Publications by authors named "Alison Ross"

39 Publications

A Simulation Toolkit for Testing the Sensitivity and Accuracy of Corticometry Pipelines.

Front Neuroinform 2021 26;15:665560. Epub 2021 Jul 26.

McGill Centre for Integrative Neuroscience, Montreal Neurological Institute, Montreal, QC, Canada.

In recent years, the replicability of neuroimaging findings has become an important concern to the research community. Neuroimaging pipelines consist of myriad numerical procedures, which can have a cumulative effect on the accuracy of findings. To address this problem, we propose a method for simulating artificial lesions in the brain in order to estimate the sensitivity and specificity of lesion detection, using different automated corticometry pipelines. We have applied this method to different versions of two widely used neuroimaging pipelines (CIVET and FreeSurfer), in terms of coefficients of variation; sensitivity and specificity of detecting lesions in 4 different regions of interest in the cortex, while introducing variations to the lesion size, the blurring kernel used prior to statistical analyses, and different thickness metrics (in CIVET). These variations are tested in a between-subject design (in two random groups, with and without lesions, using T1-weigted MRIs of 152 individuals from the International Consortium of Brain Mapping (ICBM) dataset) and in a within-subject pre-/post-lesion design [using 21 T1-Weighted MRIs of a single adult individual, scanned in the Infant Brain Imaging Study (IBIS)]. The simulation method is sensitive to partial volume effect and lesion size. Comparisons between pipelines illustrate the ability of this method to uncover differences in sensitivity and specificity of lesion detection. We propose that this method be adopted in the workflow of software development and release.
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http://dx.doi.org/10.3389/fninf.2021.665560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350777PMC
July 2021

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues.

Sci Adv 2021 Jan 27;7(5). Epub 2021 Jan 27.

Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.

Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically responsive bioartificial tissue that responds to mechanical loading to produce a preprogrammed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not by direct cellular deformation, suggesting that tissue loading is transduced into an osmotic signal that activates TRPV4. Either osmotic or mechanical loading of tissues transduced with TRPV4-responsive circuits protected constructs from inflammatory degradation by interleukin-1α. This synthetic mechanobiology approach was used to develop a mechanogenetic system to enable long-term, autonomously regulated drug delivery driven by physiologically relevant loading.
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http://dx.doi.org/10.1126/sciadv.abd9858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840132PMC
January 2021

Proteome Turnover in the Spotlight: Approaches, Applications, and Perspectives.

Mol Cell Proteomics 2020 Dec 7;20:100016. Epub 2020 Dec 7.

Department of Biological Sciences, Columbia University, New York, New York, USA. Electronic address:

In all cells, proteins are continuously synthesized and degraded to maintain protein homeostasis and modify gene expression levels in response to stimuli. Collectively, the processes of protein synthesis and degradation are referred to as protein turnover. At a steady state, protein turnover is constant to maintain protein homeostasis, but in dynamic responses, proteins change their rates of synthesis and degradation to adjust their proteomes to internal or external stimuli. Thus, probing the kinetics and dynamics of protein turnover lends insight into how cells regulate essential processes such as growth, differentiation, and stress response. Here, we outline historical and current approaches to measuring the kinetics of protein turnover on a proteome-wide scale in both steady-state and dynamic systems, with an emphasis on metabolic tracing using stable isotope-labeled amino acids. We highlight important considerations for designing proteome turnover experiments, key biological findings regarding the conserved principles of proteome turnover regulation, and future perspectives for both technological and biological investigation.
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http://dx.doi.org/10.1074/mcp.R120.002190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950106PMC
December 2020

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

The miRNA-mRNA interactome of murine induced pluripotent stem cell-derived chondrocytes in response to inflammatory cytokines.

FASEB J 2020 09 7;34(9):11546-11561. Epub 2020 Aug 7.

Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA.

Osteoarthritis (OA) is a degenerative joint disease, and inflammation within an arthritic joint plays a critical role in disease progression. Pro-inflammatory cytokines, specifically IL-1 and TNF-α, induce aberrant expression of catabolic and degradative enzymes and inflammatory cytokines in OA and result in a challenging environment for cartilage repair and regeneration. MicroRNAs (miRNAS) are small noncoding RNAs and are important regulatory molecules that act by binding to target messenger RNAs (mRNAs) to reduce protein synthesis and have been implicated in many diseases, including OA. The goal of this study was to understand the mechanisms of miRNA regulation of the transcriptome of tissue-engineered cartilage in response to IL-1β and TNF-α using an in vitro murine induced pluripotent stem cell (miPSC) model system. We performed miRNA and mRNA sequencing to determine the temporal and dynamic responses of genes to specific inflammatory cytokines as well as miRNAs that are differentially expressed (DE) in response to both cytokines or exclusively to IL-1β or TNF-α. Through integration of mRNA and miRNA sequencing data, we created networks of miRNA-mRNA interactions which may be controlling the response to inflammatory cytokines. Within the networks, hub miRNAs, miR-29b-3p, miR-17-5p, and miR-20a-5p, were identified. As validation of these findings, we found that delivery of miR-17-5p and miR-20a-5p mimics significantly decreased degradative enzyme activity levels while also decreasing expression of inflammation-related genes in cytokine-treated cells. This study utilized an integrative approach to determine the miRNA interactome controlling the response to inflammatory cytokines and novel mediators of inflammation-driven degradation in tissue-engineered cartilage.
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http://dx.doi.org/10.1096/fj.202000889RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725885PMC
September 2020

The Politics of Disease Epidemics: a Comparative Analysis of the SARS, Zika, and Ebola Outbreaks.

Glob Soc Welf 2020 3;7(1):33-45. Epub 2018 Sep 3.

Department of Health, Aging and Society, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8 Canada.

Over the past few decades, disease outbreaks have become increasingly frequent and widespread. The epicenters of these outbreaks have differed, and could be linked to different economic contexts. Arguably, the responses to these outbreaks have been "political" and inherently burdensome to marginalized populations. Key lessons can be learned from exploring the narratives about the different epidemics in varying income settings. Based on a review of the published medical, social, and political literature, which was accessed using four electronic databases-PubMed, Sociological Abstracts, Scholars Portal, and Web of Science, the overall objective of this paper discuss scholars' narratives on the "politics" of Ebola in a low-income setting, Zika virus in a middle-income setting, and SARS in a high-income setting. Various themes of the politics of epidemics were prominent in the literature. The narratives demonstrated the influence of power in whose narratives and what narratives are presented in the literature. While marginalized populations were reported to have borne the brunt of all disease outbreaks in the different contexts, the prevalence of their narratives within the reviewed literature was limited. Regardless of income setting, there is a need to give voice to the most marginalized communities during an epidemic. The experiences and narratives of those most vulnerable to an epidemic-specifically poor communities-need to be represented in the literature. This could contribute to mitigating some of the negative impact of the politics in epidemics.
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http://dx.doi.org/10.1007/s40609-018-0123-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100305PMC
September 2018

"At 80 I Know Myself": Embodied Learning and Older Adults' Experiences of Polypharmacy and Perceptions of Deprescribing.

Gerontol Geriatr Med 2019 Jan-Dec;5:2333721419895617. Epub 2019 Dec 20.

McMaster University, Hamilton, Ontario, Canada.

In response to the risks of polypharmacy for older adults, there are increasing calls for the development and implementation of deprescribing programs. This article examines the forms of expertise that inform older adults' decisions about how to use medications given concerns over polypharmacy and a clinical focus on deprescribing. In-depth interviews with older adults found that diverse knowledge sources underpin decisions regarding polypharmacy and deprescribing. Findings indicate that this knowledge is formed through a lifetime of embodied learning-the production of relevant knowledge through lived experiences of the body. By way of this embodied learning, older adults possess individualized knowledge bases that inform health and health care decisions, especially regarding the use of medications. If deprescribing programs are to be embedded into standard preventive medical care of older adults, then it is valuable for health care providers to be aware of and take seriously the contribution of embodied knowledge.
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http://dx.doi.org/10.1177/2333721419895617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926975PMC
December 2019

Confronting Medicine's Dichotomies: Older Adults' Use of Interpretative Repertoires in Negotiating the Paradoxes of Polypharmacy and Deprescribing.

Qual Health Res 2020 02 27;30(3):448-457. Epub 2019 Aug 27.

McMaster University, Hamilton, Ontario, Canada.

To address the risks associated with polypharmacy, health care providers are investigating the feasibility of deprescribing programs as part of routine medical care to reduce medication burden to older adults. As older adults are enrolled in these programs, they are confronted with two dominant and legitimate accounts of medications, labeled the medication paradox: . We investigated how the medication paradox operates in the lives of older adults. In-depth qualitative interviews were conducted and analyzed with older adults aged 70+ to identify the various paradoxes that seniors live through regarding their medications and the narratives that they engage to negotiate these contradictions. Older adults were found to have established interpretative repertoires to make sense of the incongruent narratives of the medication paradox. In this article, we demonstrate older adults' efforts to carve out their unique place in the dichotomized institution of medicine.
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http://dx.doi.org/10.1177/1049732319868981DOI Listing
February 2020

An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol.

Biochemistry 2019 07 18;58(30):3225-3231. Epub 2019 Jul 18.

Department of Pharmacology and Toxicology, College of Pharmacy , University of Arizona , 1703 East Mabel Street , P.O. Box 210207, Tucson , Arizona 85721 , United States.

A library of natural products and their derivatives was screened for inhibition of protein tyrosine phosphatase (PTP) 1B, which is a validated drug target for the treatment of obesity and type II diabetes. Of those active in the preliminary assay, the most promising was compound containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol () with hydrazine. This nitrogen-atom augmented radicicol derivative was found to be PTP1B selective relative to other highly homologous nonreceptor PTPs. Biochemical evaluation, molecular docking, and mutagenesis revealed to be an allosteric inhibitor of PTP1B with a submicromolar . Cellular analyses using C2C12 myoblasts indicated that restored insulin signaling and increased glucose uptake.
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http://dx.doi.org/10.1021/acs.biochem.9b00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610018PMC
July 2019

Publisher Correction: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.

Nat Genet 2019 Jul;51(7):1192

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41588-019-0448-1DOI Listing
July 2019

A high throughput substrate binding assay reveals hexachlorophene as an inhibitor of the ER-resident HSP70 chaperone GRP78.

Bioorg Med Chem Lett 2019 07 20;29(14):1689-1693. Epub 2019 May 20.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, PO Box 210207, Tucson, AZ 85721, USA. Electronic address:

Glucose-regulated protein 78 (GRP78) is the ER resident 70 kDa heat shock protein 70 (HSP70) and has been hypothesized to be a therapeutic target for various forms of cancer due to its role in mitigating proteotoxic stress in the ER, its elevated expression in some cancers, and the correlation between high levels for GRP78 and a poor prognosis. Herein we report the development and use of a high throughput fluorescence polarization-based peptide binding assay as an initial step toward the discovery and development of GRP78 inhibitors. This assay was used in a pilot screen to discover the anti-infective agent, hexachlorophene, as an inhibitor of GRP78. Through biochemical characterization we show that hexachlorophene is a competitive inhibitor of the GRP78-peptide interaction. Biological investigations showed that this molecule induces the unfolded protein response, induces autophagy, and leads to apoptosis in a colon carcinoma cell model, which is known to be sensitive to GRP78 inhibition.
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http://dx.doi.org/10.1016/j.bmcl.2019.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608569PMC
July 2019

Designer Stem Cells: Genome Engineering and the Next Generation of Cell-Based Therapies.

J Orthop Res 2019 06 2;37(6):1287-1293. Epub 2019 May 2.

Department of Medicine, Division of Rheumatology, Washington University, St. Louis, Missouri.

Stem cells provide tremendous promise for the development of new therapeutic approaches for musculoskeletal conditions. In addition to their multipotency, certain types of stem cells exhibit immunomodulatory effects that can mitigate inflammation and enhance tissue repair. However, the translation of stem cell therapies to clinical practice has proven difficult due to challenges in intradonor and interdonor variability, engraftment, variability in recipient microenvironment and patient indications, and limited therapeutic biological activity. In this regard, the success of stem cell-based therapies may benefit from cellular engineering approaches to enhance factors such as purification, homing and cell survival, trophic effects, or immunomodulatory signaling. By combining recent advances in gene editing, synthetic biology, and tissue engineering, the potential exists to create new classes of "designer" cells that have prescribed cell-surface molecules and receptors as well as synthetic gene circuits that provide for autoregulated drug delivery or enhanced tissue repair. Published by Wiley Periodicals, Inc. J Orthop Res 37:1287-1293, 2019.
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http://dx.doi.org/10.1002/jor.24304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546536PMC
June 2019

A Synthetic Gene Circuit for Self-Regulating Delivery of Biologic Drugs in Engineered Tissues.

Tissue Eng Part A 2019 05;25(9-10):809-820

1 Department of Orthopedic Surgery, Washington University in Saint Louis, Saint Louis, Missouri.

Impact Statement: We engineered a synthetic transcription system based on nuclear factor kappa-light-chain-enhancer of activated B cells signaling that can attenuate the effects of the inflammatory cytokine interleukin (IL)-1α in a self-regulating manner. This system responds in a time- and dose-dependent manner to rapidly produce therapeutic levels of IL-1 receptor antagonist (IL-1Ra). The use of lentiviral gene therapy allows this system to be utilized through different transduction methods and in different cell types for a variety of applications. Broadly, this approach may be applicable in developing autoregulated biologic systems for tissue engineering and drug delivery in a range of disease applications.
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http://dx.doi.org/10.1089/ten.TEA.2019.0027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533793PMC
May 2019

Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Eur J Hum Genet 2018 10 28;26(10):1462-1477. Epub 2018 Jun 28.

Genome Damage & Stability Centre, University of Sussex, Brighton, UK.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
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http://dx.doi.org/10.1038/s41431-018-0185-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138755PMC
October 2018

Publisher Correction: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.

Nat Genet 2018 05;50(5):767

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.

In the version of this article initially published, Wendy Bickmore and Madapura Pradeepa were incorrectly not indicated as corresponding authors. The error has been corrected in the HTML and PDF versions of the paper.
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http://dx.doi.org/10.1038/s41588-018-0069-0DOI Listing
May 2018

BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.

Nat Genet 2018 03 29;50(3):329-332. Epub 2018 Jan 29.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.

We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression.
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http://dx.doi.org/10.1038/s41588-018-0042-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469577PMC
March 2018

ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A.

Bioorg Med Chem Lett 2017 09 19;27(17):4082-4085. Epub 2017 Jul 19.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tuscon, AZ 85721, United States. Electronic address:

Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5' m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A. eIF4A is an ATP-dependent helicase and because it is the only enzyme in the eIF4F complex, it has been shown to be a potential therapeutic target for a variety of malignancies. To this end, we have used a simple ATPase biochemical screen to survey several hundred marine and terrestrial derived natural products. Herein, we report the discovery of two natural products from marine sources, elisabatin A (1) and allolaurinterol (2), which show low µM inhibition of eIF4A ATPase activity. Enzymological analyses revealed 1 and 2 to be ATP-competitive, and cellular evaluations showed reasonable cytotoxicity against A549 (lung cancer) and MDA-MA-468 (breast cancer) cell lines. However, only compound 2 showed potent inhibition of helicase activity congruent with its ATPase inhibitory activity.
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http://dx.doi.org/10.1016/j.bmcl.2017.07.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593424PMC
September 2017

Increasing Primary Care Access Close to Home for Residents of Remote Communities in Northern Alberta.

Healthc Q 2016 ;19(3):61-66

Alison H. Edie is a family nurse practitioner with extensive experience in the primary care of underserved populations. Her research interests are in understanding the issues and concerns of vulnerable populations with a focus on self-efficacy and health promotion practices of women and adolescents.

Residents of Canada's rural and remote communities know the challenges associated with accessing consistent healthcare. Alberta Health Services uses telehealth technology to minimize travel for rural and remote residents who require follow-up with specialists, however until recently, telehealth was only used in specialty care. This article describes a pilot project introduced in two remote northern Alberta communities to determine the feasibility and sustainability of using telehealth in the delivery of primary healthcare. Included in the article are descriptions of each phase of the project from seeking stakeholder approval through interpretation of findings and continuation of the project after it was determined successful. Jurisdictions interested in attempting their own telehealth program will be interested in the challenges and successes identified during the process. Although the project was successful, further studies are needed to determine if similar findings could be expected in other communities and populations.
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http://dx.doi.org/10.12927/hcq.2016.24863DOI Listing
May 2017

Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing.

Proc Natl Acad Sci U S A 2016 08 18;113(31):E4513-22. Epub 2016 Jul 18.

Cytex Therapeutics, Durham, NC 27705;

Biological resurfacing of entire articular surfaces represents an important but challenging strategy for treatment of cartilage degeneration that occurs in osteoarthritis. Not only does this approach require anatomically sized and functional engineered cartilage, but the inflammatory environment within an arthritic joint may also inhibit chondrogenesis and induce degradation of native and engineered cartilage. The goal of this study was to use adult stem cells to engineer anatomically shaped, functional cartilage constructs capable of tunable and inducible expression of antiinflammatory molecules, specifically IL-1 receptor antagonist (IL-1Ra). Large (22-mm-diameter) hemispherical scaffolds were fabricated from 3D woven poly(ε-caprolactone) (PCL) fibers into two different configurations and seeded with human adipose-derived stem cells (ASCs). Doxycycline (dox)-inducible lentiviral vectors containing eGFP or IL-1Ra transgenes were immobilized to the PCL to transduce ASCs upon seeding, and constructs were cultured in chondrogenic conditions for 28 d. Constructs showed biomimetic cartilage properties and uniform tissue growth while maintaining their anatomic shape throughout culture. IL-1Ra-expressing constructs produced nearly 1 µg/mL of IL-1Ra upon controlled induction with dox. Treatment with IL-1 significantly increased matrix metalloprotease activity in the conditioned media of eGFP-expressing constructs but not in IL-1Ra-expressing constructs. Our findings show that advanced textile manufacturing combined with scaffold-mediated gene delivery can be used to tissue engineer large anatomically shaped cartilage constructs that possess controlled delivery of anticytokine therapy. Importantly, these cartilage constructs have the potential to provide mechanical functionality immediately upon implantation, as they will need to replace a majority, if not the entire joint surface to restore function.
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http://dx.doi.org/10.1073/pnas.1601639113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978289PMC
August 2016

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.

Am J Hum Genet 2015 Aug 30;97(2):343-52. Epub 2015 Jul 30.

Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.
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http://dx.doi.org/10.1016/j.ajhg.2015.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573244PMC
August 2015

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

J Med Genet 2014 Oct 14;51(10):659-68. Epub 2014 Aug 14.

Clinical Genetics, Yorkshire Regional Genetics Service, Leeds, UK.

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.

Methods: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.

Results: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.

Conclusions: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.
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http://dx.doi.org/10.1136/jmedgenet-2014-102573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173748PMC
October 2014

Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder.

Am J Med Genet A 2012 Nov 28;158A(11):2733-42. Epub 2012 Sep 28.

Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.
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http://dx.doi.org/10.1002/ajmg.a.35681DOI Listing
November 2012

Dominant missense mutations in ABCC9 cause Cantú syndrome.

Nat Genet 2012 May 18;44(7):793-6. Epub 2012 May 18.

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.
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http://dx.doi.org/10.1038/ng.2324DOI Listing
May 2012

Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis.

Eur J Hum Genet 2012 Jun 15;20(6):598-606. Epub 2012 Feb 15.

Department of Human Genetics 836, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.
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http://dx.doi.org/10.1038/ejhg.2011.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355263PMC
June 2012

Synchronous metastatic seminoma and primary retroperitoneal ganglioneuroma: case report and literature review.

Can Urol Assoc J 2011 Dec;5(6):E109-12

Vancouver Island Centre, British Columbia Cancer Agency, Victoria, BC;

Testicular cancer is the most common malignancy in young men with seminomas comprising almost half of all germ cell tumours. Benign ganglioneuromas are rare tumours derived from the sympathetic nervous system. They usually occur in aldolescents and young adults and are predominantly located in the mediastinum and retroperitoneum. We report a case of a patient with synchronous metastatic testicular seminoma with retroperitoneal lymph node involvement and a benign retroperitoneal ganglioneuroma (RGN) which caused diagnostic and management challenges. The patient had a complete response following combination chemotherapy for his seminoma and subsequently underwent complete resection of his ganglioneuroma.
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http://dx.doi.org/10.5489/cuaj.10164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235184PMC
December 2011

Mutations in the pre-replication complex cause Meier-Gorlin syndrome.

Nat Genet 2011 Feb 27;43(4):356-9. Epub 2011 Feb 27.

Medical Research Council (MRC) Human Genetics Unit (HGU), Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.

Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears¹⁻³. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.
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http://dx.doi.org/10.1038/ng.775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068194PMC
February 2011

Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio.

J Gastroenterol Hepatol 2011 Jan;26(1):49-54

Department of Medicine, University of Otago, Christchurch, New Zealand.

Background And Aim: Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response.

Methods: Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared.

Results: The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol.

Conclusions: In those with a high 6-MMPN:6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.
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http://dx.doi.org/10.1111/j.1440-1746.2010.06489.xDOI Listing
January 2011

Patterns of expression of Bardet-Biedl syndrome proteins in the mammalian cochlea suggest noncentrosomal functions.

J Comp Neurol 2009 May;514(2):174-88

Institute of Child Health, University College London, London WC1N1EH, United Kingdom.

Bardet-Biedl syndrome is a heterogeneous disorder causing a spectrum of symptoms, including visual impairment, kidney disease, and hearing impairment. Evidence suggests that BBS gene mutations cause defective ciliogenesis and/or cilium dysfunction. Cochlear development is affected by BBS gene deletion, and adult Bbs6(-/-) and Bbs4(-/-) mice are hearing impaired. This study addresses BBS protein expression in the rodent cochlea, to gain a better understanding of its function in vivo. As predicted by in vitro studies, Bbs6 immunofluorescence was localized to the basal bodies of supporting cells and sensory hair cells prior to the onset of hearing. In adult tissue, Bbs6 expression persisted in afferent neurons, including within the dendrites that innervate hair cells, implicating Bbs6 in a sensory neuronal function. Bbs2, which interacts with Bbs6, was also localized to hair cell basal bodies and stereociliary bundles. Additionally, Bbs2 was expressed in supporting cells at their intercellular boundaries, in a spatiotemporal pattern mirroring the development of the microtubule network. Bbs4 localized to cilia and developing cytoplasmic microtubule arrays. Pcm-1, a microtubular protein that interacts with Bbs4 in vitro, showed a comparable expression. Depolymerization of microtubules in slice preparations of the living cochlea resulted in Bbs4 and Pcm-1 mislocalization. Pcm-1 was also mislocalized in Bbs4(-/-) mice. This suggests that Bbs4/Pcm-1 interactions may be important in microtubule-dependent cytoplasmic trafficking in vivo. In summary, our findings indicate that BBS proteins adopt a range of cellular distributions in vivo, not restricted to the centrosome or cilium, and so broaden the possible underlying pathomechanisms of the disease.
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http://dx.doi.org/10.1002/cne.22001DOI Listing
May 2009

Urachal-sigmoid fistula associated with diverticular disease.

Can Urol Assoc J 2007 Mar;1(1):52-4

Department of Urologic Sciences, University of British Columbia, Vancouver, BC.

Background: Urachal anomalies rarely present in adulthood. We report the second known case of urachal-sigmoid fistula associated with diverticular disease.

Method: We performed a case report and literature review. We searched MEDLINE and PubMed using the search words "urachus," "urachal fistula," "sigmoid colon" and "diverticulosis."

Results: Our literature review revealed 1 previous report of urachal-sigmoid fistula associated with diverticular disease. We reviewed other publications with respect to pathophysiology, diagnosis and management of urachal disease.

Conclusion: Urachal disease that presents in an adult is usually the result of some complication of a urachal anomaly. Various modes of imaging may help confirm the diagnosis, although CT sinography has been recommended and was key in the present case. Management includes eradication of infection and, usually, surgical intervention.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2422915PMC
March 2007
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