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The Manitoba Institute of Cell Biology (MICB)
gratefully acknowledges
the following organizations
for their on-going support and commitment
without which the achievements
documented in this report would not have been possible:
CancerCare Manitoba Foundation
CancerCare Manitoba
The University of Manitoba
And most especially to those who unselfishly contributed
their dollars and biological samples to cancer research.
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TABLE OF CONTENTS
Director’s Executive Summary...............................................................................4
Manitoba Institute of Cell Biology (MICB).............................................................5
MICB Advisory Board…..….....................................................................................6
MICB Principal Investigators.................................................................................7
Members who have served as scientific reviewer or on an advisory panel………9
Research Highlights.............................................................................................13
Recognizing Our Outstanding Staff………………………………………………………………….22
MICB Social Events …………………………………………………………………………………………23
Compendium of MICB Publications (2010).........................................................40
Distribution of Impact Factors and Cited Publications.......................................44
Total Number of Grant and Trainees. ................................................................51
Patents................................................................................................................52
Senior Investigators............................................................................................53
Genomic Centre for Cancer Research and Diagnosis.........................................105
Manitoba Breast Cancer Research Center.…......................................................112
Mammalian Functional Genomics Centre.……...................................................115
MICB Facilities....................................................................................................117
MICB Staff...........................................................................................................118
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Director’s Executive Summary
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As the new Acting Director of the Manitoba Institute of Cell Biology (MICB), I have come to
realize the extent of the high level of excellence in research that happens at this Institute. Our
researchers have obtained multiple prestigious research awards, studentships and fellowships worth
approximately 11 million dollars in 2010/2011. The excellence in research continues to be
recognized with many awards to our researchers and students. Our research is published in leading
peer-reviewed scientific journals accounting for 46 publications with an average impact factor of
5.4 in 2010. Our research papers are cited an average of 18 times per paper over the last 5 years.
MICB researchers were also highlighted in local and national publications. Listed below are some
of the highlights of the past year:
Our Senior Scientists continue to be successful in obtaining research funding from both local and
national agencies. Notable among our successes is Dr. Kirk McManus receiving a five year
operating grant from CIHR and Dr. Ashin Raouf receiving a Canadian Breast Cancer Foundation,
Prairie/NWT region research grant. These are our newest Senior Investigators and with this new
funding, we look forward to seeing the results of their innovative research. Dr Sabine Mai has
received the first high resolution ‘Elyra’ microscope system in North America. This is cutting edge
microscope allows for super resolution 3-dimensional image acquisition and analysis of subcellular
structures. This will ensure MICB will be at the forefront of new discoveries in the years to come.
MICB has an established reputation in training high quality graduate students and post-doctoral
fellows and are recognized for their efforts by receiving prestigious awards. This accounted for
approximately 1 million dollars in studentships and fellowships in 2010/2011. Our trainees also
were awarded for excellence in research. For example, Paula Espino was selected as a recipient of a
UM Distinguished Dissertation Award from the Faculty of Graduate Studies.
Besides trainees, technicians were recognized for their contribution to research. Anne Blanchard, a
technician with Dr. Myal’s lab was the recipient of the Karol McNeill technician award from the
Faculty of Medicine.The success of our researchers are not only measured by grants but recognized
by the community. Dr. Yvonne Myal was award with YMCA-YWCA Women of Distinction Award
for her contributions to breast cancer research. Dr. Leigh Murphy was also profiled in the WAVE
magazine for her work in the breast cancer research group at MICB.
It was not all good news this past year. Dr. David Eisenstat who has been a member of MICB since
1999, has announced his acceptance of a new Endowed Chair position at the University of Alberta.
However, our loss was balanced by the welcoming of clinician scientists Drs. Versha and Shantanu
Banerji back to MICB after their training at Harvard University.
Overall, this confirms that MICB is one of Manitoba’s leading research institute and with the
announcement by the Provincial Government of a new CancerCare Manitoba building, our future
will be bright.
MANITOBA INSTITUTE OF CELL BIOLOGY
The Manitoba Institute of Cell Biology (MICB) was founded in 1969 by CancerCare Manitoba (formerly the Manitoba Cancer Treatment and Research Foundation) and the University of Manitoba. The Institute is associated with the Faculty of Medicine and the Health Sciences Centre and is located on the 5th, 6th and 7th floors of the CancerCare Manitoba (CCMB) building at 675 McDermot Avenue in Winnipeg, Manitoba, Canada.
It is dedicated to basic and translational research in biology and its relation to health, with a primary emphasis on cancer and related diseases. Scientists study such challenging problems as the molecular origins of cancer, the role of signal transduction pathways in regulating cell proliferation, cell death, gene expression and platelet function, development of markers of risk of developing invasive breast cancer, neuronal growth and differentiation during development, programmed cell death and the biochemical action of cancer chemotherapeutics. Although not a degree‐granting institution, the Institute plays a major role in training scientists, whether graduate or postgraduate students, medical trainees and investigators who come from around the world to work with our staff. Degrees are granted through the Faculty of Medicine, Departments of Human Anatomy and Cell Science, Biochemistry and Medical Genetics, Immunology, Pharmacology and Therapeutics, Physiology and Medical Microbiology. Information on training programs can be obtained from our office and the Dean of Graduate Studies. The Institute’s web page address is:
http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/index.html
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MICB ADVISORY BOARD
The MICB Advisory Board meets 2-3 times per year and oversees the general operation of
the Institute. CancerCare Manitoba and the University of Manitoba appoint representatives
on the Board, and jointly appoint members at large.
Members during the 2010-2011 year are:
Dr. Janice Dodd (Chair)
Professor and Head
Mr. David Carrick
Department of Physiology
University of Manitoba
Aikins MacAulay &
Thorvaldson
Dr. Spencer Gibson
Acting Director
Manitoba Institute of Cell
Biology
Dr. Lesley Degner
Professor
CHSRF/CIHR Chair in
Nursing Care
Helen Glass Centre for
Nursing
Dr. H. S. Dhaliwal
President & CEO
CancerCare Manitoba
Dr. Brian Postl
Dean of Medicine
University of Manitoba
Dr. Ian Smith
Director General
National Research Council
of Canada
Institute of Biodiagnostics
Dr. K. Dakshinamurti
Division of Stroke and
Vascular Disease
St. Boniface Hospital
Research Centre
Dr. Jeff Sisler
Primary Oncologist
CancerCare Manitoba
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MICB PRINCIPAL INVESTIGATORS
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MICB PRINCIPAL INVESTIGATORS
Basic Researchers
Dr. Spencer Gibson
Acting Director and Margaret A. Sellers Chair
Professor (Biochemistry and Medical Genetics)
Interim Provincial Director of Research of CCMB
Dr. James Davie
Professor (Biochemistry and Medical Genetics)
Dr. Leigh Murphy
Professor (Biochemistry and Medical Genetics)
Dr. Geoff Hicks
Associate Professor (Biochemistry and Medical Genetics)
Dr. Sabine Mai
Professor (Physiology)
Dr. Kirk McManus
Assistant Professor (Biochemistry and Medical Genetics)
Dr. Michael Mowat
Professor (Biochemistry and Medical Genetics)
Associate Director MICB
Dr. Etienne Leygue
Professor (Biochemistry and Medical Genetics)
Dr. Afshin Raouf
Assistant Professor (Immunology)
Dr. Yvonne Myal
Director of Research and Innovation, Diagnostic Services of Manitoba
Associate Professor (Pathology)
Dr Mark Nachtigal
Assistant Professor (Biochemistry and Medical Genetics)
Clinicians
Dr. David Eisenstat
Associate Professor (Pediatrics and Child Health)
Director of Brain Tumor Disease Site Group
Dr. Sara Israels
Professor (Pediatrics and Child Health)
Head (Section of Paediatrics) Haematology/Oncology/BMT
Dr. James Johnston
Professor (Internal Medicine), Associate Director (Clinical) MICB and Clinician
(Medical Oncology and Haematology, (CCMB)
Dr. Peter Watson
Professor (Pathology and Laboratory Medicine) University of British Columbia
Director, Tumor Tissue Repository, BC Cancer Agency
Affliated Members
Dr. Janice RichmanEisenstat
Dr. Frixos Paraskevas
Assistant Professor (Internal Medicine, Pharmacology and Therapeutics)
Dr. Lorne Brandes
Professor (Internal Medicine, and Pharmacology and Therapeutics) and Clinician
(Medical Oncology and Haematology, CCMB)
Dr Robert Shiu
Professor (Physiology)
Dr Don Houston
Chair (General Hematology Disease Group CancerCare Manitoba)
Manitoba Institute of Cell Biology
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MEMBERS WHO HAVE SERVED ON SCIENTIFIC
REVIEW AND ADVISORY PANELS
Dr. Spencer Gibson
Reviewer for manuscripts for peer-reviewed scientific journal: Oncogene, Molecular
Biology of the Cell, Blood, Cancer, Cancer Research, British Journal of Cancer, Clinical
Cancer Research, Molecular Cancer Therapeutics, Molecular Pharmacology, EMBO,
BLOOD, Autophagy, Free Radical Biology and Medicine, Cell Death and
Differentiation and Carcinogenesis,
Reviewer for grant submitted to the Alberta Innovates for Health Solutions
External Reviewer for the Saskatchewan Health Research Foundation for Establishment
grant, UK Medical Research Council, Swiss Medical Research Funding Agency and
Singapore government funding agency.
National Institutes of Health BMCT Study Section, Full panel member
Special Reviewer P01 grants
Reviewer for grant submitted to the Alberta Heritage Foundation
Scientific Director of the Manitoba CLL Tissue Bank
Dr. Jim Davie
Scientific Director, Manitoba Health Research Council
Acting Associate Director, Manitoba Institute of Cell Biology
Leader, Terry Fox Research Institute Prairie Node
Member, Site Visit Team to review a CHIR/TFRI Program Project application
Member, Ontario Research Fund-Global Leadership in Genomics and Life Sciences
Cancer & Stem Cells peer-review panel
Member, Alberta Cancer Research Institute Grant Review Committee
Member of the Editorial Board: Biochemistry and Cellular Biology, Journal of
Biological Chemistry, Clinical Epigenetics, Journal of Cellular Biochemistry,
International Journal of Cell Biology, International Journal of Biochemistry and Cell
Biology, Molecular Biology Reports, Gene Therapy and Molecular Biology
Dr. David Eisenstat
Grant review committees: Leukemia and Lymphoma Society of Canada, panel member,
National Brain Tumor Society (USA), Scientific Advisory Committee and panel
member, Austrian Science Foundation,
External reviewer, C17 Research Network, Canadian Pediatric Hematology-Oncology
Program Directors, Canadian Foundation for Innovation (CFI), Brain Tumor
Funders’ Collaborative, Scientific Advisory Committee and panel member, CIHR,
Canadian Diabetes Association, Natural Sciences and Engineering Research
Council (NSERC), Samantha Dickson Charitable trust (UK), Alberta Cancer
Board,
Reviewer for manuscripts for peer-reviewed scientific journals: Acta Neuropathologica,
Acta Paediatrica, Brain Research, Cancer Research, Clinical Cancer Research,
Development, Developmental Dynamics, Journal of Engineering in Medicine,
Journal of Molecular Biology, Molecular Brain Research, Neuroscience, Stem
Cells
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Dr. Geoff Hicks
NIH Ewing Sarcoma Initiative.
International Gene Trap Consortium.
International Mouse Mutagenesis Consortium
International Knockout Mouse Project Consortium
Federation of International Mutant Mouse Resources.
Canadian Mouse Consortium, founding member.
International Knockout Mouse Consortium, founding member.
Director - Regenerative Medicine Program in the University of Manitoba’s Faculty
of Medicine.
Director, Mammalian Functional Genomics Centre.
Canadian Institutes of Health Research, Reviewer for G, CPT and MCC Panels.
Chair, CIHR Institute of Genetics New Principal Investigator Symposium.
Scientific Director, Gene Modeling Centre, University of Manitoba.
Scientific Advisory Board Member, Genome BC, Pathogenomics of Innate
Immunity.
CIHR Institute of Genetics Advisory Panel.
Scientific Advisory Board Member, Genome Quebec, Gene Regulators in Disease.
Scientific Advisory Board Member, BC Transgenics Centre.
Scientific Director, Genetic Modeling Centre, University of Manitoba.
Manitoba Health Research Council, Research Advisory Committee.
Dr. Sara Israels
Section Head, Pediatric Hematology/Oncology/BMT,
Faculty of Medicine Promotion Committee,
Chair - Dept of Pediatrics and Child Health Promotions
Department of Pediatrics Executive and Planning Committee
Hematology Fellowship Training Program Committee
Director, Haemostasis Laboratory, Health Sciences Centre
Director, Bleeding disorder Program
Head, Department of Pediatric Oncology, CancerCare Manitoba
CCMB LG Israels Memorial Lecture Committee
CCMB Medical Council
Chair Simon and Sarah Israels Thesis Prize Review Committee
CancerCare Manitoba Foundation Board of Directors
CancerCare Manitoba Foundation Project Grants and Awards Committee
Editor, Mechanisms in Hematology, 4th Edition.
External Review: Canadian Council of Pediatric Hematology/Oncology Program
Directors Executive, Royal College of Physicians and Surgeons – Specialty
Committee (Nucleus) in Pediatric Hematology/Oncology,
External Grant Reviews: Heart and Stroke Foundation of Canada, CIHR, Canadian
Blood Services/Bayer, Health Sciences Centre Research Foundation, C17
Research Network
Journal Reviews: Blood, J. Thrombosis and Haemostasis, Thrombosis and
Haemostasis, J. Pediatric Hematology/Oncology, Pediatric Research, J.
Pediatrics, Thrombosis Research
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Dr. James Johnston
Assistant Head (Clinical), Manitoba Institute of Cell Biology
Clinical Director, Manitoba CLL Tumour Bank
Cancer Biology Graduate Course Coordinator (36.720) (with Dr. Michael Mowat)
Molecular Biology Course Coordinator for Clinical Hematology/Oncology residents
Chairman for the Planning Committee for the annual Canadian CLL Meeting
Member of the Planning Committee for the annual Canadian Lymphoma Meeting
Coordinator for Hematology/Oncology Section Rounds
Chairman of the LG Israels Annual Memorial Lecture Committee
Manuscript reviewer for Blood, Cancer, Leukemia Lymphoma and Leukemia
Research
Scientific reviewer for Alberta Cancer Board
Dr. Etienne Leygue
Operating grant competition of the National Cancer Institute of Canada (NCIC)
PhD and Post-doctoral Awards, US-Army Medical Research and Material
Command (USAMRMC)
Dr. Sabine Mai
External grant reviewer for NSERC, MRC, MHRC, CIHR, Valorisation Recherche
Québec, NCIC, MMSF
External referee for Proc. Natl. Acad. Sci (USA), Oncogene, J. Cell Physiol., Gene,
Mol. Cell. Biol., Experimental Cell Research, Genes, Chromosomes and
Cancer, JCB. J Pathol
Manitoba Institute of Cell Biology Animal Care Committee
Advisory Board Member, Industrial Technology Centre, Virtual Reality Centre,
Organizing committee for the 7th Canadian Symposium of Telomeres and
Telomerase, Hamilton, ON,
Dr. Kirk McManus
Member, Grant Review Panel C, Cancer Research Society
Member, Studentship Review Committee, Manitoba Health Research Council
Member, Israels Student Thesis Award Committee, MICB
Member, Genomic Centre for Cancer Research and Diagnosis Users Committee
Member, Radiation Protection Committee, University of Manitoba
Reviewer for BMC Cancer, PLoS One, and Proceeding of the National Academy of
Sciences (USA).
Dr. Michael Mowat
Grant Review Committees Cancer Research Society, member Panel D, Metastasis
and Tumour Progression
Graduate Affairs Committee
Member, PhD Candidacy examination committees
Recruitment Committee-Assistant Professor
Chair for Oral defense of Vanessa Pinto
Associate Director (MICB)
Executive committee
Chair - CancerCare MB library committee
MICB Space Committee
Yvonne Myal
Senior Investigator, CancerCare Manitoba
Director of Research , Diagnostic Services of Manitoba
Chair, Operating Grants Steering Committee Diagnostic Services of Manitoba
Editorial Board - International Scholarly Research Network (ISRN) Molecular
Biology
Grant Review Panel – National Science Foundation
Scientific Journal Reviewer – Prostate, Breast Cancer, American Journal of 11
Pathology, Clinical and Experimental Metastasis, Genome Biology, BMC
Molecular Biology
Dr. Leigh Murphy
Director (Acting ) January 2009 to March 2011
Member, Executive Committee MICB
Member, Space Committee
Member, Manitoba Breast Tumor Bank Scientific Review Panel
Director Manitoba Tumour Bank,
Member Management Committee CTRNet
Academic Standards – member
Member, Medicine Teaching Committee - 2000 to present
Member, Candidacy examination committee - 2000 to present
Member, Search Committee Head of Pharmacology, Faculty of Medicine
Member, Selection Committee for the Head of Human Genetics, Faculty of
Medicine.
Member of the Accreditation Committee Considering the Faculty, University of
Manitoba.
Biochemistry Representative on the Reproductive Systems Committee for Medical
Student Curriculum Reform, U of Manitoba.
UMFA representative on Faculty of Medicine, Promotions and Tenure Committee
Member of the College of Reviewers for the Canada Research Chairs Program:
Alberta Cancer Board - Breast Cancer Research Program- scientific reviewer
Scientific Reviewer-Saskatchewan Health Research Foundation
Member of the DOD-BCRP-Innovator, Era of Hope Scholarship review panel
Member of the Susan Komen Postdoctoral Award review panel,
Member CIHR-Terry Fox Foundation Terry Fox Team Grants
Mark Nachtigal
Chair, Manitoba Health Research Council Fellowship Review Committee 2011
Terry Fox Research Institute – Canadian Ovarian Cancer Research Consortium,
Research Contact for the University of Manitoba 2010- present
CIHR Institute of Cancer Research Trainees Awards Committee 2010 - present
Member, CIHR Endocrinology Panel 2008 - present
Member, Correlative Science and Tumour Biology Sub Committee of the NCIC
CTG Gynecology Disease Site Group 2008 - present
Dr. Afshin Raouf
Canadian Institute of Health Research- Terry Fox Foundation Frontier Group Grant
Projects Review Committee
Manitoba Institute of Health Research-Postdoctoral Research Fellowship Review
Committee
Sarah Israels' Student Thesis Award Committee, MICB
Manitoba Breast Tumor Bank Scientific Review Panel
Immunology Department's Graduate Student Awards Committee
External Review Committee for the Canadian Breast Cancer Research Alliance Idea Grant Competition
Organizer, Immunology Department's Research in Progress Seminar Series
Ad hoc reviewer for the Canadian Journal of Physiology and Pharmacology, Breast
Cancer Research, Oncogene journal
Editor - Cancer Genomics & Proteomics (January 2010 - Present)
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RESEARCH HIGHLIGHTS
Premier Greg Selinger
announced on April 13, 2011
that the province would invest
$70 million in a new-state-ofthe-art facility for
CancerCare Manitoba.
Dr. Yvonne Myal, Professor, Department of Pathology was
honored at the YMCA-YWCA Women of Distinction
Awards ceremony yesterday, May 4, 2011.
Dr. Myal is the recipient of the Women of Distinction
Award in the Science category for her innovative research
to enhance the understanding of breast cancer.
Dr. Spencer
Gibson was
featured in the
May/June, 2011
edition of the
Winnipeg Health
and Wellness
Magazine for his
work in cancer
research.
Dr. Leigh
Murphy was
featured in the
Sept/Oct, 2011
edition of the
Winnipeg Health
and Wellness
Magazine for her
work in breast
cancer research.
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Dr. Kirk McManus was featured in the October 7, 2011 issue
of the University of Manitoba Bulletin.
Dr. McManus wrote one of the two top-ranked proposals
submitted for the Dr. Paul H. T. Thorlakson Foundation
Fund.
Congratulations to Dr. McManus who was the recipient of a
5 year CHIR operating grant.
Dr. Davie was research entitled What Makes Genes “Tick”
Role of Nuclear NKEF_A in Breast Cancer was featured the
Canadian Breast Cancer Foundation.
Dr. Davie and his team recently had their study published in:
Molecular Biology of the Cell, a prestigious international
medical journal.
Congratulations to Dr. Davie who had his Canadian Tier 1
Chair renewed.
Dr. Spencer Gibson was featured in the CLL Global
Research Foundation
THERAPY/PROGNOSTIC
Tyrosine kinase inhibitor Gefitinib as a novel therapy for
aggressive Chronic Lymphocytic Leukemia (CLL)
Abstract:
Chronic lymphocytic leukemia (CLL) patients can be divided into stable and aggressive disease
categories. Patients with aggressive CLL often become drug resistant and have short overall
survival times. CLL cells that contain the ZAP-70 protein tend to be closely associated with
aggressive disease. Currently there are no targeted treatments designed for this aggressive form of
CLL. In this study, we shall assess whether the drug gefitinib can selectively kill ZAP-70
expressing CLL cells. Gefitinib is currently used to treat lung cancer, but has potential to be
effective against CLL. We will also evaluate the ability of gefitinib to work in combination with
standard chemotherapy to kill these cells by inhibiting ZAP-70 function.
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CCMB published 156 peer-reviewed manuscripts with an average impact factor of 4.91.
The top 5 publications based on impact factor of the journal are:
1)
Cell Res. 2010 Mar;20(3):314-31. S100A8/A9 induces autophagy and apoptosis via ROSmediated cross-talk between mitochondria and lysosomes that involves BNIP3. Ghavami S,
Eshragi M, Ande SR, Chazin WJ, Klonisch T, Halayko AJ, McNeill KD, Hashemi M,
Kerkhoff C, Los M. (IF 9.417)
2)
Nucleic Acids Res. 2010 Jun;38(10):3196-208. Promoter chromatin remodeling of immediateearly genes is mediated through H3 phosphorylation at either serine 28 or 10 by the MSK1
multi-protein complex. Drobic B, Pérez-Cadahía B, Yu J, Kung SK, Davie JR. (IF 7.836)
3)
Oncogene. 2010 Jan 28;29(4):503-15. Chromosomal rearrangements after ex vivo EpsteinBarr virus (EBV) infection of human B cells. Lacoste S, Wiechec E, Dos Santos Silva AG,
Guffei A, Williams G, Lowbeer M, Benedek K, Henriksson M, Klein G, Mai S. (IF 7.414)
4)
Oncogene. 2010 Apr 8;29(14):2083-92. S100A7 (psoriasin) is induced by the proinflammatory
cytokines oncostatin-M and interleukin-6 in human breast cancer. West NR, Watson PH. (IF
7.414)
5)
Autophagy. 2010 Oct;6(7):835-7. A matter of balance between life and death: targeting
reactive oxygen species (ROS)-induced autophagy for cancer therapy. Gibson SB. (IF 6.643)


CCMB received approximately $20 million in grant funding this year.
There were 28 newly funded research projects for 2010.
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The 13th annual CancerCare Manitoba Research Day for trainees in clinical and basic medical
sciences was held April 27, 2011. Organized by the Medical Staff Association at CancerCare
Manitoba, the event is designed to promote oncology and hematology research among trainees. The
following MICB trainees received awards:
Shannon Healy, a Postdoctoral Trainee, with Dr. Jim Davie, won 1st prize in the Basic Science
Poster Presentation category and received the Rick Hester Award for her presentation entitled:
“Characterization of Nucleosomal at Immediate-Early Gene Promoters”.
Jamie L. Zagozewski, M.Sc. Student with Dr. David Eisenstat, won 2nd prize in the Basic Science
Poster Presentation category and recieved the Arnold Portigal Award for her presentation entitled:
“Transcriptional Regulation of the Retinoblastoma Family Member p107 by Dlx homeobo x genes
in forebrain and retinal development”.
Qi Zhang, a Graduate Student with Dr. David Eisenstat, won 3rd prize in the Basic Science Oral
Presentation category for his presentation entitled: “Dlx2 and Brn3b homeobox transcription factors
regulation of the Brn3a homeobox gene during vertebrate retina development ”.
Yuequin Zhou, a PhD Student with Dr. Geoff Hicks, won 3rd prize in the Basic Science Poster
Presentation category for her presentation entitled: “TLS directly targets OncomiR-1, the
microRNA-17-92 cluster ”.
Mario Fonseca, a Graduate Student with Dr. David Eisenstat received an honorable mention for his
presentation entitled “Linking DLX Transcription Factors to the WNT/β-Catenin Signaling
Pathway: Implications for Intestinal Development and Colorectal Carcinoma “.
Sajesh Babu, a Postdoctoral Trainee with Dr. Kirk McManus, received an honorable mention in the
Basic Science Poster Presentation category for his presentation entitled: “Identifying Novel
Candidate Drug Targets of Colon Cancer”.
Ju-Yoon Yoon, a PhD Student with Dr. Spencer Gibson, won 1st prize in the Basic Science Oral
Presentation category presentation for his presentation entitled “Effect of Valproic Acid on
Fludarabine Activity in Chronic Lymphocytic Leukemia Patients ”.
Sandrine Lafarge, a Postdoctoral Trainee with Dr. Spencer Gibson, won 2nd prize in the Basic
Science Oral Presentation category presentation for her presentation entitled “Chronic Lymphocytic
Leukemia: The Role of PI3KOathway in Microenvironment Interactions ”.
Macoura Gadji, a Postdoctoral Trainee with Dr. Sabine Mai received an honorable mention in the
Basic Science Oral Presentation for his presentation entitled “Genomic instability defined by
nuclear telomeric architecture in myelodysplastic syndrome and acute leukemias ”.
Rachelle Dillon, a Postdoctoral Trainee with Dr. Michael Mowat received an honorable mention in
the Basic Science Oral Presentation for her presentation entitled “Role of the Dlc1 tumor suppressor
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in breast cancer development and progression ”.
Oral presentation
1st Ju-Yoon Yoon
2nd Sandrine Lafarge
3rd Qi Zhang
Honourable mention Rachelle Dillon and Macoura Gadj
Poster Awards
1 Jamie Zagozewski (winner of the Arnold Portigal Award)
1st Shannon Healy (winner of the Hester Award)
3rd Yeuqin Zhou
Honourable mention Sajesh Babu
st
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Shilpa Choonidass, is the 2011 recipient
of the Apotex Fermentation Inc. Award
for excellence in Molecular Biology
Neil Salter, President, Health Sciences
Graduate Students Association presents
the HS-GSA Poster Award to Mario
Fonseca.
Paula Espino is the 2011 recipient of the Manitoba
Medical Service Foundation Ph.D. Award.
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Yueqin Zhou,winner of an Honourable Mention
in the 2011 Manitoba Health Research Poster
Competition, presents her research to the judges.
Christina Weise, Executive
Director, Manitoba Health
Research Council, presents
the MHRC Post Doctoral
Fellow Poster Award to
Sandrine Lafarge.
Ju-YoonYoon, winner of the Dean of
Medicine Poster Award, presents his
research to the judges.
Sajesh Babu, winner of the Dean of Medicine
Post - DocFellow Poster Award presents his
research to the judges.
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Anne Blanchard, a technician with Dr.
Myal’s lab was the recipient of the Karol
McNeill technician award from the Faculty
of Medicine
Siyuan (Sam) Cheng accepting his 5th place
award ($1,000) at the National Sanofi-Aventis
BioTech Challenge. Sam, 18, a Grade 12 student
at Fort Richmond Collegiate, combined the
standard drug treatment for leukaemia with a
lung cancer drug to greatly increase the numbers
of leukemia cells being killed. Dr. Pierre
Meulien (President and CEO of Genome
Canada), Siyuan Cheng, The Honourable Kelvin
K. Ogilvie
Suraj Srinivasan, Guangzhe Weng and George Ng, high
school students in Dr. Myal’s lab placed 3rd in the 2011
Sanofi-Aventis Biotech Challenge
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Meghan Azad, a Post Doctoral Fellow in Dr. Spencer Gibson’s lab was this
year’s recipient of the Simon and Sarah Israels Graduate Thesis Prize.
 Paula Espino was selected as a recipient of a UM Distinguished Dissertation Award
(Health Sciences Category).
 Yueqin Zhou, a PhD student in Dr. Geoff Hick’s lab was the recipient of the Dieter
Hettig Award
 Our Cancer Cure Manitoba team, Erika Gibson, Nichola Wigle, Eileen McMillan Ward, and
Le-Anne Tesluk once again participated in the 2011 Challenge for life. This 20K walk took
place on June 11, 2011 and the event was designed to increase awareness for all cancers as
well as improving public health
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Recognizing Our Outstanding
Staff
Our research could not have been conducted without the support of
our highly trained and dedicated staff. The following people are
being recognized for working at MICB for more than 10 years.
Charlene Bergen
Lab Assistant
Luke Delange
Research Associate
Don Dubik
Research Associate
Mario Fonseca
Technician
Amanda Guffei
Technician
Elizabeth Henson
Research Associate
Angela Kemp
Technician
Ludger Klewes
Research Associate
Brenda Kuschak
Research Associate
Laurie Lange
Technician
Songyan Liu
Associate Professor
Eileen McMillan Ward
Technician
Michelle Parisien
Admin Officer
Cheryl Peltier
Technician
Nikki Ryan
Admin Associate
Maria Simao
Lab Aide
Cheryl Kashton Taylor
Technician
Deborah Tsuyuki
Research Associate
Kanyarat Ung
Technician
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MICB Picnic
August 20, 2010
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MICB ANNUAL RETREAT
Lakeview Resort and Conference Center in Gimli, Manitoba
from September 24-26th , 2010
“Lymphoma” was the theme with the Keynote Speaker Dr. Neil E. Kay from the Mayo Clinic.
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BMG/MICB
Social Event
May 13, 2011
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Appreciation Dinner
Dr. Leigh Murphy as Acting Director
of MICB
Appreciation Dinner
In honor of
Dr. David Eisenstat
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Appreciation Reception
In honor of
Dr. David Eisenstat
For his dedication, innovation, vision, and
leadership in the areas of Developmental Biology
Research, Graduate and Medical Student
Education, and Neuro-Oncology.
We wish him the best as he takes on an Endowed Chair position at the
University of Alberta.
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MICB SEMINARS
The Institute offers seminars on a weekly basis, which are open to all. In the past year,
guest lecturers included:
August 27, 2009
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
3:00 – 4:00PM
Dr. Philippe Georgel
Associate Professor
Marshall University
Department of Biological Sciences
“Epigenetic
Regulations: More
than Just DNA
Methylation and
Histone
Modifications”
September 10, 2009
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Dr. Wen Zhong
Assistant Professor
Department of Textile Sciences,
University of Manitoba
“Liver Targeting
Nanoparticles
Containing
Doxorubicin via Acid
Cleavable Linkage”
October 7, 2009
Frederic Gaspard Theatre
(formerly Theatre A),
Basic Medical Sciences
Building, 730 William Ave.
11:00 – 12:00PM
Dr. Jacob Hollenberg Lectureship/
Dr. Geoffrey Greene
Virginia and D. K. Ludwig Professor
and Vice Chair, The Ben May
Department for Cancer Research ;
Professor, The Dept of Biochemistry
and Molecular Biology, University of
Chicago; Chair, Committee on
Cancer Biology; Associate Director
of Basic Sciences, Cancer Research
Center; Co-Director, Ludwig Center
for Metastasis Research
“ER and Non-ER
Targets for Breast
Cancer Prevention
and Treatment”
November 2, 2009
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
3:00 – 4:00PM
Dr. Marc Ekker
Professor , Department of Biology,
University of Ottawa
Director, Center for Advanced
Research in Environmental
Genomics
“Genetic Cascades
Involving DLx Genes
in the Mouse and
Zebrafish Forebrain”
December 3, 2009
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Dr. Hans Knecht
Director, Haematology Laboratories,
CHUS
Professor of Medicine, Division of
Haematology/Oncology, University
of Sherbrooke
“The Reed-Sternberg
Cell: Class 2009”
38
March 18, 2010
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Dr. Peter Cheung
Principal Investigator, Division of
Signaling Biology, Ontario Cancer
Institute; Assistant Professor, Dept.
of Medical Biophysics, University
of Toronto
“The roles of histone
phosphorylation and
histone variants in gene
expression regulation”
April 8, 2010
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Dr. Yvonne Myal
Director of Research and
Innovation, Diagnostic Services of
Manitoba; Associate Professor,
Department of Pathology,
University of Manitoba
“Claudin 1 in breast
cancer: tumor
suppressor, facilitator
or passive onlooker?”
April 22, 2010
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Dr. Uri Tabori
Staff Neuro Oncologist, Division of
Haematology/Oncology; Assistant
Professor of Paediatrics, University
of Toronto; Scientist, Research
Institute and The Arthur and Sonia
Labatt Brain Tumour Research
Centre, The Hospital for Sick
Children
"Telomere Biology in
Pediatric Cancer,
Personalizing
Individuals Tumors and
Cells."
April 23, 2010
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Dr. Andrew Li-Jen Kung
Director of Preclinical Imaging
Assistant Professor of Pediatrics’
Dana-Farber Cancer Institute
“Incorporation of
Imaging Endpoints in
Cancer Drug
Discovery.”
April 29, 2010
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Dr. Dr. Sean Egan
Associate Professor, Department of
Molecular and Genetics University
of Toronto
Senior Scientist, Program in
Developmental & Stem Cell
Biology Hospital for Sick Children
"Genetic Analysis of
Notch and PI3Kinduced Breast Cancer
in the Mouse
Mammary gland"
May 20, 2010
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Simon & Sarah Israels Graduate
Thesis Prize Lecture
Dr. Teralee Burton
Post-Doctoral Fellow
Manitoba Institute of Cell Biology
“The role of the procell death Bcl-2 family
member BNIP3 in
regulating GBM tumor
cell survival”
June 16, 2010
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
10:30 – 11:30AM
Dr. Gail Risbridger
Associate Dean, Research Centres
& Institutes; Director, Centre for
Urological Research (CURe)
Monash Institute of Medical
Research (MIMR), Monash
Medical Centre
"Estrogen Therapies for
Prostate Disease"
39
COMPENDIUM OF MICB
PUBLICATIONS (2010)
1: Mandal S, Davie JR. Estrogen regulated expression of the p21 Waf1/Cip1 gene in estrogen receptor
positive human breast cancer cells. J Cell Physiol. 2010 Jul;224(1):28-32.
2: Li L, Davie JR. The role of Sp1 and Sp3 in normal and cancer cell biology. Ann Anat. 2010 Sep
20;192(5):275-83. Epub 2010 Aug 6.
3: Wang X, He S, Sun JM, Delcuve GP, Davie JR. Selective association of peroxiredoxin 1 with
genomic DNA and COX-2 upstream promoter elements in estrogen receptor negative breast cancer
cells. Mol Biol Cell. 2010 Sep 1;21(17):2987-95.
4: Drobic B, Pérez-Cadahía B, Yu J, Kung SK, Davie JR. Promoter chromatin remodeling of
immediate-early genes is mediated through H3 phosphorylation at either serine 28 or 10 by the MSK1
multi-protein complex. Nucleic Acids Res. 2010 Jun;38(10):3196-208.
5: Davie JR, Drobic B, Perez-Cadahia B, He S, Espino PS, Sun JM, Chen HY, Dunn KL, Wark L, Mai
S, Khan DH, Davie SN, Lu S, Peltier CP, Delcuve GP. Nucleosomal response, immediate-early gene
expression and cell transformation. Adv Enzyme Regul. 2010;50(1):135-45.
6: Sharp JR, Bouffet E, Stempak D, Gammon J, Stephens D, Johnston DL, Eisenstat D, Hukin J,
Samson Y, Bartels U, Tabori U, Huang A, Baruchel S. A multi-centre Canadian pilot study of
metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem
glioma. Eur J Cancer. 2010 Dec;46(18):3271-9.
7: Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR,
Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF. Phase II trial of continuous dose-intense
temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr 20;28(12):20517.. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543.
8: Chen Y, Azad MB, Gibson SB. Methods for detecting autophagy and determining autophagyinduced cell death. Can J Physiol Pharmacol. 2010 Mar;88(3):285-95.
9: Ishdorj G, Johnston JB, Gibson SB. Inhibition of constitutive activation of STAT3 by curcurbitacin-I
(JSI-124) sensitized human B-leukemia cells to apoptosis. Mol Cancer Ther. 2010 Dec;9(12):3302-14.
10: Azad MB, Gibson SB. Role of BNIP3 in proliferation and hypoxia-induced autophagy: implications
for personalized cancer therapies. Ann N Y Acad Sci. 2010 Oct;1210:8-16.
11: Gibson SB. A matter of balance between life and death: targeting reactive oxygen species (ROS)induced autophagy for cancer therapy. Autophagy. 2010 Oct;6(7):835-7.
12: Xu K, Nieuwenhuis E, Cohen BL, Wang W, Canty AJ, Danska JS, Coultas L, RossantJ, Wu MY,
Piscione TD, Nagy A, Gossler A, Hicks GG, Hui CC, Henkelman RM, Yu LX, Sled JG, Gridley T,
Egan SE. Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis. Am J Physiol
Lung Cell Mol Physiol. 2010 Jan;298(1):L45-56.
13: Hayward CP, Moffat KA, Raby A, Israels S, Plumhoff E, Flynn G, Zehnder JL. Development of
North American consensus guidelines for medical laboratories that perform and interpret platelet
function testing using light transmission aggregometry. Am J Clin Pathol. 2010 Dec;134(6):955-63.
14: Israels SJ, El-Ekiaby M, Quiroga T, Mezzano D. Inherited disorders of platelet function and
challenges to diagnosis of mucocutaneous bleeding. Haemophilia. 2010 Jul;16 Suppl 5:152-9.15:
McNicol A, Israels SJ. Mechanisms of oral bacteria-induced platelet activation. Can J Physiol
Pharmacol. 2010 May;88(5):510-24.
15: Israels SJ, McMillan-Ward EM. Palmitoylation supports the association of tetraspanin CD63 with
CD9 and integrin alphaIIbbeta3 in activated platelets. Thromb Res. 2010 Feb;125(2):152-8. 40
16: Ouellet H, Johnston JB, Ortiz de Montellano PR. The Mycobacterium tuberculosis cytochrome
P450 system. Arch Biochem Biophys. 2010 Jan 17;493(1):82-95.
17: Dueck G, Chua N, Prasad A, Finch D, Stewart D, White D, van der Jagt R, Johnston J, Belch A,
Reiman T. Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin
lymphoma. Cancer. 2010 Oct 1;116(19):4541-8.
18: Myal Y, Leygue E, Blanchard AA. Claudin 1 in breast tumorigenesis: revelation of a possible
novel "claudin high" subset of breast cancers. J Biomed Biotechnol.2010;2010:956897. Epub 2010
May 13.
19: Chooniedass-Kothari S, Hamedani MK, Auge C, Wang X, Carascossa S, Yan Y, Cooper C,
Vincett D, Myal Y, Jalaguier S, Cavailles V, Leygue E. The steroid receptor RNA activator protein is
recruited to promoter regions and acts as a transcriptional repressor. FEBS Lett. 2010 Jun
3;584(11):2218-24.
20: Chooniedass-Kothari S, Vincett D, Yan Y, Cooper C, Hamedani MK, Myal Y, LeygueE. The
protein encoded by the functional steroid receptor RNA activator is a new modulator of ER alpha
transcriptional activity. FEBS Lett. 2010 Mar 19;584(6):1174-80
21: Ghavami S, Eshragi M, Ande SR, Chazin WJ, Klonisch T, Halayko AJ, McNeill KD, Hashemi
M, Kerkhoff C, Los M. S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk
between mitochondria and lysosomes that involves BNIP3. Cell Res. 2010 Mar;20(3):314-31
22: Klewes L, Höbsch C, Katzir N, Rourke D, Garini Y, Mai S. Novel automated three-dimensional
genome scanning based on the nuclear architecture of telomeres. Cytometry A. 2011 Feb;79(2):15966.
23: Rio Frio T, Lavoie J, Hamel N, Geyer FC, Kushner YB, Novak DJ, Wark L, Capelli C, ReisFilho JS, Mai S, Pastinen T, Tischkowitz MD, Marcus VA, Foulkes WD. Homozygous BUB1B
mutation and susceptibility to gastrointestinal neoplasia. N Engl J Med. 2010 Dec 30;363(27):262837.
24: Knecht H, Brüderlein S, Wegener S, Lichtensztejn D, Lichtensztejn Z, Lemieux B, Möller P, Mai
S. 3D nuclear organization of telomeres in the Hodgkin cell lines U-HO1 and U-HO1-PTPN1:
PTPN1 expression prevents the formation of very short telomeres including "t-stumps". BMC Cell
Biol. 2010 Dec 14;11:99.
25: Guffei A, Sarkar R, Klewes L, Righolt C, Knecht H, Mai S. Dynamic chromosomal
rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling
and breakage-bridge-fusion cycles. Haematologica. 2010 Dec;95(12):2038-46
26: Knecht H, Brüderlein S, Mai S, Möller P, Sawan B. 3D structural and functional characterization
of the transition from Hodgkin to Reed-Sternberg cells. Ann Anat. 2010 Sep 20;192(5):302-8.
27: Klonisch T, Wark L, Hombach-Klonisch S, Mai S. Nuclear imaging in three dimensions: a
unique tool in cancer research. Ann Anat. 2010 Sep 20;192(5):292-301.26: Millau JF, Mai S, Bastien
N, Drouin R. p53 functions and cell lines: have we learned the lessons from the past? Bioessays.
2010 May;32(5):392-400.
41
28: Millau JF, Mai S, Bastien N, Drouin R. p53 functions and cell lines: have we learned the lessons
from the past? Bioessays. 2010 May;32(5):392-400.27: Knecht H, Sawan B, Lichtensztejn Z,
Lichtensztejn D, Mai S. 3D Telomere FISH defines LMP1-expressing Reed-Sternberg cells as endstage cells with telomere-poor 'ghost' nuclei and very short telomeres. Lab Invest. 2010
Apr;90(4):611-9.
29: Mai S. Initiation of telomere-mediated chromosomal rearrangements in cancer. J Cell Biochem.
2010 Apr 15;109(6):1095-102.
30: Gadji M, Fortin D, Tsanaclis AM, Garini Y, Katzir N, Wienburg Y, Yan J, KlewesL, Klonisch T,
Drouin R, Mai S. Three-dimensional nuclear telomere architecture is associated with differential
time to progression and overall survival in glioblastoma patients. Neoplasia. 2010 Feb;12(2):183-91.
31: Silva AG, Graves HA, Guffei A, Ricca TI, Mortara RA, Jasiulionis MG, Mai S. Telomerecentromere-driven genomic instability contributes to karyotype evolution in a mouse model of
melanoma. Neoplasia. 2010 Jan;12(1):11-9.
32: Lacoste S, Wiechec E, Dos Santos Silva AG, Guffei A, Williams G, Lowbeer M, Benedek K,
Henriksson M, Klein G, Mai S. Chromosomal rearrangements after ex vivo Epstein-Barr virus (EBV)
infection of human B cells. Oncogene. 2010 Jan 28;29(4):503-15.
33: Wiener F, Schmälter AK, Mowat MR, Mai S. Duplication of Subcytoband 11E2 of Chromosome
11 Is Regularly Associated with Accelerated Tumor Development in v-abl/myc-Induced Mouse
Plasmacytomas. Genes Cancer. 2010 Aug;1(8):847-58.
34: Ben-Aroya S, Agmon N, Yuen K, Kwok T, McManus K, Kupiec M, Hieter P. Proteasome
nuclear activity affects chromosome stability by controlling the turnover of Mms22, a protein
important for DNA repair. PLoS Genet. 2010 Feb 19;6(2):e1000852.
35: Sabbir MG, Wigle N, Loewen S, Gu Y, Buse C, Hicks GG, Mowat MR. Identificationand
characterization of Dlc1 isoforms in the mouse and study of the biological function of a single gene
trapped isoform. BMC Biol. 2010 Mar 3;8:17.
36: Skliris GP, Nugent ZJ, Rowan BG, Penner CR, Watson PH, Murphy LC. A phosphorylation code
for oestrogen receptor-alpha predicts clinical outcome to endocrine therapy in breast cancer. Endocr
Relat Cancer. 2010 Jun 3;17(3):589-97.
37: Domanski D, Murphy LC, Borchers CH. Assay development for the determination
ofphosphorylation stoichiometry using multiple reaction monitoring methods with and without
phosphatase treatment: application to breast cancer signaling pathways. Anal Chem. 2010 Jul
1;82(13):5610-20.
42
38: Raouf A. Basal-like breast cancers: the phenotypic disparity between the cancer-initiating cells
and tumor histology. Breast Cancer Res. 2010;12(6):316.
39: To K, Fotovati A, Reipas KM, Law JH, Hu K, Wang J, Astanehe A, Davies AH, Lee L,
Stratford AL, Raouf A, Johnson P, Berquin IM, Royer HD, Eaves CJ, Dunn SE. Y-box binding
protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal,
mammosphere growth, and drug resistance. Cancer Res. 2010 Apr 1;70(7):2840-51.
40: Panet-Raymond V, Truong PT, Watson PH. Ipsilateral breast tumor recurrenceafter breastconserving therapy. Expert Rev Anticancer Ther. 2010 Aug;10(8):1229-38.
41: West NR, Watson PH. S100A7 (psoriasin) is induced by the proinflammatory cytokines
oncostatin-M and interleukin-6 in human breast cancer. Oncogene. 2010 Apr 8;29(14):2083-92.
42: Dillon RL, Muller WJ. Distinct biological roles for the akt family in mammary tumor
progression. Cancer Res. 2010 Jun 1;70(11):4260-4. Epub 2010 Apr 27.
43: Brandwein-Gensler M, Smith RV, Wang B, Penner C, Theilken A, Broughel D, Schiff B, Owen
RP, Smith J, Sarta C, Hebert T, Nason R, Ramer M, DeLacure M, Hirsch D, Myssiorek D, Heller K,
Prystowsky M, Schlecht NF, Negassa A. Validation of the histologic risk model in a new cohort of
patients with head and neck squamous cell carcinoma. Am J Surg Pathol. 2010 May;34(5):676-88.
44: Shepherd TG, Mujoomdar ML, Nachtigal MW. Constitutive activation of BMP signalling
abrogates experimental metastasis of OVCA429 cells via reduced cell adhesion. J Ovarian Res.
2010 Feb 26;3:5.
Research
43
DISTRIBUTION OF IMPACT FACTORS
AND CITED PUBLICATIONS
Year
Published
Author's Name
Impact
Factor
Times
Cited
Name of Publication/Book
2009
Begleiter, Asher
2.555
0
Leukemia Res.
2009
Begleiter, Asher
2.555
0
Leukemia Res.
2009
Begleiter, Asher
1.686
1
Oncol. Rep.
2008
Brandes, L.J.
1.211
1
Hum Exp Toxicol.
2008
Davie, Jim
3.122
2
J. Cell. Biochem
2008
Davie, Jim
3.122
17
J. Cell. Biochem
2008
Davie, Jim
3.122
16
J. Cell. Biochem
2008
Davie, Jim
2.606
2
J. Parenter. Enteral Nutr.
2008
Davie, Jim
2.068
3
Adv Enzyme Regul.
2008
Davie, Jim
3.122
2
J. Cell. Biochem
2009
Davie, Jim
4.926
1
Int J. Cancer
2009
Davie, Jim
3.986
87
J. Cell. Physiol.
2009
Davie, Jim
2.992
8
biochem. Cell. Biol.
2009
Davie, Jim
4.733
8
Biochim. Biophys. Acta
2009
Davie, Jim
3.99
8
Genes, chromosomes and Cancer
2010
Davie, Jim
3.986
3
J. Cell. Physiol.
2009
Davie, Jim
4.926
2
Int J. Cancer
2009
Davie, Jim
1.263
1
Am J Dermatopathology
2009
Davie, Jim
3.291
10
Eur. J. Pharm.
2009
Davie, Jim
3.291
11
Eur. J. Pharm.
2010
Davie, Jim
5.874
0
Aal Chem
2010
Davie, Jim
1.649
4
Ann. Anat.
2010
Davie, Jim
5.861
1
Mol. Biol. Cell.
2010
Davie, Jim
7.836
11
Nucleic Acids Res.
2010
Davie, Jim
2.068
3
Adv Enzyme Regul.
2011
Davie, Jim
2.992
0
Biochem. Cell. Biol.
2010
Davie, Jim
3.8
2
Curr Opin Drug Discov Devel.
2009
Davie, Jim
4.733
8
Biochim. Biophys. Acta
2008
Davie, Jim
3.122
3
J. Cell. Biochem
2008
Davie, Jim
2.606
2
J. Parenter. Enteral Nutr.
44
DISTRIBUTION OF IMPACT FACTORS
AND CITED PUBLICATIONS
2009
Eisenstat, D.D.
2.907
31
Cancer Biol. Ther.
2009
Eisenstat, D.D.
2.929
8
J. Neuro-Oncol.
2009
Eisenstat, D.D.
8.238
8
J. Neuroscience
2009
Eisenstat, D.D.
1.668
1
J. Child Neurology
2010
Eisenstat, D.D.
4.944
2
Eur J Cancer
2010
Eisenstat, D.D.
18.97
19
J. Clin Oncol.
2011
Eisenstat, D.D.
3.48
0
Neuroscience
2011
Eisenstat, D.D.
1.82
0
Curr Oncol.
2011
Eisenstat, D.D.
1.314
0
Childs Nerv. Syst.
2011
Eisenstat, D.D.
4.733
1
Biochim. Biophys. Acta
2010
Eisenstat, D.D.
18.97
38
J. Clin Oncol.
2009
Eisenstat, D.D.
2.907
1
Cancer Biol. Ther.
2009
Eisenstat, D.D.
8.238
10
J. Neuroscience
2009
Eisenstat, D.D.
2.929
9
J. Neuro-Oncol.
2008
Eisenstat, D.D.
2.942
13
Clin Gen
2008
Eisenstat, D.D.
7.836
8
Nucleic Acids Res.
2009
Gibson, Spencer B
2.555
0
Leukemia Res.
2008
Gibson, Spencer B
5.328
14
J. Biol. Chem.
2008
Gibson, Spencer B
8.209
55
Antioxid Redox Signal.
2008
Gibson, Spencer B
5.192
30
J. Cell Mol Med.
2008
Gibson, Spencer B
4.114
14
Cellular Signalling
2008
Gibson, Spencer B
2.492
22
Lymphoma and Leukemia
2008
Gibson, Spencer B
6.643
43
Autophagy
2008
Gibson, Spencer B
6.643
70
Autophagy
2008
Gibson, Spencer B
9.05
91
Cell Death Differ.
2009
Gibson, Spencer B
2.555
5
Leukemia Res.
2009
Gibson, Spencer B
2.907
31
Cancer Biol. Ther.
2009
Gibson, Spencer B
8.238
8
J. Neuroscience
2009
Gibson, Spencer B
2.555
5
Leukemia Res.
2009
Gibson, Spencer B
7.414
17
Oncogene
45
DISTRIBUTION OF IMPACT FACTORS
AND CITED PUBLICATIONS
2009
Gibson, Spencer B
4.942
7
Br J Haematol
2009
Gibson, Spencer B
2.492
3
Lymphoma and Leukemia
2009
Gibson, Spencer B
9.05
24
Cell Death Differ.
2009
Gibson, Spencer B
2.555
0
Leukemia Res.
2009
Gibson, Spencer B
9.05
46
Cell Death Differ.
2009
Gibson, Spencer B
4.942
27
Br J Haematol
2010
Gibson, Spencer B
1.849
0
Can J Physiol pharmacol
2008
Gibson, Spencer B
4.397
9
Apoptosis
2010
Gibson, Spencer B
5.225
0
Mol. Cancer Therap.
2010
Gibson, Spencer B
2.847
0
Ann N Y Acad Sci.
2010
Gibson, Spencer B
6.643
1
Autophagy
2009
Gibson, Spencer B
2.907
1
Cancer Biol. Ther.
2009
Gibson, Spencer B
8.238
10
J. Neuroscience
2009
Gibson, Spencer B
10.558
5
Blood
2010
Hicks, Geoffrey G
5.203
1
BMC Biology
2009
Hicks, Geoffrey G
1.849
1
Can J Physiol pharmacol
2008
Hicks, Geoffrey G
5.402
9
Carcinogenesis
2010
Hicks, Geoffrey G
4.137
7
Am J Physiol Lung Cell Mol Physiol
2011
Hicks, Geoffrey G
7.836
0
Nucleic Acids Res.
2010
Hicks, Geoffrey G
5.203
1
BMC Biology
2011
Hicks, Geoffrey G
19.527
0
Nature Cell Biology
2008
Israels, Sara J
6.643
70
Autophagy
2008
Israels, Sara J
9.05
91
Cell Death Differ.
2009
Israels, Sara J
2.372
2
Thromb Res
2009
Israels, Sara J
7.056
9
J. Bone Min res.
2009
Israels, Sara J
2.504
5
Am J Clin Pathol.
2009
Israels, Sara J
4.169
9
Sem Thromb Hemost
2009
Israels, Sara J
9.504
0
Circ Res
2009
Israels, Sara J
36.377
55
Nature Genetics
2010
Israels, Sara J
2.504
0
Am J Clin Pathol.
2010
Israels, Sara J
2.364
2
Haemophilia
46
DISTRIBUTION OF IMPACT FACTORS
AND CITED PUBLICATIONS
2010
Israels, Sara J
1.849
0
Can J Physiol pharmacol
2010
Israels, Sara J
2.372
1
Thromb Res
2009
Johnston, James B
2.555
0
Leukemia Res.
2008
Johnston, James B
5.328
14
J. Biol. Chem.
2008
Johnston, James B
4.114
14
Cellular Signalling
2008
Johnston, James B
2.492
22
Lymphoma and Leukemia
2009
Johnston, James B
2.555
5
Leukemia Res.
2009
Johnston, James B
2.555
5
Leukemia Res.
2009
Johnston, James B
4.942
7
Br J Haematol
2009
Johnston, James B
2.492
3
Lymphoma and Leukemia
2009
Johnston, James B
2.555
0
Leukemia Res.
2009
Johnston, James B
4.942
27
Br J Haematol
2010
Johnston, James B
3.022
1
Arch biochem and biophys
2008
Johnston, James B
9.9771
0
Proc Natl Acad Sci USA
2010
Johnston, James B
5.225
0
Mol. Cancer Therap.
2009
Johnston, James B
10.558
5
Blood
2008
Leygue, Etienne
4.131
7
Histopathology
2009
Leygue, Etienne
4.859
2
Breast Cancer Res Treat.
2009
Leygue, Etienne
2.336
11
Virchows Archiv.
2009
Leygue, Etienne
7.836
10
Nucleic Acids Res.
2010
Leygue, Etienne
1.225
4
J. Biomed Biotechnol.
2009
Leygue, Etienne
1.707
1
ACTA Biotheoretica
2008
Leygue, Etienne
4.131
4
Histopathology
2010
Leygue, Etienne
3.601
3
Febs Letters.
2010
Leygue, Etienne
3.601
3
Febs Letters.
2008
Los M
5.476
7
Neoplasia
2008
Los M
10.308
51
Trends Mol Med.
2008
Los M
2.907
2
Cancer Biol. Ther.
2008
Los M
2.385
18
2008
Los M
5.192
30
Arch. Immunol. Ther. Exp.
47
J. Cell Mol Med.
DISTRIBUTION OF IMPACT FACTORS
AND CITED PUBLICATIONS
2008
Los M
7.414
3
Oncogene
2008
Los M
6.29
31
J. Cell. Sci.
2008
Los M
4
29
Biochimica et Biophysica Acta-gene structure and
expression
2008
Mai, Sabine
3.122
2
J. Cell. Biochem
2009
Mai, Sabine
10.124
0
EMBO J.
2009
Mai, Sabine
7.621
28
Phyical review Letters
2009
Mai, Sabine
3.99
8
Genes, chromosomes and Cancer
2009
Mai, Sabine
1.707
1
ACTA Biotheoretica
2009
Mai, Sabine
3.291
4
Eur. J. Pharm.
2009
Mai, Sabine
10.124
21
EMBO J.
2009
Mai, Sabine
8.966
10
Leukemia
2008
Mai, Sabine
3.028
4
BMC Bioinformatics
2010
Mai, Sabine
2.068
3
Adv Enzyme Regul.
2010
Mai, Sabine
3.749
0
Cytometry Part A.
2010
Mai, Sabine
53.484
2
N Engl J Med
2010
Mai, Sabine
2.464
0
BMC Cell Biol.
2010
Mai, Sabine
2.364
1
Haemophilia
2010
Mai, Sabine
1.649
2
Ann. Anat.
2010
Mai, Sabine
1.649
1
Ann. Anat.
2010
Mai, Sabine
4.479
2
Bioessays
2010
Mai, Sabine
4.405
6
Lab Invest
2010
Mai, Sabine
3.122
5
J. Cell. Biochem
2010
Mai, Sabine
5.476
6
Neoplasia
2010
Mai, Sabine
5.476
3
Neoplasia
2010
Mai, Sabine
7.414
9
Oncogene
2009
Mai, Sabine
2.265
11
Oncology
2010
McManus, Kirk
9.543
7
Plos Genet.
2008
Mowat, M.R.A.
3.122
2
J. Cell. Biochem
2010
Mowat, M.R.A.
5.203
1
BMC Biology
2010
Mowat, M.R.A.
5.203
1
BMC Biology
48
DISTRIBUTION OF IMPACT FACTORS
AND CITED PUBLICATIONS
2008
Murphy, Leigh C
4.859
15
Breast Cancer Res Treat.
2008
Murphy, Leigh C
4.859
3
Breast Cancer Res Treat.
2008
Murphy, Leigh C
4.131
7
Histopathology
2009
Murphy, Leigh C
4.859
2
Breast Cancer Res Treat.
2009
Murphy, Leigh C
2.886
17
J. Steroid Biochem Mol Biol.
2009
Murphy, Leigh C
2.336
11
Virchows Archiv.
2009
Murphy, Leigh C
7.836
10
Nucleic Acids Res.
2010
Murphy, Leigh C
4.432
2
Endocr Relat Cancer.
2009
Murphy, Leigh C
1.849
1
Can J Physiol pharmacol
2008
Murphy, Leigh C
4.131
4
Histopathology
2010
Murphy, Leigh C
5.874
2
Anal Chem
2010
Murphy, Leigh C
22.469
0
Endocrine Reviews
2010
Raouf, Afshin
5.785
0
Breast Cancer Res.
2010
Raouf, Afshin
8.234
7
Cancer Res.
2009
Shiu, Robert PC
4.889
11
biochem. Pharmacol
2009
Shiu, Robert PC
1.849
1
Can J Physiol pharmacol
2009
Shiu, Robert PC
1.849
1
Can J Physiol pharmacol
2008
Watson P.H.
4.859
15
Breast Cancer Res Treat.
2008
Watson P.H.
4.19
20
Cancer Epidemiology Biomarkers & Prevention
2008
Watson P.H.
4.131
7
Histopathology
2009
Watson P.H.
4.859
2
Breast Cancer Res Treat.
2009
Watson P.H.
2.336
11
Virchows Archiv.
2010
Watson P.H.
4.432
2
Endocr Relat Cancer.
2008
Watson P.H.
4.131
4
Histopathology
2010
Watson P.H.
22.469
0
Endocrine Reviews
2010
Watson P.H.
2.976
0
Expert Review of Anticancer Therapy
2010
Watson P.H.
7.414
3
Oncogene
49
DISTRIBUTION OF IMPACT FACTORS
AND CITED PUBLICATIONS
Distribution of Impact Factor in Journals of MICB's published work: 2008‐2010
50
TOTAL NUMBER OF GRANT AWARDS 2010-2011
CCMF
CCSRI/NCIC
CIHR
CRC
Genome Prairie
Government
MHRC
MICH
Other
U of M
CBCF
MICB Funding Sources
1% 4%
22%
47%
2%
8%
8%
4%
3%
1%
0%
B.Sc Med
Types of trainees and students
BSc Med
High School
Honors
MD/PhD
3%
2% 2%
3%
2%
1%
MSc
5%
Ph.D
29%
17%
Post Doctoral Fellow
Student - CIHR Training
Program - Short Term
Student - Graduate
1%
5%
15%
15%
Student - summer
Student - visiting
Student Projects
51
PATENTS 2010-2011
CancerCare Manitoba
Mai, Sabine
Telomeric Disk
Mai, Sabine
Method of Detecting & Monitoring Cancer using 3D Analysis of
Centromeres – CentroView
Mai, Sabine
Method of Monitoring Genomic Instability Using 3D Microscopy
Mai, Sabine
Methods of Diagnosis or Detection Using 3D Analysis – TeleView/BRCA
Mai, Sabine /
Havicauva
Method & System for the 3D Analysis of Chromosomes – ChromoView
Hicks, Geoff
A Novel SMART shRNA System for Disease Diagnosis & Therapy
University of Manitoba
Eisenstat, David /
Gibson, Spencer
Mutation In The Pro-Apoptotic Protein BNIP3 As A Biomarker For Solid
Tumors
Leygue, Etienne
SBAM Promoter
Los, Marek
Anticancer, Antimicrobial And Immuno-Suppressive Properties Of BrevininLike Peptides From Rana Ridibunda
Los, Marek
Anticancer Peptides Derived From A Viral Protein Apoptin (VP3)
Los, Marek
A Novel Role For BAX In The Bystander Effect
Murphy, Leigh
Phosphorylation of Estrogen Receptor Alpha
52
SPENCER GIBSON
Ph.D. (TORONTO)
Acting Director,
Manitoba Institute of Cell Biology
Provincial Director, Research
CancerCare Manitoba
Discovering Signal Transduction Pathways Regulating Cell Death
In maintaining integrity and homeostasis of multicellular organisms, the balance between cell death
and survival is fundamentally important. When this balance is altered diseases occur such as cancer.
One protein important in regulation of cell death is the Bcl-2 BH-3 only member BNIP3. BNIP3
expression is induced under low oxygen (hypoxia) conditions and is over expressed in solid tumors
in hypoxic regions. When BNIP3 is over expressed in cancer cells it induces cell death mediated by
mitochondrial dysfunction. This cell death instead of being apoptotic is autophagic (a new form of
programmed cell death). This paradox of BNIP3 killing cancer cells and being over expressed in live
cells within tumors is a focus of our research. To date three explanations could account of these
differences. The first difference is growth factors block BNIP3 cell death function and tumors have
deregulated growth factor signaling leading to cell survival (see below). Secondly, BNIP3 is also
localized in the nucleus of tumor cells prevent its interaction with the mitochondria blocking its cell
death function. Finally, the BNIP3 gene is mutated to an inactive protein. This protein acts in a
dominant negative fashion blocking hypoxia induced cell death. The importance of these
mechanisms for cancer progression and treatment is under active investigation.
Cell survival is as important as cell death. The epidermal growth factor receptor (EGFR) is expressed
at high levels in several cancers such as breast cancer. We discovered that pretreatment of breast
cancer cell lines with epidermal growth factor (EGF) effectively blocked drug and death receptor
induced apoptosis. This protection from apoptosis is mediated by a serine threonine kinase called
AKT through up-regulation of the Bcl-2 anti-apoptotic family member Mcl-1. Besides breast cancer,
we have found that a lipid, lysophosphatic acid (LPA) blocks apoptosis in chronic lymphocytic
leukemia (CLL) cells using a similar mechanism. We are currently investigating the regulatory
elements controlling Mcl-1 expression.
Molecular-based therapies could alter the balance between cell death and survival towards killing
cancer cells. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) selectively kills
cancer cells while normal cells are resistant to TRIAL-induced apoptosis. In collaboration with Dr.
James Johnston, we are investigating the potential of TRAIL as a therapy for chronic lymphocytic
leukemia (CLL) alone or in combination with chemotherapy.
In addition, we previously discovered that chemotherapeutic drugs increase TRAIL death receptor
(DR4/5) expression and this contributes to drug-induced apoptosis. We are defining the regulatory
elements controlling DR4/5 expression in CLL cells to enhance the clinical effectiveness of TRAIL.
The goal of this research is to define the signal transduction pathways leading to cell death or
survival. This will elucidate pharmaceutical targets that could alter the cellular balance in favour of
cell death. This research will be the foundation to establish clinical trials using molecular targeted
53
therapies to increase effectiveness of chemotherapy in cancer.
Publications Since 2008
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Li, L. Chen,Y., Gibson SB, 2011 Starvation-induced autophagy is regulated by mitochondrial
reactive oxygen species leading to AMPK activation Submitted Autophagy
Ishdorj G, Li L, Gibson SB. Regulation of autophagy in hematological malignancies: role of
reactive oxygen species. Leuk Lymphoma. 2011 Sep 8.
Xiao W, Ishdorj G, Sun J, Johnston JB, Gibson SB. Death receptor 4 is preferentially recruited
to lipid rafts in chronic lymphocytic leukemia cells contributing to tumor necrosis related
apoptosis inducing ligand-induced synergistic apoptotic responses. Leuk Lymphoma. 2011
Jul;52(7):1290-301.
Ishdorj G, Johnston JB, Gibson SB. Cucurbitacin-I (JSI-124) activates the JNK/c-Jun signaling
pathway independent of apoptosis and cell cycle arrest in B leukemic cells. BMC Cancer. 2011
Jun 24;11:268.
Booy EP, Henson ES, Gibson SB. Epidermal growth factor regulates Mcl-1 expression through
the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene.
2011 May 19;30(20):2367-78.
Myskiw C, Arsenio J, Booy EP, Hammett C, Deschambault Y, Gibson SB, Cao J. RNA species
generated in vaccinia virus infected cells activate cell type-specific MDA5 or RIG-I dependent
interferon gene transcription and PKR dependent apoptosis. Virology. 2011 May
10;413(2):183-93.
Chen CI, Bergsagel PL, Paul H, Xu W, Lau A, Dave N, Kukreti V, Wei E, Leung-Hagesteijn C,
Li ZH, Brandwein J, Pantoja M, Johnston J, Gibson S, Hernandez T, Spaner D, Trudel S.
Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic
leukemia. J Clin Oncol. 2011 Mar 20;29(9):1175-81.
Bristow N, Burton TR, Henson ES, Ong-Justiniano C, Brown M, Gibson SB. Truncated forms
of BNIP3 act as dominant negatives inhibiting hypoxia-induced cell death. Biochim Biophys
Acta. 2011 Mar;1812(3):302-11.
Ishdorj G, Johnston JB, Gibson SB. Inhibition of constitutive activation of STAT3 by
curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis. Mol Cancer Ther.
2010 Dec;9(12):3302-14.
Azad MB, Gibson SB. Role of BNIP3 in proliferation and hypoxia-induced autophagy:
implications for personalized cancer therapies. Ann N Y Acad Sci. 2010 Oct;1210:8-16.
Gibson SB. A matter of balance between life and death: targeting reactive oxygen species
(ROS)-induced autophagy for cancer therapy. Autophagy. 2010 Oct;6(7):835-7.
Chen Y, Azad MB, Gibson SB. Methods for detecting autophagy and determining autophagyinduced cell death. Can J Physiol Pharmacol. 2010 Mar;88(3):285-95.
Kumar SA, Hu X, Brown M, Kuschak B, Hernandez TA, Johnston JB, Gibson SB.
Lysophosphatidic acid receptor expression in chronic lymphocytic leukemia leads to cell
survival mediated though vascular endothelial growth factor expression. Leuk Lymphoma.
2009 Dec;50(12):2038-48.
Costantini JL, Cheung SM, Hou S, Li H, Kung SK, Johnston JB, Wilkins JA, Gibson SB,
Marshall AJ. TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through
interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesionpromoting complex in B-cell leukemia. Blood. 2009 Nov 19;114(21):4703-12.
Amrein L, Panasci L, Gibson SB, Johnston JB, Soulières D, Aloyz R. Primary del 17 chronic
lymphocytic leukaemia lymphocytes are hypersensitive to dasatinib in vitro. Br J Haematol.
54
2009 Nov;147(3):396-8.
16. Seftel MD, Demers AA, Banerji V, Gibson SB, Morales C, Musto G, Pitz MW, Johnston
JB. High incidence of chronic lymphocytic leukemia (CLL) diagnosed by
immunophenotyping: a population-based Canadian cohort. Leuk Res. 2009
Nov;33(11):1463-8.
17. Chen Y, Azad MB, Gibson SB. Superoxide is the major reactive oxygen species regulating
autophagy. Cell Death Differ. 2009 Jul;16(7):1040-52.
18. Eisenstat DD, Gibson SB. RIGging functional outcomes in glioma cells: new insights into
LRIG proteins in malignant gliomas. Cancer Biol Ther. 2009 Jun;8(11):1024-6.
19. Burton TR, Gibson SB. The role of Bcl-2 family member BNIP3 in cell death and disease:
NIPping at the heels of cell death. Cell Death Differ. 2009 Apr;16(4):515-23.
20. Burton TR, Eisenstat DD, Gibson SB. BNIP3 (Bcl-2 19 kDa interacting protein) acts as
transcriptional repressor of apoptosis-inducing factor expression preventing cell death in
human malignant gliomas. J Neurosci. 2009 Apr 1;29(13):4189-99.
21. Chinnadurai G, Vijayalingam S, Gibson SB. BNIP3 subfamily BH3-only proteins:
mitochondrial stress sensors in normal and pathological functions. Oncogene. 2008 Dec;27
Suppl 1:S114-27.
Pubmed Search For Spencer Gibson
Invited Seminars and Presentations at Symposia/Meetings
1.Department of Microbiology and Immunology, Dalhousie University, August 2011
2.Department of Biochemistry, Virginia Commonwealth University, January 2011
3. The Arthur and Sonia Labatt Brain Tumour Research Centre, University of Toronto, June 2010
4. Department of Pharmacology and Toxicology, University of Manitoba, March 2009
5. Department of Pathology, University of Calgary, September, 2008
External Service:
1. Reviewer for manuscripts for peer-reviewed scientific journal: Oncogene, Molecular Biology
of the Cell, Blood, Cancer, Cancer Research, British Journal of Cancer, Clinical Cancer
Research, Molecular Cancer Therapeutics, Molecular Pharmacology, EMBO, BLOOD,
Autophagy, Free Radical Biology and Medicine, Cell Death and Differentiation and
Carcinogenesis,
2.
Participated in a teleconference to nominate members of the Cancer A and B grant
committees for Canadian Institutes of Health Research
3.
Reviewer for grant submitted to the Alberta Innovates for Health Solutions
4.
Organizer of Signal Transduction Journal Club Reviewer for manuscripts for peer-reviewed
scientific journal:
5. External Reviewer for the Saskatchewan Health Research Foundation for Establishment
grant, UK Medical Research Council, Swiss Medical Research Funding Agency and
Singapore government funding agency.
6.
National Institutes of Health BMCT Study Section, Full panel member
7. Special Reviewer P01 grants
8. Reviewer for grant submitted to the Alberta Heritage Foundation
9. Scientific Director of the Manitoba CLL Tissue Bank
55
10.
11.
12.
13.
14.
15.
16.
17.
Radiation Safety Officer for Manitoba Institute of Cell Biology
Attend Manitoba Institute of Cell Biology Senior Investigator Meetings
Attend Departmental Council Meetings
Organizer of Signal Transduction Journal Club
Administrator of the Invited Speakers Program- Molecular Biology series
Member of Standard Operating Practices Committee at Manitoba Institute of Cell Biology
Attended workshops on PCR techniques and Laboratory Animal Care and Use.
Attended the National Cancer Research Initiative meeting for Young Investigators
representing Manitoba.
18. External Reviewer for the Saskatchewan Health Research Foundation for Establishment
grant.
Professional Service
1.
Interim, Provincial Director, Research, CancerCare Manitoba
2. Acting, Director MICB
3. Administration
4.
Director of Translational Research
56
JIM DAVIE
Ph.D. (BRITISH COLUMBIA)
Epigenetic is a term used to describe changes in gene expression that are stable between cell divisions.
Chromatin modifying enzymes including lysine acetytransferases (KATs), histone deacetylases
(HDACs), histone kinases, histone phosphatases, lysine/arginine methyltransferases,
lysine/arginine demethylases, ATP-dependent chromatin remodeling complexes and DNA
methyltransferases mediate chromatin remodeling and are components of a complex epigenetic
network regulating gene expression during development, differentiation and disease. Multistep
tumorigenesis is a progression of events resulting from alterations in the processing of the
genetic information. These alterations result from stable genetic changes (mutations) in tumor
suppressor genes and oncogenes (e.g. ras) and potentially reversible epigenetic changes. DNA
methylation and histone post-translational modifications (PTMs) are two epigenetic mechanisms
that are altered in cancer cells.
The mammalian cell’s nucleus is highly organized, with transcription factors and factories, chromatin
modifying enzymes, and chromosomes having defined sites. Altered nuclear structure and
function (gene expression) underlie the development and progression of cancer.
Dr. Davie’s research program has three research themes designed to understand the roles of chromatin
dynamics and nuclear structure in gene expression in normal and cancer cells: i) to characterize
histone PTMs and chromatin modifying enzymes associated with transcribed chromatin; ii) to
investigate the mechanisms by which signal transduction pathways control chromatin dynamics;
iii) to explore the role of the nuclear matrix in chromatin dynamics and to identify nuclear matrix
proteins informative in cancer diagnosis.
Publications Since 2008
1.
Healy S, Khan DH, Davie JR. Gene expression regulation through 14-3-3 interactions with
histones and HDACs. Discov Med. 2011 Apr;11(59):349-58. Review.
2. Pérez-Cadahía B, Drobic B, Davie, JR. Activation and function of immediate early genes in the
nervous system. Biochem Cell Biol. 2011 Feb;89(1):61-73.
3.
Pérez-Cadahía B, Drobic B, Espino PS, He S, Mandal S, Healy S, Davie JR. Role of MSK1 in
the malignant phenotype of Ras-transformed mouse fibroblasts. J Biol Chem. 2011 Jan
7;286(1):42-9.
4. Pérez-Cadahía B, Drobic B, Khan P, Shivashankar CC, Davie JR. Current understanding and
importance of histone phosphorylation in regulating chromatin biology. Curr Opin Drug Discov
Devel. 2010 Sep;13(5):613-22.
5. Li L, Davie JR. The role of Sp1 and Sp3 in normal and cancer cell biology. Ann Anat. 2010 Sep
20;192(5):275-83.
6.
Wang X, He S, Sun JM, Delcuve GP, Davie JR. Selective association of peroxiredoxin 1 with
genomic DNA and COX-2 upstream promoter elements in estrogen receptor negative breast
cancer cells. Mol Biol Cell. 2010 Sep 1;21(17):2987-95.
57
7. Mandal S, Davie JR. Estrogen regulated expression of the p21 Waf1/Cip1 gene in estrogen
receptor positive human breast cancer cells. J Cell Physiol. 2010 Jul;224(1):28-32.
8.
Davie JR, Drobic B, Perez-Cadahia B, He S, Espino PS, Sun JM, Chen HY, Dunn KL, Wark L,
Mai S, Khan DH, Davie SN, Lu S, Peltier CP, Delcuve GP. Nucleosomal response, immediateearly gene expression and cell transformation. Adv Enzyme Regul. 2010;50(1):135-45.
9.
Healy S, Perez-Cadahia B, Jia D, McDonald MK, Davie JR, Gravel RA. Biotin is not a natural
histone modification. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):719-33.
10. Dunn KL, He S, Wark L, Delcuve GP, Sun JM, Yu Chen H, Mai S, Davie JR. Increased genomic
in stability and altered chromosomal protein phosphorylation timing in HRAS-transformed
mouse fibroblasts. Genes Chromosomes Cancer. 2009May;48(5):397-409.
11. Delcuve GP, Rastegar M, Davie JR. Epigenetic control. J Cell Physiol. 2009May;219(2):243-50.
Review.
12. Espino PS, Pritchard S, Heng HH, Davie JR. Genomic instability and histone H3
phosphorylation induction by the Ras-mitogen activated protein kinase pathway in pancreatic
cancer cells. Int J Cancer. 2009 Feb 1;124(3):562-7.
13. Stein GS, Davie JR, Knowlton JR, Zaidi SK. Nuclear microenvironments and cancer. J Cell
Biochem. 2008 Aug 15;104(6):1949-52.
14. Li L, Davie JR. Association of Sp3 and estrogen receptor alpha with the transcriptionally active
trefoil factor 1 promoter in MCF-7 breast cancer cells. J Cell Biochem. 2008 Oct 1;105(2):3659.
15. Delcuve GP, He S, Davie JR. Mitotic partitioning of transcription factors. J Cell Biochem. 2008
Sep 1;105(1):1-8.
16. Davie JR, He S, Li L, Sekhavat A, Espino P, Drobic B, Dunn KL, Sun JM, Chen HY, Yu J,
Pritchard S, Wang X. Nuclear organization and chromatin dynamics--Sp1, Sp3 and histone
deacetylases. Adv Enzyme Regul. 2008;48:189-208.
17. Kien CL, Peltier CP, Mandal S, Davie JR, Blauwiekel R. Effects of the in vivo supply of
butyrate on histone acetylation of cecum in piglets. JPEN J Parenter Enteral Nutr. 2008 JanFeb;32(1):51-6.
PubMed search for Jim Davie
Organizer/Chair of International Meetings
1. Organizer, Canadian Society for Biochemistry and Molecular & Cellular Biology (CSBMCB)
Meeting on “Epigenetics and Genomic Integrity”, Whistler, March, 2012
2.
Co-Organizer, FASEB Summer Conference on " Histone Deacetylases and Reversible
Acetylation in Signaling & Disease" June 2011, Colorado
3.
Co-organizer, Keystone Conference on “Chromatin Structure and the Histone Code: Mechanism
or Metaphor” January 2011, Colorado
Invited Speaker at Symposia/Meetings
1.
Keynote Speaker, Clinical Epigenetics, Homburg/Saar, Germany, March 11, 2011
2. Keystone Conference on “Chromatin Structure and the Histone Code: Mechanism or Metaphor”
January 2011, Midway, Utah
3.
2nd International Symposium in Recent Advances in Basic, Clinical and Social Sciences,
November 2009 at Shantou University, Shantou, China
4. 50th Advances in Enzyme Regulation Symposium, Sept 2009 at Bologna, Italy
5. FASEB Summer Conference on “Histone Deacetylase and Reversible Protein Acetylation in
signaling and disease”, August 9-14, 2009 at Lucca, Toscana, Italy
6.
FASEB Summer Conference on "Nuclear Structure and Cancer", June 14-19, 2009 at58Saxtons
River, Vermont
Invited Research Seminars
1.Cross Cancer Institute, Edmonton, April 2011
2.4SC, Munich Germany, March 2011
3.Medical University of South Carolina, Charleston South Carolina, March 2010
4.Department of Biochemistry and Microbiology, University of Victoria, March 2010
5.Department of Biochemistry, University of Alberta, Edmonton, October 2009
6.Center for Epigenetics, University of Florida, Gainesville, Florida, April 2009
7.Cell Differentiation and Development Center, Marshall University, Huntington, West Virginia,
February 2009
8.Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western
Ontario, London, November 2008
9.Department of Molecular Biology, College of Agriculture, University of Wyoming, Laramie,
Wyoming, October 2008
10.Department of Medical Genetics, University of Alberta, Edmonton, April 2008
Professional Service
1.Executive Director, Manitoba Health Research Council (2009 – 2010)
2.Scientific Director, Manitoba Health Research Council (2010 – 2014)
3.Acting Associate Director, Manitoba Institute of Cell Biology (2010 – 2011)
4.Leader, Terry Fox Research Institute Prairie Node (2010 – 2012, renewable)
5.Member, Site Visit Team to review a CHIR/TFRI Program Project application, 2010
6.Member, Ontario Research Fund-Global Leadership in Genomics and Life Sciences Cancer & Stem
Cells peer-review panel, 2010
7.Member, Alberta Cancer Research Institute Grant Review Committee, 2010
8.Member, Site Visit Team to review a NCIC Program Project application, 2009
9.Provincial Director (Research), CancerCare Manitoba (2000 – 2008)
10.Director, Manitoba Institute of Cell Biology (2000 – 2008)
11.Member, Grant Review Committee Biochemistry and Molecular Biology, CIHR, 2008, 2009
12.Chair, Grant Review Panel D, NCIC, 2005, 2007, 2008
13.Member, CFI New Opportunities Fund, College of Reviewers, 200414.Member, CRC, College of Reviewers, 200415.Member, MHRC Research Advisory Committee, 2008
16.Member, US NCI Prevention Control Group, 2008
17. Member, Steering Committee for the Manitoba HPV Prevention Secretariat, 2008
18. Member, Scientific and Medical Advisory Committee, Prostate Cancer Research Foundation of
Canada, June 2008
19. Member, Molecular and Cellular Oncology P01 Special Emphasis Panel, US National Cancer
Institute, Washington DC, June 4-5, 2008
20. Member, US Congressionally Directed Medical Research Programs review panel for the
pre-doctoral traineeship award in breast cancer, March 2008
21. Member, Institute of Cardiovascular Sciences Awards Committee, 2007, 2008
22. Member, Grant Review Committee, Genetics, CIHR, 2007
23. Member, review NIH Program Project application, March 2007
24. Member, NorCOMM Scientific Advisory Board (Genome Canada), 2005-present
59
Review Team Membership
1.
Chair, Senate Committee of University Research review of Institute of Cardiovascular Sciences,
2008
2. Member, Academic Program Review Committee to review Department of Biochemistry and
Microbiology at the University of Victoria, March 19-20, 2008
3. Member, Senate Committee of University Research review of Centre for Life Course Health,
2007
Member of the Editorial Board
1. Editor, Biochemistry and Cellular Biology, 1999 - present
2. Journal of Biological Chemistry (1997-2002, 2006-2011)
3. Clinical Epigenetics (current)
4. Journal of Cellular Biochemistry (current)
5. International Journal of Cell Biology (current)
6. International Journal of Biochemistry and Cell Biology
7. Molecular Biology Reports (current)
8. Gene Therapy and Molecular Biology
9. Critical Reviews in Eukaryotic Gene Expression (2005-08)
60
DAVID D. EISENSTAT
M.D. (TORONTO),
M.A. (UCSF), F.R.C.P.C.
The research conducted in my laboratory is directed toward understanding the regulation of cell
growth and differentiation during development. These investigations are of primary importance to
childhood cancers. In Manitoba, cancer is the most common cause of death in childhood and
adolescence, excluding accidents. Current treatment strategies, which primarily involve radiation and
chemotherapy, do not directly target the cancer cell. In contrast, biological response modifiers have
been used to treat several types of malignancy by harnessing normal developmental programs specific
to these relatively undifferentiated cancer cell populations. The primary aim of my research program
is to facilitate our understanding of the processes of differentiation of cells through changes in their
internal milieu and external environment. I propose to accomplish this through an improved
understanding of two important regulatory molecules: (i) the hypoxia-inducible cell death protein,
BNIP3 (in collaboration with Dr. Spencer Gibson) in brain tumours of children and adults; and (ii) the
DLX homeodomain proteins that are transcription factors in the developing brain, retina, pancreas,
intestine and enteric nervous system. The ultimate goal is to develop novel therapeutic approaches
complementing current treatment strategies by modifying neuronal differentiation programs in
paediatric malignancies, including neuroblastoma, retinoblastoma and brain tumours.
Publications Since 2008
1. Feng L, Eisenstat DD, Chiba S, Ishizaki Y, Gan L, Shibasaki K. Brn-3b inhibits generation of
amacrine cells by binding to and negatively regulating DLX1/2 in developing retina.
Neuroscience. 2011 Nov 10;195:9-20.
2. Lafay-Cousin L, Hawkins C, Carret AS, Johnston D, Zelcer S, Wilson B, Jabado N,
Scheinemann K, Eisenstat D, Fryer C, Fleming A, Mpofu C, Larouche V, Strother D, Bouffet E,
Huang A. Central nervous system atypical teratoid rhabdoid tumours: The Canadian Paediatric
Brain Tumour Consortium experience. Eur J Cancer. 2011 Oct 22.
3. Zelcer S, Keene D, Bartels U, Carret AS, Crooks B, Eisenstat DD, Fryer C, Lafay-Cousin L,
Johnston DL, Larouche V, Moghrabi A, Wilson B, Silva M, Brossard J, Bouffet E. Spinal cord
tumors in children under the age of 3 years: aretrospective Canadian review. Childs Nerv Syst.
2011 Jul;27(7):1089-94.
4.
Easaw JC, Mason WP, Perry J, Laperrière N, Eisenstat DD, Del Maestro R, Bélanger K, Fulton
D, Macdonald D; for the Canadian Glioblastoma Recommendations Committee*. Canadian
recommendations for the treatment of recurrent or progressive glioblastoma multiforme. Curr
Oncol. 2011 Jun;18(3):e126-e136.
5. Lafay-Cousin L, Keene D, Carret AS, Fryer C, Brossard J, Crooks B, Eisenstat D, Johnston D,
Larouche V, Silva M, Wilson B, Zelcer S, Bartels U, Bouffet E. Choroid plexus tumors in
children less than 36 months: the Canadian Pediatric Brain Tumor Consortium (CPBTC)
experience. Childs Nerv Syst. 2011 Feb;27(2):259-64.
6.
Baxter SA, Cheung DY, Bocangel P, Kim HK, Herbert K, Douville JM, Jangamreddy JR,
Zhang S, Eisenstat DD, Wigle JT. Regulation of the lymphatic endothelial cell cycle by the
61
PROX1 homeodomain protein. Biochim Biophys Acta. 2011 Jan;1813(1):201-12.
7. Bartels U, Baruchel S, Carret AS, Crooks B, Hukin J, Johnston D, Silva M, Strother D, Wilson B,
Zelcer S, Eisenstat D, Sung L, Bouffet E. The use and effectiveness of temozolomide in children
with central nervous system tumours: a survey from the Canadian Paediatric Brain Tumour
Consortium. Curr Oncol. 2011 Jan;18(1):e19-24.
8. Sharp JR, Bouffet E, Stempak D, Gammon J, Stephens D, Johnston DL, Eisenstat D, Hukin J,
Samson Y, Bartels U, Tabori U, Huang A, Baruchel S. A multi-centre Canadian pilot study of
metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem
glioma. Eur J Cancer. 2010 Dec;46(18):3271-9.
9. Johnston DL, Keene D, Bartels U, Carret AS, Crooks B, Eisenstat D, Fryer C, Lafay-Cousin L,
Larouche V, Moghrabi A, Wilson B, Zelcer S, Silva M, Brossard J, Bouffet E. Patterns of
enrollment of infants with central nervous system tumours on cooperative group studies: a report
from the Canadian Pediatric Brain Tumour Consortium. J Neurooncol. 2010 Sep;99(2):243-9.
10. Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald
DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF. Phase II trial of continuous dose-intense
temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr
20;28(12):2051-7. Epub 2010 Mar 22. Erratum in: JClin Oncol. 2010 Jul 20;28(21):3543.
11. Dueck CC, Grynspan D, Eisenstat DD, Caces R, Rafay MF. Ischemic perinatal stroke secondary to
chorioamnionitis: a histopathological case presentation. J Child Neurol. 2009 Dec;24(12):1557-60.
12. Melanson M, Miao P, Eisenstat D, Gong Y, Gu X, Au K, Zhu W, Begum F, Frost EE, Namaka M.
Experimental autoimmune encephalomyelitis-induced upregulation of tumor necrosis factor-alpha
in the dorsal root ganglia. Mult Scler. 2009 Oct;15(10):1135-45.
13. Johnston DL, Keene D, Bartels U, Carret AS, Crooks B, Eisenstat DD, Fryer C, Lafay-Cousin L,
Larouche V, Moghrabi A, Wilson B, Zelcer S, Silva M, Brossard J, Bouffet E. Medulloblastoma in
children under the age of three years: a retrospective Canadian review. J Neurooncol. 2009
Aug;94(1):51-6.
14. Eisenstat DD, Gibson SB. RIGging functional outcomes in glioma cells: new insights into LRIG
proteins in malignant gliomas. Cancer Biol Ther. 2009 Jun;8(11):1024-6.
15. Burton TR, Eisenstat DD, Gibson SB. BNIP3 (Bcl-2 19 kDa interacting protein) acts as
transcriptional repressor of apoptosis-inducing factor expression preventing cell death in human
malignant gliomas. J Neurosci. 2009 Apr 1;29(13):4189-99.
16. Miao P, Madec K, Gong Y, Shen H, Eisenstat D, Melanson M, Gu X, Leong C, Klowak M,
Namaka M. Axotomy-induced up-regulation of tumor necrosis factor-alpha in the dorsal root
ganglia. Neurol Res. 2008 Jul;30(6):623-31.
17. Wigle JT, Eisenstat DD. Homeobox genes in vertebrate forebrain development and disease. Clin
Genet. 2008 Mar;73(3):212-26. Epub 2008 Jan 31. Review. PubMed
Pubmed search for David Eisenstat
Abstracts and Conference Presentations since 2007
1.
Zhang Q, Cheng S, and Eisenstat DD. (2010) Dlx homeobox transcription factor regulation of
the Brn3a homeobox gene during vertebrate retina development. RD2010. XIV International
Symposium on Retinal Degeneration (accepted).[poster]
2.
Pinto VI, Lerner S, Pind M, and Eisenstat DD. (2010) DLX homeobox transcriptional regulation
of CRX and OTX2 gene expression during vertebrate retinal development. 16th Retina
International World Congress (accepted).[poster]
62
3. Globa AK, Pinto VI, and Eisenstat DD. (2010) Role of DLX genes in vertebrate retinal
development. Rising Stars of Research (accepted). [poster]
4. Eisenstat D, Bush J, Pinto V, Zagozewski J, and Bremner R. (2010) Role of DLX2 in
retinoblastoma differentiation. Pediatr Blood Cancer 54, 847. [poster]
5. Eisenstat D, Fonseca M, Friesen T, Jiang C, and Grynspan D. (2010) Linking DLX transcription
factors to the WNT/β-catenin signaling pathway: implications for intestinal development &
colorectal carcinoma. Pediatr Blood Cancer 54, 852. [poster]
6. Lipson M, Pitz M, Hosseini B, Guilbert K, and Eisenstat D. (2010) Extended adjuvant
temozolomide and cis-retinoic acid for glioblastoma multiforme: a retrospective review of clinical
outcomes in Manitoba. Can J Neurol Sci 37, (Supplement 2, MED-5). [platform]
7. Lafay-Cousin L, Rizzuti F, Strother D, Carret AS, Jabado N, Johnston D, Zelcer S, Wilson B,
Scheinemann K, Fryer C, Eisenstat D, Huang A, Hawkins C, Bouffet E, Crooks B, and Mpofu C.
(2010) CNS atypical rhabdoid teratoid tumour: the Canadian Paediatric Brain Tumour Consortium
experience. Can J Neurol Sci 37, (Supplement 2, PED-5). [platform]
8. Purdy E, Lafay-Cousin L, Keene D, Carret AS, Fryer C, Bartels U, Brossart J, Crooks B, Eisenstat
D, Johnston D, Larouche V, Moghrabi A, Silva M, Wilson B, Zelcer S, Strother D, and Bouffet E.
(2010) Collin’s Law in infant embryonal CNS tumours. Can J Neurol Sci 37, (Supplement 2, POS5). [poster]
9. Le TN, and Eisenstat DD. (2010) DLX transcriptional reguylation of GABAergic interneuron
migration – relevance to neuronal migration disorders. Can J Neurol Sci 37, S21 (E-06). [platform]
10. Bouffet E, Carret A, Crooks B, Hukin J, Eisenstat D, Wilson B, Scheinemann K, Zelcer S,
Johnston D, Silva M, Larouche V, Jabado N, Mpofu C, Keene D, and Strother D. (2010) The
Canadian Paediatric Brain Tumour Consortium (CPBTC): a national network using
teleconferencing. Neuro-oncology 12, ii17. [platform]
11. Lafay-Cousin L, Rizzuti F, Carret AS, Johnston DL, Zelcer S, Wilson B, Jabado N, Scheinemann
K, Fryer C, Eisenstat D, Crooks B, Huang A, Strother D, Hawkins C, and Bouffet E. (2010) CNS
atypical rhabdoid tumour: the Canadian Pediatric Brain Tumor Consortium experience. Neurooncology 12, ii36. [platform]
12. Scheinemann K, Bouffet E, Carret A, Crooks B, Hukin J, Eisenstat D, Wilson B, Zelcer S,
Johnston D, Larouche V, Silva M, Jabado N, Mpofu C, and Lafay-Cousin L. (2010) Pediatric
Neuro-Oncology in Canada – do we have a standard of care? Neuro-oncology 12, ii81. [poster]
13. Hukin J, Tabori U, Ailon T, McNeely D, Carret AS, Eisenstat D, Lafay-Cousin L, Johnston D,
Wilson B, Jabado N, Zelcer S, Silva M, Barr R, Milner RA, Bucevska M, and Fryer C. (2010) Late
ependymoma relapses: a Canadian Pediatric multicentre study. Neuro-oncology 12, ii103. [poster]
14. Brown RJ, Dhall G, Goldman S, Eisenstat DD, Gilles F, Evans A, and Finlay JL. (2010)
Feasibility pilot of Dasatinib in children and adolescents with central nervous system (CNS) germ
cell tumors (GCT). Neuro-oncology 12, ii107. [poster]
15. Lafay-Cousin L, Keene D, Carret AS, Fryer C, Bartels U, Brossard J, Crooks B, Eisenstat D,
Johnston D, Larouche V, Moghrabi A, Silva M, Wilson B, Zelcer S, Strother D, and Bouffet E.
(2009) Choroid plexus tumours in children less than 36 months: A Canadian Pediatric Brain
Tumor Consortium (CPBTC) experience. Pediatr Blood Cancer 53, 851. [poster]
16. Pinto V, Pind M, and Eisenstat D. (2009) DLX homeobox transcriptional regulation of Cone-Rod
homeobox (CRX) gene expression during vertebrate retinal development. Soc Neurosci Ann
Meeting 39, 164. [poster]
17. Zhang Q, Cheng SH, and Eisenstat D. (2009) Dlx transcription factors regulate the Brn3b
homeobox gene during vertebrate retina development. Developmental Biology 331, 431. [poster]
63
18. Eisenstat DD, Tan Y, and Zhang S. (2009) Boundary dispute in the developing forebrain - DLX2
vs. PAX6. Developmental Biology 331, 524. [poster]
19. Nafez S, Oikawa K, Odero G, Ge N, Zhang D, Abrenica B, Czubryt M, Eisenstat D, Albensi BC.
(2009) Early Growth Response 2 (EGR2) is induced by neuronal activity-dependent NF-KB
activation. Basic & Clinical Pharmacology & Toxicology 105 (Suppl. 1), 116-117. [poster]
20. Carter T, Fonseca M, Lum-Min SA, Hancock BJ, Eisenstat DD and Grynspan D. (2009) Absence
of evidence of apoptosis or ganglion cell damage at the transformation zone in Hirschsprung’s
Disease. Canadian Association of Pathologists 60th Annual Meeting. [poster]
21. Le T, Zhang S, and Eisenstat D. (2008) Genetic regulation of CNS stem cell differentiation and
migration – role of DLX homeobox genes. Neuro-Oncol 10, 906.[poster]
22. Zhang Q, and Eisenstat DD. (2008) DLX transcription factors regulate the Brn3b homeobox gene
during vertebrate retinal development. 3rd Alberta Vision Sciences Symposium. [platform]
23. Lafay-Cousin L, Keene D, Carret AS, Crooks B, Eisenstat D, Fryer C, Johnston D, Larouche V,
Moghrabi A, Wilson B, Whitton A, Zelcer S, and Bouffet E. (2008) CNS atypical teratoid rhabdoid
tumor (ATRT) in children less than 36 months: A Canadian pediatric brain tumor consortium
experience. Neuro-Oncol. 10, 370. [poster]
24. Le T, Pind M, and Eisenstat D. (2008) Genetic regulation of CNS stem cell differentiation and
migration: Role of DLX homeobox genes. Neuro-Oncol. 10, 382-3. [platform]
25. Stempak D, Gammon J, Stephens D, Feltis A, Bartels U, Fryer C, Hukin J, Eisenstat D, Johnston D,
Samson Y, Bouffet E, and Baruchel S. (2008) A Canadian multicenter pilot study of extended low
dose temozolomide and radiation therapy in pediatric brainstem glioma. Neuro-Oncol. 10, 391.
[platform]
26. Crooks B, Keene D, Carret AS, Bartels U, Eisenstat D, Fryer C, Lafay-Cousin L, Larouche V,
Moghrabi A, Silva M, Zelcer S, and Bouffet E. (2008) Brainstem tumors in infants < 3 years old in
Canada 1990-2005: Report of the Canadian Pediatric Brain Tumor Consortium. Neuro-Oncol. 10,
411. [poster]
27. Zelcer S, Keene D, Carret AS, Crooks B, Eisenstat D, Johnston D, Fryer C, Lafay-Cousin L,
Larouche V, Moghrabi A, Wilson B, Whitton A, and Bouffet E. (2008) Spinal cord tumors in
infancy: A Canadian pediatric brain tumor consortium report. Neuro-Oncol. 10, 416. [poster]
28. Keene D, Lafay-Cousin L, Carret AS, Crooks B, Eisenstat D, Fryer C, Johnston D, Larouche V,
Moghrabi A, Silva M, Wilson B, Zelcer S, and Bouffet E. (2008) The Canadian Pediatric Brain
Tumor Consortium national survey of CNS tumors in children under 3 years of age. Neuro-Oncol.
10, 416. [platform]
29. Johnston D, Keene D, Bartels U, Carret AS, Crooks B, Eisenstat D, Fryer C, Lafay-Cousin L,
Larouche V, Moghrabi A, Wilson B, Zelcer S, and Bouffet E. (2008) Medulloblastoma in children
under 3 years of age: A retrospective Canadian review. Neuro-Oncol. 10, 435. [poster]
30. Burton TR, Eisenstat DD, and Gibson SB. (2008) Bcl-2 Nineteen kilodalton Interacting Protein
(BNIP3) promotes tumour cell survival in Glioblastoma Multiforme (GBM) by transcriptionally
silencing pro-cell death gene expression. 13th Biannual Can. Neuro-Oncol. Conf. (Calgary AB)
[platform].
31. Carret AS, Keene D, Bartels U, Crooks B, Eisenstat D, Fryer C, Lafay-Cousin L, Larouche V,
Moghrabi A, Silva M, Wilson B, Zelcer S, and Bouffet E. (2008) Epidemiological survey of
histologically confirmed low-grade gliomas in children < 36 months of age: A Canadian pediatric
brain tumour consortium (CPBTC) study. Neuro-Oncol. 10, 447. [poster]
32. Le TN, Zhou QP, Vriend J, and Eisenstat DD. (2008) GABAergic interneuron differentiation in the
basal forebrain is mediated by direct regulation of glutamic acid decarboxylase isoforms by Dlx
homeobox genes. 4th Can. Dev. Biol. Conf. (Banff AB) [poster].
64
33. de Melo J, Zhou QP, Zhang Q, Zhang S, Fonseca M, Wigle JT, and Eisenstat DD. (2008) DLX2
homebox gene directly regulates TrkB neurotrophin receptor expression during mouse retinal
development. 4th Can. Dev. Biol. Conf. (Banff AB) [poster].
34. Burton TR, Eisenstat DD, Gibson SB. (2008) Bcl-2 Nineteen kilodalton Eshraghi M,
Jangamreddy JR, Herbert K, Eisenstat DD, Wigle JT. (2008) Transcriptional activation of
lymphatic endothelial growth factors by the PROX1 homeodomain protein. 4th Can. Dev. Biol.
Conf. (Banff AB) [poster].
35. Lou H, Eisenstat D, Parry D. (2008) Whole Blood Analysis is an Effective Way to Avoid
Pseudohyperkalemia in Patients with Acute Lymphocytic Leukemia. Clin. Biochem. 41, 185186. [poster]
36. Dueck CC, Eisenstat DD, Grynspan D, Caces R, Rafay MF. (2008) Perinatal stroke secondary to
chorioamnionitis: a histopathological case presentation. 43rd Canadian Neurological Sciences
Federation Meeting (Victoria BC) [poster]
Invited Seminars and Presentations at Symposia/Meetings
1. Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton,
AB. “Role of DLX homeobox genes in retinal development and retinoblastoma”, June 15, 2010.
2. Canadian Neurological Sciences Federation 45th Annual Congress, Quebec City, QC. NeuroOncology Course. “The past, present and future treatment of malignant gliomas in children”, June
9, 2010.
3. NeuroDevNet 1st Annual General Meeting, Montreal, QC. “Neurotransmitters and autism
spectrum disorders: is there a role for DLX homeobox genes?”, June 7, 2010.
4. Western Canada Childhood Research Network, Vancouver, BC. “Research Overview”, May 6,
2010.
5.
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta,
Edmonton, AB. “Role of DLX homeobox genes in retinal development and retinoblastoma”,
April 27, 2010.
6. Department of Biology, University of Ottawa, Ottawa, ON. “DLX homeobox genes in vertebrate
retinal development”, April 20, 2010.
7.
The Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON. “DLX
homeobox genes in vertebrate retinal development”, April 7, 2010.
8.
18th Annual St. Amant Conference: Intellectual/Developmental Disabilities and Autism.
Winnipeg, MB. “The GABA hypothesis: linking genetic regulation of forebrain development by
DLX homeobox genes to autism spectrum disorders”, Oct. 9, 2009.
9.
Princess Margaret Hospital/Ontario Cancer Institute, Toronto, ON. Gliomas: Scientific Advances
and Therapeutic Challenges. “Alterations in BNIP3 in Gliomas”, Sept. 24, 2009.
10. Health Canada, Ottawa, ON. “Therapy in Malignant Gliomas: Targeting the Epidermal Growth
Factor Receptor”, February 25, 2009.
11. Brain Tumour Foundation of Canada, London, ON. “Medulloblastoma in Children and Adults:
Advances in Biology and Treatment”. Patient Information Day, Oct. 18, 2008.
12. London Health Sciences Centre, London, ON. “Medulloblastoma in Children and Adults: Clinical
management and prognostic factors”, Oct. 17, 2008.
13. Collaborative Graduate Program in Developmental Biology, University of Western Ontario,
London, ON. “Transcriptional regulation of forebrain development and relevance to
neurodevelopmental disorders”, Oct. 17, 2008.
14. Visiting Professors in Medical Education Series, Faculty of Medicine, University of Calgary,
65
Calgary, AB. “The Advanced Degrees in Medicine Program at the University of Manitoba”,
September 17, 2008.
15. Genes and Development Research Group Seminar, Faculty of Medicine, University of Calgary,
Calgary, AB. “Regulation of brain development and neurodevelopmental disorders by homeobox
genes.” September 17, 2008.
16. University of Colorado Cancer Center Symposium Series, Denver, CO “Transcriptional
regulation of forebrain development: implications for neurodevelopmental disorders and CNS
tumors, April 14, 2008.
17. Texas Children’s Cancer Center Rounds, Texas Children’s Hospital, Houston, TX “Regulation of
forebrain development by DLX homeobox genes – implications for neurodevelopmental disorders
and tumors”, Feb. 8, 2008.
18. Neuroscience Research Colloquium, Brain Research Centre, University of British Columbia,
Vancouver, BC “ChIPping away at the brain – transcriptional regulation of forebrain development
by DLX homeobox genes”, Jan. 18, 2008
Professional Service
Grant review committees
1.
Leukemia and Lymphoma Society of Canada, panel member, 2009-present
2. National Brain Tumor Society (USA), Scientific Advisory Committee and panel member, 2009present.
3. Austrian Science Foundation, external reviewer, 2008-present.
4. Brain Tumor Society (USA), Low Grade Gliomas, panel member, 2007-2008.
5. C17 Research Network, Canadian Pediatric Hematology-Oncology Program Directors, external
reviewer, 2007-present.
6. National Cancer Institute of Canada (NCIC), Clinical Research Fellowship, panel member, 20062009.
7. Canadian Foundation for Innovation (CFI), external reviewer, 2006-present.
8. Brain Tumor Funders’ Collaborative, Scientific Advisory Committee and panel member, 2005present.
9. CIHR, external reviewer, 2004-present.
10. Canadian Diabetes Association, external reviewer, 2004-present.
11. Natural Sciences and Engineering Research Council (NSERC), external reviewer, 2003-present.
12. Samantha Dickson Charitable trust (UK), external reviewer, 2003-present.
13. Alberta Cancer Board, external reviewer, 2003-present.
14. Ontario Cancer Research Network (OCRN)/Ontario Institute of Cancer Research (OICR), panel
member, clinical & translational operating grants committee, 2002-2008.
Journal Reviewer
1. Acta Neuropathologica
2. Acta Paediatrica
3. Brain Research
4. Cancer Research
5. Clinical Cancer Research
6. Development
7. Developmental Dynamics
8. Journal of Engineering in Medicine
9. Journal of Molecular Biology
10. Molecular Brain Research
11. Neuroscience
12. Stem Cells
66
GEOFF HICKS
Ph.D. (MANITOBA)
Functional Analysis of the Mammalian Genome
Now that the human genome has been decoded, the next major challenge to the Genome Initiative will
be to bridge the gap between these rapidly expanding DNA sequence databases and gene function. To
utilize the sequence information for large-scale functional studies, we have developed a process called
tagged-sequence mutagenesis to disrupt genes expressed in mouse embryo-derived stem (ES) cells and
to characterize each mutation by direct DNA sequencing. More recently, we have developed precision
gene targeting in ES cells, which allows us to make defined changes in cancer genes. The new
technology allows us to “knockout” cancer genes, or to make the very same mutations we know occur
in the human cancers. The ability to induce, characterize and maintain mutations in ES cells
circumvents many limitations associated with conventional mammalian genetics, and will greatly
increase the number of mutant alleles (typically loss of function mutations) by which gene functions
can be studied in mice and in cell lines derived from such mice. The process will facilitate a functional
analysis of a mammalian genome in vivo and will provide animal models for human genetic diseases.
Currently, we are leading Canada’s effort to develop an Embryonic Stem Cell Library with defined
knockout gene mutations in each of the 23,000 known genes in the mouse. ES cell clones containing
specific mutations in genes of interest will be made available to investigators as a national resource.
Functional Analysis of TLS, EWS, and ALR in Normal Development and in Oncogenic
Transformation
Mutations (from the ES cell library) transmitted to the germline will focus on genes known or
suspected to be involved in tumor progression. Understanding the normal function of a gene in
mammalian development is a powerful approach to understanding how the oncogene contributes to
the respective cancer. The focus of the lab is on genes which are translocated in the development of
human cancers; specifically, the TLS and EWS genes. While the translocations and the associated
cancers for these genes are highly characterized, little is known about function of the genes themselves
or how they contribute to tumor development. Our approach is to analyze developmental defects in
mice that are either deficient for specific gene (and are otherwise genetically identical to wild-type
mice). For example TLS is a gene that is translocated in many human soft tissue sarcomas and
myelogenous leukemia. Functional analysis of mice that are homozygous for the TLS/FUS mutation
has revealed TLS plays a critical role in the normal development of blood cells and in maintaining
genomic stability. Using this approach, we have now discovered the how changes in TLS during
cancer specifically prevent its normal role to limit cell proliferation and correct mutations in other
genes -- both of which are hallmarks of cancer itself.
Regenerative Medicine and Cancer Stem Cells
Most recently, Dr. Hicks has been appointed Director of the Regenerative Medicine Program in the
University of Manitoba’s Faculty of Medicine. The 8 Principal Investigators of the program will focus
on stem cell-based applications for the treatment of human disease, including cancer, cardiovascular
disease, and spinal cord injury repair.
67
Publications since 2008
1. Ringwald M, Iyer V, Mason JC, Stone KR, Tadepally HD, Kadin JA, Bult CJ, Eppig JT, Oakley
DJ, Briois S, Stupka E, Maselli V, Smedley D, Liu S, Hansen J, Baldock R, Hicks GG, Skarnes
WC. (2011). The IKMC web portal: a central point of entry to data and resources from the
International Knockout Mouse Consortium. Nucleic Acids Res. 39:D849-55.
2. Choi, Y., Lin, Y-P., Xiong, Y., Kim, S., Bu, P., Bennett, M., He, Y., Hannon, G., Chen, C., Ozturk,
A., Hicks, GG. and He, L. (2010). miR-34a miRNA provides a barrier for somatic cell
reprogramming. Nature Cell Biology, in press.
3. Sabbir, MG., Wigle, N., Loewen, S., Gu, Y., Buse,C., Hicks, GG. and Mowat, MRA (2010).
Identification and characterization of Dlc1 isoforms in the mouse and study of the biological
function of a single gene trapped isoform. BMC Biology, 8:17-26.
4. Xu, K.. Nieuwenhuis, E., Cohen, B., Wang, W., Canty, A., Danska, J., Coultas, L., Rossant, J.,
Wu, M., Piscione, T., Gossler, A., Hicks, GG., Hui, C.-c., Henkelman, RM., Yu, L., Sled, L.,
Gridley, T. and Egan, S. (2010). Lunatic Fringe-mediated Notch signaling is required for lung
alveogenesis. Am J Physiol Lung Cell Mol Physiol. 298:45-56.
5. Blanchard, A.A.A. Nistor, A. , Castaneda, F.E.; Martin, D. , Hicks, G. Amara, F,, Shiu, R.P.C. ;
Myal,Y. (2009). Generation and Initial Characterization of the Prolactin Inducible Protein (PIP)
Null Mice: accompanying global changes in gene expression in the submandibular gland. Can J
Physiol Pharmacol. 87:859-72.
6. Schofield, PN, Bubela, T, Weaver, T, Portilla, L, Brown, SD, Hancock, JM, Einhorn, D, TocchiniValentini, G, Hrabe de Angelis, M, Rosenthal, N, Barnes, J, Collis, AJ, Desaintes, C, Dixon, JE,
Doyle, A, Eppig, J, Field, D, Grunberger, M, Heim, S, Hicks, G, Hubbard, T, Jennings, R,
Kennedy, K, Kennedy, G, Kolar, P, Livingstone, A, Lloyd, K, Masuya, H, Matteoni, R, Maurer, J,
McKenzie, A, McKerlie, C, Moore, M, Muddyman, D, Nguyen, T, Parsons, M, Quackenbush, J,
Reuveni, E, Salimova, E, Siegal, V, Skingle, M, Smedley, D, Sugden, A, Wakana and S, Walsh,
JP. (2009). Post-publication sharing of data and tools. Nature, 461:171-173.
7. Xie Y, Yang H, Pan J, Miller JH, Shih DM, Hicks GG, Xie J, Shiu RPC. (2008).
Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to
oxidants with increased G2/M arrest and multinucleation. Carcinogenesis, 29:2432.
Pubmed Search for Geoff Hicks
Invited Seminars and Presentations at Symposia and Meetings
1.“Genetically Modeling Human Disease.” Keynote Landmark Lecture, Shantou, Dec 2009.
2. “Cre-ative Thinking for Conditional Mouse Models of Immunity and Inflammation.” International
Symposium on New Frontiers in Immunology, Winnipeg, Sept 2009.
3. “Canadian Initiatives for Innovation in Conditional Mouse Modeling.” International Workshop for
Coordination of Resources for Conditional Expression of Mutated Mouse Alleles, Hatfield Heath, UK,
July 2009.
4. “Sharing Data and Resources for Functional Genomics.” Co-Ordination And Sustainability Of
International Mouse Informatics Resources, Rome, May 2009.
5. “High Throughput Functional Analysis of Human Disease.” 2nd Functional Annotation of the
Mammalian Genome, Banff, Canada. April 2009.
68
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
“Stem Cell Connections to Longevity.” East-West Alliance Conference on Longevity Across the
Life Span, Stanford Centre on Longevity, Stanford, April 2009.
“Genetic Considerations of Longevity.” East-West Alliance Conference on Longevity Across the
Life Span, Stanford Centre on Longevity, Stanford, April 2009.
“Mouse Models of Human Disease: Bringing Research Discoveries to Heath Care and
Treatment.” Amgen, Thousand Oaks CA, April 2009.
The North American Conditional Mouse Mutagenesis Program (NorCOMM) Functional
Annotation of the Mammalian Genome Conference, Banff 2009.
“NorCOMM Informatics and Web Based Tools.” International Data Coordination Meeting,
Wellcome Trust Sanger Institute, Hinxton UK, March 2009.
“Disease modeling in mice: recent advances in gene targeting and mouse phenotyping
technologies.” 3rd International Mon-Man Symposium, Melbourne, March 2009.
“Innovation in Mouse Modeling.” NZBio, Auckland, March 2009.
“Functional Genomics of Allelic Variation in Cardiovascular Disease.” EuCOMM AGM,
Munich, January 2009.
“International Knockout Mouse Consortium.” International Society of Transgenic Technologies
2008 Symposium, Toronto, Oct 2008.
“NorCOMM.” NIH KOMP Annual General Meeting, Rockville MD, Oct 2008.
“Genetic Modeling of Disease in ES cells.” CIHR Canadian Student Health Research Forum on
Stem Cells, Winnipeg, June 2008.
“High Throughput Targeting in Embryonic Stem Cells.” Human Protein Interaction Initiative
Workshop, Ottawa, June 2008.
“A functional role for the TLS proto-oncogene in DNA damage response.” University of
Alberta, May 2008.
“NorCOMM: High Throughput Mammalian Functional Analysis for the Discovery of Novel
Determinants of Human Disease.” International Knockout Mouse Consortium Meeting, Toronto,
May 2008.
“High throughput approaches to genetic modeling of disease in ES cells.” East-West Alliance
and Cambridge Cancer Research Institute, Cambridge UK, April 2008.
“A functional role for the TLS proto-oncogene in DNA damage response.” University of
Alberta, May 2008.
“NorCOMM: High Throughput Mammalian Functional Analysis for the Discovery of
Novel Determinants of Human Disease.” International Knockout Mouse Consortium
Meeting, Toronto, May 2008.
“High throughput approaches to genetic modeling of disease in ES cells.” East-West Alliance
and Cambridge Cancer Research Institute, Cambridge UK, April 2008. “Genetic
Model
Organisms.” Italian National Research Council (CNR) - Genome Canada Workshop,
Rome, April 2008.
69
Professional Service
1.Canadian Genetic Disease Network Centre of Excellence Investigator. 2000-2008
2.NIH Ewing Sarcoma Initiative. 2002-present
3.International Gene Trap Consortium. 1999-present
4.International Mouse Mutagenesis Consortium. 2001-present
5.International Knockout Mouse Project Consortium. 2004-present
6.Federation of International Mutant Mouse Resources. 2005-present
7.Canadian Mouse Consortium, founding member. 2004-present
8.International Knockout Mouse Consortium, founding member. 2004-present
Professional Activities
1.
Director - Regenerative Medicine Program in the University of Manitoba’s Faculty of Medicine.
2. Director, Mammalian Functional Genomics Centre. 1999-present
3. Canadian Institutes of Health Research, Reviewer for G, CPT and MCC Panels. 1999-present
4. Chair, CIHR Institute of Genetics New Principal Investigator Symposium. 2001-present
5. Scientific Director, Gene Modeling Centre, University of Manitoba. 1999-present
6. Scientific Advisory Board Member, Genome BC, Pathogenomics of Innate Immunity. 2006present
7. CIHR Institute of Genetics Advisory Panel. 2001-present
8. Scientific Advisory Board Member, Genome Quebec, Gene Regulators in Disease. 2006-present
9. Scientific Advisory Board Member, BC Transgenics Centre. 2007-present
10. Scientific Director, Genetic Modeling Centre, University of Manitoba. 2007-present
11. Manitoba Health Research Council, Research Advisory Committee. 2008-present
70
SARA ISRAELS
M.D. (MANITOBA) F.R.C.P.C.
Our platelet research laboratory studies basic mechanisms of platelet function and investigates
patients with inherited platelet function abnormalities, in conjunction with the clinical Haemostasis
Laboratory. Our projects include: 1) Investigating the role of CD63, a member of the tetraspanin
superfamily present on platelet dense granule and lysosomal granule membranes, and expressed on
the platelet surface following activation, where it associates with the platelet integrin alphaIIb/beta3,
and with the contractile platelet cytoskeleton. It plays a role in platelet spreading on adhesive
surfaces. We are presently investigating how it modulates “outside-in” integrin-mediated signaling
pathways. Understanding the role of CD63 has implications beyond platelet function, as it, and
similar molecules, may be involved in tumor cell migration and metastases. 2) Studies of patients
with inherited platelet function disorders, with a particular interest in families with a congenital
deficiency of platelet dense granules. 3) Investigation of in vivo platelet activation in adolescents
with diabetes mellitus 4) Development of a national registry of patients with inherited platelet
disorders, an opportunity to improve our understanding of these rare conditions, aid in their
diagnosis, and evaluate treatment options. 5) Initiatives to standardize laboratory testing of platelet
function at a national level and improve quality assurance for clinical testing.
Publications Since 2008
1.
Rimmer EK, Seftel MD, Israels SJ, Houston DS. Unintended benefit of anabolic steroid use in
hemophilia B leiden. Am J Hematol. 2011 Sep 13.
2.
Houston BL, Zelinski T, Israels SJ, Coghlan G, Chodirker BN, Gallagher PG, Houston DS,
Zarychanski R. Refinement of the hereditary xerocytosis locus on chromosome 16q in a large
Canadian kindred. Blood Cells Mol Dis. 2011 Sep 22.
3.
Israels SJ, Kahr WH, Blanchette VS, Luban NL, Rivard GE, Rand ML. Platelet disorders in
children: A diagnostic approach. Pediatr Blood Cancer. 2011 Jun;56(6):975-83.
4. Israels SJ, El-Ekiaby M, Quiroga T, Mezzano D. Inherited disorders of platelet function and
challenges to diagnosis of mucocutaneous bleeding. Haemophilia. 2010 Jul;16 Suppl 5:152-9.
Review.
5. McNicol A, Israels SJ. Mechanisms of oral bacteria-induced platelet activation. Can J Physiol
Pharmacol. 2010 May;88(5):510-24. Review
6. Israels SJ, McMillan-Ward EM. Palmitoylation supports the association of tetraspanin CD63
with CD9 and integrin alphaIIbbeta3 in activated platelets. Thromb Res. 2010
Feb;125(2):152-8.
7.
Hayward CP, Moffat KA, Spitzer E, Timleck M, Plumhoff E, Israels SJ, White J; NASCOLA
Working Group on Platelet Dense Granule Deficiency. Results of an external proficiency
testing exercise on platelet dense-granule deficiency testing by whole mount electron
microscopy. Am J Clin Pathol. 2009 May;131(5):671-5.
8. McNicol A, Israels SJ. Beyond hemostasis: the role of platelets in inflammation, malignancy
and infection. Cardiovasc Hematol Disord Drug Targets. 2008 Jun;8(2):99-117. Review.
Pubmed Search for Sara Israels
71
Book Chapters/Review Articles/Monographs
1.
Israels SJ, Schwetz N, Purves E. (2010) Home Infusion. In: All about Hemophilia (revised
edition). (In press).
2.
Rand M, Israels SJ, McNicol A (2010). Platelet Structure and Function. In: Mechanisms in
Hematology, (Israels SJ, ed.) 4th Ed. (In press).
3.
Israels SJ. (2007) Inherited abnormalities of fibrinogen. eMedicine Journal [serial online].
Available at: www.emedicine.com/ped/topic#3042.htm,
4.
Israels SJ. (2007) Factor VII deficiency. eMedicine Journal [serial online]. Available at:
www.emedicine.com/ped/topic#3041.htm,
5.
Israels SJ. (2007) Factor XIII deficiency. eMedicine Journal [serial online]. Available at:
www.emedicine.com/ped/topic#3040.htm,
6.
Israels SJ. (2007) Platelet Function in the Newborn. In: Platelets, Second Edition
(Michelson AD, ed). Academic Press. pp. 431-42.
Abstracts and Conference Presentations
1.
Israels SJ. Investigation of platelet disorders in children. American Society of Pediatric
Hematology/Oncology. Boston, May 2010
2.
Hang MX,. Blanchette V, Pullenayegum E, Babyn P, Card R, Chan A, Demers C, Gill K,
Israels S, Klaassen R, Laferriere N, Lillicrap D,. Luke , McLimont M.. Risk factors of
bleeding severity in young boys with severe hemophilia a on tailored prophylaxis: longterm (10-year) results from the canadian hemophilia primary prophylaxis study. Congress
ISTH July 2009.
3.
Blanchette VS, Babyn P, Card R, Chan A, Demers C, Gill K, Israels S, Klaassen R,
Laferriere N, Lillicrap D, Luke KH, McLimont M, et al. Long Term (10 year) results from
the Prospective Canadian hemophilia dose escalation prophylaxis trial. 2009.
4.
Sinclair GD, Blanchette V, Card RT, Chan AKC, Israels SJ, Lillicrap D, Rivard Get al.
Does heterogeneity in measured calibrated thrombin generation assay or FVIII activity
(<1%) explain clinical heterogeneity in severe hemophilia A? Congress ISTH July 2009.
5.
Moffat KA, Plumhoff E, Reyes E, Hoffman S, Israels S, Meijer P, Hayward CPM. The
interpretation of light transmittance platelet aggregation is inconsistent – results from an
international challenge. Congress ISTH July 2009.
6.
Israels SJ, McMillan-Ward EM. Palmitoylation supports the association of tetraspanin
CD63 with CD9 and the activated platelet cytoskeleton. Int. Soc. Thromb. Hemost.
Congress , July 2009
7.
Stoffman J, McNicol A, Zelinski T, Chordirker BN, Israels SJ. The association between
SHP-2 mutations and platelet function in Noonan syndrome. Blood 2008;112:450
8.
Halton J, Abish S, Barr R, Cairney E, Dix DB, Fernandez C, Grant R, Israels S, Lewis V, et
al. and the Canadian STOPP Consortium. The relationship between bone lumbar spine
bone mineral density and vertebral consortium at leukemia diagnosis. Am Soc Pediatr
Hematol/Oncol meeting. Cincinnati. May, 2008.
9.
Grant R, Halton J, Abish S, Barr R, Cairney E, Dix DB, Fernandez C, Israels S, Lewis V, et
al., and the Canadian STOPP Consortium. Osteoporosis screening in childhood acute
lymphoblastic leukemia. A first step in understanding the natural history of vertebral
compression. Am Soc Pediatr Hematol/Oncol meeting. Cincinnati. May, 2008.
Invited Seminars and Presentations at Symposia/Meetings
1.
Platelet Disorders Symposium, Chair. World Federation of Hemophilia, Buenos Aires,
Argentina, July 10, 2010.Congress, “Structure-function relationships in platelet disorders”
2.
Symposium on Congenital and Acquired Bleeding Disorders in Children. Toronto ON,
May 16, 2011. “Congenital platelet disorders”.
3.
Manitoba Society of Laboratory Technologists, Winnipeg, May 1, 2010 “Laboratory
Evaluation of von Willebrand Disease”
4.
American Society of Pediatric Hematology/Oncology, Montreal PQ, April 7-10.,
72 2010
“Investigation of platelet disorders in children”
5. “Investigation of platelet disorders in Children”. American Society of Pediatric
Hematology/Oncology, Montreal PQ, April 9, 2010.
6. “Diagnostic evaluation of platelet disorders”. Pediatric Hematology Update, Toronto ON, October
29-30, 2009.
7. “Platelet disorders: causes, prevalence and importance”. McMaster Annual Update in
Thromboembolism, Hamilton ON, October 5, 2009.
8. “Algorithm for evaluation of platelet dysfunction in children”. Canadian Pediatric Thrombosis and
Hemostasis Network, Ottawa, ON, May 8, 2009.
9. “Von Willebrand Disease: Common disease (?), difficult diagnosis (!)”. Department of Pediatrics
& Child Health Grand Rounds, University of Manitoba Pediatric Grand Rounds. December 11,
2008.
10. “Assessment of Bleeding in Infants and Children”. Department of Family Medicine, University of
Manitoba, Winnipeg, Manitoba, October 31, 2008.
11. “Pediatrics – Little People Have Blood Too”. Meet the Hematologist. CancerCare Manitoba,
October 21, 2008.
12. Workshop Session I. “Evaluation of the Child with a Suspected Bleeding Disorder”. Pediatric
Hemostasis & Thrombosis Update 2008, University of Toronto, Toronto, Ontario, October 3-4,
2008.
13. “Transfusion for Oncology Patients”. Department of Pediatrics & Child Health. CK5 Oncology
Orientation. Basic Hematology/Oncology. Ann Thomas Building, Children’s Hospital. August 8,
2008.
14. “How to assess platelet function”. Eastern Canada Hemostasis Symposium. St. John’s
Newfoundland. Sept. 19, 2008.
15. “Macrothrombocytopenia associated with 22q11.2 deletion syndrome”. Association of Hemophilia
Clinic Directors of Canada Annual Meeting, Saskatoon, Saskatchewan. May 3, 2008.
16. “Bleeding Disorders 101” The Canadian Hemophilia Society Workshop. Winnipeg, January 26,
2008.
Professional Service
University of Manitoba
1. Section Head, Pediatric Hematology/Oncology/BMT, 1993-present
2. Faculty of Medicine Promotion Committee, 2006-present
3. Dept of Pediatrics and Child Health Promotions Committee: Chair, 2004-present
4. Department of Pediatrics Executive and Planning Committee, 1997-present
5. Hematology Fellowship Training Program Committee, 1994-present
WRHA
1. Director, Haemostasis Laboratory, Health Sciences Centre 1994-present
2. Director, Bleeding disorder Program, 1989-present
CancerCare Manitoba
1. Head, Department of Pediatric Oncology, CancerCare Manitoba, 1993-present
2. CCMB LG Israels Memorial Lecture Committee, 2004-present
3. CCMB Medical Council, 2004-present
4. Simon and Sarah Israels Thesis Prize Review Committee: Chair, 2004-present
5. CancerCare Manitoba Foundation Board of Directors, 2003-present
6. CancerCare Manitoba Foundation Project Grants and Awards Committee, 2003- present
73
External
1.
Editor, Mechanisms in Hematology, 4th Edition.
2. External Review: Division of Pediatric Hematology/Oncology, The Hospital for Sick Children,
Toronto, March 2009
3. Canadian Council of Pediatric Hematology/Oncology Program Directors Executive, 2005present
4. Royal College of Physicians and Surgeons – Specialty Committee (Nucleus) in Pediatric
Hematology/Oncology, 2004-present
5. Royal College of Physicians and Surgeons – Pediatric Hematology / Oncology
Examination Committee, 2005-2009
6. External Grant Reviews: Heart and Stroke Foundation of Canada, CIHR, Canadian Blood
Services/Bayer, Health Sciences Centre Research Foundation, C17 Research Network
7.
Journal Reviews:
Blood, J. Thrombosis and Haemostasis, Thrombosis and
Haemostasis,
J. Pediatric Hematology/Oncology, Pediatric Research, J. Pediatrics,
Thrombosis Research
74
JAMES JOHNSTON
MB, BCh (TRINITY COLLEGE,
DUBLIN), FRCPC
My primary research interest is in chronic lymphocytic leukemia (CLL) and I am involved in a number
of translational research programs related to this disease. These studies involve the epidemiology and
basic science of CLL, in addition to clinical trials. To further these activities, we have developed the
CLL Clinic at CancerCare Manitoba and the Manitoba CLL Tumor Bank, which is housed in the
MICB. Our epidemiological studies have demonstrated that the incidence of CLL is much higher than
previously reported with elderly male patients having a particularly poor prognosis. Our ongoing
laboratory studies are evaluating new therapies and prognostic markers in CLL and examining the
effects of age and gender on the biology of this cancer.
Publications Since 2008
1.
Yoon JY, Kumar R, Aloyz R, Johnston JB. Response of concomitant chronic myelogenous
leukemia and chronic lymphocytic leukemia to imatinib mesylate. Leuk Res. 2011
Sep;35(9):e179-80.
2.
Ishdorj G, Johnston JB, Gibson SB. Cucurbitacin-I (JSI-124) activates the JNK/c-Jun signaling
pathway independent of apoptosis and cell cycle arrest in B leukemic cells. BMC Cancer. 2011
Jun 24;11:268.
3.
Xiao W, Ishdorj G, Sun J, Johnston JB, Gibson SB. Death receptor 4 is preferentially recruited
to lipid rafts in chronic lymphocytic leukemia cells contributing to tumor necrosis related
apoptosis inducing ligand-induced synergistic apoptotic responses. Leuk Lymphoma. 2011
Jul;52(7):1290-301.
4. Johnston JB. Mechanism of action of pentostatin and cladribine in hairy cell leukemia. Leuk
Lymphoma. 2011 Jun;52 Suppl 2:43-5.
5.
Ishdorj G, Johnston JB, Gibson SB. Inhibition of constitutive activation of STAT3 by
curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis. Mol Cancer Ther.
2010 Dec;9(12):3302-14.
6. Amrein L, Soulières D, Johnston JB, Aloyz R. p53 and autophagy contribute to dasatinib
resistance in primary CLL lymphocytes. Leuk Res. 2011 Jan;35(1):99-102.
7. Kumar SA, Hu X, Brown M, Kuschak B, Hernandez TA, Johnston JB, Gibson SB.
Lysophosphatidic acid receptor expression in chronic lymphocytic leukemia leads to cell
survival mediated though vascular endothelial growth factor expression. Leuk Lymphoma. 2009
Dec;50(12):2038-48.
8.
Costantini JL, Cheung SM, Hou S, Li H, Kung SK, Johnston JB, Wilkins JA, Gibson SB,
Marshall AJ. TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through
interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting
complex in B-cell leukemia. Blood. 2009 Nov 19;114(21):4703-12.
9.
Amrein L, Panasci L, Gibson SB, Johnston JB, Soulières D, Aloyz R. Primary del 17 chronic
lymphocytic leukaemia lymphocytes are hypersensitive to dasatinib in vitro. Br J Haematol.
2009 Nov;147(3):396-8.
10. Seftel MD, Demers AA, Banerji V, Gibson SB, Morales C, Musto G, Pitz MW, Johnston JB.
75 a
High incidence of chronic lymphocytic leukemia (CLL) diagnosed by immunophenotyping:
population-based Canadian cohort. Leuk Res. 2009 Nov;33(11):1463-8.
11. Begleiter A, Hewitt D, Gibson SB, Johnston JB. Investigation of an NQO1 polymorphism as a
possible risk and prognostic factor for chronic lymphocytic leukemia. Leuk Res. 2009
Jan;33(1):74-81.
12. Ishdorj G, Graham BA, Hu X, Chen J, Johnston JB, Fang X, Gibson SB. Lysophosphatidic acid
protects cancer cells from histone deacetylase (HDAC) inhibitor-induced apoptosis through
activation of HDAC. J Biol Chem. 2008 Jun 13;283(24):16818-29.
Pubmed search for James Johnston
Book Chapters
1. Johnston JB, Seftel M. Gibson SB, Chronic Lymphocytic Leukemia. In: J.P. Greer, J.
Foerster, J. Lukens, F. Paraskevas, G.M. Rodgers, and B.E. Glader (eds), Wintrobe’s Clinical
Hematology, 12th Edition, Baltimore, MD: Williams and Wilkins, 2008.
2.
Szwajcer D, Johnston JB, Hairy Cell Leukemia. In: J.P. Greer, J. Foerster, J. Lukens, F.
Paraskevas, G.M. Rodgers, and B.E. Glader (eds), Wintrobe’s Clinical Hematology, 12th
Edition, Baltimore, MD: Williams and Wilkins, 2008.
Invited Seminars and Presentations at Symposia/Meetings
•
Hernandez TA, Hewitt D, Seftel M, and Johnston JB. The improved survival of women
versus men in chronic lymphocytic leukemia may be partially related to IgVH
mutational status. American Assoc Cancer Res., Abstract #2210, 2008.
•
Ishdorj G, Graham, B, Hu, X, Johnston, JB, and Gibson, SB. Lysophosphatidic acid
(LPA) protected cancer cells from histone deacetylase (HDAC) inhibitor-induced
apoptosis through alteration regulation of histone acetylation. American Assoc Cancer
Res, Abstract #2675, 2008
•
Johnston JB. The Epidemiology of Chronic Lymphocytic Leukemia. Western
Lymphoma Group Meeting. Banff, May 2008.
Professional Services
Assistant Head (Clinical), Manitoba Institute of Cell Biology
Clinical Director, Manitoba CLL Tumour Bank
Cancer Biology Graduate Course Coordinator (36.720) (with Dr. Michael Mowat)
Molecular Biology Course Coordinator for Clinical Hematology/Oncology residents
Chairman for the Planning Committee for the annual Canadian CLL Meeting
Member of the Planning Committee for the annual Canadian Lymphoma Meeting
Coordinator for Hematology/Oncology Section Rounds
Chairman of the LG Israels Annual Memorial Lecture Committee
Manuscript reviewer for Blood, Cancer, Leukemia Lymphoma and Leukemia Research
Scientific reviewer for Alberta Cancer Board
CD19+/CD5+/CD23+/CD20+
69
76
ETIENNE LEYGUE
Ph.D. (PARIS)
My overall research focuses on the study of gene expression during human breast tumorigenesis
and breast tumor progression.
Designing therapies slowing down or inhibiting estrogen signaling in breast cells has already saved
thousands of women. Unfortunately, resistance to a specific drug can occur in some patients and
alternative treatments remain needed. It appears that a combination of drugs, targeting different
critical points of estrogen signaling at different times, will provide a more efficient protection and
overcome the potential resistance to a single drug.
The original face of the products of the SRA1 gene consisted of a non-coding functional RNA
(SRA), able to activate estrogen receptors action. We have however demonstrated that this RNA
also leads to the production of a protein (SRAP), which also acts as modulator of estrogen receptor
action. We found that the action of this newly discovered SRAP is depending upon the receptor
ligand, the cell context and the target genes considered.
The bi-faceted SRA RNA/SRAP system, consisting of a functional RNA and its corresponding
protein, is therefore a newly discovered mechanism used by breast cells to modulate estrogen
action. We hypothesize that characterization of SRA RNA/SRAP mechanism of action could
provide new windows of opportunity to design innovative therapeutic or preventive strategies to
fight breast cancer.
Publications Since 2008
1. Cooper C, Vincett D, Yan Y, Hamedani MK, Myal Y, Leygue E. Steroid receptor RNA activator
bi-faceted genetic system: Heads or Tails? Biochimie. 2011 Nov;93(11):1973-80.
2. Gang H, Hai Y, Dhingra R, Gordon JW, Yurkova N, Aviv Y, Li H, Aguilar F, Marshall A,
Leygue E, Kirshenbaum LA. A novel hypoxia-inducible spliced variant of mitochondrial death
gene Bnip3 promotes survival of ventricular myocytes. Circ Res. 2011 Apr 29;108(9):1084-92.
3. Myal Y, Leygue E, Blanchard AA. Claudin 1 in breast tumorigenesis: revelation of a possible
novel "claudin high" subset of breast cancers. J Biomed Biotechnol. 2010;2010:956897.
4. Chooniedass-Kothari S, Hamedani MK, Auge C, Wang X, Carascossa S, Yan Y, Cooper C,
Vincett D, Myal Y, Jalaguier S, Cavailles V, Leygue E. The steroid receptor RNA activator
protein is recruited to promoter regions and acts as a transcriptional repressor. FEBS Lett. 2010
Jun 3;584(11):2218-24.
5. Chooniedass-Kothari S, Vincett D, Yan Y, Cooper C, Hamedani MK, Myal Y, Leygue E. The
protein encoded by the functional steroid receptor RNA activator is a new modulator of ER alpha
transcriptional activity. FEBS Lett. 2010 Mar 19;584(6):1174-80.
6. Dibrov A, Myal Y, Leygue E. Computational modelling of protein interactions: energy
minimization for the refinement and scoring of association decoys. Acta Biotheor. 2009
Dec;57(4):419-28.
77
7. Dibrov A, Myal Y, Leygue E. Computational modelling of protein interactions: energy
minimization for the refinement and scoring of association decoys. Acta Biotheor. 2009
Dec;57(4):419-28.
8. Yan Y, Skliris GP, Penner C, Chooniedass-Kothari S, Cooper C, Nugent Z, Blanchard A, Watson
PH, Myal Y, Murphy LC, Leygue E. Steroid Receptor RNA Activator Protein (SRAP): a
potential new prognostic marker for estrogen receptor-positive/node-negative/younger breast
cancer patients. Breast Cancer Res. 2009;11(5):R67.
9. Cooper C, Guo J, Yan Y, Chooniedass-Kothari S, Hube F, Hamedani MK, Murphy LC, Myal Y,
Leygue E. Increasing the relative expression of endogenous non-coding Steroid Receptor RNA
Activator (SRA) in human breast cancer cells using modified oligonucleotides. Nucleic Acids
Res. 2009 Jul;37(13):4518-31.
10. Blanchard AA, Skliris GP, Watson PH, Murphy LC, Penner C, Tomes L, Young TL, Leygue E,
Myal Y. Claudins 1, 3, and 4 protein expression in ER negative breast cancer correlates with
markers of the basal phenotype. Virchows Arch. 2009 Jun;454(6):647-56.
11. Skliris GP, Hubé F, Gheorghiu I, Mutawe MM, Penner C, Watson PH, Murphy LC, Leygue E,
Myal Y. Expression of small breast epithelial mucin (SBEM) protein intissue microarrays
(TMAs) of primary invasive breast cancers. Histopathology.2008 Feb;52(3):355-69.
12. Skliris GP, Leygue E, Watson PH, Murphy LC. Estrogen receptor alpha negative breast cancer
patients: estrogen receptor beta as a therapeutic target. J Steroid Biochem Mol Biol. 2008
Mar;109(1-2):1-10. Epub 2007 Dec 8. Review.
Pubmed search for Etienne Leygue
Panels
1.Operating grant competition of the National Cancer Institute of Canada (NCIC)
2.PhD and Post-doctoral Awards, US-Army Medical Research and Material Command (USAMRMC)
Invited Seminars and Oral presentations at Symposia/Meetings
1.BIT's World Cancer Congress, Nuclear Receptor Symposium, Shanghai, China (2008)
2.BIT's World Cancer Congress, Endocrinology Session, Shanghai, China (2008)
3.Cochin Institute (Paris, France) (2007)
4.INSERM, Montpellier, France (2007)
78
72
SABINE MAI
Ph.D. (KARLSRUHE GERMANY)
Our research focuses on mechanisms of c-Myc-dependent locus-specific and karyotypic instability,
c-Myc-dependent tumor development in vivo (using the mouse model of plasmacytoma) and on the
three-dimensional (3D) nuclear organization of the mammalian genome in normal, immortalized and
tumor cells.
1) c-Myc-dependent locus-specific and karyotypic instability. We were the first to demonstrate
that the deregulated expression of the proto-oncogene c-Myc induces dynamic karyotypic alterations;
they include numerical chromosomal changes, telomere-centromere-fusions and the enhanced
formation of extrachromosomal elements (Mai et al., 1996a). Moreover, we have shown that
experimental deregulation of c-Myc mediates rearrangements, chromosomal and extrachromosomal
amplification of specific genes. Among these genes are dihydrofolate reductase (DHFR), (Mai, 1994;
Mai et al., 1996b), CCND2 (cyclin D2) (Mai et al., 1999), ribonucleotide reductase R2 (R2)
(Kuschak et al., 1999), and the carbamoyl-phosphate synthetase-aspartate transcarbamoyldihydroorotase (CAD) (Fukasawa et al., 1997) gene. Other genes, such as syndecan-1 and 2,
glyceraldehyde-3-phosphate-dehydrogenase, ribonucleotide reductase R1, and cyclin C, remain
unaffected irrespective of c-Myc protein levels (Mai et al., 1996b). We identified a mechanism that
leads c-Myc-mediated gene amplification. It involves c-Myc-dependent illegitimate locus-specific de
novo replication initiation (Kuschak et al., 2002). An additional mechanism of c-Myc activation
involves c-Myc transcription from extrachromosomal elements (EEs); this mechanism of c-Myc
deregulation was characterized in vivo in a translocation-negative mouse plasmacytoma (Wiener et
al., 1999). Analyses into the functions of EEs have demonstrated that they carry modified histones
and are transcriptional competent. Furthermore, they are able to replicate their DNA (Smith et al.,
2002). c-Myc-induced EEs therefore are functional mini-chromosomes with the ability to actively
contribute to cellular transformation. Our recent work focuses on the three-dimensional organization
of the nucleus and the role of c-Myc in nuclear remodelling and cell transformation. Highlights are
summarized below.
2) c-Myc-dependent tumor development in vivo. Mouse plasmacytomas (PCTs) develop in
susceptible mice. The traditional model uses pristane as inducing agent, and all PCTs that develop
subsequently display the constitutive deregulation of c-Myc due to its translocation to one of the
immunoglobulin (Ig) loci. The c-myc/IgH translocation is the most frequent one in pristane-induced
plasmacytomas of BALB/c mice (Potter and Wiener, 1992). Pristane-induced PCTs develop over a
long latency period (up to 300 days). If pristane is combined with v-abl or with v-abl/myc, the
latency periods drop significantly (Potter and Wiener, 1992). Such short latency tumors develop
within 45 days after v-abl/myc and display chromosomal aberrations of chromosome 11 (Wiener et
al., 2010). We are currently narrowing down the regions on chromosome 11 that are required for
accelerated PCT development using a new mouse model consisting of (T38HxBALB/c)N mice that
we developed in the lab. This work is done in collaboration with Dr. Francis Wiener (Karolinska
Institute, Stockholm, Sweden).
79
The mouse strain we generated for this study is currently being archived at Harwell, UK, and the full
strain name is C.Cg-T(X;11)38H/Smai.
3) Towards an understanding of the three-dimensional (3D) nuclear organization of the
mammalian genome in normal, immortalized and tumor cells. A few years ago, we realized that
genomic instability cannot be fully understood without a focus on the nuclear architecture of normal,
immortalized and tumor cells. The nuclear topology defines cell function and has been preserved
during evolution (Solovei et al., 2009 and Tanabe et al., 2002). To define nuclear organization, we
first focused on telomeres, the ends of chromosomes, and, when labelling them with fluorophores,
obtained specific signatures that are typical for normal, immortalized and tumor cells nuclei. In
addition, we followed their spatial distribution during the cell cycle (Chuang et al., 2004). In
collaboration with Dr. Yuval Garini and his Ph.D. student Bart Vermolen (Delft University of
Technology, Delft, The Netherlands), we developed softare that enabled the measurements the 3D
nuclear organization of telomeres (Vermolen et al., 2005). This program has allowed us to determine
significant differences between normal and tumor cells (Mai and Garini, 2005), after c-Myc
deregulation (Louis et al., 2005; Mai and Garini, 2005), after Epstein-Barr virus-infection (Lacoste et
al., 2010), during the transition of mono-nucleated to multi-nucleated Hodgkin cells (Knecht et al.,
2009), and in glioblastoma (Gadji et al., 2010). Ongoing studies also focus on breast and thyroid
cancer, multiple myeloma, myelodysplastic syndrome, and cholangiocarcinoma. In summary, the 3D
nuclear telomeric organization of normal and tumor cells, irrespective of their origin, is significantly
different.
Research Highlights
A. New insights into Hodgkin’s lymphoma.
The work summarized below is done in collaboration with Dr. Hans Knecht, CHUS, U of
Sherbrooke, QC.
1) Our first important finding relates to the transition of the mono-nucleated Hodgkin (H) cell to the
multi-nucleated Reed-Sternberg (RS) cell. The RS cell is the diagnostic cell in Hodgkin’s lymphoma.
In collaboration with Dr. Hans Knecht, we have gained insights into the biology of Hodgkin’s
lymphoma and shown that H cells give rise to the multi-nucleated RS cells through dynamic
telomere dysfunction and aberrant synchronous and asynchronous cell divisions (Knecht et al.,
2009).
2) We examined whether the presence of Epstein-Barr virus (EBV) alters the 3D nuclear telomeric
profiles in Hodgkin’s lymphoma. To this end, we have examined Hodgkin patients with and without
EBV and concluded that irrespective of the viral presence, telomeres shorten, aggregate and thus are
dysfunctional in H and RS cells (Knecht et al., 2010). The telomere dysfunction pathway is thus
similar in both patient groups.
3) Telomere dysfunction and cell division problems that precede the formation of the RS cells
suggest that RS cells are the end-stage cells of Hodgkin’s lymphoma. We therefore hypothesized that
these cells display a higher complexity of karyotypic changes than their H cell precursors. To
examine this hypothesis, we have analyzed the 3D organization of chromosomes in H and RS cells in
mono-nucleated H cells and in bi-, tri- and multi-nucleated RS cells. We found that chromosomes are
not located in their regular territories in H cells.
80
Each H cell differs from the next with respect to the nuclear chromosomal positions assumed by
chromosomes 9 and 22 that were used as indicators for the spatial organization of chromosomes. RS
cells increasingly exhibit aberrant nuclear chromosomal organization, with some of the
multinucleated sub-nuclei containing most of the genetic material and others being chromosome–
poor. Spectral karyptyping (SKY) allowed for the analysis of step-wise karyotypic evolution of H to
RS cells and confirmed the 3D nuclear topology data (Guffei et al., 2010).
4) New data from our group show that recurrent and non-recurrent Hodgkin’s patients can be
distinguished at diagnosis based on their 3D telomeric signatures. This work has been presented in
oral presentations at ASH (2010) and AACR (2011) and has just been submitted for peer-reviewed
publication.
B. New insights into the nucleus by super resolution imaging (3D-SIM; 3D-Structured
Illumination). Previous 3D imaging was limited by the physical resolution limit defined by the
physicist Ernst Abbe (1840-1905). This limit, still correct today, was not really overcome by new
technology, but ‘by-passed’ using Fourier transformation and structured illumination series thus
creating a frequency space and enhancing the resolution significantly. The beta- versions of the
instrument that we used so far (x,y: 40 nm and z: 125nm) permitted us to characterize telomeric
aggregates further and to begin an understanding of the nuclear architecture of the H and RS cells of
Hodgkin’s lymphoma (Mai, 2010; Guffei et al., 2010). The final version of the system (ELYRA),
that enables 10-fold better resolution than any conventional 3D imaging system, just arrived in
Winnipeg this summer (2011). It is the first such system in North America and was received through
our CFI LEF funding. We now anticipate a significant deepening of our knowledge about the nuclear
architecture and its functional impact on the physiology of normal and cancer cells.
C. Automation of 3D nuclear telomere analysis - towards a new clinical tool. Our overall goal is to
enhance cancer cell detection and patient treatment/monitoring using the 3D nuclear architecture of
telomeres as our guide. We have worked towards this goal since 2007. The automation of our
TeloView program (Vermolen et al., 2005) has been done in collaboration with Applied Spectral
Imaging Inc. Dr. Ludger Klewes in the lab has defined the sensitivity of tumor cell detection, and has
presented this data at the AACR/JCA conference in Waikoloa Village (2010) and at the Next
Diagnostics Summit in Washington DC (2010). Dr. Klewes study was published earlier this year
(Klewes et al, 2011). Based on this work, I was invited to the EU Mission on Diagnostics in
Oncology organized by the Department of Foreign Affairs and International Trade in November
2010. I met with companies who share an interest in this topic in Paris (France) and London (UK)
and have initiated discussions with the ultimate goal of bringing our new 3D nuclear telomere based
technology to the clinic in the near future.
D. The 3D nuclear telomeric profiles of circulating tumor cells. Since the above-mentioned EU
Mission, collaborative work has been initiated between our lab and ScreenCell (Paris, France). Dr.
Yvon Cayre (Department of Clinical Hematology, Hopital St.Antoine/Hôpital Robert Debré, Pierre
and Marie Curie University, Paris) developed a filter-based isolation method for circulating tumor
cells (CTCs) that is now commercially available though ScreenCell. This method enables the
isolation of CTCs for cell culture, for immunohistochemistry, pathology and FISH applications. In
addition, it allows for the molecular analysis of CTCs (Desitter E et al., AntiCancer Research 31:
427-442. 2011).
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Together, we have shown that the 3D profiles of CTCs allow for the identification of tumor cells.
Furthermore, the data indicate that CTCs consist of subpopulations with at least three different
nuclear telomeric signatures. We have recently presented our data at the CTC workshop in Toronto
and at the European CTC meeting in Prague.
E. Recognition of our research: three journal covers, one image of the month and two featured
articles in 2010 (for details, see publication list below), one issue cover (Advances in Cancer
Research, 2011).
Publications since 2008:
1.Chen Q, Shi X, Rudolph C, Yu Y, Zhang D, Mai S, Wang G, Schlegelberger B, Shi Q. Recurrent
trisomy and Robertsonian translocation of chromosome 14 in murine iPS cell lines. Chromosome
Research 2011. In press.
2.Gadji M, Vallente R, Klewes L, Righolt C, Wark L, Kongruttanachok N, Knecht H, Mai S. Nuclear
remodeling as a mechanism for genomic instability in cancer. Adv Cancer Res. 2011; 112:77-126.
Article and cover.
3.Dawson AJ, Bal S, McTavish B, Tomiuk M, Schroedter I, Arshad N. Ahsanuddin AN, Seftel MD,
Vallente R, Mai S, Cotter PD, Hovanes K, Gorre M, Gunn SR. Inversion and deletion of 16q22
defined by array CGH, FISH, and RT-PCR in a patient with AML. Cancer Genetics 204 (2011)
344e347.
4.Righolt C, Wiener F, Taylor-Kashton C, Harizanova J, Vermolen B, Garini Y, Young IT, Mai S.
Translocation frequencies and chromosomal proximity for selected mouse chromosomes in primary
mouse B lymphocytes. Cytometry Part A. 79A: 276-283, 2011.
5.Scaltriti M, Eichhorn PJA, Cortés J, Prudkin L, Aura C, Jiménez J, Chandarlapaty S, Serra V, Prat
A, Ibrahim YH, Guzmán M, Gili M, Rodríguez O, Rodríguez S, Pérez J, Green SR, Mai S, Rosen N,
Hudis C and Baselga J. Cyclin E amplification/overexpression is a mechanism of trastuzumab
resistance in HER2 positive breast cancer patients. Proc Natl Acad Sci (USA). 2011. Feb 14.
6.Klewes L, Höbsch C, Katzir, N, Rourke D, Garini Y, Mai S. Novel automated three-dimensional
(3D) genome scanning based on the nuclear architecture of telomeres. Cytometry Part A. 2011
Feb;79(2):159-66. doi: 10.1002/cyto.a.21012. Epub 2010 Dec 30.
7.Knecht H, Mai S. 3D imaging of telomeres and nuclear architecture : an emerging tool of 3D nanomorphology based diagnosis. J Cell Physiol. 2011 Apr;226(4):859-67. Featured article.
8.Knecht H, Brüderlein S, Wegener S, Lichtensztejn D, Lichtensztejn Z, Möller P and Mai S. 3D
nuclear organization of telomeres in the Hodgkin cell lines U-HO1 and U-HO1-PTPN1: PTPN1
expression prevents the formation of very short telomeres including “t-stumps”. BMC Cell Biology.
2010 Dec 14;11(1):99. [Epub ahead of print] BMC Cell Biology image of the month.
9.Dawson AJ, Yanofsky R, Vallente R, Bal S, Schroedter I, Liang L and Mai S. Application of
microarrays to the cytogenetic analysis of paediatric acute lymphoblastic leukemias. Current
Oncology. 2010. In press.
10.Rio Frio T, Lavoie J, Hamel N, Geyer FC, Kushner YB, Novak DJ, Wark L, Capelli C, Reis-Filho
JS, Mai S, Pastinen T, Tischkowitz MD, Marcus VA, Foulkes WD. Homozygous BUB1B Mutation
and Susceptibility to Gastrointestinal Neoplasia. N Engl J Med. 2010 Dec 30;363(27):2628-2637.
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11. Guffei A, Sarkar R, Klewes R, Righolt C, Knecht H, Mai S. Dynamic chromosomal
rearrangements in Hodgkin’s lymphoma are due to ongoing 3D nuclear remodeling and
breakage-bridge-fusions. Haematologica. 2010 Dec;95(12):2038-46. Epub 2010 Sep 7.
12. Wiener F, Schmälter A-K, Mowat MRA, Mai S. Duplication of sub-cytoband 11E2 of
chromosome 11 is always associated with accelerated tumor development in v-abl/myc induced
mouse plasmacytomas. Genes & Cancer 1(8): 847-858. 2010. Article and journal cover.
13. Klonisch K, Wark L, Hombach-Klonisch S and Mai S. Nuclear imaging in three dimensions: A
unique tool in cancer research. Ann Anat. 2010 Sep 20;192(5):292-301. Epub 2010 Aug 6.
Article and journal cover.
14. Knecht H, Brüderlein S, Mai S, Möller P, Sawan B. 3D structural and functional
characterization of the transition from Hodgkin to Reed-Sternberg cells. Ann Anat. 2010 Sep
20;192(5):302-8. Epub 2010 Aug 6. Article and journal cover.
15. Millau J-F, Mai S, Bastien N, Drouin R. p53 functions and cell lines: have we learned the
lessons from the past? BioEssays 32: 392-400. 2010.
16. Mai S. Initiation of telomere-mediated chromosomal rearrangements in cancer. Prospects
article. J Cell Biochem. 109: 1095-1102. 2010. Featured article.
17. Silva AGdS, Graves HA, Guffei A, Ricca TI, Mortara, RA, Jasiulionis MG, Mai S. Telomerecentromere-driven genomic instability contributes to karyotype evolution in a mouse model of
melanoma. Neoplasia 12 (1): 11-19. 2010.
18. Gadji M, Fortin D, Tsanaclis A-M, Garini Y, Katzir N, Wienburg Y, Yan J, Klewes L, Klonisch
T, Drouin R*, Mai S*. Three-dimensional (3D) nuclear telomere architecture is associated with
differential time to progression and overall survival in glioblastoma patients. Neoplasia. 12 (2):
183-191. 2010. (*co-corresponding authors).
19. Knecht H, Sawan B, Lichtensztejn Z, Lichtenstejn D, Mai S. 3D Telomere FISH defines LMP1
expressing Reed-Sternberg Cells as End-Stage Cells with Telomere-poor Ghost Nuclei and very
short Telomeres. Lab Invest. 2010 Apr;90(4):611-9. Epub 2010 Feb 8.
20. S. Lacoste, E. Wiechec, G. Williams, M. Henriksson, G. Klein, Mai S. Chromosomal
rearrangements after ex-vivo Epstein-Barr virus (EBV) infection of human B cells. Oncogene.
2010 Jan 28;29(4):503-15. Epub 2009 Nov 2.
21. Davie JR, Drobic B, Perez-Cadahia B, He S, Espino PS, Sun JM, Chen HY, Dunn KL, Wark L,
Mai S, Khan DH, Davie SN, Lu S, Peltier CP, Delcuve GP. Nucleosomal response, immediateearly gene expression and cell transformation.Adv Enzyme Regul. 50(1):135-45. 2010. Epub
2009 Nov 4.
22. Gadji M, Crous AM, Fortin D, Krcek J, Torchia M, Mai S, Drouin R, Klonisch T. EGF receptor
inhibitors in the treatment of glioblastoma multiform: Old clinical allies and newly emerging
therapeutic concepts. Eur J Pharmacol. 2009 Oct 18. [Epub ahead of print]
23. Gonzalez-Suarez I, Redwood AB, Vermolen B, Lichtensztejin D, Bhat A, Sullivan T, Sage J,
Stewart CL., Mai S and Gonzalo S. A-type lamins constitute a higher level of regulation of
telomere biology. EMBO J. Aug 19;28(16):2414-27. 2009. Epub 2009 Jul 23.
24. I. Bronstein, Y. Israel, E. Kepten, S. Mai, Y. Shav-Tal, E. Barkai, Y. Garini. Transient
anomalous diffusion of telomeres in the nucleus of mammalian cells. Physical Review Letters.
Jul 3;103(1):018102. 2009. Epub 2009 Jul 2.
25. Dunn KL, He S, Wark L, Delcuve GP, Sun JM, Yu Chen H, Mai S, Davie JR. Increased
genomic instability and altered chromosomal protein phosphorylation timing in HRAStransformed mouse fibroblasts. Genes Chromosomes Cancer 48(5): 397-409. 2009.
83
26. Knecht H, Sawan B, Lichtensztejn D, Lemieux B, Wellinger RJ, Mai S. The 3D nuclear
organization of telomeres marks the transition from Hodgkin to Reed-Sternberg cells.
Leukemia. 2009 Mar;23(3):565-73. Epub 2008 Nov 27.
27. Gonçalves Dos Santos Silva A, Sarkar R, Harizanova J, Guffei A, Mowat M, Garini Y, Mai S.
Centromeres in cell division, evolution, nuclear organization and disease. J Cell Biochem. 2008
Apr 18;104(6):2040-2058.
Invited Seminars and Presentations at Symposia/Meetings
1. Mai S. Telomere-driven cancer cell diagnostics. Lorus Therapeutics. Toronto, July 2011.
2. N. Benali-Furet, F. Ye, J. Wechsler, S. Mai, D. Lichtensztejn, P. Bigel, A. Carlotti, MF Avril, F.
Boitier, A. Pigné, P. Langlois, Y. Cayre. Comparative study of circulating tumor cells (CTCs)
versus primary tumors using ScreenCell technology, a rapid and save method of CTC selection
based on size. CTC conference. Prague. June 2011.
3. Mai S. 3D nuclear telomeric organization in circulating tumor cells isolation by filtration
methods. NCIC-CTG; CTC workshop Toronto. April 2011.
4. Danescu A, Di Cristofano A, Mai S, Hombach-Klonisch S. 3D nuclear organization of
telomeres during endometrial carcinoma development. Orlando, Florida. AACR. April 2011.
5. Glogowska A, Mai S, McAvoy E, Garcia A. Alzheimer’s disease patients’ telomere intensity
differs from controls: pilot study results. 10th international conference on Alzheimer’s and
Parkinson’s disease. Conference. Barcelona, Spain. March 9-13, 2011.
6. Lajoie V, Lemieux B, Sawan B, Lichtensztejn D, Lichtensztejn Z, Rowe M, Wellinger R, Mai
S, Knecht H. The Epstein-Barr Virus (EBV) Encoded Oncoprotein LMP1 Mediates Down
Regulation of Shelterin Proteins, Formation of Telomere Aggregates and Multinuclearity. 52nd
ASH Meeting, Orlando, Florida, December 2010.
7. Martin LD, Harizanova J, Zhu G, Belch A, Mai S, Pilarski L. Cancer-specific nuclear
positioning of translocation prone gene loci in non-malignant B-cells from patients with
multiple myeloma. 52nd ASH Meeting, Orlando, Florida, December 2010.
8. Nuclear remodeling in cancer. Sabine Mai. 7th Canadian Symposium of Telomeres and
Telomerase, McMaster University, Hamilton. May 2010.
9. Samassekou O, Mai S, Yan J. The alternative lengthening of telomeres alters the nuclear
architecture and causes damage at telomeres. 7th Canadian Symposium of Telomeres and
Telomerase, McMaster University, Hamilton. May 2010.
10. Knecht H, Sawan B, Mai S. 3D telomere dynamics in Hodgkin’s lymphoma: a patient based
molecular study. 7th Canadian Symposium of Telomeres and Telomerase, McMaster
University, Hamilton. May 2010.
11. Gadji M, Fortin D, Tsanaclis AM, Yan J, Reddy JJ, Klonisch T, Drouin R, Mai S. Cellular
mechanisms of recurrence in oligodendrogliomas. 7th Canadian Symposium of Telomeres and
Telomerase, McMaster University, Hamilton. May 2010.
12. Danescu A, Di Cristofano A, Mai S, Hombach-Klonisch S. Alterations in the 3D nuclear
organization of telomeres – an early step in endometrial carcinoma development. 7th Canadian
Symposium of Telomeres and Telomerase, McMaster University, Hamilton. May 2010.
84
13. Glogowska A, Suthiphongchai T, Leelawat K, Jinawarth A, Mai S. Decreased numbers of
telomeres in patients with bile duct cancer.
14. Klewes L, Katzir N, Rourke D, Garini Y, Mai S. Novel automated three-dimensional genome
scanning based on the nuclear architecture of telomeres. 7th Canadian Symposium of Telomeres
and Telomerase, MacMaster University, Hamilton. May 2010.
15. Kongruttanachok N, Sawan B, Mai S, Knecht H. Characterization of the 3D nuclear telomere
organization in Hodgkin and Reed-Sternberg cells of classical Hodgkin’s disease. 7th Canadian
Symposium of Telomeres and Telomerase, MacMaster University, Hamilton. May 2010.
16. Changement structural et nucleaire des telomeres dans la leucemie myeloide chronique
(Samassekou O, Mai S, Hebert J, Yan J). 27th Annual ACQ meeting. Montreal, April 2010.
17. Effets des agents endommagent l’AND sur l’architecture nucleaire des telomeres (Samassekou
O, Bastien N, Mai S, Yan J, Drouin R.) 27th Annual ACQ meeting. Montreal, April 2010.
18. Changement structural et nucleaire des telomeres dans la leucemie myeloide chronique
(Samassekou O, Mai S, Hebert J, Yan J). 27th Annual ACQ meeting. Montreal, April 2010.
19. Effets des agents endommagent l’AND sur l’architecture nucleaire des telomeres (Samassekou
O, Bastien N, Mai S, Yan J, Drouin R.) 27th Annual ACQ meeting. Montreal, April 2010.
20. La reorganization des telomeres et des chromosomes dans le cancer. 27th Annual ACQ meeting,
key note speaker, Montreal, April 2010.
21. Tumor initiation and progression of thyroid cancer impacts on telomeres as shown by threedimensional (3D) imaging. Landon Wark, Sabine Hombach-Klonisch, Sheue-yann Cheng,
Sabine Mai, Thomas Klonisch, Waikoloa, Hawaii, February 2010.
22. Novel automated three-dimensional genome scanning tool based on the nuclear architecture of
telomeres. Ludger Klewes, Nir Katzir, David Rourke, Yuval Garini, Sabine Mai. Waikoloa,
Hawaii, February, 2010.
23. Nuclear remodeling in cancer. McGill, Montreal, Quebec. December 2009.
24. Nuclear remodeling in cancer. Fox Chase Cancer Center, Philadelphia, USA. November 2009.
25. Three-dimensional (3D) nuclear remodeling in cancer cells. Queen’s University, Kingston.
October 2009.
26. Nuclear remodeling in cancer. CLL Meeting, Oct 2, 2009, Winnipeg.
27. Hodgkin’s lymphoma cells rearrange their genome through breakage-bridge-fusion cycles.
AACR, Denver, 2009. (Amanda Guffei, Hans Knecht, Sabine Mai).
28. Anti-estrogen resistant breast cancer cells differ in their 3-dimensional chromosomal
arrangements from their parental cells. AACR, Denver, 2009 (Johannes von VopeliusFeldt, Andreea Nistor, Sabine Mai, Sabine Hombach-Klonisch).
29. Nuclear architecture in human thyroid carcinoma revealed by three-dimensional (3D) telomere
imaging: New insight into genomic instability and potential diagnostic application. AACR,
Denver, 2009. (Thomas Klonisch, Landon Wark, Sabine Hombach-Klonisch, Cuong Hoang-Vu,
Sabine Mai)
30. Telomere-poor “ghost” nuclei define Reed-Sternberg cells as end-stage cells. AACR, Denver,
2009 (Sawan B, Lichtenzstejn Z, Lichtenzstejn D, Mai S, Knecht H.)
31. S. Mai. c-Myc –dependent genomic instability. University of Mainz, Germany. April 2008.
32. S. Mai. c-Myc –dependent genomic instability. University of München, Germany. April 2008.
33. Lacoste S, Wiechec E, Henriksson M, Klein G, Mai S. Genomic instability in freshly EpsteinBarr Virus (EBV)-infected B cells. AACR, San Diego, April 2008.
34. Harizanova J, Taylor-Kashton C, Mai S. Summary of the quantitative analyses of the threedimensional distribution of chromosomes in mouse cells. AACR, San Diego, April 2008.85
Professional Activities
1.External grant reviewer for NSERC, MRC, MHRC, CIHR, Valorisation Recherche Québec,
NCIC, MMSF
2.External referee for Proc. Natl. Acad. Sci (USA), Oncogene, J. Cell Physiol., Gene, Mol. Cell.
Biol., Experimental Cell Research, Genes, Chromosomes and Cancer, JCB. J Pathol
3.Manitoba Institute of Cell Biology, Recruitment Committee, 1996-2000
4.Department of Immunology, Recruitment Committee, 1999
5.Manitoba Institute of Cell Biology Animal Care Committee, 1997-present
6.Reviewer of MRC National Graduate Students Research Poster Competition, 1999
7.Reviewer of Manitoba Student Poster Competition, Research Day, 2000, 2001.
8.Genomic Centre for Cancer Research and Diagnosis: User Committee: 2001-present
9.CIHR Strategic Training Program “Innovative Technologies in Multidisciplinary Health Research
training” selection committee: 2002-2009
10.CIHR Strategic Training Program “Innovative Technologies in Multidisciplinary Health
Research training” Annual Review Committee: 2003-2009
11.CIHR Fellowship – Post- Ph.D. (FPF) committee: 2002-2006
12.Member of the University of Manitoba Senate: 2003-2006
13.Panel J Member NCIC: 2005-2008
14.Judge of National Poster Competition, Research Day, Winnipeg, Manitoba, 2006, 2007
15. Advisory Board Member, Industrial Technology Centre, Virtual Reality Centre, 2007-present
16.Guest editor, Seminars in Cancer Biology (2007); “Non-random genomic instability in cancer: a
fact not an illusion”
17.Canadian Breast Cancer Research Alliance IDEA grants, review panel 2007
18.Host of 6th Canadian Symposium of Telomeres and Telomerase at The Narrows Lodge, Lake
Manitoba, May 2008
19.CCSRI panel G, review panel member 2009
20.CIHR panel MCC, review panel member 2009
21.U of M Research Day on “Molecular Imaging”. Co-organizer. 2009
22.Organizing committee for the 7th Canadian Symposium of Telomeres and Telomerase, Hamilton,
ON, May 2010.
86
KIRK MCMANUS
Ph.D. (ALBERTA)
Genome instability is widely associated with a variety tumour types including colon, breast, ovarian
and various lymphoma. Mutations that cause chromosome instability (CIN) are now widely
recognized as predisposing factors that contribute to the etiology of tumorigenesis. One of my main
goals is to identify and characterize genes that regulate chromosome stability in humans to generate a
candidate list of genes that may be somatically mutated in CIN tumors. I have previously utilized
this approach to identify several key genes that are somatically mutated in colorectal carcinomas
exhibiting CIN. Interestingly, many of these genes encode proteins that regulate sister chromatid
cohesion and knock-down or knock-out of the genes underlies CIN. Because sister chromatid
cohesion appears to be a central theme in colon cancer, I hypothesize that this pathway may also be
aberrantly affected in other tumour types exhibiting CIN such as Hodgkin or non-Hodgkin
lymphoma. As a result I am currently undertaking a series of studies to investigate sister-chromatid
cohesion in various lymphoma cell lines.
Another major focus of my lab is to identify synthetic lethal (SL) interaction partners for the CIN
genes identified above. Conceptually, the somatic CIN mutations present in cancer cells represent a
genetic distinction from the normal surrounding tissues, that may permit the selective targeting and
killing of cancer cells. Accordingly, a major goal of my work is to identify SL genetic interaction
networks for those CIN genes identified above. Utilizing cross-species candidate gene approaches I
have begun to uncover candidate SL interaction partners and networks that I am beginning to
investigate through RNAi-mediated approaches coupled with high content digital imaging
microscopy. Once these interactions are confirmed and validated, chemical libraries will be screened
to identify small molecule inhibitors of the novel candidate therapeutic targets.
Publications Since 2008
1. Bell DW, Sikdar N, Lee Y-Y, Price JC, Chatterjee R, Park H-D, Fox J, Ishiai M, Rudd ML,
Pollock LM, Fogoros SF, Mohamed H, Hanigan CL, NISC, Zhang S, Cruz P, Renaud G, Hansen
NF, Cherukuri PF, Borate B, McManus KJ, Stoepel J, Sipahimalani P, Godwin AK, Sgroi DC,
Merino MJ, Elliot G, Elkahloun A, Vinson C, Takata M, Mullikin JC, Wolfsberg TG, Hieter P,
Lim D-S, Myung K. Predisposition to cancer caused by genetic and functional defects of
mammalian Atad5. PLoS Genetics. 2011;7:e1002245.
2. Ben-Aroya, S., Agmon, N., Yuen, K., Kwok, T., McManus, K., Kupiec, M., and Hieter, P. (2010)
Proteasome Nuclear Activity Affects Chromosome Stability by Controlling the Turnover of
Mms22, a Protein Important for DNA Repair. PLoS Genetics. 6, e1000852
3. McManus, K.J., Barrett I.J., Nouhi, Y. and Hieter, P.A. (2009) Specific Synthetic Lethal Killing of
RAD54B Deficient Human Colorectal Cancer Cells by FEN1 Silencing. P Natl Acad Sci USA.
106, 3276-81.
4. Houston, S.I., McManus, K.J., Adams, M.M., Sims, J.K., Carpenter, P.B., Hendzel, M.J. and Rice,
J.C. (2008) Catalytic function of the PR-Set7 histone H4 lysine 20 mono-methyltransferase is
essential for mitotic entry and genomic stability. J Biol Chem. 28, 19478-88.
87
5. Barber, T., †McManus, K., †Yuen, K.W.Y., Reis, M., Parmigiani, G., Shen D., Barrett, I., Nouhi,
Y., Spencer, F., Markowitz, S., Velculescu, V., Kinzler, K.W., Vogelstein, B., Lengauer, C., and
Hieter, P. (2008) Chromatid cohesion defects may underlie chromosome instability in human
colorectal cancers. P Natl Acad Sci USA. 105, 3443-8. authors contributed equally to this
publication.
Invited Seminars and Presentations since 2007
1.Department of Immunology, University of Manitoba, February 2011.
2.MICB, Annual MICB Retreat, Gimli, Manitoba, September 2010.
3.MICB, Annual MICB Retreat, Winnipeg, Manitoba, November 2009
4.Department of Biochemistry and Medical Genetics, University of Manitoba, September 2009
5.Biology Department, University of Windsor, Windsor, ON, December 2008 MICB, University of
Manitoba, June 2008
6.Department of Experimental Oncology, University of Alberta, April 2008 Department of Medical
Genetics, University of Alberta, April 2008
7.Abcam Conference on “Genome Instability”, Puerto Vallarta, Mexico, February 2008
Special Awards and Distinctions
1. CIHR/MHRC RPP New Investigator Award (2010-12).
Professional Service since 2007
1.Member, Grant Review Panel C, Cancer Research Society, 2010-present
2.Member, Studentship Review Committee, Manitoba Health Research Council, 2010
3.Member, Israels Student Thesis Award Committee, MICB, 2009-present
4.Member (Ad-hoc), Grant Review, Canadian Breast Cancer Foundation (Prairies/NWT Region),
2009
5.Member, Genomic Centre for Cancer Research and Diagnosis Users Committee (2010-present)
6.Member, Radiation Protection Committee, University of Manitoba (2010-present)
7.Reviewer for BMC Cancer, PLoS One, and Proceeding of the National Academy of Sciences
(USA).
Community Service
1.Invited Speaker (The Road to a Scientific Research Career), Maple Leaf School Science Club
Research Day, April 2010
2.Invited Speaker (The Long Road to a Career in Academia), Department of Biochemistry and
Medical Genetics Student Career Development Series, September 2009
3.Laboratory Tour/Demonstration, Summer Biomedical Youth Camp, August 2009
Awards to Trainees
1.Babu Sajesh (post-doctoral fellow), EMBO Travel Award, Vienna, Austria, June 2011.
2.Babu Sajesh (post-doctoral fellow), poster awards
3.Dean of Medicine PDF poster Award, Canadian Student Health Research Forum, June 2011.
4.Honorable Mention (2nd place) Award, CancerCare Manitoba Research Day, April 2011.
5.Rick Hester Prize (1st place), CancerCare Manitoba Research Day, April 2010.
88
MICHAEL MOWAT
Ph.D. (ALBERTA)
One area of research in my laboratory is the study of programmed cell death or apoptosis, a form of
cell suicide. As a result of genetic changes, cancer cells have a reduced or slowed ability to undergo
apoptosis, which can also make tumor cells more resistant to anti-cancer drug treatment. To better
understand programmed cell death, we have taken a genetic approach. Several mutant cell lines have
been isolated that are defective in apoptosis. This was done by using a specially constructed virus
that, after it infects a cell, integrates into genes and interferes with their function. After selection for
drug resistant cells, the underlying genes disrupted by the virus are studied for their role in
programmed cell death and drug resistance. By understanding the genetic basis of resistance to cell
death, completely new treatments can be devised.
A gene that came out of these screens was the Dlc-2 (Deleted in liver cancer two) tumor suppressor
gene. We are now studying the role this gene plays, along with the closely related Dlc-1 gene, in
tumor cell progression and drug response. The Dlc-1 gene is found deleted in over 50 percent of
breast, lung, liver and colon cancers. Also, the other normal copy of the gene is frequently silenced
by promoter methylation. To study the role these genes play in the body, we have developed
conditional knockout mouse models. With these mouse models, we can study the role the Dlc genes
play in lung, and breast cancer spread through the body and anti-cancer drug response.
Publications Since 2008
1. Wiener, F., Schmälter, A.K., Mowat, M. R. A. and Mai, S. Duplication of sub-cytoband 11E2 of
chromosome 11 is always associated with accelerated tumor development in v-abl/myc induced
mouse plasmacytomas. Genes & Cancer 1( 8): 847-858 (2010).
2. Xu, F., McBride, H., Acehan, D., Vaz, F., Houtkooper, R., Lee, R., Mowat, M. Hatch, G. The
Dynamics of Cardiolipin synthesis post mitochondrial fusion. Biochim Biophys Acta. Biomembranes (8):1577-85. Epub 2010 Apr 29. (2010).
3. Sabbir, M.G., Wigle, N., Shauna Loewen, S., Gu. Y., Buse C., Hicks G.G., Mowat M.R.A.
Identification and characterization of Dlc1isoforms in the mouse and study of the biological function
of a single gene trapped isoform. BMC Biology 8(1): 17-38 (2010).
4. Gonçalves Dos Santos Silva A, Sarkar R, Harizanova J, Guffei A, Mowat M, Garini Y, Mai S.
Centromeres in cell division, evolution, nuclear organization and disease. J Cell Biochem.,
104(6):2040-58 (2008)
5. Hatch, G., Gy Y., Xu, F.Y., Cizeau, J., Park, J.-S.,Newmann, S., Loewen, S., and Mowat, M.
StARD13
(Dlc-2)
StARD13(Dlc-2)
RhoGap
Mediates
Ceramide
Activation
of
Phosphatidylglycerolphosphate Synthase and Drug Response in Chinese Hamster Ovary Cells.
Molecular Biology of the Cell, 19(3):1083-92 (2008).
Pubmed search for Mike Mowat
89
Abstracts:
1.Hatch,G.M., Y.Gu, F.Y.Xu, J.Cizeau, S.Neumann, J.S.Park, S.Loewen, and M.R.A.Mowat.
RhoGAP mediates ceramide activation of phosphatidylglycerolphosphate synthase and drug response
in Chinese hamster ovary cells. The FASEB Journal., 22:lb269 (2008).
2.Sabbir, M.G., Preditis, H. and Mowat, M.R.A. Deleted in liver cancer 1 gene cooperates with
onogenic K-ras(G12D) mutation in the induction of thymic tumours through promoter methylation.
BIT’s 3rd Annual World Cancer Congress-, pg 606 Abstract book (2010).
3.Sabbir, M.G., Mowat, M.R.A. The deleted in liver cancer 1 gene (Dlc1) expression during mouse
embryonic development. Mouse Genetics Meeting, Washington DC, June (2011).
Professional Service
Grant Review Committees
Cancer Research Society, member Panel D, Metastasis and Tumour Progression 2010-11
National Cancer Institute of Canada, Panel J: Pathology and Tumour Markers
2005-08
Department Service
Biochemistry & Medical Genetics
Graduate Affairs Committee,
Member, PhD Candidacy examination committees,
Recruitment Committee-Assistant Professor
Chair for Oral defense of Vanessa Pinto
2007-present
2005-09, 2011
2010
2010
Administrative Service - MICB
Associate Director (acting)
Executive committee
Chair, CancerCare MB library committee
Member, Space Committee
2011- present
2000-11
1996-present
2000- present
Awards to trainees
Rachelle Dillon, (postdoctoral fellow), Gerald B. Price Post-Doctoral Fellowship from the Cancer
Research Society
2010-2012
90
LEIGH C. MURPHY
Ph.D. (AUSTRALIA)
Since estrogen is a major driver of human breast cancer, and the action of estrogen changes during
breast tumourigenesis and breast cancer progression, the overall aim of my research program is to
elucidate the mechanisms by which estrogen action changes during the development of breast cancer
and how breast cancers develop resistance to endocrine therapies and progress from hormone
dependence to independence. To do this my group is identifying the molecular players involved in the
estrogen receptor signaling pathways in human breast tissues, how they are altered during
tumourigenesis, and breast cancer progression to hormone independence. I am specifically
determining the types and putative function of estrogen receptor isoforms, i.e. estrogen receptor alpha
and beta and phosphorylated forms of estrogen receptor alpha, that are expressed in human breast
tissues in vivo, using tissues obtained from the Manitoba Breast Tumor Bank/Clinical Database.
Isoforms that are altered in vivo are tested in laboratory models for the functional consequences of that
alteration. Estrogen signalling may have a role in some lung cancers so in collaboration with Drs Sri
Navaratnam, Gary Harding, Alain Demers and Gefei Qing, we are developing human lung cancer
tissue microarrays and associated clinical information to explore the molecular players involved in the
estrogen signaling pathways in lung tissue and relationship to clinical outcome. In collaboration with
Dr Peter Watson and the Manitoba Tumorbank, we are also investigating tissue collection issues that
may affect detection of various gene products in banked tissues.
Publications Since 2008
1. Mariam Al-Dhaheri, George Skliris, Jiacai Wu, Jun Li, Ken Higashimato, Yidan Wang, Kevin
White, Yuerong Zhu, Leigh Murphy, Wei Xu. (2011) Identification of CARM1 as an important
determinant of ERα-dependent breast cancer cell differentiation and proliferation. Cancer Res
71(6):2118-28
2. Georgios Skliris, Zoann Nugent, Peter Watson, Leigh Murphy (2010) Estrogen receptor alpha
phosphorylated at tyrosine 537 is associated with poor clinical outcome in breast cancer patients
treated with tamoxifen. Hormones and Cancer 1 (4), pp. 215-221.
3. Georgios Skliris,
Zoann Nugent, Brian Rowan, Carla Penner, Peter Watson, Leigh
Murphy.(2010) A phosphorylation code for estrogen receptor alpha predicts clinical outcome to
endocrine therapy in breast cancer. Endocrine-Related Cancer 17(3):589-97
4. Dominik Domanski, Leigh C. Murphy, Christoph H. Borchers Assay Development for the
Determination of Phosphorylation Stoichiometry using MRM methods with and without
Phosphatase Treatment: Application to Breast Cancer Signaling Pathways. Analytical Chemistry
82(13):5610-20
5. Yi Yan, George P. Skliris, Carla C. Penner, Shilpa Chooniedass-Kothari S, Charlton Cooper,
Zoann Nugent, Andrea Fristenski, Mohamad K. Hamedani, Anne Blanchard, Yvonne Myal, Leigh
C. Murphy, Etienne Leygue (2009) Steroid Receptor RNA Activator Protein (SRAP): a Potential
New Prognostic Marker for Estrogen Receptor-positive / Node-Negative / Younger Breast Cancer
91
Patients. Breast Cancer Res 11(5):R67
6. Mariam Al-Dhaheri, George Skliris, Jiacai Wu, Jun Li, Ken Higashimato, Yidan Wang, Kevin
White, Yuerong Zhu, Leigh Murphy, Wei Xu. (2011) Identification of CARM1 as an important
determinant of ERα-dependent breast cancer cell differentiation and proliferation. Cancer Res
71(6):2118-28
7. Georgios Skliris, Zoann Nugent, Peter Watson, Leigh Murphy (2010) Estrogen receptor alpha
phosphorylated at tyrosine 537 is associated with poor clinical outcome in breast cancer patients
treated with tamoxifen. Hormones and Cancer 1 (4), pp. 215-221.
8. Georgios Skliris, Zoann Nugent, Brian Rowan, Carla Penner, Peter Watson, Leigh Murphy.(2010)
A phosphorylation code for estrogen receptor alpha predicts clinical outcome to endocrine therapy
in breast cancer. Endocrine-Related Cancer 17(3):589-97
9. Dominik Domanski, Leigh C. Murphy, Christoph H. Borchers Assay Development for the
Determination of Phosphorylation Stoichiometry using MRM methods with and without
Phosphatase Treatment: Application to Breast Cancer Signaling Pathways. Analytical Chemistry
82(13):5610-20
10. Yi Yan, George P. Skliris, Carla C. Penner, Shilpa Chooniedass-Kothari S, Charlton Cooper, Zoann
Nugent, Andrea Fristenski, Mohamad K. Hamedani, Anne Blanchard, Yvonne Myal, Leigh C.
Murphy, Etienne Leygue (2009) Steroid Receptor RNA Activator Protein (SRAP): a Potential New
Prognostic Marker for Estrogen Receptor-positive / Node-Negative / Younger Breast Cancer
Patients. Breast Cancer Res 11(5):R67
11. Blanchard A, Iwasiow B, Yarmill A, Fresnosa A, Silha J, Myal Y, Murphy LC, Chretien M, Seidah
N, Shiu RPC (2009) Targeted expression of proprotein convertase PC1 enhances mammary
development and tumorigenesis in transgenic mice. Can J Physiol Pharmacol 87:831-8
12. Cooper, Charlton; Guo, Jimin; Yan, Yi; Chooniedass-Kothari, Shilpa; Hube, Florent; Hamedani,
Mohammad; Myal, Yvonne; Murphy, Leigh; Leygue, Etienne. (2009) Increasing endogenous
relative expression of non-coding Steroid Receptor RNA Activator (SRA) in human breast cancer
cells using modified oligonucleotides. Nucleic Acids Res 37(13):4518-31
13. Anne A Blanchard, George P Skliris, Peter H Watson, Carla Penner, Ladislav Tomes, Leigh C
Murphy, Tamara L Young, Etienne Leygue and Yvonne Myal. (2009) Claudin 1, 3 and 4 protein
expression in ER negative breast cancer correlates with markers of the basal phenotype . Virchows
Archiv. 454: 647-656
14. George P. Skliris, Brian G. Rowan , Mariam Al-Dhaheri, Christopher Williams, Sandy Troup ,
Sanela Begic, Michelle Parisien, Peter H. Watson, Leigh C. Murphy. (2009) Immunohistochemical
validation of multiple phospho-specific epitopes for estrogen receptor a (ERa) in tissue microarrays
(TMA) of ERapositive human breast carcinomas. Breast Cancer Research and Treatment 118: 443453 [2008 Dec 23. Epub ahead of print]
15. Gregory E. Weitsman, Wineeta Weebadda, Kanyarat Ung and Leigh C. Murphy (2009) Reactive
oxygen species induce phosphorylation of serine 118 and 167 on estrogen receptor alpha. Breast
Cancer Research & Treatment 118: 269 [2008 Oct 21. Epub ahead of print]
16. Rebecca O. Barnes, Michelle Parisien, Leigh C. Murphy, and Peter H. Watson (2008) Influence of
Evolution in Tumor Biobanking on the Interpretation of Translational Research. Cancer
Epidemiology, Biomarkers & Prevention 17:3344-50.
17. J.M. Flynn, S.D. Dimitrijevich, M. Younes, G. Skliris, L.C. Murphy, and P.R. Cammarata. 2008
Role of wild-type estrogen receptor-β in mitochondrial cytoprotection of cultured normal male and
female human lens epithelial cells. Am J Physiol Endocrinol Metab 295(3):E637-47
18. George P. Skliris, Florent Hubé, Ionela Gheorghiu, Mark M. Mutawe, Carla Penner, Peter H.
Watson, Leigh C. Murphy, Etienne Leygue, Yvonne Myal. (2008) Expression of small breast
epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast
92cancers.
Histopathology 52:355-69
Pubmed search for Leigh Murphy
Chapters and Invited reviews
1.
Leigh C Murphy, Srivinas Seekallu, Peter H Watson. (2011) Clinical Significance of Estrogen
Receptor Phosphorylation. Endocrine-Related Cancer, invited review 2011 Jan 19;18(1):R1R14.
2.
Leygue E, Murphy LC 2011 Comparative evaluation of ER-alpha and ER-beta significance in
breast cancer: state of the art. Expert Review of Endocrinology and Metabolism, 6: 333-343 (
invited review)
3.
LC.Murphy, G.P.Skliris, B. Rowan, M. Al-Dhaheri, C Williams, C. Penner, S. Troup, S. Begic,
Michelle Parisien, P.H.Watson (2009) The Relevance of Phosphorylated Forms of Estrogen
Receptor in Human Breast Cancer in vivo . J Steroid Biochem Mol Biology114: 90-95
4.
George P. Skliris, Etienne Leygue , Peter H. Watson, Leigh C. Murphy. (2008)
Estrogen receptor alpha negative breast cancer patients: estrogen receptor beta as atherapeutic
target. J Steroid Biochem Mol Biology 109 (1-2):1-10. (review)
Invited Seminars and Presentations at Symposia/Meetings
1. 16th March, 2009, Oestrogen receptor profiling in human breast cancer. 3rd Mon-Man Workshop
on “Genetically modified mouse models of human disease” Melbourne Victoria, Australia.
2. 17th March, 2009 Estrogen receptor profiling in human breast cancer- towards better predication of
endocrine therapy response. Monash Institute of Medical research, Melbourne Vic, Australia
3. 9TH June 2010, An estrogen receptor phosphorylation code : towards better prediction of treatment
response and prognosis in human breast cancer. ICS seminars and visiting scientist program
Institute of Cardiovascular Sciences St Boniface Hospital Research Centre, Winnipeg.
4. 24-26th Sept 2010, MICB Annual Retreat Gimli, Manitoba. Update in the laboratory of Dr Leigh
Murphy
5. 28th September, 2010 A phosphorylation code for estrogen receptor alpha: a better biomarker for
prediction of prognosis in breast cancer.
6. A One-Day Symposium on Translational Research in Medicine, Faculty of Medicine, University
of Manitoba.
7. 2nd December, 2010 The Terry Fox Research Institutes Prairie Node Launch and Symposium.
Overview of the breast tumour bank and estrogen receptor profiling in human breast cancer in
vivo.
8. 27-28th January, 2011 Canadian Tumour Repository Network- Biobank Certification Workshopinvited speaker. Quality of Biospecimens for Translational Research- a researchers perspective
Special Awards and Distinctions
Member of the Canada Foundation for Innovation, 2007 to present
Community Service
Member, UICC International Fellowships Review Panel (ICRETT Panel, disciplines biochemistry
Molecular biology, biophysics) 1999 to present
Patents
Two patent applications have been filed on the 14th October, 2009 with the US Patent & Trademark
Office: the filling numbers are #1 61/251,687 and #2 61/251,690
93
Administrative Service - MICB
Director (Acting ) January 2009 to March 2011
Associate Director, April 1, 2006 to Dec 2008
Member, Executive Committee MICB - 2000 to present
Member, Space Committee - 2000 to present
Member, Manitoba Breast Tumor Bank Scientific Review Panel – 2003 to present
Director Manitoba Tumour Bank, 2011
Member Management Committee CTRNet 2011
Department
Department of Biochemistry and Medical Genetics
Academic Standards – member
Graduate Students Acceptance Committee - Chair 2000 to 2008
Member, Medicine Teaching Committee - 2000 to present
Member, Candidacy examination committee - 2000 to present
Faculty and University Level
Member, Search Committee Head of Pharmacology, Faculty of Medicine
Member, Selection Committee for the Head of Human Genetics, Faculty of Medicine.
Member of the Accreditation Committee Considering the Faculty, University of Manitoba.
Biochemistry Representative on the Reproductive Systems Committee for Medical Student
Curriculum Reform, U of Manitoba.
Chair for PhD Oral Defense of Sandra Koesters, Dept of Medical Microbiology, University of
Manitoba, February, 2007
Chair for PhD Oral Defense of Harjot Chohan, Dept of Physiology, University of Manitoba.
July, 2007
Member of review panel for Winnipeg Rh Award nominees 2005-08
UMFA representative on Faculty of Medicine, Promotions and Tenure Committee, 2010,
Professional Service
Scientific Reviewer, DOD-BCRP-Concept Grants- Endocrinology panel, February, 2008
Scientific Reviewer, CIHR- Endocrinology Panel. November 2008
Chair- Fellowship Review Panel MHRC. 2008, 2009
Scientific Reviewer USAMRMC - Breast Cancer Research Initiative, Endocrinology panel 2,
2008
Member of the College of Reviewers for the Canada Research Chairs Program: 2000 to present
Alberta Cancer Board - Breast Cancer Research Program- scientific reviewer January, 2006,
2008, 2009, 2010
Scientific Reviewer-Saskatchewan Health Research Foundation, 2009-2011
Member of the DOD-BCRP-Innovator, Era of Hope Scholarship review panel, 2011
Member of the Susan Komen Postdoctoral Award review panel, 2010, 2011
Member CIHR-Terry Fox Foundation Terry Fox Team Grants –2010; Chair of Review Panel for
Michel Tremblay “Oncometabolism Program”, 2011
94
YVONNE MYAL
Ph.D.
My long term research program is based on identifying breast/breast cancer specific biomarkers and
understanding the biological role of these markers in the progression of breast cancer from a localized
disease to metastases. Our research efforts over the last few years have been focused on two
molecules, claudin 1, and the human prolactin inducible protein/gross cystic disease fluid protein,
PIP/GCDFP-15.
PIP/GCDFP-15. PIP/GCDFP-15 is an established biomarker for abnormal breast function.
PIP/GCDFP-15 is abundantly found in the fluid of benign cysts of the breast and its gene expression
has been detected in more than 90% of breast cancers. Currently, its role in breast cancer as well as in
normal breast development is presently not known. Our laboratory generated the firs transgenic and
knockout mouse model to address the function of this protein. Recent studies from our laboratory
show that the role of the PIP/GCDFP-15 protein is multifunctional and may have an
immunomodulatory role.
Claudin 1: We are studying the role of the tight junction protein claudin 1, in breast cancer
progression and metastasis. Tight junction proteins are localized in the membrane of epithelial cells,
including mammary epithelial cells, the milk secreting cells of the breast. Most breast cancers
develop from this cell type. Tight junction proteins are important for cell-cell interaction, regulating
the transport of ions and nutrients between these cells. The breakdown of cell-cell interaction and a
loss of tight junction proteins have long been associated with the progression of several cancers.
However, such an involvement of claudin 1 in breast cancer has not been delineated. We are focusing
on in vitro and in vivo approaches to address this question, as well as examining relationships
between claudin 1 expression and tumor aggressiveness and patient survival in human invasive breast
cancer cohorts.
Publications Since 2008
1. Cooper C, Vincett D, Yan Y, Hamedani MK, Myal Y, Leygue E. Steroid receptor RNA activator
bi-faceted genetic system: Heads or tails? Biochimie. 2011 Jul 12. [Epub ahead of print]
2. Myal Y., Leygue E., Blanchard A.A (2010). Claudin 1 in breast tumorigenesis: revelation of a
possible novel “claudin high” subset of breast cancers J.Biomed. Biotechnol. 2010:956897.
3. Chooniedass-Kothari S, Hamedani MK, Auge C, Wang X, Carascossa S, Yan Y, Cooper C,
Vincett D, Myal Y, Jalaguier S, Cavailles V, Leygue E. The steroid receptor RNA activator
protein is recruited to promoter regions and acts as a transcriptional repressor. FEBS Lett.
3;584:2218-24. Epub 2010 Apr 14.
4. Chooniedass-Kothari S, Vincett D, Yan Y, Cooper C, Hamedani MK, Myal Y, Leygue E. The
protein encoded by the functional steroid receptor RNA activator is a new modular of ER alpha
transcriptional activity. FEBS Lett. 2010 Feb 12. [Epub ahead of print].
95
5. Blanchard, A.A.A., Nistor, A, Castaneda, F.E., Martin, D., Hicks, G., Amara, F, Shiu, R.P.C.,
Myal, Y. (2009). Generation and Initial Characterization of the Prolactin Inducible Protein (PIP)
Null Mice: accompanying global changes in gene expression in the submandibular gland. Can J
Physiol Pharmacol. 87(10):859-72.
6. Blanchard, A.A.A., Iwasiow B., Yarmill A., Fresnosa A., Silha, J, Myal Y., Murphy, L.C.,
Murphy, L., Chretien, M., Seidah, N. and Shiu, R.P.C. (2009). Targeted expression of proprotein
convertase PC1 enhances mammary development and tumorigenesis in transgenic mice. Can J
Physiol Pharmacol. 87(10):831-8.
7. Nistor A., Bowden G., Blanchard A.A.A and Myal Y (2009). Influence of mouse prolactininducible protein in saliva on the aggregation of oral bacteria. Oral Microbiol Immunol.
24(6):510-3.
8. Dibrov A., Myal Y. and Leygue, E(2009). Computational modelling of proteins
interactions:energy minimization for the refinement and scoring of association decoys. Acta
Biotheor. 57(4):419-28. (accepted without revisions).
9. Cooper, Charlton; Guo, Jimin; Yan, Yi; Chooniedass-Kothari, Shilpa; Hube, Florent; Hamedani,
Mohammad; Myal, Yvonne; Murphy, Leigh; Leygue, Etienne (2009). Increasing endogenous
relative expression of non-coding Steroid Receptor RNA Activator (SRA) in human breast
cancer cells using modified oligonucleotides. Nucl. Acids Res.37(13):4518-31.
10. Yi, Yan., George P. Skliris, Carla C. Penner, Shilpa Chooniedass-Kothari, Charlton Cooper,
Zoann Nugent, Mohamad K. Hamedani, Anne Blanchard, Yvonne Myal, Leigh C. Murphy,
Etienne Leygue (2009). Steroid Receptor RNA Activator Protein (SRAP): a Potential New
Prognostic Marker for Estrogen Receptor-positive / Node-Negative / Younger Breast Cancer
Patients. Breast Cancer Res. 11(5):R67
11. Blanchard Anne, Skilris George., Watson Peter., Tamara Young, Penner Carla., Tomes
Ladislav., Murphy Leigh., Leygue Etienne and Myal Yvonne (2009). Claudin 1, 3 and 4 protein
expression in ER-ve breast tumors correlates with markers of the basal phenotype. Virchows
Arch. 2009 454(6):647-56.
12. Skliris George P., Hubé Florent, Gheorghiu Ionela, Mutawe Mark, Penner Carla, Watson Peter
H, Murphy Leigh C., Leygue Etienne and Yvonne Myal (2008). Expression of small breast
epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast
cancers. Histopathology. 52(3):355-69.
Pubmed Search for Yvonne Myal
Awards and Honors
2011
2008
YWCA/YMCA Woman of Distinction Award
Merit Award (2006) for Research, Scholarly Activities and Service, University of
Manitoba (UM)/University of Manitoba Faculty Association (UMFA)
Professional Appointments
Senior Investigator, CancerCare Manitoba Aug 2010 - present
Director of Research , Diagnostic Services of Manitoba 2008 - present
Chair, Operating Grants Steering Committee Diagnostic Services of Manitoba 2008 - present
96
Editorial Boards
2011
International Scholarly Research Network (ISRN) Molecular Biology
Grant Review Panel
2011
National Science Foundation (ad hoc reviewer)
Scientific Journal Reviewer
2011
2010
2009
2009
2008
2008
Prostate
Breast Cancer
American Journal of Pathology
Clinical and Experimental Metastasis
Genome Biology
BMC Molecular Biology
97
MARK NACHTIGAL
Ph.D.
Human ovarian cancer (OvCa) is the fifth leading cause of death by cancer amongst women.
Approximately 95 women in Manitoba will be diagnosed with OvCa this year. If detected at early
stages of the disease, the cure rate approaches 90%; however, >70% of women are diagnosed with
advanced disease when rates of survival are closer to 30%. Even after initial successful responses to
therapy, OvCa recurs in ~85% of patients.
Some of the main goals for OvCa researchers are to 1) identify a molecule(s) that can be used as a test
to detect the disease at early, more treatable stages, 2) identify molecule(s) or pathways that may
constitute a new target for therapeutic intervention, especially in recurrent disease, and 3) develop
reliable models for investigating the biology of OvCa.
Dr. Nachtigal’s laboratory uses a combination of cellular and molecular approaches to investigate
human OvCa biology and address some of these goals. With the formation of the Manitoba Ovarian
Biobanking Program (MOBP) and cooperation with national programs such as the Canadian Ovarian
Cancer Research Consortium (COCRC), they will be able to more readily translate data obtained with
patient samples to clinically relevant results. In particular they have focused on investigating the OvCa
microenvironment by advancing our understanding of the autocrine pathways (cell self-signalling
pathways) that contribute to OvCa cell growth and metastasis. In particular, they have focused on
signalling by members of the transforming growth factor beta (TGFb) superfamily. This work is
complemented by their research program examining the biological process of protein bioactivation by
members of the proprotein convertase family of enzymes. They have determined that human OvCa
cells show altered responses to TGFb superfamily signalling and altered expression of different
proprotein convertase enzymes that likely contribute to the process of carcinogenesis and reduced
patient survival. They will continue to examine these pathways and enzymes to understand how they
contribute to ovarian tumourigenesis and whether they may constitute novel targets for development
of chemotherapeutic agents to reduce the burden of human ovarian cancer.
Publications Since 2008
1. Mujoomdar, ML, LM Hogan, AL Parlow and MW Nachtigal. 2011. Pcsk6 mutant mice exhibit
progressive loss of ovarian function, altered gene expression, and formation of ovarian pathology.
Reproduction 141(3): 343-355.
2. Thériault, BT and MW Nachtigal. 2011. Human ovarian cancer cell morphology, motility, and
proliferation are differentially influenced by autocrine TGFβ superfamily signaling. Cancer
Letters. Doi:10.1016/j.canlet.2011.08.033
98
Book Chapters:
Fu Y and MW Nachtigal. 2011. Epigenetic analysis of proprotein convertase regulation in Human
Cancer. In Proprotein Convertases, M Mbikay and NG Seidah, Eds., Humana Press. Invited article.
Methods in Molecular Biology 768: 231-245. doi: 10.1007/978-1-61779-204-5_12
Professional Service:
Chair, Manitoba Health Research Council Fellowship Review Committee 2011
Terry Fox Research Institute – Canadian Ovarian Cancer Research Consortium, Research Contact
for the University of Manitoba 2010- present
CIHR Institute of Cancer Research Trainees Awards Committee 2010 - present
Member, CIHR Endocrinology Panel 2008 - present
Member, Correlative Science and Tumour Biology Sub Committee of the NCIC CTG Gynecology
Disease Site Group 2008 - present
99
AFSHIN RAOUF
Ph.D.
Despite many recent advances, breast cancer remains a poorly understood disease with bad outcome for
many women. It is becoming clear that progress in treating breast cancer effectively requires a much
better understanding of the cells that generate and maintain breast tumors (cancer stem cells) and
exactly how they are abnormal in a given patient. Accumulating evidence suggests that breast cancer
tumors are maintained by a rare subset of cells that have stem cell properties (e.g. tissue regeneration),
indicating that new therapies are needed to eliminate them to achieve more effective treatments with
decreased chance of tumor recurrence. This concept reinforces the hypothesis that normal stem and
progenitor cells are important cellular targets in the initiation and recurrence of human breast cancer.
Indeed, mutations arising in stem cells could represent an efficient process for hijacking the regulated
proliferation and differentiation of primitive normal mammary cells. These possibilities have recently
focused much interest in investigating the molecular mechanisms that are active in normal mammary
stem cells and how these may be altered to produce tumors.
Dr. Raouf’s research program has 3 major objectives:
1.Identify primitive cell programs that regulate the normal function of the mammary stem and
progenitor cells.
2.Establish how the inappropriate execution of these programs causes the normal stem cells and
progenitors to acquire a cancer stem cell phenotype.
3.Determine whether this understanding can be leveraged to develop therapies against breast cancer
stem cell populations.
Toward accomplishing these objective we have developed techniques to isolate highly purified
populations of stem cells and distinct progenitors from breast tissue. We are now using these breast
stem cells and progenitors to examine the specific roles of breast oncogenes such as the NOTCH
receptors and non-coding RNA such as H19 and Insulin-like growth factor binding protein 7 (IGFBP7)
in regulating the biology and function of these rare cells in health and in disease (i.e. breast cancer).
Publications Since 2008
1. Raouf A. Basal-like breast cancers: the phenotypic disparity between the cancer-initiating cells
and tumor histology. Breast Cancer Res. 2010;12(6):316. Epub 2010 Dec 16.
2. To K., Fotovati A., Reipas K.M., Law J.H., Hu K., Wang J., Astanehe A., Davies A.H., Lee L.,
Stratford A.L., Raouf A., Johnson P., Berquin I.M., Royer H.D., Eaves C.J., and Dunn S.E. (2010)
YB-1 induces expression of CD44 and CD49f leading to enhanced self-renewal, mammosphere
growth and drug resistance. Cancer Research 70(7), 2840-2851.
3. Finkbeiner M., To K., Astanehe A., Davies A., Zhao L., Jiang H., Stratford A., Fotovati A.,
Shadeo A., Boccaccio C., Comoglio P., Mertens P., Eirew P., Raouf A., Eaves C.J., and Dunn S.E.
(2009) Profiling YB-1 target genes uncovers a new mechanism for MET receptor regulation in
normal and malignant human mammary cells. Oncogene 28(11), 1421-31.
100
4. Eirew P., Stingl J., Raouf A., Emerman J.T., and Eaves C.J. (2008) A method for
quantifying normal human mammary epithelial stem cells. Nat. Med.; 14(12), 1384-89.
5. Raouf A., Zhao Y., To K., Stingl J., Delaney A., Barbara M., Iscove N., Jones S.,
McKinney S., Emerman J., Aparicio S., Marra M.A., and Eaves C.J. (2008) Transcriptome
analysis of the normal human mammary cell commitment and differentiation process. Cell
Stem Cell 3, 109-18.
PubMed Search for Afshin Raouf
Invited Speaker at Research Seminars/Symposia/Meetings
Terry Fox Laboratory, Vancouver, BC, May 2011
Department of Immunology, University of Manitoba, September 2010
Sunnybrook Research Institute, Toronto, Ontario, October 12, 2009
University of Manitoba, Pathology Department, Winnipeg, Manitoba, June 17, 2009
University of Manitoba, Regenerative Medicine Program, Winnipeg, Manitoba, August 12, 2008
OncoMed Pharmaceutical Inc., Redwood city, California, August 08, 2008
Manitoba Institute for Cell Biology, Winnipeg, Manitoba, June 17, 2008
Campbell Family Institute for Breast Cancer Research, Toronto, Ontario, December 18, 2007
AACR Annual Conference, Los Angeles California, April, 4, 2007
Child Family Research Institute, Vancouver British Columbia, April 11, 2007
Sunnybrook Research Institute, Toronto, Ontario, February 2, 2007
Professional Service
Member, Canadian Institute of Health Research- Terry Fox Foundation Frontier Group Grant
Projects Review Committee
Member, Manitoba Institute of Health Research-Postdoctoral Research Fellowship Review
Committee
Member, Sarah Israels' Student Thesis Award Committee, MICB
Member, Manitoba Breast Tumor Bank Scientific Review Panel
Member, Immunology Department's Graduate Student Awards Committee
Member, External Review Committee for the Canadian Breast Cancer Research Alliance - Idea
Grant Competition
Organizer, Immunology Department's Research in Progress Seminar Series
Ad hoc reviewer for the Canadian Journal of Physiology and Pharmacology
Ad hoc reviewer for Breast Cancer Research journal
Ad hoc reviewer for Oncogene journal
Member of the Editorial Board
Editor, Cancer Genomics & Proteomics (January 2010 - Present)
101
PETER WATSON
M.B., B. CHIR.,
(UNITED KINGDOM) FRCPC
Peter is Chief Physician at the BC Cancer Agency Vancouver Island Centre, breast pathologist and
scientist with a focus on molecular pathology, and leader in biobanking. In the latter role he is the
director of the BCCA’s Tumor Tissue Repository program (since 2005) and founding director and
remains active as co-director of the CIHR Manitoba Breast Tumor Bank (since 1993). Co-leader of
local (VIC-PREDICT program, since 2006), provincial (MSFHR BC BioLibrary, since 2007) and
national (CIHR Canadian Tumor Repository Network, since 2003) biobanking framework programs
and is a member of the executive of the NCIC-CTG Correlative Sciences and tumor banking
committee. Peter is also a senior scientist at the Manitoba Institute of Cell Biology. His own research
program has pioneered molecular approaches to analysis of human breast tumors and has contributed
to the discovery and delineation of several potential biomarkers and therapeutic targets in breast
cancer. These include delineation of potential relevance of components of the Estrogen Receptor
network, discovery of the S100A7-Jab1 pathway, and definition of CAIX & CAXII as tissue
biomarkers of hypoxia in breast tumors.
Publications since 2008
1. Calder MD, Watson PH, Watson AJ. Culture medium, gas atmosphere and MAPK inhibition
affect regulation of RNA-binding protein targets during mouse preimplantation development.
Reproduction. 2011 Nov;142(5):689-698.
2. West NR, Panet-Raymond V, Truong PT, Alexander C, Babinszky S, Milne K, Ross LA, Loken
S, Watson PH. Intratumoral Immune Responses Can Distinguish New Primary and True
Recurrence Types of Ipsilateral Breast Tumor Recurrences (IBTR). Breast Cancer (Auckl).
2011;5:105-15.
3. Panet-Raymond V, Truong PT, Alexander C, Lesperance M, McDonald RE, Watson PH.
Clinicopathologic factors of the recurrent tumor predict outcome in patients with ipsilateral
breast tumor recurrence. Cancer. 2011 May 15;117(10):2035-43
4. Murphy LC, Seekallu SV, Watson PH. Clinical significance of estrogen receptor
phosphorylation. Endocr Relat Cancer. 2011 Jan 19;18(1):R1-14
5. Panet-Raymond V, Truong PT, Alexander C, Lesperance M, McDonald RE, Watson PH.
Clinicopathologic factors of the recurrent tumor predict outcome in patients with ipsilateral
breast tumor recurrence. Cancer. 2010 Nov 29.
6. Panet-Raymond V, Truong PT, Watson PH. Ipsilateral breast tumor recurrence after breastconserving therapy. Expert Rev Anticancer Ther. 2010 Aug;10(8):1229-38.
7. Skliris GP, Nugent ZJ, Rowan BG, Penner CR, Watson PH, Murphy LC. A phosphorylation code
for oestrogen receptor-alpha predicts clinical outcome to endocrine therapy in breast cancer.
Endocr Relat Cancer. 2010 Jun 3;17(3):589-97.
8. West NR, Watson PH. S100A7 (psoriasin) is induced by the proinflammatory cytokines
oncostatin-M and interleukin-6 in human breast cancer. Oncogene. 2010 Apr 8;29(14):2083-92.
9. Skliris GP, Nugent Z, Watson PH, Murphy LC. Estrogen receptor alpha phosphorylated at
tyrosine 537 is associated with poor clinical outcome in breast cancer patients treated with
tamoxifen. Horm Cancer. 2010 Aug;1(4):215-21.
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Watson PH, Wilson-McManus JE, Barnes RO, Giesz SC, Png A, Hegele RG, Brinkman JN,
Mackenzie IR, Huntsman DG, Junker A, Gilks B, Skarsgard E, Burgess M, Aparicio S,
McManus BM. Evolutionary concepts in biobanking - the BC BioLibrary. J Transl Med. 2009
Nov 12;7:95.
West NR, Farnell B, Murray JI, Hof F, Watson PH, Boulanger MJ. Structural and functional
characterization of a triple mutant form of S100A7 defective for Jab1 binding. Protein Sci. 2009
Dec;18(12):2615-23.
León R, Murray JI, Cragg G, Farnell B, West NR, Pace TC, Watson PH, Bohne C, Boulanger
MJ, Hof F. Identification and characterization of binding sites on S100A7, a participant in cancer
and inflammation pathways. Biochemistry. 2009 Nov 10;48(44):10591-600.
Martin ML, Wall EM, Sandwith E, Girardin A, Milne K, Watson PH, Nelson BH. Density of
tumour stroma is correlated to outcome after adoptive transfer of CD4+ and CD8+ T cells in a
murine mammary carcinoma model. Breast Cancer Res Treat. 2010 Jun;121(3):753-63.
Yan Y, Skliris GP, Penner C, Chooniedass-Kothari S, Cooper C, Nugent Z, Blanchard A,
Watson PH, Myal Y, Murphy LC, Leygue E. Steroid Receptor RNA Activator Protein (SRAP): a
potential new prognostic marker for estrogen receptor-positive/node-negative/younger breast
cancer patients. Breast Cancer Res. 2009;11(5):R67.
Milne K, Köbel M, Kalloger SE, Barnes RO, Gao D, Gilks CB, Watson PH, Nelson BH.
Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20,
FoxP3 and TIA-1 as positive prognostic factors. PLoS One. 2009 Jul 29;4(7):e6412. PubMed
Murphy LC, Skliris GP, Rowan BG, Al-Dhaheri M, Williams C, Penner C, Troup S,Begic S,
Parisien M, Watson PH. The relevance of phosphorylated forms of estrogen receptor in human
breast cancer in vivo. J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):90-5.
Blanchard AA, Skliris GP, Watson PH, Murphy LC, Penner C, Tomes L, Young TL, Leygue E,
Myal Y. Claudins 1, 3, and 4 protein expression in ER negative breast cancer correlates with
markers of the basal phenotype. Virchows Arch. 2009 Jun;454(6):647-56.
Yang T, Martin ML, Nielsen JS, Milne K, Wall EM, Lin W, Watson PH, Nelson BH.Mammary
tumors with diverse immunological phenotypes show differing sensitivity to adoptively
transferred CD8+ T cells lacking the Cbl-b gene. Cancer Immunol Immunother. 2009
Nov;58(11):1865-75
Bell CE, Larivière NM, Watson PH, Watson AJ. Mitogen-activated protein kinase (MAPK)
pathways mediate embryonic responses to culture medium osmolarity by regulating Aquaporin 3
and 9 expression and localization, as well as embryonic apoptosis. Hum Reprod. 2009
Jun;24(6):1373-86.
Wolf R, Voscopoulos C, Winston J, Dharamsi A, Goldsmith P, Gunsior M, Vonderhaar BK,
Olson M, Watson PH, Yuspa SH. Highly homologous hS100A15 and hS100A7 proteins are
distinctly expressed in normal breast tissue and breast cancer. Cancer Lett. 2009 May
8;277(1):101-7. Epub 2009 Jan 10.
Skliris GP, Rowan BG, Al-Dhaheri M, Williams C, Troup S, Begic S, Parisien M, Watson PH,
Murphy LC. Immunohistochemical validation of multiple phospho-specific epitopes for estrogen
receptor alpha (ERalpha) in tissue microarrays of Eralpha positive human breast carcinomas.
Breast Cancer Res Treat. 2009 Dec;118(3):443-53.
Hewitt R, Watson PH, Dhir R, Aamodt R, Thomas G, Mercola D, Grizzle WE, Morente MM.
Timing of consent for the research use of surgically removed tissue: is postoperative consenting
acceptable? Cancer. 2009 Jan 1;115(1):4-9.
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George P. Skliris, Brian G. Rowan , Mariam Al-Dhaheri, Christopher Williams, Sandy Troup ,
Sanela Begic, Michelle Parisien, Peter H. Watson, Leigh C. Murphy. (2009)
Immunohistochemical validation of multiple phospho-specific epitopes for estrogen receptor a
(ERa) in tissue microarrays (TMA) of ERapositive human breast carcinomas. Breast Cancer
Research and Treatment 118: 443-453 [2008 Dec 23. Epub ahead of print]
Rebecca O. Barnes, Michelle Parisien, Leigh C. Murphy, and Peter H. Watson (2008) Influence
of Evolution in Tumor Biobanking on the Interpretation of Translational Research. Cancer
Epidemiology, Biomarkers & Prevention 17:3344-50.
George P. Skliris, Florent Hubé, Ionela Gheorghiu, Mark M. Mutawe, Carla Penner, Peter H.
Watson, Leigh C. Murphy, Etienne Leygue, Yvonne Myal. (2008) Expression of small breast
epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast
cancers. Histopathology 52:355-69
Gulisa Turashvili, Steven McKinney, Lisa Martin, Karen A Gelmon, Peter Watson, Norman
Boyd and Samuel Aparicio. Columnar cell lesions, mammographic density and breast cancer
risk. Breast Cancer Research and Treatment. 2008.
Wang, J., Barnes, R.O., West, N.R., Olson, M., Chu, J.E., Watson, P.H., Jab1 is a target of EGFR
signalling in ER-alpha negative breast cancer. Breast Cancer Research Jun 5 10:R51. 2008
Pubmed search for Peter Watson
104
GENOMIC CENTRE FOR
CANCER RESEARCH AND DIAGNOSIS
The Genomic Centre for Cancer Research and Diagnosis (GCCRD) is comprised of one project
manager (Dr. Rhea Vallente), one part-time technician (Landon Wark) and one full-time computer
technician (Daniel Lichtenzstejn). These personnel provide training of new personnel, assist in
imaging and maintain and/or upgrade the GCCRD equipment, software and data (back-ups,
networking and archiving).
The GCCRD is overseen by a user committee, consisting of Dr. Sabine Mai (GCCRD Director), Dr.
Jim Davie (GCCRD Co-Director), Drs. James Johnston, Spencer Gibson (MICB Acting Director),
Kirk McManus, Michael Mowat and Leigh Murphy.
One of the GCCRD mandates is education. We have been involved in running weekend and
summer workshops with students from the Pembina Trails School Division. Since its inception in
2002, around 200 high school students have been trained in basic plasmid preparation techniques,
restriction digestions, gel electrophoresis, chromosome harvesting techniques, fluorescent in situ
hybridization and imaging. Twenty-six of these students were from our international exchange
program that involved high schools in Germany and Australia. More than 400 high school students
have come through since 2000 (tours, weekend workshops and summer training).
In 2002 to 2009, we conducted a CIHR-funded Strategic Training Program entitled: “Innovative
Technologies in Multidisciplinary Health Research Training.” This training program provided us
with $2.1 million over a span of years. Dr. Sabine Mai was the Principal Investigator of this grant,
with co-mentors from the University of Manitoba, Queen’s University (Kingston, ON), BC Cancer
Agency (Vancouver, BC), McGill University (Montreal, QC) and Bar-Ilan University (Israel). The
GCCRD serves as the training base for innovative technologies as outlined in the grant and in our
training website (http://www.itmhrt.ca ). Zelda Lichtensztejn coordinated the workshops and all
educational aspects that are part of the training program. Three workshops were held each year at
the MICB since the implementation of the program, resulting in a total of 19 workshops.
Participants have come from the MICB, the University of Manitoba, universities and institutions
across Canada, the United Kingdom, France, the Netherlands, Sweden, France, Germany, Brazil, the
United States, The Philippines, Cuba, Estonia, Denmark, Israel, Switzerland and Thailand.
To date, the GCCRD continues to provide imaging workshops twice a year, one in the summer and
another in the fall. Participants from various institutions in Canada, the United States and other
countries from around the world continue to avail of this useful technology, spending a week of
training in various fluorescence and microscopy techniques that are applicable to the biomedical
field.
Throughout the year, the GCCRD is involved in tours through the facility. Daniel Lichtenzstejn and
Rhea Vallente participate in organizing these tours with the rest of the MICB staff. On average, 1-3
tour groups of up to 20 individuals visit the Centre every month. Tours generally involve high
school students from Winnipeg (e.g., Balmoral Hall, St. John’s Raven’s Court
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Kildonan East Collegiate), as well as representatives from the industry, the government and the
interested public.
Mission of the Centre
The Genomic Centre has been created as a regional/national facility for research in genomic instability
and mechanisms of neoplasia. The objectives are focused on research in early detection of cancer and
novel cancer treatments as well as teaching and training of highly qualified personnel.
The Genomic Centre has been designed as a high-technology facility for digital imaging and analysis.
The activities have been divided into two major areas, basic research and technical services, that are
envisioned to promote a better interaction between different fields of research.
The basic research component of the Genomic Centre is developed in collaboration with scientific
groups from Canada, USA, Asia and Europe. Technical services, on the other hand, are offered on a
fee basis, and these are mainly focused on fluorescent in situ hybridization, immunohistochemistry
and microdissection of biological material. The Centre does not carry out clinical diagnostics, but
collaborations with clinical genetics laboratories are strongly encouraged.
Description of Workstations
Each GCCRD workstation is organized independently but is interconnected to the rest of the Centre
through our own server, which is maintained by our in-house computer technician. Below is a
description of each system indicating the current available features and applications. The workstations
are regularly upgraded as new software versions become available, thus further increasing the current
technical capabilities of each system.
Workstation #1: Pathology microscope
Equipment and Software:
1. Zeiss Axioskop 2 microscope
2. AxioCam ICc color camera
3. Pentium IV computer
4. Software: Axiovision ver. 4.8
System capabilities: Pathology samples can be imaged at this station using bright field, phase
contrast, fluorescent and polarized light. Image cropping, resizing, resolution changes or other
alterations using Photoshop are possible at this station. This microscope system is also used for
teaching.
Applications: Data archiving, pathology/histology screening of clinical slides, image enhancement
for publications.
Fluorescent Workstation #2: Scanning Metasystems Microscope
Equipment and Software:
1. Zeiss AxioplanII microscope
2. Multiple scanning platform
3. Zeiss AxioCam MR Monochrome camera
4. Pentium IV computer
5. Software: Isis v 4.4.18, Ikaros v 4.4.18, Metafer4.
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System Capabilities: The Ikaros software is mainly used for karyotyping, as it is supplied with a
classifier for human chromosomes. It also allows manual classification of chromosomes of other
species if one is familiar with these chromosomes. The Isis software is used for FISH, M-FISH and
CGH for the analysis of chromosomes, interphase nuclei and tissue sections. Integration of Isis and
the Metafer4 slide scanning programs allows for automatic scanning for metaphases, FISH signals and
other specifically labeled cells. The detected images are displayed in a gallery and appropriate images
may be automatically relocated on the slide for further detailed.
Fluorescent Workstation #3: MetaSystems
Equipment and Software:
1. Zeiss Axioplan II microscope
2. Hamamatsu CCD camera (model C5985)
3. Intel Pentium IV computer
4. Software: Isis (version 5.0), Ikaros (version 5.0), In Focus.
System Capabilities: The Ikaros software is used for karyotyping, as it is supplied with a classifier for
human chromosomes. It also allows manual classification of chromosomes of other species if one is
familiar with these chromosomes. The Isis software is used for FISH, M-FISH and CGH for the
analysis of chromosomes, interphase nuclei and tissue sections. Our system allows for the analysis of
up to nine individual fluorophores for M-FISH, with a capacity for fully automated image acquisition,
automated filter exchange with real-time image display, plus automatic and interactive time control
for each color channel. The In Focus application offers 3-D analysis of FISH-probed and fluorescent
immunostained cells and tissues. The MetaSystems software offers a case database for both Isis and
Ikaros and also offers statistical analysis.
Applications: Fluorescence in situ hybridization (FISH); karyotyping, both fluorescent and brightfield
microscopy; multicolor-FISH (M-FISH); comparative genomic hybridization (CGH); stepwise
analysis of cells and tissues after FISH or immunofluorescence.
Fluorescent Workstation #4: Live-Cell System
Equipment and Software:
1. Zeiss Axiovert 200 microscope
2. AxioCam MRM and AxioCam HSM
3. Full incubation with CO2 control
4. Dual Xenon 2.8 Ghz speed with 3.0 Gb RAM; 2 X 500-Gb hard drive
5. AxioVision ver. 4.8
System Capabilities:
The Axio Vision v. 4.8 software allows for the acquisition and quantification of
fluorescent signal intensities of both FISH and FIHC experiments. Once intensity levels are
measured, the software will then transfer the data directly to Microsoft Excel for further data
processing. Quantitative fluorescent immunohistochemical analysis can be performed with varying
degrees of automation or with total manual control, as is required by the investigator. This software
package can also be used as a densitometry tool for measuring band intensities on any scanned
autoradiogram, with data transferred to Microsoft Excel. Finally, this software version is capable of
multi-plane image acquisition and deconvolution, for the reconstruction of a three-dimensional image.
Acquired images can be stamped with pixel/or mm length as well as sample names, date and
time.
All images are also stored with exposure property details that are relevant to image
analysis. The system features fully automated image acquisition for each type of fluorescent analysis,
automated filter exchange with live image computer screen plus automatic and interactive time control
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for each color channel.
It features joystick motorized stage movement, as well as fully motorized functions that are completely
software driven. As an inverted microscope the Zeiss Axiovert 100 microscope is also equipped with a
heated stage and CO2 chamber, allowing users to combine cell culture with microscopy and imaging,
and other live cell analyses.
Applications: Live cell analysis; brightfield and fluorescence imaging; visualization of protein, DNA
and RNA within cells; image overlay and analysis; cell morphology studies; densitometry.
Fluorescent Workstation #5: Spectral Karyotyping (SKY)
Equipment and Software:
1. Zeiss Axioplan 2 microscope
2. Spectral CubeR (Applied Spectral Imaging Inc.) SD-300
3. Interferometer
4. Hamamatsu (model C5985) CCD Camera
5. Intel Pentium IV Computer 6. Software: Case Data Manager 5.0.0.11, Spectral Imaging 4.5, SkyView v 4.5, FishView v5.0,
BandView v5.0
System Capabilities:
The Applied Spectral Imaging Inc. (ASI) system is a highly specialized
workstation that enables the user to visualize a spectral range of 400-1000 nm and differentiate
fluorophores that differ by as little as 10-20 nm. The Spectral Imaging software is dedicated to image
acquisition and the SkyView software allows the user to analyze the images acquired. The Applied
Spectral Imaging system features fully automated image acquisition for spectral analysis of cells and
tissues.
Applications: Spectral karyotyping (SKY); spectral signatures of cells and tissue; spectral FISH;
spectral imaging.
Fluorescent Workstations #6: Deconvolution-2 (Decon-2)
Equipment and Software:
1. Zeiss AxioImager.Z.2 microscope
2. AxioImager MRm
3. Intel Pentium IV computer
4. Axiovision software ver. 4.8.1
System Capabilities:
The AxioVision software allows for the acquisition and analysis of fluorescent
signal intensities of both fluorescent in situ hybridization (FISH) and fluorescent immunohistochemistry
experiments. Images can be stamped with microscope parameters, captions and comments. It also
displays cells and tissue sections in 3-D space and has multi-channel fluorescent imaging
capabilities. AxioVision now supplies everything
from correct image recording to image enhancement using 3-D deconvolution, including image
animations such as continuous rotation in space. Also possible are accurate measurements of distances,
angles, areas and coordinates, with measurement results presented in a list on the image. The system
features fully automated image acquisition for each type of fluorescent analysis, automated filter
exchange with a live image computer screen plus an automatic and interactive time control for each
color channel. The microscope itself operates with a joystick stage movements and fully motorized
functions that may be completely software driven.
Applications: Imaging of fluorescent samples for 3D analysis; visualization of protein, DNA and RNA
within the same cell; image overlay and analysis; cell morphology studies.
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Workstation #7: Laser Chromosome Microdissection
Equipment and Software:
1. Zeiss Axioskop II microscope
2. MicroPoint Ablation laser head
3. Fiber optic element
4. Dichroic reflector Dry-Cell resonator
5. PC-10 Micropipette Puller
6. Zeiss MC200 CHIP camera
Systems Capabilities: The system functions as a dissection unit operating with a nitrogen-pumped
dye laser beam with both brightfield and fluorescent light sources. This feature makes possible a
high-energy deposition to cut, separate or simply dissect micron-sized areas of biological
material. The system is equipped with a PC-10 micropipette puller, which is used to make
micropipettes, micromanipulators and micro-needles for dissecting biological materials.
Applications: Laser micro-dissection of tissues, cells and chromosomes.
Fluorescent Workstation #8: Applied Imaging
Equipment and Software:
1. Zeiss Axiophot microscope
2. SenSys camera including SensiCam and two 35 mm cameras
3. Power Macintosh 8100/100 computer
4. IPLab version 3.5 software (Scanalytics), MacProbe version 4.4 (Applied Imaging)
System Capabilities:
This system has the capability for quantitative high-resolution FISH and
fluorescent immunohistochemical imaging. It is also capable of performing comparative genomic
hybridization and microarray analysis. All fluorescent images can be measured to assess relative
fluorescent intensities as well as length or distance of acquired signals using densitometry. MacProbe
allows the analysis of a single chromosome or create a comparative genomic hybridization (CGH)
profile from a karyotype.
Applications: High-resolution photography of cells, tissues, and chromosomes by light microscopy;
high-resolution image acquisition and analysis of immunostained cells or tissues; measurement of
relative distance/length and relative fluorescent intensity of fluorescent signals in cells or on
chromosomes; CGH.
System Capabilities: The Applied Spectral Imaging Inc. (ASI) system is a highly specialized
workstation that enables the user to visualize a spectral range of 400-1000 nm and differentiate
fluorophores that differ by as little as 10-20 nm. The Spectral Imaging software is dedicated to image
acquisition and the SkyView software allows the user to analyze the images acquired. The Applied
Spectral Imaging system features fully automated image acquisition for spectral analysis of cells and
tissues.
Applications: Spectral karyotyping (SKY); spectral signatures of cells and tissue; spectral FISH;
spectral imaging.
Fluorescent Workstations #9: Deconvolution-1
Equipment and Software:
1. Zeiss AxioImager.Z.2 microscope
2. Zeiss AxioCam HRm
3. Pentium IV computer
4. AxioVision version 4.8.1
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System Capabilities:
The AxioVision software allows for the acquisition and analysis of fluorescent
signal intensities of both fluorescent in situ hybridization (FISH) and fluorescent
immunohistochemistry experiments. Images can be stamped with microscope parameters, captions
and comments. It also displays cells and tissue sections in 3-D space and has multi-channel
fluorescent imaging capabilities. AxioVision now supplies everything
from correct image recording to image enhancement using 3-D deconvolution, including image
animations such as continuous rotation in space. Also possible are accurate measurements of
distances, angles, areas and coordinates, with measurement results presented in a list on the
image. The system features fully automated image acquisition for each type of fluorescent analysis,
automated filter exchange with a live image computer screen plus an automatic and interactive time
control for each color channel. The microscope itself operates with a joystick stage movements and
fully motorized functions that may be completely software driven.
Applications: Imaging of fluorescent samples for 3D analysis; visualization of protein, DNA and
RNA within the same cell; image overlay and analysis; cell morphology studies.
Fluorescent Workstation #10: AxioImager.Z.1 (formerly called Apotome)
Equipment and Software:
1. Zeiss AxioImager Z1 microscope
2. Zeiss Axio Cam HRm
3. Zeiss Apotome system
4. AxioVision version 4.8.1
System Capabilities:
The Z1 station allows fast, high-quality production of optical sections through
fluorochromed biological specimens. The capability of Z1 to make optical sections is a prerequisite
for the acquisition of stacks of images and subsequent 3D reconstruction (3D rendering). For the
reconstructions, AxioVision with various rendering modes (shadow, transparency, surface or
maximum projection) is used. AxioVision is also capable of processing time series image stacks, as
well as creating AVIs and Quicktime movies of reconstructions. The AxioVision software allows for
the acquisition and analysis of fluorescent signal intensities of both fluorescent in situ hybridization
(FISH) and fluorescent immunohistochemistry experiments. Images can be stamped with microscope
parameters, captions and comments. It also displays cells and tissue sections in 3-D space and has
multi-channel fluorescent imaging capabilities. AxioVision now supplies everything from correct
image recording to image enhancement using 3-D deconvolution, including image animations such as
continuous rotation in space. Also possible are accurate measurements of distances, angles, areas and
coordinates, with measurement results presented in a list on the image. The system features fully
automated image acquisition for each type of fluorescent analysis, automated filter exchange with a
live image computer screen plus an automatic and interactive time control for each color channel. The
microscope is fully motorized, all functions that may be completely software driven.
Applications: Photomicrography of fluorescent samples for 3-D analysis, visualization of protein,
DNA and RNA within the same cell, image overlay and analysis, cell morphological studies
Fluorescent Workstation #10: Elyra PS.1 Superresolution Structured Illumination System (SRSIM)
Equipment and Software:
1.Zeiss AxioObserver.Z1 microscpe
2.Zeiss camera Andor iXon 885 885 (SIM)
3.Zeiss camera Andor iXon 897 (PAL-M)
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4. LSM 710 34-channel
5. AxioVision version 4.8.1
System Capabilities: The Elyra PS.1 is the most flexible superresolution system available. It works
with all conventional fluorescent proteins and dyes. Almost any sample that is generated for
fluorescent microscopy can be imaged with SR-SIM. By using a precise spatial modulation of the
excitation light with an algorithm that computes superresolution information from interference
patterns in the raw data, SR-SIM delivers double the resolution in XY and Z compared to
deconvolution or confocal microscopy.
Applications: The Elyra system is best used for viewing structures that are too small to be captured
using regular fluorescence microscopes, offering a resolution of up to 20 nm.
The GCCRD website can be viewed at the following URL:
http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/GCCRD/Index3.htm
111
MANITOBA BREAST CANCER
RESEARCH CENTER
Manitoba Breast Tumour Bank
Overview
The Manitoba Breast Tumor Bank is a collection of tissue and related clinical data. The Bank operates
within the Department of Pathology of the Winnipeg Regional Health Authority and University of
Manitoba, and CancerCare Manitoba. The Bank was originally established by the National Cancer
Institute of Canada in 1993 with funds from the Canadian Cancer Society and is now supported by
CancerCare Manitoba Foundation in partnership with the University of Manitoba and the Canadian
Institutes of Health Research (CIHR). The Bank provides an important resource both for breast cancer
research at the University of Manitoba and for researchers across Canada and internationally.
During the assessment of each breast biopsy specimen small tissue samples are taken by Pathologists
to process and examine under a microscope and these samples are then stored as a ‘clinical archive’.
After all diagnosis has been completed the Bank organizes these tissues and related clinical data into
‘cases’ for both future research and future clinical purposes and stores these ‘cases’ in CancerCare
Manitoba. Researchers can apply to study these cases only through a review process and if they obtain
approval for their research project from an institutional ethics review board. If approved, researchers
are provided with tissue sections and the related clinical information from a set of typically 100 or
more ‘cases’. These cases are carefully selected from the computer database on the basis of selection
criteria such as size and type of tumor that are relevant to the research question under study. All cases
are distinguished by a Tumor Bank number but are anonymous due to the absence of any tag that
might allow it to be traced to an individual patient. Researchers are charged to cover the costs of
storage and release but no tissue or information is sold. The Bank has supported over 100 research
studies on breast cancer across North America, Europe and Australia.
The Bank stores three types of information on each case within a secure location in CancerCare
Manitoba. This information relates to the tissue, clinical, and follow-up information. Tissue
information includes the composition of the tissue, the size and type of tumor. Clinical information
includes the patient age, clinical symptoms and the results of clinical tests such as x-rays. Follow-up
information includes the type of treatment after surgery and the response to this treatment. Information
is never released from the Bank with any label that might allow it to be traced to an individual.
Information is only released as part of a set of anonymized cases, where each case is labeled by an
anonymous tumor bank number and consists of a section of tissue with related information.
Update
With the renewal of the Manitoba Breast Tumour Bank by CIHR in 2006, came an expanded mandate
to collect from other disease sites, to date the bank has accrued 55 Head & Neck cases and 80 lung
cases with matched paraffin and frozen blocks. The Tumour Bank also developed standard operating
protocols for collection and banking of prostate cancers and normal breast tissues from reduction
mammaplasties and this collection began December 2009. To date, the bank has accrued 60 prostate
cases and 30 normal breast tissue cases.
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Operations: Consent. Informed consent continues to be obtained for use of samples and data for
research. Potential clients are first asked by the clinic staff if they are willing and interested in being
approached to participate in a Tissue Bank research study. Those clients who sign a preliminary
invitation to participate form are then contacted by the consent nurse to discuss and consider
participation in the MTB project. This informed consent process was initiated initially for breast
tissue collection in Dec 13th 2004. The total number of consented subjects for breast as of Dec 2010
is 2,810.
Operations: Supplies and Expenses. During the previous 12 months of full operation (April 1st to
March 31st) in our lab area within CancerCare Manitoba, the MTB supplies expenses have been
$32,003.
Operations: Access, Release, and Revenue. We have released breast cases in support of research
studies to 6 local laboratories who have been charged $7,682.62 for the cost recovery of laboratory
materials used in the process of release. We have also released material to 5 external laboratories
(investigators in Saskatchewan, Nova Scotia, BC, Sydney, Australia and Phoenix, USA) who have
been invoiced for a total of $16,715.25 to date, for materials received. We also have one application
just approved from the British Columbia Cancer Agency. We have also provided lab services to 6 U
of M researchers to help facilitate their research projects, and they have been invoiced for a total of
$8,970.02.
Operations: Personnel. The overall operation of the MBTB is now directed by Dr. Leigh Murphy
and Co-directed by Dr. Peter Watson; he remains directly involved with the MBTB and CTRNet.
The director and co-director have been assisted by the MTB coordinator, Michelle Parisien, and the
following personnel: Pathologist Dr. Carla Penner (0.3 FTE, MICB funded), Lab manager, Dr
Almuktafi Said, Lab Technician Sandra Troup (CIHR funded), Lab Technician, Andrea Fristensky (1
FTE MICB and CIHR funded), and Clinical consent manager, Kendra-Ann Seenandan-Sookdeo (0.5
FTE, MICB funded), and Data Coordinator Shannon Kornelsen (1 FTE MICB funded).Operations:
The MBTB website can be reviewed at:
http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/MBTB/Index4.htm.
The Molecular Profiling Unit
The Molecular Profiling Unit contains technology platforms that are used to investigate gene
expression at the RNA and protein levels, in multiple breast tumour biopsy samples using high
through-put systems.
The unit contains several Ventana
auto-staining machines for high through-put
immunohistochemistry (IHC) and in situ hybridization (ISH) analyses of multi-tissue sections; an
automated Tumour Imaging System which captures and documents high resolution images of the
contents of the tumour sections that have been processed on the Ventana previously; a Nucleic Acid
Workstation for the automated extraction of RNA and DNA from multiple samples; a DNA microchip
reader which allows the measurement of expression of every gene in the human or mouse genome at
the level of RNA in any tissue sample. So the capability of the unit is to profile multiple tumour
samples either at the level of specific gene families through hypothesis driven research, or to more
globally profile at the gene expression level to identify new patterns of gene expression which are
associated with risk of disease, disease outcome and response to treatment. The unit has made further
progress associated with molecular profiling of estrogen receptor isoforms in human breast cancer,
identifying potentially better markers of responsiveness to endocrine therapies, identifying potential
markers of risk of invasive breast cancer. The unit will cooperate with other platforms within the
Breast Cancer Research Centre and MICB generally, and perform molecular profiling required by the
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research programs within and associated with the MICB.
Nygard International Molecular Biology Breast Cancer Research Unit
The proteomics facility in the Nygard International Breast Cancer Research Unit is equipped with
Ciphergen Protein Chip mass spectrometer, HPLC, FPLC, real-time PCR, protein
electrophoresis (1D and 2D) and Imager system to study the molecular biology of cancer,
especially to identify biomarkers of breast cancer and prostate cancer. The Facility is involved in
gene expression, protein purification and identification activities required in on-going cancer
research projects. The Facility also services and helps the students and staffs in MICB for their
projects related to proteomics.
The Facility achieved to identify a protein, PRDX 1, that preferentially cross-linked to DNA in
estrogen receptor negative (ER-) but not ER+ or normal breast epithelial cells. One paper
(Selective Association of Peroxiredoxin 1 with Genomic DNA and COX-2 Upstream Promoter
Elements in Estrogen Receptor Negative Breast Cancer Cells) was published on MBC in 2010.
We also identified several DNA-bound proteins present only in metastatic prostate cancer cells.
The Facility provided support to Dr. Leygue’s, Dr. Murphy’s, Dr. Mowat’s, Dr. Gibson’s, Dr.
Mai’s, Dr. Eisenstat’s, Dr Hick’s and Dr Raouf’s students, postdoctoral fellows and technicians to
perform real-time PCR, 2D protein electrophoresis, Imager analysis, and proteomics analysis.
Shihua He manages the facility and supervises the performance, operation and maintenance of the
instruments, provides advice in the use of mass spectrometry and image methods for the analysis
and characterization of protein.
Nehal Patel performs cell culture, protein isolation and two dimensional protein electrophoresis
and imager analysis of samples from cancer cells under the supervision of Dr. He.
Technician Parthipan Kamaleswaran is trained to operate and maintain the equipment within this
Proteomics Facility. He performs cell and tissue sample preparation, protein expression and
isolation, purification and analysis under the supervision of Shihua He.
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MAMMALIAN FUNCTIONAL
GENOMICS CENTER
Introduction. The Manitoba Institute of Cell Biology is an international leader and major innovator
in Functional and Cancer Genomics. With the recent completion of the human genome, the next
major hurdle for the Human Genome Project will be to discover what these genes do. Given that we
know there are as many as 5,000 human diseases with a genetic determinant, this new field of
functional genomics will have a tremendous impact on health care and prevention. Our disease focus
is clearly cancer.
The Manitoba Institute of Cell Biology has been leading the field by establishing the first Mammalian
Functional Genomics Centre in Canada. The approach combines the wealth of sequence information
available from the Genome Project with powerful cutting-edge genetic technologies in mice. The
result is a national resource that will provide over 40,000 genetic "knock-out" mutations in mouse
stem cells. Each mouse stem cell has a single gene missing as well as the capacity to actually form an
intact mouse. Because mice are genetically 95% similar to humans they provide an ideal experimental
model system for human disease. The mice that the Functional Genomics Centre can generate are
100% genetically identical to their mouse littermates - except for the one missing gene of interest. As
such, any deficiency, defect or disease that might appear in the mutant mouse will be directly linked to
the function of the single gene in question. The importance of discovering gene function in the context
of the whole animal cannot be said too strongly for this is the context of disease itself - it cannot be
modeled or predicted any other way. In this regard, the mutant mice themselves will not only provide
insights into the genetic basis for the development of human diseases, but will also provide an
experimental model to study the treatment and potential cures for human disease. On a practical note,
development of the mice themselves initiates a chain of propriety that would be considered in all
future discoveries as a result of the mice.
Programs. The MICB Mammalian Functional Genomics Centre, directed by Dr. Geoff Hicks,
continues to provide international leadership in what is currently being dubbed as the next Human
Genome Project. The centre has established a high throughput technology for the genome-wide
creation of a library of transgenic knockout mice. Knockout mice are considered to be one of the most
powerful approaches to discovering gene function and can be used to reveal how disease-related
genes, like cancer-causing genes, work. It’s a critical first piece of the puzzle towards understanding
what causes diseases in humans, and more importantly, how medicine can intervene or prevent the
ensuing disease processes.
Dr. Hicks’ Knockout program aims to generate a knockout mouse for every single gene in the
genome. The mice are freely available to the scientific community at large, thereby providing this
powerful tool directly to the hands of every disease expert in the world. The impact of this project is
considered to be so important that it has led to a worldwide effort to achieve the mouse resource as
soon as possible, the International Mouse Knockout Project. Major funding for the centre was recently
renewed by CIHR will provide the centre with an additional $2.0 M in operating funds over four
years. Most notably, Dr. Hicks is also the lead investigator for a $23 Million Genome Canada
application that will provide funding to support the Canadian initiatives related to the International
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Knockout Mouse Project.
This Canadian led initiative is now recognized as one of the cornerstone international programs in
Mammalian Functional Genomics.
The next step in the overall strategy is to generate and functionally analyze knockout mice. Dr.
Hicks has established a leading edge Transgenics program located in both the MFGC and a state of
the art transgenic mouse barrier facility located in the Faculty of Medicine’s Brodie Building. The
later, known as the University of Manitoba Genetic Modeling of Disease Centre (GMC, Dr. Geoff
Hicks is the Scientific Director), provides both the faculty and the province with a full suite of
transgenic services. GMC services are provided in a cost-recovery fee basis to ensure all members of
the Institute and Faculty can have ready access to this powerful approach to study disease genes and
mouse models of human disease. Services provided include the generation of mice from ES cells,
cryopreservation of ES cells, germ cells, and the rederivation of mouse models brought into the
faculty from around the world.
Dr. Hicks has also established the Canadian Mouse Consortium (www.MouseCanada.ca). The CMC
integrates all the major mouse centres across Canada and will provide essential transgenic services to
any Canadian disease-focused research program. Finally, the MFGC also provides additional key
service platforms to the Institute. These include a high throughput DNA sequencing facility, a flowcytometry facility and a long term cryogenic cell storage facility. Once again, these are provided to
MICB members as cost-recovery services that significantly reduce the operating costs of MICB
research programs. As these services are used by all member of MICB, the Institute provides support
for the on-going maintenance of the key instruments.
In summary, the MICB Mammalian Functional Genomics Centre is currently a leader in the field and
creating an invaluable genetic resource. The Centre's goal is to develop this resource to its fullest
potential by focusing its efforts on the functional analysis of genes that are known, or suspected to
be, determinants of cancer and human disease. We are hopeful that the true impact of the project will
be to discover experimental mouse models of human disease that would greatly accelerate the
development of pharmaceutical therapies, or even cures, for human cancer.
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MICB FACILITIES
DNA Sequencing Facility
The MICB DNA Sequencing Facility provides DNA sequencing for more than 45 labs at the MICB
and University of Manitoba. Established and supervised by Dr. Don Dubik since March of 1998, the
facility is self-sufficient and provides sequencing service at less than half the cost of most other
Canadian facilities. The facility contains two sequencers: a single column ABI 310 and an eight
column Beckman CEQ8000. The ABI 310 is the principle sequencer for the facility while the
CEQ8000 is used by Dr. Hicks’ Functional Genomics Group.
For information about the MICB Sequencing Facility see our website at:
http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/Sequence/Index2.hm
MICB Equipment Maintenance and Glass-washing Area
Salaries are provided for facility monitors and an equipment manager who oversees the use and
operation of multi-lab equipment totalling well over $10M. Service contracts and a repair budget are
also provided for joint used equipment. A wash-up area and salaries for two full-time staff are
provided.
CLL Tissue Bank
Salaries and supplies for a Chronic Lymphocytic Leukemia (CLL) Tissue Bank are provided. The
purpose of this bank is to facilitate basic scientific research in CLL. This tissue bank stores CLL
samples as well as relevant scientific and clinical information related to each sample stored. The bank
is accessed by MICB senior investigators interested in CLL research with the expectation of
expanding the bank as a national resource with networks established across Canada with long-term
national funding. Salaries for a technician, research nurse and supplies are provided by the Institute.
Confocal Microscope Facility
An advanced confocal microscope, one of only three in Canada, was purchased by MICB with the
assistance of the Canadian Institutes of Health Research, the Canadian Foundation for Innovation and
the Guardian Angel Benefit, a fundraising committee of the CancerCare Manitoba Foundation. The
microscope is unique because it is capable of examining the biology and metabolic processes inside
cells. With the help of laser light, it creates optical slices of cancer cells and allows detailed
examination of various cell building blocks, including DNA within the nucleus of the cell.
Electron Microscope Facility
The electron microscope facility allows for the visualization of cellular structures and detection of
specific proteins within cells. This technology has been utilized clinically for platelet disorders as well
as research projects. The facility has been used by senior investigators at MICB (Drs. Israels, Gibson
and Eisenstat) for their research on primary cells, cell lines and tissues using transmission electron
microscopy. We share a new digital camera and image analyser system with the Department of
Human Anatomy and Cell Science.
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MICB STAFF
Research Affiliates
Frixos Paraskevas, M.D.
Lorne Brandes, M.D.
Janice Richman-Eisenstat, M.D.
Robert Shiu, Ph.D
Professional Associates
Genevieve Delcuve, Ph.D.
Research Nurse
Donna Hewitt
Research Associates
Brenda Kuschak, M.Sc.
Shihua He, Ph.D.
Luke de Lange, Ph.D.
Ketan Badiani, Ph.D.
Elizabeth Henson, M.Sc.
Molly Pind, M.Sc.
Hou Yu Chen, M.D.
Protiti Khan, Ph.D.
Shunzen Zhang, M.Sc
Ludger Klewes, Ph.D.
Debbie Tsuyuki, Ph.D.
Don Dubik, Ph.D.
Soma Mandal, Ph.D.
Charlton Cooper, M.Sc.
Post-Doctoral Fellows
Sandrine Lacoste
Srinivas Seekallu
Robin Erickson
Babu Sajesh
Rachelle Dillon
Kathiravelu Loganathan
Ganchimeg Ishdorj
Mohammad Sabbir
Arzu Osturk
Narisorn Konguttanachok
Lin Li
Animal Care Technician
Terry Germscheid
Chris Taylor
Project Managers
Michelle Parisien
Michael Jackson
Rhea Vallente
Director – Bioinformatics
Songyan Liu
Pathologist
Carla Penner
Consent Nurse
Kendra-Ann Seenandan-Sookdeo
Information Coordinator
Kathy Bowler
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MICB STAFF
Technicians
Heather Prieditis
Eileen McMillan-Ward
Mario Fonseca
Michelle Brown
Cheryl Taylor-Kashton
Amanda Guffei
Angela Kemp
Cheryl Peltier
Charlton Cooper
Daniel Lichtensztejn
Xuemei Wang
Jennifer Constantini
Mehdi Eshraghi
Shirley Chang
Caroline Gebel
Yunli Zhang
Jackie Schwartz
Linda Curtis
Djula Arapovic
Andrea Fristensky
Lisa Salter
Wenyan Xiao
Sandra Troup
Landon Wark
Yulian Niu
Kanyarat Ung
Laurie Lang
Mohammad Hamedani
Agnes Fresnoza
Suhaila Selamat
Parthipan Kamaleswaran
Chaobo Jiang
Cheryl Camia
Zelda Lichtensztejn
Barbara Iwasiow
Tracie Parkinson
Administrative Assistants
Nikki Ryan
Dale Ross
Jennifer Cabral
Wendy Bencharski
Administrative Officer
Cecile Verrier
Office Assistants
Mary Marko
Sharon Klassen
Genome Prairie
Reno Pontarollo
Faye Pagdonsolan
Senior Health Outcomes Analyst
Zoanne Nugent
Systems Developer
Aaron Suggit
Lab Aides
Alice Smith
Maria Simao
Leta Klann
Lab Assistant
Charlene Bergen
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MICB STAFF
Graduate Students (M.Sc.)
Chaitrabhargav Shivashankar
Vanessa Pinto
Meenal Moudgil
Mehdi Eshraghi
Cordula Buse
Hongmei Zeng
Caroline Shields
Yi Yan
Daniel Vincent
Jamie Zagozewski
Graduate Students (Ph.D)
Meghan Azad
Qi Zhang
Sara Mohammad-Ali-Beiggi
Paula Espino
Trung Le
Yueqin Zhou
Ju-Yoon Yoon
Evan Booy
Dilshad Khan
Shilpa Chooniedass
Students (Project)
Solmaz Nafez
Ayat Mneina
Wenjun Zhu
Graduate Students (B.Sc.)
Mark Lipson
Sumit Sandu
Tyler Friesen
Ceri Richards
Student (Resident)
Dave Dawe
Johnathan Bush
Student (Pre-Masters)
Alexander Graves
Visiting Student
Rudee Sakulratchata
Raenu Yucharoen
Students (Summer 2009-2010)
Sari Yakubovich
Abhinay Sathya
Rodriguez Prerana
Yujia Sun
Upama Banik
Sunjay Lakhi
Volunteer Researchers
Dana Henderson
Andrew Ho
Yaping Wang
Wanyu Zhang
Andrea Globo
Becca Lang
Lauren Luo
Ethan Qing
Eric Tsang
Jennifer Schacter
Juliet Daet
Michael Hsu
Suresh Kumar
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