Issue 27 by The Meducator

APRIL 2015 | ISSUE 27

Adverse Drug Effects S y s t e m i c S u b j e ct I n c e n t i v e to U n d e r - r e p o rt

Cancer stem cells Ta r g e t i n g t h e r o ot o f m a l i g n a n cy

Combatting the West African Ebola Epidemic: I n t e rv i e w w i t h M a r k B r e n d e r, d i r e cto r o f Pa rt n e r s i n H e a lt h Ca n a d a

WWW.MEDUCATOR.ORG

table of

contents

table table of of contents contents

April 2015 | I S S UE 2 7

02 03 05 07 09 13 15 35 39 42 43 46

INTRODUCTION MEDPULSE MEDBULLETIN PATHOPROFILE OPINION FORUMSPACE CRITICAL REVIEW RESEARCH INSIGHT GLOBAL PERSPECTIVES ROUNDTABLE INTERVIEW SPOTLIGHT CONTRIBUTORS

OPINION 09 A D V E R S E D R U G E F F ECT S 11 V I E W P O I N T S : V O L U N T o u ris m

CRITICAL REVIEW

15 C h il d r e n wi t h Disa b ili t i e s 19 Can c e r S t e m C e lls 23 Cir c u lat ing t u m o r D N A 27 G li o b las t o m a 31 O b e si ty an d F at ty A c i d s

RESEARCH INSIGHT 35 H y p ox ia in Dr o s o p h ila D e v e lo p m e n t

GLOBAL PERSPECTIVES 39 E m e rg e n cy S e rvi c e s m e d u c a t o r | A pril 2 0 1 5 m e d u cato r | A p r i l 2015

brain

CO V E R A R T I S T M e lissa L e e

The cover of this issue depicts the enigmatic Rod of Asclepius, who is the eponymous ancient Greek deity of healing and medicine. The single snake curved around the staff has long been the subject of repeated attempts to decode or interpret its meaning. Some say the shedding of snake skin represents the rejuvenation of a successful medical procedure. Others suggest the contrast between the two subjects of the icon represent the duality often encountered in medicine: life and health versus death and sickness. Of course, the ambiguous nature of the Rod of Asclepius could be interpreted as a signifier for the degree of uncertainty that is present whenever we attempt to decode the human body. A disease that exemplifies this concept is cancer, the mechanisms of which have not yet been fully elucidated. In this issue, editors Maylynn Ding and Ishan Aditya work with graphic artist Eliya Zhao to investigate angiogenesis, a process required for cancer progression, in Pathoprofile. Krushangi Patel‘s Critical Review examines methods to reduce the rate of relapse in cancer patients by identifying cancer stem cells that evade conventional treatments. Focusing on diagnosis, Mark Mansour’s Critical Review investigates the use of circulating tumour DNA in the blood as a novel cancer biomarker. Alexandra Kilian focuses on a particularly malignant type of brain cancer in her Critical Review, “Glioblastoma Tumours,” and discusses current treatment options and notable developments in the field. Besides highlighting the complexities of cancer, Issue 27 explores a variety of other pertinent matters in health sciences. Hannah Roche discusses the state of emergency services worldwide in Global Perspectives, contrasting her experiences in Asia and West Africa with McMaster University’s own Emergency First Response Team. In the Viewpoints feature, McMaster Debate Society members Hrishikesh Suresh and Gynter Kotrri present reasons for and against “voluntourism,” an increasingly popular trend. Issue 27 also features an interview with Mark Brender, director of Partners in Health (PIH) Canada, who elaborates on the role of PIH in combatting the spread of Ebola in West Africa. Then, coming closer to home, Allie Annibale explores barriers in accessing care for children with special needs in Northern Ontario, highlighting unique challenges faced by Aboriginal communities. The McMaster Health Forum continues its longstanding contribution to The Meducator, as Tony Jin, Alexandra Kilian, and Anna Kurdina highlight mental health challenges of university students. The current state of clinical drug testing is challenged by Matthew Breton in his Opinion piece, in which he describes issues with the system of adverse drug effects reporting. To round off the article selection, YongChang Li, Brandon Cheuk, Bokang Zeng, and Joshua Chun provide an overview of fatty acid synthesis and obesity-related diseases in their Critical Review.

introduction

INTRODUCTION ISSUE 27

dear reader,

This year also marks the launch of The Meducator’s online initiative, Round Table. The intent of this project is to create an online forum for members in the community to discuss novel ideas through the framework of an annual question. For the 2014-2015 academic year, we asked, “Within the next 25 years, what will be health care’s greatest challenge?” Trends and responses are summarized in an infographic in this issue.

m e d u cato r

Over the course of this past year, we have watched The Meducator grow in new and exciting ways that we would not have thought possible. We would like to extend a huge thank you to all of our staff members for their enthusiasm, passion, and dedication. Special thanks goes out to Kimia Sorouri, Annie Zhu, and Sebastian Swic for their impressive leadership as team managers for our Editorial Board, Graphics Team, and Video Team. Finally, on behalf of the entire team, we would like to thank you, the reader, for exploring the rich and exciting field of health sciences with us. Your curiosity is what inspires us to come together, and this publication would not be possible without your support. We look forward to seeing what great things will be accomplished down the road!

| A p r i l 2015

RONALD LEUNG

Bachelor of Health Sciences (Hons.) Class of 2016

GRACE ZHANG

Bachelor of Health Sciences (Hons.) Class of 2016

Dec. 2014: Cases of avian influenza A (H7N9) virus with high fatality rate in China spark concern of possible mutation facilitating person-to-person transmission.

Endangering Health

Jan. 2015: Continuing conflict between Ukranian government forces and Russia-backed separatists put more than 5 million people at risk as the health system buckles, WHO reports.

united kingdom, mar 2015

sierra leone, jan 2015

ottawa, jan 2015

cuba, feb 2015

california, jan 2015

H7N9 Outbreak

Anti-HIV Trial Recedes

Jan 2015: A large-scale clinical trial for antiHIV medications in South Africa, Uganda, and Zimbabwe ended early after finding no significant benefit of the treatment. Later investigation revealed that low compliance was a major problem.

Ebola Crisis Containment

Jan. 2015: Pujehun is the first district in Sierra Leone to be declared Ebola-free, after 42 days with no new recorded cases. The district council is credited with implementing early measures to contain the spread of disease.

MEDPULSE taking the pulse of the world.

china, dec 2014

myanmar, feb 2015

middle east, feb 2015

south africa, jan 2015

ukraine, jan 2015

Drug-Resistant Malaria Measles outbreak

Jan. 2015: Persistent anti-vaccine views amongst concerned parents sparks outbreaks of measles, many cases stemming from Disneyland in Anaheim, California.

Physician-Assisted Suicide

Jan. 2015: The Supreme Court of Canada issued a ruling on physician-assisted suicide in an unanimous decision to legalize this form of euthanasia.

Dangerous Strain of HIV

Feb. 2015: Aggressive variant of HIV found in Cuba: AIDS appears in as quickly as three years, compared to ten in the most common strain.

Feb. 2015: A deadly malaria strain has been detected in Myanmar that is resistant to artemisinin, the most rapid action anti-malaria drug currently in use.

Mental Health Crisis

Feb. 2015: Brutality from extremist group ISIS, combined with stigma and lack of treatment, sparks concern of trauma and severe mental health problems amongst survivors of conflict.

Healthcare Performance

Mar. 2015: Report by The Commonwealth Fund ranked the UKâ&#x20AC;&#x2122;s healthcare system, the National Health Service, first in efficiency, performance, quality of care, and management of chronic illnesses.

MEDBULLETIN HIV/AIDS

Viruses

ISHA N A DIT YA

AVRILYNN DING

Human Immunodeficiency Virus (HIV) is one of the most prevalent viruses in the world, yet there is no cure for HIV infections. 1 HIV is unique as it targets the body’s immune system, which is responsible for removing viruses and other pathogenic material from the body. Thus, once an individual contracts HIV, he or she has HIV for life. As the virus progresses to its later stages, it results in Acquired Immunodeficiency Syndrome (AIDS), compromising immune response against other infectious agents.

Almost 90 years after the discovery of the first antibiotic, antibiotic resistance has emerged as a major threat to public health. The overuse and misuse of antibiotics has led to an increase in the number and types of resistant microorganisms. 1 The World Health Organization’s first report on the topic, published in April 2014, found that antibiotic resistance in bacteria responsible for common infections has reached alarming levels worldwide. 2

medbulletin

New Approach to Blocking HIV Raises Hopes for an AIDS Vaccine

Lead scientist Dr. Michael Farzan and colleagues from The Scripps Research Institute (TSRI) recently developed a new compound that may be able to function as a vaccine against AIDS. 1,2 The compound, referred to as eCD4-lg, stimulates muscle cells in monkeys to synthesize proteins that resemble normal antibodies. 1,2 The proteins’ head and tail simultaneously block two sites on each “spike” that the virus uses to attach itself to target cells. When both sites become blocked on every spike, the virus is rendered helpless and is then discarded by the immune system.

m e d u cato r

| A p r i l 2015

This promising technique has now protected four monkeys for nearly a year against repeated infection attempts with large doses of several strains of SHIV, a variant of HIV that is specific for laboratory monkeys. 1,2 Currently, this novel compound is the “broadest and most potent entry inhibitor described so far,” according to Dr. Farzan. 1

The method developed by the TSRI team is much simpler than the current method that scientists have been experimenting with, which involves giving monkeys cocktails of antibodies that individually neutralize limited strains of HIV. 1,2 While the results have yet to be applied to human models, eCD4-Ig has the potential to revolutionize HIV prevention therapies. ■

McNeil Jr., Donald. New Approach to Blocking H.I.V. Raises Hopes for an AIDS Vaccine [Internet]. Nytimes.com. 2015 [cited 20 February 2015]. Available from: http://www.nytimes.com/2015/02/19/ health/new-approach-to-blocking-hiv-raises-talk-of-an-aids-vaccine.html?ref=health&_r=0 2. Gardner MR, Kattenhorn LM, Kondur HR, von Schaewen M, Dorfman T, Chiang JJ, et al. AAVexpressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. 2015 Mar 5;519(7541):87–91. 3. eCD4-lg [Image on the internet]. 2015 February 19 [cited 2015 March 8]. Available from: http:// shifter.pt/2015/02/investigadores-produzem-potente-anticorpo-contra-o-hiv/

Viruses as a Solution to Antibiotic Resistance Crisis

Recently, researchers from the Hebrew University of Jerusalem demonstrated that viruses may offer a possible solution. 3 Bacteriophages are viruses that have evolved to efficiently infect and kill bacteria. 4 The research team studied the bacteriophage EFDG1 and its lethality against the drug-resistant bacterium Enterococcus faecalis . Isolated from Jerusalem sewage runoff, EFDG1 is neither rare nor difficult to obtain. 3 E. faecalis is a highly resilient bacteria strain responsible for many life-threatening diseases such as meningitis and endocarditis. Treatment success has been limited by difficulties in eradicating the bacteria’s biofilm and the frequent emergence of multi-drug resistant strains. 5 In their study, the team showed that EFDG1 almost completely eradicated strains of E. faecalis with various antibiotic resistance profiles in both liquid and biofilm cultures. EFDG1 was also found to prevent E. faecalis root canal infection in human tissue models. Whole genome sequencing also revealed the EFDG1 genome does not contain harmful genes to humans, suggesting it may be safe to use in phage therapy against E. faecalis infections in humans. 3 While using phages to fight bacteria is not a novel idea, it is a route that has been largely abandoned with the success of chemical antibiotics. 5 However, in light of rising antibiotic resistance and the slump in antibiotic discovery, the study demonstrates bacteriophages are potential tools for developing antimicrobial treatments. Further research is required to adapt the bacteriophage for use in treatment and to identify any harmful side effects. ■

Whiteman H. Antibiotic resistance: how has it become a global threat to public health? Medical News Today [Internet]. 2014 Sep 10 [cited 2015 Feb 21]. Available from: http://www.medicalnewstoday.com/articles/282357.php

Antimicrobial resistance: global report on surveillance. Geneva (Switzerland): World Health Organization; 2014 Apr. 257 p.

Khalifa L, Brosh Y, Gelman D, Coppenhagen-Glazer S, Beyth S, Poraduso-Cohen R, et al. Targeting Enterococcus faecalis biofilm using phage therapy. Appl Environ Microbiol. 2015 Feb 6;AEM.00096–15.

Bacteriophage. In: Encyclopædia Britannica [Internet]. Encyclopædia Britannica Online.

Encyclopædia Britannica Inc. 2014 [last modified 2014 Nov 13; cited 2015 Feb 21]. Available from: http://www.britannica. com/EBchecked/topic/48324/bacteriophage/

How a bacterial virus found in Jerusalem sewage could prevent root canal infections. Hebrew University of Jerusalem [Internet]. 2015 Feb 17 [cited 2015 Feb 21]. Available from: http://new.huji.ac.il/en/article/25479

CSU Animation and Visual Effects. Bacteriophage Lytic Cycle [Image from the internet]. 2012 December 23 [cited 2015 March 8]. Available from: http://i.ytimg.com/vi/UjVcn5Mmz-U/maxresdefault.jpg

How a bacterial virus found in Jerusalem sewage could prevent root canal infections. Hebrew University of Jerusalem (Israel). 2015 Feb 17 [cited 2015 Feb 21]. Available from: http://new.huji.ac.il/en/article/25479

genetics

engineering

MAY LYNN DING

KIMI A SOROURI

Mitochondria are organelles present in all eukaryotic cells that contain their own genome in the form of mitochondrial DNA (mtDNA). 1 This mtDNA represents a very small portion of the cell’s total genome. Most of the cell’s genome is packaged as chromosomes within the nucleus. Unlike nuclear genome, which is derived from both the egg and the sperm upon fertilization, mtDNA of an embryo comes almost exclusively from the egg. In other words, mtDNA is of maternal origin. 1 Mutations in mtDNA have been recognized as significant contributors to a large spectrum of incurable, multi-organ diseases such as epilepsy and diabetes. 1,2

Over the past two decades, biomedical engineering has experienced a boom as technological advances have caught up with our understanding of the human body. This multidisciplinary integration has significantly impacted the fields of regenerative medicine and tissue engineering. Seeing as current tissue engineering applications include heart valves, cartilage tissue, and prosthetics, generating entire organs could soon become a reality. 1

IN VITRO FERTILIZATION: Three-Parent Babies TO PREVENT Congenital Mitochondrial Disease

Tissue engineering and advancements in regenerative medicine also present ethical issues with regard to aging. Will aging become a condition that is treated rather than a natural phenomenon? The lack of regulation on regenerative research is a reflection of the overall ambiguity of the debate on human lifespan extensions and its effects on human nature and natural law. Therefore, the future of regenerative medicine is murky at best, and it begs the question, how long should we live? ■ m e d u cato r

The new therapy, which involves germline genetic manipulation, has raised some ethical concerns. Opponents argue the use of this technique may set a precedent for future creation of designer babies, and children with three genetic parents may struggle with personal identity. 3,5 Proponents point out the potential medical benefits if the technique is used under stringent regulations. On February 24, 2015, the House of Lords passed a legislation allowing the IVF mtDNA transfer technique, making the United Kingdom the first country to approve its use. 5 ■

In 2013, researchers at the Johns Hopkins University School of Medicine conducted a clinical trial of 18 patients who received successful tissue-engineered knee cartilage repairs. 2 As of 2015, tissue engineering with cells ranging from cornea epithelia to esophageal tissues are being tested in multiple clinical trials internationally. 3 Despite the enormous benefits of such a field, many ethical questions remain to be answered. Literature often alludes to the use of human embryonic stem cells in future therapeutic cloning. However, many barriers to the research process exist, including obtaining informed consent from stem cell donors and the non-reversible nature of tissue-engineered implants in clinical trials. 4

medbulletin

A recent focus in addressing congenital mitochondrial diseases is preventing the transmission of faulty mtDNA from parent to offspring. 2 A research group led by Dr. Doug Turnbull at Newcastle University pioneered a new in vitro fertilization (IVF) technique that allows for the replacement of maternally derived mtDNA with healthy mtDNA from a female donor. 3,4 This technique, called mtDNA transfer, has two approaches. In the first approach, the nuclear genome is removed from the egg of the affected mother and inserted into an enucleated egg from the female donor. 4 The second approach is similar, but the mother’s egg is first fertilized with the father’s sperm before insertion into the enucleated egg. The enucleated egg retains healthy mtDNA from the female donor. 4

Regenerative Medicine and Tissueengineering: Destined for Glory or Doom?

| April

Tachibana M, Sparman M, Sritanaudomchai H, Ma H, Clepper L, Woodward J, et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature. 2009 Sep 17;461(7262):367–72.

Amato P, Tachibana M, Sparman M, Mitalipov S. Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases. Fertility and Sterility. 2014 Jan;101(1):31–5.

Callaway E. Scientists cheer vote to allow three-person embryos. Nature [Internet]. 2015 Feb 3 [cited 2015 Feb 25]; Available from: http://www.nature.com/doifinder/10.1038/nature.2015.16843

Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature. 2010 May 6;465(7294):82–U89.

Vogel G. Mitochondrial gene therapy passes final U.K. vote. Science Insider [Internet]. 24 Feb 2015 [cited 2015 Feb 25 2015]. Available from: http://news.sciencemag.org/biology/2015/02/mitochondrial-gene-therapy-passesfinal-u-k-vote

Tan S. In Vitro Fertilization [Image on the internet]. 2013 August 22 [cited 2015 March 8]. Available from: http://www. cbc.ca/news/health/ivf-technique-could-be-simpler-scientists-say-1.1307958

Yang J, Yamato M, Shimizu T, Sekine H, Ohashi K, Kanzaki M, et al. Reconstruction of functional tissues with cell sheet engineering. Biomaterials. 2007 Dec;28(34):5033–43. 2. Sharma B, Fermanian S, Gibson M, Unterman S, Herzka DA, Cascio B, et al. Human Cartilage Repair with a Photoreactive Adhesive-Hydrogel Composite. Science Translational Medicine. 2013 Jan 9;5(167):167ra6–167ra6. 3. Shimizu T, Matsuura K. Myocardial Tissue Engineering [Internet]. Hoboken: Pan Stanford; 2014 [cited 2015 Mar 25]. Available from: http://public.eblib.com/choice/PublicFullRecord.aspx?p=1407642 4. De Vries RBM, Oerlemans A, Trommelmans L, Dierickx K, Gordijn B. Ethical aspects of tissue engineering: a review. Tissue Eng Part B Rev. 2008 Dec;14(4):367–75. 5. Partridge B, Hall W. The search for Methuselah. Should we endeavour to increase the maximum human lifespan? EMBO reports. 2007 Oct;8(10):888–91.

2015

pathoproﬁle TUMOUR-INDUCED

Angiogenesis is the process of blood vessel formation from existing vasculature. 1 Since Folkman’s discovery of the crucial role of angiogenesis in cancer progression in 1971, research into 1

ANGIOGENESIS

is growth of blood vessels from existing vasculature that penetrates tumours to supply oxygen, nutrients, and to remove waste products. 2 Tumours depend on angiogenesis for two processes: growth and metastasis. Metastasis is the spread of a primary tumour to other regions of the body, relying heavily on the body’s own vascular network. 2

AUTHORS MAYLYNN DING ISHAN ADITYA ARTIST ELIYA ZHAO

A tumour, or neoplasm, is a cluster of mutated cells that are either benign or malignant.3 Benign tumours grow relatively slowly and do not intermix with neighbouring normal cells.

However, malignant tumours rapidly proliferate in order to facilitate invasion into neighbouring tissue. These tumours may metastasize and constitute cancer in other regions in the body.3

In the human body, angiogenesis is regulated by a homeostatic balance of pro- and anti-angiogenic factors. 5 In healthy adults, the angiogenic switch is either off or at balance. As such, angiogenesis pathways are not activated and endothelial cells in the body remain quiescent, or “inactive”.

Tumour cells typically rely on passive diffusion in order to receive oxygen and nutrients as well as to remove waste products. 4 Since tumours require more nutrients as their growth progresses, they reach a maximum size before experiencing nutrient deﬁciency. This gives rise to a 3-layer tumour structure, which consists of a necrotic core surrounded by dormant cells, and an outer layer containing proliferating cells.4

In physiological conditions such as hypoxia or in wound healing, the balance tilts towards the pro-angiogenic factors, activating endothelial cells and promoting angiogenesis.5 In the same manner, pathological conditions such as cancerous tumours can exploit these pro-angiogenic signaling pathways. 2

Hypoxia describes a condition of oxygen that often leads to angiogenesis.6 If the tissues are lacking oxygen, angiogenesis is necessary to stimulate the formation of new blood vessels to carry blood-dissolved oxygen and nutrients to tissues.6 Hypoxia successfully signals for the initiation of angiogenesis by upregulating the transcription of pro-angiogenic factors.6,7 This upregulation is primarily dependent on hypoxic activation of a transcription factor called Hypoxia Inducible Factor 1 or HIF-1.8 HIF-1 is a heterodimer protein consisting of two different protein subunits: HIF-1 alpha and HIF-1 beta.8 Under baseline physiological conditions, HIF-1 heterodimers do not form in cells. Both subunits of HIF-1 are produced, but HIF-1 alpha is targeted for degradation as soon as it is produced via the ubiquitin-proteasome degradation pathway.9

Contrarily, the HIF-1 beta subunit remains present in the cell nucleus. However, under hypoxic conditions, the degradation of HIF-1 alpha is inhibited. This leads to its accumulation within the cell and subsequent dimerization with beta subunit within the cell nucleus to form HIF-1. 9 The HIF-1 dimer, a transcription factor, will bind to the Hypoxia Response Elements (HREs) within the promoter regions of target pro-angiogenic genes. 9

In sprouting angiogenesis, the more well-understood type, a new vessel branches off from two adjacent, pre-existing vessels, causing them to fuse together to create a new blood vessel.5 There are four steps to sprouting angiogenesis, which include:

1 Tip Cell Fusion

2 Pericyte Recruitment

Protrusion of opposing capillary walls into the lumen and construction of a contact zone between facing endothelial cells. Endothelial cells of the tip cell phenotype lead the developing blood vessel sprout. The sprout elongates with the proliferation of endothelial stalk cells trailing behind the tip cell.

Reorganization of their intercellular junctions and central perforation of the endothelial bilayer.

Formation of an interstitial pillar core via invasion of supporting cells (e.g. myoﬁblasts) and deposition of matrix.

Enlargement in the thickness of the pillars. Pericytes are recruited to the newly formed blood vessel via the secretion of Platelet Derived Growth Factor (PDGF) by endothelial cells. Pericyte recruitment is essential for blood vessel maturation and to maintain quiescence. 10

Vascular Endothelial Growth Factor (VEGF) is a pro-angiogenic factor that plays a key role in regulation of tumour-induced angiogenesis. 11 It is one of the most well characterized and well studied pro-angiogenic factors. The VEGF Superfamily consists of 7 families: VEGF-A to VEGF-F, as well as placental growth factor (PLGF). 12 Tip cells located on the leading front of sprouting blood vessels have numerous ﬁlopodia cytoplasmic projections, which express a large number of VEGF receptors.13 VEGF-A secreted by the tumour binds to these receptors to guide the developing blood vessel sprout to the hypoxic angiogenic centre. 13 The binding of VEGF to its receptors results in the downstream activation of multiple signaling pathways that promote cell survival, cell proliferation, cell migration, and vascular permeability.12,13

The tumour microenvironment is the cellular environment in which the tumour exists, including surrounding blood vessels, immune cells, ﬁbroblasts, signaling molecules, and the extracellular matrix (ECM). 14 In addition to pro-angiogenic growth factors, tumour cells release cytokines that recruit other cells and change the phenotype of neighboring cells. These cells comprise the tumour microenvironment and can also release pro-angiogenic factors.12,14 For example, carcinogenic associated ﬁbroblasts (CAFs) are recruited to the tumour area. 14,15 CAFs are responsible for depositing ECM proteins and ECM modifying enzymes for the degradation of ECM in the tumour environment required for new blood vessel sprouts. 15 Tumour-associated macrophages release many pro-angiogenic factors, including VEGF. 14 Overall, the tumour microenvironment allows the tumour to exploit and induce different steps of angiogenesis.12

Current research into tumour-induced angiogenesis is concerned with the development of anti-angiogenic factors that can halt cancer progression. 16 To date, thousands of patients have received anti-angiogenic treatments. However, the treatments show no evidence of improving the long-term prognosis. 16,17 Recent research has revealed the tumour-induced angiogenic pathway to be increasingly complex. Future anti-angiogenic therapies that target multiple angiogenic factors will most likely be used in combination with other therapeutic approaches to control cancer.

1. Ribatti D. Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis. 2008 Mar;11(1):3–10. 2. Gupta MK, Qin RY. Mechanism and its regulation of tumor-induced angiogenesis. World J Gastroenterol. 2003 Jun;9(6):1144-55. 3. Plank M, Sleeman B. Tumour-Induced Angiogenesis: A Review. J Theor Med. 2003;5(3-4):137-153. 4. Chaplain M. Avascular growth, angiogenesis and vascular growth in solid tumours: The mathematical modelling of the stages of tumour development. Math Comput Model. 1996 Mar;23(6):47-87. 5. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nat. 2011;473(7347):298-307. 6. Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M. Induction of HIF-1α in response to hypoxia is instantaneous. FASEB J. 2001 May;15(7):1312–1314. 7. Carroll V, Ashcroft M. HIF-a regulation by proline hydroxylation. Expert Rev Mol Med. 2005

Apr;7(6):1462-1463. 8. Hayawaka H, Shibasaki F. Regulation of Angiogenesis by Hypoxia-Inducible Factors. In: Mehta JL, Dhalla N, editors. Biochemical Basis and Therapeutic Implications of Angiogenesis. New York: Springer Science Business Media; 2013. p. 187-210. 9. Ushio-Fukai M. Redox signaling in angiogenesis: Role of NADPH oxidase. Cardiovasc Res. 2006 Jul 15;71(2):226–35. 10. Ribatti D, Crivellato E. “Sprouting angiogenesis”, a reappraisal. J Dev Biol. 2012;372(2):157-165. 11. Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013 Jan;153(1):13–9. 12. Claesson-Welsh L, Welsh M. VEGFA and tumour angiogenesis. J Intern Med. 2013 Feb;273(2):114–27. 13. Hoeben A, Landuyt B, Highley MS, Wildiers H, Oosterom ATV, Bruijn EAD. Vascular Endothelial Growth Factor and

Angiogenesis. Pharmacol Rev. 2004 Dec 1;56(4):549–80. 14. Bruce D, Tan P. Endothelial Growth Factor Receptors in Angiogenesis. In: Mehta JL, Dhalla N, editors. Biochemical Basis and Therapeutic Implications of Angiogenesis. New York: Springer Science Business Media; 2013. p. 187-210. 15. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inﬂammation and cytokines in the tumour microenvironment. J Immunol Res. 2014;2014:149185. 16. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag. 2006;2(3):213-219. 17. Welti J, Loges S, Dimmeler S, Carmeliet P. Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest. 2013;123(8):3190-3200.

opinion

THE INCENTIVE BIAS

Subject Under-reporting of Adverse Drug Effects

MATTHEW BRETON

m e d u cato r

A pril 2 0 1 5

Bachelor of Health Sciences (Honours), Class of 2016 McMaster University Correspondence: matthew.breton@learnlink.mcmaster.ca

Stripped for cash and food, and surrounded by a pile of bills, I upholstery decorated with the sweat-stains of four decades enrolled in a clinical trial. For four two-and-a-half day periods, worth of participants. The meals were warm, never hot. I found a I was confined to a miserable facility that served food subpar hair in my hash brown during one breakfast – I wasn’t permitted to my already lenient university-student standards. The study another. We were not allowed to leave the confinement area compared the bioavailability and side effects of a brand-name nor do anything that resembled exercise. Our sleeping quarters drug to its generic counterpart. The design was a crossover consisted of four bunk beds enclosed in a cubicle, separated from randomized control trial, meaning that each subject received the main corridor by only a thin curtain with little soundproofing. either of two interventions per confinement period. The trial Worse yet, we were restricted to the beds to which we were promised a large sum of money upon completion of all four assigned. Three nights sleeping under a snorer is an arduous periods. Engaging directly with the trial and interacting with enough of a trial. other subjects exposed me to a regularly neglected perspective that is crucial to the conduct of clinical trials: the view of the If clinical trials offer such dismal conditions, who in their right participant. mind would choose to enroll? The answer is simple: people who need the money and are feeling out of options. I needed Some companies pay you an extra $100 when you successfully to pay rent, my bunkmate needed to pay for his sister’s court refer a friend to the study. Apparently, that is how much a soul fees, another participant needed to pay his mortgage, and so costs. The centre was crowded and smelly, boasting ruined on. While my companions during the study came from vastly

different stages of life, the lowest common denominator that united us all was our need for money. This desperation is imperative to consider when creating study protocols.

doing to them, their actions threaten themselves and those for whom the drug is intended. Side effects can serve as potent indicators of underlying health complications. Silent participants risk exacerbating such conditions by not effectively communicating health changes to clinicians. Participants risk harming themselves and ultimately future patients. Not only are side effects suffered in silence, but health providers are also blinded from the true extent of the drug’s adversity. Information that may deter patients from pursuing certain options is never expressed. This results in patients who are unaware of, and thus unprepared for, the risks associated with their intervention.

m e d u cato r | A pril 2 0 1 5

THE POST-GRADUATE REVIEWER WISHES TO REMAIN ANONYMOUS

opinion

The clinicians encouraged us to report any side effects or changes in our health that arose during or between testing periods, though we were warned at the beginning of the study that if our health became compromised, we would be relieved for our own sake. During the second period, I suffered an intense migraine after dosing. Before I could ask the doctor for medicine, another participant warned me not to report my headache in case I would be removed from the study. However, when I reported my symptoms, nothing happened; I was given Tylenol to relieve the pain, Moreover, under-reported drug effects incur unnecessary and I went on to complete the study. costs to healthcare. Drugs are more likely to be erroneously marketed when their associated adverse reactions are Although I did not heed my companion’s warning, I was under-reported in testing.2 This skews cost-benefit introduced to a mindset that justifies withholding of analyses of the drug and leads to prolonged delays in the information as a participant. Before agreeing to the study, marketing and regulation process. This bias misinforms I researched the drug in question to determine its safety. companies, physicians, and patients. Underestimating the I discovered that headaches were reported in 33% of risks that come with a drug leads to increased hospital visits, patients in previous trials. Throughout the weeks, I found physician time, and related treatment costs.3 The ability that nearly all of the participants in my study cohort were for physicians and patients to be sufficiently informed suffering from headaches, yet virtually none reported it to about the risks of their medications relies on the proper the clinicians. These symptoms were discussed secretly reporting of adverse drug effects during clinical trials. amongst the participants, admitted in the confidence that no one would tell the clinicians. Their need for the In order to foster a transparent relationship between paycheck caused the participants to make their goal of clinicians and participants, the incentive bias must completing the study overshadow safety and transparency. be eradicated. Contracts that promise compensation This bias skews data and helps market potentially irrespective of changes in health will help reassure dangerous drugs. participants and re-establish safety and transparency as the highest priorities. Clinicians should communicate the This incentive bias arises in the financial hardships of importance of reporting fidelity and address participants’ clinical trial participants. In order to voluntarily subject concerns about compensation. Moreover, data should be oneself to such experimentation for ten days, the reward collected on the incidence of side effects in the population must be of utmost importance. It may mean the difference after drugs have been marketed. Patient populations between rent and eviction. In any case, the incentive to have no need to withhold changes in health from their remain in the study at all costs is high. I learned that physician; indeed, reporting side effects is beneficial subjects would much rather suffer a migraine unaided for them as it directly relates to their long-term care. If adverse drug effects in the patient population differ in than report it and risk being removed. number from those in the trial population, re-evaluation Evidently, problems exist in a study design that make is necessary to determine the cause of such discrepancies participants reluctant to report adverse drug effects. Indeed, and prompt future drug regulations. we were regularly asked the open-ended question, “How are you feeling?” One randomized trial demonstrated Currently, no standards exist for identifying adverse that the rate of adverse events changed from 14% to 77% effects during clinical trials.4 Companies who penalize when researchers switched from open-ended questions to compensation in cases of health status changes due to a checklist.1 Studies have also found that newly marketed experimental interventions should adjust their policy. To drugs have under-reported adverse drug reactions.2 When optimize drug data and the provision of healthcare, the study subjects are more concerned with completing the incentive bias in clinical trials must be acknowledged and study than they are with what the experimental drug is combated. ■

Edited by MAXWELL TRAN | ART BY MELISSA LEE 1.

Bent S, Padula A, Avins AL. Brief communication: Better ways to question patients about adverse medical events: a randomized, controlled trial. Ann Intern Med. 2006;144(4):257–61. Martin RM, Kapoor KV, Wilton LV, Mann RD. Underreporting of suspected adverse drug reactions to newly

marketed (“black triangle”) drugs in general practice: observational study. BMJ. 1998;317(7151):119– 20. Ioannidis JPA, Evans SJW, Gøtzsche PC, O’Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extension of the CONSORT

statement. Ann Intern Med. 2004;141(10):781–8. U.S. Food and Drug Administration. Expedited Safety Reporting Requirements for Human Drug and Biological Products. Federal Register; 1997 p. 5223752253.

VIEWPOINTS

Voluntourism implications Beyond the pictures

Hrishikesh Suresh & Gynter Kotrri Bachelor of Health Sciences (Honours), Class of 2016 Correspondence: hrishikesh.suresh@learnlink.mcmaster.ca & gynter.kotrri@learnlink.mcmaster.ca

Definition

The term “voluntourism” refers to a form of tourism in which travelers participate in short-term voluntary work.

opinion

Introduction

For an idea that is generally portrayed as having only positive outcomes for the service providers and the recipients, voluntourism has quite a few negative outcomes. While people usually have good intentions when they decide to go on such trips, a combination of marketing, ignorance, and disorganization has prevented them from providing the intended assistance.

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Argument 1: Intentions

The intentions behind a particular action can be as important as the action itself. In some cases of volunteer tourism, the primary intention behind volunteering is not humanitarian service. There are a significant number of people who choose these trips over local service because of the associated glamour in travelling overseas to developing nation. Often, this occurs because although people are aware of issues in their local communities, they choose to divert their attentions to global issues, and sympathize with those suffering in developing nations. For instance, there are areas in Hamilton where the life expectancy of the population is lower than that of developing nations.1 Misguided intentions can cause people to forget the alternative of volunteering locally, which may be more cost-efficient and beneficial.

Argument 2: Insufficient Impact

As the adage goes, “give a man a fish and you feed him for a day; teach a man to fish and you feed him for a lifetime.” This is illustrative of the fact that assistance is far more effective when sustainability is the goal, rather than an immediate remedy. The services provided by certain organizations are contingent on the volunteers’ presence and their capabilities to facilitate such an operation. Once the volunteers complete their service term, new infrastructure is not created to ensure continued access to the provided service. The volunteers are typically not skilled workers, which limits their abilities to contribute. In addition, these voluntourism programs simply provide temporary solutions instead of

establishing sustainability. Local populations need a way to access the necessary resources, as well as the services of trained personnel; neither are usually provided as part of such trips. Instead, the these short-term missions create a dependency on external assistance.

Argument 3: Reinforcing Stereotypes

Not a single nation that faces issues such as poverty would like their national identity to be defined by that issue. In order to encourage people to volunteer for such trips, the organizations behind them usually draw a large amount of attention to the negative issues within the countries. This has the consequence of mistakenly conveying that the only notable aspect of developing nations is the abject poverty and lack of access to resources. While such issues are indeed more prevalent in developing nations, branding these nations with images of suffering is doing them an injustice. Such stereotypes convince people that these issues characterize developing nations, and that developing nations are entirely dependent on foreign aid.

Conclusion

While people may wish to help, the current organization of voluntourism does not provide an adequate solution to the issues experienced by developing nations. We might be tempted to think that doing something is better than nothing, but it is important to consider all the potential consequences. Voluntourism has the potential to improve lives, but in its current state, causes significant harm.

by helping others; this untapped potential should be used to help communities in need. Although a great number of problems do exist in the local community, it should not lead to the neglect of issues in other developing nations, where the economic and living situations are often very destitute. The world today has become increasingly interdependent. No longer can problems be compartmentalized into problems that are either local or global. Moreover, effective solutions to developing nations can be effectively translated to local communities. As new problems are constantly arising and old ones continue to persist, time and resources should simultaneously be spent on international issues.

Argument 2: Insufficient Impact

Pros Introduction

The desire to help developing nations has never been greater in recent history. This desire has been institutionalized through the creation of travel organizations that allow individuals to work toward providing aid to communities. This recent development, known as voluntourism, should be embraced and commended.

Argument 1: Intentions

Conclusion

Opposition against voluntourism tends to focus on the misguided intentions of the volunteers and the lack of a lasting impact. However, this overshadows the valuable contributions made by volunteers and the organizations they represent. A little help goes a long way in helping communities in need.

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Worlds apart. The Hamilton Spectator [Internet]. 2010 Aug 25 [cited 2015 Mar 10]. Available from: http://www.thespec.com/newsstory/2168237-worlds-apart

Voluntourism can also encourage individuals who were once ignorant (or would have otherwise remained ignorant) to explore new places and form new opinions of the people living there. In turn, volunteers can take their newfound knowledge and appreciation for the local culture back to their home country to dispel common stereotypes about these developing nations. As a consequence, rather than perpetuating negative stereotypes, voluntourism provides a platform for enthusiastic volunteers to communicate the positive aspects of the countries they have visited.

Argument 3: Reinforcing Stereotypes

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At the core of voluntourism is the desire to help others. In itself, this idea is extremely noble. Although there may be a small degree of self-serving purpose in voluntourism, it can be argued that all forms of altruism are inherently self-fulfilling. This perspective can cause the positive intention associated with voluntourism to be overlooked. A great need for help exists in developing nations looking for immediate economic relief through aid programs and local projects. A growing number of volunteers are looking to attain spiritual and personal growth

Lastly, in many situations, little skill is required for volunteers to have a lasting impact on an under-resourced community. Most individuals are able to contribute to problems such as homelessness or the lack of irrigation systems through manual labour. Who is to say that, at the same time, you should not enjoy beautiful scenery and indulge in local culture?

opinion

Creating sustainable change in under-resourced communities is very difficult. Even some of the largest and most influential financial and political institutions have failed to reduce poverty and improve the quality of life in developing nations. A few examples include the United Nations Millennium Development Goals, the reduction of poverty by the World Bank, and the eradication of malaria by the World Health Organization. The failure of voluntourism organizations to create sustainable change is not attributed to their incompetence, but rather to the complexity of the problems. Sustainable change should not be a necessary requisite for overseas aid programs, for even the smallest impact is better than not providing any care at all.

ART BY David Hu

FORUMSPACE

The Elephant in the Room Addressing Student Mental Health at McMaster University Shicheng (Tony) Jin1 , Alexandra Kilian1 , Anna Kurdina 1

Bachelor of Health Sciences (Honours), Class of 2017 McMaster University Correspondence: anna.kurdina@learnlink.mcmaster. ca, shicheng.jin@learnlink.mcmaster.ca, and alexandra. kilian@learnlink.mcmaster.ca

The McMaster Health Forum strives to be a leading hub for improving health outcomes at the regional and provincial levels in Canada. Through problem-solving and discussion, they harness information, convene stakeholders, and prepare action-oriented leaders to meet pressing health issues creatively.

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forumspace

Introduction

In the spring of 2013, the Canadian Association of College and University Student Services published staggering results on student mental health based on the first and largest nationwide health survey of postsecondary students in Canada. Of note, almost 90% of students reported feeling overwhelmed and exhausted. Additionally, 20% experienced overwhelming depression, while the rate of anxiety was even higher at 56.4%.1 These results emphasize the prevalence of mental health concerns among the student population and the gravity of this issue. Extreme consequences of poor mental health can include substance abuse, mood disorders and suicide.2,3 This article aims to explore the important issues pertaining to student mental health, potential solutions, as well as considerations for the implementation of these solutions.

risk factors for mental illness are found in the university setting, including access to drugs and alcohol, isolation, poor nutrition, and financial and academic stress.5 As such, it has been demonstrated that students transitioning into university are particularly at risk of mental illness.8

Coping with Stigma Stigma, a negative stereotype toward mental illness, is the most frequently reported reason for abstaining to seek help.9 Public stigma can be propagated through social prejudices, while self-stigma stems from an individualâ&#x20AC;&#x2122;s internalized feelings of shame. In any case, these negative perceptions inhibit oneâ&#x20AC;&#x2122;s motivations to seek help.10 This is particularly applicable to university settings, as it was reported that students fear that their mental illness could be perceived as a weakness by their peers and could potentially compromise their career prospects.3

To address this problem, McMaster University has Mental health and mental illness are often discussed implemented various programs to educate faculty, staff, without clear definition. This contributes to the problem and students about available mental health resources. as students are not always able to understand whether However, the methods by which these programs are their state falls outside of the norm. Mental health is a delivered, governed, and financed limit the accessibility, continuum that can be defined as a state of well-being, and therefore the influence, of these initiatives.9 Although including the ability to operate on oneâ&#x20AC;&#x2122;s full potential, a number and variety of facilities are available, the lack cope with stress, and contribute to the community.4,5 of coordination and overarching governance between It is different for each individual, as it is affected by a them limit collaboration and give rise to a fragmented, variety of social, economic, family and individual factors. and often inefficient, system for students to navigate.9 Mental health can be enhanced and promoted through As well, the limited funding for these services render it the development of strong support networks and difficult to satisfy the high volume of student demand coping mechanisms to empower and encourage student and to launch services that require significant human integration.6 Lack of these factors can contribute to the and financial investment. development of mental illness, which can be defined as emotional, behavioural, and mental changes that result in significant distress and impaired functioning.7 Many

Addressing the Problem Many viable approaches can be implemented to address student mental health needs at McMaster University. Using available evidence, three comprehensive options are outlined.9 1) Create and promote a one-stop access-point portal to provide information and access to available mental health resources

2) Reduce mental illness-associated stigma and promote early identification of mental illness

3) Coordinating available on- and off-campus mental health resources to support greater accessibility and continuity of care for those in need Improving communication between fragmented supports creates a stronger network of on- and off-campus mental health services, which can aid students in navigating the system to find resources that address their unique needs. 9 This would also develop networks that ensure continuity of care is preserved, which is integral to support students who have made the initial steps to seek help.9

Conclusion

4. World Health Organization. Mental Health. World Health Organization 2012;Available from: http://www. who.int/topics/mental_health/en/ 5. Keyes CL. The mental health continuum: From languishing to flourishing in life. Journal of Health and Social Behaviour 2002;43(2):207-22. 6. Provenher HL, Keyes CLM. Complete mental health recovery: Bridging mental health illness with positive mental health. Journal of Public Mental Health 2011;10(2):57-69. 7. Public Health Agency of Canada. Mental Illness. Public Health Agency of Canada 2012;Available from: http://www.phac-aspc.gc.ca/cd-mc/mi-mm/index-eng. php 8. Steinhardt M, Dolbier C. Evaluation of a resilience intervention to enhance coping strategies and protective factors and decrease symptomatology. J Am Coll Health J ACH. 2008 Feb;56(4):445–53. 9. Tamboly S, Gauvin FP. Issue Brief: Addressing Student Mental Health Needs at McMaster University. Hamilton, Canada: McMaster Health Forum, 10 April 2013. 10. Eisenberg D, Downs MF, Golberstein E, Zivin K. Stigma and help seeking for mental health among college students. Medical Care Research and Review 2009;66(5):522-41. 11. Griffiths F, Lindenmeyer A, Powell J, Lowe P, Thorogood M. Why are health care interventions delivered over the internet? A systematic review of the published literature. Journal of Medical Internet Research 2006;8(2):e10. 12. Brouwer W, Kroeze W, Crutzen R, de NJ, de Vries NK, Brug J et al. Which intervention characteristics are related to more exposure to internet-delivered healthy lifestyle promotion interventions? A systematic review. Journal of Medical Internet Research 2011;13(1):e2. 13. Ybarra ML, Eaton WW. Internet-based mental health interventions. Mental Health Services Research 2005;7(2):75-87. 14. Hailey D, Roine R, Ohinmaa A. The effectiveness of telemental health applications: A review. Canadian Journal of Psychiatry 2008;53(11):769-78. 15. Isaac M, Elias B, Katz LY, Belik SL, Deane FP, Enns MW et al. Gatekeeper training as a preventative intervention for suicide: A systematic review. Canadian Journal of Psychiatry 2009;54(4):260-8. 16. Harden A, Weston R, Oakley A. A Review of the Effectiveness and Appropriateness of Peer Delivered Health Promotion Interventions for Young People. London, United Kingdom: EPPI-Centre; 1999. 17. Dumesnil H, Verger P. Public awareness campaigns about depression and suicide: A review. Psychiatric Services 2009;60(9):1203-13. 18. Dalky HF. Mental illness stigma reduction interventions: Review of intervention trials. Western Journal of Nursing Research 2012;34(4):520-47. 19. Author N/A. Woman Embarrassed [Image on the internet]. 2014 April 28 [cited 2015 March 8]. Available from: http://i.huffpost.com/gen/1762830/images/oWOMAN-EMBARRASSED-facebook.jpg

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Though the conversation surrounding student mental health has changed and become more commonplace, there remain clear areas for improvement. Through enhanced collaboration and communication, McMaster services can target mental health stigma and address the demand for mental health supports while improving service access and coordination, promotion, and continuity of mental health care. These steps have the potential to improve service efficiency and effectiveness and thus should be seriously considered for the well-being of the community. ■

3. Storrie K, Ahern K, Tuckett A. A systematic review: Students with mental health problems - A growing problem. International Journal of Nursing Practice 2010;16(1):1-6.

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Reducing the stigma surrounding mental health can open discussions about student mental health within the university community. Providing the necessary resources, education, and training to McMaster staff and students ensures that students have a diverse range of people to turn to for their individual needs. In addition, the university community should also have the necessary skills, attitudes, and knowledge to provide a stigma-free environment for students

Moreover, encouraging McMaster community members to reach out to at-risk groups, such as first-year students, may facilitate open and inclusive discussion and reduce the stigmatization surrounding mental health.9,16 Ongoing programs and events aimed at reducing stigma have been shown to be effective at improving knowledge and attitudes surrounding help-seeking. In particular, campaigns involving direct contact with individuals affected by mental illnesses may be a meaningful medium to reduce stigmatization.17,18

2. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009 Jun;10(6):434–45.

forumspace

The creation of an online interface can be used to address student mental health needs at McMaster. Web-based platforms are convenient, overcome user isolation, and allow the timely provision of information.11 Various McMaster mental health services and resources can be compiled to create a one-stop portal with information about mental health groups and services. Online portals will allow students to stay connected to relevant resources, events, workshops, and campaigns. Brouwer et al. provide evidence indicating that internet-delivered interventions with website updates contribute to longer and more frequent visits to web-based health interventions.12 Furthermore, online platforms which allow students to have human interactions via online mental health screening tools, therapy and support groups, and tele-mental health have been shown to have positive health outcomes.13,14

and to proactively identify and address student mental health concerns.9,15

1. American College Health Association. American College Health Association-National College Health Assessment II: Canadian Reference Group Data Report Spring 2013. Hanover, MD: American College Health Association; 2013.

More details on this topic are available in the Forum Issue Brief “Addressing student mental health needs at McMaster University”, which can be found at http://www.mcmasterhealthforum.org/

ARTIST BELLE CAO

CRITICAL REVIEW

Children With Disabilities

The Social Determinants of Health Affecting the Life Trajectories of Northern Ontario Children with Special Needs

ALEXANDRA ANNIBALE Bachelor of Health Sciences (Honours) – Child Health Specialization, Class of 2015 McMaster University Correspondence: alexandra.annibale@learnlink.mcmaster.ca

low population density, as compared with Southern Ontario. Northern Ontario, which covers an expanse of land the size of France and Germany combined, has a total population of approximately 840,000.4 This has resulted in a landscape of many small, geographically isolated communities, which presents a challenge for the efficient, equitable, and cost-effective distribution of health care resources. For example, there are too few family physicians available to service Northern Ontario, and even fewer specialists.5 It is interesting to note that for many Northern Ontario communities, the closest primary care provider (i.e. either a physician, or a nurse in an independent remote nursing station) is more than a sixty minute commute away.6 In contrast, this is not the case in any community south of Haliburton, Ontario. Primary care is crucial for early intervention and preventative care for children, and Northern Ontario’s chronically understaffed healthcare services extend to include specialized therapists that children with special needs depend on to reach their full potential.7

ABSTRACT The geographical and cultural characteristics of Northern Ontario shape a distinct set of social determinants of health for children growing up with special needs. These determinants, which affect certain cultural groups to a more significant degree, impact a family ’s ability to access critical health care resources for the healthy development of a child with special needs. This critical review will explore the nature of these social determinants of health, their observed impacts on child development in current research, and opportunities for health policy to fill current gaps in healthcare resources, with an emphasis on the Northern Ontario context.

Overcoming Special Needs in Ontario

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The term “special need,” as outlined by the Ontario Ministry of Children and Youth Services, refers to any physical, emotional, behavioural, mental health, or developmental need.1 The literature has identified four key resources that children with special needs universally require, which exceed the health needs of a typically developing child. First, access to preventative care and early While the overall prevalence of special needs intervention programs is vital for many families, among children in Northern Ontario has not as it imparts benefits on children who have been explicitly documented in either Canadian a variety of special needs in a cost-efficient Census data or Northern Health Regions and effective manner.2 Second, professionally information, one can infer from other data that administered therapies, including behavioural, this population is underserved. There are five physical, rehabilitative, or speech therapies will major children’s treatment centres in Northern likely be required. Third, access to specialized Ontario, extending from Thunder Bay to education programs may allow children with Sudbury, which serve a total of 7,680 children.8 special needs to more capably develop their The Ontario Child Health Study (OCHS) abilities. Finally, respite care for families of reports that the prevalence of psychiatric children with special needs can effectively assist disorders among all children in the province caregivers with day-to-day support. Obtaining is approximately 20%.9 Given that there are these resources inherently requires human and approximately 130,000 children in Northern economic resources exceeding those typically Ontario, these children’s treatment centres needed to raise healthy children.3 Compared are only treating 6% of the population of the to the rest of the province, the barriers to region’s children for all special needs.10,11 This these resources are particularly high and inference does not even account for the children often insurmountable in Northern Ontario. with developmental, physical, or rehabilitative needs. Of course, the OCHS data indicates that Overcoming Geographical the deficit in children’s health and disability Barriers support services is a province-wide challenge that is not specific to Northern Ontario. The first social determinant of health in Northern Ontario to be discussed is the region’s

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While it is conceivable that these deficits well-documented that individuals who identify are more severe in Northern Ontario, where as Aboriginal are at higher risk for a number of there is a lower population density and negative health outcomes, as compared to nonfewer available clinicians, further study is Aboriginal individuals. For example, Aboriginal required in order to empirically and accurately individuals in Canada are 7% more likely to demonstrate any potential difference between have an unmet healthcare need than nonthe province’s northern and southern regions. Aboriginal individuals.13 It has been suggested that Aboriginal communities have been It would also not be accurate to state that negatively impacted by the historical, social and children with special needs outside of these five emotional consequences of residential schools, children’s treatment centres do not have access which have had negative and intergenerational to any health support services. They may receive consequences on mental health, education, and provincially mandated support through the poverty.14 Of particular concern to children special education curriculum and healthcare with special needs is the fact that on-reserve service delivery through hospitals and funding for special education in Ontario is Community Care Access Centres (CCACs). not explicitly mandated at the federal level of However, challenges have been identified government, which is the level of government with regard to the quality and accessibility of at which Aboriginal affairs are managed. This community-based services. Arguably, this is a means that many children either do not acquire consequence of the low population density and access to these services, or are forced to seek geographical expanse of Northern Ontario. A schools offering special needs education off2013 report from the Ministry of Children and reserve. In some cases, the latter has been Youth Services, which synthesized research documented to force families to move away from and survey information among families the reserve community, resulting in a loss of the with children with special needs in Ontario, child’s connection to their traditional practices, states that there is a lack of education on the and extended family support network.15 informational and referral roles of the CCACs in helping families get in touch with valuable Interestingly, there are certain Aboriginal health services.12 The report also outlines a cultural perspectives that may also influence troubling statistic related to the allocation of the frequency with which children with resources through population-based funding: in special needs from Aboriginal communities a remote Northern community, it costs twice as seek and receive certain treatments and much money to treat a child with special needs disability support resources. It is important as it does anywhere else in Ontario. Finally, to acknowledge that many Aboriginal groups isolated, remote Northern communities, which have distinct perspectives on what it means to are most susceptible to the effects of recession be in good health, which may differ from the and poverty, experience chronic lack of suitable typical Western-medicine paradigm in some respite care available to families. Caregiving regards. For example, Alberta’s Ministry of responsibilities for children with significant Education found that some Aboriginal families physical or behavioural needs therefore fall in Alberta were not quick to seek assessment chiefly on parents, which can then limit for children with learning disabilities (LD). the potential for both parents to pursue Commonly, these families would look employment opportunities. This, in turn, can unfavourably on the idea of “labelling” a child further contribute to an overall lower family in a way that does not view their unique income and perpetuate a cycle of poverty.3 abilities as a gift, and would thus be skeptical of the approach the Western paradigm of Unique Challenges for an LD assessment with a psychologist.16

Aboriginal Communities

A second determinant of health that impacts a Northern Ontarian child’s health outcomes and access to special needs treatment is his or her Aboriginal status. Aboriginal communities are experiencing the fastest rate of population growth out of any other demographic in Northern Ontario, and also have a higher proportion of children and youth than any other demographic in the region.13 Unfortunately, it is

Changing Policy to Improve Service Delivery Knowledge of these social determinants and their effects on the health outcomes for children with special needs leave government agencies, community service providers, and other advocates for change in a challenging position. They must decide how to best alleviate the negative effects of these determinants

to more equitably and effectively provide care and support to Northern Ontarian families that have a child with special needs. Fortunately, there are tangible opportunities for improvement, and stakeholders are implementing recommendations from government strategic plans. For example, much improvement has come from the Hospital for Sick Children’s Telemedicine partnership with several Northern Ontario communities. This videoconferencing technology has successfully overcome the barrier of limited access to primary care, diagnosis, and followup with specialists, benefitting children with special needs in remote regions.17

the long-term effects of the First Nations and Inuit Health Strategic Plan that was implemented in 2012. This planning model, which aims to utilize empirical knowledge about social determinants of Aboriginal health, outlines wellness milestones that the Canadian government hopes to achieve in order to serve Aboriginal families in a culturally sensitive way.19 It will significantly benefit the continuity of care for children with special needs if federal policy is to be passed within this framework, mandating the provision of special education services for all on-reserve schools.

10.

Conclusion

Dr. Stelios Georgiades is an assistant professor in Psychiatry and Behavioural Neurosciences and a Core Member at the Offord Centre for Child Studies. His research investigates the development of Autism Spectrum Disorders and other neurodevelopmental disorders and also seeks to develop empirical models for use in diagnosis, treatment, and prognosis of disorders such as these.

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Reviewed by Dr. STELIOS GEORGIADES

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critical review

With regards to improvements to physician While Ontario strongly values a high quality of recruitment, the Northern Ontario School of life for children, the province continues to miss Medicine (NOSM) has performed extensive the mark on more than one measure. Children research on the measures necessary to secure in Northern Ontario do not yet enjoy the level physician retention in Northern Ontario regions. of accessibility to disability support services They have produced compelling research to that are available in Southern Ontario, as a suggest that medical training and extensive direct result of their underserved geographical exposure to the distinct needs of rural northern region. Many families belonging to Aboriginal communities are key to attracting physicians communities also face the challenges of limited to practice in the North.4 Last year, more than disability support, and often to an even greater 50% of the graduating class had elected to degree than any other demographic in Northern remain in Northern Ontario following their Ontario. These families continue to advocate degree, and many are pursuing specialties for increased awareness of Aboriginal cultural in pediatrics.18 Since its inception, NOSM values among healthcare professionals in has upheld a mandate to produce healthcare Ontario. Certainly, much work has yet to be done professionals who are committed to serving in order to bridge the province’s north-south the distinct needs of Northern Ontario, and gap in quality of care for children with special who are explicitly educated about the cultural needs. Further research and analysis of the needs and practices of Aboriginal populations. impacts of these social determinants is crucial; we must continue to inform child health policy Health inequality between Aboriginal and non- in order to implement change intelligently. ■ Aboriginal populations is not a new or unique challenge to Northern Ontario, but given the significant proportion of Northern Ontarian children that are affected by these inequalities, addressing Aboriginal needs is crucial to the improving delivery of care to children with special needs. It will be interesting to observe

6aad35780767 Solomon P, Salvatori P, Berry S. Perceptions of important retention and recruitment factors by therapists in northwestern Ontario. The Journal of Rural Health. 2001; 17(3), 278-285. Ontario. Enhancing Supports for Children and Youth with Special Needs in Northern Ontario. Ministry of Children and Youth Services. Queen’s Printer for Ontario. 2013. Available from: http:// news.ontario.ca/mcys/en/2013/09/ enhancing-supports-for-children-andyouth -with-special-needs-in-northernontario.html Offord DR, Boyle MH, Szatmari P, RaeGrant NI, Links PS, Cadman DT, Woodward CA. Ontario Child Health Study: II. Six-month prevalence of disorder and rates of service utilization. Archives of General Psychiatry, 1987; 44(9), 832-836. Statistics Canada. Canada (Code 01) and Ontario (Code 35) (table). Census Profile. 2011 Census. Statistics Canada Catalogue no. 98-316-XWE. Ottawa. Released October 24, 2012. http://www12.statcan.gc.ca/censusrecensement/2011/dppd/prof/index. cfm?Lang=E Invest Northern Ontario. District Statistics. Facts and Figures. 2014. Available from: http://www.investnorthernontario.com/index.aspx?l=0,1,5,30 MacCharles T. Services for Children and Youth with Special Needs in Ontario, and their Families: Opportunities for Improving their Experiences and Outcomes. Ministry of Children and Youth Services. 2013. Available from: http:// www.children.gov.on.ca/htdocs/English/documents/topics/specialneeds/ PAreport.pdf Carter T. Literature Review on Issues and Needs Aboriginal People. Federation of Canadian Municipalities. 2004. Available from: http://geograph. uwinnipeg.ca/Carter/Publications/ Background/Final%20_Lit_review_Issues%20.pdf King M, Smith A, Gracey M. Indigenous health part 2: the underlying causes of the health gap. The Lancet. 2009; 374(9683), 76-85. Phillips R. Special Education in First Nations Schools in Canada: Policies of Cost Containment. Alberta Journal of Educational Research. 2010;56(1). Alberta Education (2005). Our Words, Our Ways: Teaching First Nations, Métis and Inuit Learners. Recognizing gifts and strengths (pp. 123-149). Available from: http://education.alberta.ca/media/307140/o08.pdf SickKids Newsroom. The Hospital for Sick Children opensTelemedicine Clinic for children in Northern Ontario communities. Public Affairs. 1996. Available from: http://www.sickkids.ca/aboutsickkids/newsroom/past-news/1996/ the-hospital-for-sick-children-openstelemedicine-clinic-for-children-innorthern-ontario-communities.html Northern Ontario Medical Journal (NOMJ). Salute to NOSM graduates. 2013. Available from: http://www. nomj.ca/2013/06/24/salute-to-nosmgraduates-3.html Health Canada. First Nations and Inuit Health Branch Strategic Plan: A Shared Path to Improved Health. First Nations and Inuit Health. 2012. Available from: http://www.hc-sc.gc.ca/fniah-spnia/ pubs/strat-plan-2012/index-eng.php

Ontario. Special Needs. Ministry of Children and Youth Services. 2011. Available from: http:// www.children.gov.on.ca/htdocs/English/topics/ specialneeds/index.aspx. 2. Hanson MJ, Lynch, EW. Early intervention: Implementing child and family services for infants and toddlers who are at risk or disabled. 1995; 78757-6897. 3. Brehaut, JC, Kohen DE, Garner RE, Miller AR, Lach LM, Klassen AF, Rosenbaum PL. Health

among caregivers of children with health problems: findings from a Canadian population- based study. American Journal of Public Health. 2009; 99(7), 1254. 4. Strasser R, Lanphear J. The Northern Ontario School of Medicine: Responding to the needs of the people and communities of Northern Ontario. Education for Health. 2008; 21(3), 212. 5. Young NL, Barden WS, Mills WA, Burke TA, Law M, Boydell K. Transition to adult oriented

health care: perspectives of youth and adults with complex physical disabilities. Physical & occupational therapy in pediatrics. 2009; 29(4), 345-361. 6. Glazier RH, Gozydra P, Yeritsyan N. Geographic Access to Primary Care and Hospital Services for Rural and Northern Communities. 2011: Institute of Evaluative Sciences. Available from: http://www.ruralontarioinstitute. ca/file.aspx?id=4451b6c0-815f-4ffb-a79e-

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Edited by Sharon Yeung

ARTIST MICHAEL SUN

CRITICAL REVIEW

Cancer Stem Cells Targeting the Core of the Cancer

KRUSHANGI PATEL Honours Life Sciences, Class of 2016 McMaster University Correspondence: patelks@mcmaster.ca

After four days, cells transition to a pluripotent state in which they can give rise to any cell lineage in the body. Subsequent divisions restrict cell fates further and ultimately, unipotent SCs are restricted to differentiate into one cell type to maintain and repair tissues.3 SCs exhibit three unique properties that are imperative for tissue growth and maintenance. The first property of SCs is their ability to maintain an undifferentiated state from which they are able to form multiple cell lineages to allow for the development and replenishing of different tissues.2,3 Secondly, they are capable of extensive proliferation even after long periods of quiescence. Lastly, their capacity for self-renewal maintains the SC population within the body. Disruption of the dynamic equilibrium between SC differentiation and proliferation can potentially lead to the development of pathological states. 2,3,4

ABSTRACT Cancer relapse is a major challenge faced after conventional cancer treatment. Emerging research has led to the identification of cancer stem cells (CSCs), which evade conventional treatment and fuel tumour growth and metastasis. CSCs comprise a relatively small population of the tumour but have considerable impact in the relapse of many cancers. Research in the past decade has been instrumental in the development of drugs that eliminate CSCs. This review discusses the CSC model for cancer growth and challenges associated with its validation, as well as drug therapies that show potential for eradicating CSCs. Researchers believe that elimination of CSCs can allow for longer lasting or even permanent remission of cancer.

Introduction

CSCs are a small subgroup of tumour-initiating cells identified in several human cancers including brain, breast, and hematopoietic cancers.2 These cells share strikingly similar characteristics with normal SCs, as they are able to maintain a state of self-renewal and differentiate into the diverse cells that collectively comprise a tumour.2, 5 CSCs may be derived from mutated stem or progenitor cells.2,3 Progenitor cells are a subclass of SCs with more restricted fates but have lost A

MUTATIONS

NORMAL STEM CELL OR PROGENITOR CELL

NEW CANCER STEM CELL

PRIMARY TUMOUR

REFRACTORY CANCER STEM CELL

RELAPSED TUMOUR

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CHEMOTHERAPY

FIGURE 1: Tumour formation and survival due to CSCs. (A) A mutation in a normal SC or progenitor cell can cause it to develop into a CSC, initiating cancer development. (B) Current therapeutics such as chemotherapy are able to eliminate tumour masses but may fail to destroy CSCs, resulting in a relapse. (C) Metastatic CSCs are able to develop secondary tumours away from the primary tumour site.2

SCs are characterized by their plasticity and versatility. Human embryonic SCs are characterized as totipotent for up to four days after fertilization during which they are capable of forming any and all cells in the human body as well as extra-embryonic tissues.

Cancer Stem Cells

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Characteristics of Stem Cells

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In 1963, Canadian scientists James E. Till and Ernest A. McCulloch found evidence of selfrenewing cells in the bone marrow of mice.1 This groundbreaking discovery was the beginning of uncovering the immense therapeutic potential of these unique cells, known as stem cells (SCs). SCs have the ability to self-renew and differentiate into many specialized cell types, making them a promising treatment tool in regenerative medicine. Over the past few decades, research has identified a subgroup of SCs that may contribute to the initiation and survival of several cancers. These cancer SCs (CSCs) share similar properties with normal SCs and drive cancer growth and metastasis. Although chemotherapy is largely effective in eradicating tumour cells, it has been suggested that the small population of CSCs persist due to their drug-resistant nature and regenerative ability. Often, this results in relapse even after successful tumour treatment (Figure 1).

TUMOUR CELL ESCAPE

PRIMARY TUMOUR

METASTATIC CANCER STEM CELL

METASTASES

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the ability to self-renew.2 Self-renewal in surface markers. The CSCs identified by sorting normal SCs is regulated via the Bcl-2, Notch, are then transplanted into immunodeficient Sonic hedgehog, and Wnt pathways. When a mice so their growth and any subsequent SC or progenitor cell acquires a mutation that pathology can be studied in a living system.11 causes these pathways to become dysregulated; The first concern regarding this method is that the resulting uncontrolled proliferation can lead transplanted cells may not represent the true to oncogenesis.6 Hence, the SC or progenitor nature of CSCs; hence, the graft-generated cell has the potential to become a CSC. tumour may not accurately represent the complexity of human tumours.11 Similarly, an Although most of the tumour mass consists of immunodeficient animal transplanted with proliferating cells, a small population of CSCs is cancer cells may not be a true representation vital for tumour survival.7 CSCs can be isolated of a cancer patient.11 Additionally, dissociation from the tumour based on certain cell surface from tissue alters the microenvironment markers. Although definite markers are yet to of the cells, which may disrupt cell surface be elucidated, many CSCs express CD44 and marker expression or other properties.12 It is CD133.5 CD44 is expressed by both normal recommended that researchers confirm that SCs and CSCs, such as those found in breast cells are in fact CSCs by testing for CSC and pancreatic cancers.8 It has been observed characteristics rather than only identifying that CD44+ CSCs can adhere to blood vessels CSCs based on their cell surface markers.13 The and migrate into the bloodstream.8 Thus, CD44 shortcomings in methodology raise concerns may play a role in cancer metastasis. Similar regarding the validity of the model since results to CD44, CD133 is expressed in CSCs such obtained in the lab may not provide an accurate as those in brain, colon, and lung cancers, as understanding of CSC biology in cancer patients. well as in normal SCs.9 In CSCs, CD133 expression has been linked to self-renewal, Even with these limitations, the CSC model metastasis, chemoresistance, and resistance gained support after several studies were able to cell apoptosis.9 Studies have attempted to to trace cell ancestry with lineage tracing use CD44 and CD133 for targeted therapy; and identify CSCs as cells that initiate and however, they have been largely unsuccessful sustain tumours. Schepers et al. (2012) studied due to overlapping expression and functions primary intestinal adenomas in mice and of the markers in normal and cancer SCs. In found that the SC marker Lrg5 marked a order to target CSCs, researchers will need to small population of the adenoma cells. This elucidate unique functional differences between subset of cells was able to generate other Lrg5+ CSC and normal SC markers to prevent toxicity cells as well as other cell types comprising the to normal cells. tumour.14 These results are consistent with the CSC model, which describes CSCs as a rare population of cells within tumours with selfControversy Regarding the renewal and differentiation properties.14 Chen Cancer Stem Cell Model et al., (2012) studied glioblastoma in mice While the CSC model has gained substantial and administered the chemotherapeutic agent support in recent years, some researchers remain Temozolomide to arrest tumour growth. Even skeptical about CSCâ&#x20AC;&#x2122;s role in the initiation and after chemotherapy, a subset of cells persisted maintenance of tumours. In contrast to the and gave rise to new tumour cells. While the CSC model, the original stochastic model for study has not characterized the subset as cancer growth argues that any cell comprising a CSCs, pulse chase experiments showed that tumour has the potential to initiate and sustain the tumour re-growth originated from the the tumour by acquiring somatic mutations small group of persisting cells.15 Combination and developing metastatic capabilities.10 therapy of Temozolomide with Ganciclovir, an antiviral medication that ablates quiescent cells The CSC model has not yet been universally as they enter the cell cycle, impeded tumour accepted in place of the stochastic model due to growth by eradicating this subset of cells.15 the inconsistency of results and the validity of The results of this study are consistent with the methods used to identify CSCs. One of the the CSC model, which characterizes CSCs as greatest concerns regarding its validity arises drug-resistant cells driving tumour growth.15 from the CSC transplantation method used for Although the CSC model has not yet been isolating CSCs to study them in animal models. proven, these lines of evidence and multiple This method involves the sorting of single cell others support the existence of CSCs and suspensions from tumour masses based on CSC their role in tumour growth and maintenance.

2. 3.

Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963 Feb 2 [cited 2014 Dec 2];197(4866):452–4. Jordan CT, Guzman ML, Noble M. Cancer SCs. N Engl J Med. 2006 Sept 21 [cited 2014 Nov 30];355(12):1253–62. Guo W, Lasky JL, Wu H. Cancer SCs. Pediatr Res [Internet]. 2006 Apr [cited 2014 Nov 6];59(4):59R– 64R. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/16549550

Al-Hajj M & Clarke MF. Self-renewal and solid tumor SCs. Oncogene [Internet]. 2004 Sept 20 [cited 2014 Dec 4];23(43):7274-82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15378087 Visvader JE, Lindeman GJ. Cancer SCs in solid tumours: accumulating evidence and unresolved questions. Nature Rev Cancer [Internet]. 2008 Oct [cited 2014 Dec 23];8(10):755–68. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18784658 Reya T, Morrison SJ, Clarke MF, Weissman IL. SCs, cancer, and cancer SCs. Nature. 2001 Nov [cited

8. 9.

2014 Dec 4];414:105–11. Clevers H. The cancer SC: premises, promises and challenges. Nat Med [Internet]. 2011 Mar [cited 2014 Dec 4];17(3):313–9. Available from: http://www. ncbi.nlm.nih.gov/pubmed/21386835 Pham PV, Nguyen ST, Phan NL, Phan NK. The research and biology of cancer. 1st ed. Iconcept Press Publisher; 2013. Li Z. CD133: a SC biomarker and beyond. Exp Hematol Oncol [Internet]. 2013 Jan [cited 2015 Feb 8];2(1):17.

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Edited by avrilynn ding 1.

Dr. Kimberly Dej is the Associate Director of the Life Sciences Program at McMaster University. As an Assistant Professor in the Department of Biology, she teaches undergraduate courses in cellular and molecular biology and strongly encourages undergraduate involvement in research. Her research interests focus on pathways that regulate chromosome behaviour during mitosis.

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Reviewed by Dr. kimberly dej

10. Odoux C, Fohrer H, Hoppo T, Guzik L, Stolz DB, Lewis DW, et al. A stochastic model for cancer SC origin in metastatic colon cancer. Cancer Res [Internet]. 2008 Sep 1 [cited 2015 Feb 3];68(17):6932-41. 11. Sakariassen P, Immervoll H, Chekenya M. Cancer SCs as mediators of treatment resistance in brain tumors: status and controversies. Neoplasia [Internet]. 2007 [cited 2015 Feb 7];9:882-892. 12. Wicha MS, Liu S, Dontu G. Cancer SCs: an old idea - a paradigm shift. Cancer Res [Internet]. 2006 Feb 15 [cited 2015 Feb 8];66(4):1883–90. 13. Diehn M, Clarke MF. Cancer SCs and radiotherapy: new insights into tumor radioresistance. J Natl Cancer Inst [Internet]. 2006 Dec 20 [cited 2015 Feb 12];98(24):1755–7. 14. Schepers A, Snippert H, Stange D, Born M, Es J, Wetering M. et al. Lineage tracing reveals Lgr5+ SC activity in mouse intestinal adenomas. Science [Internet]. 2012 [cited 2015 Feb 10];337:730–5. 15. Chen J, Li Y, Yu T-S, McKay RM, Burns DK, Kernie SG, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature [Internet]. 2012 Aug 23 [cited 2015 Feb 13];488:522–6. 16. Marchal JA, Carrasco E, Ramirez A, Jimenez G, Olmedo C, Peran M, et al. Bozepinib , a novel small antitumor agent , induces PKR-mediated apoptosis and synergizes with IFNα triggering apoptosis, autophagy and senescence. Drug Dev Ther [Internet]. 2013 Oct 25 [cited 2014 Dec 7];7:1301–13. 17. Ramírez A, Boulaiz H, Morata-tarifa C, Perán M, Jiménez G, Picon-ruiz M, et al. HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib. Oncotarget [Internet]. 2014 May 13 [cited 2014 Dec 7];5(11). 18. Verastem Incorporation [Internet]. Needham (MA): Verastem Incorporation; 2014 [cited 2014 November 25]. Available from: http://www.verastem.com 19. Zhang J, Hochwald SN. The role of FAK in tumor metabolism and therapy. Pharmacol Therapeut [Internet]. 2014 May [cited 2014 Dec 16];142(2):154–63. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/24333503 20. Keegan M, Ring JE, Kolev VN, Shapiro IM, Padval MV, Xu Q, et al. VS-6063 (Defactinib) targets mesothelioma cancer SCs directly and through inhibition of tumorassociated macrophages and cytokine production. Annals of Oncology [Internet]. 2014 [cited 2014 Dec 16];25(4):543-563. 21. Zhao X, Guan J-L. Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliver Rev [Internet]. 2011 Jul 18 [cited 2014 Dec 21];63(8):610–5. Available from: http:// www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3132829&tool=pmcentrez&ren dertype=abstract 22. Schultze A & Fiedler W. Therapeutic potential and limitations of new FAK inhibitors in the treatment of cancer. Expert Opin Investig [Internet]. 2010 [cited 2014 Dec 16];19(6):777–88. 23. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CHM, Jones DL, et al. Cancer SCs - perspectives on current status and future directions: AACR Workshop on cancer SCs. Cancer Res [Internet]. 2006 Oct 1 [cited 2014 Dec 5];66(19):9339–44. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/16990346 24. Guan J. Role of focal adhesion kinase in integrin signaling. Int J Biochem Cell Biol [Internet]. 1997 Apr 14 [cited 2014 Dec 16];29(97):1085–96. 25. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer SCs determine tumor growth and metastatic activity in human pancreatic cancer. Cell SC [Internet]. 2007 Sep 13 [cited 2014 Dec 23];1(3):313–23. Available from: http://www.ncbi.nlm.nih. gov/pubmed/18371365 26. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res [Internet]. 2005 July 1 [cited 2014 Dec 7];(13):5506–12. 27. Prince ME, Kaczorowski RSA, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, et al. Identification of a subpopulation of cells with cancer SC properties in head and neck squamous cell carcinoma. PNAS [Internet]. 2007 Jan 16 [cited 2014 Dec 4];104(3):973-978. 28. Rando TA. SCs, ageing and the quest for immortality. Nature [Internet]. 2006 Jun 29 [cited 2014 Dec 17];441(7097):1080– 6. Available from: http://www.ncbi.nlm.nih. gov/pubmed/16810243 29. Rosen JM & Jordan CT. The increasing complexity of the cancer SC paradigm. NIH [Internet]. 2010 May 19 [cited 2014 Dec 6];324(5935):1670–3. 30. Schultze A, & Fiedler W. (2011). Clinical importance and potential use of small molecule inhibitors of focal adhesion kinase. Anticancer Agents Med Chem. 2011 [cited 2014 Dec 12];11(7):593–599. 31. Zachary I. Focal adhesion kinase. Int J Biochem Cell Biol [Internet]. 1997 Jan 10 [cited 2014 Dec 16];29(I):929–34.

critical review

in the lining of internal organs. It is currently in phase two of randomized, double-blind clinical Primary, as well as metastatic CSCs are trials.18 It effectively reduces CSC metastasis largely drug-resistant. They are able to evade and proliferation through inhibition of focal conventional treatment by means of cell adhesion kinase (FAK).19 FAK is a non-receptor cycle arrest at the G0 or G1 phase since tyrosine kinase that is localized at adhesions chemotherapeutic drugs generally target cells along cells attached to the extracellular matrix that are actively dividing.5 For this reason, (ECM). It plays an important role in regulating alternative treatments to chemotherapy must cell migration through integrin signaling.20, 21 be applied in order to target quiescent CSCs Increased FAK expression has been linked to to achieve long lasting remission. Much about the metastatic nature of several tumours and the mechanism whereby primary CSCs initiate FAK is essential for the survival of CSCs.21 and sustain tumours remains unclear. However, Inhibition of FAK by Defactinib reduces research has identified various targets from cell adhesion to the ECM and decreases cell which potential drug therapies have been motility, thus preventing tumour metastasis.22 developed. Bozepinib and Defactinib are novel Defactinib has been highly effective thus far therapeutic agents that target CSCs by altering in clinical trials and shows great potential for signaling pathways to induce apoptosis or improving cancer prognosis. reduce proliferation, and may provide effective therapeutic options in combination with Conclusion chemotherapy. Recent research identified CSCs as dysregulated Bozepinib is a novel anti-cancer drug that cells with SC properties that sustain tumours has been effective in treating breast and colon and evade conventional treatments. While cancers, and has been proven effective against eradicating CSCs may be the answer for CSCs in vitro. The drug is currently being preventing relapses, experimental limitations considered for clinical trials.16 Bozepinib in CSC research need to be addressed in treatment reduces CSC proliferation and order convince the scientific community. In migration, and the expression of proteins particular, xenotransplantation methods may such as beta-catenin, c-MYC, and SOX-2 require modifications or supplemental analysis which contribute to SC characteristics.16 More to ensure the experiment model accurately importantly, Bozepinib induces apoptosis in represents CSCs in patients. Through CSCs after eight hours of treatment.17 Studies current research progress, certain CSChave seen a reduction in CSC sphere size and specific treatment options are already under number with Bozepinib combination therapy development. While Bozepinib and Defactinib in animal models.17 While experiments in mice have shown great potential, many other drugs observed no acute toxicity, weight loss, unusual target cell markers or pathways that are shared behaviour, or kidney and liver damage, more by normal SCs and CSCs, thus raising concerns information is required to fully understand regarding toxicity towards normal SCs. Future Bozepinib’s mechanism of action. However, research should aim to identify CSC-specific if approved, Bozepinib may greatly reduce markers in order to reduce the risk of toxicity chances of cancer relapse. towards healthy cells. The development of drug therapies specifically targeting CSCs Defactinib is a promising new agent for can greatly improve the efficacy of cancer malignant mesothelioma, a cancer that forms treatment and reduce chances of relapse. ■

Drug Therapy

ARTIST MICHAEL SUN

CRITICAL REVIEW

Circulating Tumour DNA A BLood test for monitoring cancer

MARK MANSOUR Bachlor of Health Sciences (Honours) Program, Class of 2016 McMaster University Correspondence: mark.mansour@learnlink.mcmaster.ca

ABSTRACT

DNA fragments found in blood plasma, known as circulating tumour DNA (ctDNA), act novel biomarkers for cancer diagnosis. Through a simple blood draw, ctDNA allows for the genetic characterization of a patientâ&#x20AC;&#x2122;s cancer, which in turn can guide clinical decisions when prescribing a narrow spectrum chemotherapy drug. Current methods in cancer genotyping involve invasive biopsy resections which often compromise patient quality of life, are subject to issues regarding cell heterogeneity, make it difficult to detect secondary tumours, and often provide insufficient yields for genetic sequencing. Meanwhile, ctDNA allows clinicians and researchers alike to monitor the progression of a patientâ&#x20AC;&#x2122;s condition by prospectively collecting multiple blood samples. While not considered common clinical practice, ctDNA analysis has been successfully used to diagnose breast, gastric, colorectal, utero-ovarian, and lung cancers while clinical trials are currently being done for various others. Through ctDNA sequencing, clinicians are capable of characterizing a tumour in a noninvasive manner, consequently allowing them to deliver patient-specific cancer care.

INTRODUCTION

Among many of the medical specialities affected by advanced NGS technology, oncology is undoubtedly one of the most impacted. Whereas broad-spectrum chemotherapy drugs were used in the past, often to no avail, NGS provides the gateway to more specific diagnosis of the genetically diverse nature of cancer.1 NGS eventually became imperative in the advancement of cancer treatment research.

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In traditional methods of tumour genetic sequencing, microscope slides are created for analysis by a pathologist to determine the location of specific cancer cells within the tissue.8 This method, while the current medical standard, is subject to inaccuracies due to the qualitative nature of the histological examination.9 Many cancer cells may present themselves identically, or since ctDNA is found may be indistinguishable within blood, only from normal cells when small amounts are viewed, but may differ in necessary to obtain genotype.9 Consequently, sufficient genetic when specific groups material to determine of cells are dissected from the rest of the the normal genome tissue, contamination from white blood from other subclones cells and the mutated may decrease the validity cancer genome. of the genetic analysis, increasing the possibility of a false positive or negative.10 Additionally, common tissue embedding methods, which utilize formalin-fixed paraffin-embedded (FFPE) compounds ,compromise the quality and integrity of the nucleic acid yields making it difficult to

The cancer biomarker that shows the most promise is circulating tumour DNA (ctDNA), which is composed of 180 base pairs of nucleic acid fragments found in blood plasma.3 CtDNA is found in negligible amounts in normal individuals but is markedly increased in patients with most cancers.4 As ctDNA arises from the same chromosomes originating in cancer cells, they

One of the greatest challenges of current cancer genomics is the heterogeneity of tumours, where the tissue is not composed of a single cell type but a diverse population.5 Frequently, many types of cancers exist within a single tumour, each composed of a different cell-type with its own unique mutation. Additionally, cancer cells may develop further mutations creating their own population of subclones (Figure 1).6 Problems arise from a clinical standpoint when the diverse subclonality of a tumour cannot be treated with a single drug and often paves the way for drug resistance.7 Consequently, this requires the patients to take a complex regimen of different chemotherapeutics, which may aggravate their conditions and compromise their health.

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Genetic sequencing of tumours is currently the standard for cancer diagnosis and prescription of chemotherapy.2 However, it is often impossible to obtain the biopsy samples needed for such genetic analysis due to concerns regarding quality of life.2 Therefore, genetically specific, valid, and reliable biomarkers are needed to avoid the invasive procedures inherent in modern cancer care.

CHALLENGES OF MODERN CANCER GENOMICS

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The advancement of next generation sequencing (NGS) technology since the Human Genome Project has had profound effects on the field of medical genetics. In recent years, it has become possible to sequence specific genes implicated in a suspected disease. This allows for a more targeted diagnosis of actionable mutations for a fraction of the cost and time than was possible with prior methods, such as shotgun and Sanger sequencing.1

provide an appealing alternative to the biopsies which are frequently used in the clinic.3 The following review will discuss the challenges of modern cancer genotyping, the ways in which ctDNA is an appealing diagnostic biomarker, and the recent clinical advances in ctDNA analysis.

identify actionable mutations.9

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ADVANTAGES OF ctDNA ANALYSIS

specifically obtained DNA derived from cancer which is non-specific to any one subclone.4 Therefore, it is relatively simple to gain a collective understanding of the types of cancer that exist within a patientâ&#x20AC;&#x2122;s body, regardless of their location, phenotype, or genetic makeup.

CtDNA analysis proves to be an appealing complement to current biopsy resection techniques. Frequently in cancer diagnosis, a resection is performed to remove the primary malignancy. Afterwards, it becomes BIOLOGICAL PLAUSIBILITY difficult to detect and remove metastatic secondary OF ctDNA ANALYSIS tumours as their frequency make it difficult to resect. In these cases, where multiple metastases are present The biological plausibility of using blood plasma to throughout the body, ctDNA provides an outlet to genotype tumours was first demonstrated when cancer detect actionable mutations for all secondary tumours patients were found to have significantly elevated levels of ctDNA.12 Cancer cells are highly susceptible to immune responses from the body as they are METASTASIS PRIMARY RESISTANCE identified as mutated cells.13 As a result, programmed cell death promotes the expression of pro-apoptotic genes (Figure 2).3,12,13 Among the various changes DISEASE PROGRESSION in cell physiology that occur during apoptosis, the up-regulation of non-specific endonucleases are of significant importance in determining the TISSUE BIOPSY biological origin of ctDNA.12,13 These non-specific FIRST LINE SECOND LINE endonucleases cleave chromosomal DNA without TARGETED (TARGET A) (TARGET B) THERAPY necessitating a signal sequence, causing them to break down DNA at the linker regions between adjacent nucleosomes. Since these events of immune-induced LIQUID BIOPSY apoptosis do not occur at high enough rates in healthy individuals, but are significantly elevated at the site of a tumour, the biological plausibility of using ctDNA NONTUMOR ctDNA TUMOR CELLS as a cancer biomarker is validated.12 DNA FIGURE 1: Circulating tumour DNA and cancer cell heterogeneity. During the progression of disease, new genetically distinct cancer cells emerge, each resistant to a different or multiple types of drugs. In biopsy samples it is difficult to distinguish between different types of cancer cells, but ctDNA analysis is non-discriminatory between different cancer types, allowing for the determination of all genetic subclones of a tumour.11

throughout the body, without the need for surgical intervention.

Additionally, as biopsy samples are difficult to obtain, and are limited in quantity, they cannot be used to monitor the changing condition of the patients as they move through their treatment regimen.11 However, since ctDNA is found within blood, only small amounts are necessary to obtain sufficient genetic material to determine the normal genome from white blood cells and the mutated cancer genome. Since multiple blood samples can be collected prospectively, it can be easily determined if certain subclones have been eliminated or if new ones have emerged.11 Therefore, the convenience of ctDNA analysis can inform clinical decisions whenever it is necessary to change the course of treatment as the patientâ&#x20AC;&#x2122;s cancer changes.

Analysis of ctDNA is also advantageous in that it is capable of culling mutations of a heterogeneous group of cancer cells without the need for qualitative histological analysis.4 Blood plasma contains

RECENT ADVANCES IN CLINICAL RESEARCH The usage of ctDNA analysis for cancer genotyping has been demonstrated to be an appropriate substitute for traditional biopsy sequencing methods across a diverse range of cancers. In a recent clinical trial by Lebofsky et al., a 20 mL blood draw was performed on 34 patients and a corresponding tumour biopsy was also taken when possible.14 Within their patient sample, a total of 29 common cancer mutations, including BRAF, KRAS, TP53, PIK3CA, were found in metastatic ovarian, breast, cervical, thyroid, and colorectal cancers across multiple locations in the body. Furthermore, 28 of these 29 mutations were found in the ctDNA analysis, with an extra APC mutation not found in the tumour biopsy. In addition to the striking 97% sensitivity of the ctDNA analysis, all the patients were found to have sufficient blood plasma nucleic acid yields for sequencing. On the other hand, DNA could not be isolated from seven tumour biopsies due to failure of the resection procedure or insufficient cellularity (less than 30% cancer cell percentage in the tissue), and were deemed unreliable for the detection of actionable mutations. Therefore, ctDNA was shown to be a highly sensitive and more reliable

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1. Thomas F, Desmedt C, Aftimos P, Awada A. Impact of tumor sequencing on the use of anticancer drugs. Current Opinion in Oncology. 2014;26(3):347-356. 2. Overman M, Modak J, Kopetz S, Murthy R, Yao J, Hicks M et al. Use of Research Biopsies in Clinical Trials: Are Risks and Benefits Adequately Discussed? Journal of Clinical Oncology. 2012;31(1):17-22. 3. Mouliere F, Robert B, Arnau Peyrotte E, Del Rio M, Ychou M, Molina F et al. High Fragmentation Characterizes TumourDerived Circulating DNA. PLoS ONE. 2011;6(9):e23418. 4. Catarino R, Coelho A, Araújo A, Gomes M, Nogueira A, Lopes C et al. Circulating DNA: Diagnostic Tool and Predictive Marker for Overall Survival of NSCLC Patients. PLoS ONE. 2012;7(6):e38559. 5. Bozic I, Nowak M. Timing and heterogeneity of mutations associated with drug resistance in metastatic cancers. Proc Natl Acad Sci USA. 2014;111(45):1596415968. 6. Gerlinger M, Rowan A, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. New England Journal of Medicine. 2012;366(10):883-892. 7. Thomas F, Desmedt C, Aftimos P, Awada A. Impact of tumor sequencing on the use of anticancer drugs. Current Opinion in Oncology. 2014;26(3):347-356. 8. Overman M, Modak J, Kopetz S, Murthy R, Yao J, Hicks M et al. Use of Research Biopsies in Clinical Trials: Are Risks and Benefits Adequately Discussed?. Journal of Clinical Oncology. 2012;31(1):17-22. 9. Diaz L, Bardelli A. Liquid Biopsies: Genotyping Circulating Tumor DNA. Journal of Clinical Oncology. 2014;32(6):579586. 10. Holdhoff M, Schmidt K, Donehower R, Diaz L. Analysis of Circulating Tumor DNA to Confirm Somatic KRAS Mutations. JNCI Journal of the National Cancer Institute. 2009;101(18):1284-1285. 11. Heitzer E, Ulz P, Geigl J. Circulating Tumor DNA as a Liquid Biopsy for Cancer. Clinical Chemistry. 2014;61(1):112-123. 12. Madhavan D, Wallwiener M, Bents K, Zucknick M, Nees J, Schott S et al. Plasma DNA integrity as a biomarker for primary and metastatic breast cancer and potential marker for early diagnosis. Breast Cancer Res Treat. 2014;146(1):163-174. 13. Choi J, Reich C, Pisetsky D. The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells. Immunology. 2005;115(1):55-62. 14. Lebofsky R, Decraene C, Bernard V, Kamal M, Blin A, Leroy Q et al. Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Molecular Oncology. 2014. 15. Hamakawa T, Kukita Y, Kurokawa Y, Miyazaki Y, Takahashi T, Yamasaki M et al. Monitoring gastric cancer progression with circulating tumour DNA. British Journal of Cancer. 2014. 16. Lin P, Lin J, Lin C, Lin H, Yang S, Jiang J et al. Clinical Relevance of Plasma DNA Methylation in Colorectal Cancer Patients Identified by Using a Genome-Wide HighResolution Array. Annals of Surgical Oncology. 2014. 17. Jin H, Ma Y, Shen Q, Wang X. Circulating Methylated DNA as Biomarkers for Cancer Detection. Methylation - From DNA, RNA and Histones to Diseases and Treatment. 2012.

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Dr. John Waye received a B.Sc. degree in Microbiology from the University of Guelph, a M.Sc. in Biology from McMaster University, and a Ph. D. in Molecular Genetics from the University of Toronto. Dr. Waye is a Professor in the Department of Pathology and Molecular Medicine at McMaster University, and an Associate Member in the Department of Medicine. His research involves human molecular genetics, including genetic determinants of human disease and the interpretation of forensic DNA testing.

FIGURE 2: Circulating tumour DNA in the bloodstream. When cancer cells undergo apoptosis, small fragments of DNA are released into the bloodstream. The fragments can be extracted from a blood draw and genetically sequenced to determine the genomic nature of the tumour it was derived from.17

critical review

diagnostic tool when compared to tumour biopsy BLOOD VESSEL sequencing. In addition to being a highly sensitive PRIMARY TUMOR biomarker for mutations, ctDNA has also been demonstrated to correlate ctDNA to disease progression. In gastric cancer, Hamakawa et al. used the percentage of ctDNA harbouring a DEAD TUMOR CELL TP53 mutation (the most common in this type of cancer) relative to total plasma DNA as a method to predict recurrence following a tumour resection.15 They found that following surgery, ctDNA containing TP53 mutations had dropped in concentration in all 70% of blood plasma. While ctDNA analysis of their patients. In those that had relapsed, was not found to be as sensitive as tumour TP53 ctDNA had increased over time before genomic DNA sequencing in cancers caused being diagnosed using the gold standard by hypermethylation, blood plasma may act as CT scan. Consequently, prospective ctDNA an appropriate substitute where obtaining a analysis can be used as a predictive tool when tissue sample is not feasible. monitoring the progression of a patient’s condition following a surgery or a round of CONCLUSIONS chemotherapy. CtDNA is a highly sensitive biomarker of Beyond determining genomic mutations multiple cancers and may be used instead associated with cancer, ctDNA analysis of genomic analysis of secondary metastatic has shown modest success in determining tumours where obtaining tissue samples is not epigenetic modifications by utilizing ctDNA. feasible or DNA extraction is not appropriate. Colorectal cancers are typically associated The usage of ctDNA in cancer genomics has with hypermethylation of promoter-affiliated a profound impact in the clinic as it can be CpG islands.16 This typically results in the used to guide the prescription and treatment suppression of gene expression without any with chemotherapeutics. It is advantageous detectable modification of the nucleotide over current gold standards in that it is simple sequence. Consequently, traditional genetic and non-invasive, allowing for multiple sequencing is inadequate for diagnosis and genetic tests to be performed over the course DNA methylation panels are required instead. of a treatment and following a procedure. Lin et al. have recently demonstrated the While ctDNA has been shown to be almost possible usage of a colorectal DNA methylation equivalent to tumour DNA analysis when panel with ctDNA.16 In their large sample of identifying missense mutations, its potential 353 colorectal cancer patients, they sequenced is limited when determining epigenetic the three most common hypermethylated modifications. Future research should be regions, AGBL4, FL11, and TWIST1, in directed towards conducting genetic analysis their tumours, normal tissue, and ctDNA. All in epigenetics with greater sensitivity and three genes were hypermethylated in >80% of evaluating the value of using ctDNA in tumour biopsies, but were only found in 65 to determining the prognosis of patients. ■ Reviewed by Dr. John Waye

ARTIST Eliya Zhao

CRITICAL REVIEW

Glioblastoma Tumours COMPLEX CHALLENGES AND DEADLY OUTCOMES

Alexandra Kilian Bachelor of Health Sciences (Honours), Class of 2017 McMaster University Correspondence: alexandra.kilian@learnlink.mcmaster.ca

ABSTRACT Glioblastoma (GBM) tumours are the most common primary brain tumours among adults, with many treatment challenges. In addition to being highly malignant and fatal tumours, GBMs are also heterogeneous in tissue and genetic composition, difficult to target, frequently recurring and often treatment-resistant. As a result of these challenges, GBM treatment has been essentially unchanged for decades, with minute improvements in patient prognosis, despite active research efforts. Currently, patients have a mean survival time of less than fifteen months. This article aims to explore the current questions in GBM research, including the role and limitations of surgery and chemotherapy treatments, the relationship between age and prognosis, and the controversy surrounding the optimal extent of resection. Additionally, this article outlines the impact of notable research developments in the field, including the role of nanotechnology in the first successful chemo-radiotherapy treatment on otherwise treatment-resistant GBM cells.

introduction

of necrotic tissue, others being highly hemorrhagic, and so on.1 There are many GBM subtypes, which are classified by genetic alterations. Certain genetic alterations affect response to treatment, and thus prognosis.9,10

Surgery, currently the first line of treatment, is inherently limited due to the highly infiltrative nature of the disease. It is not curative as there will always be microscopic amounts of disease remaining postoperatively, requiring additional therapy.1,11 Still, the diffuse nature of the disease limits the effectiveness of adjuvant therapies, as it is difficult to target 100% of the microscopic disease without irreparably damaging the brain tissue involved.11

There are multiple explanations for the difficulties that exist in developing GBM treatments. Firstly, GBMs are heterogeneous and complex with varied clinical profiles.1 Even within a single GBM tumour, there is regional variability, with some areas being composed

Age is a significant prognostic factor of survival for patients undergoing surgery for primary and recurrent GBM, with younger patients having better post-operative outcomes.4,7,16,17 Multiple studies have outlined that agedependent tumour composition and genetic

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aggressive treatment: ONLY FOR YOUNGER PATIENTS?

a MULTITUDE OF CHALLENGES

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GBM tumours may not discriminate, but the blood brain barrier (BBB) does. The selectivity of the BBB, based on lipophilicity, charge, and size of the molecule, disqualifies the use of most chemotherapeutic agents in the treatment of CNS tumours and hinders the development of new, effective agents.2,11,12 The finite arsenal of chemotherapy drugs is limited The current treatment protocol for a newly further by the intrinsic chemoresistance of diagnosed GBM tumour is a debulking surgery GBM tumours. In part, this chemoresistance followed by postoperative adjuvant therapy. is genetically driven. Within GBM tumours, a Adjuvant therapy consists of radiation with population of cells known as CD133 has been concurrent chemotherapy, followed by adjuvant identified.11,13 These cells are found in other chemotherapy.2,3 Regardless of the treatment highly aggressive tumours and are resistant modality pursued, GBM tumours eventually to both radiotherapy and chemotherapy. As recur, as they are difficult to target and resistant such, during the treatments, these cells may to many treatments.4,5 The current statistics survive and subsequently drive a recurrence conclude that GBM tumours have a mean that is mostly composed of these â&#x20AC;&#x153;super cells.â&#x20AC;? recurrence time of less than seven months Additionally, the hypoxic tumour environment and patients have a predicted mean survival can decrease the effectiveness of chemotherapy time of less than fifteen months after primary drugs.14,15 In order to combat natural resistance diagnosis.6,7 Overall, the prognosis is grim, and prevent the development of acquired with only 3-5% of patients surviving more resistance, researchers and clinicians are than 3 years after primary diagnosis.8 This looking into combinatorial therapies, as article aims to explore the current challenges in well as potential treatments involving the developing treatments for GBM tumours and manipulation of the tumour environment.11,14 major questions in clinical GBM management.

critical review

Glioblastoma (GBM) tumours are the most common and most aggressive primary brain tumours among adults. GBM tumours belong to a family of tumours called gliomas, which develop from the glial cells of the nervous system.1 Despite decades of research efforts, a cure for this deadly tumour remains evasive.

critical review

alterations significantly affect prognosis.18,19,20 In 2004, one of the largest series of primary GBM tumours was analyzed for genetic alterations. A significant association was found between age and different genetic alterations, specifically with regards to the TP53 mutation, EGFR amplification, CDKN2A/ p16 alterations, and loss of chromosome 1p in tumour cells. These findings led to the conclusion that the relationship between age and genetic differences impacted, in part, patient prognosis.19 More recently, Lee et al. concluded that, in their patient cohort, the survival benefit after first surgery observed in younger patients is related to the increased prevalence of the ProNeural (PN) subtype of GBM tumours among younger patients when compared to older patients.20 This relationship is significant, as it has been established that PN GBMs are less aggressive and allow for improved survival when compared to other GBM subtypes.9,10,21 Despite convincing evidence in support of age-dependent genetic differences leading to differences in tumour characteristics, many other factors may mediate the relationship between age and prognosis. For example, with increasing age, there is a decrease in host resistance, increased frequency of developing co-morbidities, and a greater risk of developing treatment-related complications after aggressive treatments, including chemotherapy, radiation, and surgery.22

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It is well known that GTR may increase the risk of neurological morbidity compared to STR.29 In the case of GBM tumours, this is a particularly important consideration as GTR is rarely possible without significant morbidity due to the infiltrative nature of the disease.

In 2013, Gonda et al. published an editorial that examined the value of GTR, based on a review of randomized control trials. Although cases were made in support of and against extended resection at primary presentation, the conclusion reached by the authors supported attempting GTR when possible. The authors emphasized that the greatest benefit of GTR is seen in patients that later respond to chemotherapy treatments, namely temozolomide (TMZ) and bis-chloroethylnitrosourea (BCNU). In addition, the publication also identified key research directions, including the identification of responders to adjuvant treatment, particularly chemotherapy, and assessing quality of life after GTR. By identifying responders to adjuvant treatment, the unnecessary risk of post-operative deficits after GTR can be These findings naturally lead to questioning the avoided in patients who are unlikely to respond role of aggressive treatment in elderly patients. to treatment and, therefore, benefit less from Indeed, several clinical studies have explored GTR. However, until the identification process this question and found that, based on age alone, is deemed reliable, responders cannot be elderly patients can tolerate and benefit from denied the potential benefit of GTR, and thus standard GBM treatment, including surgery.23,24 GTR must be attempted where appropriate.29 However, as in all patients, other factors that may indicate a poor prognosis may preclude elderly THE ROLE OF CHEMOTHERAPY patients from benefiting from an aggressive resection and should be taken into consideration At primary presentation, the patient undergoes when developing a treatment plan.25 tumour debulking to decrease the volume of

the tumour, in order to make it more amenable to chemotherapy and radiation.31 Currently, The ongoing controversy the primary chemotherapy drug for GBM surrounding optimal extent of treatment is TMZ. TMZ can akylate and resection methylate the DNA of tumour cells, causing cell death.32 However, as mentioned previously, Considering the infiltrative nature of GBM genetic profiles can differ among tumours, tumours, the extent of resection (EOR) is an influencing tumour response to TMZ and important aspect to consider when outlining other chemotherapies. A protein known as O6surgical guidelines. EOR is a measure of how alkylguanine DNA alkyltransferase (AGT) can much of the tumour is removed during surgery. repair the damage done by TMZ in tumour In addition to contradicting reports in the cells, thereby preventing cell death. In patients literature, EOR is a difficult variable to assess where the gene encoding for AGT is silenced, objectively as it depends on the tumourâ&#x20AC;&#x2122;s the DNA repair occurs to a lesser extent and anatomical location and relationship to results in an improved treatment response.33 eloquent brain regions such as sensory, motor In addition to TMZâ&#x20AC;&#x2122;s potential to stop tumour

hOW MUCH IS TOO MUCH?

or language areas.26,27,28 In most cases, a gross total resection (GTR) is considered to have been achieved when no residual tumour remains on post-operative scans or when a volumetric analysis shows that >95% of the tumour was removed.7 Sub-total resection (STR) indicates that not all visualized tumour was removed.7,29

growth, the agent can also act as a radiosensitizer, which is why radiotherapy is delivered simultaneously with chemotherapy after surgery.2 At recurrence, many treatment options are already exhausted. Most patients have undergone the maximum radiation dosage, and thus further radiation is not administered.34 Chemotherapy and surgery remain as limited treatment options. Not all recurrent tumours are operable and many patients have prior chemotherapy exposure, which can result in drug resistance.34

gold from the nanosphere and the platinum from chemotherapy also released high-energy electrons in the presence of radiation. This created reactive oxygen species (ROS) in the tumour cell environment, ultimately leading to cell death. When the cell lines were treated with the cisplatin-tethered gold nanospheres without radiation, significant cell death was followed by eventual re-growth of the population. Comparatively, when the nanospheres were enhanced with radiation, the patient-derived invitro cell population was completely eradicated, and there was no population renewal. This successful outcome emphasizes the significant role of multi-modal therapies in combating complex diseases and acts as a beacon of hope for developing cancer treatments in the future.

Reviewed by dr. Gurmit Singh

Edited by sANA GILL

24.

25.

26.

27.

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29.

31.

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for recurrent glioblastoma on overall survival. J Neurosurg. 2012 Oct 5;117(6):1032–8. Krex D, Klink B, Hartmann C, Deimling A von, Pietsch T, Simon M, et al. Long-term survival with glioblastoma multiforme. Brain. 2007 Oct 1;130(10):2596–606. Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010 Jan 19;17(1):98–110. Cooper LAD, Gutman DA, Long Q, Johnson BA, Cholleti SR, Kurc T, et al. The Proneural Molecular Signature Is Enriched in Oligodendrogliomas and Predicts Improved Survival among Diffuse Gliomas. PLoS ONE. 2010 Sep 3;5(9):e12548. Lima FRS, Kahn SA, Soletti RC, Biasoli D, Alves T, da Fonseca ACC, et al. Glioblastoma: therapeutic challenges, what lies ahead. Biochim Biophys Acta. 2012 Dec;1826(2):338–49. Mrugala MM. Advances and Challenges in the Treatment of Glioblastoma: A Clinician’s Perspective. Discov Med. 2013 Apr 25;15(83):221– 30. Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, et al. CD133+ and

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CD133− Glioblastoma-Derived Cancer Stem Cells Show Differential Growth Characteristics and Molecular Profiles. Cancer Res. 2007 May 1;67(9):4010–5. Sun S, Lee D, Leung GKK. Chemoresistance in Glioma. In: Lee NP, Cheng CY, Luk JM, editors. New Advances on Disease Biomarkers and Molecular Targets in Biomedicine [Internet]. Humana Press; 2013 [cited 2014 Jul 25]. p. 243–70. Available from: http://link.springer.com/chapter/10.1007/978-1-62703-456-2_14 Haar CP, Hebbar P, Iv GCW, Das A, Iii WAV, Smith JA, et al. Drug Resistance in Glioblastoma: A Mini Review. Neurochem Res. 2012 Jun 1;37(6):1192–200. Park JK, Hodges T, Arko L, Shen M, Dello Iacono D, McNabb A, et al. Scale to Predict Survival After Surgery for Recurrent Glioblastoma Multiforme. J Clin Oncol. 2010 Aug 20;28(24):3838–43. Barker FG 2nd, Chang SM, Gutin PH, Malec MK, McDermott MW, Prados MD, et al. Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery. 1998 Apr;42(4):709–720; discussion 720–723. Simmons ML, Lamborn KR, Takahashi M, Chen P, Israel MA, Berger MS, et al. Analysis of Com-

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Holland EC. Glioblastoma multiforme: The terminator. Proc Natl Acad Sci. 2000 Jun 6;97(12):6242–4. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med. 2005;352(10):987– 96. Ghose A, Lim G, Husain S. Treatment for glioblastoma multiforme: current guidelines and Canadian practice. Curr Oncol. 2010 Nov;17(6):52–8. Harsh GR 4th, Levin VA, Gutin PH, Seager M, Silver P, Wilson CB. Reoperation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery. 1987 Nov;21(5):615–21. Yung WKA, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588–93. Brandes AA, Tosoni A, Spagnolli F, Frezza G, Leonardi M, Calbucci F, et al. Disease progression or pseudoprogression after concomitant radiochemotherapy treatment: Pitfalls in neurooncology. Neuro-Oncol. 2008 Jun 1;10(3):361–7. Bloch O, Han SJ, Cha S, Sun MZ, Aghi MK, McDermott MW, et al. Impact of extent of resection

21.

30.

Dr. Gurmit Singh is a Professor in the Pathology and Molecular Medicine Department, an Associate Member in the Biochemistry and Biomedical Department, and a Senior Scientist at Cancer Care Ontario. He studied at Dalhousie University, where he attained his PhD in Pharmacology and a BSc degree in Biochemistry. His general research interest lies in exploring the preclinical drug development in breast and prostate cancer therapy. In specific, his research efforts are focused on understanding the mechanisms of cancer-induced depression and bone pain, mitochondrial stress signalling and oxidative stress, and glutamatergic intercellular communication in bone metastasis.

20.

critical review

In 2008, Mandl et al. compared reoperation to other salvage treatments,including chemotherapy or stereotactic radiosurgery (SRS), for treatment of recurrence. The study concluded that the reoperation at recurrence, though not found to be significantly correlated with increased morbidity or mortality, had limited benefit without salvage conclusion treatment in the form of chemotherapy or SRS. The authors recommended that reoperation Though the prognosis for GBM patients remains should only be performed if the recurrence grim, it is important to acknowledge that progress results in significant mass effect and when the has been made. Molecular signaling pathways reoperation can be followed by salvage therapy.35 have been deduced, surgical techniques have been improved, and chemotherapy and radiation In July 2014, the first successful multi-modal treatments have advanced, leading to incremental chemo-radiotherapy treatment on otherwise improvements in survival. Though perhaps not treatment-resistant GBM cells was described in as promising as one would hope, each gradual the literature.36 The research team employed the extension of a life is still a clinical and scientific principles of nanotechnology to combine gold achievement. More importantly, beyond science and cisplatin, a chemotherapy drug, creating and medicine, it is a personal success. Extension cisplatin-tethered gold nanospheres. Individually, of life by a month can be incredibly valuable to both gold and cisplatin have cytotoxic effects. a patient and their family. As such, the neuroWhen combined and enhanced with radiation, oncology community should continue to fight the cytotoxic effects were amplified. Both the for and rejoice in these small successes. ■

19.

plex Relationships between Age, p53, Epidermal Growth Factor Receptor, and Survival in Glioblastoma Patients. Cancer Res. 2001 Feb 2;61(3):1122–8. Batchelor TT, Betensky RA, Esposito JM, Pham L-DD, Dorfman MV, Piscatelli N, et al. Age-Dependent Prognostic Effects of Genetic Alterations in Glioblastoma. Clin Cancer Res. 2004 Jan 1;10(1):228–33. Lee Y, Scheck AC, Cloughesy TF, Lai A, Dong J, Farooqi HK, et al. Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age. BMC Med Genomics. 2008 Oct 21;1(1):52. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006 Jan 3;9(3):157–73. Iwamoto FM, Cooper AR, Reiner AS, Nayak L, Abrey LE. Glioblastoma in the elderly. Cancer. 2009 Aug 15;115(16):3758–66. Mohan DS, Suh JH, Phan JL, Kupelian PA, Cohen BH, Barnett GH. Outcome in elderly patients undergoing definitive surgery and radiation therapy for supratentorial glioblastoma multiforme at a tertiary care institution. Int J Radiat Oncol. 1998 Dec 1;42(5):981–7. Chaichana KL, Garzon-Muvdi T, Parker S, Weingart JD, Olivi A, Bennett R, et al. Supratentorial Glioblastoma Multiforme: The Role of Surgical Resection Versus Biopsy Among Older Patients. Ann Surg Oncol. 2011 Jan 1;18(1):239– 45. Chaichana KL, Chaichana KK, Olivi A, Weingart JD, Bennett R, Brem H, et al. Surgical outcomes for older patients with glioblastoma multiforme: preoperative factors associated with decreased survival. J Neurosurg. 2011 Mar;114(3):587–94. Lamborn KR, Chang SM, Prados MD. Prognostic factors for survival of patients with glioblastoma: Recursive partitioning analysis. Neuro-Oncol. 2004 Jul 1;6(3):227–35. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001 Aug;95(2):190–8. Barbagallo GMV, Jenkinson MD, Brodbelt AR. “Recurrent” glioblastoma multiforme, when should we reoperate? Br J Neurosurg. 2008 Jan 1;22(3):452–5. Gonda DD, Warnke P, Sanai N, Taich Z, Kasper EM, Chen CC. The value of extended glioblastoma resection: Insights from randomized controlled trials. Surg Neurol Int [Internet]. 2013 Aug 28 [cited 2014 Jun 6];4. Available from: http:// www.ncbi.nlm.nih.gov/pmc/articles/ PMC3768170/ Oppenlander ME, Wolf AB, Snyder LA, Bina R, Wilson JR, Coons SW, et al. An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity. J Neurosurg. 2014 Apr;120(4):846–53. DeVita VT. The James Ewing lecture. The relationship between tumor mass and resistance to chemotherapy. Implications for surgical adjuvant treatment of cancer. Cancer. 1983 Apr 1;51(7):1209–20. Newlands ES, Stevens MFG, Wedge SR, Wheelhouse RT, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev. 1997 Jan;23(1):35–61. Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, de Tribolet N, Weller M, et al. MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma. N Engl J Med. 2005;352(10):997–1003. Rostomily R, Spence A, Duong D, McCormick K, Bland M, Berger M. Multimodality Management of Recurrent Adult Malignant Glioma: Results of a Phase II Multiagent Chemotherapy Study and Analysis of Cytoreductive Surgery. Neurosurgery. 1994 Sep;35(3):378–88. Mandl ES, Dirven CMF, Buis DR, Postma TJ, Vandertop WP. Repeated surgery for glioblastoma multiforme: only in combination with other salvage therapy. Surg Neurol. 2008 May;69(5):506– 9. Setua S, Ouberai M, Piccirillo SG, Watts C, Welland M. Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma. Nanoscale. 2014 Aug 21;6(18):10865–73.

ARTIST David Hu

CRITICAL REVIEW

Fatty Acid Synthesis and Obesity A TARGETED APPROACH TO POTENTIAL THERAPEUTIC IMPLICATIONs

YongChang Li, Brandon Cheuk, Bokang Zeng, Joshua Chun Honours Biochemistry and Biomedical Sciences, Class of 2015 McMaster University Correspondence: liyc3@mcmaster.ca Glucose

ABSTRACT Obesity is a medical condition attributed to abnormalities in fatty acid metabolism. According to the World Health Organization, over 1.4 billion adults are overweight, and 500 million of these adults are categorized as obese. The World Health Organization has categorized this significant onset of obesity as an epidemic. The lipid synthesis process and its role in obesity-related diseases have been investigated extensively. In this article, we summarized the mechanism of fatty acid synthesis and its dysfunction in type 2 diabetes. We also investigated the effects of methods to mediate weight loss, such as exercise, and both commercial and novel drugs.

Introduction

Findings: Fatty Acid Synthesis and its role in type 2 Diabetes

NADP

Fatty Acid Synthesis

Malate

Acetyl-CoA Carboxylase

Acetyl-CoA Citrate

Malonyl-CoA NADPH

Fatty Acid Synthase NADP

Pyruvate

Fatty Acid Citrate

Figure 1: Schematic of the fatty acid synthesis mechanism (Adapted from Gropper et al, 20081)

TCA Cycle Mitochondria

Rough

Smooth

Endoplasmic Reticulum

fat in the patient’s tissues. It is speculated that the disorientation of lipid homeostasis is the precursor to developing type 2 diabetes. The accumulation of fat in muscle and other tissues plays an integral role in inducing insulin resistance in pre-diabetic patients and decreased activity of pancreatic β-cells5. Clinical evidence indicates that elevated FFA levels may accelerate patients’ transition from impaired glucose intolerance to insulin-resistant type 2 diabetes. High FFA concentrations may affect the insulin signalling pathway by interfering with the insulin signalling cascade responsible for glucose transport in cells. Dresner et al. investigated the effect of increased FFA concentrations on phosphatidylinositol 3-kinase (PI3K), a core signalling component involved in insulin signalling.6 They found that an increased FFA concentration completely eliminated PI3K activity in tested cells, thus disrupting the overall glucose transporting mechanisms. Experimental results have shown that high FFA concentrations demonstrated up to a 50% decrease in PI3K activities in rat models. Other experiments have further demonstrated

MUSCLE CELLS

Muscle cells unable to metabolise glucose due to insulin resistance

Metabolic abnormalities, inheritance and other factors leading to insulin resistance

Insulin secreted into the blood stream

A P R I L 2015

PANCREAS

BLOODSTREAM

Figure 2: Overview of insulin resistance in type 2 diabetes. Metabolic abnormalities, inheritable and external factors lead to insulin resistance of the muscle cell. Glucose remains in the bloodstream, unable to enter the muscle cell or be metabolized. (Adapted from Kahn et al., 20063)

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Type 2 diabetes is a disease characterized by insulin resistance and reduced production of insulin in pancreatic β-cells (Figure 2). Studies have determined a close association between type 2 diabetes and obesity.3 Type 2 diabetes patients often show signs of significant malfunction in their lipid regulation mechanisms.4 This is evident in the elevated levels of free fatty acids (FFA) and triglycerides in their circulation due to either increased fatty acid synthesis or decreased fatty acid catabolism.5 These symptoms are often coupled with excessive deposition of

Pyruvate

critical review

The human body requires the synthesis of lipids through a process known as de novo lipogenesis, which involves carbohydrates and proteins. Factors such as insulin signal the activation of lipid storage and synthesis. Fatty acid synthesis is an essential step in de novo lipogenesis to create fatty acids, which are the building blocks of lipids. In adults, fatty acid synthesis is conducted primarily in the liver and lactating mammary glands, while a lesser amount is generated in adipose tissue.1,2 The synthesis process begins with an Acetyl-CoA molecule translocating out of the mitochondria, where it is then converted to malonyl-CoA (a derivative with 3 carbons) in the cytoplasm. Malonyl-CoA is then catalyzed by the fatty acid synthase enzyme and reduced by the NADPH cofactor to form fatty acids.1 The overall pathway of lipogenesis is described in Figure 1 along with its related metabolic processes.

NADPH

Glycolysis

critical review

that high FFA concentrations affect various upstream proteins in the insulin signalling pathway. Insulin receptor substrate 1 (IRS1) and protein kinase C theta (PKC-θ) were two of the affected proteins.7 (Figure 3) Insulin-stimulated IRS-1 tyrosine phosphorylation decreased and subsequently led to the reduction of glucose transport.7

FIGURE 3: Mechanism of fatty acid-induced insulin resistance in human skeletal muscles. (Adapted from Boden et al., 20027)

IRS-1/IRS-2 serine/threonine phosphorylation IRS-1/IRS-2 tyrosine phosphorylation

Serine/threonine kinase cascade

Glucose PKCθ

PI 3 kinase GLUT-4

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Drugs for Fatty acid

Fatty acid synthase is a major player in the fatty synthesis inhibition acid biosynthesis pathway. Specifically, fatty acids are synthesized by this enzyme from the Inhibitors for fatty acid synthesis are possible intermediates acetyl-CoA and malonyl-CoA. treatment options for obesity. Cerulenin, an Recent findings have shown the involvement antifungal antibiotic, is a natural fatty acid of fatty acid synthase synthase inhibitor.11 dysregulation in insulinCerulenin targets related metabolic disorders.8 β-ketoacyl-acyl carrier fasn has also been A dysregulation of fatty acid protein synthase (KAS). synthase may very well be found to activate the KAS is one of the enzymes the missing link between expression of several in the fatty acid synthase obesity, insulin resistance, complex responsible for the key genes, including and type 2 diabetes. In a condensation reaction of a tenfold increase in study by Wang et al., a acetyl-CoA and malonylinsulin-like growth significant overtranscription ACP to generate acetoacylfactor binding protein ACP, coenzyme A, and of the fatty acid synthase gene, FASN, was observed in 1 (IGFBP) levels. carbon dioxide.11,12 The genetically obese mice.9 They cerulenin substrate inhibits demonstrated a coordinated KAS and thereby causes a regulation between de novo buildup of malonyl-CoA, lipogenesis and the FASN gene. Moreover, which signals for adequate adiposity and amongst 196 subjects, Berndt et al. saw a marked feeding status. Through a series of reactions, increase in FASN mRNA expression in obese the inhibition of FAS causes the subject to individuals in comparison to leaner subjects.10 decrease food intake.11 Cerulenin is a covalent They also observed higher fasting insulin plasma competitive inhibitor of KAS. The cerulenin levels and lowered insulin activity, suggesting a C2 irreversibly binds to the main active site causal relationship between FASN and insulin of KAS at Cysteine 163 in its hydrophobic pocket. However, cerulenin contains an resistance. FASN has also been found to activate epoxide in its molecular structure. Thus, its unstable and reactive structure makes it less attractive as a clinical treatment for obesity.11 Insulin

Plasma Glucose

the expression of several key genes, including a tenfold increase in insulin-like growth factor binding protein 1 (IGFBP) levels.8 IGFBP1 is negatively regulated by insulin and is a possible indicator of insulin resistance, presenting a strong correlation between high FASN levels and insulin resistance.

Fatty acyl CoA diacylglycerol ceramindes

Fatty Acid

Derivatives and analogs of the original compound can occasionally have a greater medical value due to their altered biochemical properties. C75 is a synthesized cerulenin analog which competitively binds to the FAS cysteine active site.12 Loftus et al. showed that C75 treatment resulted in increased weight loss in mice by over 45% (at 60 mg/kg body weight per day) compared to fasting mice.13 No evidence for toxicity was observed in the mice and the treatment was well-tolerated. C75 is a safer alternative to be considered for weight loss treatment. Continued research and clinical trials are required to determine if it is suitable for humans.

In a 2003 study, Goodpaster et al. demonstrated that a lifestyle change involving a modified diet and a regular exercise regimen can result

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Reviewed by Dr. RICHARD EPAND

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Dr. Richard Epand is a Professor Emeritus in the Biochemistry and Biomedical Sciences Department at McMaster University. He studied at the Johns Hopkins University where he earned his A.B. and at Columbia University, where he earned his Ph.D in Biochemistry. His research focuses on biological membranes and the various cell processes with which they are involved.

Gropper SS, Smith JL, Groff JL. Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. 2008. Harvey RA. Lippincott’s Illustrated Reviews: Biochemistry. Lippincott WIlliams & Wilkins Publishing. 2010; ISBN10:160831412X Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006 Dec 14;444(7121):840-6. Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care. 2004 Jun;27(6):1496-504. Boden G, Laakso M. Lipids and glucose in type 2 diabetes: what is the cause and effect? Diabetes Care. 2004 Sep;27(9):2253-9. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999 Jan;103(2):253-9. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest. 2002; Jun;32 Suppl 3:14-23. Menendez JA, Vazquez-Martin A, Ortega FJ, Fernandez-Real JM. Fatty acid synthase: association with insulin resistance, type 2 diabetes, and cancer. Clin Chem. 2009 Mar;55(3):425-38. doi: 10.1373/clinchem.2008.115352. Wang Y, Jones Voy B, Urs S, Kim S, Soltani-Bejnood M, Quigley N, et al. The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. J Nutr 2004;134:1032-1038 Berndt J, Kovacs P, Ruschke K, Klöting N, Fasshauer M, Schön MR, et al. Fatty acid synthase gene expression in human adipose tissue: association with obesity and type 2 diabetes. Diabetologia 2007;50:1472-1480. Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO. Inhibition of betaketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin Structure and mechanism. J Biol Chem. 2001; Mar 2;276(9):6551-9. Giuliano D’agnony, Ira S. Rosenfeld, Juichi Awaya, Satoshi m Ō ura, P.Roy Vagelos, Inhibition of fatty acid synthesis by the antibiotic cerulenin: Specific inactivation of -β ketoacyl-acyl carrier protein synthetase. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 1973; Nov 29, v326:2 Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000; Jun 30;288(5475):2379-81. Richard D, Trayhurn P. Effect of exercise training on the rates of fatty acid synthesis in mice. Can J Physiol Pharmacol. 1984; Jun;62(6):695-9. Askew EW, Barakat H, Kuhl GL, Dohm GL. Response of lipogenesis and fatty acid synthetase to physical training and exhaustive exercise in rats. Lipids. 1975; Aug;10(8):491-6. Askeq EW, Dohm GL, Doub WH Jr, Husotn RL, Van Natta PA. Lipogenesis and glyceride synthesis in the rat: response to diet and exercise. J Nutr. 1975; Feb;105(2):190-9. Goodpaster BH, Delany JP, Otto AD, Kuller L, Vockley J, South-Paul JE, Thomas SB, Brown J, McTigue K, Hames KC, Lang W, Jakicic JM. Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial. JAMA. 2010; Oct 27;304(16):1795-802.

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critical review

in significant weight loss in severely obese patients.17 Participants of the study followed a modified diet that reduced energy intake from 2100 kcal/day to 1200 kcal/day. The diet was Many studies have shown that there is a composed of 20-30% fat, 50-55% carbohydrate, relationship between exercise training and and 20-25% protein. A progressive exercise body weight. A decrease in weight gain and a regimen accompanied the diet. Patients corresponding decrease in body fat is observed performed moderate intensity physical activity in following exercise. During exercise training, a daily 60 minute sessions, for five days each week. proportion of the energy is derived from fat Following the one year study, patients showed oxidation, along with energy obtained through a significant decrease in waist circumference, the glycolytic processes. The catabolic aspect of energy production has been thoroughly visceral abdominal fat, hepatic fat content, investigated.14 However, there has been blood pressure, and insulin resistance. Waist less research on the effect of exercise on circumference, for example, went from an average the anabolic process of fatty acid synthesis. of 124.35 cm to 114.15 cm after one year. This It has been suggested that exercise training holistic lifestyle intervention study demonstrated changes lipid metabolism. Specifically, a successful alternative treatment of obesity carbohydrates are more likely to be synthesized where significant weight loss and the reduction 17 as glycogen stores, rather than fat stores. Richard of cardiometabolic risk factors were observed. and Trayhurn hypothesized that there is an Conclusion imbalance in lipid metabolism during exercise, in which there is a preference for lipid breakdown over synthesis.14 To prove their hypothesis, they Obesity continues to be a global epidemic investigated the role of exercise training on fatty and significant threat to human health. In acid synthesis in mice. Mice were forced to swim this review article, we discussed the role of for two hours each day for a 28 day period. They fatty acid synthesis and fatty acid synthase then measured the rate of fatty acid synthesis in obesity and type 2 diabetes. We also by measuring the incorporation of tritium elucidated possible treatments through both from 3H2O into fatty acids.14 The research data exercise and medicinal approaches. Richard indicated that the trained mice had a rate of fatty and Trayhurn demonstrated that physically acid synthesis three times lower than sedentary fit mice that engaged in regular exercise had mice in brown adipose tissue when measured decreased rates of fatty acid synthesis. Stable at rest15. Trained mice also showed a six fold analogs of cerulenin such as C75 are promising decreased rate of fatty acid synthesis in epididymal candidates for the treatment of obesity in the white adipose tissue when measured at rest.16 future. In 2003, Goodpaster et al. conducted a Richard and Trayhurn’s results corroborated the diet and exercise training intervention to treat results of other studies that found a decrease obesity. Therefore, an appropriate combination in fatty acid synthetase activity in the liver and of pharmacological treatments and exercise glucose-6-phosphate dehydrogenase activity in training can provide a stronger and more white adipose tissue.14 All three studies suggest efficient treatment for obesity. However, many that exercise training promotes a decrease in of these studies are limited to preliminary the rate of fatty acid synthesis, and thus can experimentations on animal models. Additional aid in the prevention of diabetes, obesity, and research and clinical trials are required to fatty liver disease following a suitable regimen. determine an appropriate treatment for obesity. ■

The Effect of Exercise on fatty acid synthesis and obesity

Edited by MATTHEW YAU

ARTIST MELISSA LEE

CRITICAL REVIEW

Hypoxia in Drosophila Embronic Development Implications for organ preservation

KELLY DONG Bachelor of Health Sciences (Honours) Program, Class of 2018 McMaster University Correspondence: kelly.dong@learnlink.mcmaster.ca

hours at 22°C (Figure 1). They were then dechorionated with a waterIn organ preservation, the prevalent problem has always been time: time bleach mixture to remove the outer to analyze the organ, match the organ to a recipient, store the organ, membrane of the embryo so that the transport the organ, and transplant the organ. Due to the quick rate at unfertilized embryos could be easily which tissue deteriorates outside the body, whether that be a result of identified and removed. The embryos loss of blood flow or cellular damage from the hypothermic method` were later transferred to a drop of gas of storage. The experiment investigates the effect that low oxygen (hypoxia) and low temperature has on the development of embryos as permeable halocarbon oil an alternative that may be less detrimental. As demonstrated on the test (a 1:1 mix of series 700 and subject Drosophila melanogaster (fruit flies), both factors can induce series 56 halocarbon oil – from a state of suspended animation, which is a condition in which the test Halocarbon Products Corp., subject stops aging during development. Hypoxia can successfully arrest New Jersey, USA) in order development for up to three times the regular development time, which is around 22 hours at 25°C. At lower temperatures, a greater number to keep the embryos hydrated. of oxygen concentrations are viable and are able to induce suspended Then, jeweller’s forceps were animation for a greater period of time. The results of the experiment may used to separate the fertilized suggest that hypoxia is a possible alternative that may extend the time embryos from the unfertilized and reduce tissue damage for organ preservation. or overdeveloped embryos under a dissecting microscope INTRODUCTION (Figure 2). Next, the embryos were transferred onto grape agar plates Organ preservation today uses hypothermia in halocarbon oil and placed into a clear (low temperature) primarily as the method of plastic bottle. The bottle was flushed out preserving the organs. Using this approach, organs with the lower percentage of oxygen must be cooled from around 37°C to 4°C within and sealed in polyethylene plastic a short amount of time. However, the cooling poly-tubing. Finally, it was placed in causes oxidative stress and produces an excess of an incubator at the tested temperature, cytokine production, which causes inflammation. whether that be at 15°C, 20°C, or 25°C. As a result, most organs can only be stored for a maximum of 6 to 10 hours, depending on the After the time in hypoxia (24h, 48h, 78h), type of organ.1 the embryos were returned to normoxia (i.e., the normal oxygen concentration in This research investigates the use of a completely the atmosphere) and room temperature different agent to preserve organs: hypoxia to develop. The embryos were counted (low oxygen), which can be a less detrimental after 1 or 2 days in normoxia to examine alternative. The hypothesis is that a combination the number of embryos that developed of lower temperature and hypoxia can maximize after suspended animation. the duration of suspended animation and the survival thereafter. Drosophila melanogaster was RESULTS used as a model organism in order to study hypoxia tolerance. The results showed that the hypoxic environment successfully halted the development of the embryos. In addition, MATERIALS AND METHODS with the 15°C temperature, they could also be stored for up to 72 hours, which The study consisted of over 50 trials, each was three times the normal growth rate containing 50 embryos. Each trial combined of the embryos. either 1%, 2% or a control of 21% oxygen (the FIGURE 1: Embryogenesis remaining consisted of nitrogen) at 15°C, 20°C, The average survival (% eggs hatched) for of Drosophila over 11 hours: or 25°C. Each experiment was left in the control samples was 84%, whereas the hypoxic- The images here was taken depleted oxygen and lowered temperature for 1, treated samples had 53% to 67% survival (Figure by Kelly Dong and Max Reed 2, or 3 days to examine the effectiveness of the 3), although there were instances of variation at the University of Waterloo using a confocal laser scanning conditions in achieving a non-lethal arrest over discussed later. Thus, hypoxia could induce fluorescence microscope to an extended period of time. suspended animation in Drosophila embryos indicate the development of a while maintaining the viability of the majority of Drosophila embryo. The fifth image is the stage at which First, the Drosophila embryos were collected the embryos. the embryos were placed in using an automated Drosophila egg collector hypoxia, which is a variable that (Flymax Scientific Equipment Ltd.) after 6–8 The survival rates for 1% and 2% oxygen treatment was controlled for all the trials. ABSTRACT

critical review meducm a teod ru c |a tAoprr i |l A2P0 R 15 I L 2014

critical review m e d u cato r | A p r i l 2015 m e d u cato r | A P R I L 2014

FIGURE 2: Dechorionated Drosophila: From left to right: fertilized, unfertilized, and overdeveloped embryos taken by Kelly Dong and Max Reed under a standard light microscope. The fertilized embryos were sorted from the rest to be used for experimentation.

for each temperature were analyzed using pooled of the normal biological context.4 Inactivation t-tests.2 At 25°C, a t-test verified that there of PKG has indicated a decrease in glutamine was a 95% probability of a significant difference synthesis capacity after an initial surge in in survival between oxygen concentrations. glutamine levels. One third of nitrogen needed to Specifically, embryos in 1% repair tissue damage, especially in a time of stress, oxygen had higher survival at is derived from glutamine. Glutamine is shown room 25°C. However, at lower to increase protein synthesis and wound healing temperatures, there was no rate. PKG allows the cells to adapt to metabolic significant difference in survival processes and repair cells.5 Therefore, the NO/ rates between the different PKG pathway may be a fundamental reason oxygen concentrations. This that Drosophila may enter a state of suspended finding demonstrated that lower animation with limited cellular damage.6 Future temperatures were ideal as both work would consist of examining this pathway of the low oxygen concentrations in humans to determine possible therapies and could viably induce suspended refine the induction into suspended animation. animation with similar results. The embryos also were ALTERNATIVE CONSIDERATIONS able to stay longer in the The success of the experiment shows that low hypoxic environment at lower oxygen environments may be a useful additive temperatures. The lowest to the current method of organ preservation, or temperature, which was 15°C, allowed the even a potential alternative. The ability to store embryos to survive up to three days. However, the embryos for up to 72 hours in the experiment the higher the temperature, the fewer days already exceeds the current limits for organ the embryos could survive after the hypoxic preservation. Certainly, hypoxia may be used to treatment. At 20°C, the embryos could stay in induce the same result with less damage. In the suspended animation for 2 days and at 25°C for process of organ transplantation, there are also only one day. additives that prevent damage due to hypoxic treatment. The lack of blood flow can cause There were two distinct survival rate ranges in ischemic damage (damage from lack of blood the aggregation of trials. The majority of the flow), which in turn causes hypoxic damage trials had ~60% survival. However, several trials (damage from lack of oxygen). Compounds such had a survival rate of ~30%, regardless of the as fructose or sodium free environment already temperature or oxygen levels. This observed exist to prevent such damage.7 Therefore, the difference in survival rate occurred immediately survival rates in this study may be in reality lower after the older female Drosophila were changed as there are no agents added to prevent hypoxic for newer flies. Thus, the maternal age may have a damage. factor in viability as well. Due to the introduction of a new variable, these trials were not included in ADDITION OF MODERATE HYPOTHERMIA While hypoxia acts as a trigger for suspended the rest of the results. animation on its own, the combination of low Therefore, Drosophila were successfully able temperature ameliorates the results. This may be to enter a state of suspended animation using because cooling itself prevents hypoxic damage, hypoxia with relatively high survival for up to only in moderation. It has been shown in adult three days. Low temperatures optimized the animals that cooling the brain by 3–4°C after survival; hypoxic concentrations all resulted in hypoxic damage reduces the magnitude. In high viability and the embryos could be kept for a contrast, greater hypothermia has no beneficiary longer period of time in suspended animation. A effect in terms of reducing hypoxic damage.8 basis for further research is the effect of maternal age on the survival rate of the Drosophila after APPLICATIONS IN ORGAN AND TISSUE PRESERVATION suspended animation. Tissues, stem cells, and organs are in high DISCUSSION demand for those who suffer internal damage and require a transplantation. However, there is a huge concern regarding not only the storage, but TRIGGER PATHWAY In Drosophila suspended animation is triggered also the transportation of organs from the donor by a nitric oxide (NO)/ protein kinase G (PKG) to the recipient. Using hypoxia as an additive to pathway, which is activated under hypoxic lower temperatures may be a method of storing conditions.3 Protein kinase G is associated with organs for longer durations with less damage cell division. PKG in combination with PKA and than hypothermia – allowing more successful PKB is required for growth in vitro, or outside transplantations to occur.

100

15°C

20°C

25°C

% Survival

80 70

Control

1% Oxygen

50 40

2% Oxygen

30 20 10 0

FIGURE 3: Survival Rate of All Groups: The percentage of embryos that survived after one day in the tested oxygen concentrations and temperatures. The bars indicate the standard error from the indicated average among the different trials. Each test group had at least 3 different trials. The control had no significant difference across all temperatures, so the normoxic control trials were all included in the control bar.

Trial Number In addition, the method provides a greater amount of time to examine the organ outside of the body. This gives much more time to determine the compatibility of organs with its recipient and reduces the percentage of rejected organs, which improves the organ screening process.

that increase maternal age causes a decrease in quality of the embryo, which is linked to the timing of the genomic activation.12

CONCLUSION

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Belzer, FO and Southard, JH. Principles of solid-organ preservation by cold storage. Transplantation. 1988; 45:673–676 Zar J. Biostatistical analysis. 1st ed. Upper Saddle River, N.J.: Prentice Hall; 1999. Wingrove J, O’Farrell P. Nitric Oxide Contributes to Behavioral, Cellular, and Developmental Responses to Low Oxygen in Drosophila. Cell. 1999;98(1):105–114. Cowley S, Ko M, Pick N, Chow R, Downing K, Gordhan B et al. The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/ glutamine levels and is important for growth in vivo. Molecular Microbiology. 2004;52(6):1691–1702. Francis S, Busch J, Corbin J. cGMPdependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacological Reviews. 2010;62(3):525–563. Teodoro R, O’Farrell P. Nitric oxideinduced suspended animation promotes survival during hypoxia. The EMBO Journal. 2003;22(3):580–587. Klintmalm G, Levy M. Organ procurement and preservation. 1st ed. Austin, Tex.: Landes Bioscience; 1999. Edwards A, Wyatt J, Thoresen M. Treatment of hypoxic-ischaemic brain damage by moderate hypothermia. Archives of Disease in Childhood-Fetal and Neonatal Edition. 1998;78(2):85–88. Thomson, H. Gunshot victims to be suspended between life and death - health - 26 March 2014 - New Scientist [Internet]. Newscientist.com. 2014 [cited 14 September 2014]. Available from: http://www.newscientist.com/article/ mg22129623.000-gunshot-victims-tobe-suspended-between-life-and-death. html Pandey, UB, Nichols C. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacological Reviews. 2011;63(2):411–436. Lutz S,Weisser HJ, Heizmann J,Pollak S. mtDNA as a tool for identification of human remains. International Journal of Legal Medicine 1996; 109(4): 205-209. Janny L, Menezo Y. Maternal age effect on early human embryonic development and blastocyst formation. Molecular reproduction and development. 1996;45(1):31–37.

critical review

The experiment shows that the combination of Recently, hypothermia has been used to transport low oxygen and low temperature successfully human bodies in critical situations from the slows the development of Drosophila for up to emergency location to the hospital. The idea three times the normal duration. This proves to is that the same processes used to slow down be a viable alternative to the injurious methods of chemical pathways in organ preservation may be hypothermia alone. similarly applied to preserve a comatose human. Thus, the patient may have a higher probability of The method of using hypoxia with the addition surviving in the hospital.9 Similarly, the research of a slightly lower temperature may avoid the conducted demonstrates that hypoxia in addition damage caused by the cooling of the organs. to a slightly lowered temperature may induce the Furthermore, the solutions in which the organs same effect with less tissue damage. are cooled can also help prevent hypoxic damage. These factors together may increase the success IMPLICATIONS OF MATERNAL AGE rate of using hypoxia to preserve the tissue in ON ORGAN SCREENING comparison to hypothermia alone. Therefore, this Drosophila have a correlation to human genetics approach may increase the donor pool and the and chemical pathways, as around 75% of human success of organ transplantation. This research disease genes having a functioning counterpart.10 has implications in improving the utilization of Nonetheless, it is important to continue this organs in the health-care system and maximizing research with human tissue and organs to allow for the probability of organ acceptance. ■ a more comprehensive assessment. Interestingly, it has also been found that the age of the mothers ACKNOWLEDGEMENTS may affect the ability for the embryos to survive, which may be linked to the mitochondria DNA Special thanks to Professor Bruce Reed from that comes exclusively from females.11 The the University of Waterloo, and the Science difference in survival rate of the embryos after the Department of Centennial, in particular Ms. change in age of the mothers may be due to the Ridge, Ms. Tanner, Mr. Gajic, and Ms. Brown. depletion of maternal pools in the mitochondria Also, thanks to Professor Patrick O’Farrell of with increasing age. This may change the way that the University of California, San Francisco and organ donors are screened as well, as donors with Professor Elizabeth Meiering of the University of younger mothers may have organs that last longer Waterloo for their input and advice. in storage. In human embryos, it has been shown

911: Whatâ&#x20AC;&#x2122;s Your Emergency? The Essence of Time in the Context of Trauma Hannah Roche Bachelor of Health Sciences (Honours), Class of 2017 McMaster University Correspondence: Hannah.Roche@learnlink.mcmaster.ca

global perspective

GLOBAL PERSPECTIVE

ABSTRACT Emergency medicine is a central branch of medicine focusing on the immediate decisions and action necessary to prevent death or disability, both in pre-hospital and hospital settings. I have had the opportunity to observe the inner workings of the emergency medical systems both locally here in Hamilton, and globally in places like that of Thailand and Guinea. The stark contrast of emergency health care between developed and developing nations raises distinct observations concerning measures that need to be taken. While in Canada we wait mere hours in clean, warm emergency rooms, millions - even billions - of people around the globe may wait days, months or even years to be seen or treated. This inevitably leads to a drastically increased, and simultaneously avoidable, mortality rate. Yet the issue is not typically an isolated one. Issues of mportance, in the context of a developing nation, are often rooted and intertwined in ongoing struggles of poverty, corruption, and violence. Awareness of a lack of resources is the first crucial step in moving towards a change in failing systems. This perspective aims to compare and contrast the emergency medical systems in place in Hamilton and abroad, in an effort to bring to light the immediate need for drastic intervention. Moreover, this intervention must stem from within each nation and the infrastructure in place, resulting from a desire to tackle this specific branch of the overwhelming cycle of poverty, disease, and death.

A Right and a Privilege

Each year, Canada sees approximately 3 million inpatient hospitalizations, under the care of over 10,000 emergency physicians in over 240 emergency departments.6,7 Closer to home, over 200,000 people in the Hamilton region receive emergency medical treatment each year.8 Hamilton Emergency Medical Services (EMS) is comprised of 178 full time paramedics, with 42 of those positions for Advanced Care Paramedics.8 The average response time for the Hamilton EMS is 10.0 minutes, referring to the time taken for an ambulance or a paramedic emergency response vehicle to arrive on scene.8 The government is also working to better the system - Ontario’s Wait Time Strategy was launched in 2008 in order to reduce the amount of time citizens spend in Ontario’s emergency departments.9,10 EMERGENCY MEDICINE ACROSS GLOBAL PLATFORMS

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In 2013, I spent an extended period of time working in Conakry, Guinea, West Africa, in a centre to house and care for children infected or orphaned by HIV/AIDS. During my time there, I found two-year-old Marie* lying on the ground, her leg visibly deformed. It took almost no time to recognize the signs of a broken femur. However, it was a Friday afternoon and the nearest hospital was closed for the weekend. In Conakry, there would be no treatment for Marie until Monday. There was a distinct lack of pain medications and no possible way to explain to the child what was happening. It took four days to get Marie into a spica cast** and back SADLY, THIS IS A FAR to the center safely. Even CRY FROM REALITY FOR this wasn’t done through A VAST MAJORITY OF the system, but through a CITIZENS; THERE IS A charitable NGO. This was GLARING CONTRAST IN an injury that would push EMERGENCY HEALTH CARE anyone to the front of the BETWEEN DEVELOPED AND line in a Canadian health DEVELOPING NATIONS. care system, but in Guinea, Marie was made to bear it without treatment for almost four days. Moreover, femur fractures like these and associated injuries remain a major cause of morbidity in children.11,12,13 In countries like Guinea where hospitals operate only on particular days and have high medical fees that discourage the average individual, the basic right of health care may seem a mere pipe dream. Guinea, a country with a population of 12 million, has merely three government hospitals.15,16 According to the WHO, Canada has 19.1 physicians

This is no exaggeration: 2.2 billion people live in abject poverty, defined as living on less than $2 a day3. Much of the planet’s population does not have any access, let alone immediate access, to emergency health care. Gary Haugen, founder and president of International Justice Mission (IJM), states with painful precision: “Given that there are at least 2.2 billion very poor people in the world, any condition that affects ‘most poor people’ affects a lot of people.”4 Unfortunately, this is the case with emergency medicine as well.

EMERGENCY MEDICINE AT HOME

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To criticize the speed of Canadian emergency medical systems is a privilege in and of itself. We fail to realize how fortunate we are to have a readily accessible worldclass health care system. Having to wait four hours after sustaining a concussion cannot compare to the situations found in developing countries. What would you do if those four hours became four days? Worse yet, what if those four days became four years?

To begin to discuss emergency medicine in developed and developing countries, we first must define “emergency medicine”. Yale University’s School of Medicine defines emergency medicine as “the specialty concerned with the stabilization, management, diagnosis, and disposition of individuals with acute illness and injury, and action necessary to prevent death or further injury.”5 Emergency medicine weaves together virtually all fields of medicine and surgery into the tapestry we know as health care.

global perspective

The gold standard of human rights measurement, The Universal Declaration of Human Rights, Article 25, states that: “everyone has the right to a standard of living adequate for the health and well-being of himself and of his family, including food, clothing, housing and medical care.”1 In addition to this, the World Health Organization (WHO) in conjunction with the Office of the United Nations High Commissioner for Human Rights, declares that the Right to Health is an inclusive right, consisting of freedoms as well as entitlements. Among these entitlements is the explicit understanding of “equal and timely access to basic health services”, and these services “must be available, accessible, acceptable, and of good quality.”2 Sadly, this is a far cry from reality for a vast majority of citizens; there is a glaring contrast in emergency healthcare between developed and developing nations.

WHAT IS EMERGENCY MEDICINE?

per 10,000 people while Guinea has only one.14,15,16 In a similar case, it wasn’t four days but four years before a patient received proper treatment. In 2012, I sat in an operating room in a jungle hospital located along the Thai-Burmese border. Four years earlier, a 50-year-old patient had fallen off his roof, sustaining significant injury to his lower limbs. It had taken him nearly four years to save enough money to seek the medical attention that he desperately needed. X-ray imaging revealed poorly healed pelvic, femoral, and patellar fractures. Doctors were forced to re-fracture and replace both his hip and his knee. His case wasn’t unusual. Many others outside the reach of the hospital and accessible health care will also suffer from a lack of medical care. Thailand has only three physicians for every 10,000 people, and many other low income countries have similarly inadequate numbers of physicians and medical facilities required for the population.15,16

global perspective

This provides a startling contrast to the situation here at McMaster where the Emergency First Response Team (EFRT) exists. This volunteer group of McMaster students provides 24/7 emergency response to all medical emergencies on the McMaster campus in less than three minutes. The EFRT is a microcosm of the bigger picture, a sample, as it were, of the Hamilton and Canadian emergency systems that illustrates the privilege that we have in our access to such emergency care.

The emergency medical systems available to a majority of the world may seem anachronistic to us. Despite their dedication and effort, many basic resources are unavailable to the doctors and medical staff there. These discrepancies between care in Canada and other parts of the world force me to issue a call to action. First, it is critical that we recognize and are grateful for the emergency medical systems at our disposal, and this undoubtedly means treating them with respect. Secondly, we must acknowledge the obstacles that people across the world face, especially the 2.2 billion living under $2 a day. The lack of medical infrastructure compounds the inequality and poverty that

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**A spica cast begins at the chest and extends all the way down the fractured leg.

Conakry, Guinea, West Africa Our “ambulance” in Conakry.

CASOG (Centre D`appui Aux Sans Abri Et Orphelins De Guinee) - Kids in Crisis Centre Conakry, Guinea, West Africa The concrete playground where Marie suffered her devastating injury.

Dr. Harry Shannon is a Professor in the Department of Clinical Epidemiology & Biostatistics at McMaster University. He received a B.A. in Mathematics at Oxford University, a M.Sc. in Mathematical Statistics at Birmingham University, and a Ph.D. in Applied Statistics at London University. His research interests include global health, evaluation of humanitarian aid, and workplace safety. Dr. Shannon has been a coinvestigator on several international health projects, including a post-2010 earthquake survey in Haiti and a survey in refugee camps in Lebanon. Edited by Abirami Kirubarajan| | Artwork by Belle Cao 1.

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* Marie’s name has been changed to protect her anonymity.

FUTURE STEPS

Reviewed by Dr. Harry Shannon

2. 3. 4. 5. 6.

will inevitably lead to delayed treatment – treatment that should take place within hours, not years. I encourage readers to play a part and take action in improving the emergency medical systems not only in Canada, but also around the world. ■

The Universal Declaration of Human Rights [Internet]. [cited 2014 Dec 30]. Available from: http:// www.un.org/en/documents/udhr/ WHO | The right to health [Internet]. WHO. [cited 2015 Jan 3]. Available from: http://www.who.int/ mediacentre/factsheets/fs323/en/ The World Bank Group. Poverty Overview [Internet]. 2014 Oct. Available from: http://www.worldbank. org/en/topic/poverty/overview Haugen GA, Boutros V. The Locust Effect: Why the End of Poverty Requires the End of Violence. Oxford University Press; 2014. 385 p. Yale University. What is Emergency Medicine? [Internet]. Yale School of Medicine; Available from: http:// medicine.yale.edu/emergencymed/whatis.aspx CAEP. Human Resources Issues In Emergency Medicine [Internet]. Canadian Association of Emergency Physicians (CAEP); Available from: http://caep.ca/ advocacy/romanow-commission/human-resourcesissues

7. StatsCan. Health Care Professionals [Internet]. Statistics Canada; Available from: http://www.statcan. gc.ca/pub/91-550-x/2008001/part-partie1-eng. htm 8. Cbulthui. About Us - EMS [Internet]. [cited 2015 Jan 3]. Available from: http://www.hamilton. ca/CityDepartments/EmergencyServices/EMS/ About+Us+-+EMS.htm 9. Government of Ontario M of H and L-TC. Wait Times - Ministry Programs - Public Information - MOHLTC [Internet]. [cited 2015 Jan 3]. Available from: http:// www.health.gov.on.ca/en/public/programs/waittimes/strategy.aspx 10. MacAdam M. Improving Hospital Performance [Internet]. Bertelsmann Stiftung; Available from: http:// www.hpm.org/en/Surveys/CPRN_-_Canada/13/ Improving_Hospital_Performance.html 11. Brown D, Fisher E. Femur Fractures in Infants and Young Children. Am J Public Health. 2004 Apr;94(4):558–60.

12. Dodd A. Paediatric femoral shaft fractures: What are the concomitant injuries? 44(11):1502–6. 13. Rewers A, Hedegaard H, Lezotte D, Meng K, Battan FK, Emery K, et al. Childhood Femur Fractures, Associated Injuries, and Sociodemographic Risk Factors: A Population-Based Study. Pediatrics. 2005 May 1;115(5):e543–e552. 14. The toll of a tragedy. The Economist [Internet]. 2014 Dec 29 [cited 2014 Dec 30]; Available from: http:// www.economist.com/blogs/graphicdetail/2014/12/ ebola-graphics 15. The World Bank Group. Physicians (per 1,000 people) [Internet]. World Health Organization, Global Atlas of the Health Workforce; Available from: http:// data.worldbank.org/indicator/SH.MED.PHYS.ZS 16. WHO | Registration update - countries or areas [Internet]. WHO. [cited 2014 Dec 30]. Available from: http://www.who.int/gpsc/5may/registration_update/en/

ROUNDTABLE

Within the next 25 years, what will be health care’s greatest challenge? The Meducator asked faculty, students, and the greater Hamilton community this question as part of our new Round Table initiative. The question is meant to inspire unpredictable answers, challenge people into thinking thoughts they normally might not have, and provoke us to ask each other questions we have been asking ourselves. We’ve presented a collection of the responses here to consider new perspectives. Emerging from your contributions is a way of thinking that encourages us to imagine new ideas, draw attention to existing ones, and question old ones. Please see below.

AGING “While medicine and health care are seeking to extend life, we must also find sustainable ways to improve quality of life and train compassionate, capable healthcare providers.” - Johnny-Wei Bai, U of T Medical School Student

HUMAN COMPASSION “Medicine is both a science and an art.” - Humna Amjad, BHSc (Honours) student “We will have to look at opportunities [...] for personalized care [...] based on the fundamental information we gather.” - Dr. Gurmit Singh, McMaster University Professor

Medical Interns have spending less time with patients at a declining rate since 2003, using only on average eight minutes per patient. http://www.ncbi.nlm.nih.gov/pubmed/23595927

“...it is inevitable that the next 25 years will witness the retirement of millions” - Anna Goshua, BHSc (Honours) student “We need to invest more resources into long-term care facilities as well as geriatric care.” - Jack Zhang, BHSc (Honours) student

PRIVACY “ Socially and habitually we have not yet internalized a set of principles for the use of electronic health records that prioritize protection of privacy.” - Barb Bloemhof, Economist and BHSc Instructor

According to HIPAA*, there has been a 138% increase in the number of health records breached from 2012 to 2014. http://www.healthcareitnews.com/news/hipaa-data-breaches-climb-138-percent

“People like aging at home anyways.” - Sharon Smith, Student Occupational Therapist

By 2040, it is estimated that worldwide, there will be 1.3 billion people age 65+. http://www.nia.nih.gov/newsroom/2009/07/ unprecedented-global-aging-examined-new-censusbureau-report-commissioned-national

DRINKING WATER “Today, over a billion people are already at risk for water shortage, as they lack access to clean water for basic hygiene and sanitation.” - Ashley Lam, BHSc (Honours) student

In just 20 years, the UN World Water Assessment Programme anticipates a 30% decrease in the amount of available water on Earth. http://www.sciencedaily.com/releases/2014/07/140729093112.htm

INTEGRITY “Is medicine turning to a “vending machine” model where patients [..] press the button for the test they want, and we comply out of fear of litigation and complaints?” - McMaster University Family Physician “The Doctor and our industry deserve a lot more scrutiny than they currently don’t get.” - Dr. Drew Bednar, Orthopedics Professor

From a survey of 300 physicians, more than 76% believed that malpractice litigation had hindered them from providing quality care to patients. http://www.aaos.org/news/bulletin/janfeb07/clinical2.asp

SUPERBUGS “...as life moves on in the next 25 years, what saved the global population for the past half century may also be what leads to the next catastrophe.” - Wayne Fang, BHSc (Honours) “Infections transmitted through contaminated medical equipment [...] have ravaged through hospitals” - Alanna Miller, Life Science

Approximately 20% of new diseases are resistant bacteria resulting from antibiotic overuse. http://www.npr.org/templates/story/story.php?storyId=19226040

Full responses can be found at www.meducator.org/roundtable1

* Health Insurance Portability and Accountability Act

INTERVIEW SPOTLIGHT

Mark Brender The Role of Partners in health in Combatting the west african Ebola epidemic

Vishalini Sivarajah1 , Priyank Bhatnagar1 , Hannah Cho 2 , and Saeha Shin1 Bachelor of Health Sciences, Class of 2015 Bachelor of Biology and Pharmacology, Class of 2016 McMaster University Correspondence: vishalini.sivarajah@learnlink.mcmaster.ca

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What would you say are the goals of PIH Canada?

The goal of PIH Canada has always been to bring more resources to the work that PIH is doing, and to find ways that we can add unique Canadian value. When we started, we decided to focus on two countries, Haiti and Rwanda. Both countries have had strong ties to Canadians. There is a  Partners in Health (PIH) is a not-for-profit international organization large Haitian community in committed to providing a preferential option for the poor in health care. PIH Montreal, and we should never was founded in 1987 by Paul Farmer, Ophelia Dahl, Jim Kim, Thomas White, forget the work of Canadians, and Todd McCormack in Boston, Massachusetts. Partners In Health Canada including Roméo Dallaire, in (PIHC) was founded in Toronto in 2011. Recently, PIH has taken a major role Rwanda before and during the in combatting the Ebola epidemic. As members of the McMaster University 1994 genocide. PIH operations chapter of Students for PIHC, we had the opportunity to speak with PIHC are also the largest in Haiti and director Mark Brender about PIH’s work, including its involvement in West Africa. Rwanda, so it made a lot of sense to focus on those two countries.

Wellbody Alliance. These are community-based organizations that grew out of relationships built in Boston where PIH was founded. Soon, PIH was asked by the governments in Liberia and Sierra Leone to expand our involvement. Our work has ranged from providing direct care to Ebola patients in Ebola treatment units to hiring community health workers. We also hire Ebola survivors “Our goal isn’t just to serve as support to provide care, but staff or caregivers for to provide public orphaned children. sector health Overall, we’re working professionals in partnership with with the skills and communities to help rebuild shattered training that they health systems. need in order to

serve patients well

Could you tell us a little bit about how PIH has been involved in combatting the Ebola crisis in West Africa?

You said that PIH works with the government in affected countries. Have you faced issues working with local governments?

Everywhere that we’ve worked, I think there are always challenges. But there came a point in PIH’s evolution when there was a realization that if we’re not building capacity within the public sector, it’s the wrong way to go. Only the public sector can really bestow rights on its citizens.

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Over the past three years, we have been working to raise awareness for PIH Canada in order to build our fundraising capacity, and to reach out to potential donors who are interested in global health and social justice work. We also think that we have something to add to the discussion around health equity, using the PIH example over the past three decades as proof of what is possible. On a programmatic level, PIH Canada is leading a variety of projects, from HIV treatment to cancer care to gender-based violence treatment and prevention, as well as the first emergency medicine residency in Haiti’s history. Our goal isn’t just to provide care, but to provide public sector health professionals with the skills and training that they need in order to serve patients well and build stronger health systems.

interview spotlight

Mark Bender with the PIH McMaster Team

The PIH model is not and build stronger just about stopping the health systems.” transmission of Ebola, but also working to integrate prevention and treatment. We need to use the attention given to Ebola as an opportunity to build a platform of primary care. The reason Ebola has taken such a hold is because of weak health systems. If the goal is the long-term improvement of Sierra Leone and Liberia’s response to similar health crises in the future, we really need to focus on helping the government train more health workers, improve infrastructure, and generate knowledge about treatment protocols so that we can do better in the future.

Initially, PIH became involved by supporting two organizations that were already working in Liberia and Sierra Leone – Last Mile Health and

Non-governmental organizations cannot deliver on the right to health care, clean water, or adequate food. But governments with few resources can’t do it on their own either, and it doesn’t happen overnight. That’s why there needs to be long-term commitments, starting at the community level. When people “It’s important to can be accompanied be well educated by a community health on what’s going worker on a regular on – listening to basis, and they can go and learning from to a health centre with organizations adequate resources, we start to build health and people doing in the community. It’s the work on the a model we aspire to ground.” wherever we work.

interview spotlight

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If a certain amount of money were donated to PIH at this moment in order to combat the Ebola crisis, what would be prioritized? Our patients’ immediate needs should always be prioritized, of course. The larger answer, though, is that we need much more than that. We need to provide jobs and health care outside of the Ebola crisis as well. The crisis has really devastated the health systems because many health workers don’t have the proper equipment to do their jobs and stay safe. People die from AIDS, malaria, and childbirth - not because we don’t know how

to treat these patients, but because Ebola decimated whatever health infrastructure existed. Health workers are scared to go to work. Also, people living in poverty may have needs across the spectrum. They need health care, food, and social supports so that they don’t to choose between, say, putting food on the table or sending their children to school. We need to work on this not just in the upcoming months, but on an on-going basis to help survivors and communities deal with these issues in a comprehensive fashion.

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What can students do to help during the Ebola crisis?

It’s important to be well educated on what’s going on by learning from organizations and people doing the fieldwork. People can also donate; students may not have a disposable income, but it really is true that all contributions are incredibly important. It also helps to realize that there are marginalized and underserved communities everywhere including Canada, whether it be in inner cities or Aboriginal communities in the north. This work needs to happen in so many places, and there are so many wonderful ways to contribute. ■

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To learn more about PIH Canada, their work, and vision. Please visit http://pihcanada.org/ . To learn more about PIH McMaster, please contact the article’s authors.

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