Lin C.H.,Choc Childrens Hospital |
Lin C.H.,University of California at Irvine |
Ji T.,University of California at Irvine |
Ji T.,Peking University |
And 3 more authors.
Advances in Experimental Medicine and Biology | Year: 2014
Osteosarcoma (OS) is the most common primary bone malignancy diagnosed in children and adolescents with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the last two decades. With current treatments, 60–70 % of patients with localized disease survive. Given a propensity of Wnt signaling to control multiple cellular processes, including proliferation, cell fate determination, and differentiation, it is a critical pathway in OS disease progression. At the same time, this pathway is extremely complex with vast arrays of cross-talk. Even though decades of research have linked the role of Wnt to tumorigenesis, there are still outstanding areas that remain poorly understood and even controversial. The canonical Wnt pathway functions to regulate the levels of the transcriptional co-activator β-catenin, which ultimately controls key developmental gene expressions. Given the central role of this mediator, inhibition of Wnt/β- catenin signaling has been investigated as a potential strategy for cancer control. In OS, several secreted protein families modulate the Wnt/β-catenin signaling, including secreted Frizzled-related proteins (sFRPs), Wnt inhibitory protein (WIF), Dickkopf proteins (DKK-1,2,3), sclerostin, and small molecules. This chapter focuses on our current understanding of Wnt/β-catenin signaling in OS, based on recent in vitro and in vivo data. Wnt activates noncanonical signaling pathways as well that are independent of β-catenin which will be discussed. In addition, stem cells and their association with Wnt/β-catenin are important factors to consider. Ultimately, the multiple canonical and noncanonical Wnt/β-catenin agonists and antagonists need to be further explored for potential targeted therapies. © Springer International Publishing Switzerland 2014.
Ji T.,University of California at Irvine |
Ji T.,Peking University |
Lin C.,University of California at Irvine |
Lin C.,CHOC Childrens Hospital |
And 5 more authors.
Molecular Cancer | Year: 2013
Background: Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Limited by the severe toxicity of conventional agents, the therapeutic bottleneck of osteosarcoma still remains unconquered. Flavokawain B (FKB), a kava extract, has been reported to have significant anti-tumor effects on several carcinoma cell lines both in vitro and in vivo. Its efficacy and low toxicity profile make FKB a promising agent for use as a novel chemotherapeutic agent.Results: In the current study, we investigated the anti-proliferative and apoptotic effects of FKB against human osteosarcomas. Exposure of OS cells to FKB resulted in apoptosis, evidenced by loss of cell viability, morphological changes and the externalization of phosphatidylserine. Apoptosis induced by FKB resulted in activation of Caspase-3/7, -8 and -9 in OS cell lines, 143B and Saos-2. FKB also down-regulated inhibitory apoptotic markers, including Bcl-2 and Survivin and led to concomitant increases in apoptotic proteins, Bax, Puma and Fas. Therefore, the induction of apoptosis by FKB involved both extrinsic and intrinsic pathways. FKB also caused G2/M phase cell cycle arrest, which was observed through reductions in the levels of cyclin B1, cdc2 and cdc25c and increases in Myt1 levels. Furthermore, migration and invasion ability was decreased by FKB in a dose-dependent manner. The cytotoxicity profile showed FKB had significant lower side effects on bone marrow cells and small intestinal epithelial cells compared with Adriamycin.Conclusions: Taken together, our evidence of apoptosis and cell cycle arrest by FKB treatment with less toxicity than the standard treatments provides an innovative argument for the use of FKB as a chemotherapeutic and chemopreventive compound. In vivo experiments utilizing FKB to reduce tumorigenesis and metastatic potential will be crucial to further justify clinical application. © 2013 Ji et al.; licensee BioMed Central Ltd.
Merchant D.C.,California State University, Fullerton |
Merchant D.C.,CHOC Childrens Hospital
Journal for Nurses in Staff Development | Year: 2012
This literature review found that current evidence supports high-fidelity simulation as leading to enhance teamwork and crisis management skills of healthcare providers. High-fidelity simulation should be considered as a strategy in staff development efforts to enhance safe delivery of patient interventions and professional competencies in high-risk, low-incidence clinical situations among practicing nurses. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams &Wilkins.
Kunicki T.J.,CHOC Childrens Hospital |
Kunicki T.J.,Scripps Research Institute |
Williams S.A.,CHOC Childrens Hospital |
Nugent D.J.,CHOC Childrens Hospital |
And 2 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012
Objective-: The interindividual variation in platelet α 2β 1 exceeds a 2-fold variance in platelet α IIbβ 3 level. Our Objective was to parse the contribution of mean platelet volume (MPV) and integrin gene alleles to this variation in large cohorts of patients with acute coronary syndrome (ACS) and normal subjects. Methods and Results-: Platelet α IIbβ 3 and α 2β 1 levels were measured by flow cytometry in whole blood from 320 ACS patients and 128 normal subjects and compared with MPV, platelet count, ITGA2 rs1126643, and ITGB3 rs5918 alleles. In all subjects, a strong direct correlation was found between MPV and α IIbβ 3 level (P<0.001). Neither MPV nor α IIbβ 3 level correlated with ITGB3 rs5918 alleles. In the case of α 2β 1 level, MPV contributed modestly, whereas ITGA2 rs1126643 exerted a greater effect. An inverse correlation was found between MPV and the rs1126643 minor allele. Conclusion-: MPV is the major effector of platelet α IIbβ 3 level, whereas the ITGA2 rs1126643 alleles influence α 2β 1 level more than MPV does. The rs1126643 minor allele, associated with lower MPV, likely exerts this effect via the influence of α 2β 1 on megakaryocyte maturation. Because of the hyperactivity of larger platelets, MPV is an accurate metric of risk for adverse outcome in ACS. © 2011 American Heart Association, Inc.
Buchbinder D.,CHOC Childrens Hospital |
Hsieh L.,CHOC Childrens Hospital |
Krance R.,Texas Childrens Hospital |
Nugent D.J.,CHOC Childrens Hospital
Pediatric Transplantation | Year: 2014
Thrombocytopenia is a frequent complication following HSCT in pediatric patients. Romiplostim is a TPO receptor agonist that has been utilized successfully in the treatment of pediatric patients with immune thrombocytopenia. We describe a three-yr-old male with X-linked CGD treated with an unrelated donor bone marrow transplant. His course was complicated by the development of symptomatic thrombocytopenia. He was started on romiplostim with prompt improvement in his thrombocytopenia. We found the use of romiplostim to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of immunosuppressive agents such as corticosteroids. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Buchbinder D.,CHOC Childrens Hospital
Journal of pediatric oncology nursing : official journal of the Association of Pediatric Oncology Nurses | Year: 2011
Although increasing numbers of studies have examined late effects in survivors, there is a paucity of long-term outcome studies in their siblings, so-called sibling survivors. Our aim was to provide a review of publications relevant to survivorship and its impact on the long-term psychosocial health of sibling survivors using a family systems framework. A review of publications identified 19 articles that reported findings suggesting that aspects of psychosocial health may be impaired in sibling survivors. Baseline functioning of sibling survivors may be altered at the start of survivorship secondary to apprehension, memories, and emotions. New demands are placed on sibling survivors, including doubts, questions, and worries due to survivorship. Survivor disfigurement may also place demands on sibling survivors associated with behavioral problems. Associated with these changes, there may be alterations in adaptation, including depression, somatic complaints, and posttraumatic stress symptoms. Sibling survivors may also report health risk behaviors and decreased vitality. Identification of the impact of survivorship on the long-term psychosocial health of sibling survivors may help ensure the long-term psychosocial health of all survivors.
Cohen J.,CHOC Childrens Hospital
AACN Advanced Critical Care | Year: 2010
Health care providers are poised to make an impact with this population through prevention, education of the public regarding current immunization schedules and recurrence of pertussis, vaccine safety, and ensuring that personal vaccinations are up-to-date. Children do not have to suffer from illness or die because of preventable illnesses such as pertussis. © 2010 American Association of Critical-Care Nurses.
Galant S.P.,CHOC Childrens Hospital |
Morphew T.,Southern California Chapter of Asthma and Allergy Foundation of America |
Guijon O.,CHOC Childrens Hospital |
Pham L.,CHOC Childrens Hospital
Pediatric Pulmonology | Year: 2014
Rationale: Although inhaled corticosteroids (ICS) are considered first line controller therapy in children with persistent asthma, heterogeneity of the ICS response can be an important clinical problem. The purpose of this study is to determine the value of the bronchodilator response (BDR) in identifying the ICS responder and establish the optimal BDR cut-point that could be particularly useful in the clinic setting when baseline spirometry is normal.Methods: Mexican American asthmatic children, 5-18 years, with normal baseline spirometry who required low dose (step 2), or medium dose (step 3) ICS therapy were evaluated by skin prick test for atopy, and preand post-bronchodilator spirometry. ICS responders were defined by a ≥7.5% improvement in the FEV1 following 4-6 weeks of therapy. The optimal cut-point was determined by Receiver Operator Characteristic (ROC) curves as the best balance between sensitivity and specificity.Results: There were 34.8% of the 132 study patients who were ICS responders. ROC curves showed the BDR ≥10% to be an optimal cut-point with sensitivity 46%, specificity 76%, positive predictive value (PPV) 50%, and negative predictive value (NPV) 72%. Atopic females with a BDR ≥10% had a PPV of 73%. Conclusions: The composite phenotype of female gender, atopic, and the BDR of ≥10% identified 73% as ICS responders compared to 50% in our overall population with a BDR of ≥10% alone, with minimal false positives. We suggest that the BDR in conjunction with gender and atopic status be considered as potentially useful predictors of the ICS responder, particularly when baseline spirometry is normal. Pediatr Pulmonol. © 2014 Wiley Periodicals, Inc.
Buchbinder D.,CHOC Childrens Hospital |
Ragni M.V.,CHOC Childrens Hospital
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013
A 32-year-old male with severe hemophilia presents for his annual evaluation. He has a history of multiple joint bleeds that he has always treated on-demand, that is, after they occur. You have recommended prophylaxis, that is, preventively, before they occur, to decrease his episodes of bleeding; however, he had been reluctant to comply in the past. He is having difficulty keeping up at work because of interruptions, pain, and lost time at work. He is willing to consider a trial of prophylaxis. You discuss the impact of hemophilia on his health-related quality of life (HRQOL) and consider measuring his HRQOL over time using a generic measure of HRQOL to determine whether prophylaxis will reduce interruptions, pain, and lost time from work and improve his HRQOL.
Zhang Z.,China University of Petroleum - East China |
Zhang Z.,University of California at Irvine |
Ali M.M.,University of California at Irvine |
Eckert M.A.,University of California at Irvine |
And 6 more authors.
Biomaterials | Year: 2013
Poor efficacy and off-target systemic toxicity are major problems associated with current chemotherapeutic approaches to treat cancer. We developed a new form of polyvalent therapeutics that is composed of multiple aptamer units synthesized by rolling circle amplification and physically intercalated chemotherapy agents (termed as "Poly-Aptamer-Drug"). Using a leukemia cell-binding aptamer and doxorubicin as a model system, we have successfully constructed Poly-Aptamer-Drug systems and demonstrated that the Poly-Aptamer-Drug is significantly more effective than its monovalent counterpart in targeting and killing leukemia cells due to enhanced binding affinity (~40 fold greater) and cell internalization via multivalent effects. We anticipate that our Poly-Aptamer-Drug approach will yield new classes of tunable therapeutics that can be utilized to effectively target and treat cancers while minimizing the side effects of chemotherapy. © 2013 Elsevier Ltd.