Publications by authors named "William Loudon"

29 Publications

  • Page 1 of 1

Analysis of Unintentional Falls in Pediatric Population and Predictors of Morbidity.

J Surg Res 2021 Jun 12;267:48-55. Epub 2021 Jun 12.

Division of Pediatric Surgery, Children's Hospital of Orange County, Orange, California.

Introduction: Unintentional falls are a leading cause of pediatric traumatic injury. This study evaluates clinical outcomes of fall-related injuries in children under the age of 10.

Methods: The National Trauma Database was queried for children who experienced an unintentional fall. Patients were stratified by age in two groups: 1-5 and 6-10 years old. The primary outcome was post discharge extension of care, defined as transfer to skilled nursing facility or rehabilitation center after discharge from the hospital. Descriptive statistics and a multivariable logistic regression analysis were used to compare the two groups.

Results: From 2009 to 2016, a total of 8,277 pediatric patients experienced an unintentional fall, with 93.6% of patients being discharged home. Falls were more common in younger children, with greater odds of post discharge extension of care. Predictors of increased associated risk of extended medical care included intracranial hemorrhage (OR 1.05, 95% CI 1.03-1.06) and thoracic injuries (OR 1.03, 95% CI 1.00-1.1.05) (P< 0.05). Mortality in pediatric patients suffering unintentional falls was a rare event occurring in 0.7% of cases in children 1-5 years old and 0.4% of children 6-10 years old.

Conclusion: The majority of children experiencing an unintentional fall are discharged home, with mortality being very rare. However, younger age is prone to more severe and serious injury patterns. Intracranial hemorrhage and thoracic injury were a predictor of need for extended medical care.
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http://dx.doi.org/10.1016/j.jss.2021.04.036DOI Listing
June 2021

A Multi-Modal Family Peer Support-Based Program to Improve Quality of Life among Pediatric Brain Tumor Patients: A Mixed-Methods Pilot Study.

Children (Basel) 2020 Apr 20;7(4). Epub 2020 Apr 20.

Department of Neurosurgery, CHOC Children's Main Campus Orange, Orange, CA 92868, USA.

Background: Pediatric brain tumor (PBT) survivors and their families are at risk for diminished psychosocial and quality of life outcomes. Community-based programs that leverage peer support in the context of integrative modalities such as traditional Chinese medicine (TCM) represent a promising avenue for meeting the multidimensional needs of survivors and their families.

Methods: Parents and children were enrolled in a 12-week program that included weekly group TCM, a moderated private Facebook support group designed through social support and modeling theory, and weekly parent-only health behavior education and yoga. Process measures and quantitative and qualitative survey data was collected to gauge participant adherence, acceptability, and satisfaction, as well as exploratory outcomes.

Results: Eleven parents completed surveys at all time points. Six of nine families attended at least 80% of the group TCM sessions, and eight of nine families interacted in the Facebook support group at least five days a week. Parents reported high levels of satisfaction and perceived benefits for the program. Baseline emotional distress, health behaviors, and QoL measurements improved during the three-month intervention. Qualitative data indicated parents perceived both in-person and the Facebook group peer support contributed to the benefits of the program.

Conclusion: This feasibility study demonstrated that a multimodal peer support-based intervention that included in-person and online group interaction is feasible and acceptable to parents of pediatric brain tumor patients. Further research on interventions for caregivers that include in-person and online group-based peer support is warranted, with the goal of exploring similar outcomes in other childhood cancer diagnoses.
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http://dx.doi.org/10.3390/children7040035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231280PMC
April 2020

Breathing Signature as Vitality Score Index Created by Exercises of Qigong: Implications of Artificial Intelligence Tools Used in Traditional Chinese Medicine.

J Funct Morphol Kinesiol 2019 Dec 3;4(4). Epub 2019 Dec 3.

Neuro-Oncology and Stem Cell Research Laboratory (NSCL), CHOC Children's Research Institute (CCRI), Children's Hospital of Orange County (CHOC), 1201 W. La Veta Ave., Orange, CA 92868-3874, USA.

Rising concerns about the short- and long-term detrimental consequences of administration of conventional pharmacopeia are fueling the search for alternative, complementary, personalized, and comprehensive approaches to human healthcare. Qigong, a form of Traditional Chinese Medicine, represents a viable alternative approach. Here, we started with the practical, philosophical, and psychological background of Ki (in Japanese) or Qi (in Chinese) and their relationship to Qigong theory and clinical application. Noting the drawbacks of the current state of Qigong clinic, herein we propose that to manage the unique aspects of the Eastern 'non-linearity' and 'holistic' approach, it needs to be integrated with the Western "linearity" "one-direction" approach. This is done through developing the concepts of "Qigong breathing signatures," which can define our life breathing patterns associated with diseases using machine learning technology. We predict that this can be achieved by establishing an artificial intelligence (AI)-Medicine training camp of databases, which will integrate Qigong-like breathing patterns with different pathologies unique to individuals. Such an integrated connection will allow the AI-Medicine algorithm to identify breathing patterns and guide medical intervention. This unique view of potentially connecting Eastern Medicine and Western Technology can further add a novel insight to our current understanding of both Western and Eastern medicine, thereby establishing a vitality score index (VSI) that can predict the outcomes of lifestyle behaviors and medical conditions.
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http://dx.doi.org/10.3390/jfmk4040071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919646PMC
December 2019

Scalp Intravenous Catheter Infiltration Leading to Subdural and Intraparenchymal Fluid Collection and Severe Neurologic Sequelae: A Case Report.

Perm J 2019 ;23

University of California Irvine Medical Center, Orange.

Introduction: Preterm infants require intravenous (IV) access for administration of medications, IV fluids, and parenteral nutrition. The scalp is a common site for obtaining IV access, and in children with hydrocephalus or wide fontanelles and sutures, there is a high probability of penetrating the meninges and brain matter with the scalp IV needle. If this penetration occurs and remains unnoticed, the contents of the IV infusion can infiltrate into the brain and cause severe brain damage.

Case Presentation: A 3-day-old female neonate, born with myelomeningocele, was receiving total parenteral nutrition through a scalp-vein IV. She experienced a sudden increase in head circumference, a bulging fontanelle, and respiratory distress. Magnetic resonance images demonstrated subdural fluid collection, and the patient underwent emergency surgery. The dura, when opened, exuded milky-white fluid consistent in color with parenteral nutrition. Postoperative imaging showed a parenchymal abnormality caused by the intracranial and intraparenchymal infusion of parenteral nutrition. Four years later, the child had a shunt and had mild cognitive impairment.

Discussion: In cases of accidental intracranial administration of parenteral nutrition, we recommend that aggressive therapy be pursued to minimize the risks of developing comorbidities such as meningitis and to allow for maximal functional recovery.
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http://dx.doi.org/10.7812/TPP/18-043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443361PMC
September 2019

Single-cell transcriptomes reveal the mechanism for a breast cancer prognostic gene panel.

Oncotarget 2018 Sep 7;9(70):33290-33301. Epub 2018 Sep 7.

Division of Periodontology, Diagnostic Sciences and Dental Hygiene, and Division of Biomedical Sciences, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.

The clinical benefits of the MammaPrint signature for breast cancer is well documented; however, how these genes are related to cell cycle perturbation have not been well determined. Our single-cell transcriptome mapping (algorithm) provides details into the fine perturbation of all individual genes during a cell cycle, providing a view of the cell-cycle-phase specific landscape of any given human genes. Specifically, we identified that 38 out of the 70 (54%) MammaPrint signature genes are perturbated to a specific phase of the cell cycle. The MammaPrint signature panel derived its clinical prognosis power from measuring the cell cycle activity of specific breast cancer samples. Such cell cycle phase index of the MammaPrint signature suggested that measurement of the cell cycle index from tumors could be developed into a prognosis tool for various types of cancer beyond breast cancer, potentially improving therapy through targeting a specific phase of the cell cycle of cancer cells.
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http://dx.doi.org/10.18632/oncotarget.26044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161791PMC
September 2018

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

J Transl Med 2018 06 29;16(1):179. Epub 2018 Jun 29.

University of North Carolina, Chapel Hill, NC, USA.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.
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http://dx.doi.org/10.1186/s12967-018-1552-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026340PMC
June 2018

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

J Transl Med 2018 05 29;16(1):142. Epub 2018 May 29.

University of North Carolina, Chapel Hill, NC, USA.

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax-L) to standard therapy for newly diagnosed glioblastoma.

Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.

Conclusions: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.
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http://dx.doi.org/10.1186/s12967-018-1507-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975654PMC
May 2018

Relapse pathway of glioblastoma revealed by single-cell molecular analysis.

Carcinogenesis 2018 07;39(7):931-936

Division of Periodontology, Diagnostic Sciences and Dental Hygiene, and Division of Biomedical Sciences, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.

Glioblastoma multiforme (GBM) remains an incurable brain tumor. The highly malignant behavior of GBM may, in part, be attributed to its intraclonal genetic and phenotypic diversity (subclonal evolution). Identifying the molecular pathways driving GBM relapse may provide novel, actionable targets for personalized diagnosis, characterization of prognosis and improvement of precision therapy. We screened single-cell transcriptomes, namely RNA-seq data of primary and relapsed GBM tumors from a patient, to define the molecular profile of relapse. Characterization of hundreds of individual tumor cells identified three mutated genes within single cells, involved in the RAS/GEF GTP-dependent signaling pathway. The identified molecular pathway was further verified by meta-analysis of RNA-seq data from more than 3000 patients. This study showed that single-cell molecular analysis overcomes the inherent heterogeneity of bulk tumors with respect to defining tumor subclonal evolution relevant to GBM relapse.
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http://dx.doi.org/10.1093/carcin/bgy052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248540PMC
July 2018

Microfluidic enrichment of plasma cells improves treatment of multiple myeloma.

Mol Oncol 2018 06 12;12(7):1004-1011. Epub 2018 May 12.

Division of Periodontology, Diagnostic Sciences & Dental Hygiene, Division of Biomedical Sciences, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.

Cytogenetic alterations form the basis for risk stratification for multiple myeloma (MM) and guide the selection of therapy; however, current pathology assays performed on bone marrow samples can produce false-negatives due to the unpredictable distribution and rarity of MM cells. Here, we report on a microfluidic device used to facilitate CD45 depletion to enhance the detection of cytogenetic alterations in plasma cells (PCs). Bone marrow samples from 48 patients with MM were each divided into two aliquots. One aliquot was subjected to classic flow cytometry and fluorescent in situ hybridization (FISH). The other first went through CD45 cell depletion, further enriched by microfluidic size selection. The enriched samples were then analyzed using flow cytometry and FISH and compared to those analyzed using the classic method only. Unlike the traditional method, the microfluidic device removed the CD45 leukocytes and specifically selected PCs from the remaining white blood cells. Therefore, the microfluidic method (MF-CD45-TACs) significantly increased the percentage of CD38 /CD138 cells to 37.7 ± 20.4% (P < 0.001) from 10.3 ± 8.5% in bone marrow. After the MF-CD45-TAC enrichment, the detection rate of IgH rearrangement, del(13q14), del(17p), and 1q21 gains, rose to 56.3% (P < 0.001), 37.5% (P < 0.001), 22.9% (P < 0.001), and 41.7% (P = 0.001), respectively; all rates of detection were significantly increased compared to the classically analyzed samples. In this clinical trial, this microfluidic-assisted assay provided a precise detection of cytogenetic alterations in PCs and improved clinical outcomes.
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http://dx.doi.org/10.1002/1878-0261.12201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026869PMC
June 2018

Tissue Elasticity Bridges Cancer Stem Cells to the Tumor Microenvironment Through microRNAs: Implications for a "Watch-and-Wait" Approach to Cancer.

Curr Stem Cell Res Ther 2017 ;12(6):455-470

Neuro-Oncology and Stem Cell Research Laboratory, Center for Neuroscience Research, CHOC Children's Hospital Research Institute, 1201 West La Veta Ave., Orange, CA 92868, United States.

Background: Targeting the tumor microenvironment (TME) through which cancer stem cells (CSCs) crosstalk for cancer initiation and progression, may open new treatments different from those centered on the original hallmarks of cancer genetics thereby implying a new approach for suppression of TME driven activation of CSCs. Cancer is dynamic, heterogeneous, evolving with the TME and can be influenced by tissue-specific elasticity. One of the mediators and modulators of the crosstalk between CSCs and mechanical forces is miRNA, which can be developmentally regulated, in a tissue- and cellspecific manner.

Objective: Here, based on our previous data, we provide a framework through which such gene expression changes in response to external mechanical forces can be understood during cancer progression. Recognizing the ways mechanical forces regulate and affect intracellular signals with applications in cancer stem cell biology. Such TME-targeted pathways shed new light on strategies for attacking cancer stem cells with fewer side effects than traditional gene-based treatments for cancer, requiring a "watchand- wait" approach. We attempt to address both normal brain microenvironment and tumor microenvironment as both works together, intertwining in pathology and physiology - a balance that needs to be maintained for the "watch-and-wait" approach to cancer.

Conclusion: This review connected the subjects of tissue elasticity, tumor microenvironment, epigenetic of miRNAs, and stem-cell biology that are very relevant in cancer research and therapy. It attempts to unify apparently separate entities in a complex biological web, network, and system in a realistic and practical manner, i.e., to bridge basic research with clinical application.
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http://dx.doi.org/10.2174/1574888X12666170307105941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587377PMC
May 2018

First report of tumor treating fields use in combination with bevacizumab in a pediatric patient: a case report.

CNS Oncol 2017 01 5;6(1):11-18. Epub 2016 Dec 5.

Department of Neurology, University of California, IrvineOr Medical Center, Orange, CA, USA.

We report the first case of a pediatric patient with glioblastoma (GBM; WHO grade IV astrocytoma) successfully treated with tumor treating fields (TTF). The patient was diagnosed with GBM when 13 years of age and progressed through surgical resection, radiotherapy and chemotherapy. Discrete tumor growth visualized on MRI with stable neurological examination was monitored for 6 months with subsequent stable disease observed radiographically and clinically for 7 months while adherent to Optune (TTF). TTF thereby played a role in forestalling recurrent GBM growth in this young woman for 7 months without significant adverse effects. We propose that TTF therapy is a potential valuable treatment in this small, but sick, patient population.
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http://dx.doi.org/10.2217/cns-2016-0018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027925PMC
January 2017

Tissue elasticity regulated tumor gene expression: implication for diagnostic biomarkers of primitive neuroectodermal tumor.

PLoS One 2015 16;10(3):e0120336. Epub 2015 Mar 16.

Neuro-Oncology and Stem Cell Research Laboratory, Center for Neuroscience Research, CHOC Children's Hospital Research Institute, University of California Irvine, 1201 West La Veta Ave., Orange, CA, 92868, United States of America; Department of Neurology, University of California Irvine School of Medicine, Orange, CA, 92697-4292, United States of America; Department of Biological Science, California State University, Fullerton, CA, 92834, United States of America.

Background: The tumor microenvironment consists of both physical and chemical factors. Tissue elasticity is one physical factor contributing to the microenvironment of tumor cells. To test the importance of tissue elasticity in cell culture, primitive neuroectodermal tumor (PNET) stem cells were cultured on soft polyacrylamide (PAA) hydrogel plates that mimics the elasticity of brain tissue compared with PNET on standard polystyrene (PS) plates. We report the molecular profiles of PNET grown on either PAA or PS.

Methodology/principal Findings: A whole-genome microarray profile of transcriptional expression between the two culture conditions was performed as a way to probe effects of substrate on cell behavior in culture. The results showed more genes downregulated on PAA compared to PS. This led us to propose microRNA (miRNA) silencing as a potential mechanism for downregulation. Bioinformatic analysis predicted a greater number of miRNA binding sites from the 3' UTR of downregulated genes and identified as specific miRNA binding sites that were enriched when cells were grown on PAA-this supports the hypothesis that tissue elasticity plays a role in influencing miRNA expression. Thus, Dicer was examined to determine if miRNA processing was affected by tissue elasticity. Dicer genes were downregulated on PAA and had multiple predicted miRNA binding sites in its 3' UTR that matched the miRNA binding sites found enriched on PAA. Many differentially regulated genes were found to be present on PS but downregulated on PAA were mapped onto intron sequences. This suggests expression of alternative polyadenylation sites within intron regions that provide alternative 3' UTRs and alternative miRNA binding sites. This results in tissue specific transcriptional downregulation of mRNA in humans by miRNA. We propose a mechanism, driven by the physical characteristics of the microenvironment by which downregulation of genes occur. We found that tissue elasticity-mediated cytokines (TGFβ2 and TNFα) signaling affect expression of ECM proteins.

Conclusions: Our results suggest that tissue elasticity plays important roles in miRNA expression, which, in turn, regulate tumor growth or tumorigenicity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120336PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361745PMC
January 2016

Cancer genomic research at the crossroads: realizing the changing genetic landscape as intratumoral spatial and temporal heterogeneity becomes a confounding factor.

Cancer Cell Int 2014 12;14(1):115. Epub 2014 Nov 12.

CHOC Children's Hospital Research Institute, University of California Irvine, 1201 West La Veta Ave, Orange, CA 92868 USA ; Department of Neurological Surgery, Saint Joseph Hospital, Orange, CA 92868 USA ; Department of Neurological Surgery, University of California Irvine School of Medicine, Orange, CA 92862 USA ; Department of Biological Science, California State University, Fullerton, CA 92834 USA.

The US National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) created the Cancer Genome Atlas (TCGA) Project in 2006. The TCGA's goal was to sequence the genomes of 10,000 tumors to identify common genetic changes among different types of tumors for developing genetic-based treatments. TCGA offered great potential for cancer patients, but in reality has little impact on clinical applications. Recent reports place the past TCGA approach of testing a small tumor mass at a single time-point at a crossroads. This crossroads presents us with the conundrum of whether we should sequence more tumors or obtain multiple biopsies from each individual tumor at different time points. Sequencing more tumors with the past TCGA approach of single time-point sampling can neither capture the heterogeneity between different parts of the same tumor nor catch the heterogeneity that occurs as a function of time, error rates, and random drift. Obtaining multiple biopsies from each individual tumor presents multiple logistical and financial challenges. Here, we review current literature and rethink the utility and application of the TCGA approach. We discuss that the TCGA-led catalogue may provide insights into studying the functional significance of oncogenic genes in reference to non-cancer genetic background. Different methods to enhance identifying cancer targets, such as single cell technology, real time imaging of cancer cells with a biological global positioning system, and cross-referencing big data sets, are offered as ways to address sampling discrepancies in the face of tumor heterogeneity. We predict that TCGA landmarks may prove far more useful for cancer prevention than for cancer diagnosis and treatment when considering the effect of non-cancer genes and the normal genetic background on tumor microenvironment. Cancer prevention can be better realized once we understand how therapy affects the genetic makeup of cancer over time in a clinical setting. This may help create novel therapies for gene mutations that arise during a tumor's evolution from the selection pressure of treatment.
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http://dx.doi.org/10.1186/s12935-014-0115-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236490PMC
November 2014

Training stem cells for treatment of malignant brain tumors.

World J Stem Cells 2014 Sep;6(4):432-40

Shengwen Calvin Li, Mustafa H Kabeer, Long T Vu, Vic Keschrumrus, Brent A Dethlefs, William G Loudon, Neuro-Oncology and Stem Cell Research Laboratory, Center for Neuroscience Research, Children's Hospital of Orange County, University of California-Irvine, Orange, CA 92868, United States.

The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for patients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution (i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system.
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http://dx.doi.org/10.4252/wjsc.v6.i4.432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172671PMC
September 2014

Cultivating stem cells for treating amyotrophic lateral sclerosis.

World J Stem Cells 2012 Dec;4(12):117-9

Shengwen Calvin Li, William G Loudon, CHOC Children's Hospital, University of California Irvine, Orange, CA 92868, United States.

This editorial addresses the current challenges and future directions in the use of stem cells as an approach for treating amyotrophic lateral sclerosis. A wide variety of literature has been reviewed to enlighten the reader on the many facets of stem cell research that are important to consider before using them for a cell based therapy.
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http://dx.doi.org/10.4252/wjsc.v4.i12.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600561PMC
December 2012

Cancer stem cells from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall.

Cancer Cell Int 2012 Sep 20;12(1):41. Epub 2012 Sep 20.

Neuro-Oncology Research Laboratory, Center for Neuroscience and Stem Cell Research, Children's Hospital of Orange County (CHOC) Research Institute, 455 South Main Street, Orange, CA 92868, USA.

Unlabelled:

Background: The cancer stem cell (CSC) hypothesis posits that deregulated neural stem cells (NSCs) form the basis of brain tumors such as glioblastoma multiforme (GBM). GBM, however, usually forms in the cerebral white matter while normal NSCs reside in subventricular and hippocampal regions. We attempted to characterize CSCs from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall.

Methods: We described isolating CSCs from a GBM involving the lateral ventricles and characterized these cells with in vitro molecular biomarker profiling, cellular behavior, ex vivo and in vivo techniques.

Results: The patient's MRI revealed a heterogeneous mass with associated edema, involving the left subventricular zone. Histological examination of the tumor established it as being a high-grade glial neoplasm, characterized by polygonal and fusiform cells with marked nuclear atypia, amphophilic cytoplasm, prominent nucleoli, frequent mitotic figures, irregular zones of necrosis and vascular hyperplasia. Recurrence of the tumor occurred shortly after the surgical resection. CD133-positive cells, isolated from the tumor, expressed stem cell markers including nestin, CD133, Ki67, Sox2, EFNB1, EFNB2, EFNB3, Cav-1, Musashi, Nucleostemin, Notch 2, Notch 4, and Pax6. Biomarkers expressed in differentiated cells included Cathepsin L, Cathepsin B, Mucin18, Mucin24, c-Myc, NSE, and TIMP1. Expression of unique cancer-related transcripts in these CD133-positive cells, such as caveolin-1 and -2, do not appear to have been previously reported in the literature. Ex vivo organotypic brain slice co-culture showed that the CD133+ cells behaved like tumor cells. The CD133-positive cells also induced tumor formation when they were stereotactically transplanted into the brains of the immune-deficient NOD/SCID mice.

Conclusions: This brain tumor involving the neurogenic lateral ventricular wall was comprised of tumor-forming, CD133-positive cancer stem cells, which are likely the driving force for the rapid recurrence of the tumor in the patient.
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http://dx.doi.org/10.1186/1475-2867-12-41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546918PMC
September 2012

Convergence of normal stem cell and cancer stem cell developmental stage: Implication for differential therapies.

World J Stem Cells 2011 Sep;3(9):83-8

Shengwen Calvin Li, Katherine L Lee, William G Loudon, Neuro-Oncology Research Laboratory, Center for Neuroscience and Stem Cell Research, Children's Hospital of Orange County, University of California Irvine, 455 South Main Street, Orange, CA 92868, United States.

Increased evidence shows that normal stem cells may contribute to cancer development and progression by acting as cancer-initiating cells through their interactions with abnormal environmental elements. We postulate that normal stem cells and cancer stem cells (CSC) possess similar mechanisms of self-renewal and differentiation. CSC can be the key to the elaboration of anti-cancer-based therapy. In this article, we focus on a controversial new theme relating to CSC. Tumorigenesis may have a critical stage characterized as a "therapeutic window", which can be identified by association of molecular, biochemical and biological events. Identifying such a stage can allow the production of more effective therapies (e.g. manipulated stem cells) to treat several cancers. More importantly, confirming the existence of a similar therapeutic window during the conversion of normal stem cells to malignant CSC may lead to targeted therapy specifically against CSC. This conversion information may be derived from investigating the biological behaviour of both normal stem cells and cancerous stem cells. Currently, there is little knowledge about the cellular and molecular mechanisms that govern the initiation and maintenance of CSC. Studies on co-evolution and interdependence of cancer with normal tissues may lead to a useful treatment paradigm of cancer. The crosstalk between normal stem cells and cancer formation may converge developmental stages of different types of stem cells (e.g. normal stem cells, CSC and embryonic stem cells). The differential studies of the convergence may result in novel therapies for treating cancers.
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http://dx.doi.org/10.4252/wjsc.v3.i9.83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192222PMC
September 2011

Increase developmental plasticity of human keratinocytes with gene suppression.

Proc Natl Acad Sci U S A 2011 Aug 18;108(31):12793-8. Epub 2011 Jul 18.

Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

Recent evidence indicates that p53 suppression increased the efficiency of induced pluripotent stem cell (iPSC) generation. This occurred even with the enforced expression of as few as two canonical transcription factors, Oct4 and Sox2. In this study, primary human keratinocytes were successfully induced into a stage of plasticity by transient inactivation of p53, without enforced expression of any of the transcription factors previously used in iPSC generation. These cells were later redifferentiated into neural lineages. The gene suppression plastic cells were morphologically indistinguishable from human ES cells. Gene suppression plastic cells were alkaline phosphatase-positive, had normal karyotypes, and expressed p53. Together with the accumulating evidence of similarities and overlapping mechanisms between iPSC generation and cancer formation, this finding sheds light on the emerging picture of p53 sitting at the crossroads between two intricate cellular potentials: stem cell vs. cancer cell generation. This finding further supports the crucial role played by p53 in cellular reprogramming and suggests an alternative method to switch the lineage identity of human cells. This reported method offers the potential for directed lineage switching with the goal of generating autologous cell populations for novel clinical applications for neurodegenerative diseases.
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http://dx.doi.org/10.1073/pnas.1100509108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150912PMC
August 2011

Mechanisms for progenitor cell-mediated repair for ischemic heart injury.

Curr Stem Cell Res Ther 2012 Jan;7(1):2-14

CHOC Children's Hospital Research Institute, University of California, Irrine, Orange, 92868, USA.

Recent studies have shown that treatments involving injection of stem cells into animals with damaged cardiac tissue result in improved cardiac functionality. Clinical trials have reported conflicting results concerning the recellularization of post-infarct collagen scars. No clear mechanism has so far emerged to fully explain how injected stem cells, specifically the commonly used mesenchymal stem cells (MSC) and endothelial precursor cells (EPC), help heal a damaged heart. Clearly, these injected stem cells must survive and thrive in the hypoxic environment that results after injury for any significant repair to occur. Here we discuss how ischemic preconditioning may lead to increased tolerance of stem cells to these harsh conditions and increase their survival and clinical potential after injection. As injected cells must reach the site in numbers large enough for repair to be functionally significant, homing mechanisms involved in stem cell migration are also discussed. We review the mechanisms of action stem cells may employ once they arrive at their target destination. These possible mechanisms include that the injected stem cells (1) secrete growth factors, (2) differentiate into cardiomyocytes to recellularize damaged tissue and strengthen the post-infarct scar, (3) transdifferentiate the host cells into cardiomyocytes, and (4) induce neovascularization. Finally, we discuss that tissue engineering may provide a standardized platform technology to produce clinically applicable stem cell products with these desired mechanistic capacities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544365PMC
http://dx.doi.org/10.2174/157488812798483449DOI Listing
January 2012

Therapeutic window, a critical developmental stage for stem cell therapies.

Curr Stem Cell Res Ther 2010 Dec;5(4):297-3

Neuro-Oncology Research Laboratory, Center for Neuroscience and Stem Cell Research, CHOC Children's Hospital, 455 S. Main Street, Orange, CA 92868-3874, USA.

In children, cancers are the deadliest of diseases and second only to accidents as the leading cause of death. The deadliest of the brain cancers are the malignant gliomas. Approximately two-thirds of children can survive less malignant types of brain cancers, however, in ~67% of these survivors recurs under the current regimes of surgery followed by administration of high doses toxic drugs and exposure to high doses of radiation. Even more distressing is that fortunate survivors are generally left with life-long cognitive disabilities. A new medical approach is desperately needed. Stem cells, with their natural ability to seek out brain tumors, could be used to accurately deliver therapy directly to the cancer sparing normal tissues for suppression of tumor growth. Despite exciting initial reports, clinical potency of stem cell therapy in animal brain tumor models has to date proven disappointing. Attempts to extrapolate the animal study results to humans are stymied by the fact that stem cells are heterogeneous, resulting in differences in their efficacy. Indeed, therapeutic success relies on an effective strategy to select for a stem cell sub-population within some particular stage of the development at which they are competitive and capable of targeting brain tumors. To improve this during developmental path, concept of a 'therapeutic window' is proposed. The "therapeutic window" for stem cells or more specifically a "biochemical therapeutic window" can be determined from biochemical assays and a "biological therapeutic window" from biological assays or even a molecular window for genetic description. Taken together, we can use selective processes to generate more effective stem cells to treat cancers as is clearly needed today.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546416PMC
December 2010

A biological global positioning system: considerations for tracking stem cell behaviors in the whole body.

Stem Cell Rev Rep 2010 Jun;6(2):317-33

Center for Neuroscience and Stem Cell Research, Children's Hospital of Orange County Research Institute, University of California Irvine, 455 South Main Street, Orange, CA 92868, USA.

Many recent research studies have proposed stem cell therapy as a treatment for cancer, spinal cord injuries, brain damage, cardiovascular disease, and other conditions. Some of these experimental therapies have been tested in small animals and, in rare cases, in humans. Medical researchers anticipate extensive clinical applications of stem cell therapy in the future. The lack of basic knowledge concerning basic stem cell biology-survival, migration, differentiation, integration in a real time manner when transplanted into damaged CNS remains an absolute bottleneck for attempt to design stem cell therapies for CNS diseases. A major challenge to the development of clinical applied stem cell therapy in medical practice remains the lack of efficient stem cell tracking methods. As a result, the fate of the vast majority of stem cells transplanted in the human central nervous system (CNS), particularly in the detrimental effects, remains unknown. The paucity of knowledge concerning basic stem cell biology--survival, migration, differentiation, integration in real-time when transplanted into damaged CNS remains a bottleneck in the attempt to design stem cell therapies for CNS diseases. Even though excellent histological techniques remain as the gold standard, no good in vivo techniques are currently available to assess the transplanted graft for migration, differentiation, or survival. To address these issues, herein we propose strategies to investigate the lineage fate determination of derived human embryonic stem cells (hESC) transplanted in vivo into the CNS. Here, we describe a comprehensive biological Global Positioning System (bGPS) to track transplanted stem cells. But, first, we review, four currently used standard methods for tracking stem cells in vivo: magnetic resonance imaging (MRI), bioluminescence imaging (BLI), positron emission tomography (PET) imaging and fluorescence imaging (FLI) with quantum dots. We summarize these modalities and propose criteria that can be employed to rank the practical usefulness for specific applications. Based on the results of this review, we argue that additional qualities are still needed to advance these modalities toward clinical applications. We then discuss an ideal procedure for labeling and tracking stem cells in vivo, finally, we present a novel imaging system based on our experiments.
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http://dx.doi.org/10.1007/s12015-010-9130-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887536PMC
June 2010

Stem cell engineering for treatment of heart diseases: potentials and challenges.

Cell Biol Int 2009 Mar 3;33(3):255-67. Epub 2008 Dec 3.

Children's Hospital of Orange County Research Institute, CA 92868, USA.

Heart disorders are a major health concern worldwide responsible for millions of deaths every year. Among the many disorders of the heart, myocardial infarction, which can lead to the development of congestive heart failure, arrhythmias, or even death, has the most severe social and economic ramifications. Lack of sufficient available donor hearts for heart transplantation, the only currently viable treatment for heart failure other than medical management options (ACE inhibition, beta blockade, use of AICDs, etc.) that improve the survival of patients with heart failure emphasises the need for alternative therapies. One promising alternative replaces cardiac muscle damaged by myocardial infarction with new contractile cardiomyocytes and vessels obtained through stem cell-based regeneration. We report on the state of the art of recovery of cardiac functions by using stem cell engineering. Current research focuses on (a) inducing stem cells into becoming cardiac cells before or after injection into a host, (b) growing replacement heart tissue in vitro, and (c) stimulating the proliferation of the post-mitotic cardiomyocytes in situ. The most promising treatment option for patients is the engineering of new heart tissue that can be implanted into damaged areas. Engineering of cardiac tissue currently employs the use of co-culture of stem cells with scaffold microenvironments engineered to improve tissue survival and enhance differentiation. Growth of heart tissue in vitro using scaffolds, soluble collagen, and cell sheets has unique advantages. To compensate for the loss of ventricular mass and contractility of the injured cardiomyocytes, different stem cell populations have been extensively studied as potential sources of new cells to ameliorate the injured myocardium and eventually restore cardiac function. Unresolved issues including insufficient cell generation survival, growth, and differentiation have led to mixed results in preclinical and clinical studies. Addressing these limitations should ensure the successful production of replacement heart tissue to benefit cardiac patients.
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http://dx.doi.org/10.1016/j.cellbi.2008.11.009DOI Listing
March 2009

A novel and generalizable organotypic slice platform to evaluate stem cell potential for targeting pediatric brain tumors.

Cancer Cell Int 2008 May 22;8. Epub 2008 May 22.

Center for Neuroscience and Stem Cell Research, Neuroscience Institute, Children's Hospital of Orange County Research Institute, 455 S, Main Street, Orange, CA 92868, USA.

Brain tumors are now the leading cause of cancer-related deaths in children under age 15. Malignant gliomas are, for all practical purposes, incurable and new therapeutic approaches are desperately needed. One emerging strategy is to use the tumor tracking capacity inherent in many stem cell populations to deliver therapeutic agents to the brain cancer cells. Current limitations of the stem cell therapy strategy include that stem cells are treated as a single entity and lack of uniform technology is adopted for selection of clinically relevant sub-populations of stem cells. Specifically, therapeutic success relies on the selection of a clinically competent stem cell population based on their capacity of targeting brain tumors. A novel and generalizable organotypic slice platform to evaluate stem cell potential for targeting pediatric brain tumors is proposed to fill the gap in the current work flow of stem cell-based therapy. The organotypic slice platform has advantages of being mimic in vivo model, easier to manipulate to optimize parameters than in vivo models such as rodents and primates. This model serves as a framework to address the discrepancy between anticipated in vivo results and actual in vivo results, a critical barrier to timely progress in the field of the use of stem cells for the treatment of neurological disorders.
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http://dx.doi.org/10.1186/1475-2867-8-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2474582PMC
May 2008

Vault reduction cranioplasty for extreme hydrocephalic macrocephaly.

J Neurosurg 2007 Oct;107(4 Suppl):332-7; discussion 330-1

Department of Neurosurgery, University of California, Irvine, USA.

Due to early diagnosis and treatment of hydrocephalus, neurosurgeons rarely are called upon to treat patients with extreme hydrocephalic macrocephaly. Macrocephaly can limit mobility and hygiene. The critical evaluation and surgical correction of the morphological problem of macrocephaly secondary to hydrocephalus is complex. Various techniques such as quadrantal, picket fence, crossbar, and modified rr techniques have been used to reduce the size of the cranial vault to decrease cranial volume while achieving good cosmesis. Limitations of vault reduction cranioplasty include the inability to alter the anteroposterior and lateral diameters of the skull base, the inability to shorten the superior sagittal sinus, and the need to avoid infolding of the brain due to the risk of venous infarcts. Reduction cranioplasty is indicated in the occasional patient whose large head size represents a mechanical or cosmetic problem of sufficient magnitude to seriously interfere with motor development and functioning, with resultant development of pressure sores and difficulties with nursing care. Reduction cranioplasty should be avoided in patients under the age of 3 years.
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http://dx.doi.org/10.3171/PED-07/10/332DOI Listing
October 2007

Cranial vault reduction cranioplasty in children with hydrocephalic macrocephaly.

J Craniofac Surg 2006 Jul;17(4):645-55

Aesthetic and Plastic Surgery Institute, University of California - Irvine Medical Center, California 92868-3298, USA.

Craniofacial surgeons are rarely presented patients with extreme hydrocephalic macrocephaly due to early diagnosis and treatment of the hydrocephalus. Macrocephaly can significantly limit or prohibit mobility, hygiene and can drastically change lifestyle and developmental issues. The authors herein report on four consecutive total cranial vault reduction cranioplasty procedures for correction of hydrocephalic macrocephaly. The patients had a reduction in cranial volume ranging from 111-641 mL. All patients survived the procedure. Improvement in head control and aesthetics were improved in all patients. All of the patients required at least one shunt revision following the procedure. We conclude that total cranial vault reshaping is safe and effective for the treatment of macrocephaly secondary to hydrocephalus.
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http://dx.doi.org/10.1097/00001665-200607000-00007DOI Listing
July 2006

Acquired unilateral coronal craniosynostosis.

J Craniofac Surg 2006 May;17(3):561-7

The Aesthetic and Plastic Surgery Institute, University of California, Irvine, CA 92868-3298, USA.

Coronal craniosynostosis of both the sporadic and syndromic types have been comprehensively described and extensively investigated. Previously, there have been no cases reported of acquired unilateral coronal craniosynostosis. We present a case of a 22-month-old male who developed a left unilateral coronal craniosynostosis following multiple surgical interventions for birth-related intracranial injuries. The genesis and molecular biology of craniosynostosis are discussed; patient presentation and treatment are reviewed.
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http://dx.doi.org/10.1097/00001665-200605000-00030DOI Listing
May 2006

Improved survival in central nervous system aspergillosis: a series of immunocompromised children with leukemia undergoing stereotactic resection of aspergillomas. Report of four cases.

J Neurosurg 2005 Oct;103(4 Suppl):374-8

Department of Neurological Surgery, University of California, Irvine School of Medicine, Irvine, USA.

Central nervous system (CNS) aspergillosis remains a daunting diagnosis. This opportunistic mycosis historically carries a mortality rate approaching 100% in immunocompromised patients, with death ensuing within days after the onset of neurological symptoms. From their literature review, the authors concluded that children contracting CNS aspergillosis while undergoing systemic chemotherapy for leukemias represent a particularly unfortunate prognostic group. Antifungal medications prove ineffective for treating CNS aspergillosis in patients immunocompromised because of their chemotherapy regimens. In contrast, withholding chemotherapy to reverse immunosuppression, thereby improving the efficacy of antifungal medications, allows for progression of the primary leukemic disease. The authors present a series of four immunosuppressed patients whose course of treatment for leukemia was complicated by CNS Aspergillus sp. abscesses. Multiple cerebral fungal abscesses developed in two patients and a single cerebral abscess developed in two. All four patients underwent frameless stereotactic resection of the aspergilloma. All children later experienced resolution of their CNS infections and full neurological recovery. At 2- to 4-year follow ups, one patient has died of leukemia and the other three continue to thrive without evidence of recurrent aspergillosis. Given the grave natural history cited in the literature for this disease when medical treatment is instituted alone, the authors stress the crucial role of stereotactic neurosurgery for the intelligent treatment of immunocompromised children suspected of harboring a CNS aspergilloma abscesses. The authors propose that the goal for successful treatment in these patients should be gross-total resection of the abscess, its wall, and its capsule.
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http://dx.doi.org/10.3171/ped.2005.103.4.0374DOI Listing
October 2005
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