Applying for scholarships this fall? The MBPGSU is piloting a new project to help you out. Join us Monday, September 12th from 4-5pm in room 7-605 at PMH for an organizational meeting and to find out more about how the program will work. What: Scholarship Workshops When: Mondays 4-5pm, room 7-605 PMH from September 12th to October 10th
Questions? Contact Shawn Stapleton (email@example.com) for more information.Read More
By Diana Merino Each month we will review/feature an article published by one of our very own MBP students in the biology and/or physics stream.
This article features the publication "Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study" by Villani et al., Lancet Oncol. 2011 Jun; 12(6): 559-67. (PMID: 21601526) [Link to Paper]
Click! That’s all it takes to get your genome sequenced nowadays. But how would you benefit from knowing the genetic code that determines the most infinitesimal details of your being? What could you do with this information?
Imagine you sequence your genome and an underlying disease predisposition is uncovered in between your millions of T’s, C’s, A’s, and G’s...what would you do now? Would you benefit from subjecting yourself to constant tests and medical examinations with the hope of preventing disease?
These are perhaps some of the questions that individuals with Li-Fraumeni Syndrome (LFS) might have asked themselves at one point or another. LFS is a cancer predisposition syndrome in which patients have increased incidence for soft tissue sarcomas, osteosarcomas, brain tumors, adrenocortical carcinoma, leukemia and premenopausal breast cancer. About 70-83% of patients carry a germline mutation (a mutation found in every single cell) in the tumor suppressor gene TP53, which increases their lifetime risk of cancer to as high as 73% in males, and 93% in females. Although LFS patients would greatly benefit from a comprehensive surveillance protocol, no strict guidelines have been implemented to date, mostly due to the complexity of this syndrome as exemplified by the diverse range of tumors and variability of age at onset.
The latest Malkin lab publication examines the benefit of a comprehensive biochemical and imaging surveillance protocol in LFS families carrying mutations in TP53.
Dr. Anita Villani and colleagues identified 33 TP53 mutation carriers from 8 LFS families through a multi-institutional effort between the Hospital for Sick Children in Toronto, the Children’s Hospital of Los Angeles, and the Huntsman Cancer Institute at the University of Utah in Salt Lake City. 18 out of the 33 carriers decided to undergo clinical surveillance, which included various biochemical and imaging tests, such as blood tests, urinalysis, MRI and ultrasound scans. This surveillance strategy is specific for each cancer type associated with LFS and varied between children and adult patients due to the different frequency of diagnoses observed in each age category. For this analysis, the primary and secondary outcome measures were the detection of new cancers and overall survival, respectively.
The findings of this study were quite striking. In the surveillance group, 10 asymptomatic tumors were detected in 7 patients. These tumors included small, high-grade tumors and low-grade or premalignant tumors. All seven patients (100%) were alive after a median follow-up time of 24 months. On the other hand, 12 symptomatic tumors presented in 10 patients in the non-surveillance group. These tumors were mostly high-grade, high-stage tumors. Only 2 out of the 10 patients (20%) survived until the end of follow-up (p=0.0417). Overall survival analysis revealed that TP53 mutation carriers with LFS in the surveillance group had a 3-year overall survival of 100%, while those in the non-surveillance group had a 3-year overall survival of only 21% (p=0.0155).
The authors note that the surveillance protocol enabled the detection of smaller, pre-symptomatic malignancies that were managed before progression and metastasis. In most cases, the early detection of these malignancies prevented the use of systemic or radiation treatment and favouring the use of definitive localized treatments, which reduced the side-effects and the health burden that commonly used cancer therapies inflict on patients.
It is also important to note that part of the success of the surveillance strategy tested is adherence to follow-up appointments. The article addresses this by suggesting that adherence in patients with surveillance methods could be improved by continuous attention and engagement of a multidisciplinary team of specialists.
In patients with cancer susceptibility syndromes, the possibility of burnout is quite high due to lifetime surveillance. As such, it is crucial to implement surveillance protocols that address this issue and institute initiatives that decrease the risk of burnout through accountability systems.
In a day and age in which access to our genetic code is as simple as a cheek swab and a credit card payment, it is crucial to have the proper insight as to how this knowledge can be used for our benefit. This article demonstrates that personalized surveillance protocols, which are designed taking into consideration each individual’s genetic susceptibilities, are extremely effective at detecting early tumors and improving overall survival. In patients with LFS, the implementation of genetic testing and personalized screening strategies is necessary as it will help patients lead longer lives, increase quality of life through early tumor detection and avoidance of side effects associated to systemic treatments, and enable them to make informed lifestyle decisions.Read More
There is a proposal to change the Student Seminars schedule so that students speak at their home location. This will result in fewer physics students speaking downtown and fewer biology students speaking uptown. Both locations will still have talks from senior PhD students, 2nd year students and 1st year students. Additional comments can be posted as a comment to this post or emailed to firstname.lastname@example.org.Read More
by Haydn Liang
Graduate Research in Sunnybrook vs. Downtown
Almost all graduate programs in the faculty of medicine are research-based. Most of this work is carried out in hospital research centres or at research facilities on the University of Toronto campus. While most hospital laboratories are close to the university in downtown Toronto, there is also a major hub of research located uptown at Sunnybrook Research Institute. This creates considerable problems for students looking to work with a professor with a project of their interest as significant cutting edge research is conducted at Sunnybrook, notably in the field of medical imaging.
With all these choices available to graduate students, where should you choose to do your graduate work? On one hand working in downtown puts students close to where they might want to take courses and pursue extracurricular endeavours and join student unions; on the other hand many projects at Sunnybrook are at the leading edge of scientific innovation. To make this decision more balanced, Sunnybrook also offers students a free shuttle bus between the hospital and downtown. It runs from 6am to 6pm and takes about 30 minutes to bring you Women’s College, 1 block east of Queen’s park station.
At the end of the day, it’s really all about what you feel is important though personally: the thought of working on a project that you are not really interested in for no less than a few years makes for a very painful graduate school experience.
(Haydn Liang is a PhD candidate in MBP in the biology stream who conducts his research at Sunnybrook Hospital, if you have questions for him you can contact him at Haydn.Liang at utoronto ca - Ed. Samuel Oduneye)Read More
By Alison Aiken This post highlights the work of Ryan Draker from Dr. Peter Cheung’s lab, published earlier this year in Nucleic Acids Research (PMID: 21245042) [Link to Paper].
In order for DNA to fit into cells, it gets coiled around octamers of small, positively charged proteins: the histones. Two each of histones H2A, H2B, H3 and H4 form the core of the nucleosome, around which DNA is coiled. Variant histones, which can differ significantly from core histones in their amino acid composition, can replace core histones in the nucleosome and are normally deposited in specific regions. A variant of H2A, H2A.Z, has been implicated in several cellular processes, including the regulation of transcription. Interestingly, H2A.Z can have either a positive or negative influence on gene transcription. This histone variant can be post-translationally modified by either acetylation or mono-ubiquitylation. Previous work by the Cheung lab has shown that H2A.Z is ubiquitylated by Ring1b, an E3 ligase that is part of the Polycomb Repressive Complex 1, and that mono-ubiquitylated H2A.Z is associated with transcriptionally inactive chromatin. The authors hypothesize, therefore, that the deubiquitylase(s) for H2A.Z would play an important role in the activation of transcription.Read More
Bullet-proof your resume. In addition to journal publications, posters and oral presentations constitute yet another way of bolstering your academic C.V. Rome was not built in a day, and neither is a great resume, so don’t miss this opportunity.
Hone your presentation skills. Being able to convey your ideas and findings in an eloquent and concise manner is an integral part of being a successful researcher. The JLM Research Symposium presents a unique opportunity for MBP students (especially first years!) to confront their fears of public speaking and practice presenting to a diverse scientific audience (hint: think MBP seminars!)
Compete for prizes. Veterans of the scientific conference circuit will also get a chance to square off against past and new challengers. Prizes (and bragging rights) will be awarded for best poster, as well as best MSc and PhD oral presentations.
Peer feedback/Showcase your research. Participation will also enable you to garner valuable feedback from your fellow peers. Getting an outsider’s perspective is sometimes what is needed to get you thinking outside of the box.
Note: Abstract submission will be open from April 4 - May 18. Fill out the registration form and submit your abstracts (500 words or less) either to email@example.com or through our online form.Read More
By Greg Anderson This post highlights some excellent recent work published by MBP student Monique Rennie at the Mouse Imaging Centre (MICe). The full article is published as Rennie et al., Am J Physiol Heart Circ Physiol 300: H675-H684, 2011.
At least once a day, I find myself in a state of shock-and-awe as I witness someone my own age or younger smoking a cigarette. For some reason, this is more surprising to me than, say, a 60-year old man smoking. It's not as though anyone born post-1980 doesn't know about the dangers of smoking; it's been drilled into our heads from a very young age. Yet the habit persists. Maybe not as many people smoke now as opposed to 1960, but still, the tradition lingers. And now, here to shed more light on the dangers of pre-pregnancy smoking comes new research conducted by members of the Medical Biophysics department.
Polycyclic aromatic hydrocarbons (PAHs) are the main toxic components of cigarettes, in addition to being common environmental pollutants. The negative effects of PAHs on growing fetuses is perhaps their most devastating feature: exposure can lead to fetal growth restriction, reduced fetoplacental blood flow, and a whole host of other morbidities. So while the proportion of women who smoke during pregnancy has dramatically decreased in recent decades, it turns out that this may not be enough. You see, PAHs have the uncanny ability to accumulate in both adipose and mammary tissue of smokers, thus allowing the toxic chemicals to be released into the blood stream during pregnancy. However, there is a scarcity of information on the actual effects of PAH accumulation on pregnancy outcomes in the literature. Thus, Monique and her team set out to try to get to the bottom of some of these nagging questions, using some very sophisticated and novel imaging techniques. "This is a fantastic paper (not to toot my own horn), because those who care only about imaging physics will find it interesting just as much as those who only care about the biological effects of smoking on pre-pregnancy fetuses will" says Monique (after being cornered by yours truly).
Using micro-computed tomography (micro-CT) and some novel vessel tracking software developed by Dr. John Sled, Monique has shown that it's possible to image the growing vasculature of the placenta and to quantify many physical characteristics of these blood vessel trees. In fact, using this vessel tracking software, the number, physical dimensions, and physical characteristics (such as blood pressure) of the developing placental vasculature can be accurately determined. This is an extremely important step in the field of developmental biology, as it allows this field to rely less on qualitative, descriptive science and turns it into a more quantitative and numbers-driven science. As well, the ability to manipulate these vascular trees in 3 dimensions is extremely advantageous, as questions of form and function can now begin to be answered.
Mice in this study were injected with either corn oil (control) or PAHs over a 9-week period to simulate smoking the equivalent of 7 cigarettes a day in humans. Following the last PAH administration, the female mice were then mated with normal male mice, and their fetuses were dissected at embryonic day 15.5 (this is close to the end of pregnancy; most mice have a gestation period of approximately 18-20 days). Following micro-CT analysis, some extremely interesting results were obtained. Compared to control mice, the PAH-treated mice had placental vasculatures that were normal in size (i.e. the span and depth), but that had a 27% reduction in the number of arteriole-sized blood vessels within the vascular tree. The absence of this vast a number of arterioles in the vascular tree led to a subsequent 30% increase in fetoplacental arterial vascular resistance (which is very harmful to the developing fetus as it corresponds to a 19% decrease in umbilical blood flow), as well as leading to an increase in tortuosity of the vascular tree itself. Both of these factors contribute to fetal weight restriction. What would be interesting to see is how the pups born of these PAH-treated mothers would respond to cognitive tasks later in life.
So there you have it: even quitting smoking before becoming pregnant can have dire consequences on the health of unborn children. Using sophisticated, in-house generated computer algorithms, Monique has been able to show that PAHs can negatively affect the placental vasculature not by necessarily changing its size, but by causing it to become more sparse, thus leading to increased vascular resistance. As an imaging paper, this study helps transform developmental biology into a more quantifiable and definitive science (as well as providing biologists with images that truly make one say, "wow"); as a biological paper, this study sheds even more light onto the devastating side-effects of smoking by providing clear, quantitative results. Truly this is the type of work that defines "medical biophysics", and reflects the unique nature of our department. As if anyone needed more reasons to quit smoking, now we're reminded of Helen Lovejoy's' famous Simpsons quote: "Won't somebody please think of the children!?"Read More
The James Lepock Memorial Student Research Symposium is set for June 2, 2011 at Princess Margaret Hospital. This annual event is organized in the style of a scientific conference and is an opportunity for MBP graduate students to showcase their research activities. It's a great way to get exposure within our community and to gain experience in making poster and oral presentations.Read More