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Robinson K.E.,Vanderbilt University | Fraley C.E.,Vanderbilt University | Pearson M.M.,Vanderbilt University | Kuttesch Jr. J.F.,Penn State Hershey Childrens Hospital | Compas B.E.,Vanderbilt University
Journal of the International Neuropsychological Society | Year: 2013

Deficits in neurocognitive functioning are an important area of late effects in survivors of pediatric brain tumors; however, a quantitative analysis of the magnitude of these deficits in survivors of brain tumors of the posterior fossa has not been conducted. Despite tumor locations in the posterior regions of the brain, individual studies have documented deficits in a variety of domains, reflective of impairment in other brain regions. The current study provides a comprehensive meta-analysis of literature on neurocognitive late effects found in survivors of posterior fossa tumors. Results indicated significant deficits in both specific and broad indices of neurocognitive functioning, and the overall magnitude of effects across domains ranged from medium to large (g = -0.62 to -1.69) with a large mean overall effect size (g = -1.03). Moderator analyses indicated significantly greater effects for survivors diagnosed at a younger age and those who received radiation therapy. These findings underscore the importance of monitoring neurocognitive late effects in survivors of pediatric brain tumors of the posterior fossa, as well as the need for more consistent consideration of demographic, diagnostic, and treatment-related variables to allow for examination of factors that moderate these deficits. Copyright © 2012 The International Neuropsychological Society.

Gunay-Aygun M.,National Human Genome Research Institute | Gunay-Aygun M.,U.S. National Institutes of Health | Falik-Zaccai T.C.,Institute of Human Genetics | Falik-Zaccai T.C.,Technion - Israel Institute of Technology | And 23 more authors.
Nature Genetics | Year: 2011

Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder that is characterized by large platelets that lack γ-granules. Here we show that mutations in NBEAL2 (neurobeachin-like 2), which encodes a BEACH/ARM/WD40 domain protein, cause GPS and that megakaryocytes and platelets from individuals with GPS express a unique combination of NBEAL2 transcripts. Proteomic analysis of sucrose-gradient subcellular fractions of platelets indicated that NBEAL2 localizes to the dense tubular system (endoplasmic reticulum) in platelets. © 2011 Nature America, Inc. All rights reserved.

Popernack M.L.,Penn State Hershey Childrens Hospital | Gray N.,Duke University | Reuter-Rice K.,Duke University
Journal of Pediatric Health Care | Year: 2015

Traumatic brain injury (TBI) is the leading cause of death in children in the United States. Each year 37,200 children sustain a severe TBI, with up to 1.3 million life-years potentially adversely affected. Severe pediatric TBI is associated with significant mortality and morbidity. Of the children who survive their injury, more than 50% experience unfavorable outcomes 6 months after the injury. Although TBI-associated death rates decreased between 1997-2007, disabilities for TBI survivors continue to have both a direct and indirect impact on the economic and human integrity of our society. The degree of disability varies with the severity and mechanism of the injury, but a realm of physical and emotional deficits may be evident for years after the injury occurs. This article describes the pathophysiology of moderate to severe TBI, its associated complications, and opportunities to improve patient outcomes through use of acute management and rehabilitation strategies. To address the many challenges for TBI survivors and their families, including significant financial and emotional burdens, a collaborative effort is necessary to help affected children transition seamlessly from acute care through long-term rehabilitation. © 2015 National Association of Pediatric Nurse Practitioners.

Krishnadas D.K.,University of Louisville | Bao L.,Penn State Hershey Childrens Hospital | Bai F.,University of Louisville | Chencheri S.C.,University of Louisville | Lucas K.,University of Louisville
Tumor Biology | Year: 2014

Rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma are the most common types of sarcoma in children. Despite standard therapy, nearly one third of the patients with Ewing's sarcoma relapse, and there are limited options with curative potential. Immunotherapy is a promising approach as it can target tumor-specific antigens that are specifically expressed on tumors while sparing non-malignant cells. We have demonstrated that a demethylating chemotherapeutic drug, 5-aza-2'-deoxycytidine (decitabine, DAC) can upregulate the expression of cancer-testis (CT) antigens, MHC molecules, and intracellular cell adhesion molecule-1 on pediatric sarcoma cell lines, resulting in enhanced killing of tumor cells by CT antigen-specific cytotoxic T lymphocytes derived from pediatric sarcoma patients. A significant increase in the mRNA expression levels of MAGE-A1 and MAGE-A3 were found in 70 %, and NY-ESO-1 in 80 % of the sarcoma lines following exposure to pharmacological levels of DAC. The high expression levels of MAGE-A1, MAGE-A3, and NY-ESO-1 were sustained in sarcoma lines and primary tumor lines over 30 days after the cessation of DAC. Furthermore, DAC treatment induced upregulation of MAGE-A1, MAGE-A3, or NY-ESO-1 protein expression in seven of nine lines studied. These studies show that demethylating chemotherapy could be combined with CT antigen-directed immunotherapy for treating pediatric sarcoma. © 2014 International Society of Oncology and BioMarkers (ISOBM).

Halstead E.S.,Penn Medicine | Carcillo J.A.,Childrens Hospital of Pittsburgh | Schilling B.,University of Duisburg - Essen | Greiner R.J.,Penn State Hershey Childrens Hospital | Whiteside T.L.,University of Pittsburgh
Pediatric Research | Year: 2013

Background:Sepsis continues to be a leading cause of death in infants and children. Natural killer (NK) cells serve as a bridge between innate and adaptive immunity, yet their role in pediatric sepsis has not been well characterized.Methods:We tested the hypothesis that decreased NK cell cytotoxicity is a common feature of pediatric systemic inflammatory response syndrome (SIRS)/sepsis patients by measuring, using flow cytometry, NK cell cytotoxicity and cell surface phenotype in the peripheral blood of 38 pediatric intensive care patients who demonstrated signs and symptoms of SIRS and/or sepsis.Results:NK cell cytotoxicity was significantly reduced in peripheral blood mononuclear cells (PBMCs) of pediatric SIRS/sepsis patients as compared with healthy controls, and the percentage of CD56 dim CD16 + cytotoxic NK cells in PBMCs was lower in patients with SIRS/sepsis than in normal donors. However, on a per cell basis, CD56 dim CD16 + NK cells in patients mediated cytotoxicity as well as those in normal donors.Conclusion:The NK cell dysfunction in pediatric SIRS/sepsis patients reflects a quantitative rather than a qualitative difference from healthy controls. Copyright © 2013 International Pediatric Research Foundation, Inc.

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