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We performed a prospective study of all inpatient and outpatient methicillin-resistant Staphylococcus aureus (MRSA) isolates identified at the University of Chicago Hospitals from November 2003 through November 2004. Differences in [...]

Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation., Author(s): Jennifer A Doll [1, 7]; Veronica M Stellmach [1, 7]; Noel P Bouck [2, 3]; Anders RJ Bergh [6]; Chung Lee [4]; Lisa P Abramson [5]; Mona L Cornwell [...]

Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder of bone and connective tissue, also known as brittle bone disease. Null mutations in SERPINF1, which encodes pigment epithelium‐derived factor (PEDF), cause severe type VI OI, characterized by accumulation of unmineralized osteoid and a fish‐scale pattern of bone lamellae. Although the potent anti‐angiogenic activity of PEDF has been extensively studied, the disease mechanism of type VI OI is not well understood. Using Serpinf1(−/−) mice and primary osteoblasts, we demonstrate that loss of PEDF delays osteoblast maturation as well as extracellular matrix (ECM) mineralization. Barium sulfate perfusion reveals significantly increased vessel density in the tibial periosteum of Serpinf1(−/−) mouse compared with wild‐type littermates. The increased bone vascularization in Serpinf1(−/−) mice correlated with increased number of CD31(+)/Endomucin(+) endothelial cells, which are involved in the coupling angiogenesis and osteogenesis. Global transcriptome analysis by RNA‐Seq of Serpinf1(−/−) mouse osteoblasts reveals osteogenesis and angiogenesis as the biological processes most impacted by loss of PEDF. Intriguingly, TGF‐β signaling is activated in type VI OI cells, and Serpinf1(−/−) osteoblasts are more sensitive to TGF‐β stimulation than wild‐type osteoblasts. TGF‐β stimulation and PEDF deficiency showed additive effects on transcription suppression of osteogenic markers and stimulation of pro‐angiogenic factors. Furthermore, PEDF attenuated TGF‐β‐induced expression of pro‐angiogenic factors. These data suggest that functional antagonism between PEDF and TGF‐β pathways controls osteogenesis and bone vascularization and is implicated in type VI OI pathogenesis. This antagonism may be exploited in developing therapeutics for type VI OI utilizing PEDF and TGF‐β antibody. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth. Here, we show that the inhibition of angiogenesis in vitro and in vivo and the induction of apoptosis by thrombospondin-1 all required the sequential activation of CD36, p59[sup.fyn], caspase-3 like proteases and p38 mitogen-activated protein kinases. We also detected increased endothelial cell apoptosis in situ at the margins of tumors in mice treated with thrombospondin-1. These results indicate that thrombospondin-1, and possibly other broad-spectrum natural inhibitors of angiogenesis, act in vivo by inducing receptor-mediated apoptosis in activated microvascular endothelial cells., Author(s): Benilde Jimenez [1, 4, 5]; Olga V. Volpert [1, 5]; Susan E. Crawford [1, 2]; Maria Febbraio [3]; Roy L. Silverstein [3]; Noel Bouck (corresponding author) [1] Naturally occurring [...]

A study was conducted to analyze the influence of altered transport of glucose into the hepatocyte on abnormal hepatic glucose metabolism in the intrauterine growth-retarded fetus and newborn. Glucose transport and the localization of glucose transporters protein in rat livers were examined. Results indicated that the metabolic and physiological factors that cause intrauterine-growth-retarded changes glucose transporter expression in fetal liver.

Cell growth, differentiation and immune modulation is controlled in part by the cytokine, transforming growth factor beta (TGF-beta). Although numerous studies have investigated the TGF-beta, questions about its activation still remain. To address this, the homotrimeric protein, thrombospondin-1 (TSP-1) was studied for its potential as an activator of the TGF-beta in young mouse pups. Histological comparisons of pups null for TSP-1 with pups null for TGF-1 demonstrated similar pathology for multiple organ systems. This suggests that TGF-beta activation is affected by TSP-1.

Abstract Background The extent of enhanced bone marrow angiogenesis in chronic lymphocytic leukemia (CLL) and relationship to proangiogenic factors and prognostic indicators is largely unexplored. Methods To further investigate the role of angiogenesis in CLL by evaluating the topography and extent of angiogenesis in a group of CLL bone marrow biopsies, to study the expression of pro and antiangiogenic vascular factors in CLL cells to more precisely document the cell types producing these factors, and to evaluate the role, if any, of localized hypoxia in upregulation of angiogenesis in CLL We used immunohistochemistry (IHC) (n = 21 pts) with antibodies to CD3 and CD20, proangiogenic (VEGF, HIF-1a) and antiangiogenic (TSP-1) factors, and VEGF receptors -1 and -2 to examine pattern/extent of CLL marrow involvement, microvessel density (MVD), and angiogenic characteristics; flow cytometry (FC) was performed on 21 additional cases for VEGF and TSP-1. Results CLL patients had higher MVD (23.8 vs 14.6, p~0.0002) compared to controls (n = 10). MVD was highest at the periphery of focal infiltrates, was not enhanced in proliferation centers, and was increased irrespective of the presence or absence of cytogenetic/immunophenotypic markers of aggressivity. By IHC, CLL cells were VEGF(+), HIF-1a (+), TSP-1(-), VEGFR-1(+), and VEGFR-2(+). By FC, CLL cells were 1.4–2.0-fold brighter for VEGF than T cells and were TSP-1(-). Conclusion CLL demonstrates enhanced angiogenesis, with increased MVD, upregulated VEGF and downregulated TSP-1. Upregulation of HIF-1a in all CLL cases suggests localized tissue hypoxia as an important stimulant of microvessel proliferation. The presence of VEGF receptors on CLL cells implies an autocrine effect for VEGF. Differences in MVD did not correlate with traditional genetic/immunophenotypic markers of aggressiveness.