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Suppipat K.,Texas Childrens Cancer and Hematology Centers | Daniel Lacorazza H.,Baylor College of Medicine
Current Cancer Drug Targets | Year: 2014

The extensive use of the same chemotherapeutics over several decades has resulted in a growing incidence of chemoresistant cancer cells and secondary malignancies. Therefore, there is an increasing need for new drugs to treat high-risk cancer patients with a higher selectivity for cancer cells and lower toxicity to normal cells. Sulforaphane is released upon hydrolysis of glucoraphanin, a constituent of cruciferous vegetables, by myrosinases that are present in the plant or intestinal microbes. Despite a large number of studies describing the chemopreventive and chemotherapeutic properties of sulforaphane in solid tumors, there is little information on the properties of sulforaphane in hematological malignancies. In this review, we discuss the anti-carcinogenic properties of sulforaphane, the need of higher doses than dietary intake, and the challenges related to testing sulforaphane as an adjunctive agent in combination with the current standard of care for frontline blood cancer. © 2014 Bentham Science Publishers. Source

Goldenberg N.A.,Johns Hopkins University | Goldenberg N.A.,Johns Hopkins Hospital | Takemoto C.M.,Johns Hopkins University | Yee D.L.,Baylor College of Medicine | And 3 more authors.
Blood | Year: 2015

Venous thromboembolism (VTE) is increasingly diagnosed in pediatric patients, andanticoagulantusein thispopulationhas become common, despite the absence of US Food and Drug Administration (FDA) approval for this indication. Guidelines for the use of anticoagulants in pediatrics are largely extrapolated from large randomized controlled trials (RCTs) in adults, smaller dose-finding and observational studies in children, and expert opinion. The recently FDA-approved direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban, provide potential advantages over oral Vitamin K antagonists and subcutaneous low-molecular-weight heparins (LMWHs). However, key questions arise regarding their potential off-label clinical application inpediatric thromboembolic disease. In this Perspective, we provide background on the use of LMWHssuch as enoxaparin as the mainstay of treatment of pediatric provoked VTE; identify key questions and challenges with regard to DOAC trials and future DOAC therapy in pediatric VTE; and discuss applicable lessons learned from the recent pilot/feasibility phase of a large multicenter RCT of anticoagulant duration in pediatric VTE. The challenges and lessons learned present opportunities to improve evidence for anticoagulant therapies in pediatric VTE through future clinical trials. © 2015 by The American Society of Hematology. Source

Sartain S.E.,Texas Childrens Cancer and Hematology Centers | Sartain S.E.,Baylor College of Medicine | Turner N.A.,Rice University | Moake J.L.,Rice University
Journal of Immunology | Year: 2016

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe renal injury secondary to an overactive alternative complement pathway (AP). AHUS episodes are often initiated or recur during inflammation. We investigated gene expression of the surface complement regulatory proteins (CD55, CD59, CD46, and CD141 [thrombomodulin]) and AP components in human glomerular microvascular endothelial cells (GMVECs) and in HUVECs, a frequently used investigational model of endothelial cells. Surface complement regulatory proteins were also quantified by flow cytometry. All experiments were done with and without exposure to IL-1β or TNF. Without cytokine stimulation, we found that GMVECs had greater AP activation than did HUVECs. With TNF stimulation, THBD gene expression and corresponding CD141 surface presence in HUVECs and GMVECs were reduced, and gene expression of complement components C3 (C3) and factor B (CFB) was increased. Consequently, AP activation, measured by Ba production, was increased, and conversion of protein C (PC) to activated PC by CD141-bound thrombin was decreased, in GMVECs and HUVECs exposed to TNF. IL-1β had similar, albeit lesser, effects on HUVEC gene expression, and it only slightly affected GMVEC gene expression. To our knowledge, this is the first detailed study of the expression/display of AP components and surface regulatory proteins in GMVECs with and without cytokine stimulation. In aHUS patients with an underlying overactive AP, additional stimulation of the AP and inhibition of activated PC-mediated anticoagulation in GMVECs by the inflammatory cytokine TNF are likely to provoke episodes of renal failure. © 2016 by The American Association of Immunologists, Inc. Source

Turner N.A.,Rice University | Sartain S.E.,Texas Childrens Cancer and Hematology Centers | Sartain S.E.,Baylor College of Medicine | Hui S.-K.,Baylor College of Medicine | And 2 more authors.
PLoS ONE | Year: 2015

It was recently reported that factor H, a regulatory component of the alternative complement pathway, is stored with von Willebrand factor (VWF) in the Weibel-Palade bodies of endothelial cells. If this were to be the case, it would have therapeutic importance for patients with the atypical hemolytic-uremic syndrome that can be caused either by a heterozygous defect in the factor H gene or by the presence of an autoantibody against factor H. The in vivo Weibel-Palade body secretagogue, des-amino-D-arginine vasopressin (DDAVP), would be expected to increase transiently the circulating factor H levels, in addition to increasing the circulating levels of VWF. We describe experiments demonstrating that factor H is released from endothelial cell cytoplasm without a secondary storage site. These experiments showed that factor H is not stored with VWF in endothelial cell Weibel-Palade bodies, and is not secreted in response in vitro in response to the Weibel-Palade body secretagogue, histamine. Furthermore, the in vivo Weibel-Palade body secretagogue, DDAVP does not increase the circulating factor H levels concomitantly with DDAVP-induced increased VWF. Factor I, a regulatory component of the alternative complement pathway that is functionally related to factor H, is also located in endothelial cell cytoplasm, and is also not present in endothelial cell Weibel-Palade bodies. Our data demonstrate that the factor H and factor I regulatory proteins of the alternative complement pathway are not stored in Weibel-Palade bodies. DDAVP induces the secretion into human plasma of VWF - but not factor H. © 2015 Turner et al. Source

Darby J.B.,Section of Hospital Medicine | Liddell L.,Baylor College of Medicine | DeGuzman M.,Section of Immunology | McClain K.L.,Texas Childrens Cancer and Hematology Centers | And 4 more authors.
Pediatrics | Year: 2015

A 2-year-old female presents for evaluation of 4 weeks of daily fevers. When the fevers began, she had mild upper respiratory tract symptoms, which quickly resolved. The fevers persisted, however, with a maximum of 40°C. The child's review of symptoms was significant for a 1-kg weight loss over the past month. Ten months before presentation, she had moved from Saudi Arabia with her family. One week before the onset of symptoms, she had visited a petting zoo. During episodes of fever, the patient was ill-appearing and had an elevated heart rate and respiratory rate. On examination, she was found to be thin, febrile, tachycardic, and with scattered lymphadenopathy. Results of laboratory tests were remarkable for an elevated white blood cell count of 16 100 cells per uL with a neutrophilic predominance. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated at 99 mm/h and 27 mg/dL, respectively. A chest radiograph indicated a small amount of fluid in the interlobar fissures. Our expert panel examines her case, offers a definition of fever of unknown origin, and makes diagnostic considerations. Copyright © 2015 by the American Academy of Pediatrics. Source

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