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Alderfer M.A.,Childrens Hospital of Philadelphia | Long K.A.,University of Pittsburgh | Lown E.A.,San Francisco State University | Marsland A.L.,University of Pittsburgh | And 3 more authors.

Objectives: To promote a broader understanding of the psychosocial impact of childhood cancer on siblings, a systematic review was undertaken. Directions for future research are proposed and clinical strategies are suggested for addressing the needs of these children. Methods: Searches of Medline, PsycINFO and CINAHL revealed 65 relevant qualitative, quantitative, or mixed methods' papers published between 1997 and 2008. These papers were rated for scientific merit and findings were extracted for summary. Results: Siblings of children with cancer do not experience elevated mean rates of psychiatric disorders, but a significant subset experiences post-traumatic stress symptoms, negative emotional reactions (e.g. shock, fear, worry, sadness, helplessness, anger, and guilt), and poor quality of life in emotional, family, and social domains. In general, distress is greater closer to time of diagnosis. School difficulties are also evident within 2 years of diagnosis. Qualitative studies reveal family-level themes such as loss of attention and status as well as positive outcomes including increased sibling maturity and empathy. Conclusions: Research regarding siblings of children with cancer continues to be methodologically limited. The conclusions of qualitative and quantitative studies differ considerably. We propose a research agenda to propel this field forward including greater attention to alterations in normative development (as opposed to psychiatric conditions), development of more appropriate quantitative measures, examination of potential moderators of adaptation, and use of prospective longitudinal designs. Siblings of children with cancer are a psychosocially at-risk group and should be provided with appropriate supportive services. Copyright © 2009 John Wiley & Sons, Ltd. Source

Ma J.,University of Sichuan | Li M.,University of Sichuan | Hock J.,Maine Institute for Human Genetics and Health | Yu X.,University of Sichuan
Journal of Orthopaedic Research

Individuals with nerofibromatosis Type 1 (NF1) frequently suffer a spectrum of bone pathologies, such as abnormal skeletal development (scoliosis, congenital bowing, and congenital pseudoarthroses, etc), lower bone mineral density with increased fracture risk. These skeletal problems may result, in part, from abnormal osteoclastogenesis. Enhanced RAS/PI3K activity has been reported to contribute to abnormal osteoclastogenesis in Nf1 heterozygous (Nf1+/-) mice. However, the specific downstream pathways linked to NF1 abnormal osteoclastogenesis have not been defined. Our aim was to determine whether mammalian target of rapamycin (mTOR) was a key effector responsible for abnormal osteoclastogenesis in NF1. Primary osteoclast-like cells (OCLs) were cultured from Nf1 wild-type (Nf1+/+) and Nf1+/- mice. Compared to Nf1+/+ controls, there were 20% more OCLs induced from Nf1+/- mice. Nf1+/- OCLs were larger and contained more nuclei. Hyperactive mTOR signaling was detected in Nf1+/- OCLs. Inhibition of mTOR signaling by rapamycin in Nf1+/- OCLs abrogated abnormalities in cellular size and number. Moreover, we found that hyperactive mTOR signaling induced abnormal osteoclastogenesis major through hyper-proliferation. Our research suggests that neurofibromin directly regulates osteoclastogenesis through mTOR signaling pathway. Inhibiting mTOR may represent a viable strategy to treat NF1 bone diseases. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:144-152, 2012 Copyright © 2011 Orthopaedic Research Society. Source

Chen Y.,University of Massachusetts Medical School | Sullivan C.,Maine Institute for Human Genetics and Health | Peng C.,University of Massachusetts Medical School | Shan Y.,University of Massachusetts Medical School | And 3 more authors.

We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5-/- LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5-/- LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and β-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML. © 2011 by The American Society of Hematology. Source

Little K.M.,La Jolla Institute for Allergy and Immunology | Little K.M.,University of Virginia | Smalley D.M.,Maine Institute for Human Genetics and Health | Ley K.,La Jolla Institute for Allergy and Immunology
Seminars in Thrombosis and Hemostasis

All cell types shed ectosomes and exosomes, collectively known as microparticles (MP; 0.1 to 1.5 m in diameter), when activated or stressed; normal human plasma contains ∼2 g MP protein/mL. The cellular composition of plasma MP is altered in many diseases, including acute coronary syndrome, diabetes mellitus, sepsis, and sickle cell disease. We measured the plasma MP protein composition of 42 patients (median age 69.5 years, most with cardiovascular disease) by label-free liquid chromatography coupled to tandem mass spectrometry. Among 458 proteins detected with high confidence (identified by at least two unique peptides with SEQUEST XCor (Thermo Electron Corp., San Jose, CA) 2.0, 2.2, and 3.3 for charge states +1, +2, and +3, respectively), 130 were present in most patients, representing a core set of plasma MP proteins. This core is enriched in cytoskeletal, integrin complex, and hemostasis proteins, and spectral counts of several proteins correlate with patient age and gender. We conclude that the MP proteome may be a useful and reliable source of biologically relevant disease biomarkers. Copyright © 2010 by Thieme Medical Publishers, Inc. Source

Sullivan C.,Maine Institute for Human Genetics and Health | Peng C.,University of Massachusetts Medical School | Chen Y.,University of Massachusetts Medical School | Li D.,Edith Cowan University | Li S.,University of Massachusetts Medical School
Biochemical Pharmacology

Inhibition of BCR-ABL with kinase inhibitors has become a well-accepted strategy for targeted therapy of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) and has been shown to be highly effective in controlling the disease. However, BCR-ABL kinase inhibitors do not efficiently kill leukemic stem cells (LSCs), indicating that this therapeutic strategy does not lead to a cure of CML. Development of curative therapies of CML require the identification of genes/pathways that play critical roles in survival and self-renewal of LSCs. Targeting of these key BCR-ABL downstream genes provides an opportunity to eradicate LSCs, as shown in our work that identifies the Alox5 gene as a key regulator of the function of CML LSCs. Immediate clinical trials are necessary to test the effectiveness of targeting a key BCR-ABL downstream gene in eradicating LSCs in CML patients. In this review, we will discuss current targeted therapies of CML using BCR-ABL kinase inhibitors, with a focus on the importance of developing a targeted therapy of CML through identification of target genes in CML LSCs. © 2010 Elsevier Inc. Source

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