Portland, OR, United States
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Buckon C.,Shriners Hospitals for Children Portland | Sienko S.,Shriners Hospitals for Children Portland | Bagley A.,Shriners Hospitals for Children Northern California | Sison-Williamson M.,Shriners Hospitals for Children Northern California | And 5 more authors.
PLoS Currents | Year: 2016

Background: In the absence of a curative treatment for Duchenne Muscular Dystrophy (DMD), corticosteroid therapy (prednisone, deflazacort) has been adopted as the standard of care, as it slows the progression of muscle weakness and enables longer retention of functional mobility. The ongoing development of novel pharmacological agents that target the genetic defect underlying DMD offer hope for a significant alteration in disease progression; however, substantiation of therapeutic efficacy has proved challenging. Identifying functional outcomes sensitive to the early, subtle changes in muscle function has confounded clinical trials. Additionally, the alterations in disease progression secondary to corticosteroid therapy are not well described making it difficult to ascertain the benefits of novel agents, often taken concurrently with corticosteroids. Objective: The purpose of this study was to examine outcome responsiveness to corticosteroid therapy and age at the onset of a natural history study of ambulatory boys with DMD. Methods: Eighty-five ambulatory boys with DMD (mean age 93 mo, range 49 to 180 mo) were recruited into this study. Fifty participants were on corticosteroid therapy, while 33 were corticosteroid naïve at the baseline assessment. Within each treatment group boys were divided in two age groups, 4 to 7 years and 8 and greater years of age. The Biodex System 3 Pro isokinetic dynamometer was used to assess muscle strength. Motor skills were assessed using the upper two dimensions (standing/walking, running & jumping) of the Gross Motor Function Measure (GMFM 88) and Timed Motor Tests (TMTs) (10-meter run, sit to stand, supine to stand, climb 4-stairs). Two way analysis of variance and Pearson correlations were used for analysis. Results: A main effect for age was seen in select lower extremity muscle groups (hip flexors, knee extensors and ankle dorsiflexors), standing dimension skills, and all TMTs with significantly greater weakness and loss of motor skill ability seen in the older age group regardless of treatment group. Interaction effects were seen for the walking, running, and jumping dimension of the GMFM with the naïve boys scoring higher in the younger group and boys on corticosteroid therapy scoring higher in the older group. The TMT of climb 4-stairs demonstrated a significant treatment effect with the boys on corticosteroid therapy climbing stairs faster than those who were naïve, regardless of age. Examination of individual items within the upper level GMFM dimensions revealed select motor skills are more informative of disease progression than others; indicating their potential to be sensitive indicators of alterations in disease progression and intervention efficacy. Analysis of the relationship between muscle group strength and motor skill performance revealed differences in use patterns in the corticosteroid versus naïve boys. Conclusion: Significant muscle weakness is apparent in young boys with DMD regardless of corticosteroid treatment; however, older boys on corticosteroid therapy tend to have greater retention of muscle strength and motor skill ability than those who are naive. Quantification of muscle strength via isokinetic dynamometry is feasible and sensitive to the variable rates of disease progression in lower extremity muscle groups, but possibly most informative are the subtle changes in the performance characteristics of select motor skills. Further analysis of longitudinal data from this study will explore the influence of corticosteroid therapy on muscle strength and further clarify its impact on motor performance. © 2016, Public Library of Science. All rights reserved.


Heberer K.,University of California at Los Angeles | Fowler E.,University of California at Los Angeles | Staudt L.,University of California at Los Angeles | Sienko S.,Shriners Hospitals for Children Portland | And 6 more authors.
Gait and Posture | Year: 2016

Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder characterized by progressive proximal to distal muscle weakness. The success of randomized clinical trials for novel therapeutics depends on outcome measurements that are sensitive to change. As the development of motor skills may lead to functional improvements in young boys with DMD, their inclusion may potentially confound clinical trials. Three-dimensional gait analysis is an under-utilized approach that can quantify joint moments and powers, which reflect functional muscle strength. In this study, gait kinetics, kinematics, spatial-temporal parameters, and timed functional tests were quantified over a one-year period for 21 boys between 4 and 8 years old who were enrolled in a multisite natural history study. At baseline, hip moments and powers were inadequate. Between the two visits, 12 boys began a corticosteroid regimen (mean duration 10.8 ± 2.4 months) while 9 boys remained steroid-naïve. Significant between-group differences favoring steroid use were found for primary kinetic outcomes (peak hip extensor moments (p = .007), duration of hip extensor moments (p = .007), peak hip power generation (p = .028)), and spatial-temporal parameters (walking speed (p = .016) and cadence (p = .021)). Significant between-group differences were not found for kinematics or timed functional tests with the exception of the 10 m walk test (p = .03), which improves in typically developing children within this age range. These results indicate that hip joint kinetics can be used to identify weakness in young boys with DMD and are sensitive to corticosteroid intervention. Inclusion of gait analysis may enhance detection of a treatment effect in clinical trials particularly for young boys with more preserved muscle function. © 2016 Elsevier B.V.


PubMed | Shriners Hospitals for Children Portland, Shriners Hospitals for Children Northern California, University of California at Los Angeles and University of California at Davis
Type: | Journal: Gait & posture | Year: 2016

Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder characterized by progressive proximal to distal muscle weakness. The success of randomized clinical trials for novel therapeutics depends on outcome measurements that are sensitive to change. As the development of motor skills may lead to functional improvements in young boys with DMD, their inclusion may potentially confound clinical trials. Three-dimensional gait analysis is an under-utilized approach that can quantify joint moments and powers, which reflect functional muscle strength. In this study, gait kinetics, kinematics, spatial-temporal parameters, and timed functional tests were quantified over a one-year period for 21 boys between 4 and 8 years old who were enrolled in a multisite natural history study. At baseline, hip moments and powers were inadequate. Between the two visits, 12 boys began a corticosteroid regimen (mean duration 10.82.4 months) while 9 boys remained steroid-nave. Significant between-group differences favoring steroid use were found for primary kinetic outcomes (peak hip extensor moments (p=.007), duration of hip extensor moments (p=.007), peak hip power generation (p=.028)), and spatial-temporal parameters (walking speed (p=.016) and cadence (p=.021)). Significant between-group differences were not found for kinematics or timed functional tests with the exception of the 10m walk test (p=.03), which improves in typically developing children within this age range. These results indicate that hip joint kinetics can be used to identify weakness in young boys with DMD and are sensitive to corticosteroid intervention. Inclusion of gait analysis may enhance detection of a treatment effect in clinical trials particularly for young boys with more preserved muscle function.


PubMed | Shriners Hospitals for Children Portland, Shriners Hospitals for Children Northern California, University of California at Los Angeles and University of California at Davis
Type: | Journal: PLoS currents | Year: 2016

In the absence of a curative treatment for Duchenne Muscular Dystrophy (DMD), corticosteroid therapy (prednisone, deflazacort) has been adopted as the standard of care, as it slows the progression of muscle weakness and enables longer retention of functional mobility. The ongoing development of novel pharmacological agents that target the genetic defect underlying DMD offer hope for a significant alteration in disease progression; however, substantiation of therapeutic efficacy has proved challenging. Identifying functional outcomes sensitive to the early, subtle changes in muscle function has confounded clinical trials. Additionally, the alterations in disease progression secondary to corticosteroid therapy are not well described making it difficult to ascertain the benefits of novel agents, often taken concurrently with corticosteroids.The purpose of this study was to examine outcome responsiveness to corticosteroid therapy and age at the onset of a natural history study of ambulatory boys with DMD.Eighty-five ambulatory boys with DMD (mean age 93 mo, range 49 to 180 mo) were recruited into this study. Fifty participants were on corticosteroid therapy, while 33 were corticosteroid nave at the baseline assessment. Within each treatment group boys were divided in two age groups, 4 to 7 years and 8 and greater years of age. The Biodex System 3 Pro isokinetic dynamometer was used to assess muscle strength. Motor skills were assessed using the upper two dimensions (standing/walking, running & jumping) of the Gross Motor Function Measure (GMFM 88) and Timed Motor Tests (TMTs) (10-meter run, sit to stand, supine to stand, climb 4-stairs). Two way analysis of variance and Pearson correlations were used for analysis.A main effect for age was seen in select lower extremity muscle groups (hip flexors, knee extensors and ankle dorsiflexors), standing dimension skills, and all TMTs with significantly greater weakness and loss of motor skill ability seen in the older age group regardless of treatment group. Interaction effects were seen for the walking, running, and jumping dimension of the GMFM with the nave boys scoring higher in the younger group and boys on corticosteroid therapy scoring higher in the older group. The TMT of climb 4-stairs demonstrated a significant treatment effect with the boys on corticosteroid therapy climbing stairs faster than those who were nave, regardless of age. Examination of individual items within the upper level GMFM dimensions revealed select motor skills are more informative of disease progression than others; indicating their potential to be sensitive indicators of alterations in disease progression and intervention efficacy. Analysis of the relationship between muscle group strength and motor skill performance revealed differences in use patterns in the corticosteroid versus nave boys.Significant muscle weakness is apparent in young boys with DMD regardless of corticosteroid treatment; however, older boys on corticosteroid therapy tend to have greater retention of muscle strength and motor skill ability than those who are naive. Quantification of muscle strength via isokinetic dynamometry is feasible and sensitive to the variable rates of disease progression in lower extremity muscle groups, but possibly most informative are the subtle changes in the performance characteristics of select motor skills. Further analysis of longitudinal data from this study will explore the influence of corticosteroid therapy on muscle strength and further clarify its impact on motor performance.


Hurlin P.J.,Shriners Hospitals for Children Portland | Hurlin P.J.,Oregon Health And Science University
Cold Spring Harbor Perspectives in Medicine | Year: 2013

The study of MYC has led to pivotal discoveries in cancer biology, induced pluripotency, and transcriptional regulation. In this review, continuing advances in our understanding of the function of MYC as a transcription factor and how its transcriptional activity controls normal vertebrate development and contributes to developmental disorders is discussed. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Shung C.-Y.,Shriners Hospitals for Children Portland | Shung C.-Y.,Oregon Health And Science University | Ota S.,Shriners Hospitals for Children Portland | Zhou Z.-Q.,Shriners Hospitals for Children Portland | And 3 more authors.
Human Molecular Genetics | Year: 2012

Mutations in fibroblast growth factor (FGF) receptors are responsible for a variety of skeletal birth defects, but the underlying mechanisms responsible remain unclear. Using a mouse model of thanatophoric dysplasia type II in which FGFR3K650E expression was directed to the appendicular skeleton, we show that the mutant receptor caused a block in chondrocyte differentiation specifically at the prehypertrophic stage. The differentiation block led to a severe reduction in hypertrophic chondrocytes that normally produce vascular endothelial growth factor, which in turn was associated with poor vascularization of primary ossification centers and disrupted endochondral ossification. We show that the differentiation block and defects in joint formation are associated with persistent expression of the chondrogenic factor Sox9 and down-regulation of β-catenin levels and activity in growth plate chondrocytes. Consistent with these in vivo results, FGFR3K650E expression was found to increase Sox9 and decrease β-catenin levels and transcriptional activity in cultured mesenchymal cells. Coexpression of Fgfr3K650E and Sox9 in cells resulted in very high levels of Sox9 and cooperative suppression of β-catenin-dependent transcription. Fgfr3K650E had opposing effects on Sox9 and β-catenin protein stability with it promoting Sox9 stabilization and β-catenin degradation. Since both Sox9 overexpression and β-catenin deletion independently blocks hypertrophic differentiation of chondrocytes and cause chondrodysplasias similar to those caused by mutations in FGFR3, our results suggest that dysregulation of Sox9 and β-catenin levels and activity in growth plate chondrocytes is an important underlying mechanism in skeletal diseases caused by mutations in FGFR3. © The Author 2012. Published by Oxford University Press. All rights reserved.


Zhou Z.-Q.,Shriners Hospitals for Children Portland | Shung C.-Y.,Shriners Hospitals for Children Portland | Shung C.-Y.,Oregon Health And Science University | Ota S.,Shriners Hospitals for Children Portland | And 4 more authors.
PLoS ONE | Year: 2011

Background: During limb development, chondrocytes and osteoblasts emerge from condensations of limb bud mesenchyme. These cells then proliferate and differentiate in separate but adjacent compartments and function cooperatively to promote bone growth through the process of endochondral ossification. While many aspects of limb skeletal formation are understood, little is known about the mechanisms that link the development of undifferentiated limb bud mesenchyme with formation of the precartilaginous condensation and subsequent proliferative expansion of chondrocyte and osteoblast lineages. The aim of this study was to gain insight into these processes by examining the roles of c-Myc and N-Myc in morphogenesis of the limb skeleton. Methodology/Principal Findings: To investigate c-Myc function in skeletal development, we characterized mice in which floxed c-Myc alleles were deleted in undifferentiated limb bud mesenchyme with Prx1-Cre, in chondro-osteoprogenitors with Sox9-Cre and in osteoblasts with Osx1-Cre. We show that c-Myc promotes the proliferative expansion of both chondrocytes and osteoblasts and as a consequence controls the process of endochondral growth and ossification and determines bone size. The control of proliferation by c-Myc was related to its effects on global gene transcription, as phosphorylation of the C-Terminal Domain (pCTD) of RNA Polymerase II, a marker of general transcription initiation, was tightly coupled to cell proliferation of growth plate chondrocytes where c-Myc is expressed and severely downregulated in the absence of c-Myc. Finally, we show that combined deletion of N-Myc and c-Myc in early limb bud mesenchyme gives rise to a severely hypoplastic limb skeleton that exhibits features characteristic of individual c-Myc and N-Myc mutants. Conclusions/Significance: Our results show that N-Myc and c-Myc act sequentially during limb development to coordinate the expansion of key progenitor populations responsible for forming the limb skeleton. © 2011 Zhou et al.


Link J.M.,Shriners Hospitals for Children Portland | Hurlin P.J.,Shriners Hospitals for Children Portland
Biochimica et biophysica acta | Year: 2015

The MYC family of proteins plays essential roles in embryonic development and in oncogenesis. Efforts over the past 30 years to define the transcriptional activities of MYC and how MYC functions to promote proliferation have produced evolving models of MYC function. One picture that has emerged of MYC and its partner protein MAX is of a transcription factor complex with a seemingly unique ability to stimulate the transcription of genes that are epigenetically poised for transcription and to amplify the transcription of actively transcribed genes. During lymphocyte activation, MYC is upregulated and stimulates a pro-proliferative program in part through the upregulation of a wide variety of metabolic effector genes that facilitate cell growth and cell cycle progression. MYC upregulation simultaneously sensitizes cells to apoptosis and activated lymphocytes and lymphoma cells have pro-survival attributes that allow MYC-driven proliferation to prevail. For example, the MAX-interacting protein MNT is upregulated in activated lymphocytes and was found to protect lymphocytes from MYC-dependent apoptosis. Here we review the activities of MYC, MNT and other MAX interacting proteins in the setting of T and B cell activation and oncogenesis. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology. Copyright © 2014 Elsevier B.V. All rights reserved.


PubMed | Shriners Hospitals for Children Portland
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2012

Mnt (Maxs next tango) is a Max-interacting transcriptional repressor that can antagonize both the proproliferative and proapoptotic functions of Myc in vitro. To ascertain the physiologically relevant functions of Mnt and to help define the relationship between Mnt and Myc in vivo, we generated a series of mouse strains in which Mnt was deleted in T cells in the absence of endogenous c-Myc or in the presence of ectopic c-Myc. We found that apoptosis caused by loss of Mnt did not require Myc but that ectopic Myc expression dramatically decreased the survival of both Mnt-deficient T cells in vivo and Mnt-deficient MEFs in vitro. Consequently, Myc-driven proliferative expansion of T cells in vitro and thymoma formation in vivo were prevented by the absence of Mnt. Consistent with T-cell models, mouse embryo fibroblasts (MEFs) lacking Mnt were refractory to oncogenic transformation by Myc. Tumor suppression caused by loss of Mnt was linked to increased apoptosis mediated by reactive oxygen species (ROS). Thus, although theoretically and experimentally a Myc antagonist, the dominant physiological role of Mnt appears to be suppression of apoptosis. Our results redefine the physiological relationship between Mnt and Myc and requirements for Myc-driven oncogenesis.


PubMed | Shriners Hospitals for Children Portland
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

Mutations that cause increased and/or inappropriate activation of FGFR3 are responsible for a collection of short-limbed chondrodysplasias. These mutations can alter receptor trafficking and enhance receptor stability, leading to increased receptor accumulation and activity. Here, we show that wildtype and mutant activated forms of FGFR3 increase expression of the cytoplasmic deacetylase HDAC6 (Histone Deacetylase 6) and that FGFR3 accumulation is compromised in cells lacking HDAC6 or following treatment of fibroblasts or chondrocytes with small molecule inhibitors of HDAC6. The reduced accumulation of FGFR3 was linked to increased FGFR3 degradation that occurred through a lysosome-dependent mechanism. Using a mouse model of Thanatophoric Dysplasia Type II (TDII) we show that both HDAC6 deletion and treatment with the small molecule HDAC6 inhibitor tubacin reduced FGFR3 accumulation in the growth plate and improved endochondral bone growth. Defective endochondral growth in TDII is associated with reduced proliferation and poor hypertrophic differentiation and the improved bone growth was associated with increased chondrocyte proliferation and expansion of the differentiation compartment within the growth plate. These findings further define the mechanisms that control FGFR3 accumulation and contribute to skeletal pathology caused by mutations in FGFR3.

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