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"Nordling, William J"
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Outcomes and Stages of Child-Centered Play Therapy for a Child With Highly Disruptive Behavior Driven by Self-Concept Issues
Descriptions in this case study of child‐centered play therapy (CCPT) for a boy referred for highly disruptive behavior include observations of his process through stages of CCPT, teacher and parent ratings on the Child Behavior Checklist (Achenbach & Rescorla, 2001), and explanations of how CCPT worked for him.
Journal Article
LASSIM—A network inference toolbox for genome-wide mechanistic modeling
Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM), which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE) for gene regulatory networks (GRNs). LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets. The rationale behind LASSIM is that biological GRNs can be simplified using a limited subset of core genes that are assumed to regulate all other gene transcription events in the network. The LASSIM method is implemented as a general-purpose toolbox using the PyGMO Python package to make the most of multicore computers and high performance clusters, and is available at https://gitlab.com/Gustafsson-lab/lassim. As a method, LASSIM works in two steps, where it first infers a non-linear ODE system of the pre-specified core gene expression. Second, LASSIM in parallel optimizes the parameters that model the regulation of peripheral genes by core system genes. We showed the usefulness of this method by applying LASSIM to infer a large-scale non-linear model of naïve Th2 cell differentiation, made possible by integrating Th2 specific bindings, time-series together with six public and six novel siRNA-mediated knock-down experiments. ChIP-seq showed significant overlap for all tested transcription factors. Next, we performed novel time-series measurements of total T-cells during differentiation towards Th2 and verified that our LASSIM model could monitor those data significantly better than comparable models that used the same Th2 bindings. In summary, the LASSIM toolbox opens the door to a new type of model-based data analysis that combines the strengths of reliable mechanistic models with truly systems-level data. We demonstrate the power of this approach by inferring a mechanistically motivated, genome-wide model of the Th2 transcription regulatory system, which plays an important role in several immune related diseases.
Journal Article
Critical Variables Affecting Clinical-Grade Production of the Self-Inactivating Gamma-Retroviral Vector for the Treatment of X-linked Severe Combined Immunodeficiency
In two earlier trials, patients with X-linked Severe Combined Immune Deficiency (SCID-X1) were successfully cured following gene therapy with a gamma-retroviral vector (gRV) expressing the common gamma chain of the interleukin-2 receptor (IL2RG). We have previously demonstrated that GMP-grade SIN gRV can be produced at high titers using transient transfection in bioreactors (van der Loo et al, Gene Ther 2011). Herein we report on the large-scale production of a clinical-grade SIN IL2RG gRV pseudotyped with the Gibbon Ape Leukemia Virus envelope for a new gene therapy trial for SCID-X1, and highlight variables that were found to be critical for transfection-based large-scale SIN gRV production. The vector was certified and released for treatment of SCID-X1 in a multi-center international phase I/II trial which is currently recruiting patients in Paris, London, Los Angeles, Boston and Cincinnati.
Journal Article