Issue 22

DECEMBER 2012 | ISSUE 22

Salinomycin A NOVEL ANTI-CANCER AGENT CHILDHOOD ANEMIA IN THE DEVELOPING WORLD IMMEDIATE ACTION REQUIRED SHORTCOMINGS IN MENTAL HEALTH SUPPORT A GAP ANALYSIS IN RICHMOND, BC

. m e d u c ato r . o r g november 2011 | IssueW20W|Wwww.meducator.org

table of

contents

05 INTERVIEW WITH DR. PATANGI RANGACHARI: FINDING THE RIGHT MENTAL COUNTRY Dr. Rangachari discusses his view on health professional education, emphasizing that students should be in no rush to make their career choices.

DECEMBER 2012 ISSUE 22 INTRODUCTION 02 MEDBULLETIN 03 INTERVIEW SPOTLIGHT: DR. PATANGI RANGACHARI 05 OPINION: TUMOUR HETEROGENEITY AND TREATMENT 09 MACABSTRACTS 12 FORUMSPACE: CANADA’S AGING POPULATION 13 RESEARCH INSIGHT: IRON-DEFICIENCY ANEMIA 15 RESEARCH INSIGHT: MENTAL HEALTH AND ADDICTIONS 19 RESEARCH INSIGHT: SALINOMYCIN 23 CONTRIBUTORS 28 ADDRESS

The Meducator, BHSc (Honours) Program Michael G. DeGroote Centre for Learning and Discovery Room 3308 Faculty of Health Sciences 1280 Main Street West Hamilton, Ontario L8N 3Z5

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09 OPINION: TUMOUR HETEROGENEITY AND TREATMENT One step forward or two steps back?

Branavan Manoranjan and Mohsin Ali discuss the positive and negative implications of intratumour heterogeneity on current cancer treatment methods.

15 Preventing IronDeficiency Anemia in Children in Developing Countries Nupur Dogra reviews recent evidence about the adverse effects of iron deficiency in children on development and health, and how treatment programs can address this problem in developing countries.

19 A Gap Analysis of Mental Health and AddiCtions Support Services in Richmond, BC Mental health and addictions (MHA) is an area of concern for health providers across Canada. Shelly Chopra conducts a gap analysis of MHA services in Richmond, British Columbia.

23 Salinomycin: A Notch Signalling Antagonist Carlos Muzlera presents the findings from his research conducted in Dr. John Hassell’s laboratory, which aims to develop a novel way of targeting cancer stem cells.

We are excited to share with you our new vision for The Meducator. Forged through many months of research and experimental toiling, our new layout embraces the vitality and passion of our audience. Work is also well under way on our new mediarich web portal, which will go live next semester.

In this issue, we are proud to feature articles from numerous disciplines within the health sciences. Carlos Muzlera delves into the biochemistry of breast cancer therapy in his investigation of salinomycin, a Notch signaling antagonist. Branavan Manoranjan and Mohsin Ali explore the topic of cancer therapy further in our informed opinion column, by taking an in-depth look at the history of cancer treatment and discussing the future of personalized oncology therapy.

Meanwhile, population health comes to the fore in Nupur Dogra’s review on the cognitive, social, and emotional effects of iron deficiency anemia in children of the developing world. Looking closer to home, Shelly Copra explores the critical gaps in mental health and addiction support services in Richmond, B.C. In the ForumSpace column – our collaborative effort with the McMaster Health Forum – Forum fellows Emily Milko and Sherna Tamboly discuss the pressures on the Canadian healthcare system and the urgent need to embrace evidence-informed policies and sustainable reforms in light of the aging Boomer generation.

Also featured in this issue are the winning abstracts of the 2012 McMaster NeuroXchange conference, selected by The Meducator team.

introduction

INTRODUCTION ISSUE 22

dear reader,

Finally, we sat down with Dr. P.K. Rangachari, Professor Emeritus of Medicine at McMaster University, for an eye-opening discussion of his thoughts on education and the increasingly competitive race for professional school. In particular, he urges students to find the right “mental country”.

We wanted to take this opportunity to express our heartfelt gratitude towards the members of The Meducator team. This issue would not have been possible without the tireless work of our Creative Director and the extraordinarily talented Graphics & Design team, as well as the diligence and commitment of our Managing Editor and the Editorial Board.

Last but not least, we thank you – the reader – for picking up a copy of The Meducator.

We hope you will enjoy reading this issue as much as we enjoyed making it.

A ndrew W ebster

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LEBEI PI

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MEDBULLETIN DO FAT CELLS

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NEED SLEEP?

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NEURONS

FROM NON-NEURONAL BRAIN CELLS

EMBRYONIC

INTERNEURONS RESTORE BRAIN FUNCTION

K E I TH L E E

B ER NAR D H O

B H AVIK MISTR Y

Sl e ep depri vat i o n has l o n g b e e n kn ow n to affect b ra i n a n d i m m u n e fu n ct i o n , cau s i n g d ef i c i ts i n l e a r n i n g , mem o ry an d wo u n d h e a l i n g . 1- 2 A re cent s t u dy a l s o s u g g es ts that in s u ffi ci e nt s lee p m ay i n c re as e th e ris k of o bes i ty a n d d i a b etes , thro u g h a re du ct i o n i n fat ce l l s e n s i ti v i ty to i n s u li n , a h o r m o n e that i n d u ces cellu lar u ptake of g l u co s e. 1

Stem cel l researc h has often invol ved p rog rammin g somatic cel l s from other p arts of the b od y to for m n euron s, wh ic h are then tran sp l anted into the b rain . Ear l ier this year, Stanford U n iversity researc hers rep orted the s uccessful conversion of mouse sk in cel l s d irectl y into n eural p rec ursor cel l s, w hic h d ifferentiate into the three main cel l typ es of the n ervous system. 1

Sc ientists from th e Unive rs ity of Cal ifor n ia, San Francis co, re ce nt ly p ub l ished a ser ies of innovat ive exp er iments that s ugges t the p ossib il ity of t rans plant ing emb ryon ic n euron s to t re at mult iple b rain d iseases. Le d by Profess or Arturo Al varez -B uy lla and forme r g rad uate stud ent De re k Sout h we ll, the researc hers explore d the p rop erties of a s pe cial ty pe of b rain cel l k n ow n as GA BA-s e cret ing inter n euron s. Def icie ncy in t h es e cel l typ es has b een linke d to s eve ral n eurol og ical d isorde rs , including ep il ep sy, Huntin g ton’s dis e as e and Par k in son ’s d isease. Th es e s o-calle d GABAerg ic inter n eurons are crit ical d ue to their inh ibitory funct ion w ithin the cerebral cortex, wh ich counteract exc itatory ne urons .

To i nves t i gate th i s h y p othes i s , Un i vers i ty of C h i ca g o res e a rc he rs co n du cted a ran d o m i ze d c ro ss ove r stu dy. 1 S even h e a l th y a d u l ts , aged 18 to 3 0 , we re tes te d u n d e r two ex pe ri m e nta l co n d i ti o n s i n a ran do m i zed o rde r : fo u r co n s e c u ti ve ni gh ts of 8 . 5 h o u rs of s l e e p, fo llowed by fo u r co n s e c u ti ve n i g h ts w i t h 4 . 5 h o u rs . Afte r e a c h fo u r day pe ri o d, parti c i p a nts u n d e rwe nt an i nt raven o u s g l u co s e to l e ra n ce tes t to m eas u re tota l b o d y i n s u l i n se n s i t i vi ty. Th e res e a rc h e rs a l s o bi o ps i e d abdo m i n a l fat ce l l s f ro m each part i ci pa nt to tes t the i r res po n s e to i n s u l i n . Fo o d i nta ke was st ri ct ly co nt ro lle d a n d i d e nti ca l i n bot h s ce n ari o s to e n s u re d i et wo u l d not co nfo u n d t he res u l ts .

Res u lts s h owed that tota l b o d y in s u li n s en s i t i v i ty was , o n ave ra g e, 16% lower afte r fo u r n i g h ts of sleepi n g 4 . 5 h o urs co m p a re d to 8 .5 ho u rs . S i m i larly, i n s u l i n s e n s i ti v i ty i n bi o ps i e d fat ce lls d e c re as e d by 3 0% un der res t ri cte d s l e e p co n d i ti o n s .

Th es e res u lts s u g g es t th at, th ro u g h its effe cts o n fat ce l l s , s l e e p m ay play an i m po rta nt ro l e i n re g u l ati n g wh o le - bo dy m eta b o l i s m , wi th potent i al i m pli cati o n s i n m eta b o l i c di s o rders s u ch as d i a b etes . Fu tu re res earch can prov i d e f u rth e r i n s i g h t into t h e i m po rta n ce s l e e p fo r o u r healt h .

Recentl y, researc hers at the J ohan n es Guten b erg Un iversity M ain z in Ger man y, l ed by Dr. B en ed ikt Ber n in g er, converted n on -n euron al ce l l s in the b rain into n euron s. 2 They assert that n euron s c reated from b rain cel l s are b etter ab l e to ad apt comp ared to somatic cel l s, b ecause their simil ar fun ction an d l ocation i m p l ies a comp arab l e d ifferentiation p athway. 2 B er n in g er an d col l eag ues foc used on p er icytes, w hic h maintain the b l ood -b rain b ar r ier an d p l ay a rol e i n woun d heal in g . They man ip ul ated two g en es, Sox2 an d Mash1 , to tur n ad ul t human b rain p er icytes i nto n euron -l ike cel l s. These g en es, a ccord in g to p rev ious researc h, are p owerful rep rog rammin g factors for d i rect conversion of somatic cel l s i nto n euron al cel l s. 3 The researc hers c ul tured mouse cereb ral p er icytes, e mp l oyin g retrov ir uses to in sert the two g en es. Within four weeks, the p er icytes exhib ited n euron l i ke p rop erties suc h as the ab il ity to p rod uce el ectr ical imp ul ses an d sy n ap se w ith other n euron s, two c ritical features for integ ration into n eural n etwor ks.

This wor k raises the p ossib il ity of f u n ction al conversion of en d og en ous a dul t human b rain cel l s into n euron s.

W hil e muc h researc h is req uired b efore these resul ts are ap p l icab l e to human s, this is n on ethel ess a nother step in the searc h for n eurod eg en erative d isease tre atments.

The b rain has a ve ry limite d cap ac ity to accom modate addit ional cel l s, w hic h is wh y t h e s uccessful tran sp l antation of inte rne urons into the b rain has se nt a s h ockwave throug hout the ne uros cie nce commun ity. After dis cove ring t h at these inter n eurons we re able to surv ive, the research e rs conducte d further stud ies in wh ich t h ey var ied the amount of inte rne urons tran sp l anted . Res ults from t h es e exp er iments showed t h at only a fixe d an d smal l n umb er of t rans plante d emb ryon ic interne urons would surv ive in the b rains of adult re cipie nt mice. The freq uency of inh ibitory syn aptic events d i d not ch ange wit h in c reasin g n umb e r of t rans plante d inter n euron s. I nte res t ingly, t h es e tran sp l anted interne urons did not req uire surv ival signals from ot h e r typ es of cel l s th at are ty pically n eed ed . The res ults from t h es e exp er iments p rovide ins igh t into b rain p l astic ity, wh ile s ugges t ing a p otential therapy for pat ie nts wit h n eurol og ical d isorde rs .

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1. Broussard JL, Ehrmann DA, Van Cauter E, Tasali E, Brady MJ. Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study. Ann Intern Med 2012;157(8):549-557.

2. Gümüştekín K, Seven B, Karabulut N, Aktaş O, Gürsan N, Aslan S, Keleş M, Varoglu E, Dane S. Effects of sleep deprivation, nicotine, and selenium on wound healing in rats. Int J Neurosci 2004;114(11):143342.

DNA TRANSFER FOR MITOCHONDRIAL GENETIC DEFECTS

MOLECULAR

INSIGHT ON MEMORY FORMATION

Althou gh bot h s pe r m a n d ov u m contribu te n u clear D N A to the genetic m akeu p of the offs p r i n g , the ovu m als o co nt ri b u tes D N A f ro m the mito ch o n dri a – th e e n e rg y produc in g cellu lar o rg a n e l l e. D efe cts i n the m i to ch o n dri a o cc u r i n o n e i n 4,000 i n di v i du als , an d a re i nvo l ve d i n diseas es s u ch as Pa r k i n s o n ’ s and can ce r. 1-2 Re centl y, a te a m of researc he rs le d by D r. S h o u k h rat Mitalipov h ave u s e d a n i n n ovati ve method to prevent g e n eti c d efe cts attribu ted n ot to n u c l e a r D N A , b u t to mitoch o n dri al D N A . Th e te a m successfu lly i m plem ente d a p ro cess called s pi n dle- ch ro m o s o m a l co m p l ex transfer ( ST ) i n rh es u s m a ca q u e monkeys , i n w h i ch n u c l e a r D N A from an ov u m co ntai n i n g d efe cti ve mitoc hon dri a i s i m p l a nte d i nto a health en u cleated ov u m f ro m a donor. 1 Th i s effe ct ive l y p reve nts the offs pri n g fro m i n he r i ti n g the defective m i to ch o n dri a l g e n es f ro m the mot h er. 2 Th u s far, n e g ati ve l o n g term effects h ave n ot b e e n d ete cte d in follow - u p s t u di es . 1 I t i s i nte res ti n g to note t h at offs pri n g f ro m th e ST process po ss ess D NA f ro m thre e sources— t h e fat h e r, th e m oth e r (nuc lear D NA ) , an d the d o n o r (mitoc h o n dri al D NA , co m p r i s i n g less th an 1% of t h e offs p r i n g ’ s genetic m ateri al) . 3 Th o u g h thi s method requ i res fu rt h e r “ twe a k i n g ” , Mitalipov h o pes t h i s p ro cess wi l l b e available to wo m en s o o n , d es p i te sceptic i s m fro m ge n eti c s p e c i a l i s ts . 1 Regardless of t h e f u tu re h u rd l es to overco m e i n i m p l e m e nti n g ST, both part i es agree t h at thi s n ew tec hnology h o lds gre at p ote nti a l fo r address i n g ce rtai n ge n eti c d i s o rd e rs .

P rote i n k in ase A (PKA) p l ays a c r i ti ca l rol e in memory for mation . 1 Less u nd erstood , however, is how P KA i nteracts w ith other mol ec ul es, particularly its significance in forming s h o rt- , inter med iate- an d l on g -ter m m e m o r i es. A team of n eurosc ientists f ro m N ew Yor k Un iversity an d the U n i ve rs ity of Cal ifor n ia, I rv in e, re ce ntl y c haracter ized the mol ec ul ar i nte ra cti on s that may control the fo r m ati on of memor ies. 2 Th e n eurotran smitter seroton in co ntr i b utes to simp l e for ms of l e a r n i n g suc h as sen sitiz ation an d c l ass i ca l con d ition in g in Aplysia ( s e a s l ug s). 3 Aplysia was therefore u s e d by Dr. Thomas Carew an d co l l e a g ues to investig ate the effect of m o l e c ul es PKA an d mitog en a cti vated p rotein k in ase (MA PK ) on m e m o ry for mation . I n their stud y, s e roto n i n rel ease was in d uced by ta i l n e rve shoc k (TN S) to the sea s l u g , l e a d in g to activation of PKA a n d MA PK sig n al in g cascad es l in ked to l e a r n in g an d memory for mation .

The res ul ts sug g est that var iation s i n th e i nteraction s b etween MA PK a n d P KA cause d ifferent typ es of m e m o r i es to for m. For examp l e, in s ho rt- te r m memor ies, n o interaction wi th MAPK occ ur red ; on l y PKA was a cti ve. I n contrast, in inter med iatea n d l o n g -ter m memor ies, b oth MA PK a n d P KA activ ity was p resent .2 Th e s tu dy p rov id es in sig ht into how MA P K a nd PKA are sp atiotemp oral l y a r ra n g e d in a sin g l e n euron to fa c i l i tate syn aptic p l astic ity, u l ti m atel y l ead in g to memory fo r m ati on . This researc h n ot on l y offe rs g reater un d erstan d in g into the m o l e c u l ar arc hitecture of memory fo r m ati on , b ut it al so p aves the way fo r the eventual d evel op ment of the rap eutics targ etin g rel ated d i s e as es, suc h as retrog rad e a m n es i a.

2. Karow M, Sánchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascón S, Khan MA, Lie DC, Dellavalle A, Cossu G, Goldbrunner R, Götz M, Berninger B. Reprogramming of pericytederived cells of the adult human brain into induced neuronal cells. Cell Stem Cell 2012;11(4):471-476.

3. Berninger B, Costa MR, Koch U, Schroeder T, Sutor B, Grothe B, Götz M. Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia.

J Neurosci 2007;27(32):8654-8664.

4. Nushimune Laboratory. Mouse Hippocampal Neurons [Image on the internet].

Available from: http://www.indkc.org/ images.html [Accessed 10th Nov 2012]

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1. Southwell DG, Paredes MF, Galvao RP, Jones DL, Froemke RC, Sebe JY, Alfaro-Cervello C, Tang Y, Garcia-Verdugo JM, Rubenstein JL, Baraban SC, AlvarezBuylla A. Intrinsically determined cell death of developing cortical interneurons. Nature 2012;491(7422):109-113.

2. Human Embryo [Image on the internet].

Available from: http://www.dailygalaxy. com/my_weblog/2009/03/the-worldsfi-1.html [Accessed 10th Nov 2012].

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1. Cyranoski D. DNA-swap technology almost ready for fertility clinic. Nature.

[Online] October 24 2012. Available from: http://www.nature.com/news/ dna-swap-technology-almost-ready-forfertility-clinic-1.11651 [Accessed 28th October 2012].

2. Tachibana M, Sparman M, Sritanaudomchai H, Ma H, Clepper L, Woodward J, Li Y, Ramsey C, Kolotushkina O, Mitalipov S. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009;461(7262):367-72.

3. The Associated Press. Embryo from 2 women and 1 man made in lab.

Canadian Broadcasting Corporation.

[Online] October 24 2012. Available from: http://www.cbc.ca/news/health/ story/2012/10/24/parent-embryo.html [Accessed 28th Oct 2012].

4. The Ladder [Image from the internet].

Available from: http://www.esotericonline.net/group/dna [Accessed 10th Nov 2012].

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1. Michel M, Kemenes I, Muller U, Kemenes G. Different phases of long-term memory require distinct temporal patterns of PKA activity after single-trial classic conditioning. Learn Mem 2008;15(9):694702.

2. Ye X, Marina A, Carew TJ. Local synaptic integration of mitogen-activated protein kinase and protein kinase A signaling mediates intermediate-term synaptic facilitation in Aplysia. PNAS 2012;109(44):18162-7.

3. Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, McNamara JO, White LE. (eds.) Neuroscience. 4th ed.

USA: Sinauer; 2007.

4. Forgotten Memories Linger in the Brain [Image from the internet]. Available from: http://scienceline.org/2009/11/ forgotten-memories-linger-in-the-brain [Accessed 10th Nov 2012].

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HUMNA AMJ AD

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1. Lujan E, Chanda S, Ahlenius H, Südhof TC, Wernig M. Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. PNAS 2012;109(7):2527-2532.

medbulletin

K IMIA S O R O UR I

3. Adipose Connective Tissue [image on the internet]. Available from: http:// sciweb.hfcc.edu/Biology/AP/134/lab/ lab%20guide%20images/Histology/adipose.ct.html [Accessed 10th Nov 2012]

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interview spotlight

INTERVIEW SPOTLIGHT

dr.patangi rangachari

Growing up, I spent four years in a school run by the Irish Christian Brothers whose approach to education was very simple: they simply caned their students. To add to this, they basically had no concept of teaching science. So, initially, I had absolutely no interest in science and wanted to be a historian. However, one of the papers that we had to study dealt with the development of science and I began to realize that it wasn’t as dull as my teachers were desperately making it out to be; it actually had a rich history. Soon afterward, I started to negotiate with my chemistry teachers to let me take test tubes home. I set up a lab at home where I could do chemistry experiments, [and make] The Meducator recently sat down with Dr. Patangi Rangachari, telescopes and microscopes. Basically, my teachers Professor (Emeritus) of Medicine at McMaster University and had nothing to do with my sudden interest in 3M National Teaching Fellow, to discuss his experiences as a science. A classmate who went on to become a professor and his perspective on health professional education. distinguished organic chemist was the true spark. I From his policy of “drift” to the notion of a “pluripotent wanted to become a chemist, but my attempts were student”, Dr. Rangachari emphasized that students should be de-railed by a bureaucratic blunder and the only in no rush to make their career choice. He shared his insight spots open were in a pre-med program. However, into the purpose of learning and described the potentially I soon realized that the chemistry that I wanted detrimental effects of not choosing the right “mental country”. to do was actually biochemistry, and the only way

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FINDING THE RIGHT MENTAL COUNTRY

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Could you provide us with some background on your education, from when you were a student to your career now as an educator?

Dr. Patangi Rangachari lecturing first year students in a cellular biology class at Health Sciences Centre, McMaster University

Your experiences suggest that students have a lot to gain from not rushing to begin their career.

What are your thoughts on the increasing number of students moving to professional education before finishing their undergraduate degree?

One of my students came to see me at the end of her second year in the B.H.Sc. Program, as she was interested in applying to medical school. I knew she was a terrific

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Although I did my Ph.D. in Edmonton, I desperately wanted to go to California because this was an exhilarating time and San Francisco was the place to be.

At the research institute, I worked amongst outstanding scientists – the atmosphere was absolutely giddy with excitement. I went on to Paris, then India, and back to Paris. While in France, my former Ph.D. supervisor,

who had moved to Hamilton, had invited me to come to McMaster. I only came because I got a scholarship from the Canadian Heart Foundation. To be honest, I thought the concept of problem-based learning in the medical school here was a joke, but that was before I sat in on a tutorial. I saw students arguing passionately about complicated topics, but when I asked my supervisor how many classes in pharmacology the students had taken, he said none – the students were just learning it on their own. Absolute revelation and I got completely hooked.

In between then and now, I went to Harvard and came back but there was a phase transition and I moved into education.

interview spotlight

I could do this was to first get into a medical school.

So I drifted into medical school without any intention of helping anybody. This school had an amazing array of teachers. My biochemistry professor had received his doctorate working with Jacques Monod, who had discovered the lac operon, and my professor of physiology had studied at Oxford, and was one of the world’s premier sensory physiologists and a personal friend of Hodgkin, Huxley, Sanger and other eminent scientists.

These were the people that were at the cutting edge of research. It was exhilarating to be around these people, and their enthusiasm was very infectious. By contrast, the clinical years were dreadfully dull. In fact, after I was done my studies, I dumped my stethoscope in the bin. I was hoping to stay and get my post-graduate degree, but India is always filled with politics and so I was advised to leave because I would not have been able to survive there with all the tensions. I started looking for spots to go to, and ended up in Edmonton, at the University of Alberta.

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kid, and I replied, “Are you nuts?” She said that she would be losing one year. I asked, “What exactly are you going to be losing?” I eventually dissuaded her from applying. And afterwards, she did one of my later courses and she said she was glad she stayed.

Where is the hurry? All of the best students I’ve had in the medical program came in with a range of experiences. One was a lawyer working in Ethiopia with refugees. She drifted and got interested in health while she was practicing law.

Another was a businesswoman with a million dollar portfolio in California. When one of her close friends died of AIDS, she got involved in palliative care, and suddenly had another way of looking at the world. The point is these are not ordinary professions. These require multiple proficiencies in dealing with many different things and there is no hurry. Ask yourself what you are going to do with that extra year. There is an old story about a Chinese philosopher who landed in New York. The taxi driver dragged the philosopher into his cab and raced through the streets of Manhattan and got him to the hotel. The driver remarked, “I did it in one less minute”. The philosopher then asked, “What are you going to do with that extra minute?”

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interview spotlight

What skills should undergraduate science students acquire before graduating and pursuing higher education?

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I want students to be like pluripotent stem cells: “educatorblasts” that can differentiate in any environment. I mean, just look at my own life. I wanted to be a historian and ended up being a pharmacologist. I just navigated my way through life. People have to be pluripotent because times change, positions change, and avenues of exploration discontinue.

Dr. Patangi Rangachari is an expert on problem-based learning at McMaster University.

He believes in allowing students to explore answers to their questions, free from the constraints of traditional lecturing and testing. As a professor emeritus, he continues to share his enthusiasm for trying non-conventional educational approaches with students in the Bachelor of Health Sciences program. He also recently published a book titled Students Matter: The Rewards of University Teaching, with 12 other educators from around the world.

The next generation of physicians has been trained in an extremely competitive environment due to sheer numbers alone. Would you say that these doctors are part of a well-filtered group or would you say the current competition is producing a more homogenous population of doctors?

The point is that these doctors are filtered against one set of criteria. There is a very interesting writer by the name of Freeman Dyson who by profession is a particle physicist. In his book Disturbing the Universe, he writes about the fact that the great phase transitions in our world have happened because the rules of the game have changed. These are qualitative, not quantitative, shifts. We did not get the Agricultural Revolution because we had more intensive, better-trained hunter gatherers. He has commented on the rapidity with which a dominant technology that appears permanent, disappears to be replaced by another. These

phase transitions produce radical societal changes.

Evolution works this way: the niche changes, and living beings adapt. And now, by actually selecting people for one pathway, we are preventing them from adapting to a changing environment. By having excessive criteria for selecting “in-ness”, we forget that the rules of the game will change. We didn’t get the computer revolution because we had better valves; we started changing the valves into semi-conductors. We didn’t get better photographs because we had better film; we changed the way that images are captured.

So yes, you need intensive training but progress depends on the margins of incomprehensibility. Phase transitions are going to happen. You are not going to be able to predict what will happen, but you can develop a mindset that is ready to take advantage of the circumstances.

That’s what I mean by being pluripotent: to have the skills necessary to navigate your way through life.

Students Matter: The Rewards of University Teaching, a book you co-wrote with 14 other biomedical scientists and educators from around the world, was recently released.

Could you provide our readers with some background on the motivation for writing this book?

The idea of this book started when Dr. Howard Barrows, the “inventor” of the simulated patient approach and one of the early proponents of problem-based learning, was alive. We often met to talk about teaching. Some books on education at the time claimed that university Dorsey JK, Rangachari PK, Barrows HS, professors neglected Brink CB, Costa MJ, Duffin JM, et al., students and focused editors. Students Matter: The Rewards of University Teaching. 1st ed. Carbondale: more on their own SIU School of Medicine; 2012. research priorities. We wanted to counter that argument and point out that many practicing scientists are not only serious about their own research, but also spend a lot of time teaching and improving the learning experience for students. Teaching is not simply an addon, but a key component of what we do on a daily basis.

It is an obligation. In this book, we wanted to share our experiences in teaching, discuss why we became teachers, and inspire others to teach.

interview spotlight

Filtering is fine and I have no problem with it. But don’t be too satisfied that you have done a good job with a filter. In a sense, all these filtering mechanisms are like the passport and immigration processes. A lot of these people getting into medical school are in a sense immigrating to a new country. They are so busy trying to fill the forms and get the visas that they never ask the question of whether or not they should actually go to the country. And once they are there, all the disappointment begins and they realize that maybe this is the wrong place to be. This is exactly like getting into medical school. You do your MCAT, do the pre-requisites, kill yourselves getting high GPAs, fill out forms and get into medical school. A lot of medical residents are facing mental dilemmas and issues now because fundamentally they should not be doctors. They got into medical school because they had worked and prepared themselves but they never asked, “Is this the right country for me?”

about. You’re going to be in that mental space for the next 50 years of your life. And you need to think about that mental space. It’s not easy to do.

I find life exciting because I got into the country I wanted to be in. Not just Canada; the mental country I want to be in. And that’s what students should think

interview conductors

ILIA OSTROVSKI

Bachelor of Health Sciences, Class of 2014

SHELLY CHOPRA

Bachelor of Health Sciences, Class of 2014

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HUMNA AMJAD

Bachelor of Health Sciences, Class of 2015

8

OPINION

Tumour heterogeneity and treatment: ONE STEP FORWARD OR TWO STEPS BACK? Branavan Manoranjan Bachelor of Health Sciences (Honours) Alumni, Class of 2011 M.D./Ph.D. Candidate, Michael G. DeGroote School of Medicine

MOHSIN ALI

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opinion

Bachelor of Health Sciences (Honours) Continuing Student, Class of 2012

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T

he pillars to establish cancer as a genetic disease began to be built in 1890 with David von Hansemann’s description of mitosis in 13 different carcinoma samples.1 Observing under a microscope, he found anomalies such as multipolar mitoses and asymmetric distribution of chromosomes, and postulated that aberrant cell divisions were responsible for the change in chromatin content found in cancer cells. After the turn of the century, in 1914, Theodor Boveri detailed these cytogenetic anomalies, suggesting that an incorrect combination of chromosomes generates a proliferative malignant cell, which is then capable of passing these functional defects to its daughter cells.2 The foundation of cancer as a genetic disease was laid.

The pathophysiology of cancer was explored using light microscopy in the ensuing decades, leading to the identification of morphological—i.e., histopathological— differences within and between tumours. Such intratumour and intertumour heterogeneity was linked to disease prognosis and risk-stratification for therapeutic interventions. For example, in medulloblastoma (MB)— the most frequent malignant paediatric brain tumour— morphological differences among tumour cells separate this childhood brain tumour into five histological subtypes: classical, desmoplastic/nodular, MB with extensive nodularity, anaplastic MB, and large-cell MB.3 Patients with anaplastic and large-cell MB tend to be stratified into the high-risk subgroup, whose treatment consists of higher doses of radiation and longer cycles of chemotherapy.4 Therefore, heterogeneity as determined by histology was used to guide treatment prior to the advent of genomic high-throughput sequencing in the late twentieth century.

opinion M E D U CATO R | D E C E M B E R 2 0 1 2

Unfortunately, data collected over the past 50 years for various general public, the age of molecular-subtype-guided therapy cancers, including MB, indicate inconsistencies in clinical brings hope of a new world in which patients will undergo outcomes based on histopathological subtypes.4 Although a needle biopsy of a tumour in an outpatient clinic, followed the cellular architecture of a tumour when viewed under a by a rapid turn-around in which an active treatment will be microscope may provide clues into regional changes in tumour devised on the basis of the distinct genetic characteristics cell phenotype, one may not appreciate the genomic landscape of their tumour. However, serious flaws exist in this of the tumour. Robert Weinberg’s discovery in 1982 of the portrayal of oncology treatment: this depiction considers first oncogene,5-6 Ras, in bladder carcinoma cell lines, shifted only intertumour heterogeneity—the molecular differences the therapeutic framework for cancer from histology-based between tumours—and does not incorporate recent to one guided by identifying genomic anomalies. Within oncological research suggesting an underestimation of the the last decade especially, several solid tumour malignancies heterogeneity within a tumour, intratumour heterogeneity. (breast,7 colon,8 and brain4,9) have benefitted from molecular techniques that analyze the DNA fingerprints of a tumour— A critical appraisal of the current practice of molecular e.g., high-throughput gene expression microarray, DNA subtyping to characterize intertumour heterogeneity copy number, and transcriptome analyses. These genomic to personalize anticancer treatments bears two major platforms have discovered countless somatic mutations, copy limitations. First, the molecular profile used to describe an number alterations, and cytogenetic anomalies that cluster entire tumour is based upon a single, small specimen of the tissue-specific tumours into various molecular subgroups.4,7-9 bulk tumour. This assumes the genomic landscape of the MB, again, serves as a prime example. tumour is consistent throughout the Its recent classification based on entire mass, a concept that is challenged genomic differences re-conceptualized by recent investigation.11 Second, genetic Although tumours may and cytogenetic anomalies identified by the heterogeneity that exists within arise from different subtyping have yet to be investigated in the five histopathological subtypes,4 while contextualizing the role of key terms of their functional significance, tissues—e.g., breast, developmental cell signalling pathways. that is, whether such mutations pancreas, or cerebellum Specifically, the current consensus for the significantly alter—whether reducing (in the case of MB)— molecular classification of this childhood or enhancing—protein function.11 These brain tumour consists of four subgroups, limitations are compounded by our they are, in fact, unique each distinct in terms of prognosis rudimentary knowledge of the extent of diseases as indicated and predicted therapeutic response.4 intratumour heterogeneity at the genetic Groups 1 and 2 are characterized by and epigenetic levels, since current gene by their molecular upregulation of genes in the Wnt expression platforms cannot resolve subgroups. These findings and Sonic hedgehog (Shh) pathways, differences in mRNA expression or suggest the need for respectively. These two subgroups are DNA copy number alterations between separated from each other and other individual cells of the same tumour. personalized therapy subgroups using bioinformatics and targeted against the both are associated with improved Charles Swanton’s group from Cancer clinical outcomes. Groups 3 and 4, Research UK’s London Research particular anomalies in comparison, are characterized by Institute recently shed light on present in a given intratumour heterogeneity using a greater propensity for metastatic subgroup. disease and poor clinical outcomes. deep-sequencing technologies, which There has not been a signalling-pathway assess genetic differences at the singlephenotype attributed to Groups 3 and 4 nucleotide level.12 They examined and, therefore, they remain poorly understood. multiple tumour biopsy samples from four consecutive patients with metastatic renal carcinoma before and The identification of unique molecular subgroups speaks after cytoreductive nephrectomy, a surgical treatment for to the wide range of intertumour heterogeneity in cancer. kidney cancer patients. The results were quite astounding.

Although tumours may arise from different tissues—e.g., Multiregional genetic analysis of the four tumours showed breast, pancreas, or cerebellum (in the case of MB)—they intratumour heterogeneity in every tumour: 65% of somatic are, in fact, unique diseases as indicated by their molecular mutations found in single biopsies were not uniformly subgroups. These findings suggest the need for personalized detectable throughout all sampled regions within the same therapy targeted against the particular anomalies present tumour. The most concerning finding was their detection in a given subgroup. The clinical utility of this hypothesis of gene expression signatures that indicated both good and is being assessed through preliminary trials exploring the poor prognosis in different regions of the same tumour. These use of Shh pathway inhibitors in patients with Shh-driven findings have major implications for oncology treatment, Group 2 MBs.10 This drive for personalized medicine in cancer which is currently moving toward therapy driven by various treatment encourages further segregation of subgroups into gene expression platforms that may not account for this subtypes, as is the case for Group 3 MB: high-risk patients intratumour heterogeneity. With respect to MB, these results are stratified into those with amplification of the MYC suggest that a tumour may appear to have a Group 2 Shhgene (Group 3α), and those without it (Group 3β).4 To the driven MB profile in one region based on transcriptome

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1.

von Hansemann D. Ueber asymmetrische Zelltheilung in Epithelkrebsen und deren biologische Bedeutung. Virchow’s Arch Path Anat. 1890;119(2):299326.

2. Boveri T. Zur Frage der Entstehung maligner Tumoren. Jena, Germany: Gustav Fischer; 1914.

3. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114(2):97-109.

4. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012;123(4):465-472.

5. Shih C, Weinberg RA. Isolation of a transforming sequence from a human bladder carcinoma cell line.

Cell 1982;29(1):161-169.

6. Parada LF, Tabin CJ, Shih C, Weinberg RA. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene.

Nature 1982;297(5866):474-478.

7. Cancer Genome Atlas Network.

Comprehensive molecular portraits of human breast tumours. Nature 2012;490(7418):61-70.

opinion

8. Cancer Genome Atlas Network.

Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487(7407):330-337.

9. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.

Cancer Cell 2010;17(1):98-110.

10. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM, Von Hoff DD, de Sauvage FJ, Low JA Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009;361(12):1173-1178.

11. Swanton C. Intratumor heterogeneity: evolution through space and time. Cancer Res 2012;72(19):4875-4882.

12. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883-92.

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13. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM. Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006;66(19):9339-9344.

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14. Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV, Chomienne C, Ishikawa F, Schuringa JJ, Stassi G, Huntly B, Herrmann H, Soulier J, Roesch A, Schuurhuis GJ, Wöhrer S, Arock M, Zuber J, Cerny-Reiterer S, Johnsen HE, Andreeff M, Eaves C. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer 2012;12(11):767-775.

15. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature 2004;432(7015):396-401.

analysis, but may be a Group 3 or Group 4 MB in other regions of the tumour. Therefore, decisions based upon a single tumour biopsy, the standard for tumour diagnosis and the cornerstone of personalized medicine, cannot be considered representative of the landscape of genomic abnormalities in a tumour.

The question remains: does personalized medicine have a role in oncology? Interestingly, the work done by Charles Swanton’s group confirms the presence of genetic lesions expressed in the original tumour cells that are consistent across the majority of cells within the bulk tumour.12 Therefore, if one was to target these so-called actionable mutations,11 thought to be early drivers of disease leading to the ubiquitous somatic events present in every tumour subclone and region, one may effectively target the top of the tumour’s genomic hierarchy. However, the difficulty remains in discerning such actionable mutations from other mutations that have evolved over the course of tumourigenesis, responding to cues received within the tumour milieu. One likely and possible approach is to combine the breakthroughs made in cancer genomics and stem cell biology. The cancer stem cell (CSC) hypothesis suggests that a relatively small fraction of tumour cells, termed CSCs, initiate

and maintain tumour growth.13-15 They contrast with other cells of the bulk tumour, which are characterized by a limited proliferative capacity and a more specified lineage potential. A CSC maintains two key properties: self-renewal and differentiation.13-15 Self-renewal is defined as the ability of a parental cell to generate an identical daughter cell, and a second cell of the same or different phenotype. Through the process of differentiation, a CSC gives rise to the heterogeneous cell lineages that comprise the tumour. Consequently, by isolating tissuespecific CSCs through unique cell-surface proteins, one may comparatively profile the genetic landscape of the CSC with those cells of the bulk tumour mass, thereby identifying actionable mutations at the top of the genomic landscape, in cells (CSCs) at the top of the tumour hierarchy.

The identification of intratumour heterogeneity may appear to have brought cancer treatment two steps back. But the future outlook for patients might now include more efficacious, novel therapeutic targets at cell-specific actionable mutations, potentially moving the field of oncology, in terms of understanding tumour biology and personalized medicine, one giant leap forward.

MACABSTRACTS

Effect of neurofibrillary tangles on behavioural flexibility in rats: animal models for fronto-temporal dementia and Alzheimer’s disease

Neurofibrillary tangles (NFTs) are aggregations of abnormal tau protein implicated in neurodegenerative diseases such as behaviouralvariant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD), dementias that exhibit a large degree of symptom overlap.

NFTs are prominent in the prefrontal and entorhinal cortices in early-stage bvFTD and AD, respectively. We modeled this sitespecific neurodegeneration in rats via microinjection of a viral vector to express an excess of mutated tau protein in these target areas. We then examined the impact of this somatic gene transfer on performance in the following behavioural flexibility task. The rats were initially trained to find food rewards in a plus maze using a place strategy: to always go to the same place in the environment, i.e., north or south. Subsequently, they switched to a response strategy: to always make the same body response, i.e., turn right or left. Rats

Spinal cord injury affects millions across the globe, and its prevalence is rising with the increasing rate of accidents. Not much is known regarding the cellular mechanism of injury, and, unfortunately, there are few viable treatment options. One option may be transplantation of peripheral nerves into the site of injury, but the peripheral nervous system is not readily accessible, and doing so could disrupt the functioning of other areas. One part of the nervous system, however, is accessible: the enteric system, embedded in the lining of the gastrointestinal tract. This system bears similarities to the central nervous system, has remarkable plasticity, and releases growth factors, which not only facilitate regeneration of neurons, but also protect the

Compound 186 is a negative allosteric modulator of dopamine D2 receptors: Implications for improving schizophrenia therapy

Department of Psychology, University of Toronto; Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center 1

2

made a total of six switches between place and response strategies, and their acquisition and retention of each switch was measured and compared to controls. We found that bvFTD model rats could acquire the place strategy, but were impaired when acquiring the response strategy. AD model rats were impaired in acquiring both strategies.

For both groups, there were no impairments in retention of either strategy. Together, these findings suggest patterns of performance on a behavioural flexibility paradigm can differentiate between animal models of early bvFTD and AD. Future research can use these findings to screen novel candidate drugs, and study mechanisms underlying AD and bvFTD.

*Correspondence should be addressed to: pallavi.sriram23@gmail.com

Dhara Shah*, Cai Jiang, Kiran Reddy, Caixin Su, Shucui Jiang Division of Neurosurgery, Department of Surgery, McMaster University

enteric nervous system from damage. Previous research shows rat enteric glial cells induce regeneration in rodent neurons in vivo with a crushed spinal cord and in vitro to dorsal root ganglia treated with semaphorin-3A to mimic spinal cord injury. We study whether human enteric glia bear similar effects in vitro on rodent dorsal root ganglia.

Our experiments to date show this treatment is viable, emphasizing its use in clinical trials. It proves to be a particularly successful transplantation technique since the donor cells originate from the host, thereby minimizing the chance of rejection.

macabstracts

Human enteric glial cells alleviate damaged adult sensory neurons in rats

Pallavi Sriram1, Mark Morrissey1, Stephanie Tanninen1, Geith Maal-Bared1, Ronald L. Klein2 AND Kaori TakeharaNishiuchi1

*Correspondence should be addressed to: dhara1989@hotmail.com Jayant Bhandari*1, Jordan Mah2, Ritesh Daya3, Rodney L. Johnson4, Ram K. Mishra3 Departments of Biology, 2Biochemistry and Biomedical Sciences, and Psychiatry and Behavioral Neuroscience, McMaster University; 4 Department of Medicinal Chemistry, University of Minnesota 1

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1: neurofibrillary tangles

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Excessive dopamine transmission in the striatum via the dopamine D2 decrease in NPA binding with compound 186, in a dose-dependent receptor (D2R) has been implicated in inducing the so-called positive manner. Our study suggests a potential method to treat dopaminergic symptoms of schizophrenia (e.g., hallucinations, delusions). While disorders such as schizophrenia. Because many current treatments for antipsychotic drugs alleviate these symptoms by blocking the active schizophrenia block the active site of D2R elicit severe side effects, site of this receptor, drugs known as allosteric modulators could also such as tardive dyskinesia and diabetes, it is important to consider decrease dopamine’s ability to bind this receptor by binding to an changing the therapeutic approach from using antagonists to allosteric allosteric site on D2R. We evaluated the ability of a newly synthesized modulators. molecule, compound 186, to modulate the binding of tritiated norpropylapomorphine (NPA)—a high-affinity D2R agonist—in the bovine *Correspondence should be addressed to: jayantkbhandari@gmail.com striatum. Through receptor binding assays, we found a significant

Image from: http://www.newswise.com

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FORUMSPACE

Canada’s Aging Population

SHOULD STUDENTS BE WORRIED?

forumspace

EMILY MILKO AND SHERNA TAMBOLY Emily Milko is a fourth year student in the Honours Arts & Science program doing her thesis in the field of health policy. Sherna Tamboly is a fourth year Bachelor of Health Sciences student with a specialization in global health. Both are McMaster Health Forum Fellows for this academic year and are co-chairs of the McMaster Health Forum Student Subcommittee.

The Problem Seniors, aged 65 and over, are the fastest growing group in Canada and are projected to represent one-quarter of the population by 2051.1 This demographic trend prompts a pressing need for a comprehensive care system to address the unique physical, functional, and social needs of a heterogeneous aging population.2 In order for the health system to both adapt to meet these needs and maintain financial sustainability, there needs to be evidence-informed policies and sustainable reforms.3

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Current Solutions: Need for Change

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Integration Networks and Community Care Access Centers (CCACs) were allocated funding to enhance home care services, and consequently reduce the reliance of older adults on hospitals and long-term care homes.4 This strategy also aimed to reduce the number of “alternate level of care” patients – hospital inpatients – who can receive better quality care at long-term care facilities, at rehabilitation facilities, or in their own homes.7 However, investigations have found that thousands of seniors have insufficient access to home care, forcing them and their families to pay out-of-pocket for all or part of the services.8 Additionally, CCACs have been forced to cut back hours of care due to budget constraints.8 Between 2005 and 2008, there was a 129% increase in the wait times for placement into long-term care homes.4 As a result, thousands of seniors were forced to rely on hospital care, which cost the province approximately nine times the cost of home care per day.8

Despite having comprised only 13.7% of Ontario’s population in 2008, those aged Homegrown Solutions: 65 and over consumed approximately 44% What IS being done at of Ontario’s provincial health spending.4 McMaster This places considerable pressure on a cashstrapped province already struggling to This pressing health challenge is being eliminate a $14.4 billion deficit and to curb addressed at McMaster University with a unsustainable spending.5 To provide high- number of evidence-informed initiatives. In quality and accessible healthcare services November 2011, the McMaster Health Forum to older adults, Ontario had invested $1.1 convened a stakeholder dialogue entitled billion over four years, starting in 2007, “Organizing a Care System for Older Adults with its Aging at Home Strategy.6 Through in Ontario”, which discussed how to support this strategy, Ontario’s 14 Local Health optimal aging in Ontario. First, there is a

Though students might feel too young to worry about chronic disease and aging, it is never too early to engage in preventive measures to ensure optimal aging, such as regular activity and good nutrition.

TABLE 1: How will the aging population affect students?

Students have parents or grandparents who are already, or will soon be, navigating the health system to aid in optimal aging, and by association students will be affected by the challenges their parents and grandparents may face with the health system.

Students will soon be entering the workforce, and with greater responsibility comes higher taxes paid to the government. Thus, their money will finance the health system for older adults, and students should ensure they are informed to ensure its effective and efficient use.

with arthritis, and better car designs for older drivers and passengers, among others.11

Conclusion There is a vast amount of research that has been and will continue to be done to support the aging population in making evidenceinformed decisions and in receiving evidence-informed treatment, care and support. This paints a much less threatening future for Canada’s older adults, who can feel confident in knowing they will receive the best possible care, and also for students who, as future members of the workforce, can be confident in knowing that research and proper planning can help offset the looming economic and social impacts of the aging population.

1. Aging with dignity. The Globe and Mail 2012 Sep 9.

2. Carstairs S, Keon WJ. Canada’s Aging Population: Seizing the Opportunity. Ottawa, Canada: Special Senate Committee on Aging; 2009.

3. Canadian Health Services Research Foundation. Synthesis Report Better with Age: Health Systems Planning for the Aging Population.

Ottawa, Canada: Canadian Health Services Research Foundation; 2011.

4. Wilson MG, Lavis JN. Evidence Brief: Organizing a Care System for Older Adults in Ontario. Hamilton, Canada: McMaster Health Forum; 2011 Nov 14.

5. Ontario deficit to be $14.4B this year: Duncan. CTV News 2012 Oct 15.

6. Ontario Ministry of Health and Long-Term Care. Aging at Home Strategy. Toronto, Canada: Ontario Ministry of Health and Long-Term Care; 2010.

7. Walker D. Caring for our Aging Population and Addressing Alternate Level of Care. Toronto, Canada: Ontario Ministry of Health and Long-Term Care; 2011 Jun. 8. Boyle T, Welsh M. Seniors find little care in provincial aging strategy.

The Toronto Star 2011 Feb 18.

9. Wilson MG, Lavis JN. Dialogue Summary: Organizing a Care System for Older Adults in Ontario. Hamilton, Canada: McMaster Health Forum; 2011 Nov 14.

10. McMaster Health Forum. Five partners at McMaster will establish one-stop source for information and tools related to healthy aging.

Hamilton, Canada: McMaster Health Forum; 2012 Sep. 11. Davis, SS. With $10-million gift, McMaster embarks on study of ‘optimal aging’. The Globe and Mail 2012 Sep 7.

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In the year since the dialogue, McMaster has made huge strides in addressing optimal aging, highlighted by the $10 million Suzanne Labarge donation to McMaster to support research and knowledge translation focused on optimal aging. Part of the donation will be used towards a project led in part by the Forum, for the creation of the McMaster Optimal Aging Portal to make high-quality research evidence available to citizens, providers and policymakers in accessible languages.10 Additional projects funded by this donation include research into the benefits of yoga for older women

EFFECT

forumspace

need for individualized FACTOR self-management support for older adults and their families, outside of the PREVENTION medical model of acute care, in ways that support healthy aging.

This includes physical activity FAMILY TIES and even the effective use of smart-phones, tablets and other technologies.

Secondly, there is a need to coordinate integrated MONEY healthcare services to support healthy aging, such as modifying existing funding and remuneration models to support healthcare providers to better manage complex and chronic conditions. Lastly, there is the need to coordinate accessible and diverse community resources built around the needs of older adults.9

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RESEARCH INSIGHT

Preventing Iron-Deficiency Anemia in Children in Developing Countries WHY IT IS NECESSARY AND HOW IT MUST BE APPROACHED

NUPUR DOGRA Bachelor of Health Sciences (Honours), Class of 2013 Correspondence should be addressed to: nupur.dogra@learnlink.mcmaster.ca

ABSTRACT ABSTRACT Iron deficiency (ID) has been identified as the most common nutritional deficiency condition in the world, with a high prevalence in both developed and developing countries.

ID and iron-deficiency anemia (IDA) affect the cognitive, socioemotional and motor development of children. Using evidence from 2002 onwards, a literature review of the impact of ID and IDA on child development and the interventions preventing them was conducted. Review of recent evidence presents 1) altered cognitive functions, 2) decreased socio-emotional development, and 3) impediment of motor skills development due to ID and IDA. In conclusion, the effects of ID and IDA on child development are significant and often irreversible. Viable and effective preventive programs, such as iron supplementation, diet diversification, food fortification and early and home interventions, are favoured over curative measures.

Introduction

Objectives of Literature Review

This literature review serves to provide an understanding of the impact of ID and IDA on infant and child development. Infants and children are defined as individuals <2 years of age and >2 years of age respectively. This literature review also provides an overview of the effectiveness of current intervention programs in LMI countries that target IDA in infants and children.

Search Strategy and Selection Criteria The primary literature search was conducted in April 2012. The Ovid database, which included AMED, EMBASE, Global Health, PUBMED, PsychINFO and MEDLINE, was searched for evidence published from 2002 to present.

The following search strategy was applied to the OVID database, which combined the following search terms: • Iron deficiency OR iron-deficiency anemia • (Iron deficiency OR iron-deficiency anemia) AND child development • Child development AND (motor skills OR motor activity OR cognitive development OR socio-emotional development) • (Iron deficiency OR iron-deficiency anemia) AND prevention • (Iron deficiency OR iron-deficiency anemia) AND interventions

The incidence and prevalence of IDA is particularly high among infants, children and adolescents in low- and middle-income (LMI) countries. 33% to 66% of children in developing countries are affected by this nutritional disorder.2 The peak prevalence of IDA occurs among infants, reasons for which have been linked to poorer cognitive, motor and socioemotional development.6 Furthermore, despite iron therapy, infants with severe IDA are unable to reach the same developmental level as nonID and non-IDA infants.7

Limits: Infants and children (0-18 years), English, Humans, 1995 – 2012.

The initial search identified approximately 77 papers that met the review inclusion criteria.

There is a need to After critical appraisal, 10 reviews implement preventive (a combination of systematic programs and and literature reviews) and 8 interventions for primary studies (a combination infants and children of observational studies and in LMI countries randomized controlled trials) were selected for inclusion.

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Iron has an essential role in the formation and function of blood cells in the human body.3 As such, ID can lead to iron-deficiency anemia (IDA).4 According to the World Health Organization (WHO), anemia is defined as having a blood hemoglobin level two standard deviations (SDs) below the mean level for a normal population of the same sex and age bracket.5 IDA results from an imbalance of iron needs and iron intake and absorption. Increased iron needs are often due to rapid growth (during infancy), pregnancy, and blood loss (heavy menstrual periods, frequent blood donations or gastrointestinal conditions, e.g. hookworm).4 Decreased iron intake or absorption are often because of a dietary iron deficiency or inefficient utilization of iron ingested from food.4

research insight

Two billion people – almost 30% of the world’s population – are anemic.1 Nearly half of the cases result from iron deficiency (ID), which is recognized as the world’s most common nutritional deficiency.2

While the burden of ID and IDA is well-documented, the current challenge is to provide adequate control and preventative measures for these conditions.

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IDA in Infants and Children

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research insight

FIGURE 1: Reducing anemia through iron fortification of grain in Udapur, India. image from http://www.povertyactionlab. org/evaluation/reducinganemia-through-ironfortification-grain-udaipurindia

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FIGURE 2: Reducing anemia in rural China through education and nutrition. image from: http://reap.stanford.edu/ docs/nutrition_and_ education

Anemia is estimated to be the direct cause of 134,000 deaths in young children every year.7 The prevalence of anemia among infants between 6 to 9 months of age is alarmingly high in many parts of the world, estimated to be 64-93% in Sub-Saharan Africa, 7085% in Southeast Asia, and 59-75% in Latin America and the Caribbean.8 Of these cases, approximately 50% are the result of ID (IDA).8 IDA prevalence peaks during the ages of 6 to 24 months.6 Rapid development and high nutritional demands during the second six months of life, along with depleting prenatal iron stores, creates vulnerability.

Key factors for ID, and consequently IDA, include dietary factors, elevated iron demands, and the socioeconomic status of infants and children.9 Dietary factors include low iron content in consumed foods and high iron absorption inhibitor content.9 For example, tannin in tea and phytic acid in grain fibres inhibits non-heme iron absorption.10 In Middle Eastern and North African cultures, tea is routinely given to children and infants, which strongly decreases their dietary absorption of iron.3 Moreover, the related socioeconomic status of individuals contributes to the iron levels of infants and children. Limited food availability, inadequate access to health care, poor environmental sanitation and personal hygiene are all socioeconomic factors that increase the prevalence of ID and IDA.9

Cognitive dysfunctions and irregular brain development are worrying manifestations.

Certain regions of the brain, such as the basal ganglia, substantia nigra and deep cerebellar nuclei, require a considerable concentration of iron.2 In addition, the hippocampus is particularly susceptible to ID during the brain growth spurt that occurs between 6 to 24 months of age.13 Many central nervous system (CNS) processes, such as dopamine synthesis, are dependent on iron-containing enzymes, such as tyrosine hydroxylase.14 Consequently, IDA can adversely affect the neuroanatomical and neurochemical processes and has been shown to result in cognitive developmental delays.

Due to these effects, infants with ID and IDA undergo altered behavioural and socioemotional development. In a study by Chang et al., preschool-aged IDA children demonstrated lower frustration tolerance and higher passive and physical self-soothing behaviour during a delay-of-gratification situation.15 Additionally, a separate study linked ID (with or without anemia) with increased shyness, decreased soothability and decreased engagement in infants from 6 to 12 months of age.16

Motor functions depend on basal ganglia processes within the brain.17 Animal model studies suggest that decreased iron changes the density of dopamine receptors in the striatum (part of the basal ganglia), even with iron restoration.17 As such, it is plausible that ID and IDA impede the normal development of The presence of anemia during infancy is motor skills in infants and children. In a study significant as it inhibits normal cognitive, socio- by Shafir et al., IDA infants demonstrated emotional and motor development later in difficulty in toy retrieval tasks requiring life. A study by Shafir et al. indicated that in a sequential movement with bi-manual sample population consisting of Costa Rican coordination. Infants also exhibited delayed and delayed adolescents who had chronic, severe ID (with development of gross motor skills 17 refinement of fine motor skills. or without anemia) during infancy, there are no indications that iron therapy catches them up in terms of motor development.11 Also, the same There is convincing evidence to support cohort exhibited poorer behavioural functions, that ID and IDA affect brain growth, often such as greater anxiety and depressive behaviour, irreversibly. The biological effects of ID and as young adults (19 years of age).11 Evidently, the IDA further impact the socio-emotional and effects of ID and IDA in infancy and childhood motor development of infants and children. extend into adulthood.

Impact of IDA on Cognitive, SociO-Emotional and Motor Development In many studies, IDA has been linked to cognitive and socio-emotional difficulties, as well as poor development of fine and gross motor skills.2,6,12-17

Programs for IDA Prevention

Given that iron deficiency is the most common nutrient deficiency and that there is increasing evidence that ID and IDA cause adverse effects among infants and children, it is imperative that governments, health care providers and parents act to prevent ID and IDA among such a vulnerable population.

According to Huma et al., the three main strategies for ID and IDA prevention include iron supplementation, diet diversification, and iron fortification in food. Supplementation is administered through injections, capsules, and tablets, which provide substantial benefits to infants during their first year of life.18 However, monetary input and costly distribution systems are drawbacks to providing large scale supplementation in LMI countries.9 Furthermore, vulnerable at-risk groups may not have access to supplementation if they inhabit hard-to-reach places or areas of war.9

1. Tulchinsky TH, Varavikova EA. The new public health. 2nd ed. Burlington, MA: Elsevier Academic Press; 2009.

Conclusion

7. Skolnik R. Essentials of global health.

Sudbury, MA: Jones and Bartlett; 2008.

This review demonstrates that iron deficiency and iron-deficiency anemia negatively impact infant and child development. The high prevalence of ID and IDA among infants and children in LMI countries can be attributable to the poor dietary, socioeconomic, and disease conditions in those countries.

The effects of ID and IDA on cognitive, socio-emotional, and motor development are significant and long-lasting. Thus, there is a need to implement preventive programs and interventions for infants and children in LMI countries. This review examined several Fortification of food entails the addition of viable prevention strategies, including diet essential nutrients to staple foods to prevent supplementation, diet diversification and food nutritional deficiencies.20 The majority of fortification. Additionally, this review explored Western countries fortify staple foods, such early and home interventions that may prevent as flour and bread, with iron. LMI countries, ID and IDA in infants and children, such as including Saudi Arabia, Egypt, and Iran have delayed umbilical cord clamping and motheralso begun enriching wheat flour with iron as child interactions. of 2002.9 Since fortification of wheat is simple and inexpensive, it is a major strategy used to Future steps include researching the prevent anemia.1 This may not be successful, methods of ID and IDA prevention program however, if foods are discoloured or poor-tasting implementation in LMI countries. Assessing from the addition of iron, as it may result in these implementation strategies may provide poor consumer acceptance.9 Additionally, one insight into how to reduce ID and IDA study suggests that food fortification alone, prevalence rates. Ensuring iron sufficiency among infants of 4 to 6 months, may not be among infants and children in LMI countries sufficient for ID prevention, and that routine will increase the likelihood for children to iron supplementation may be required.19 be vibrant and productive members of their The WHO also promotes prevention of ID and

communities in the future.

Dr. Isaac Odame is an academic clinician in the Division of Haematology/Oncology and the co-director of the haemoglobinopathy program at The Hospital for Sick Children (SickKids).

As the Medical Director of the Global Sickle Cell Disease Network, he is committed to advancing the research and clinical treatment of sickle cell disease. In particular, Dr. Odame has advocated for improving the management of sickle cell disease in low-income countries.

3.

Semba RD, Bloem MW, editors. Nutrition and health in developing countries. 2nd ed. Totowa, NJ: Humana Press; 2008.

4. Nutrition for Everyone: Basics: Iron and Iron Deficiency [Internet]. Atlanta, GA: Centres for Disease Control and Prevention; [original date unknown; updated 2011 Feb 23; cited 2012 Nov 10]. Available from: http://www.cdc.gov/nutrition/ everyone/basics/vitamins/iron.html 5. Baker RD, Greer FR, The Committee on Nutrition. Diagnosis and prevention of iron deficiency and iron-deficiency a in infants and children (0-3 years of age).

Pediatrics. 2010;126(5):1040-50.

6. Lozoff B. Iron deficiency and child development. Food Nutr Bull.

2007;28(4):S560–S571.

8. Chaparro CM. Setting the stage for child health and development: prevention of iron deficiency in early infancy.

J Nutr. 2008:138;2529–33.

9. Huma N, Rehman SU, Anjum FM, Murtaza MA, Sheikh MA. Food fortification strategy – preventing iron deficiency anemia: a review. Crit Rev Food Sci Nutr. 2007:47;259–265.

10. Christian P. Iron deficiency and anemia: causes, consequences, and solutions. Proceedings of the International Nutrition; 2005: Baltimore, MD: Johns Hopkins Bloomberg School of Public Health; 2006.

11. Shafir T, Angulo-Barroso R, Calatroni A, Jimenez E, Lozoff B. Effects of iron deficiency in infancy on patterns of motor development over time. Hum Mov Sci 2006: 25;821–38.

12. Yadav D, Chandra J. Iron deficiency: beyond anemia. Indian J Pediatr.

2011:78;65–72.

13. Beard JL. Why iron deficiency is important in infant development. J Nutr.

2008:138;2534–36.

14. Grantham-McGregor S, Ani C. A review of studies on the effect of iron deficiency on cognitive development in children. J. Nutr. 2001:131;649S–668S. 15. Chang S, Wang L, Wang Y, Brouwer ID, Kok FJ, Lozoff B, et al. Iron-deficiency anemia in infancy and social emotional development in preschoolaged Chinese children. Pediatrics.

2011:127(4);e927-e933.

16. Lozoff B, Clark KM, Jing Y, ArmonySivan R, Angelilli ML, Jacobson SW. Dose-response relationships between iron deficiency with or without anemia and infant social-emotional behavior. J Pediatr. 2008:152;696-702.

17. Shafir T, Angulo-Barroso R, Jing Y, Angelilli ML, Jacobson SW, Lozoff B. Iron deficiency and infant motor development. Early Hum Dev. 2008:84;479–485.

18. Lozoff B, De Andraca I, Castillo M, Smith JB, Walter T, Pino P. Behavioural and developmental effects of preventing iron-deficiency anemia in healthy full-term infants. Pediatrics.

2003:112(4);846–54.

19. Ghorashi Z, Nezami N, Behbahan AG, Ghorashi S. Supplemental food may not prevent iron-deficiency anemia in infants. Indian J Pediatr.

2008:75(11);1121–24.

20. Phu PV, Hoan NV, Salvignol B, Treche S, Wieringa FT, Khan NC. Complementary foods fortified with micronutrients prevent iron deficiency and anemia in Vietnamese infants. J. Nutr.

2010:140;2241–47.

21. Black MM, Quigg AM, Hurley KM, Pepper MR. Iron deficiency and irondeficiency anemia in the first two years of life: strategies to prevent loss of developmental potential. Nutr Rev. 2011:69(1);S64–S70.

22. Lozoff B, Smith JB, Clark KM, Perales CG, Rivera F, Castillo M. Home intervention improves cognitive and social-emotional scores in irondeficient anemic infants. Pediatrics.

2010:126(4);e884–e894.

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Reviewed by dr. ISAAC ODAME

2. Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol. 2006;13(3):158–165.

research insight

Food-based strategies, such as diet diversification and fortification, appear to be more sustainable and cost-effective options.9 Diet diversification programs include those that provide nutritional education and those that promote improved eating practices. For example, some programs encourage increased intake of iron-rich foods (e.g. meat) and consumption of fruits rich in ascorbic acid (e.g. citrus fruits) as a means of increasing iron absorption.3 These programs also include techniques such as soaking and thermal processing to reduce phytic acid content in whole grains and legumes.9 However, socioeconomic factors may prevent some families from eating according to the diets promoted by such programs.9

IDA through other programs, including early and home interventions.21,22 In a meta-analysis of 15 international control studies, it was found that delayed umbilical cord clamping at birth improves the iron status of infants.21 This practice involves waiting two minutes after birth before clamping the umbilical cord, increasing iron stores in newborn infants.21 Home and early childhood interventions, targeting motherchild interactions, include verbal and non-verbal activities. Developmentally appropriate playtime activities can improve cognitive, socio-emotional, and motor development in infants and children at risk of ID and IDA.22

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RESEARCH INSIGHT

A Gap Analysis of Mental Health and Addictions Support Services in Richmond, BC A COMMUNITY-BASED RESEARCH STUDY

SHELLY CHOPRA Bachelor of Health Sciences (Honours), Class of 2014 Correspondence should be addressed to: shelly.chopra@learnlink.mcmaster.ca

ABSTRACT Across

the research is conducted. The process relies on consultation with resources and expertise based within the community to ensure actionoriented outcomes. 3 The need for community-based research in the area of MHA support services was clearly identified by the RCSAC MHA working group.1 Although focus groups and analyses specific to certain populations had been conducted in the past, no broad gap identification and validation research on MHA services had been undertaken in Richmond prior to this study. The RCSAC recognized the importance of a service gap analysis to ensure that recommendations for future initiatives are based on the informed perspectives of Richmond MHA service providers.

Canada, mental health and addictions (MHA) has become an area of concern for health providers: it is estimated that one in five adults is affected by a mental illness or addiction. In line with the provincial Ministries of Health Services and Child and Family Development ten-year plan to address MHA in BC, a community-based MHA service gap analysis was undertaken in the present study in Richmond, BC. The primary objectives of this research project were to identify and validate gaps in MHA support services in Richmond based on the informed perspectives of MHA community service providers.

In addition to independent and consumer informants, a total of 22 administrators and frontline workers from 10 Richmondbased organizations were interviewed for the purposes of gap validation. Analysis of key informant responses for recurring themes elucidated four main areas of improvement: navigation of MHA services, continuum of support, personalized support, and outreach. Following a meeting among key informants to discuss the results of the current gap analysis, the expectation was raised of developing a strategic action plan to address gaps in MHA service in Richmond, BC.

RATIONALE FOR MHA GAP ANALYSIS

OBJECTIVES

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The objectives of this community research The Richmond Community Services project were: Advisory Committee (RCSAC) consists of governmental and non-governmental 1. To identify gaps and key areas of improvement organization representatives from Richmond, in current MHA support services for adults and British Columbia (BC) that meet to identify youth in Richmond. community concerns relating to social services, 2. To validate identified gaps and areas of and to advise elected officials and staff on improvement in current MHA support services. possible plans of action to resolve the concerns. 3. To initiate the development of a strategic Evaluation of mental health and addictions plan with recommendations for programs and (MHA) support services in Richmond has services designed to resolve validated gaps in been a key topic of discussion during recent current MHA support services.

RCSAC meetings.1 Furthermore, MHA has also become an important area of concern Methods for health providers across Canada. It is estimated that one in five Canadian adults Most gaps in MHA service were identified is affected by a mental illness or addiction during RCSAC meetings. The Richmond that spans the course of 12 months.2 In 2010, Integrated Comprehensive Addictions System, the BC Ministries of Health Services and a precursor table to the RCSAC MHA working Child and Family Development developed group, also identified specific gaps in addictions a ten-year plan to address mental health services. and substance abuse in the province. In line with the vision, goals, and population health MHA service gap validation was principally through approach of this plan, the RCSAC undertook completed a community-based service gap analysis to interviews with representatives from IT IS ESTIMATED THAT identify and validate shortcomings of MHA each partner organization. For most ONE IN FIVE CANADIAN organizations, a frontline worker and ADULTS IS AFFECTED BY support services in Richmond. an administrator were interviewed A MENTAL ILLNESS OR Community-based research is defined by data to systematically capture a broader ADDICTION OVER THE collection and analysis that is relevant to the perspective on the identified gaps. COURSE OF 12 MONTHS development of the community in which All informants were provided with

research insight

Introduction

20

TABLE 1: The following community organizations served as key informants during the data collection and compilation stages of the gap analysis.

the opportunity to confirm the transcription All interviewee responses were compiled into a of their responses via e-mail correspondence, summary table and analyzed on a gap-by-gap allowing for inaccuracies to be rectified. basis. Similar comments concerning gaps and areas of improvement were extracted from the data pool.

PARTNER ORGANIZATIONS

RESULTS AND DISCUSSION Canadian Mental Health Association (CMHA) provides adults with mental illnesses vocational training, employment opportunities, supported education, and recreational programs. Representatives from CMHA Richmond sit on the RCSAC.4 CHIMO Crisis Services provides crisis intervention counseling and prevention workshops about MHA issues for the Richmond community. Representatives from CHIMO Crisis Services sit on the RCSAC.5 Richmond Addiction Services (RASS) offers a range of preventative, consultative and clinical services and programs for youth under 25, families, and seniors facing addictions issues. Representatives from RASS sit on the RCSAC.6

research insight

Richmond Mental Health Consumer and Friends Society (RCFC) offers peerto-peer support and recreational programs to adults with mental illnesses.

Representatives from RCFC sit on the RCSAC.7 Richmond School District (RSD) is the governing body of public elementary and secondary schools in Richmond. The District works in partnership with Vancouver Coastal Health and non-governmental organizations to provide mental health services to youth aged 4 to 18 in school. Representatives from RSD sit on the RCSAC. 8-10 Richmond Youth Service Agency (RYSA) offers youth in Richmond a range of services from Aboriginal programs to leadership and empowerment activities.

Representatives from RYSA sit on the RCSAC.11 The Supporting Families with Parental Mental Illness and Addictions (SFWPMIA) table offers group-based social and recreational programs for parents with mental illness and/or addictions and their children.

Representatives from the SFWPMIA table sit on the RCSAC. The City of Richmond Seniors Services and Social Planning divisions are involved with Richmond MHA service providers. Staff from the City of Richmond act as support to the RCSAC.

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Touchstone Family Association (TFA) offers counseling services, outreach, and social programs to youth and families in Richmond. Representatives from TFA sit on the RCSAC.12

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Turning Point Recovery Society (TPRS) in Richmond provides residential recovery for vulnerable men and women who require support, counseling, and a safe residence. Representatives from TPRS sit on the RCSAC.13 Vancouver Coastal Health Authority (VCH) manages clinical services offered to individuals in Richmond with MHA issues. Representatives from VCH Richmond sit on the RCSAC.14

A total of 27 gaps were identified and validated through key informant interviews. Analysis of informant responses for recurring themes elucidated four main areas of improvement: navigation of MHA services, continuum of MHA support, personalized MHA support, and MHA outreach.

NAVIGATION OF MHA SERVICES The overarching gap in Richmondâ&#x20AC;&#x2122;s current MHA support services, which was agreed upon by most interviewees, was the lack of protocols and pathways for organizations to facilitate easy access to needed services and support for their clients. Currently in Richmond, referral services such as VCHâ&#x20AC;&#x2122;s Central Intake Line utilize both VCH and community resources to meet client needs.

Committees such as the Richmond Collaborative Committee for Children and Youth have non-governmental MHA organizations as members working in collaboration to address the needs of Richmond youth.17 The majority of these committees and services bridge selectively affiliated service providers. However, there is no reliable network, inclusive of all partner MHA governmental and non-governmental organizations in Richmond, for administrators and frontline workers to rely upon for information and referral purposes. Development of a MHA service network in Richmond would allow for the formation of pathways defining the relationship between organizations as well as the protocols to be followed to access services offered by different organizations.

CONTINUUM OF MHA SUPPORT Some gaps discussed during the interviews dealt with the lack of a continuum of support available to MHA clients during their recovery process.

The main areas where a gap in service exists include clinical detoxification and transitional housing for adults and

With over 25 years of experience in the not-for-profit health sector and in community-based volunteering, Belinda has honed an understanding of the social determinants of health and the mechanisms needed to improve health outcomes. In her professional role as Leader, Community Engagement with Vancouver Coastal Health, Belinda has contributed extensively to the development of partnerships and community capacity, which has resulted in building healthier communities across the Lower Mainland Region of British Columbia.

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Reviewed by Belinda Boyd

1. RCSAC General Meeting: Thursday, April 12, 2012 – Meeting Minutes.

Richmond Community Services Advisory Committee; 2012. Available from: http://www.rcsac.ca/meetings 2. Healthy Minds, Healthy People: A Ten Year Plan to Address Mental Health and Substance Use in British Columbia. British Columbia: Ministry of Health Services, Ministry of Child and Family Development; 2010 [cited 2012 August 22]. Available from: http://www.health.gov.bc.ca/ library/publications/year/2010/ healthy_minds_healthy_people.pdf.

3. Israel B a, Schulz a J, Parker E a, Becker a B. Review of communitybased research: assessing partnership approaches to improve public health. Annual review of public health [Internet]. 1998 Jan;19:173– 202. Available from: http://www. ncbi.nlm.nih.gov/pubmed/9611617 4. Vision [Internet]. Richmond: Canadian Mental Health Association – Richmond Branch;2012 [cited 2012 August 22]. Available from: http:// www.richmond.cmha.bc.ca/aboutus/vission-mission.

5. About CHIMO [Internet]. Richmond: CHIMO Crisis Services; [cited 2012 August 22].Available from: http:// www.chimocrisis.com/01chimo/ index.html.

6. About Richmond Addiction Services [Internet].Richmond: Richmond Addiction services;[cited 2012 August 22]. Available from:http:// www.richmondaddictions.ca/home/ about-rass.html.

7. Our Programs [Internet]. Richmond: Richmond Mental Health Consumer and FriendsSociety; [cited 2012 August 22]. Available from: http:// www.rcfc-society.org/programs.php.

8. Richmond School Program [Internet].

Richmond: Richmond Youth Service Agency; [cited2012 August 22].

Available from:http://www.rysa. bc.ca/content/programsAndActivities/schoolBasedPrograms/ programs/school.php.

9. District Programs Based On Student Needs [Internet]. Richmond: Richmond SchoolDistrict No. 38; 2011 [cited 2012 August 22].

Available from:http://www.sd38. bc.ca/schools/ Secondary%20Program%20Files/Student%20Needs.

10. Champion, K. Adolescent Support Team. Report to: Personnel and Finance Committee(Richmond). 2012 May 14 [cited 2012 August 22].

11. Who We Are [Internet]. Richmond: Richmond Youth Service Agency; 2008 [cited 2012August 22].

Available from:http://www.rysa. bc.ca/content/aboutUs/whoWeAre/ whoWeAre.php.

12. About Us [Internet]. Richmond: Touchstone Family Association; [cited 2012 August 22].Available from: http://www.touchfam.ca/ about.html.

13. Mission and Purpose [Internet].

Vancouver: Turning Point Recovery Society; [cited 2012August 22].

Available from: http://www.turningpointrecovery.com/mission.htm.

14. Strategy [Internet]. Vancouver: Vancouver Coastal Health; 2011 [cited 2012 August 22].Available from: [http://www.vch.ca/about_us/ strategy/.

15. Healthy Together - Linking Vancouver Coastal Health – Richmond to the People ofRichmond. Richmond: Vancouver Coastal Health; 2011 [cited 2012 August 22]. Availablefrom: http://vch.eduhealth.ca/PDFs/ BA/IA.022.H347.pdf.

16. Find Services. Vancouver: Vancouver Coastal Health; 2011 [cited 2012 August 22].Available from: http://www. vch.ca/locations_and_services/ find_health_services/.

17. Vancouver Community Central Intake Line – Telephone. Vancouver: Vancouver Coastal Health; 2011 [cited 2012 October 17].

Available from: http://www.vch. ca/403/7676/?program_id=1031. find_health_services/.

research insight

youth. During the interviews, it was noted that MHA support services. Some interviewees clients who have completed residential recovery purported that the current approach to MHA programs and now require transitional housing service delivery needs to be modified prior to are unable to find this support in the Richmond the development of tangible MHA outreach community. Turning Point Recovery Society, in programs. Much of the consultative and clinical partnership with other organizations, is planning work currently done by Richmond MHA to fill this gap by building second-stage housing service providers is only as a response to clients units in Richmond by 2015. Furthermore, in crisis, and it is dependent on the initiative Richmond does not have a facility designed with of the client to attend organized sessions. A a clinical detoxification capacity. While there community outreach approach will encourage are no plans to establish such a facility, smaller organizations to seek out individuals that may be scale services such as the Acute Home-Based at risk for MHA issues and provide the necessary Treatment Program are working to offer clinical consultative and clinical support necessary for detoxification on an individual basis. them to remain productive members of their community and workforce.

PERSONALIZED MHA Future Directions SUPPORT IT IS EVIDENT THAT A COLLABORATIVE EFFORT All interviewees conveyed From the information gathered AMONG MHA SERVICE the need for provision of through the interviews, it is consultative and clinical PROVIDERS IN RICHMOND evident that a collaborative IS REQUIRED IN ORDER support tailored to the effort among MHA service needs and backgrounds TO TACKLE THE VALIDATED providers in Richmond is GAPS IN A SYSTEMATIC of individual MHA required in order to tackle the MANNER clients. The major groups validated gaps in a systematic requiring this specialized manner. As a first step, it MHA support were would be important to review identified as older adults, youth, individuals all interviewee comments and host a meeting with concurrent MHA disorders, individuals among service providers to reconfirm the with a developmental disability, South Asians, presence of the identified gaps. At this time, it and Aboriginal peoples. Most interviewees would also be beneficial to prioritize the gaps agreed that there is sufficient need in Richmond and discuss recommendations for gap resolution. to establish support services and/or housing Following this meeting, an action plan may be programs for older adults, youth, and individuals developed to outline the key gaps to be addressed, with multiple disorders. However, culturally- initiatives to resolve the gaps, the timeline and relevant programs and services for MHA expected outcomes of the proposed initiatives, clients were not as clearly supported. Some and the follow-up evaluation strategy. This plan interviewees indicated that while increasing will be designed and executed with the support cultural competency among service providers of MHA service providers in Richmond. may be beneficial, there might not be a critical Acknowledgements number of individuals with MHA issues that require culturally-conscious support.

I would like to extend my sincere gratitude to Belinda Boyd, Leader in Community MHA OUTREACH Engagement for VCH Richmond, and the Key informants recognized outreach services, members of the Richmond Community Services particularly those catered towards youth, as an Advisory Committee for their continual support important area for improvement in Richmond’s during the completion of this project.

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RESEARCH INSIGHT

Salinomycin: A Notch Signaling Antagonist A NOVEL WAY OF TARGETING CANCER STEM CELLS

CARLOS MUZLERA Honours Biochemistry/Biomedical Sciences Specialization, Class of 2014 Laboratory of Dr. John Hassell, Department of Biochemistry and Biomedical Sciences, McMaster University Correspondence should be addressed to: muzlercu@mcmaster.ca

ABSTRACT

Dr. Hassell’s research team aims to investigate the roles of therapeutically-relevant genes or gene signatures in the development of “tumour-initiating cells” or breast cancer stem cells. His research team also explores the effects of antagonistic compounds on certain regulatory receptor pathways using in vitro breast cancer cultures and transgenic mouse models. The following research focuses on validating the inhibitory effects of an anti-breast cancer stem cell agent, salinomycin, on downstream Notch signaling. It suggests the possibility of targeting cancer stem cells, the primary culprit in tumour initiation, chemoresistance, and metastasis, by inhibiting key regulatory pathways - such as Notch signaling - that maintain this “stem-like” population.

Introduction to Cancer Stem Cells

FIGURE 1: Model of how the CSC hypothesis can be incorporated in the design of anteoplastic treatments.

(A) Current cancer therapies designed for broad cytotoxicity kill the majority of tumour cells within a given tissue.

However, those CSCs that remain possess the potential to regenerate new heterogeneous tumours and metastases. (B) The CSC hypothesis, in contrast, proposes the utility of cancer stem cell-targeting agents that, although may not theoretically shrink the tumour immediately, can achieve eradication of selfrenewal and regeneration.11

M E D U CATO R | D E C E M B E R 2 0 1 2

In the past decade, a cellular hierarchy has been theoretically established in numerous hematopoietic and solid tumours, with a rare fraction of tumour cells termed “cancer stem cells” (CSCs) or “tumourinitiating cells” (TICs) sitting at the top of this hierarchy.9,10 The CSC hypothesis states that, in addition to the ability to resist chemotherapies and radiotherapies, CSCs share three main traits with their normal

Cancer has typically been identified as the result of accumulated genetic mutations in a single clonal population of cells.11,16 Specifically, the very slow cell turnover rate and self-renewing capacity of normal stem cells to maintain a stable stem cell pool increase the likelihood of these cells to accumulate mutations from one generation to the next.9,17,18 Furthermore, the CSC hypothesis predicts that current chemotherapies are targeting the terminally differentiated, bulk tumour cells, while selecting for the treatment refractory, proliferative cells that are responsible for patient relapse, representing a paradigm shift in the conceptual approach to oncogenesis and cancer treatment (Figure 1A).11 Eradication of CSCs is strongly thought to be a revolutionary event in permitting progression-free survival; however, longterm outcome data from clinical trials with a CSC-specific agent have yet to be compiled

research insight

In 2012, an estimated 577,190 Americans will die from cancer, corresponding to more than 1,500 deaths per day.1 An astonishing 15% of these individuals will be female victims of breast cancer.1 Although major advances are being made in uncovering the mysteries and molecular dynamics of cancer biology, pharmacological treatment of cancer still relies primarily on traditional chemotherapeutic remedies.5 As such, chemoresistance and recurrent metastases continue to contribute significantly to cancer mortality rates.2-4 In fact, the efficacy and response to chemotherapy in a malignant tumour drops down from 60-100% in the first tumour to approximately 20% in the recurrent tumour.6 The adaptability and heterogeneity of tumours endow them with drug-resistance, disease recurrence, and capacity for metastasis.7,8 Hence, there is a compelling rationale to identify the mechanism by which tumours survive to seed relapse after remission and the physiological signatures of the recurrent tumour.

tissue-specific stem cell counterparts.11,12,13 These traits include: the ability to differentiate into any of the heterogeneous cell types that make up the organism, organ or tumour (in the case of CSCs);57,9,11,14 self-renewing capacity, or the ability to indefinitely give rise to identical daughter cells;5-7,9,11,14 and homeostatic control, which is the ability to respond to extracellular cues and genetic constraints to balance differentiation.11,14,15

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research insight M E D U CATO R | D E C E M B E R 2 0 1 2

25

FIGURE 2: Simplified mechanism of the Notch signaling pathway.

The Notch signaling pathway is activated by enzymatic cleavages that occur to the heterodimeric Notch receptor (in red). Humans possess four homologous Notch receptors, each of which consists of an extracellular domain (NECD), transmembrane domain (NTM) and an intracellular domain (NICD).

After being synthesized, the Notch receptors are anchored into the cell membrane, where they may bind their canonical ligands, which are also transmembrane proteins.

This triggers the endocytosis of NECD and exposes NTM to cleavage by an ADAM metalloprotease (S2).

A Notch extracellular truncation (NEXT) intermediate is produced and is further cleaved by γ γ-secretase (S3) to generate the active NICD. NICD is then translocated to the nucleus where it binds transcription factor CSL (or RBP-jk in mice). Upon binding CSL, which is normally in a transcriptionally repressed state, NICD replaces a corepressor complex on CSL with a co-activator complex that includes Mastermind (MAML). This Notch transcriptional activating complex goes on to enhance transcription of Notch target genes, which code for proteins involved in self-renewal and in preventing differentiation.43

to confirm this hypothesis.19 In mouse xenograft models of breast cancer, it takes thousands of injected tumour cells to generate a tumour, but only 20 to 50 putative breast cancer stem cells (BCSCs) can produce a heterogeneous tumour in keeping with the BCSC hierarchy.6 This rare population, making up 11-35% of total cancer cells in a breast tumour, has been identified by the cell surface marker combination, CD44 + /CD24 -/low. 6,20 Classification of CSCs by cell-surface markers has enabled the isolation of these cells by flow cytometry for comparative studies of these cells before and after treatment.21

of self-renewal. Targeting these signaling pathways has become a topic of great interest, as their inhibition has been associated with differentiation of CSCs, loss of tumourigenic potential, and sensitization to classical chemotherapeutic regimens.24,25 My goal, under the supervision of Dr. John Hassell, has been to identify small-molecule compounds that inhibit Notch signaling, with the hypothesis that a specific inhibitor of the Notch signaling may result in regression and/or elimination of BCSC-mediated tumourigenesis (Figure 1B). Notch signaling has been the designated target because it is an evolutionarily-conserved pathway that functions to regulate cell-fate decisions and tissue development in all three germ layers.6,29 Consequently, any mutation or perturbation to the canonical signaling pathway can have a vastly oncogenic effect.30,31 This has been illustrated in breast cancer, as Notch is aberrantly activated in the malignant state when compared to normal mammary epithelium,16,17 suggesting a mechanism for developing resistance to current cancer therapies.32,33

The most successful inhibitors of Notch signaling to date in both pre-clinical and Signaling Pathways In clinical studies have been γ-secretase inhibitors (Figure 2).34-36 Selective inhibition Breast Cancer Stem Cells as of γ-secretase prevents Notch receptor Therapeutic Targets cleavage and consequently, NICD-mediated Tissue differentiation is now believed to be a transcriptional regulation in BCSCs.36 complex, tightly regulated process in which Preclinical studies with γ-secretase inhibitors several developmental signaling pathways have identified novel chemotherapeutic process genes responsible for a number of properties through functioning as a potent cell-fate decisions by integrating information Notch inhibitor leading to tumour regression from extracellular cues.22 In mammary gland using in vitro and in vivo models of breast development (as well as the development of tumours.39 Moreover, γ-secretase inhibitors many other solid or hematopoietic tissues), have been shown to suppress the self-renewing many of these signaling pathways are highly capacity and anchorage-independent growth implicated in stem-cell maintenance and of TICs in numerous solid tumours including regulation of molecular checkpoints for breast, gastrointestinal, and pancreatic differentiation.22,23,26 These include epidermal cancers.36,37 Unfortunately, multiple organ growth factors, as well as the Wnt/β-catenin, systems and molecular targets including Hedgehog and Notch signaling pathways.27,28 the amyloid precursor protein implicated Interestingly, it has been found on multiple in Alzheimer’s disease rely on the function accounts that human breast tumours contain of γ-secretase.5 Accordingly, inhibitors of a BCSC population with similar properties γ-secretase have revealed off-target and to normal mammary stem cells, and these highly potent effects on Notch signaling with BCSCs often exhibit constitutive activation varying degrees of toxicity to patients in a of one or more of these signaling pathways.23 dose-dependent manner.5 Therefore, a specific, These data suggest that breast tumours small-molecule Notch inhibitor has yet to be may originate from pluripotent mammary discovered that exhibits the same therapeutic stem/progenitor cells that have experienced potential as γ-secretase inhibitors without the aberrant activation in developmental signaling severity of its side effects.38 cascades as a result of an accumulation of genetic mutations throughout the process The oncogenic effects of Notch are due to the

formation of the transcriptional activating complex, which activates transcription involved in promoting cell proliferation and blocking differentiation.40 Our lab has focused its attention on identifying small-molecules that can disrupt the formation of this transcriptional activating complex and/or its ability to exert transcriptional control in human breast cancer cell lines. Thus, we have designed a cell-based assay that uses a set of infected breast cancer cell lines that can reliably assess the functional activity of Notch signaling downstream of γ-secretase. The goal of this research is to identify and validate a small-molecule inhibitor of the Notch pathway in multiple human breast cancer subtypes that will also target CSCs.

research insight

FIGURE 4: Dose-response curve of HCC 1954 N11R cells treated with salinomycin at 16 concentrations. The graph shows the percentage of firefly luciferase activity normalized to renilla luciferase activity with respect to DMSOtreated cells. Cells were treated with Salinomycin at 16 concentrations, starting at 100μM with two-fold dilutions. Firefly and renilla luciferase luminescence was read 24 hours after treatment. The decrease in normalized luciferase activity indicates a selective decline in the luminescence of firefly luciferase with respect to renilla luciferase. The IC50 for salinomycin in this cell line is 812nM, which is the quantity of a drug or compound required to inhibit a particular biological process by 50%.

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promoter that promotes constitutive expression of renilla luciferase (Figure 2).

When HCC 1954 N11R cells are exposed to doxycycline, this induces over-expression A Functional Cell-based Dose of NICD, leading to high activation of NICD/ CSL/Mastermind-mediated transcription Response Assay: Validation of firefly luciferase. This is quantified by the of Salinomycin-mediated measure of luminescence produced by the Inhibition of Notch Signaling firefly luciferase enzyme upon addition of Downstream of γ-secretase its substrate. When cells are treated with We have recently derived HCC 1954 N11R, a candidate Notch inhibitors, we expect the breast cancer cell line that utilizes a luciferase luminescence signal from firefly luciferase to reporter system to report Notch signaling decrease in a dose-dependent fashion, while activity downstream of γ-secretase. This cell the renilla luciferase signal remains constant line has also undergone lentiviral infection because it serves as an internal negative to generate a collection of stable clones that control. Compounds that are toxic to the cells contain three engineered genomic constructs. or inhibit general transcription or translation The first is a vector containing the NICD gene will also reduce the renilla luciferase signal, that can be inducibly expressed by the Tet-On making that compound a false hit in our assay. promoter upon the addition of the antibiotic doxycycline. This is how the γ-secretase A previously conducted screen in the Hassell cleavage step is skipped, and overexpression Lab, with over 1,300 natural bioactive of NICD leads to ligandindependent activation of the Notch pathway.29 The second construct is a firefly luciferase reporter that is expressed from its promoter containing a 1x RBP-jk binding site. This is the binding sequence that the CSL Notch transcription factor binds to, and is a putative binding site amongst many Notch target gene promoters.29 The final construct is a renilla luciferase reporter under the control of the Cytomegalovirus (CMV) promoter, a strong viral

FIGURE 3: Schematic of the HCC 1954 N11R cell line and its integrated inducible system that reports on NICD activity..The HCC 1954 cell line was virally infected with three genomic constructs shown within the nucleus (dotted red line) of the cell diagram above. The resulting HCC 1954 N11R cells possess the NICD gene regulated by a TetOn system, which is activated upon addition of doxycycline antibiotic.

Over-expression of NICD permits increased transcription of the firefly luciferase reporter from the 1xRBPjk promoter sequence by forming the transcriptional activating complex with CSL and MAML. These cells also contain an internal negative control, the renilla luciferase reporter under transcriptional control of the CMV promoter, which constitutively expresses the renilla luciferase transcript.

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research insight

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26. Li, Y., Welm, B., Podsypanina, K., Huang, S., Chamorro, M., Zhang, X. et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci USA 100, 15853-8 (2003).

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30. O’Toole, S. A. et al. High Notch1 protein expression is an early event in breast cancer development and is associated with the HER-2 molecular subtype. Histopathology 56, 286-96 (2010).

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compounds and pharmaceuticals, yielded a total of 27 unique hits.

After follow-up validation experiments, salinomycin was determined to produce the most specific and reproducible inhibition of Notch signaling in our inducible system (Figure 4). The ramifications of these results are as encouraging as they are enlightening. Salinomycin has been reported to exhibit selective toxicity to BCSCs.41 Mouse treatment with salinomycin regresses mammary tumour growth in vivo and induces epithelial differentiation of tumour cells.41 In addition, salinomycin treatment results in reduced expression of characteristic BCSC genes by global gene analysis.41 This evidence supports the hypothesis that a pan Notch inhibitor will repress mammary tumour growth by inhibiting the proliferation of BCSCs. Furthermore, it shows that oncogenic characteristics of BCSCs, such as self-renewal and proliferation, are largely dependent on their capacity to maintain activation of Notch signaling. This sheds light on a new approach to targeting BCSCs and perhaps CSCs in other cancer types such as T-cell acute lymphoblastic leukemia, which is known to contain activating mutations in Notch.42 It has always been difficult for investigators to isolate and validate large quantities of CSCs due to the heterogeneity of primary tumours, the minority of cells that possess the CSC phenotype in primary samples, and the ambiguity associated with the exact phenotypic definition of CSCs across cancer types.22,24,25 However, our evidence supports the possibility of identifying inhibitors of Notch signaling (or other developmental signaling pathways) as an indirect approach to developing drugs that can target this “stem-like” population of cells.

This may allow investigators to conduct high-throughput screens for this purpose.

Conclusion CSCs have been at the forefront of cancer research to reveal the molecular processes that regulate tumour initiation, maintenance, chemoresistance, and metastasis.7 Several regulatory signaling pathways are implicated in the maintenance of this CSC population, many of which are druggable targets.14,16,22-24 Our research investigates candidate inhibitors of Notch signaling, a process shown to experience high levels of activation in BCSCs. The identification of salinomycin, an antagonist of BCSCs, as our most selective inhibitor of Notch signaling suggests the significant role of Notch in sustaining this tumourigenic population. New screening strategies may be established to indirectly identify antagonists of BCSCs by identifying compounds that inhibit the regulatory pathways that endow them with tumourigenicity.

Reviewed by dr. ROBIN HALLETT Dr. Robin Hallett is a post-doctoral research fellow in the department of Biochemistry and Biomedical Sciences at McMaster University and is supervised by Dr. John Hassell (director of the Centre for Functional Genomics). Dr Hassell’s group focuses on repurposing old drugs for use as anti-cancer agents and uses a variety of experimental techniques, such as high-throughput screening, gene expression profiling and connectivity mapping to achieve these ends.

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