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2013 ANNUAL REPORT


Cover Image: “Cancer cells change their neighbours” Image shows induction of a bone degrading enzyme (Tartrate Resistant Alkaline Phosphatase “TRAP” stained in pink) after the precursor cells were incubated with small packets of biological material (microvesicles) shed from a prostate cancer cell line. This may be one mechanism of how prostate cancers spread to the bone. Credit: Lara Petelin (Honours student from the Hill Group)


OUR VISION IS TO IMPROVE HUMAN HEALTH OUR MISSION IS TO TRANSLATE BASIC SCIENCE INTO BETTER TREATMENTS

RESEARCH AREAS Cancer

Genomic Medicine

Immunology

FAST FACTS 270 Researchers, Support Staff and Students Students from more than 30 countries Two spin-off companies: Dendright and Coridon State of the art facilities 1


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HIGHLIGHTS OF 2013

MESSAGE FROM INSTITUTE DIRECTOR

ENGAGEMENT

DISCOVERY

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SUPPORTING INFORMATION Sponsors and Donors Grants and Awards Publications Glossary

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HIGHLIGHTS OF 2013

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Queensland Government 2013 Premier’s Science Fellowship awarded to Professor Matthew Brown

Professor Matthew Brown elected as an Australian Academy of Science Fellow in 2013

Professor Ranjeny Thomas’s rheumatoid arthritis research enters R&D and licence deal with Janssen Biotech Inc

Increased community engagement

New Chinese Connections Funding secured for the Diamantina Individualised Oncology Care Centre (DIOCC) supported by the ACRF LEO Pharma backs first study of its kind investigating the genetic changes that lead to Squamous Cell Carcinoma

The Translational Research Institute (TRI) officially opened by the Governor-General, Her Excellency the Honourable Quentin Bryce AC CVO

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MESSAGE FROM THE DIRECTOR


2013 has been an outstanding year for our Institute. At the end of 2012 we moved into our new home, the Translational Research Institute, which many of you have by now have had a chance to come and visit. It’s an extraordinary piece of architecture and a wonderful place to work. As an environment to perform cutting edge science, it’s perfect. The lift in atmosphere it has brought to the Institute is palpable. We are also extremely fortunate to have such a well equipped facility and to be so strongly associated with Princess Alexandra Hospital. Having an excellent coffee shop in the forecourt of TRI has helped no end in that regard! By the year’s end all partner institutes that make up TRI had moved in. We were seeing a lot of collaborative research occurring between institutes, resulting in increased productivity for all.

Professor Matthew Brown elected as an Australian Academy of Science Fellow in 2013 The Australian Academy of Science comprises Australia’s leading research scientists. Each year, Fellows are elected by academy members. Professor Matthew Brown was one of 20 scientists elected as an Australian Academy of Science Fellow in 2013. The fellowships honour a select group of Australian scientists for their outstanding contributions to science.

A particular theme of 2013 has been increasing engagement of UQ Diamantina Institute, be it with other campuses of The University of Queensland, other research institutes at TRI, Princess Alexandra Hospital, industry partners, or the general community. The majority of our research staff are contributing to some form of teaching across UQ’s Science and Medical programs. This has helped lift our profile and engagement within the University, reflected most obviously by increasing interest from students wanting to come and study with us. You can imagine the impact these bright, inquisitive and hard-working students are having on our institute. We are working to ensure we give them the best possible start to their research careers. We developed industry partnerships with leading international pharmaceutical companies in therapies of rheumatoid arthritis and in skin cancer research, which are mentioned in this report.

These partnerships will greatly increase our chances of moving our basic research discoveries into clinical applications for these diseases. We have also held lots of educational events and visits to TRI for the general public. Our SPARQ-ed school science outreach program has expanded. Both initiatives go a way to demystifying science and show that whilst scientists might be geeks, the work they do is of great benefit to you. I hope you enjoy reading this report and hearing the fascinating discoveries our researchers have made. From research into what causes rheumatoid arthritis, to genetic advances transforming clinical care of patients with heritable diseases, and possible new treatments for some cancers.

Professor Matthew Brown Director, UQ Diamantina Institute

Queensland Government 2013 Premier’s Science Fellowship awarded to Professor Matthew Brown Professor Matthew Brown was awarded the $1.25 million Premier’s Science Fellowship to develop his work identifying genes that underlie the causes of rheumatoid arthritis and tuberculosis. Premier Campbell Newman congratulated Professor Brown on his groundbreaking work, and thanked him for the remarkable quality of his research, which had helped position Queensland as a global leader in genetic research and diagnostic testing.

The Hon. Campbell Newman MP Premier of Queensland and Professor Matthew Brown

“This fellowship will allow Professor Brown to advance his gene-mapping research in ways that will benefit Queensland industry and our health,” Mr Newman said.

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ENGAGEMENT Translational Partners UQ Community Broader Community Industry and Commercial Partners China Connections

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TRANSLATIONAL PARTNERS Partner in the Translational Research Institute (TRI)

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2013 saw the unique partnership between medical and research visionaries realised when the Governor-General, Her Excellency the Honourable Quentin Bryce AC CVO, officially opened the Translational Research Institute (TRI).

The Institute, with a co-located biopharmaceutical manufacturing facility, enables the discovery, manufacture and testing of therapies and vaccines that will have profound impact on the health of people world-wide.

Led by world-renowned scientist and co-inventor of the cervical cancer vaccine, Professor Ian Frazer AC, TRI is a joint venture between leading research institutes, The University of Queensland’s Diamantina Institute, School of Medicine and Mater Research, Queensland University of Technology’s Institute of Health and Biomedical Innovation and the Princess Alexandra Hospital’s Centres for Health Research.

Multi-disciplinary teams of doctors and researchers work together to develop and test potential new treatments. TRI provides UQDI a unique opportunity to expand our collaborative networks and to engage with translational partners.


Professor Matthew Brown Director, The University of Queensland Diamantina Institute, with a patient

Clinical Connections UQDI has had a long history with the Princess Alexandra Hospital (PAH) and its origin and name are derived from this interaction. The Institute has positioned itself as a major research centre for the Princess Alexandra Hospital and has close ties with particular departments in the hospital, notably Rheumatology, Haematology and Cancer Services. Many of the clinical scientists employed by UQDI undertake clinics within the hospital environment. This ensures they maintain a clinical focus with their work and allows for the direct translation of their research to the patients where possible. It also brings about opportunities for patients to become involved in clinical trials. In 2013 the Princess Alexandra Hospital Health symposium was titled “Making Advances Matter – research, education and training”. Each year, this symposium is structured to emphasise the translational research and partnerships in the health care disciplines. UQDI researcher, Dr Michelle Hill, represented the institute on the Organising Committee. UQDI had a number of key note speakers presenting at the Symposium including Dr Liliana Endo-Munoz, Dr Helen Benham, Prof Ian Frazer, Associate Professor Nikolas Haass, Professor Ranjeny Thomas and Associate Professor Ray Steptoe with UDQI Director Matthew Brown acting as a guest adjudicator for the Young Investigator Awards. UQDI student, Veronique Chachay was recognised with an award for Best Clinical Poster presentation.

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UQ COMMUNITY The University of Queensland (UQ) is consistently ranked among the Top 100 universities in the world measured through a number of major independent university rankings. The fact that several international rankings place UQ in the top 50 in the world highlights the excellence of the University’s research and teaching performance. The UQ Diamantina Institute (UQDI) is a significant contributor to this success.

MESSAGE FROM PROFESSOR G.Q. MAX LU The University of Queensland, Provost and Senior Vice-President The University of Queensland Diamantina Institute Advisory Board, Chair

On behalf of the UQDI Advisory Board, I am delighted to present the 2013 Annual Report showcasing another highly successful year for the Insititute. UQDI plays a significant role within the UQ community and further expanded its collaborative ties in 2013. In association with UQ’s Institute for Molecular Biosciences and Queensland Brain Institute, UQDI facilitated the University of Fudan Summer Research Program. Playing host to 23 undergraduate science and biomedical students, this joint event further strengthens the University’s ties with China and its leading universities. Programs like this facilitate UQ’s goal to sharpen its focus on developing research partnerships with targeted international universities and research institutions in areas of complementary strength. UQDI’s academic staff undertook a variety of undergraduate teaching roles from guest lectures and tutoring to course coordination activities. In 2013, these activities occurred throughout eight different UQ schools and faculties with 60% of UQDI’s academic staff involved. The Institute’s ongoing engagement with

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the undergraduate students represents a core component of its future. The result is a win-win for all parties, increasing engagement of the Institute with the broader University. UQ’s success in attracting research funding from governments, industry and private benefactors acknowledges that they share the University’s vision in research excellence. In 2013, UQDI contributed to this success by receiving more than $11m from competitive funding sources, equating to a strong growth of 21% and 11% respectively in the last two years. In addition to this, the Institute has seen a significant increase in donations and bequests. It is strong performances like this that enable the University’s overall research income to continue to grow despite a difficult economic climate. Leadership remains a key priority for the University, and 2013 delivered many opportunities for UQ to celebrate its amazing depth of talent. In March 2013, the Australian Academy of Science named 20 new Fellows for their outstanding contributions to science, joining the existing 19 UQ scientists admitted to the academy as fellows since 1988. UQDI’s Director, Professor Matthew Brown was one of the new fellows announced for his work in the development of genome-wide association studies resulting in identification of thousands of genes responsible for common diseases. On behalf of the UQDI Advisory Board, I congratulate all involved in making 2013 an outstanding year for UQDI.


BROADER COMMUNITY Lions Medical Research Foundation In February 2013, UQDI hosted 130 representatives of the Lions Medical Research Foundation (LMRF) and the entrants in the Lions Miss Personality Quest. We were delighted that Ray Phippard and his wife Beryl were able to be present, as Ray was one of the founding members. Over the years the Foundation has supported a number of our researchers in the early part of their careers which has had a huge impact on their work and career progression. We were also pleased that Ken Bird,

a former Director of Lions International and who helped establish Lions in the Moreton Bay area, was able to attend. At the event, researchers Dr Gethin Thomas and Dr Tony Kenna gave an overview of their work in genetics and inflammatory disease. Dr Antje Blumenthal and Dr James Wells spoke on infection and the role of antibiotics. Assoc Professor Nick Saunders and Dr Fiona Simpson gave an insight into their work in detection and treatment of skin cancer.

The Lions Medical Research Foundation (LMRF) has a long history of supporting scientists in the important work that they do. In an effort to foster the next generation of medical researchers, the LMRF supports students from regional and remote Queensland participating in SPARQ-ed Research Immersion programs. Travel scholarships are paid directly to the families of student participants to help defray the costs in travelling to and staying in Brisbane during the program.

Rotary Club of Nundah Community engagement is strengthened by events such as the Research Partners Reception hosted by UQDI in May 2013. At this event, the Rotary Club of Nundah made a generous ‘on the spot’ gift to support Dr Fiona Simpson’s work in cancer research.

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INDUSTRY AND COMMERCIAL PARTNERS Rheumatoid arthritis research enters R&D and licence deal with Janssen Biotech Inc A new rheumatoid arthritis treatment moved a step closer to reality with the announcement of collaboration between a University of Queensland start-up company and a major pharmaceutical firm. The collaboration with Johnson & Johnson pharmaceutical company Janssen Biotech Inc will see the new vaccine move closer to a phase 1 clinical trial. UQ Diamantina Institute lead autoimmunity researcher Professor Ranjeny Thomas said the development and potential commercialisation of the immunotherapy

treatment could eventually benefit the world’s millions of rheumatoid arthritis sufferers. Rheumatoid arthritis is a painful condition caused by immune system dysfunction.

in a targeted therapy and allows suitable patients to be selected based on specific biomarkers, thereby improving response rates. It targets the underlying cause of rheumatoid arthritis rather than simply treating the inflammatory symptoms.

It destroys joints and causes cardiovascular complications that can reduce life spans by 10 years.

It’s hoped the treatment will prove effective for rheumatoid arthritis patients and that it could lead to innovation of treatments for other diseases, such as type 1 diabetes.

The technology is being commercialised by Dendright Pty Ltd, a start-up company of UniQuest. UniQuest is UQ’s main commercialisation company. The technology behind the treatment differs from existing drugs in that it results

“The development and potential commercialisation of the immunotherapy treatment could eventually benefit the world’s millions of rheumatoid arthritis sufferers.”

Professor Ranjeny Thomas

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Strategic partnership formed with LEO Pharma to investigate the world’s second most common skin cancer Australia has one of the highest incidences of squamous cell carcinoma in the world, with two in three Australians diagnosed with the disease by the time they are 70.

UQ’s reputation for ground-breaking skin cancer research, including a new method to screen for the genetic indicators of skin cancer, led to the partnership.

A strategic partnership between The University of Queensland and global pharmaceutical company LEO Pharma will investigate the genetic causes of squamous cell carcinoma.

Assoc Professor Nick Saunders, Professor Ian Frazer and Professor Matthew Brown from the UQ Diamantina Institute and Professor Peter Soyer and Dr Tarl Prow from UQ’s School of Medicine will work together at the Translational Research Institute to determine which genes are responsible for squamous cell carcinoma.

The research collaboration is the first study of its kind to examine the genetic changes that lead to skin cancer as it occurs. New data will be revealed about the basic causes of skin cancer and how mutations in skin cells lead to tumours.

The three-year research collaboration was facilitated by UQ’s research commercialisation company UniQuest.

“This is the first study of its kind to examine the genetic changes that lead to skin cancer as it occurs.”

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“We hope these programs will bring our top researchers closer together and create ongoing research links focused around student exchange and joint PhD programs.�

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Dr Gethin Thomas, Deputy Director of Education at UQDI


CHINA CONNECTIONS Fudan University Three of The University of Queensland’s top research institutes hosted 23 undergraduate science and biomedical students from China’s Fudan University in July 2013. The visiting international students undertook a six-week research experience program in the lab that best suits their research interests at UQ’s Diamantina Institute (UQDI), Institute for Molecular Bioscience (IMB) and Queensland Brain Institute (QBI). UQ’s Deputy Vice-Chancellor (Research) Professor Max Lu welcomed the students in true Queensland style at a barbeque hosted at IMB on 17 July 2013. This research experience program exchange between the two universities

was initially established thanks to a collaboration between The University of Queensland Diamantina Institute and Fudan University. Dr Gethin Thomas, Deputy Director of Education at UQDI, said of the exchange program, “Fudan University if one of China’s top institutions and has an excellent reputation in biomedical research.” Fudan University is one of China’s leading universities and is a fellow member of Universitas 21, an international network of 21 leading research-intensive universities in 15 countries that aims to facilitate collaboration and cooperation between member universities.

Wenzhou Medical University Similar to the Fudan University, UQDI strengthened ties into China through the Wenzhou Medical University in recognition of Dr Jian Zhou (co-inventor of the cervical cancer vaccine) who was a graduate of the college. Wenzhou Medical University is a multi-disciplinary university under the administration of the Department of Education of Zhejiang Province. It has three campuses, covering a total area of 800,000 square meters; the main campus is located at Chashan University Town of Wenzhou. The college has a total enrolment of over 11,900 undergraduates and more than 600 postgraduates. Under the scheme UQDI would support PhD students from Wenzhou Medical University, China, to undertake doctoral studies at the Institute supported through a benefactor program. The scheme will also include a summer scholarship program similar to the University of Fudan program.

Students from the 2013 Fudan Summer Research Program

Statue of Dr Jian Zhou at Wenzhou Medical University

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DISCOVERY


RESEARCH HIGHLIGHTS Genetic breakthrough changing the understanding of how rheumatoid arthritis develops Potential new therapeutic target to reduce Squamous Cell Carcinoma tumour growth Research opens new therapeutic avenues in the treatment of Chronic Lymphocytic Leukaemia

Identification of 13 new regions of the genome that influence Ankylosing Spondylitis development

Whole Exome Sequencing is shown to be a sensitive, fast, affordable genetic analysis that could potentially save lives

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Assoc Professor Nicholas Saunders

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“When the drug (DZNep) was tested in a model of Head and Neck Squamous Cell Carcinoma it caused significant reduction in tumour growth.�


TARGETING GENE CONTROL IN HEAD AND NECK SQUAMOUS CELL CARCINOMA REDUCES TUMOUR GROWTH Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the most prevalent cancers in the world. There are more than 500,000 new cases diagnosed every year, and unless it is detected early, these patients face a poor outcome. The five year survival rate for HNSCC patients is around 50%, a figure that has not changed significantly in the last 30 years. The causes of HNSCC remain poorly understood but recent advances have identified a key difference between normal cells and HNSCC cells. During normal cell development, cells in the body become specialised so they can perform specific functions, for example heart cells, kidney cells, brain cells and so forth. It is now known that instead of becoming specialised, HNSCC cells instead remain in an immature, unspecialised state. This increases their potential to become malignant and is an important step in the progression of cancer. Yet no one knew how HNSCC cells are able to do this. In the January 15, 2013 issue of Clinical Cancer Research, a team of UQDI researchers led by Associate Professor

Nicholas Saunders revealed that a small change in a single protein called Histone H3 helps drive progression of HNSCC.

Moreover, when the drug was tested in a mouse model of HNSCC, it caused a significant reduction in tumour growth.

Histone proteins play an important role in cells. Clustered together, these proteins behave like spools that the DNA winds around, thus providing crucial structural support. Moreover by controlling access to the genetic material wrapped around them, histones can determine whether certain genes are turned ‘on’ or ‘off’.

This was the first report where the drug DZNep has been used to treat Head and Neck Squamous Cell Carcinoma. Moreover, the findings demonstrate that the ‘on’/’off’ status of genes involved in cell specialisation may represent a new therapeutic target for HNSCC.

Histone H3 in particular controls a suite of genes that enable cells to specialise. The UQDI research team showed that, in HNSCC, a single amino acid in histone H3 is slightly altered. This minor change has major downstream effects. The genes controlled by H3 become switched ‘off’; consequently the cells can no longer specialise and can become malignant. The researchers wanted to know if this could be reversed. They treated HNSCC cells with a drug called DZNep (3-deazaneplanocin A), which prevents that problematic change to histone H3. As a result, the genes were switched ‘on’ again and the tumour cells became less malignant and more specialised.

This important research has contributed greatly to the overall understanding of how this form of cancer develops. It has also opened new avenues for further research into possible treatments that may one day improve the survival rate of patients. Gannon OM, Merida de Long L, Endo-Munoz L, Hazar-Rethinam M, Saunders NA; Clinical Cancer Research (2013) 19(2):428-41 http://clincancerres.aacrjournals.org/ content/19/2/428.long

This research was partly funded by an Accelerate Partnerships grant from the Queensland-Chinese Academy of Sciences (Q-CAS) Collaborative Science Fund

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MELANOMA PATIENTS COULD AVOID TOXIC CHEMOTHERAPY IF NEW DRUG TARGET SUCCEEDS Melanoma is an aggressive form of skin cancer and the fourth most common cancer in Australia. The disease is relatively insensitive to chemotherapy and once the cancer spreads there are few effective treatments, leaving patients with a poor prognosis. As a result, more than 1500 Australians die from melanoma each year. Nearly half of all melanoma patients carry a mutation in their BRAF gene, which makes this group of patients sensitive to a new generation of drugs called BRAF inhibitors. However, resistance to these drugs quickly develops. “Treatment with BRAF inhibitors is a great improvement, but the effects are short-lived,” says UQDI Professor Brian Gabrielli. “We need other therapies, and there are still all those other patients who have nothing. Finding new drug targets is critically important.” As healthy cells grow and divide they pass through a series of checkpoints. Tumour suppressor genes help regulate these checkpoints during the cell cycle. These genes are often disrupted during cancer development. For cancer cells, this enables them to accumulate genetic mutations that facilitate growth, spreading and drug resistance. But it also makes

cancer cells vulnerable: too many mutations can prove lethal to the cells. To compensate, cancer cells increase their dependence on other pathways for survival. One such back up pathway in melanoma involves a protein called Checkpoint Kinase 1 (Chk1). Because chemotherapy causes widespread DNA damage that can kill melanoma cells, they rely on Chk1 to fix that damage so they can survive. Drugs that inhibit Chk1 therefore make these melanoma cells highly vulnerable to chemotherapy. Professor Gabrielli wanted to know if Chk1 inhibitors have potential as a drug therapy in their own right, thus avoiding the toxicity of chemotherapies altogether. He and his colleagues tested Chk1 inhibitors against a panel of different melanoma cell types. The drugs killed more than 60% of the melanoma panel, but did not affect normal cells. The research was published in the February 7, 2013 issue of Oncogene. “Finding that the Chk1 inhibitors had activity as single agents, and potent activity was really exciting,” says Professor Gabrielli, who now wants to test them in mouse models of melanoma.

He also wants to find out exactly how they are working and why they’re lethal for some types of melanoma and not others. He explains that not only will this help us better understand the underlying biology of melanoma and perhaps other cancers, but it could also enable the development of tests that could identify which patients will benefit from the drugs. This could make a big difference in the design of clinical trials. “You can have the best drug in the world but if it’s only effective in 10 – 15% of patients and you do a clinical trial on the general patient group, it won’t be successful,” he says. In this case, further drug development might cease because it was ineffective on the majority of the patients tested. “But if you know to target that 10 – 15 % of patients, then you have an effective therapy for that specific patient group.” Brooks K, Oakes V, Edwards B, Ranall M, Leo P, Pavey S, Pinder A, Beamish H, Mukhopadhyay P, Lambie D, Gabrielli B; Oncogene (2013) 32(6): 788-96. http://www.nature.com/onc/journal/ v32/n6/full/onc201272a.html

This work was supported by funding from Cancer Council Queensland, the National Health and Medical Research Council and the Australia Research Council.

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“Inhibiting a particular protein (Chk1) has been shown to kill certain melanoma cells meaning some patients could avoid toxic chemotherapy.�

Professor Brian Gabrielli

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PROMISING NEW DRUG TARGET FOR CHRONIC LYMPHOCYTIC LEUKAEMIA Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in adults. Around 1000 new cases are diagnosed every year in Australia. Although the management of the disease has improved over the past decade it remains incurable and the underlying biology is not well understood.

CD62L helps guide healthy lymphocytes to the bone marrow and lymph nodes, and thus plays a role in normal immunity and inflammation. CLL cells were known to produce the protein as well, but no one had examined whether these cancer cells were using it to prolong their survival.

CLL is a cancer that arises from a type of white blood cell called lymphocytes, but CLL cells appear to survive longer than healthy lymphocytes, explains UQDI Associate Professor Nicholas Saunders.

When the researchers blocked the protein’s activity, the majority of CLL cells died. This approach was as effective as current chemotherapies, but with an important difference: healthy cells were unaffected. This research demonstrates for the first time that CD62L can be targeted as a highly specific treatment for chronic lymphocytic leukaemia.

To find out how CLL cells are able to do this, he and UQDI researcher Ms Melinda Burgess collaborated with scientists and clinicians from Griffith University, the University of Florida, and Queensland Health’s Department of Haematology at the Princess Alexandra Hospital in Brisbane. Using blood samples collected from patients with CLL, the researchers compared the proteins that sit on the surface of both healthy lymphocytes and CLL cells and discovered that CLL cells display much higher levels of a protein called CD62L.

The discovery, published in the journal Clinical Cancer Research in October 2013, opens up new therapeutic avenues that could significantly improve patient outcomes. The researchers then went further and blocked the protein’s activity in the presence of chemotherapeutic drugs; in both cases, the combined approach killed even more cancer cells. This suggests that, if needed, both therapies

This important discovery was made possible thanks to the Cancer Council Queensland and their support of a Senior Research Fellowship awarded to Associate Professor Nicholas Saunders.

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could be used together in order to overcome drug resistance to any single treatment. “This was a truly collaborative paper,” says Assoc Professor Saunders, explaining that the study benefited from a diversity of expertise from the clinicians and scientists involved. Not only do the findings have good potential for translation to the clinic, but the research also provides valuable information about the underlying drivers of cell survival in CLL. Work is underway to determine exactly how CD62L is instrumental in this process, which in turn could yield further avenues for treatment. Burgess M, Gill D, Singhania R, Cheung C, Chambers L, Renyolds BA, Smith L, Mollee P, Saunders N, McMillan NA; Clinical Cancer Research (2013) 19(20): 5675-85. http://clincancerres.aacrjournals.org/ content/19/20/5675.long


“This research is able to demonstrate for the first time that there is a greater combined effect when this antibody therapy is combined with standard chemotherapy.”

“The majority of chronic lymphocytic leukaemia cells died as a result of treatment with the antibody, whereas the healthy cells were unaffected.”

Assoc Professor Nicholas Saunders

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“These findings highlight the power of modern genetics to transform research in diseases which have challenged standard approaches for decades, bringing about real advances for patients.�

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DEVELOPMENT OF THE IMMUNOCHIP FOR MAPPING GENETIC VARIATIONS IN AUTOIMMUNE DISEASE Ankylosing Spondylitis (AS) is a highly heritable disease where the immune system attacks the spinal and pelvic joints, leading to inflammation and new bone growth. As a result, the condition effectively fuses the spine and/or pelvis into a fixed position causing pain, stiffness, and often significant disability. AS currently affects more than 80,000 Australians, or 0.5% of the population. There are no treatments available that can induce remission of the disease. It is known that susceptibility to AS is predominantly genetic. The first clues to understanding AS came in the 1970s, when it was discovered that nearly all AS patients carried a particular gene called HLA-B27. The link between AS and HLA-B27 is one of the strongest-known genetic associations of any common disease, but it has since become clear that a number of other genetic factors also influence AS development and progression. In order to better understand the underlying biology of AS and identify potential interventions, a more comprehensive picture of the genetics of AS is needed. In 2013, a team of UQDI researchers worked with scientists and physicians from 17 countries across Europe, East Asia, North America, Australia, New Zealand and Latin America in order to further investigate the genetic causes of AS.

In a pivotal study published in the July 2013 issue of Nature Genetics, the UQDI team, led by Professor Matthew Brown, used existing data from autoimmune and inflammatory diseases to develop a custom ‘Immunochip’ as a cost-effective technology platform for studying the genetic factors that influence the immune system’s behaviour in AS. They then collected genetic material from more than 10,000 AS patients and used the Immunochip to map the common genetic variations responsible for the disease. As a result of this work, they confirmed the association of 12 of the 13 regions of the genome that have been previously reported as associated with AS, and even identified new genetic variations within these regions. The team then identified 13 new regions of the genome that influence AS development, bringing the total number of genetic regions associated with AS to 43, of which all bar one (HLA-B27, identified in 1972) have been identified by Professor Brown’s group. “Our research will assist in developing potential treatments,” said Adrian Cortes, first author on the Nature Genetics paper. “Some of these treatments are already in clinical trials, thanks to the UQDI team’s previous discoveries.”

In particular, these findings highlight the role of some major biological pathways in AS development, including those involved in how immune cells communicate with each other during a reaction. Moreover, several of the genes identified are involved in the interaction between the immune system and bacteria in the intestine, suggesting that gut microbes may play a key role in driving AS. Taken together these findings give us a better understanding of the underlying biology of AS and have opened new avenues for further research. “This study is a big step forward in solving the causes of this common disease, and is very likely to lead to new treatments for AS and related diseases in the near future,” explains Professor Brown. “It shows the power of modern genetics to transform research in diseases which have challenged standard research approaches for decades, bringing about real advances for patients.” International Genetics of Ankylosing Spondylitis Consortium (IGAS), Cortes A, et al; Nature Genetics (2013) 45(7): 730-8. Numerous authors http://www.nature.com/ng/journal/ v45/n7/full/ng.2667.html

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A POWERFUL NEW WAY TO INVESTIGATE THE COMPLEX INTERPLAY BETWEEN GENES, DISEASE AND THEIR BIOLOGICAL INTERMEDIATES Professor David Evans, Chair of Genomic Medicine at UQDI, collaborated with an international team of genomics researchers to explore the immense amount of information stored in an individual’s genetic code. Their aim was to develop a powerful method of screening tens of thousands of biological traits, for example an individual’s body mass index (BMI), for potential causal relationships with diseases like type 2 diabetes. Genome wide association studies (GWAS) are currently used to analyse the relationship between genetic variants and disease. Typically these studies test the relationship between millions of genetic variants and disease one genetic marker at a time. Genetic markers that are significantly associated with disease may then provide clues about which biological pathways are important in disease development. “If you find an association, it might tell you something about the disease,” explains Professor Evans. “However looking at one genetic marker at a time, as is normally done, may not be the most powerful strategy, as typically genetic variants only have very small effects on overall risk of disease.” This is because common diseases like type 2 Diabetes tend to be polygenic, in other words they are caused by multiple genetic variations, with any one variant accounting for only a small part of the overall risk of disease. Professor Evans and his colleagues wanted to find a more powerful method of examining the underlying causes of disease. To do this, they focussed on biological intermediates. “Biological intermediates are anything on the causal pathway from gene to disease,” he says. They include gene expression levels, variations in gut bacteria, BMI, changes in levels of proteins such as insulin, and so forth.

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According to Professor Evans, there is a translational advantage to looking at biological intermediates. “If you find a genetic variant associated with a disease it’s difficult to modify that, but if you identify a biological intermediate that causally affects someone’s risk of disease, then that is something you may be able to modify more easily. For example, you can modify a patient’s BMI (a measure of an individual’s weight relative to their height) or you can modify their cholesterol.” Because of all the GWAS studies performed to date, there is now a vast amount of information available linking biological intermediates with single genetic variations, called SNPs. The new method developed by Professor Evans and his colleagues takes all that data and identifies which combinations of SNPs are associated with a particular biological intermediate, then cross references that information to see if those SNPs are also related to a disease. The method allows the researchers to target hundreds of thousands of biological intermediates simultaneously. As a proof of principle, they looked at three examples of biological intermediates where they were confident that they knew the relationship between the intermediates and risk of disease. They first looked at BMI and assessed whether a combination of genetic variants related to BMI were also related to seven different diseases, including type 2 diabetes. The method correctly identified a causal relationship between type 2 diabetes and BMI but did not pick up relationships with other unrelated diseases, such as rheumatoid arthritis. They also looked at C-reactive protein, a marker of inflammation. The method correctly indicated that C-reactive protein was correlated with a variety of diseases, like type 2 diabetes and coronary heart disease, but did not cause them.

Finally, when they looked at LDL cholesterol the new method accurately detected a causal relationship with coronary heart disease but not with other unrelated diseases, such as bipolar disorder. These experiments demonstrated that the new approach Professor Evans and his collaborators developed is a powerful way to investigate the complex interplay between a person’s genetics, intermediates like BMI and disease such as type 2 diabetes. It is capable of identifying biological intermediates that cause disease while distinguishing these instances from those that are simply correlated with disease. With further investigation and refinement this powerful new way of screening could be used to identify other biological intermediates that could be monitored to help manage or reduce the risk of disease. For example, it’s already known that BMI and cholesterol levels can be reduced to help mitigate a variety of diseases such as coronary heart disease and type 2 diabetes. This work opens up new avenues for discovery of thousands of other potentially modifiable intermediates. Finding these new intermediates would then have the potential to empower patients to make distinct lifestyle changes that could, in turn, improve their health and diminish the burden of disease. Evans DM, Brion MJ, Paternoster L, Kemp JP, McMahon G, Munafo M, Whitfield JB, Medland Se, Montgomery GW; GIANT Consortium, CRP Consortium, TAG Consortium, Timpson NJ, St Pourcain B, Lawlor DA, Martin NG, Dehghan A, Hirschhorn J, Davey Smith G; PLoS Genetics (2013) 9(10): e1003919. doi: 10.1371/ journal.pgen.1003919. http://www.plosgenetics.org/article/ info%3Adoi%2F10.1371%2Fjournal. pgen.1003919


“International collaboration has led to a new method of genetically screening 10,000’s of biological traits for potential causal relationships with diseases such as type 2 diabetes and coronary heart disease.”

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Professor Emma Duncan

“This highly translational research demonstrates that Whole Exome Sequencing is an efficient, sensitive method that enables fast, affordable genetic screening in the clinic and will change clinical practice in this area.�

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WHOLE EXOME SEQUENCING DELIVERS RAPID, AFFORDABLE GENETIC SCREENING FOR PATIENTS Genomic medicine researchers at the University of Queensland Diamantina Institute have demonstrated how a new sequencing technique can be used to screen for diseases that arise from mutations in multiple genes. This approach enables sensitive, fast, affordable genetic analysis that could potentially save lives. Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare tumours that usually arise in the tissue associated with the adrenal glands, though PGL can also form near blood vessels elsewhere in the body. Although these tumours don’t often become malignant, both PCC and PGL can secrete high levels of hormones called catecholamines. These, in turn, can cause extreme and sudden hypertension which can result in heart failure, stroke and/or sudden death. For patients, they are usually unaware that these rare tumours have formed until they present to the emergency department with high blood pressure, headache, sweating and palpitations; and affected individuals can suddenly die. PCC and PGL are associated with multiple genetic variations in up to 13 different genes. Indeed, many patients have a family history of the tumours. As such, genetic testing can play an important role in screening family members in order to identify individuals at risk, as this can then direct screening for tumours prior to the development of life-threatening symptoms. Genetic screening can also help predict tumour behaviour, as some mutations are known to increase the likelihood of malignancy. Moreover, screening can rule out constant monitoring in family

members who don’t carry the genetic risk variant. Although the benefits of genetic testing are clear, the current PCC/PGL screening method is costly; and while gene-by-gene testing might help manage those costs, unless the mutation is found in the first one or two genes tested the entire process can take months to years, delaying diagnosis. In 2013, a team of UQDI researchers, together with colleagues at the University of Sydney at the Royal North Shore Hospital, showed that a new technique, whereby all 21,000 genes are sequenced in parallel, can be used to rapidly screen all genes associated with PCC and PGL. This approach just focuses on the ‘exons’, which are the coding regions within a gene. Because the mutations associated with PCC and PGL are usually located in exons, the researchers believed this approach, called whole exome sequencing (WES), would be effective. To see if the WES approach works, the researchers analysed the genetic data from eleven unrelated patients diagnosed with PCC or PGL. The presence of disease-associated mutations in these patients had been confirmed previously using the slower, more costly methods. Professor Emma Duncan, PhD student Aideen McInerney-Leo and their colleagues showed that WES accurately identified the correct mutations in all eleven patients. This highly translational research demonstrates that WES is an efficient, sensitive method that enables fast, affordable genetic screening for PCC

and PGL in the clinic. By improving the ability to diagnose these diseases quickly and accurately and guide clinical decisions at an earlier stage, WES is expected to benefit clinical practice in this area greatly. For the patient, receiving an accurate diagnosis reduces ambiguity, decreases the feeling of isolation and arms them with useful knowledge about their condition. This exciting research is a great example of how technology developed for gene discovery and research leads to real applications for disease. Moreover, this work suggests the utility of WES in screening for other conditions where multiple genes are involved. McInerney-Leo AM, Marshall MS, Gardiner B, Benn DE, McFarlane J, Robinson BG, Brown MA, Leo PJ, Clifton-Bligh RJ, Duncan EL; Clinical Endocrinology (2014) 80(1); 25-33. Advance online publication 25 October 2013. http://onlinelibrary.wiley.com/ doi/10.1111/cen.12331/ abstract;jsessionid=8FDACD0CD CF9F7740E84671F9E7C70ED.f02t01

Funding for this breakthrough research was provided entirely by the Royal Brisbane and Women’s Hospital Foundation. The research was carried out at the UQ Centre for Clinical Research (UQCCR) located at UQ’s Herston Campus and the UQ Centre for Clinical Genomics (UQCCG).

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DISCOVERY OF HIDDEN GENETIC LINKS OFFERS HOPE FOR RHEUMATOID ARTHRITIS SUFFERERS Rheumatoid arthritis (RA) is a painful, debilitating condition caused by immune system dysfunction. It affects around 1 in 100 Australians and is more common in women than men. It is believed that 65% of the risk of developing RA is due to genetic influence. Nearly 60 regions of the genome, called ‘loci’, had been identified as influencing RA-risk, but these only accounted for half the heritability. There are two major forms of the disease: ACPA-positive and ACPA-negative. ACPA-positive RA patients carry a set of genetic variations that cause the immune system to mistake certain protein fragments in the joints as foreign, triggering an immune attack. There appeared to be very little genetic overlap between ACPA-positive and ACPA-negative RA, suggesting they were genetically distinct. In 2013 researchers from the University of Queensland Diamantina Institute took part in the largest ever genetic study of rheumatoid arthritis. The ground breaking study nearly doubled the number of regions of the genome associated with the disease and revealed previously hidden links between the different types of RA. The findings were published online in the prestigious journal Nature in December 2013.

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UQDI Director Professor Matthew Brown and Professor Peter Visscher (UQDI, QBI) collaborated on the international study in order to determine whether the similarities between the different types of RA were hidden in the missing heritability. Using a meta-analysis, which combined data from numerous genome-wide association studies (GWAS), the international team of researchers analysed 10 million genetic variations from nearly 30,000 RA patients and 70,000 healthy controls. As a result, 42 new genetic regions were identified as being linked with RA. A significant number of these are shared between the different types of RA. “It shows that the two types of RA are in fact very similar genetically,” explains Professor Brown. “Again this implies that treatments targeting one should largely be effective in the other, and that the causes of each are similar.” The study also revealed that two-thirds of the genetic regions associated with RA play roles in other human conditions including immune-related diseases, cardiovascular diseases, and cancer. In particular there was significant overlap between the genes associated with cancers of the blood, bone marrow and the lymph nodes, suggesting that some of the same things may be malfunctioning in these conditions.

The research consortium narrowed in on 98 genes as the most likely culprits in the development of RA. They showed that existing RA drugs were much more likely to target genes known to be associated with the disease than unrelated genes. They then studied the remaining genes and identified several that are already targets of approved treatments for other diseases, including cancer. These drugs could now potentially be repurposed for RA treatment. “This exciting discovery highlights the power of modern genetics to make a difference in serious diseases like rheumatoid arthritis,” Professor Brown said. The results of the meta-analysis also provide scientists with a vast array of new genetic and cellular pathways to investigate, each set to expand our knowledge of how RA develops and progresses. As a consequence, not only will this work facilitate the development of novel drugs, it is anticipated to shed light on the how all these RA-risk genes interact with environmental triggers. Okada Y, et al; Nature (2014) 506(7488); 376-81. Advance online publication 25 December 2013. Numerous authors http://www.nature.com/nature/journal/ v506/n7488/full/nature12873.html


“The largest ever genetic study of rheumatoid arthritis, nearly doubling the number of regions of the genome associated with the disease”

“Existing drugs currently used to treat other diseases could now be used in the treatment of rheumatoid arthritis”

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A NEW UNDERSTANDING OF HOW RHEUMATOID ARTHRITIS DEVELOPS Rheumatoid arthritis (RA) affects millions of people worldwide, causing increasing pain and disability. The disease decreases quality of life and reduces life expectancy. The majority of patients with RA are ‘ACPA-positive’, meaning they have an immune reaction to protein fragments called ‘citrullinated peptides’. These peptides are normally present in the body and increase in times of biological stress, including inflammation. Environmental triggers, such as smoking, can also increase their levels. In 2013, UQDI Professor Ranjeny Thomas and her research group teamed up with Monash University scientists to learn how changes in a key immune protein help drive the most common form of RA, ACPA-positive. Their findings, published in the Journal of Experimental Medicine in November, 2013, have significantly altered the understanding of how this disease develops. Genetic variations associated with susceptibility to RA introduce minor changes in a protein called HLA-DRβ1, which helps the immune system distinguish between ‘self’ and ‘foreign’. Interestingly, people who are resistant to RA have a different cluster of changes in the same protein. These people never develop the disease. It was thought that variations in this protein must influence the way it presents citrullinated peptides to the body’s immune system. According to this theory, the RA-resistant form of the protein allows the immune system to ignore these peptides whereas the RA-susceptible

form causes the immune system to mistake them for foreign invaders. To find out how such small changes to HLA-DRβ1 are able to cause such a dramatic difference in outcome, Professor Thomas and her colleagues solved the structures of both the RA-resistant form of this protein and the RA-susceptible form. As expected, the RA-susceptible form of HLA-DRβ1 holds onto citrullinated peptides. Contrary to previous theory, the RA-resistant form also holds onto citrullinated peptides in the same way. This research showed there was no difference in the way these two different forms of the protein present these peptides to the immune system. Instead, the important difference lies in how they deal with normal, non-citrullinated peptides. The RA-resistant form of HLA-DRβ1 holds onto both citrullinated and non-citrullinated peptides, but the RA-susceptible form is picky. It doesn’t like these normal non-citrullinated peptides, and will only hold onto citrullinated peptides. This means it’s always presenting a citrullinated peptide to the immune system, increasing the chance of a mistaken immune reaction. Professor Thomas and her colleagues then discovered that this is not the only thing that goes wrong. The mistaken immune reaction should be kept in check by a special group of regulatory cells that teach the immune system to ignore the body’s own citrullinated peptides. Yet in ACPA-positive RA this doesn’t happen. The researchers showed that this crucial population of regulatory cells is much smaller in

ACPA-positive RA patients than in healthy people — there simply aren’t enough of them to quell an immune reaction. After disease development, inflammation increases, and even more citrullinated peptides are produced, propagating a continuous cycle. As a result of this research, it is now clear how the genetic susceptibility to RA intersects with the immune response in people prone to RA. This greatly increases our understanding of how the disease develops. The findings also highlight the importance of Professor Thomas’ rheumatoid arthritis vaccine technology, designed to turn off the unwanted immune reaction in patients with high risk RA genes. It works in part by giving the regulatory cells a much needed boost. This vaccine approach is currently being developed by Dendright Pty Ltd (a UniQuest start-up company) in collaboration with Janssen Biotech Inc. If successful in patients with RA, the approach may also have application in the prevention of RA, and in other autoimmune diseases such as type 1 diabetes, improving the health of millions. Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, McCluskey J, Toes RE, La Gruta NL, Purcell AW, Reid HH, Thomas R, Rossjohn J; Journal of Experimental Medicine (2013) 210(12):2569-82. http://jem.rupress.org/ content/210/12/2569.long

This research was supported by the National Health and Medical Research Council of Australia and the Australian Research Council. Professor Ranjeny Thomas is the Arthritis Queensland Chair of Rheumatology.

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Professor Ranjeny Thomas

“This research greatly improves our understanding of rheumatoid arthritis development and challenges prior thinking about how environmental factors like smoking, influence the disease.�

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5

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LEARNING


UQDI has implemented a range of programs to assist in the learning pathways of students, staff and the community.

UQDI has a growing Research Higher Degree (RHD) student program under-pinned by feed-through initiatives such as -

Highly specialised UQDI research staff are involved in undergraduate and postgraduate learning programs across the university at a variety of different levels. This includes guest lectures, tutoring and in some cases course coordination. This involvement occurs across a range of different UQ schools and faculties.

The Summer and Winter vacation scholarships The Institute’s Clinical-Scientist recruitment initiatives

RHD program students are supervised and educated by highly qualified UQDI scientists. Their experience is enriched through access to the seminar series, research skills courses and other professional development training. Students can also access opportunities such as travel awards to visit other labs to broaden their experience.

The Winter Course in Advanced Immunology The Institute’s Honours student program Fudan student program to attract high caliber international students.

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STUDYING AT UQDI RESEARCH HIGHER DEGREE (RHD) STUDENT PROGRAM

UNDERGRADUATE UDQI’s ongoing involvement in the undergraduate teaching programs of the university represents a core component of its future. Approximately 60% of the senior academic staff are involved in some form of undergraduate teaching. The goals are to increase engagement of the Institute with the broader university, increase our student load, and to provide our research academics with teaching opportunities. This has been a major contributor to our growth in student numbers. We expect this will also lead to increased research collaborations with teaching units within the university hospital training centres.

HONOURS There is significant competition at UQ to attract the best undergraduate students to undertake Honours within the different schools and faculties. High quality Honours students frequently progress to Research Higher Degree (RHD) studies.

The RHD program at UQDI is an important part of its operations. Currently these students represent 19% of the institute’s composition. At the end of 2013 UQDI had 52 research higher degree (RHD) students enrolled with five being part-time students. Within the program 43 students are studying a PhD whilst nine are MPhil students UQDI currently has 31 domestic students (60%) and 21 international students (40%).

Total RHD Enrolled 60 50 40 30 20 10 0 2008

UQDI had 13 Honours students enrolled in 2013, the highest number ever. Several of UQDI’s 2013 Honours students applied to enrol for PhDs. In order to raise our profile with potential students in 2013, UQDI offered four scholarships to students undertaking their Honours studies with the Institute. Each scholarship was worth $3200 and assisted the student whilst undertaking their studies. The scholarships were judged on: Academic success including prior academic record, prizes and awards Prior research experience including presentations and publications

2009

2010

2012

2013

Total RHD Enrolments

New Domestic & International RHD Student Enrolments 10 9 8 7 6 5 4 3 2 1 0

2008

2009

Involvement in academic and non-academic leadership roles

2010

2011

New RHD Enrolments Domestic

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2011

International

2012

2013


CLINICAL SCIENTIST RECRUITMENT INITIATIVES 
 Biomedical research is on the cusp of making major breakthroughs in diseases that affect society on a global scale. Until recently, most discoveries were often the result of lab-based non-clinical research and not directly from observed clinical problems. However moving forward future discoveries will more likely stem from studies deriving directly from clinical interactions which require increased involvement of research-aware clinicians. This is commonly referred to as “Translational Research”. There is, however, a globally recognised shortage of scientifically engaged and qualified clinicians capable of bridging basic research and clinical practice. In order to actively bridge the gap between the clinic and research, UQDI is recruiting students and newly qualified clinicians into a number of unique research higher degree training programs, making the most of our close linkage with the PA Hospital.

Senior Clinician-Scientist Program 

 Through the generosity of a UQDI donor we received funding support to train additional senior clinician-scientists. This scheme provides a $25,000 “top-up” for four qualified clinicians who wish to undertake an MPhil. Clinicians at this level make substantial financial sacrifices to undertake research thus these top-ups help ameliorate the financial loss. In 2013, four clinicians were enrolled in this scheme. In 2014 we look to broaden our recruitment drive for clinician-scientists by promoting the research education program to the various medical registry organisations.

Masters of Philosophy (MPhil) in Translational Research
 UQDI is making plans to introduce an internationally recognised postgraduate research degree that provides pathways for medical graduates to acquire new skills, or extend and renew their understanding of Translational Research and the processes underlying it. The course will consist of a 12-month research project supplemented by lectures and workshops highlighting specific key skills and knowledge critical to pursuing translational research including research ethics, study design, data analysis and statistics and bioinformatics. The program is designed to give students theoretical and practical knowledge of the modern concepts and methodologies in translational research. It also aims to provide clinicians seeking entry into advanced specialist training programs a competitive edge.

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Students Performing Advanced Research Queensland (SPARQ-ed) is a unique educational outreach partnership of UQDI and Queensland’s Department of Education, Training and Employment (DETE). It aims to engage school students in the scientific process by connecting school communities with UQDI’s medical researchers. The model on which SPARQ-ed operates is one where students of all ages from schools across Queensland can experience the work done by UQDI’s world ranked researchers. In 2013, after four years operating in space generously provided by the PA Hospital, SPARQ-ed moved into its purpose-built facility located on the ground floor of the Translational Research Institute (TRI), consisting of a specialised teaching laboratory and online learning hub. Departmental administration of SPARQ-ed transferred to the Queensland Academies (QA) in 2013, opening up new opportunities for expansion of SPARQ-ed programs to QA’s extensive networks of partnership schools and online learning. SPARQ-ed continues to be jointly supported by UQDI, which provides vital infrastructure support and access to research staff, and DETE (via the Queensland Academy for Science Mathematics and Technology), which employs the teaching staff. In addition to this, SPARQ-ed receives financial support from the Lions Medical Research

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Foundation in recognition of its role in fostering the next generation of medical researchers. SPARQ-ed has seen a steady increase in engagement in its workshops since its inception, in particular in the number of students taking part in the Research Immersion Programs. In 2013 more than 100 students from both Government and non-Government schools across Queensland took part in the Research Immersion Program. Research Immersion Programs are unique, five day workshops based around a project designed in conjunction with one of UQDI’s research groups, with the aim of the results of each project making some contribution to the work done by that group. Unlike offerings at other science outreach centers, the Research Immersion Programs provide an opportunity for students from outside metropolitan Brisbane to take part, with a family homestay service available to students from regional and remote Queensland. Just over half the students who participated in the Research Immersion Programs in 2013 came from outside the Brisbane metropolitan area.

Dr Peter Darben SPARQ-ed Coordinator


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6

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SUPPORTING INFORMATION


Sponsors and Donors The University of Queensland Diamantina Institute would like to acknowledge with thanks our sponsors and donors who have partnered with us in research throughout 2013.

$200,000 plus

Anonymous I Merchant Charitable Foundation

$5,000 - $25,000

Dr Brian Hirschfeld I Dr Keith Hirschfeld I Ray and Beryl Phippard

under $5,000

A G Mullins I Adrian J Masci I Amanda C Scarpato I Anonymous I Andrew Pentland I Babdoyle Industrial Court I Beth Wardlaw I Caloundra Ladies’ Choir I Camillo Masci I Cecily M Saunders Daphne Cowan I Denise A Masci I Dulcie Zimmerle I Elisabeth A Biermann Esther Ross I F Ranalli I Glenda V Jones I Jeremy Chandler I John Carius I Maria A Cudicio Paul De Luca Mens Hairdressing I Rotary Club of Nundah Inc. I Yesim Coskun I Yuen E Ong

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Grants and Awards Funding secured for the Diamantina Individualised Oncology Care Centre (DIOCC) supported by the ACRF In 2013 The University of Queensland Diamantina Institute secured a $2 million grant from the Australian Cancer Research Foundation for a new cancer treatment centre.

The centre will allow clinician-researchers to translate scientific discoveries into treatments that will advance the fight against cancers such as skin, breast, leukaemia and lymphoma.

The agreement between ACRF and UQDI for the Diamantina Individualised Oncology Care Centre (DIOCC) will mean improved research opportunities and outcomes for cancer patients.

Cancer screening and analysis at the new centre aims to develop targeted treatments for individual patients.

DIOCC will provide an innovative, world-leading program of near-patient cancer research using state-of-the-art technology — encompassing genomics, proteomics and metabolomics. The centre will be based at the Princess Alexandra Hospital and the Translational Research Institute. An advantage of UQDI’s location within TRI and on the Princess Alexandra Hospital campus is that the DIOCC will combine both laboratory-based studies with clinical studies and trials.

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ACRF Chairman Mr Tom Dery said the centre would develop and fast-track treatment approaches for use in clinical practice. “The future of cancer prevention and treatments depends on Australia’s best researchers having access to the most cutting-edge resources and technologies,” Mr Dery said. “The Australian Cancer Research Foundation is very proud to make these important facilities available to Queensland’s world-class cancer scientists - helping them to speed up important cancer research discoveries.”


JDRF Career Development Award helps to unravel the mysteries of type 1 diabetes In 2013 Dr Emma Hamilton-Williams was awarded a $750,000 five-year JDRF Career Development Award for her research into identifying immune pathways responsible for causing the debilitating disease. Type 1 diabetes (T1D) occurs when the pancreas ceases to make insulin, a hormone produced by beta cells in the pancreas. Insulin allows the body’s cells to take up glucose from the blood, and is needed to regulate the body’s carbohydrate and fat metabolism. Australia has one of the highest rates of T1D in the world, with about 1825 Australians diagnosed each year. It is also one of the most common chronic diseases in children, and can potentially lead to temporary or permanent blindness, chronic kidney disease and amputation. Dr Hamilton-Williams said significant advances have been made in treatments, but there is still no cure. She and her group are researching the link between genetic and non-genetic factors influencing the development of type 1 diabetes in the hope of developing novel therapies to target those at risk. “Children and families with type 1 diabetes still have their hopes pinned on researchers to find a true cure for their disease. We need to do all the research we can,” she said.

It has already been discovered that there is an association between gut bacteria and several autoimmune and inflammatory diseases. Dr Hamilton-Williams said increasing evidence also suggested a role for gut bacteria in T1D. “The composition of bacteria in the gut is influenced by both environmental and genetic factors. My research will test whether genes that have a predisposition to increasing the risk of developing type 1 diabetes alter the intestinal environment, therefore affecting the intestinal immune response, causing type 1 diabetes,” she said. Volunteers will be recruited to observe the difference between patients with T1D, their healthy siblings and unrelated healthy individuals. The siblings have some subclinical autoimmunity and about six per cent, on average, will later develop diabetes. The team will also use DNA sequencing to assess which populations of bacteria are in the gut of the study participants. This will allow Dr Hamilton-Williams to test in pre-clinical models whether the transfer of gut bacteria from a protected individual to a genetically susceptible individual can prevent disease. “This work may also uncover novel targets that could be used to design drugs to prevent or treat type 1 diabetes.”

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Granting Bodies in 2013

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New grants awarded in 2013 (UQDI researchers are indicated in bold)

Granting Scheme Investigators Project Title

Funding Total Grant Years Amount

AAS - France-Australia Science Innovation Collaboration (FASIC) Program Early Career Fellowships

LE CAO, Kim-Anh

Development of multivariate statistical approaches for cross-platform analyses

2013 - 2013

$5,200

ABBVIE Pty Ltd

BROWN, Matthew A

Value of Diffusion Weighted MRI in Axial Spondyloarthritis

2013 - 2013

$153,617

ARC Linkage Projects

KENDALL, Mark A; FRAZER, Ian H & Forster, A.

Investigating a novel, physical adjuvant for improving immune responses of vaccines

2013 - 2016

$1,458,345

Arthritis Foundation of Queensland

THOMAS, Ranjeny

Professorial Chair in Rheumatology

2013 - 2014

$276,000

Australian Cancer Research Foundation

BROWN, Matthew A; FRAZER, Ian H; Gandhi, M.; Gill, D.; HILL, Michelle; Marlton, P.; MARTIN, Jennifer; SAUNDERS, Nicholas A; SHAW, Paul N; SOYER, Hans P; Walpole, E.; Brown, N.; LEO, Paul J & others

The Diamantina Individualised Oncology Care Centre (DIOCC)

2013 - 2015

$2,340,000

Bond University

BROWN, Matthew A; Calder, A.; Fiatarone Singh, M. & Brown, N.

Collaborative Research Network for Advancing Exercise and Sports Science in Australia (Collaborative Research Network administered by Bond University)

2013 - 2016

$467,978

Brien Holden Vision Institute

HUGENHOLTZ, Philip & Louise, J.

Microbial communities that reside in the human ocular

2015 - 2015

$55,000

Cancer Council Queensland

SMITH, Aaron G & STURM, Rick

Investigating the role of NR4A nuclear receptors in melanocytic DNA repair and tumorigenicity

2014 - 2015

$220,000

Cancer Council Queensland

PROW, Tarl & SOYER, Hans P

Automated image analysis development for early non-melanoma skin cancer detection

2014 - 2015

$174,900

Cancer Council Queensland

WELLS, James & FRAZER, Ian H,

Chemokine involvement in the differential response of Actinic Keratosis and Squamous Cell Carcinoma to Imiquimod therapy

2014 - 2015

$220,000

Cancer Council Queensland

LEGGATT, Graham R & MATTAROLLO, Stephen R

Memory CD8 T cell subsets in non-melanoma skin cancer

2014 - 2015

$220,000

Cancer Research Institute (USA)

FRAZER, Ian H

Optimising immunotherapy for squamous cancer

2013 - 2014

$200,000

Canine Research Foundation

SEDDON, Jennifer; O’LEARY, Caroline A; SOMMERLAD, Susan F & Duffy, D.

Mapping canine sensorineural deafness in the Australian cattle dog

2014 - 2014

$20,265

Cedars-Sinai Medical Center

BROWN, Matthew A

Genetics of Ankylosing Spondylitis Study (NIH grant administered by the University of Texas)

2013 - 2013

$13,690

Department of Health and Ageing

HOLLINGWORTH, Samantha A; OSTINI, Remo; DAVID, Michael; MARTIN, Jennifer & TETT, Sue

Utilisation review of Ezetimibe

2013 - 2013

$70,417

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48

Granting Scheme Investigators Project Title

Funding Total Grant Years Amount

Feline Health Research Fund

RAND, Jacquie & O’LEARY, Caroline A

A Pilot Study: What are the genetic loci associated with diabetes mellitus in Australian Burmese cats?

2013 - 2013

$2,750

Garnett Passe/Rodney Williams Memorial Foundation

FRAZER, Ian H & PERRY, Christopher

Viral Oncogenesis in Oral Squamous Cell Carcinoma (Garnett Passe and Rodney Williams Memorial Foundation Conjoint Grant)

2014 - 2016

$161,100

John & Mary Kibble Trust

O’LEARY, Caroline A & DUFFY, David

What is the molecular genetic cause for haemanglosarcoma in dogs?

2013 - 2013

$8,220

Juvenile Diabetes Research Foundation

HAMILTON-WILLIAMS, Emma

A genetic link between gut microbial flora and T1D susceptibility

2013 - 2017

$803,313

Juvenile Diabetes Research Foundation Iin Australia

THOMAS, Ranjeny; Craig, M.; Jones, T. & Morahan, G.

The Australian Diabetes Data Network (ADDN) Biobank

2013 - 2014

$64,535

Leon Stone Sarcoma Research Grant

MUNOZ, Liliana B; SAUNDERS, Nicholas A; Straw, R. & SOMMERVILLE, Scott M

Novel therapeutics for the treatment of canine and human osteosarcoma metastasis - 2014 Leon Stone Sarcoma Research Grant

2014 - 2014

$36,000

Mater Misericordiae Health Services Brisbane Limited

DUNCAN, Emma L; JOHNSON, Stephanie R; VENTER, Deon J & HARRIS, Mark

Gene identification for disorders of glucose-mediated insulin secretion using next-generation resequencing: streamlining the old and discovering the new

2013 - 2013

$55,000

Motor Neurone Disease Research Institute of Australia Inc

BENYAMIN, Beben; VISSCHER, Peter & WRAY, Naomi

Trans-ethnic and trans-omic statistical analyses to identify new ALS risk variants

2014 - 2014

$110,000

National Breast Cancer Foundation Early Career Fellowships

DUIJF, Pascal

NBCF Early Career Fellowship Chromosome instability: Novel opportunities for the diagnosis and treatment of breast cancer

2014 - 2017

$730,400

National Breast Cancer Foundation Novel Concept Award

HILL, Michelle

Glycosylation-specific circulating glycoprotein biomarkers for early detection of metastatic breast cancer

2014 - 2015

$219,833

NHMRC Career Development Fellowship

MATTAROLLO, Stephen R

NHMRC Career Development Fellowship (R.D. Wright Biomedical CDF Level 1): Combination immunotherapeutic strategies for haematological cancers

2014 - 2017

$411,767

NHMRC Centres of Research Excellence

GRAY, Len; THEODOROS, Deborah G; SMITH, Anthony; RUSSELL, Trevor G; SOYER, Hans P; HAYMAN, Noel E; WHITTY, Jenny & GILLESPIE, Nicole A

The Centre of Excellence in Telehealth

2013 - 2018

$2,495,359

NHMRC Project Grant

SOYER, Hans P; STURM, Rick; DUFFY, David & SCHAIDER, Helmut

Genetic polymorphisms associated with clinical and dermoscopic naevus signature patterns

2014 - 2016

$814,994

NHMRC Project Grant

MOWRY, Bryan; VISSCHER, Peter; Thara, R. & GRATTEN, Jake

Genetic analysis of de novo and inherited exome variation in schizophrenia

2014 - 2016

$1,319,165

NHMRC Project Grant

GANDHI, Maher; Fulham, M.; Trotman, J.; LE CAO, Kim-Anh & Berkahn, L.

Circulating Biomarkers in advanced classical Hodgkin Lymphoma

2014 - 2016

$513,447

NHMRC Project Grant

GABRIELLI, Brian G & PAVEY, Sandra J

Identifying the mechanism of the G2 phase UV checkpoint and repair response commonly defective in melanoma

2014 - 2016

$549,409


Granting Scheme Investigators Project Title

Funding Total Grant Years Amount

NHMRC Project Grant

BROWN, Matthew A; RADFORD-SMITH, Graham L; MORRISON, Mark & Ciccia, F.

Interactions between host and the gut microbiome in the pathogenesis of ankylosing spondylitis and Crohn’s disease

2014 - 2017

$557,477

NHMRC Project Grant

FRAZER, Ian H; HUGENHOLTZ, Philip; Dinger, M.; SOYER, Hans P; Playford, E. & PROW, Tarl

Determinants of progression of actinic keratoses to squamous cancer

2014 - 2018

$1,129,978

NHMRC Project Grant

HAASS, Nikolas & WENINGER, Wolfgang

Real-time Imaging of cell cycle progression in melanoma

2013 - 2013

$139,503

PA Research Foundation

MORRISON, Mark

Bringing genomes to life: isolation of genetically tractable, not-yet-cultured members of the human microbiota using metaparental mating methods

2014 - 2014

$22,000

PA Research Foundation

LEGGATT, Graham R & PANIZZA, Benedict J

Local immune response to perineural squamous cell carcinoma

2014 - 2014

$22,000

Paragon Biomedical Inc

BROWN, Matthew A

A Multicenter, Randomized, DoubleBlind Study Efficacy and Safety of Continuing versus Withdrawing Adalimumab Therapy in Maintaining Remission in Subjects with Non-Radiographic Axial Spondyloarthritis

2014 - 2014

$170,686

Prince Charles Hospital Foundation

HUGENHOLTZ, Philip & Chambers, D.

The normal pulmonary flora - fact or fiction?

2014 - 2014

$45,244

Prince Charles Hospital Foundation

HUGENHOLTZ, Philip; Chambers, D.; Yerkovich, S. & WILLNER, Dana L

The lung transplant mycobiome

2013 - 2014

$71,143

Queensland Health

FAY, Michael; ROSE, Stephen E; MARTIN, Jennifer & BOYD, Andrew W

The effect of valproate in the treatment of high grade glioma: validation of pathology and imaging biomarkers

2013 - 2014

$42,000

Research Donation Generic

BROWN, Matthew A

Fluidigm C1 Single Cell Preparation

2013 - 2013

$230,000

Royal Brisbane and Women’s Hospital Foundation

GARDINER, Robert A; LAVIN, Martin F; HILL, Michelle; ROBERTS, Matthew J; SCHIRRA, Horst J & Yaxley, J.

Exploring new Paradigms in Pre-prostate cancer detection and management

2014 - 2014

$77,000

The Leukaemia Foundation of Queensland

MATTAROLLO, Stephen

Combining vaccination and antibody-based immunotherapy to treat B cell lymphomas

2014 - 2014

$110,000

University of Bristol

BROWN, Matthew A

Genetics of High Bone Mass

2013 - 2018

$91,302

University of Colorado

VISSCHER, Peter & Keller, M.

Estimating the Frequencies and Population Specificities of Risk Alleles (NIH grant administered by the University of Colorado)

2013 - 2014

$152,219

University of Colorado

VISSCHER, Peter & Keller, M.

Estimating the Frequencies and Population Specificities of Risk Alleles (NIH grant administered by the University of Colorado)

2013 - 2014

$152,219

University of Newcastle

HUGENHOLTZ, Philip; Hansbro, P. & COOPER, Matthew

Modification of the microbiome andutilisation of microbial products as novel treatments for COPD (NHMRC project grant administered by the University of Newcastle)

2014 - 2017

$488,479

University of Technology Sydney

TYSON, Gene W; HUGENHOLTZ, Philip; Seymour, J. & Stocker, R.

Microscale experiments to understand a microscale world: Combining microfluidics and ecogenomics to investigate microbial processes in the ocean

2013 - 2015

$1,661,018

49


50

Granting Scheme Investigators Project Title

Funding Total Grant Years Amount

University of Texas Health Science Center at Houston

BROWN, Matthew A & Reveille, J.

Program Project Grant - Genetics and Ankylosing Spondylitis (AS) Pathogenesis (NIH grant administered by the University of Texas)

2013 - 2013

$212,575

UQ Collaboration and Industry Engagement Fund

COOPER, Matthew & HUGENHOLTZ, Philip

Novel treatments for inflammatory bowel disease

2014 - 2014

$84,960

UQ Collaboration and Industry Engagement Fund

SCHAIDER, Helmut & SOYER, Hans P

Targeted expression of US28/ GNA12/13 fusion proteins for cancer therapy.

2014 - 2015

$73,928

UQ Early Career Researcher

DUIJF, Pascal

Instigators of chromosome instability: Novel opportunities to treat cancer

2014 - 2014

$30,000

UQ Early Career Researcher

HEMANI, Gibran

Translating statistical associations to biological understanding in epistatic expression QTL

2013 - 2013

$34,000

UQ Major Equipment and Infrastructure

MENZIES, Neal W; SCHENK, Peer M P; BOTELLA, Jimmy; BATLEY, Jacqueline; EDWARDS, David B; AITKEN, Elizabeth A B; GODWIN, Ian D; BIRCH, Robert G; BEVERIDGE, Christine A; HENRY, Robert J; HUGENHOLTZ, Philip; KOCHANEK, Jitka; LOVELOCK, Catherine & others

Accelerated crop development and environmental compliance of agricultural and food systems

2013 - 2013

$117,000

UQ Postdoctoral Fellowships for Women

MARTIN, Jennifer & LIPMAN, Jeffrey

The effect of a Bayesian method of gentamicin monitoring on clinical outcomes and cost: Comparison to existing dosing strategies

2013 - 2015

$169,294

UQ Postdoctoral Research Fellowship

RAPHAEL, Anthony P; PROW, Tarl & SOYER, Hans P

Influence of skin cancer on topical elongate microparticle drug delivery

2014 - 2016

$308,375

UQ Postdoctoral Research Fellowship

KLING, Jessica & BLUMENTHAL, Antje

The role of Wnt signalling in shaping IL-17 responses during infectious and inflammatory diseases

2014 - 2016

$287,945

UQ Postdoctoral Research Fellowship

JAZAYERI, Seyed Davoud & FRAZER, Ian H

Sterile inflammation as a determinant of immune responses in skin

2014 - 2016

$308,375

UQ Postdoctoral Research Fellowship

REHAUME, Linda M & THOMAS, Ranjeny

Dissecting the cellular mechanisms underlying arthritis and inflammatory bowel disease pathologies in a novel murine model of spondyloarthropathy

2013 - 2015

$318,587

UQ Travel Awards for International Collaborative Research (Category 1)

Deng, L. & HUGENHOLTZ, Philip

UQ Travel Award - Category 1 Dr Li Deng

2014 - 2014

$1,630

UQ-Ochsner Seed Fund for Collaborative Research MABS funds

BAZAN, Hernan & BROWN, Matthew A

Alteration of the Transcriptome During Acute Carotid Atherosclerotic Plaque Rupture

2014 - 2014

$36,423

UQ-Ochsner Seed Fund for Collaborative Research MABS funds

HILL, Michelle; JOSHI, Virendra & BARBOUR, Andrew P

New blood tests for Barrett’s oesophagus and oesophageal cancer

2014 - 2014

$45,000

UWA-UQ Bilateral Research Collaboration Award

THOMAS, Ranjeny & DEGLI-ESPOSTI, Mariapia

Chlamydia induced uveitis in the SKG mouse model of Spondyloarthropthy

2014 - 2014

$14,000

Victor Chang Cardiac Research Institute Limited

DUNCAN, Emma L; Dunwoodie, S. & Sparrow, D.

Determining the causes of congenital vertebral defects (NHMRC Project Grant administered by Victor Chang Cardiac Research Institute)

2013 - 2013

$237,569


UQDI Publications Book Chapters 2013 1.

Punyadeera, C. & Slowey, P. (2013) Saliva as an emerging biofluid for clinical diagnosis and applications of MEMS/NEMS in salivary diagnostics. In Karthikeyan Subramani, Waqar Ahmed, James K. Hartsfield Jr (Eds.), Nanobiomaterials in clinical dentistry 1st ed. (pp. 453-468). Kidlington, Oxford, United Kingdom: Elsevier.

2.

Yang, J., Lee, (.Goddard, M. & Visscher, P. (2013) Genome-wide complex trait analysis (GCTA): methods, data analyses, and interpretations. In Cedric Gondro, Julius van der Werf, Ben Hayes (Eds.), Genome-Wide Association Studies and Genomic Prediction (pp. 215-236). New York, NY U.S.A.: Humana Press.

3.

Duncan, E. & Brown, M. (2013) Genome-wide Association Studies. Genetics of Bone Biology and Skeletal Disease: 93-100.

4.

Rentería ME, Cortes A., Medland S.E Using PLINK for Genome-Wide Association Studies (GWAS) and Data Analysis in Genome-Wide Association Studies and Genomic Prediction Methods in Molecular Biology Volume 1019, 2013, pp 193-213

5.

Yang J, Lee SH, Goddard ME, Visscher P. Genome-Wide Complex Trait Analysis (GCTA): Methods, Data Analyses, and Interpretations. in Genome-Wide Association Studies and Genomic Prediction: Springer; 2013. p. 215-36.

6.

Thomas R, Cope A.P. Pathogenesis of rheumatoid arthritis. Chapter 109 p839-858 in Oxford Textbook of Rheumatology, edited by Richard A Watts, Philip Conaghan, Chris Denton, Helen Foster, John Isaacs, Ulf Müller-Ladner

7.

Brown, M.A. Epidemiology and Genetics of Rheumatic Diseases in Textbook of orthopaedics, trauma and rheumatology: Mosby Elsevier; 2013.

8.

McMillan NA. Lowering the siRNA Delivery Barrier: Alginate Scaffolds and Immune. Nanotechnology for the Delivery of Therapeutic Nucleic Acids. 2013:193.

Journal Articles 2013 1.

Adams, G., Porceddu, S., Pryor, D., Panizza, B., Foote, M., Rowan, A. et al. (2013) Outcomes after primary chemoradiotherapy for N3 (>6 cm) head and neck squamous cell carcinoma after an FDG-PET--guided neck management policy.. Head and Neck, 2013.

2.

Adams RL, Cheung C, Banh R, Saal R, Cross D, Gill D, Self M, Klein K, Mollee P. (2013) Prognostic value of ZAP-70 expression in chronic lymphocytic leukaemia as assessed by quantitative polymerase chain reaction and flow cytometry. Cytometry B Clin Cytom. 2013 Oct 11. doi: 10.1002/cyto.b.21138. [Epub ahead of print]

3.

Anderson, R., Henry, M., Taylor, R., Duncan, E., Danoy, P., Costa, M. et al. (2013) A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways. BMC Medicine, 11(1): 188.1-188.13.

4.

Beaumont KA, Mohana-Kumaran N, Haass NK. Modeling Melanoma In Vitro and In Vivo. Healthcare. 2014; 2(1):27-46.epub 2013

5.

Belavy D, Sunn N, Lau Q, Robertson T. (2013) Absence of neurotoxicity with perineural injection of ultrasound gels: assessment using an animal model. BMC Anesthesiol. 2013 Sep 3;13(1):18. doi: 10.1186/1471-2253-13-18.

6.

Benham H, Norris P, Goodall J, Wechalekar MD, Fitzgerald O, Szentpetery A, et al. Th17 and Th22 cells in psoriatic arthritis and psoriasis. Arthritis Res Ther. 2013;15(5):R136. Epub 2013/11/30.

7.

Bentley L, Esapa CT, Nesbit MA, Head RA, Evans H, Lath D, et al. An N-ethyl-N-nitrosourea induced Corticotropin releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess. Endocrinology. 2013.

8.

Benyamin, B., St Pourcain, B., Davis, O., Davies, G., Hansell, N., Brion, M. et al. (2013) Childhood intelligence is heritable, highly polygenic and associated with FNBP1L. Molecular Psychiatry, Article in press.

9.

Berndt, S., Gustafsson, S., Maegi, R., Ganna, A., Wheeler, E., Feitosa, M. et al. (2013) Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nature Genetics, 45(5): 501-U69.

10. Bjornvad CR, Rand JS, Tan HY, Jensen KS, Rose FJ, Armstrong PJ, et al. Obesity and sex influence insulin resistance and total and multimer adiponectin levels in adult neutered domestic shorthaired client-owned cats. Domestic Animal Endocrinology. 2013 Dec 5. pii: S0739-7240(13)00152-5. doi: 10.1016/j.domaniend.2013.11.006. [Epub ahead of print] 11. Boutros, R., Mondesert, O., Lorenzo, C., Astuti, P., McArthur, G., Chircop, M. et al. (2013) CDC25B overexpression stabilises centrin 2 and promotes the formation of excess centriolar foci. PLoS One, 8(7): e67822.1-e67822.13. 12. Bønnelykke, K., Matheson, M., Pers, T., Granell, R., Strachan, D., Alves, A. et al. (2013) Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. Nature Genetics, 45(8): 902-906. 13. Bradbury L, Hollis K, Chay J, Robinson P, Brown M. Ustekinumab in Ankylosing Spondylitis and Ulcerative Colitis. Intern Med J. 2013;43:34-5. 14. Brandner JM, Haass NK. Melanoma’s connections to the tumour microenvironment. Pathology. 2013;45(5):443-52. Epub 2013/07/16. 15. Brion, M., Shakhbazov, K. & Visscher, P. (2013) Calculating statistical power in Mendelian randomization studies. International Journal of Epidemiology, 42(5): 1497-1501.

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16. Brooks, K., Chia, K., Spoerri, L., Mukhopadhyay, P., Wigan, M., Stark, M. et al. (2013) Defective decatenation checkpoint function is a common feature of melanoma. Journal of Investigative Dermatology, 134(1): 150-158. 17. Brooks, K., Oakes, V., Edwards, B., Ranall, M., Leo, P., Pavey, S. et al. (2013) A potent Chk1 inhibitor is selectively cytotoxic in melanomas with high levels of replicative stress. Oncogene, 32(6): 788-796. 18. Brooks, K., Oakes, V., Edwards, B., Ranall, M., Leo, P., Pavey, S. et al. (2013) A potent Chkl inhibitor is selectively cytotoxic in melanomas with high levels of replicative stress. Oncogene, 32(6): 788-796. 19. Brown M. Genomics and the future of medical practice. Australasian Biotechnology. 2013;23(3):19. 20. Burgess M, Gill DS, Singhania R, Cheung C, Chambers L, Reynolds BA, et al. CD62L as a therapeutic target in chronic lymphocytic leukemia. Clin Cancer Res. 2013;epub ahead of print. Epub 2013/08/21. 21. Burgess M, McMillan N, Saunders N, Cheung C, Hallek M, Gill DS. Serum Levels Of CD178 (Soluble FasL) Predict Treatment Re sponse and Survival In Chronic Lymphocytic Leukaemia (CLL). Blood. 2013;122(21):2866-. 22. Burgess M, Singhania R, Cheung C, Chambers L, Brent R, Smith L, et al. CD62L Expression Is Associated With Chronic Lymphocytic Leukemia (CLL) Cell Survival In Vitro and Represents a Novel Therapeutic Target In CLL. Blood. 2013;122(21):4136-. 23. Caldon CE, Sergio CM, Burgess A, Deans AJ, Sutherland RL, Musgrove EA. Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1. Cell Cycle. 2013;12(4):606-17. Epub 2013/01/18. 24. Centis E, Marzocchi R, Suppini A, Dalle Grave R, Villanova N, Hickman IJ, et al. The role of lifestyle change in the prevention and treatment of NAFLD. Curr Pharm Des. 2013;19(29):5270-9. Epub 2013/02/12. 25. Cheetham, S., Gruhl, F.Mattick, J. & Dinger, M. (2013) Long noncoding RNAs and the genetics of cancer. British Journal of Cancer, 108(12): 2419-2425. 26. Chia, N., Bryce, M., Hickman, P., Potter, J., Glasgow, N., Koerbin, G. et al. (2013) High-resolution SNP microarray investigation of copy number variations on chromosome 18 in a control cohort. Cytogenetic and Genome Research, 141(1): 16-25. 27. Choyce, A., Yong, M., Narayan, S., Mattarollo, S., Liem, A., Lambert, P. et al. (2013) Expression of a single, viral oncoprotein in skin epithelium is sufficient to recruit lymphocytes. PLoS One, 8(2): e57798.1-e57798.8. 28. Clifton-Bligh, R., Hofman, M., Duncan, E., Sim, I., Darnell, D., Clarkson, A. et al. (2013) Improving diagnosis of tumor-induced osteomalacia with Gallium-68 DOTATATE PET/CT. Journal of Clinical Endocrinology and Metabolism, 98(2): 687-694. 29. Coffey, J., Corrie, S. & Kendall, M. (2013) Early circulating biomarker detection using a wearable microprojection array skin patch. Biomaterials, 34(37): 9572-9583. 30. Coleman, M., Bridge, J., Lane, S., Dixon, C., Hill, G., Wells, J. et al. (2013) Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy. Blood, 121(6): 1049-1058. 31. Cortes, A., Field, J., Glazov, E., Hadler, J., Stankovich, J. & Brown, M. (2013) Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes. Human Molecular Genetics, 22(11): 2283-2292. 32. Cortes, A., Hadler, J., Pointon, J., Robinson, P., Karaderi, T., Leo, P. et al. (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nature Genetics, 45(7): 730-740. 33. Costello ME, Elewaut D, Kenna TJ, Brown MA. Microbes, the gut and ankylosing spondylitis. Arthritis Res Ther. 2013;15(3):214. Epub 2013/06/12. 34. Crichton, M., Chen, X.Huang, H. & Kendall, M. (2013) Elastic modulus and viscoelastic properties of full thickness skin characterised at micro scales. Biomaterials, 34(8): 2087-2097. 35. Cui XB, Chen YZ, Pang XL, Liu W, Hu JM, Li SG, et al. Multiple polymorphisms within the PLCE1 are associated with esophageal cancer via promoting the gene expression in a Chinese Kazakh population. Gene. 2013. Epub 2013/08/29. 36. Croci, I., Byrne, N., Choquette, S., Hills, A., Chachay, V., Clouston, A. et al. (2013) Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease. Gut, 62(11): 1625-1633. 37. Dave, R., Dinger, M., Andrew, M., Askarian-Amiri, M., Hume, D. & Kellie, S. (2013) Regulated expression of PTPRJ/CD148 and an antisense long noncoding RNA in macrophages by proinflammatory stimuli. PLoS One, 8(6): e68306.1-e68306.13. 38. Davidson, S., Jiang, L., Cortes, A., Wu, X., Glazov, E., Zheng, Y. et al. (2013) High-throughput sequencing of IL23R reveals a low-frequency, nonsynonymous single-nucleotide polymorphism that is associated with ankylosing spondylitis in a Han Chinese population. Arthritis and Rheumatism, 65(7): 1747-1752. 39. Davis LK, Yu D, Keenan CL, Gamazon ER, Konkashbaev AI, Derks EM, et al. Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture. Plos Genet. 2013;9(10):e1003864. 40. de Candia, T., Lee, S., Yang, J., Browning, B., Gejman, P., Levinson, D. et al. (2013) Additive genetic variation in schizophrenia risk is shared by populations of African and European descent. American Journal of Human Genetics, 93(3): 463-470. 41. den Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B., Peal, D., Evans, D. et al. (2013) Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature Genetics, 45(6): 621-634. 42. Duijf, P. & Benezra, R. (2013) The cancer biology of whole-chromosome instability. Oncogene, 32(40): 4727-4736. 43. Duijf, P., Schultz, N. & Benezra, R. (2013) Cancer cells preferentially lose small chromosomes. International Journal of Cancer, 132(10): 2316-2326. 44. Dutton JL, Li B, Woo W-P, Marshak JO, Xu Y, Huang M-l, et al. A Novel DNA Vaccine Technology Conveying Protection against a Lethal Herpes Simplex Viral Challenge in Mice. Plos One. 2013;8(10):e76407.

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45. Evans DM, Brion MJA, Paternoster L, Kemp JP, McMahon G, Munafò M, et al. Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates. Plos Genet. 2013;9(10):e1003919. 46. Fakiola, M., Strange, A., Cordell, H., Miller, E., Pirinen, M., Su, Z. et al. (2013) Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis. Nature Genetics, 45(2): 208-213. 47. Ferreira MA, Matheson MC, Tang CS, Granell R, Ang W, Hui J, et al. Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. Journal of Allergy and Clinical Immunology. 2013. 48. Feulner, P., Gratten, J., Kijas, J., Visscher, P., Pemberton, J. & Slate, J. (2013) Introgression and the fate of domesticated genes in a wild mammal population. Molecular Ecology, 22(16): 4210-4221. 49. Foo, J., Wan, Y., Schulz, B., Kostner, K., Atherton, J., Cooper-White, J. et al. (2013) Circulating Fragments of N-Terminal Pro-B-Type Natriuretic Peptides in Plasma of Heart Failure Patients. Clinical Chemistry, 59(10): 1523-1531. 50. Forbes, M., Raj, A.Martin, J. Lampe, G. & Powell, E. (2013) Khat-associated hepatitis. Medical Journal of Australia, 199(7): 498-499. 51. Forrester, J., Steptoe, R., Klaska, I., Martin-Granados, C., Dua, H., Degli-Esposti, M. et al. (2013) Cell-based therapies for ocular inflammation. Progress in Retinal and Eye Research, 35: 82-101. 52. Gadd VL, Melino M, Roy S, Horsfall L, O’Rourke P, Williams MR, et al. Portal, but not lobular, macrophages express matrix metalloproteinase-9: association with the ductular reaction and fibrosis in chronic hepatitis C. Liver Int. 2013;33(4):569-79. 53. Gaffney, D., Soyer, H. & Simpson, F. (2013) The epidermal growth factor receptor in squamous cell carcinoma: an emerging drug target. Australasian Journal of Dermatology, Article in press. 54. Gannon, O., de Long, L.Endo-Munoz, L. Hazar-Rethinam, M. & Saunders, N. (2013) Dysregulation of the repressive H3K27 trimethylation mark in head and neck squamous cell carcinoma contributes to dysregulated squamous differentiation. Clinical Cancer Research, 19(2): 428-441. 55. Gibson, G. & Visscher, P. (2013) From personalized to public health genomics. Genome Medicine, 5(60): 1-2. 56. Goldinger, A., Henders, A., McRae, A., Martin, N., Gibson, G., Montgomery, G. et al. (2013) Genetic and nongenetic variation revealed for the principal components of human gene expression. Genetics, 195(3): 1117-1128. 57. Gorayski P, Boros S, Ong B, Olson S, Foote M. Radiation-induced primary cerebral atypical teratoid/rhabdoid tumour in an adult. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2013. Epub 2013/09/11. 58. Gratten, J., Visscher, P.Mowry, B. & Wray, N. (2013) Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease. Nature Genetics, 45(3): 234-238. 59. Gregson, C., Paggiosi, M., Crabtree, N., Steel, S., McCloskey, E., Duncan, E. et al. (2013) Analysis of body composition in individuals with high bone mass reveals a marked increase in fat mass in women but not men. Journal of Clinical Endocrinology and Metabolism, 98(2): 818-828. 60. Haass N. B-RAF New World. Australas J Dermatol. 2013;54:12-. 61. Haass N, Beaumont K, Anfosso A, Hill D, Jurek R, Mrass P, et al. The Microphthalmia-Associated Transcription Factor (MITF) Regulates the Proliferative Architecture of the Melanoma Microenvironment. J Dtsch Dermatol Ges. 2013;11:4262. Halbritter, J., Bizet, A., Schmidts, M., Porath, J., Braun, D., Gee, H. et al. (2013) Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans. American Journal of Human Genetics, 93(5): 915-925. 63. Hamilton-Williams, E., Rainbow, D., Cheung, J., Christensen, M., Lyons, P., Peterson, L. et al. (2013) Fine mapping of type 1 diabetes regions Idd9.1 and Idd9.2 reveals genetic complexity. Mammalian Genome, 24(9-10): 358-375. 64. Hemani, G., Yang, J., Vinkhuyzen, A., Powell, J., Willemsen, G., Hottenga, J. et al. (2013) Inference of the Genetic Architecture Underlying BMI and Height with the Use of 20,240 Sibling Pairs. American Journal of Human Genetics, 93(5): 865-875. 65. Hickman, I., Byrne, N., Croci, I., Chachay, V., Clouston, A., Hills, A. et al. (2013) A Pilot Randomised Study of the Metabolic and Histological Effects of Exercise in Non-alcoholic Steatohepatitis. Journal of Diabetes and Metabolism, 4(8). 66. Hill D, Beaumont K, Anfosso A, Miyawaki A, Weninger W, Lovat P, et al. Induction of Endoplasmic Reticulum Stress as a Strategy for Melanoma Therapy. J Dtsch Dermatol Ges. 2013;11:6267. Inder, K., Davis, M. & Hill, M. (2013) Ripples in the pond - using a systems approach to decipher the cellular functions of membrane microdomains. Molecular Biosystems, 9(3): 330-338. 68. Jarnbhrunkar, S., Yu, M., Yang, J., Zhang, J., Shrotri, A., Endo-Munoz, L. et al. (2013) Stepwise pore size reduction of ordered nanoporous silica materials at angstrom precision. Journal of the American Chemical Society, 135(23): 8444-8447. 69. Jiang, L., Willner, D.Danoy, P. Xu, H. & Brown, M. (2013) Comparison of the performance of two commercial genome-wide association study genotyping platforms in Han Chinese samples. G3-Genes Genomes Genetics, 3(1): 23-29. 70. Kendall BJ, Macdonald GA, Hayward NK, Prins JB, O’Brien S, Whiteman DC, et al. The risk of Barrett’s esophagus associated with abdominal obesity in males and females. Int J Cancer. 2013;132(9):2192-9. Epub 2012/10/05. 71. Kenna, T. & Brown, M. (2013) The role of IL-17-secreting mast cells in inflammatory joint disease. Nature Reviews Rheumatology, 9(6): 375-379. 72. Kenna TJ, Brown MA. Immunopathogenesis of ankylosing spondylitis. International Journal of Clinical Rheumatology. 2013;8(2):265-74. 73. Khairuddin N, Blake SJ, Firdaus F, Steptoe RJ, Behlke MA, Hertzog PJ, et al. In vivo comparison of local versus systemic delivery of immunostimulating siRNA in HPV-driven tumours. Immunol Cell Biol. 2013.

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Glossary/Acronyms A Amino Acid - a small organic molecule which has a component which acts as a base (an amine group –NH2) and one which acts as an acid (carboxyl group – COOH). Amino acids are the building blocks of proteins. Hanging off the central carbon atom is a side chain (often given the abbreviation R) which differentiates one amino acid from another. There are approximately 20 different amino acids which are used to make proteins. Ankylosing Spondylitis (AS) an autoimmune condition which causes inflammation of the joints in the spine and which may eventually lead to fusing of vertebrae. Antibody - a specialised protein molecule produced as part of the immune response which binds specifically to other molecules. Autoimmune Disease a condition which results from the body’s immune system attacking its own tissues. B Bacterium - a microorganism with a cell wall but which lacks membrane-bound organelles. Benign Tumour – a localised tumour which is not considered to be at risk of metastasis. Biomarker - a protein whose presence or level of expression is an indicator of a cellular process. C Capsid - the coat of protein which surrounds the genetic material of a virus. Cell - membrane bound bodies which form the basis of all living things. Cell Cycle - the normal progression of development and reproduction through which cells pass. Checkpoint - a point in the cell cycle where a cell must meet certain conditions before it can pass onto the next stage.

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Chromosome - a length of DNA containing a long sequence of genes.

Epithelium - a type of tissue which lines a surface in the body.

Chronic - a state of a disease characterised by lower-grade symptoms experienced over an extended period of time.

Exome - the proportion of the genome which is transcribed into mRNA for translation into proteins. In humans, the exome accounts for 1% of the total genome.

Citrullinated Peptide - protein fragments where the amino acid arginine has been slightly modified to become a citrulline.

Exon - a region of coding DNA in a gene. Exons are often separated by non-coding introns which must be removed from the mRNA transcribed from the gene before it can be translated into a protein.

Cytokine - a substance responsible for chemical communication between cells, particularly with respect to stimulating an immune response.

Expression - the production of a protein under the instruction of a gene.

Cytotoxic - capable of killing cells.

G

D

Gene - the unit of inheritance. Genes are sections of DNA which code for the production of a particular protein or protein subunit.

Differentiation - the formation of specialised cells from generic pre-cursor or stem cells, or, in cell culture, telling apart two types of cell. DNA - deoxyribonucleic acid. DNA is composed of two antiparallel chains of nucleotides arranged in a double helix conformation. DNA resembles a twisted ladder, with the “rails” consisting of alternating phosphate groups and the 5-carbon sugar deoxyribose, and the “rungs” composed of pairs of nitrogenous bases joined by hydrogen bonding. It is capable of making copies of itself (with the aid of enzymes such as the DNA polymerases) and the order of its bases stores the information needed to manufacture proteins. E Enzyme - a protein molecule which catalyses (helps along) a chemical reaction by lowering its activation energy. Enzymes do this by bringing molecules close together to join them together, or by undergoing a conformational change which breaks a bond. Epidermis - the outer layer of the skin. Epigenetic - the study of heritable changes in our genome that occur without altering the DNA or genetic code.

Genome - the entire collection of genes in an organism. GWAS (Genome-Wide Association Study) a method of analysis which involves comparing the frequency of SNPs in the genomes of individuals affected by a particular condition with that of individuals not affected by that condition. H Histone - a family of proteins intimately associated with DNA in the nucleus. DNA wraps around histones to form nucleosomes. This process assists in chromosomal packing and gene regulation. I Immunity - protection from a disease causing agent. Inflammation - a response by the body to damage or the presence of foreign objects. Inflammation is a complex process involving the interaction of many different substances. Some act as cytokines which attract specialised white blood cells to deal with the cause of the damage, while others may make blood vessels “leaky”, releasing fluid into tissues to dilute the damaging agent.


In Vitro - “in glass” - experiments performed outside a living organism. In Vivo - “in life” - experiments performed inside a living organism. K Kinase - an enzyme which attaches a phosphate group to a protein. L Leukaemia - a condition characterised by the cancerous transformation of the stem cells which produce white blood cells. Leukocyte - a white blood cell. Lymphocyte - a type of white blood cell involved in the immune response. M Malignant Tumour - a tumour which is capable of metastasis, also known as a cancerous tumour. Melanoma - an aggressive cancer derived from the melanocytes in the skin. Melanocyte - a pigment containing cell found in the bottom layer of the epidermis in the skin. Metastasis - the spread of cancerous cells from one part of the body to another, often resulting in the development of a secondary tumour. Microbe - a microscopic living organism or microorganism, which may be a single cell or a multicellular organism. Microbiome - bacteria resident in the intestines. Monocyte - a type of circulating white blood cell which can differentiate into macrophages or dendritic cells. Multicellular - an organism consiting of more than cell organised in functional systems. Mutation - any change to the normal DNA sequence.

N Nucleic Acid - a type of macromolecule consisting of a chain of nucleotides. The sugar and phosphate groups in the nucleotides form a “backbone”, while the nitrogenous bases jut off to the side. DNA and RNA are nucleic acids. Nucleosome - a body formed by DNA coiling around histones. Nucleotide - a chemical group consisting of a phosphate group, a 5-carbon sugar (either deoxyribose or ribose) and a nitrogenous base (either adenine, guanine, thymine, cytosine of uracil). Nucleotides form the basis of a strand of DNA. Nucleus - a membrane bound body inside cells which contains the chromosomal DNA. O Oncogene - a gene which causes or is associated with the development of cancer. Organelle - a sub-cellular component which carries out a particular task. P Peptide - a length of amino acids joined by peptide bonds. Peptide Bond - the covalent linkage in protein chains between the amino group of one amino acid and the carboxyl group of the next. Prognosis - the likelihood that a patient with a particular condition will survive. Protein - a large biological molecule composed of a chain of smaller molecules called amino acids. Proteins perform a range of roles in the cell, including structure, catalysis of chemical reactions, recognition of substances and regulation of cellular processes. R Rheumatoid Arthritis - an autoimmune disease which results from the body’s immune system attacking the cartilage tissue in the joints.

Ribosome - a body within the cell composed of protein and rRNA which carries out translation. Ribonucleic Acid (RNA) - a nucleic acid which differs from DNA in that it contains the sugar ribose (instead of deoxyribose) and the nucleotide base uracil instead of thymine. RNA is usually single stranded, although it may double over on itself to create double-stranded regions and hairpin structures. The three major forms of RNA are mRNA (messenger) which is transcribed from the DNA and which carries the instructions for protein synthesis to the ribosome, tRNA (transfer) which bear the amino acids used in protein synthesis, and rRNA (ribosomal) which is found in the ribosome. Recently, attention has been directed to other forms of RNA which play a role in gene regulation: shRNA (short hairpin), siRNA (short interfering) and miRNA (micro). S SNP (Single Nucleotide Polymorphism) - a change in the nucleotide sequence of a length of DNA involving the substitution of a single nucleotide. Squamous Cell Carcinoma (SCC) a cancer which affects squamous epithelium, a tissue which consists of layers of flattened cells (eg. the skin, the lining of the mouth). Stem Cell - a cell capable of proliferation which can give rise to other stem cells or to cells which can differentiate into mature functional cells. T Therapeutic - treatment aimed at curing or managing a disease or condition once it has been contracted. Tumour - a mass of tissue, often consisting of abnormal or undifferentiated cells. Tumours may be considered as benign or malignant. V Vaccine - a treatment aimed at artificially stimulating an immune response against a specific agent.

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@UQDiamantinaInstitute @UQDI_news

The University of Queensland Diamantina Institute Level 7, Translational Research Institute 37 Kent St, Woolloongabba, QLD Australia 4102 Phone +61 7 3443 6999 Email di.enquiries@uq.edu.au Web www.di.uq.edu.au The University of Queensland Diamantina Institute thanks our benefactors who partner us in research. CRICOS Provider Number 00025B

UQ Diamantina Institute Annual Report 2013  
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