St Judes Childrens Research Hospital
St Judes Childrens Research Hospital
Stuber M.L.,University of California at Los Angeles |
Meeske K.A.,Childrens Hospital of Los Angeles |
Krull K.R.,St Judes Childrens Research Hospital |
Leisenring W.,Fred Hutchison Cancer Research Center |
And 8 more authors.
Pediatrics | Year: 2010
OBJECTIVE: This study compared the prevalence of symptoms of post-traumatic stress disorder (PTSD), with functional impairment and/or clinical distress, among very long-term survivors of childhood cancer and a group of healthy siblings. METHODS: A total of 6542 childhood cancer survivors >18 years of age who received diagnoses between 1970 and 1986 and 368 siblings of cancer survivors completed a comprehensive demographic and health survey. RESULTS: A total of 589 survivors (9%) and 8 siblings (2%) reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of PTSD. Survivors had more than fourfold greater risk of PTSD, compared with siblings (odds ratio [OR]: 4.14 [95% confidence interval [CI]: 2.08-8.25]). With controlling for demographic and treatment variables, increased risk of PTSD was associated with educational level of high school or less (OR: 1.51 [95% CI: 1.16-1.98]), being unmarried (OR: 1.99 [95% CI: 1.58-2.50]), having annual income below $20 000 (OR: 1.63 [95% CI: 1.21-2.20]), and being unemployed (OR: 2.01 [95% CI: 1.62-2.51]). Intensive treatment also was associated with increased risk of full PTSD (OR: 1.36 [95% CI: 1.06-1.74]). CONCLUSIONS: PTSD was reported significantly more often by survivors of childhood cancer than by sibling control subjects. Although most survivors apparently are faring well, a subset reported significant impairment that may warrant targeted intervention. Copyright © 2010 by the American Academy of Pediatrics.
Willis C.M.,Stanley Manne Childrens Research Institute |
Willis C.M.,Northwestern University |
Willis C.M.,St Judes Childrens Research Hospital |
Kluppel M.,Stanley Manne Childrens Research Institute |
Kluppel M.,Northwestern University
PLoS ONE | Year: 2014
Expression of the glycosaminoglycan chondroitin sulfate-E (CS-E) is misregulated in many human cancers, including breast cancer. Cell-surface associated CS-E has been shown to have pro-tumorigenic functions, and pharmacological treatment with exogenous CS-E has been proposed to interfere with tumor progression mediated by endogenous CS-E. However, the effects of exogenous CS-E on breast cancer cell behavior, and the molecular mechanisms deployed by CS-E are not well understood. We show here that treatment with CS-E, but not other chondroitin forms, could interfere with the invasive protrusion formation and migration of breast cancer cells in three-dimensional organotypic cultures. Microarray analysis identified transcriptional programs controlled by CS-E in these cells. Importantly, negative regulation of the pro-metastatic extracellular matrix gene Col1a1 was required for the anti-migratory effects of exogenous CS-E. Knock-down of Col1a1 gene expression mimics the effects of CS-E treatment, while exposing cells to a preformed collagen I matrix interfered with the anti-migratory effects of CS-E. In addition, CS-E specifically interfered with Wnt/beta-catenin signaling, a known pro-tumorigenic pathway. Lastly, we demonstrate that Col1a1 is a positively regulated target gene of the Wnt/beta-catenin pathway in breast cancer cells. Together, our data identify treatment with exogenous CS-E as negative regulatory mechanism of breast cancer cell motility through interference with a pro-tumorigenic Wnt/beta-catenin - Collagen I axis. © 2014 Willis Klüppel.
Poplack D.G.,Texas Childrens Cancer Center |
Fordis M.,Center for Collaborative and Interactive Technologies |
Landier W.,City of Hope |
Bhatia S.,City of Hope |
And 2 more authors.
Nature Reviews Clinical Oncology | Year: 2014
Survivors of childhood cancer are at risk of long-term adverse effects and late effects of the disease and/or its treatment. In response to national recommendations to improve evidence-based follow-up care, a web-based support system for clinical decision making, the Passport for Care (PFC), was developed for use at the point of care to produce screening recommendations individualized to the survivor. To date, the PFC has been implemented in over half of the nearly 200 clinics affiliated with the Children's Oncology Group across the USA. Most clinician users report that the PFC has been integrated into clinic workflows, and that it fosters improved conversations with survivors about the potential late effects a survivor might experience and about the screening and/or behavioural interventions recommended to improve health status. Furthermore, clinicians using the PFC have indicated that they adhered more closely to follow-up care guidelines. Perspectives on the challenges encountered and lessons learned during the development and deployment of the PFC are reviewed and contrasted with other nationwide approaches to the provision of guidance on survivor follow-up care; furthermore, the implications for the care of childhood cancer survivors are discussed. © 2014 Macmillan Publishers Limited. All rights reserved.
Agwu A.L.,00 N Wolfe Street |
Korthuis P.T.,Agency for Health Care Research and Quality |
Siberry G.K.,Oregon Health And Science University |
Ellen J.M.,U.S. National Institutes of Health |
And 2 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2011
Objectives: Increasing numbers of youth are becoming HIV-infected and need highly active antiretroviral therapy (HAART). We hypothesized that behaviorally HIV-infected youth (BIY) ages 18 to 24 years are less likely than adults (25 years or older) to receive HAART and, once initiated, more likely to discontinue their first HAART regimen. Methods: Longitudinal analysis of treatment-naïve patients (age 18 years or older) meeting criteria for HAART and followed at HIV Research Network sites (2002-2008). Time from meeting criteria to HAART initiation and duration on first regimen were assessed using Cox proportional hazards regression. Results: A total of 3127 (268 youth, 2859 adult) treatment-naïve, HIV-infected patients met criteria. BIY were more likely to be black (66.8% vs 51.1%; P < 0.01) and less likely to identify injection drug use HIV risk (1.1% vs 8.8%; P < 0.01) than adults 25 years of age or older. Nearly 69% of BIY started HAART versus 79% of adults (P < 0.001). Adults 25 to 29 years of age (adjusted hazards ratio [AHR], 1.39; 95% confidence interval [CI], 1.12-1.73) and 50 years of age or older (AHR, 1.24; 95% CI, 1.00-1.54), but not 30 to 49 years (AHR, 1.19; 95% CI, 0.99-1.44) were more likely to initiate HAART than BIY. Attending four or more HIV provider visits within 1 year of meeting criteria was associated with HAART initiation (AHR, 1.91; 1.70-2.14). CD4 200 to 350 versus less than 200 cells/mm3 (AHR, 0.57; 95% CI, 0.52-0.63), and injection drug use (AHR, 0.80; 95% CI, 0.69-0.92) were associated with a lower likelihood of HAART initiation. There were no age-related differences in duration of the first regimen. Conclusion: BIY are less likely to start HAART when meeting treatment criteria. Addressing factors associated with this disparity is critical to improving care for youth. Copyright © 2011 Lippincott Williams & Wilkins.
Liu Y.,University of Texas Southwestern Medical Center |
Shoji-Kawata S.,University of Texas Southwestern Medical Center |
Shoji-Kawata S.,National Center for Global Health and Medicine |
Sumpter Jr. R.M.,University of Texas Southwestern Medical Center |
And 13 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013
A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy- inducing peptide, Tat-Beclin 1, derived from the autophagy protein Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed "autosis," has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxiä Cischemia in vivo. A chemical screen of ~5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na+,K +-ATPase, inhibit autotic cell death in vitro and in vivo. Furthermore, genetic knockdown of the Na+,K+-ATPase α1 subunit blocks peptide and starvation-induced autosis in vitro. Thus, we have identified a unique form of autophagy-dependent cell death, a Food and Drug Administration-approved class of compounds that inhibit such death, and a crucial role for Na+,K+-ATPase in its regulation. These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented.
Kannan S.,University of Texas M. D. Anderson Cancer Center |
Fang W.,University of Texas M. D. Anderson Cancer Center |
Song G.,St Judes Childrens Research Hospital |
Mullighan C.G.,St Judes Childrens Research Hospital |
And 3 more authors.
Blood | Year: 2011
Notch signaling plays both oncogenic and tumor suppressor roles, depending on cell type. In contrast to T-cell acute lymphoblastic leukemia (ALL), where Notch activation promotes leukemogenesis, induction of Notch signaling in B-cell ALL (B-ALL) leads to growth arrest and apoptosis. The Notch target Hairy/Enhancer of Split1 (HES1) is sufficient to reproduce this tumor suppressor phenotype in B-ALL; however, the mechanism is not yet known. We report that HES1 regulates proapoptotic signals by the novel interacting protein Poly ADP-Ribose Polymerase1 (PARP1) in a cell type-specific manner. Interaction of HES1 with PARP1 inhibits HES1 function, induces PARP1 activation, and results in PARP1 cleavage in B-ALL. HES1-induced PARP1 activation leads to self-ADP ribosylation of PARP1, consumption of nicotinamide adenine dinucleotide +, diminished adenosine triphosphate levels, and translocation of apoptosis-inducing factor from mitochondria to the nucleus, resulting in apoptosis in B-ALL but not T-cell ALL. Importantly, induction of Notch signaling by the Notch agonist peptide Delta/Serrate/Lag-2 can reproduce these events and leads to B-ALL apoptosis. The novel interaction of HES1 and PARP1 in B-ALL modulates the function of the HES1 transcriptional complex and signals through PARP1 to induce apoptosis. This mechanism shows a cell type-specific proapoptotic pathway that may lead to Notch agonist-based cancer therapeutics. © 2011 by The American Society of Hematology.
Dai Q.,University of Alabama at Birmingham |
Reddy V.V.B.,University of Alabama at Birmingham |
Choi J.K.,St Judes Childrens Research Hospital |
Faye-Petersen O.M.,University of Alabama at Birmingham
Pediatric and Developmental Pathology | Year: 2014
We report a case of a male newborn with trisomy 21 and transient abnormal myelopoiesis at birth whose placenta showed extravasated fetal blasts in the perivillous (maternal) space. Concern for possible maternal spread of fetal malignancy prompted a Kleihauer-Betke test and flow cytometric analysis of the maternal peripheral blood on postpartum day 2. Notably, no evidence of the persistence of fetal cells in the maternal blood was identified, a finding that likely reflected successful maternal immunologic clearance of the fetal blasts and erythrocytes, and/or blast cellular fragility and limited viability. Ours is the first report, to our knowledge, documenting maternal peripheral-blood follow-up evaluation of this disorder in the English literature. We discuss our case in the context of a comprehensive review of fetoneonatal solid tumor and leukemic proliferative disorders with placental involvement and evidence of maternal metastasis. © 2014 Society for Pediatric Pathology
Lange J.M.,University of Washington |
Takashima J.R.,Fred Hutchinson Cancer Research Center |
Peterson S.M.,Fred Hutchinson Cancer Research Center |
Kalapurakal J.A.,Northwestern University |
And 3 more authors.
Cancer | Year: 2014
METHODS: A total of 2492 female participants in National Wilms Tumor Studies 1 through 4 (1969-1995) were followed from age 15 years through the middle of 2013 for incident BC. The median age at the time of last contact was 27.3 years. The authors calculated cumulative risk at age 40 years (CR40), hazard ratios (HR) by Cox regression, standardized incidence ratios (SIRs) relative to US population rates, and 95% confidence intervals (95% CIs).BACKGROUND: The standard treatment of pulmonary metastases in patients with Wilms tumor (WT) includes 12-gray radiotherapy (RT) to the entire chest. To the authors' knowledge, the risk of breast cancer (BC) in a large cohort of female survivors of WT has not previously been reported.RESULTS: The numbers of survivors with invasive BC divided by the numbers at risk were 16 of 369 (CR40, 14.8% [95% CI, 8.7-24.5]) for women who received chest RT for metastatic WT, 10 of 894 (CR40, 3.1% [95% CI, 1.3-7.41]) for those who received only abdominal RT, and 2 of 1229 (CR40, 0.3% [95% CI, 0.0-2.3]) for those who received no RT. The SIRs for these 3 groups were 27.6 (95% CI, 16.1-44.2) based on 5010 person-years (PY) of follow-up, 6.0 (95% CI, 2.9-11.0) based on 13,185 PY of follow-up, and 2.2 (95% CI, 0.3-7.8) based on 13,560 PY of follow-up, respectively. The risk was high regardless of the use of chest RT among women diagnosed with WT at age ≥10 years, with 9 of 90 women developing BC (CR40, 13.5% [95% CI, 5.6-30.6]; SIR, 23.6 [95% CI, 10.8-44.8] [PY, 1463]).CONCLUSIONS: Female survivors of WT who were treated with chest RT had a high risk of developing early BC, with nearly 15% developing invasive disease by age 40 years. Current guidelines that recommend screening only those survivors who received ≥20 Gy of RT to the chest might be reevaluated. © 2014 American Cancer Society.
Green D.R.,St Judes Childrens Research Hospital |
Levine B.,Howard Hughes Medical Institute
Cell | Year: 2014
The health of metazoan organisms requires an effective response to organellar and cellular damage either by repair of such damage and/or by elimination of the damaged parts of the cells or the damaged cell in its entirety. Here, we consider the progress that has been made in the last few decades in determining the fates of damaged organelles and damaged cells through discrete, but genetically overlapping, pathways involving the selective autophagy and cell death machinery. We further discuss the ways in which the autophagy machinery may impact the clearance and consequences of dying cells for host physiology. Failure in the proper removal of damaged organelles and/or damaged cells by selective autophagy and cell death processes is likely to contribute to developmental abnormalities, cancer, aging, inflammation, and other diseases. © 2014 Elsevier Inc.
Tripathi P.,University of Cincinnati |
Koss B.,St Judes Childrens Research Hospital |
Opferman J.T.,St Judes Childrens Research Hospital |
Hildeman D.A.,University of Cincinnati
Cell Death and Differentiation | Year: 2013
Members of the Bcl-2 family have critical roles in regulating tissue homeostasis by modulating apoptosis. Anti-apoptotic molecules physically interact and restrain pro-apoptotic family members preventing the induction of cell death. However, the specificity of the functional interactions between pro- and anti-apoptotic Bcl-2 family members remains unclear. The pro-apoptotic Bcl-2 family member Bcl-2 interacting mediator of death (Bim) has a critical role in promoting the death of activated, effector T cells following viral infections. Although Bcl-2 is an important Bim antagonist in effector T cells, and Bcl-xL is not required for effector T-cell survival, the roles of other anti-apoptotic Bcl-2 family members remain unclear. Here, we investigated the role of myeloid cell leukemia sequence 1 (Mcl-1) in regulating effector T-cell responses in vivo. We found, at the peak of the response to lymphocytic choriomeningitis virus (LCMV) infection, that Mcl-1 expression was increased in activated CD4+ and CD8+ T cells. Retroviral overexpression of Mcl-1-protected activated T cells from death, whereas deletion of Mcl-1 during the course of infection led to a massive loss of LCMV-specific CD4 + and CD8+ T cells. Interestingly, the co-deletion of Bim failed to prevent the loss of Mcl-1-deficient T cells. Furthermore, lck-driven overexpression of a Bcl-xL transgene only partially rescued Mcl-1-deficient effector T cells suggesting a lack of redundancy between the family members. In contrast, additional loss of Bax and Bak completely rescued Mcl-1-deficient effector T-cell number and function, without enhancing T-cell proliferation. These data suggest that Mcl-1 is critical for promoting effector T-cell responses, but does so by combating pro-apoptotic molecules beyond Bim. © 2013 Macmillan Publishers Limited All rights reserved.