exhibited significantly increased microvessel density. Cellular levels of angiogenic factors such as vascular endothelial growth factor (VEGF) are abnormally elevated and provide an independent predictor of outcome in adults with AML. 15 Also, there is a 6-to 7-fold increase in microvessel density in BM biopsies of newly diagnosed untreated ALL in children. 16 Moreover, the myeloproliferative diseases (polycythemia vera, CML, and myelofibrosis) have also significantly increased neo...