Publications by authors named "E Elizabeth Patton"

165 Publications

The twin pillars of Disease Models & Mechanisms.

Dis Model Mech 2021 Feb 22;14(2). Epub 2021 Feb 22.

MRC Human Genetics Unit and Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK

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http://dx.doi.org/10.1242/dmm.048951DOI Listing
February 2021

Melanoma models for the next generation of therapies.

Cancer Cell 2021 Feb 4. Epub 2021 Feb 4.

Center for Cancer Research, NCI, NIH, 37 Convent Drive, Bethesda, MD 20892, USA. Electronic address:

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.
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http://dx.doi.org/10.1016/j.ccell.2021.01.011DOI Listing
February 2021

MITF reprograms the extracellular matrix and focal adhesion in melanoma.

Elife 2021 Jan 13;10. Epub 2021 Jan 13.

Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

The microphthalmia-associated transcription factor (MITF) is a critical regulator of melanocyte development and differentiation. It also plays an important role in melanoma where it has been described as a molecular rheostat that, depending on activity levels, allows reversible switching between different cellular states. Here, we show that MITF directly represses the expression of genes associated with the extracellular matrix (ECM) and focal adhesion pathways in human melanoma cells as well as of regulators of epithelial-to-mesenchymal transition (EMT) such as CDH2, thus affecting cell morphology and cell-matrix interactions. Importantly, we show that these effects of MITF are reversible, as expected from the rheostat model. The number of focal adhesion points increased upon MITF knockdown, a feature observed in drug-resistant melanomas. Cells lacking MITF are similar to the cells of minimal residual disease observed in both human and zebrafish melanomas. Our results suggest that MITF plays a critical role as a repressor of gene expression and is actively involved in shaping the microenvironment of melanoma cells in a cell-autonomous manner.
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http://dx.doi.org/10.7554/eLife.63093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857731PMC
January 2021

Deciphering melanoma cell states and plasticity with zebrafish models.

J Invest Dermatol 2020 Dec 16. Epub 2020 Dec 16.

MRC Human Genetics Unit, and CRUK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, Western General Campus, University of Edinburgh, Edinburgh EH4 2XU. Electronic address:

Dynamic cellular heterogeneity underlies melanoma progression and therapy resistance. Advances in single cell technologies have revealed an increasing number of tumor and microenvironment cell states in melanoma but little is understood about their function in vivo. Zebrafish models are a powerful system for discovery, live-imaging and functional investigation of cell states throughout melanoma progression and treatment. By capturing dynamic melanoma states in living animals, zebrafish have the potential to resolve the complexity of melanoma heterogeneity from a single cell through to disease processes within the context of the whole body, revealing novel cancer biology and therapeutic targets.
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http://dx.doi.org/10.1016/j.jid.2020.12.007DOI Listing
December 2020

NRAS melanoma tumor formation is reduced by p38-MAPK14 activation in zebrafish models and NRAS-mutated human melanoma cells.

Pigment Cell Melanoma Res 2020 Sep 10. Epub 2020 Sep 10.

University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Oncogenic BRAF and NRAS mutations drive human melanoma initiation. We used transgenic zebrafish to model NRAS-mutant melanoma, and the rapid tumor onset allowed us to study candidate tumor suppressors. We identified P38α-MAPK14 as a potential tumor suppressor in The Cancer Genome Atlas melanoma cohort of NRAS-mutant melanomas, and overexpression significantly increased the time to tumor onset in transgenic zebrafish with NRAS-driven melanoma. Pharmacological activation of P38α-MAPK14 using anisomycin reduced in vitro viability of melanoma cultures, which we confirmed by stable overexpression of p38α. We observed that the viability of MEK inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK inhibition. Our study demonstrates that activating the p38α-MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo. SIGNIFICANCE: The significance of our study is in the accountability of NRAS mutations in melanoma. We demonstrate here that activation of p38α-MAPK14 pathway can abrogate NRAS-mutant melanoma which is contrary to the previously published role of p38α-MAPK14 pathway in BRAF mutant melanoma. These results implicate that BRAF and NRAS-mutant melanoma may not be identical biologically. We also demonstrate the translational benefit of our study by using a small molecule compound-anisomycin (already in use for other diseases in clinical trials) to activate p38α-MAPK14 pathway.
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http://dx.doi.org/10.1111/pcmr.12925DOI Listing
September 2020

Spontaneously occurring melanoma in animals and their relevance to human melanoma.

J Pathol 2020 Sep 31;252(1):4-21. Epub 2020 Jul 31.

Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.

In contrast to other cancer types, melanoma incidence has been increasing over the last 50 years, and while it still represents less than 5% of all cutaneous malignancies, melanoma accounts for the majority of skin cancer deaths, due to its propensity to metastasise. Whilst melanoma most commonly affects the skin, it can also arise in mucosal surfaces, the eye, and the brain. For new therapies to be developed, a better understanding of the genetic landscape, signalling pathways, and tumour-microenvironmental interactions is needed. This is where animal models are of critical importance. The mouse is the foremost used model of human melanoma. Arguably this is due to its plethora of benefits as a laboratory animal; however, it is important to note that unlike humans, melanocytes are not present at the dermal-epidermal junction in mice and mice do not develop melanoma without genetic manipulation. In contrast, there are numerous reports of animals that spontaneously develop melanoma, ranging from sharks and parrots to hippos and monkeys. In addition, several domesticated and laboratory-bred animals spontaneously develop melanoma or UV-induced melanoma, specifically, fish, opossums, pigs, horses, cats, and dogs. In this review, we look at spontaneously occurring animal 'models' of melanoma and discuss their relevance to the different types of melanoma found in humans. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland..
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http://dx.doi.org/10.1002/path.5505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497193PMC
September 2020

PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation.

Dev Cell 2020 08 10;54(3):317-332.e9. Epub 2020 Jul 10.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address:

Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.
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http://dx.doi.org/10.1016/j.devcel.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435699PMC
August 2020

Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution.

Mol Cell 2020 08 11;79(3):472-487.e10. Epub 2020 Jun 11.

Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK. Electronic address:

It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.
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http://dx.doi.org/10.1016/j.molcel.2020.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427332PMC
August 2020

Here's looking at you, kid? Maternal depression and adolescent attention to self- or other-directed emotional faces.

J Affect Disord 2020 07 24;272:38-45. Epub 2020 Apr 24.

Department of Psychological Sciences, Case Western Reserve University, 11200 Bellflower Road, Cleveland, OH 44106-7123, United States.

Background: Maternal depression history represents a significant risk factor for developing psychopathology in children, altered emotional responding may represent a central risk pathway. However, additional research is needed on factors that affect the strength or direction of response alterations in relation to depression-risk in youth. In particular, facial orientation and gaze direction may alter personal relevance, with emotions directed towards an individual heightening motivational salience, compared to emotions directed away.

Methods: Mother-daughter dyads (N = 56) were recruited based on presence or absence of maternal depression history and absence of youth depression. In line with theoretical perspectives suggesting diminished sensitivity to emotional context in relation to depression risk, we examined three Event-Related Potential (ERP) components in relation to forward versus averted emotional faces in a sample of girls with and without a maternal history of depression: the N200, N400, and Late Positive Potential (LPP).

Results: Results showed a significant maternal depression history by face-orientation effect. Low-risk girls exhibited more negative N200 and N400 amplitudes for straight (M = -3.72, SE = 0.83; M = -3.57, SE = 0.86) versus averted (M = -2.15, SE = 0.76; M = -1.68, SE = 0.81) faces, while girls of mothers with histories of depression showed undifferentiated N200 or N400 responses in relation to face orientation. For LPP amplitudes, low-risk girls exhibited significantly more positive LPP amplitudes than high-risk girls, but only for averted faces (M = 0.69, SE = 0.59 and M = -2.63, SE = 0.74, respectively).

Limitations: Cross-sectional design and limited sample.

Conclusions: Results indicate that familial depression risk is associated with altered responsivity to face-orientation, these were interpreted as representing differential sensitivity to the personal-relevance of emotional stimuli.
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http://dx.doi.org/10.1016/j.jad.2020.03.149DOI Listing
July 2020

Fgfr3 Is a Positive Regulator of Osteoblast Expansion and Differentiation During Zebrafish Skull Vault Development.

J Bone Miner Res 2020 09 26;35(9):1782-1797. Epub 2020 May 26.

Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, Université de Paris, Imagine Institute, Paris, France.

Gain or loss-of-function mutations in fibroblast growth factor receptor 3 (FGFR3) result in cranial vault defects highlighting the protein's role in membranous ossification. Zebrafish express high levels of fgfr3 during skull development; in order to study FGFR3's role in cranial vault development, we generated the first fgfr3 loss-of-function zebrafish (fgfr3 ). The mutant fish exhibited major changes in the craniofacial skeleton, with a lack of sutures, abnormal frontal and parietal bones, and the presence of ectopic bones. Integrated analyses (in vivo imaging and single-cell RNA sequencing of the osteoblast lineage) of zebrafish fgfr3 revealed a delay in osteoblast expansion and differentiation, together with changes in the extracellular matrix. These findings demonstrate that fgfr3 is a positive regulator of osteogenesis. We conclude that changes in the extracellular matrix within growing bone might impair cell-cell communication, mineralization, and new osteoblast recruitment. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4042DOI Listing
September 2020

Persistent pruritic papules on the buttocks.

Cutis 2019 Dec;104(6):E4-E6

Dermatology Associates, St. Luke's Hospital, Duluth, Minnesota, USA.

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December 2019

Consequences of Military Sexual Trauma for Perinatal Mental Health: How Do We Improve Care for Pregnant Veterans with a History of Sexual Trauma?

J Womens Health (Larchmt) 2020 01 18;29(1):5-6. Epub 2019 Nov 18.

Division of Gynecology, Department of Surgery, VA Boston Healthcare System, Boston, Massachusetts.

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http://dx.doi.org/10.1089/jwh.2019.8154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366263PMC
January 2020

Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease.

Cancer Res 2019 Nov 3;79(22):5769-5784. Epub 2019 Oct 3.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.

The melanocyte-inducing transcription factor (MITF)-low melanoma transcriptional signature is predictive of poor outcomes for patients, but little is known about its biological significance, and animal models are lacking. Here, we used zebrafish genetic models with low activity of Mitfa (MITF-low) and established that the MITF-low state is causal of melanoma progression and a predictor of melanoma biological subtype. MITF-low zebrafish melanomas resembled human MITF-low melanomas and were enriched for stem and invasive (mesenchymal) gene signatures. MITF-low activity coupled with a p53 mutation was sufficient to promote superficial growth melanomas, whereas BRAF accelerated MITF-low melanoma onset and further promoted the development of MITF-high nodular growth melanomas. Genetic inhibition of MITF activity led to rapid regression; recurrence occurred following reactivation of MITF. At the regression site, there was minimal residual disease that was resistant to loss of MITF activity (termed MITF-independent cells) with very low-to-no MITF activity or protein. Transcriptomic analysis of MITF-independent residual disease showed enrichment of mesenchymal and neural crest stem cell signatures similar to human therapy-resistant melanomas. Single-cell RNA sequencing revealed MITF-independent residual disease was heterogeneous depending on melanoma subtype. Further, there was a shared subpopulation of residual disease cells that was enriched for a neural crest G-like state that preexisted in the primary tumor and remained present in recurring melanomas. These findings suggest that invasive and stem-like programs coupled with cellular heterogeneity contribute to poor outcomes for MITF-low melanoma patients and that MITF-independent subpopulations are an important therapeutic target to achieve long-term survival outcomes. SIGNIFICANCE: This study provides a useful model for MITF-low melanomas and MITF-independent cell populations that can be used to study the mechanisms that drive these tumors as well as identify potential therapeutic options. http://cancerres.aacrjournals.org/content/canres/79/22/5769/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116150PMC
November 2019

Supporting women in science at PCMR.

Pigment Cell Melanoma Res 2019 07;32(4):484-485

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http://dx.doi.org/10.1111/pcmr.12798DOI Listing
July 2019

Where Does Work Belong? Home-Based Work and Communication Technology within the American Middle-Class Postwar Home.

Authors:
Elizabeth Patton

Technol Cult 2019;60(2):523-552

This article examines how the idea of working within the home was constructed and disseminated by certain business industries via mass media during the postwar period. I draw evidence from popular culture, mass media, and marketing and advertising materials to demonstrate that postwar suburban consumers received conflicting messages about the public/private dichotomy. Public discourse on the role of the suburban home promoted the reemergence of the cult of domesticity and the primacy of family life over work. However, efforts by the housing, telecommunications, and office technology industries contradicted this message to promote home-based labor within the suburban home to expand their consumer markets. An examination of the postwar American home, specifically the study/home office as a technologized workspace reveals that the growth of American consumerism advanced the expansion of market labor in the home, especially for women.
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http://dx.doi.org/10.1353/tech.2019.0034DOI Listing
January 2019

Reproductive Health of Women Veterans: A Systematic Review of the Literature from 2008 to 2017.

Semin Reprod Med 2018 11 19;36(6):315-322. Epub 2019 Apr 19.

Division of Gynecology, Department of Surgery, VA Boston Healthcare System, Boston, Massachusetts.

The literature on the reproductive health and healthcare of women Veterans has increased dramatically, though there are important gaps. This article aims to synthesize recent literature on reproductive health and healthcare of women Veterans. We updated a literature search to identify manuscripts published between 2008 and July 1, 2017. We excluded studies that were not original research, only included active-duty women, or had few women Veterans in their sample. Manuscripts were reviewed using a standardized abstraction form. We identified 52 manuscripts. Nearly half (48%) of the new manuscripts addressed contraception and preconception care ( = 15) or pregnancy ( = 10). The pregnancy and family planning literature showed that (1) contraceptive use and unintended pregnancy among women Veterans using VA healthcare is similar to that of the general population; (2) demand for VA maternity care is increasing; and (3) women Veterans using VA maternity care are a high-risk population for adverse pregnancy outcomes. A recurrent finding across topics was that history of lifetime sexual assault and mental health conditions were highly prevalent among women Veterans and associated with a wide variety of adverse reproductive health outcomes across the life course. The literature on women Veterans' reproductive health is rapidly expanding, but remains largely observational. Knowledge gaps persist in the areas of sexually transmitted infections, infertility, and menopause.
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http://dx.doi.org/10.1055/s-0039-1678750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613775PMC
November 2018

The Role of Pharmacy Refill Measures in Assessing Adherence and Predicting HIV Disease Markers in Youth with Perinatally-Acquired HIV (PHIV).

AIDS Behav 2019 Aug;23(8):2109-2120

Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, Mail Code 0935, La Jolla, CA, 92093, USA.

Antiretroviral (ARV) adherence is critical in monitoring disease response in youth with perinatally-acquired HIV (PHIV). We used pharmacy refill (PR) information for PHIV youth from the PHACS Memory Sub-study to calculate medication availability over 2, 4, and 6 months. PR, a proxy of adherence, was compared with self-reported 7-day adherence in predicting suppressed viral load (SVL < 400 copies/mL) and higher CD4% (≥ 25%). Among 159 PHIV youth, 79% were adherent by 7-day recall, and 62, 55, and 48% by PR over 2, 4, and 6 months, respectively. Agreement between 7-day recall and PR adherence was weak (Kappa = 0.09-0.25). In adjusted logistic regression models, adherence showed associations with SVL for 7-day recall (OR 2.78, 95% CI 1.08, 7.15) and all PR coverage periods (6-month: OR 3.24, 95% CI 1.22, 8.65). Similar associations were observed with higher CD4%. PR measures were predictive of study retention. Findings suggest a possibly independent role of PR adherence measures.
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http://dx.doi.org/10.1007/s10461-019-02468-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650348PMC
August 2019

Spotlight on zebrafish: the next wave of translational research.

Dis Model Mech 2019 03 7;12(3). Epub 2019 Mar 7.

Departments of Molecular Genetics and Microbiology, and Immunology, Box 3020, Duke University School of Medicine, Durham, NC 27710, USA

Five years after the launch of the Disease Models & Mechanisms (DMM) Special Issue on zebrafish as a disease model, the field has progressed significantly. Zebrafish have been used to precisely model human genetic variants, to unpick the mechanisms of metabolic and other diseases, to study infection, inflammation and cancer, and to develop and test new therapeutic approaches. In this Editorial, we highlight recent research published in DMM that uses zebrafish to develop new experimental tools and to provide new insight into disease mechanism and therapy. The broad spectrum of subjects and approaches covered in these articles underscores the versatility of zebrafish in translational research. Further, it highlights the zebrafish community's ethos of creativity and collaboration in translating basic biological research into clinically relevant advances affecting how we understand and treat human disease.
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http://dx.doi.org/10.1242/dmm.039370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451428PMC
March 2019

Endothelin receptor Aa regulates proliferation and differentiation of Erb-dependent pigment progenitors in zebrafish.

PLoS Genet 2019 02 27;15(2):e1007941. Epub 2019 Feb 27.

Department of Biology and Biochemistry and Centre for Regenerative Medicine, University of Bath, Claverton Down, Bath, United Kingdom.

Skin pigment patterns are important, being under strong selection for multiple roles including camouflage and UV protection. Pigment cells underlying these patterns form from adult pigment stem cells (APSCs). In zebrafish, APSCs derive from embryonic neural crest cells, but sit dormant until activated to produce pigment cells during metamorphosis. The APSCs are set-aside in an ErbB signaling dependent manner, but the mechanism maintaining quiescence until metamorphosis remains unknown. Mutants for a pigment pattern gene, parade, exhibit ectopic pigment cells localised to the ventral trunk, but also supernumerary cells restricted to the Ventral Stripe. Contrary to expectations, these melanocytes and iridophores are discrete cells, but closely apposed. We show that parade encodes Endothelin receptor Aa, expressed in the blood vessels, most prominently in the medial blood vessels, consistent with the ventral trunk phenotype. We provide evidence that neuronal fates are not affected in parade mutants, arguing against transdifferentiation of sympathetic neurons to pigment cells. We show that inhibition of BMP signaling prevents specification of sympathetic neurons, indicating conservation of this molecular mechanism with chick and mouse. However, inhibition of sympathetic neuron differentiation does not enhance the parade phenotype. Instead, we pinpoint ventral trunk-restricted proliferation of neural crest cells as an early feature of the parade phenotype. Importantly, using a chemical genetic screen for rescue of the ectopic pigment cell phenotype of parade mutants (whilst leaving the embryonic pattern untouched), we identify ErbB inhibitors as a key hit. The time-window of sensitivity to these inhibitors mirrors precisely the window defined previously as crucial for the setting aside of APSCs in the embryo, strongly implicating adult pigment stem cells as the source of the ectopic pigment cells. We propose that a novel population of APSCs exists in association with medial blood vessels, and that their quiescence is dependent upon Endothelin-dependent factors expressed by the blood vessels.
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http://dx.doi.org/10.1371/journal.pgen.1007941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392274PMC
February 2019

Identifying Windows of Susceptibility by Temporal Gene Analysis.

Sci Rep 2019 02 26;9(1):2740. Epub 2019 Feb 26.

Neural Stem Cell Institute, Rensselaer, NY, 12144, USA.

Increased understanding of developmental disorders of the brain has shown that genetic mutations, environmental toxins and biological insults typically act during developmental windows of susceptibility. Identifying these vulnerable periods is a necessary and vital step for safeguarding women and their fetuses against disease causing agents during pregnancy and for developing timely interventions and treatments for neurodevelopmental disorders. We analyzed developmental time-course gene expression data derived from human pluripotent stem cells, with disease association, pathway, and protein interaction databases to identify windows of disease susceptibility during development and the time periods for productive interventions. The results are displayed as interactive Susceptibility Windows Ontological Transcriptome (SWOT) Clocks illustrating disease susceptibility over developmental time. Using this method, we determine the likely windows of susceptibility for multiple neurological disorders using known disease associated genes and genes derived from RNA-sequencing studies including autism spectrum disorder, schizophrenia, and Zika virus induced microcephaly. SWOT clocks provide a valuable tool for integrating data from multiple databases in a developmental context with data generated from next-generation sequencing to help identify windows of susceptibility.
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http://dx.doi.org/10.1038/s41598-019-39318-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391370PMC
February 2019

Notochord Injury Assays that Stimulate Transcriptional Responses in Zebrafish Larvae.

Bio Protoc 2018 Dec;8(23):e3100

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, The United Kingdom.

Zebrafish have become an increasingly important model organism in the field of wound healing and regenerative medicine, due to their high regenerative capacity coupled with high-resolution imaging in living animals. In a recent study, we described multiple physical and chemical methods to induce notochord injury that led to highly specific transcriptional responses in notochord cellular subpopulations. The notochord is a critical embryonic structure that functions to shape and pattern the vertebrae and spinal column. Here, we describe precision needle injury, tail-notochord amputation, and chemical inhibition of caveolin that trigger a wound-specific expression response in the notochord sheath cell subpopulation. We propose that these procedures can be used to study distinct cell populations that make up the cellular processes of notochord repair.
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http://dx.doi.org/10.21769/BioProtoc.3100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309551PMC
December 2018

Bright insights into palladium-triggered local chemotherapy.

Chem Sci 2018 Oct 17;9(37):7354-7361. Epub 2018 Jul 17.

Cancer Research UK Edinburgh Centre , Institute of Genetics and Molecular Medicine , University of Edinburgh , Crewe Road South , Edinburgh EH4 2XR , UK . Email:

The incorporation of transition metal catalysts to the bioorthogonal toolbox has opened the possibility of producing supra-stoichiometric amounts of xenobiotics in living systems in a non-enzymatic fashion. For medical use, such metals could be embedded in implantable devices ( heterogeneous catalyst) to "synthesize" drugs in desired locations ( in a tumour) with high specificity and for extended periods of time, overcoming the useful life limitations of current local therapy modalities directed to specific organ sites ( brachytherapy, controlled release systems). To translate this approach into a bona fide therapeutic option, it is essential to develop clinically-accessible implantation procedures and to understand and validate the activation process in relevant preclinical models. Herein we report the development of a novel Pd-activatable precursor of the red-fluorescent drug doxorubicin and Pd devices of optimized size and activity. Screening in state-of-the-art cancer models provided fundamental insights into the insertion protocols, safety and stability of the devices and into the prodrug distribution profile before and after activation.
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http://dx.doi.org/10.1039/c8sc02291gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237126PMC
October 2018

ALDH1 Bio-activates Nifuroxazide to Eradicate ALDH Melanoma-Initiating Cells.

Cell Chem Biol 2018 12 4;25(12):1456-1469.e6. Epub 2018 Oct 4.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK. Electronic address:

5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1 melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1 melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1 cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.
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http://dx.doi.org/10.1016/j.chembiol.2018.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309505PMC
December 2018

BRAF/MAPK and GSK3 signaling converges to control MITF nuclear export.

Proc Natl Acad Sci U S A 2018 09 27;115(37):E8668-E8677. Epub 2018 Aug 27.

Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Headington, OX3 7DQ Oxford, United Kingdom;

The close integration of the MAPK, PI3K, and WNT signaling pathways underpins much of development and is deregulated in cancer. In principle, combinatorial posttranslational modification of key lineage-specific transcription factors would be an effective means to integrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia-associated transcription factor MITF plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts, and mast cells and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell-cycle progression, cell migration, metabolism, and lysosome biogenesis. However, how the activity of this key transcription factor is controlled remains poorly understood. Here, we show that GSK3, downstream from both the PI3K and Wnt pathways, and BRAF/MAPK signaling converges to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activating a previously unrecognized hydrophobic export signal. Nonmelanocyte MITF isoforms exhibit poor regulation by MAPK signaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import-export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal.
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http://dx.doi.org/10.1073/pnas.1810498115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140509PMC
September 2018

Fishing for ancestry.

Elife 2018 08 2;7. Epub 2018 Aug 2.

MRC Human Genetics Unit & Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.

The same genes and signalling pathways control the formation of skin appendages in both fish and land animals.
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http://dx.doi.org/10.7554/eLife.39524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072438PMC
August 2018

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

J Clin Invest 2018 04 12;128(4):1496-1508. Epub 2018 Mar 12.

Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, London, United Kingdom.

Background: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).

Methods: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.

Results: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.

Conclusion: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.

Funding: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).
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http://dx.doi.org/10.1172/JCI98589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873857PMC
April 2018

defines a wound-specific sheath cell subpopulation associated with notochord repair.

Elife 2018 02 6;7. Epub 2018 Feb 6.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.

Regenerative therapy for degenerative spine disorders requires the identification of cells that can slow down and possibly reverse degenerative processes. Here, we identify an unanticipated wound-specific notochord sheath cell subpopulation that expresses Wilms Tumor (WT) 1b following injury in zebrafish. We show that localized damage leads to Wt1b expression in sheath cells, and that cells migrate into the wound to form a stopper-like structure, likely to maintain structural integrity. sheath cells are distinct in expressing cartilage and vacuolar genes, and in repressing a Wt1b-p53 transcriptional programme. At the wound, and cells constitute separate, tightly-associated subpopulations. Surprisingly, expression at the site of injury is maintained even into adult stages in developing vertebrae, which form in an untypical manner via a cartilage intermediate. Given that notochord cells are retained in adult intervertebral discs, the identification of novel subpopulations may have important implications for regenerative spine disorder treatments.
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http://dx.doi.org/10.7554/eLife.30657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811212PMC
February 2018

Rethinking Medicaid Coverage and Payment Policy to Promote High Value Care: The Case of Long-Acting Reversible Contraception.

Womens Health Issues 2018 Mar - Apr;28(2):137-143. Epub 2018 Jan 10.

Center for Health Policy Research, Milken Institute School of Public Health, George Washington University, Washington, DC.

Context: Long-acting reversible contraception (LARC) is the most effective reversible method to prevent unplanned pregnancies. Variability in state-level policies and the high cost of LARC could create substantial inconsistencies in Medicaid coverage, despite federal guidance aimed at enhancing broad access. This study surveyed state Medicaid payment policies and outreach activities related to LARC to explore the scope of services covered.

Methods: Using publicly available information, we performed a content analysis of state Medicaid family planning and LARC payment policies. Purposeful sampling led to a selection of nine states with diverse geographic locations, political climates, Medicaid expansion status, and the number of women covered by Medicaid.

Results: All nine states' Medicaid programs covered some aspects of LARC. However, only a single state's payment structure incorporated all core aspects of high-quality LARC service delivery, including counseling, device, insertion, removal, and follow-up care. Most states did not explicitly address counseling, device removal, or follow-up care. Some states had strategies to enhance access, including policies to increase device reimbursement, stocking and delivery programs to remove cost barriers, and covering devices and insertion after an abortion.

Conclusions: Although Medicaid policy encourages LARC methods, state payment policies frequently fail to address key aspects of care, including counseling, follow-up care, and removal, resulting in highly variable state-level practices. Although some states include payment policy innovations to support LARC access, significant opportunities remain.
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http://dx.doi.org/10.1016/j.whi.2017.10.013DOI Listing
May 2018