The transcriptional landscape of Shh medulloblastoma
(2021) Nature Communications, 12 (1), art. no. 1749, .
Skowron, P.a b c , Farooq, H.a b c , Cavalli, F.M.G.a c , Morrissy, A.S.d e f , Ly, M.a b c , Hendrikse, L.D.a c g , Wang, E.Y.a c g , Djambazian, H.h i , Zhu, H.g j , Mungall, K.L.k , Trinh, Q.M.j , Zheng, T.l , Dai, S.m , Stucklin, A.S.G.a c , Vladoiu, M.C.a b c , Fong, V.a c , Holgado, B.L.a c , Nor, C.a c , Wu, X.a c , Abd-Rabbo, D.j , Bérubé, P.h , Wang, Y.C.h , Luu, B.a c , Suarez, R.A.a c , Rastan, A.a c n , Gillmor, A.H.d e f , Lee, J.J.Y.a b c , Zhang, X.Y.a , Daniels, C.a c , Dirks, P.a c o p , Malkin, D.g q , Bouffet, E.c q , Tabori, U.c n q , Loukides, J.c , Doz, F.P.r , Bourdeaut, F.r , Delattre, O.O.s , Masliah-Planchon, J.t , Ayrault, O.u , Kim, S.-K.v , Meyronet, D.w , Grajkowska, W.A.x , Carlotti, C.G.y , de Torres, C.z , Mora, J.z , Eberhart, C.G.aa , Van Meir, E.G.ab , Kumabe, T.ac , French, P.J.ad , Kros, J.M.ae , Jabado, N.af , Lach, B.ag ah , Pollack, I.F.ai , Hamilton, R.L.aj , Rao, A.A.N.ak , Giannini, C.al , Olson, J.M.am , Bognár, L.an , Klekner, A.an , Zitterbart, K.ao , Phillips, J.J.ap aq , Thompson, R.C.ar , Cooper, M.K.as , Rubin, J.B.at , Liau, L.M.au , Garami, M.av , Hauser, P.av , Li, K.K.W.aw , Ng, H.-K.aw , Poon, W.S.ax , Yancey Gillespie, G.ay , Chan, J.A.f , Jung, S.az , McLendon, R.E.ba bb , Thompson, E.M.bb , Zagzag, D.bc , Vibhakar, R.bd , Ra, Y.S.be , Garre, M.L.bf , Schüller, U.bg bh bi , Shofuda, T.bj , Faria, C.C.bk bl , López-Aguilar, E.bm , Zadeh, G.bn bo , Hui, C.-C.a p , Ramaswamy, V.a c g q , Bailey, S.D.bp bq , Jones, S.J.k br bs , Mungall, A.J.k , Moore, R.A.k , Calarco, J.A.bt , Stein, L.D.p bu , Bader, G.D.p bv , Reimand, J.g j p , Ragoussis, J.h i , Weiss, W.A.l ap bw , Marra, M.A.k br , Suzuki, H.a c , Taylor, M.D.a b c g o bx
a Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
b Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
c The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
d Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
e Alberta Children’s Hospital Research Institute, Calgary, AB, Canada
f Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
g Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
h McGill University Genome Centre, McGill University, Montreal, QC, Canada
i Department of Human Genetics, McGill University, Montreal, QC, Canada
j Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
k Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada
l Department of Neurology, University of California San Francisco, San Francisco, CA, United States
m Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, United States
n Institute of Medical Science, University of Toronto, Toronto, ON, Canada
o Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada
p Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
q Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
r SIREDO Center (pediatric, adolescent and young adults oncology), Institut Curie, University of Paris, Paris, France
s INSERM U 830, Institut Curie, Paris, France
t Unit of Somatic Genetics, Institut Curie, Paris, France
u PSL Research University, Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Institut Curie, Paris, France
v Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea
w Hospices Civils de Lyon, Institute of Pathology, University Lyon 1, Department of Cancer Cell Plasticity–INSERM U1052 Cancer Research Center of Lyon, Lyon, France
x Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland
y Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil
z Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
aa Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, MD, United States
ab Department of Hematology & Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, United States
ac Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
ad Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands
ae Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
af Division of Experimental Medicine, McGill University, Montreal, QC, Canada
ag Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, ON, Canada
ah Department of Pathology and Laboratory Medicine, Hamilton General Hospital, Hamilton, ON, Canada
ai Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
aj Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
ak Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, United States
al Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
am Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
an Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre, Debrecen, Hungary
ao Department of Pediatric Oncology, Masaryk University School of Medicine, Brno, Czech Republic
ap Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States
aq Department of Pathology, University of California San Francisco, San Francisco, CA, United States
ar Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, United States
as Department of Neurology, Vanderbilt Medical Center, Nashville, TN, United States
at Departments of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
au Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
av 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
aw Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
ax Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
ay Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, United States
az Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Jeollanam-do, South Korea
ba Department of Pathology, Duke University, Durham, NC, United States
bb Department of Neurosurgery, Duke University, Durham, NC, United States
bc Department of Pathology and Neurosurgery, NYU Grossman School of Medicine and NYU Langone Health, New York, NY, United States
bd Department of Pediatrics, University of Colorado Denver, Aurora, CO, United States
be Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul, South Korea
bf U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova, Italy
bg Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Germany
bh Research Institute Children’s Cancer Center, Hamburg, Germany
bi Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Germany
bj Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, Osaka, Japan
bk Division of Neurosurgery, Centro Hospitalar Lisboa Norte (CHULN), Hospital de Santa Maria, Lisbon, Portugal
bl Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
bm Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional century XXI, Mexico City, Mexico
bn Division of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
bo MacFeeters-Hamilton Center for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
bp Department of Surgery, Division of Thoracic and Upper Gastrointestinal Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
bq Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
br Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
bs Department of Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, BC, Canada
bt Department of Cell & Systems Biology, University of Toronto, Toronto, ON, Canada
bu Adaptive Oncology, Ontario Institute for Cancer Research, Toronto, ON, Canada
bv The Donnelly Centre, University of Toronto, Toronto, ON, Canada
bw Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
bx Department of Surgery, University of Toronto, Toronto, ON, Canada
Abstract
Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention. © 2021, The Author(s).
Funding details
Stand Up To CancerSU2CSU2C-AACR-DT1113
University of TorontoU of T
Brain Tumour Foundation of Canada
Cancer Research SocietyCRS
Cancer Research UKCRUK
Government of Canada
SU2C-AACR-DT-19-15
Government of Ontario
Genome British Columbia
National Institutes of HealthNIH
Swifty Foundation
Worldwide Cancer ResearchWCR
Brain Tumour Charity
Pediatric Brain Tumor FoundationPBTF
10XS170
Canadian Cancer Society
Genome Canada
National Institutes of HealthNIH
National Institutes of HealthNIHR01CA159859, R01CA148699
X10S172, HHSN268201000029C
Ontario Institute for Cancer ResearchOICR
National Center for Research ResourcesNCRRP41 GM103504
Hospital for Sick ChildrenSickKids
Canada Foundation for InnovationCFI
Canadian Institutes of Health ResearchCIHR
Roswell Park Cancer InstituteRPCI10XS171
Ontario Research FoundationORF
National Cancer InstituteNCI
Terry Fox Research InstituteTFRI
Document Type: Article
Publication Stage: Final
Source: Scopus
Severity of parkinsonism associated with environmental manganese exposure
(2021) Environmental Health: A Global Access Science Source, 20 (1), art. no. 27, .
Racette, B.A.a b , Nelson, G.b c , Dlamini, W.W.a , Prathibha, P.d , Turner, J.R.d , Ushe, M.a , Checkoway, H.e , Sheppard, L.f , Nielsen, S.S.a
a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110, United States
b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa
c Research Department of Infection & Population Health, UCL Institute for Global Health, University College London, London, United Kingdom
d Department of Energy, Environmental, and Chemical Engineering, Washington University, Campus Box 1180, One Brookings Drive, St. Louis, MO 63130, United States
e Department of Family Medicine & Public Health, University of California, 9500 Gilman Drive, # 0725, La Jolla, San Diego, CA 92093-0725, United States
f Departments of Biostatistics and Environmental and Occupational Health Sciences, University of Washington, Box 357232, Seattle, WA 98195, United States
Abstract
Background: Exposure to occupational manganese (Mn) is associated with neurotoxic brain injury, manifesting primarily as parkinsonism. The association between environmental Mn exposure and parkinsonism is unclear. To characterize the association between environmental Mn exposure and parkinsonism, we performed population-based sampling of residents older than 40 in Meyerton, South Africa (N = 621) in residential settlements adjacent to a large Mn smelter and in a comparable non-exposed settlement in Ethembalethu, South Africa (N = 95) in 2016–2020. Methods: A movement disorders specialist examined all participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3). Participants also completed an accelerometry-based kinematic test and a grooved pegboard test. We compared performance on the UPDRS3, grooved pegboard, and the accelerometry-based kinematic test between the settlements using linear regression, adjusting for covariates. We also measured airborne PM2.5-Mn in the study settlements. Results: Mean PM2.5-Mn concentration at a long-term fixed site in Meyerton was 203 ng/m3 in 2016–2017 – approximately double that measured at two other neighborhoods in Meyerton. The mean Mn concentration in Ethembalethu was ~ 20 times lower than that of the long-term Meyerton site. UPDRS3 scores were 6.6 (CI 5.2, 7.9) points higher in Meyerton than Ethembalethu residents. Mean angular velocity for finger-tapping on the accelerometry-based kinematic test was slower in Meyerton than Ethembalethu residents [dominant hand 74.9 (CI 48.7, 101.2) and non-dominant hand 82.6 (CI 55.2, 110.1) degrees/second slower]. Similarly, Meyerton residents took longer to complete the grooved pegboard, especially for the non-dominant hand (6.9, CI -2.6, 16.3 s longer). Conclusions: Environmental airborne Mn exposures at levels substantially lower than current occupational exposure thresholds in the United States may be associated with clinical parkinsonism. © 2021, The Author(s).
Author Keywords
Case control studies; Manganese; Parkinson disease; Parkinsonism
Funding details
National Institute of Environmental Health SciencesNIEHSK01ES028295, K24ES017765, R01ES025991-02S1
Document Type: Article
Publication Stage: Final
Source: Scopus
Simulation of harmonic shear waves in the human brain and comparison with measurements from magnetic resonance elastography
(2021) Journal of the Mechanical Behavior of Biomedical Materials, 118, art. no. 104449, .
Li, Y.a c , Okamoto, R.b , Badachhape, A.b , Wu, C.a , Bayly, P.b , Daphalapurkar, N.c d
a Department of Engineering Mechanics, Dalian University of Technology, Dalian, China
b Department of Mechanical Engineering and Materials Science, Washington University in Saint Louis MO, United States
c Hopkins Extreme Materials Institute, Johns Hopkins University, Baltimore, MD, United States
d Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States
Abstract
Magnetic Resonance Elastography (MRE) provides a non-invasive method to characterize the mechanical response of the living brain subjected to harmonic loading conditions. The peak magnitude of the harmonic strain is small and the excitation results in harmless deformation waves propagating through the brain. In this paper, we describe a three-dimensional computational model of the brain for comparison of simulated harmonic deformations of the brain with MRE measurements. Relevant substructures of the head were constructed from MRI scans. Harmonic wave motions in a live human brain obtained in an MRE experiment were used to calibrate the viscoelastic properties at 50 Hz and assess accuracy of the computational model by comparing the measured and the simulated harmonic response of the brain. Quantitative comparison of strain field from simulations with measured data from MRE shows that the harmonic deformation of the brain tissue is responsive to changes in the viscoelastic properties, loss and storage moduli, of the brain. The simulation results demonstrate, in agreement with MRE measurements, that the presence of the falx and tentorium membranes alter the spatial distribution of harmonic deformation field and peak strain amplitudes in the computational model of the brain. © 2021
Author Keywords
Brain biomechanics; Finite element method; Shear waves; Viscoelasticity
Funding details
National Institutes of HealthNIHR01NS055951
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
Brain network reorganisation in an adolescent after bilateral perinatal strokes
(2021) The Lancet Neurology, 20 (4), pp. 255-256.
Laumann, T.O.a c , Ortega, M.a , Hoyt, C.R.a f , Seider, N.A.a , Snyder, A.Z.a b , Dosenbach, N.U.a b d e f , Siegel, J.S.g , Nguyen, A.L.g , Dierker, D.L.g , Coalson, R.S.g , Adeyemo, B.g , Marek, S.g , Gilmore, A.W.g , Nelson, S.M.g , Shimony, J.S.g , Greene, D.J.g , Raichle, M.E.g , Gordon, E.M.g , Petersen, S.E.g , Schlaggar, B.L.g , Brain Network Plasticity Grouph
a Department of Neurology, Washington University, St Louis, MO 63110, United States
b Department of Radiology, Washington University, St Louis, MO 63110, United States
c Department of Psychiatry, Washington University, St Louis, MO 63110, United States
d Department of Biomedical Engineering, Washington University, St Louis, MO 63110, United States
e Department of Pediatrics, Washington University, St Louis, MO 63110, United States
f Program in Occupational Therapy, Washington University, St Louis, MO 63110, United States
Document Type: Letter
Publication Stage: Final
Source: Scopus
A Better Blood Test to Differentiate Epileptic From Psychogenic Nonepileptic Seizures?
(2021) Neurology, 96 (10), pp. 467-468.
Young, G.B., Thio, L.L.
From the Department of Clinical Neurological Sciences (G.B.Y.), University of Western Ontario, London, Canada; and Paediatric Neurology (L.L.T.), Washington University, St. Louis, MO
Document Type: Editorial
Publication Stage: Final
Source: Scopus