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Search Results: 1 - 10 of 145799 matches for " Solomon F. Ofori-Acquah "
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Spatiotemporal Dysfunction of the Vascular Permeability Barrier in Transgenic Mice with Sickle Cell Disease
Samit Ghosh,Fang Tan,Solomon F. Ofori-Acquah
Anemia , 2012, DOI: 10.1155/2012/582018
Abstract: Sickle cell disease (SCD) is characterized by chronic intravascular hemolysis that generates excess cell-free hemoglobin in the blood circulation. Hemoglobin causes multiple endothelial dysfunctions including increased vascular permeability, impaired reactivity to vasoactive agonists, and increased adhesion of leukocytes to the endothelium. While the adhesive and vasomotor defects of SCD associated with cell-free hemoglobin are well defined, the vascular permeability phenotype remains poorly appreciated. We addressed this issue in two widely used and clinically relevant mouse models of SCD. We discovered that the endothelial barrier is normal in most organs in the young but deteriorates with aging particularly in the lung. Indeed, middle-aged sickle mice developed pulmonary edema revealing for the first time similarities in the chronic permeability phenotypes of the lung in mice and humans with SCD. Intravenous administration of lysed red blood cells into the circulation of sickle mice increased vascular permeability significantly in the lung without impacting permeability in other organs. Thus, increased vascular permeability is an endothelial dysfunction of SCD with the barrier in the lung likely the most vulnerable to acute inflammation.
Spatiotemporal Dysfunction of the Vascular Permeability Barrier in Transgenic Mice with Sickle Cell Disease
Samit Ghosh,Fang Tan,Solomon F. Ofori-Acquah
Anemia , 2012, DOI: 10.1155/2012/582018
Abstract: Sickle cell disease (SCD) is characterized by chronic intravascular hemolysis that generates excess cell-free hemoglobin in the blood circulation. Hemoglobin causes multiple endothelial dysfunctions including increased vascular permeability, impaired reactivity to vasoactive agonists, and increased adhesion of leukocytes to the endothelium. While the adhesive and vasomotor defects of SCD associated with cell-free hemoglobin are well defined, the vascular permeability phenotype remains poorly appreciated. We addressed this issue in two widely used and clinically relevant mouse models of SCD. We discovered that the endothelial barrier is normal in most organs in the young but deteriorates with aging particularly in the lung. Indeed, middle-aged sickle mice developed pulmonary edema revealing for the first time similarities in the chronic permeability phenotypes of the lung in mice and humans with SCD. Intravenous administration of lysed red blood cells into the circulation of sickle mice increased vascular permeability significantly in the lung without impacting permeability in other organs. Thus, increased vascular permeability is an endothelial dysfunction of SCD with the barrier in the lung likely the most vulnerable to acute inflammation. 1. Introduction Sickle cell disease (SCD) is characterized by the production of red blood cells with increased propensity for lysis and adhesion [1]. Its clinical manifestations fall broadly into two subphenotypes defined by hyperhemolysis and vasoocclusion [2]. At least 30% of the hemolysis in SCD is intravascular [3], which means that the endothelial wall in this disease is persistently exposed to cell-free hemoglobin. The endothelium is a semipermeable barrier that regulates the response of the vascular wall to inflammatory agonists. This response involves activation of adhesion molecule expression, increased permeability of the endothelium, and extravasations of fluid from the blood into interstitial tissue compartments [4]. Increased vascular permeability results from opening of gaps at sites of endothelial cell-cell contacts. There are multiple indicators of systemic inflammation in SCD [5]. In addition, markers of vascular inflammation have also been documented [6–8]. There is increased expression of adhesion molecules in the pulmonary endothelium of the Berkeley sickle mice [9], although the histology of these same mice shows less severe inflammatory and ischemic changes and no evidence of pneumonia [10]. Nonetheless, they spontaneously develop pulmonary hypertension [11], which is a major problem in SCD
Essential role for ALCAM gene silencing in megakaryocytic differentiation of K562 cells
Fang Tan, Samit Ghosh, Flaubert Mbeunkui, Robert Thomas, Joshua A Weiner, Solomon F Ofori-Acquah
BMC Molecular Biology , 2010, DOI: 10.1186/1471-2199-11-91
Abstract: In this study, we show that ALCAM expression is silenced in erythromegakaryocytic progenitor cell lines. In agreement with this finding, the ALCAM promoter is occupied by GATA-1 in vivo, and a cognate motif at -850 inhibited promoter activity in K562 and MEG-01 cells. Gain-of-function studies showed that ALCAM clusters K562 cells in a process that requires PKC. Induction of megakaryocytic differentiation in K562 clones expressing ALCAM activated PKC-δ and triggered apoptosis.There is a lineage-specific silencing of ALCAM in bi-potential erythromegakaryocytic progenitor cell lines. Marked apoptosis of ALCAM-expressing K562 clones treated with PMA suggests that aberrant ALCAM expression in erythromegakaryocytic progenitors may contribute to megakaryocytopenia.Hematopoiesis is controlled by interactions between hematopoietic stem cells and their microenvironment. These interactions influence retention of stem cells in specific niches, and stem and progenitor cell expansion, lineage divergence and differentiation [1]. Adhesion molecules are major regulators of cell-cell interactions and they influence multiple aspects of hematopoiesis [1-4]. Indeed, antibodies against various adhesion molecules including VLA-4 and VCAM-1 inhibit the ability of hematopoietic stem cells to populate the bone marrow of irradiated mice [5], and gene knock-out studies of integrins have shown their critical role in homing and colonization of late-stage primary hematopoietic organs such as the embryonic liver [6,7]. More recently, N-cadherin expression has been implicated in retention of hematopoietic stem cells in the bone marrow niche [8-10] although this claim is not supported by other studies [11]. In contrast to their role in homing, our understanding of adhesion molecule biology in lineage commitment and differentiation is poorly defined.Hematopoietic cell antigen, also known as activated leukocyte cell adhesion molecule (ALCAM/CD166), is a member of the immunoglobulin super-family. It is
Sickle Cell Disease: Genetics, Cellular and Molecular Mechanisms, and Therapies
Betty S. Pace,Solomon F. Ofori-Acquah,Kenneth R. Peterson
Anemia , 2012, DOI: 10.1155/2012/143594
Abstract:
Sickle Cell Disease: Genetics, Cellular and Molecular Mechanisms, and Therapies
Betty S. Pace,Solomon F. Ofori-Acquah,Kenneth R. Peterson
Anemia , 2012, DOI: 10.1155/2012/143594
Abstract:
Global Gene Expression Profiling of Endothelium Exposed to Heme Reveals an Organ-Specific Induction of Cytoprotective Enzymes in Sickle Cell Disease
Samit Ghosh,Fang Tan,Tianwei Yu,Yuhua Li,Olufolake Adisa,Mario Mosunjac,Solomon F. Ofori-Acquah
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018399
Abstract: Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion and ischemia reperfusion injury. These events cause endothelial dysfunction and vasculopathies in multiple systems. However, the lack of atherosclerotic lesions has led to the idea that there are adaptive mechanisms that protect the endothelium from major vascular insults in SCD patients. The molecular bases for this phenomenon are poorly defined. This study was designed to identify the global profile of genes induced by heme in the endothelium, and assess expression of the heme-inducible cytoprotective enzymes in major organs impacted by SCD.
Elevated Circulating Angiogenic Progenitors and White Blood Cells Are Associated with Hypoxia-Inducible Angiogenic Growth Factors in Children with Sickle Cell Disease
Solomon F. Ofori-Acquah,Iris D. Buchanan,Ifeyinwa Osunkwo,Jerry Manlove-Simmons,Feyisayo Lawal,Alexander Quarshie,Arshed A. Quyyumi,Gary H. Gibbons,Beatrice E. Gee
Anemia , 2012, DOI: 10.1155/2012/156598
Abstract: We studied the number and function of angiogenic progenitor cells and growth factors in children aged 5–18 years without acute illness, 43 with Hemoglobin SS and 68 with normal hemoglobin. Hemoglobin SS subjects had at least twice as many mononuclear cell colonies and more circulating progenitor cell than Control subjects. Plasma concentrations of erythropoietin, angiopoietin-2, and stromal-derived growth factor (SDF)-1α were significantly higher in children with Hemoglobin SS compared to Control subjects. In a multivariate analysis model, SDF-1α concentration was found to be associated with both CPC number and total white blood cell count in the Hemoglobin SS group, suggesting that SDF-1α produced by ischemic tissues plays a role in mobilizing these cells in children with Hemoglobin SS. Despite having a higher number of angiogenic progenitor cells, children with Hemoglobin SS had slower migration of cultured mononuclear cells.
Heme Mediated STAT3 Activation in Severe Malaria
Mingli Liu, Audu S. Amodu, Sidney Pitts, John Patrickson, Jacqueline M. Hibbert, Monica Battle, Solomon F. Ofori-Acquah, Jonathan K. Stiles
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034280
Abstract: Background The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated. Methods We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line. Results The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling. Conclusion Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria.
Activated leukocyte cell adhesion molecule in breast cancer: prognostic indicator
Judy A King, Solomon F Ofori-Acquah, Troy Stevens, Abu-Bakr Al-Mehdi, Oystein Fodstad, Wen G Jiang
Breast Cancer Research , 2004, DOI: 10.1186/bcr815
Abstract: The immunohistochemical distribution and location of ALCAM was assessed in normal breast tissue and carcinoma. The levels of ALCAM transcripts in frozen tissue (normal breast, n = 32; breast cancer, n = 120) were determined using real-time quantitative PCR. The results were then analyzed in relation to clinical data including the tumor type, the grade, the nodal involvement, distant metastases, the tumor, node, metastasis (TNM) stage, the Nottingham Prognostic Index (NPI), and survival over a 6-year follow-up period.Immunohistochemical staining on tissue sections in ducts/acini in normal breast and in breast carcinoma was ALCAM-positive. Differences in the number of ALCAM transcripts were found in different types of breast cancer. The level of ALCAM transcripts was lower (P = 0.05) in tumors from patients who had metastases to regional lymph nodes compared with those patients without, in higher grade tumors compared with Grade 1 tumors (P < 0.01), and in TNM Stage 3 tumors compared with TNM Stage 1 tumors (P < 0.01). Tumors from patients with poor prognosis (with NPI > 5.4) had significantly lower levels (P = 0.014) of ALCAM transcripts compared with patients with good prognosis (with NPI < 3.4), and tumors from patients with local recurrence had significantly lower levels than those patients without local recurrence or metastases (P = 0.04). Notably, tumors from patients who died of breast cancer had significantly lower levels of ALCAM transcripts (P = 0.0041) than those with primary tumors but no metastatic disease or local recurrence. Patients with low levels of ALCAM transcripts had significantly (P = 0.009) more incidents (metastasis, recurrence, death) compared with patients with primary breast tumors with high levels of ALCAM transcripts.In the present panel of breast cancer specimens, decreased levels of ALCAM correlated with the nodal involvement, the grade, the TNM stage, the NPI, and the clinical outcome (local recurrence and death). The data suggest that
Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer
Judy A King, Fang Tan, Flaubert Mbeunkui, Zachariah Chambers, Sarah Cantrell, Hairu Chen, Diego Alvarez, Lalita A Shevde, Solomon F Ofori-Acquah
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-266
Abstract: A common site for transcription initiation of the ALCAM gene was identified and the ALCAM promoter sequenced. The promoter contains multiple cis-active elements including a functional p65 NF-κB motif, and it harbors an extensive array of CpG residues highly methylated exclusively in ALCAM-negative tumor cells. These CpG residues were modestly demethylated after 5-aza-2-deoxycytidine treatment. Restoration of high-level ALCAM expression using an ALCAM cDNA increased clustering of MDA-MB-435 tumor cells perfused through the pulmonary vasculature of ventilated rat lungs. Anti-ALCAM antibodies reduced the number of intravascular tumor cell clusters.Our data suggests that loss of ALCAM expression, due in part to DNA methylation of extensive segments of the promoter, significantly impairs the ability of circulating tumor cells to adhere to each other, and may therefore promote metastasis. These findings offer insight into the mechanisms for down-regulation of ALCAM gene expression in tumor cells, and for the positive prognostic value of high-level ALCAM in breast cancer.ALCAM/CD166 is an immunoglobulin cell adhesion molecule expressed by neuronal, endothelial, hematopoietic and epithelial cells [1-13]. It's up-regulation in cancer was first identified at the RNA level in melanoma cell lines as memD [14]. Subsequently, increased ALCAM expression was found in melanoma tumors in situ [13,15]. More widespread deregulation of ALCAM expression has since been reported in several other tumors including those of the prostate [16,17], esophagus [18], colon [19], bladder [20] and pancreas [21]. Alterations in ALCAM expression in tumors have recently been reviewed by Ofori-Acquah and King [22].In a study of primary breast cancer tissues and non-neoplastic mammary tissue from the same mastectomies, we discovered that the level of ALCAM transcripts was lower in breast cancer tissues from patients who had metastases to regional lymph nodes [23], and that primary tumors from patients who
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