Ludwiglink April 2013

LudwigLink April 2013

The endless why TRANSITIONS

Ludwig postdocs were the kids who Small but mighty staff members are not straying far from wanted to know: why is the sun yellow, home. Gerd Ritter has been named will we ever discover aliens, how much Although it was the smallest Ludwig site, developmental research director within does the earth weigh, why can’t we eat its contributions to cancer research were Ludwig’s technology development rocks, or when is the world’s birthday? monumental. Many seminal findings team. He is now responsible for moving With every answer came more questions. in tumor immunology, the study of Ludwig’s discoveries forward by assessing the interaction between cancer and promising work in the pipelines of our Science, at its heart, is driven by human the immune system, can trace their research teams and collaborators and curiosity and our ability to dream origins to Ludwig New York, located putting it on the path to development. and imagine. These traits can lead at the Memorial-Sloan Ketting Cancer to wonderful discoveries and results. Center (MSKCC). The branch was Sacha Gnjatic has moved to the Tisch Ludwig scientists have a built-in passion established and led by Lloyd Old until Cancer Institute at the Icahn School of for science. Many of our postdocs will his death in 2011, and its scientists were Medicine at Mount Sinai in New York. become the next generation of scientific committed to developing a continuum And Achim Jungbluth has moved to the leaders in academia and industry. And between laboratory discovery and clinical Pathology Department within MSKCC. they’ve never stopped asking those pesky application. They pursued targeted questions. approaches to cancer, including tumor Ludwig research in New York continues antigen-specific cancer vaccines and in the form of a new collaborative So we’ve added a new feature to the therapeutic antibodies, to track down laboratory at MSKCC headed by Jedd newsletter called “Ask a scientist.” In and destroy cancer cells without many Wolchok. The lab focuses on developing every issue we’ll pose a question and of the debilitating toxic side effects of new ways to use the immune system ask several postdocs for an answer. This chemotherapy and radiation. to treat cancer. It is closely aligned issue’s question is “What do you think has with the Ludwig Center at MSKCC been the biggest achievement of the war Although the New York site’s closure and works with that group to monitor on cancer?” Check out their answers on at the end of December had been immune responses in patients receiving page 6. anticipated for some time, senior scientific experimental immunotherapy treatments.

No one has a crystal ball that can predict the course of scientific discovery. But we New Swiss cancer center can be sure that today’s Ludwig postdocs will play a major role in it.

Rachel Steinhardt, Director of Communications

Ludwig champions close collaborations between clinicians and researchers and is constantly seeking innovative approaches to translate research findings into improved clinical care.

The AGORA Cancer Center, which is underway in Lausanne, Switzerland, is expected to open in early 2016 and will bring together 400 researchers and clinicians under one roof to stimulate collaboration and resource sharing. It will be a key component of a new Swiss Cancer Center. Its ultimate goal is to move viable treatments from the ‘bench ©Behnisch Architekten to the bedside’ as soon as they emerge Architectural renderings of the interior of the AGORA Cancer Center in Lausanne. The new from research. center will feature open floor plans with collaboration areas and lighting that enhance an aura of sustainability and community. These ‘casual meeting places’ will intensify interactions, facilitate The new cancer research building teamwork, and allow communication to occur more naturally, without visual hindrances. will host integrated research groups from Ludwig, University Hospital of Lausanne, University of Lausanne and École Polytechnique Fédérale de Lausanne. The building is one of many significant investments that Lausanne is making in cancer research. This is a major area of emphasis for the University Hospital, the University of Lausanne and École Polytechnique Fédérale de Lausanne.

“Bringing together doctors, researchers and bioengineers under one roof will stimulate collaborative efforts that will lead to major breakthroughs in therapeutic strategies aimed at cancer patients,” said George Coukos, who leads the Ludwig Center for Cancer Research of the University of Lausanne.

Did you know…? the US, 85 percent in the UK, 82 percent in Switzerland and 80 percent in Spain. International Hug Day was January 21. In the 1950s, it was roughly 60 percent in the US. No one deserves a hug more than a scientist. Here’s just one reason why: Breast cancer is the most common cancer And we have scientists to thank for these encouraging in both developed and developing regions. It’s the leading statistics. With earlier disease detection, treatment advances cause of cancer death among women worldwide, with including hormones and biological therapies, and continuing almost half a million deaths annually. clinical trials, the prognosis is good.

The good news is the five-year survival rate from breast Have you hugged a scientist today? cancer among women age 15 and older is 89 percent in

2 AWARDS Blue skies

Scientists often cannot predict future applications of their research. But they need to have the freedom to carry out flexible, curiosity-driven research that might lead to outcomes not envisaged at the outset. Encouraging an avenue for ‘blue skies’ research could have immense influence on future scientific discoveries.

The European Research Council understands the value of blue skies research and awarded George Coukos, who leads the Ludwig Center for Cancer Research of the University of Lausanne, an advanced grant for his work on engineering T cells that target tumor blood vessels. George’s work focuses on developing chimeric antigen receptor (CAR) immunotherapies against cancer. In CAR immunotherapy, a patient’s T cells are modified so that once the cells are reintroduced into the patient they recognize, bind to and destroy target cancer cells. This work could advance cancer therapy, as genetically modifying T cells to express synthetic CARs is an attractive strategy for producing antitumor effects.

The European Research Council is the National treasure first pan-European funding organization for pioneering research. The advanced Lucy Shapiro, a renowned molecular microbiologist, member of Ludwig’s Scientific grants allow the brightest scientists Advisory Committee and the Virginia and D.K. Ludwig Professor at Stanford to work on their best ideas without University, has been awarded the National Medal of Science, the nation’s highest worrying about short-term priorities. honor bestowed on scientists. She was one of 12 eminent US researchers who received the award from President Obama in a White House ceremony on February Perfect host 1. The National Medal of Science was established by Congress in 1959 and is administered by the National Science Foundation. Nuclear medicine uses molecular imaging techniques and radiopharmaceuticals to detect and treat cancer, cardiovascular disease and neurodegenerative diseases. Melbourne, 2014 to 2018, with Ludwig researcher research on unique disease profiles in Australia, has been chosen to host the Andrew Scott as president-elect. “This the developing world. The WFNMB is 2018 World Congress of the World win is a very important step forward for the premier body for nuclear medicine Federation of Nuclear Medicine and the organization, and will bring nuclear worldwide, and has key interactions with Biology (WFNMB). With more than medicine specialists and other medical all global nuclear medicine societies, as 2,500 expected delegates, it will highlight specialists from all over the world well as with the International Atomic outstanding nuclear medical research, together to collaborate in this specialized Energy Agency and the World Health diagnostics and therapeutics in Australia field of medicine,” Andrew said. Organization. and worldwide. It will also showcase one of Ludwig’s areas of expertise in the The WFNMB charter includes Kudos to Andrew on a great opportunity region. integrating clinical care and research to promote and encourage the between developed and developing advancement of nuclear medicine Additionally, the leadership of the World countries, creating opportunities for worldwide. Federation will reside in Australia from shared activities, and performing

3 NEWS ROUNDUP Everything old is new again inputs: nutrients, growth factors, energy (5hmC), scientists are shedding new and stress. light on just what the heck it does. In A Pap test can save a woman’s life. the December 21 issue of Cell, Ludwig For almost 70 years, it has prevented Although mTorc1 has been implicated researcher Skirmantas Kriaucionis countless deaths from cervical cancer. previously in the development of other in Oxford and Nathaniel Heintz at Now a team led by Ludwig scientists cancers, this is the first time it has been Rockefeller University showed that Bert Vogelstein and Ken Kinzler at shown to promote the growth of colon 5hmC and another epigenetic marker, Johns Hopkins have developed a test and gastric cancers associated with 5-methylcytosine (5mC), have opposite that piggybacks on the widely used Pap inflammation. effects on gene expression. As a global test and expands it to look for genetic depletion of 5hmC takes place in abnormalities associated with ovarian “We were excited to discover that the a broad range of tumor cells, these cancer and cancer of the endometrium, growth of these cancers in laboratory findings could be valuable in cancer the lining of the uterus. models could be prevented by treatment research. with mTorc1 inhibitors that are already In a pilot study, in clinical trials for other types of Each type of cell selectively expresses a the PapGene cancer,” Matthias said. “In the future, unique suite of genes and silences those test, which relies we hope that this finding might lead to irrelevant to its function. Scientists have on genomic better treatment options for colon and long known that such gene silencing can sequencing of gastric cancers that are associated with occur by the chemical modification of cancer-specific inflammation.” cytosine—one of the four bases of DNA mutations, that write the genetic code—to create accurately detected Their findings were published in the 5mC. all 24 (100 percent) February issue of the Journal of Clinical Bert Vogelstein endometrial Investigation. Appropriate placement of this marker cancers and 9 is essential to many normal biological of 22 (41 percent) ovarian cancers. Opposites attract processes, including embryonic Endometrial cancers are often detected development. Conversely, its faulty in the early stages of the disease and Epigenetic markers on an individual’s distribution contributes to the evolution can usually be cured when caught early. DNA may explain why some people of a broad range of cancers. However, there’s no simple screening become more susceptible to disease tool for ovarian cancer, and it is usually as they age. With new tools and But 5mC is not the only epigenetic diagnosed at an advanced stage, earning techniques to study the epigenetic marker on the genomic block. 5hmC it the moniker “the silent killer.” marker 5-hydroxymethylcytosine continued on next page

Results of the study were published in the January 9 issue of Science Translational Medicine. It offers hope and great promise in battling the deadliest of all gynecological cancers. The research is part of the Hilton- Ludwig Cancer Prevention Initiative.

Holy inflammation, Batman! Ludwig researchers led by Matthias Ernst in Melbourne have identified a complex of proteins that promotes growth of some types of colon and gastric cancers associated with chronic inflammation. Known as mammalian target of rapamycin complex 1 or mTorc1, the proteins signal inside cells to promote growth. Medications that block the function of this complex, they have shown, could be developed into a new treatment for these diseases. mTorc1 integrates four major signal Skirmantas Kriaucionis

4 seems to play a similarly vital role in the selective expression of the genome, and changes in its distribution occur in a broad range of tumor cells. Skirmantas’s lab is now assessing the role of 5hmC in the development of different types of blood cells, with the aim of deciphering how its loss contributes to the generation of blood cancers.

The gist of it A gastrointestinal stromal tumor (GIST) is a rare type of tumor that usually affects the stomach or small intestine. Although there are no known causes of GIST, 95 percent of people with this condition have a type of GIST that Irving Weissman originates when a protein called KIT becomes abnormal. In roughly three- keep growing and dividing, resulting in imatinib (Gleevec), a drug approved by quarters of GIST cases, mutations uncontrolled cell growth that leads to the US Food and Drug Administration. in KIT are present that drive the tumor formation. The drug works by inhibiting, or turning proliferation of these tumors. off, the signal from the KIT protein, In a study published online February so that most of the cancer cells stop This condition is called KIT-positive 4 in Proceedings of the National Academy of growing. (KIT+) GIST. Normally, KIT signals Sciences, Ludwig scientists at Stanford cells in the body to grow and divide led by Irving Weissman showed that the SR1 treatment may also prove useful in only when new cells are needed. In anti-KIT monoclonal antibody SR1 other KIT+ tumors, such as in breast KIT+ GIST, KIT becomes abnormal can significantly inhibit stromal tumor cancer, melanoma and neuroblastoma, because of a mutation, and the signal GIST cell growth. It could become an a malignant tumor that develops from to the cells does not turn off. KIT sends alternative or supplementary therapy nerve tissue. out a constant signal that tells cells to for patients who develop resistance to

Turning it on and primary myelofibrosis, related diseases in which abnormal blood cells and fibers, Thrombopoietin promotes the growth respectively, build up inside the bone and proliferation of platelet cells, which marrow. are involved in blood clotting, and the thrombopoietin receptor is important This finding is significant for both the in blood formation. Thrombopoietin basic science of signal transduction and signaling may also help renew stem cells applied cancer research. The amino acid within the bone marrow that have the in question, tryptophan, is found at similar potential to develop into red blood cells, points in other cell surface receptors, and white blood cells, and platelets. molecular biologists had presumed that it marks the point at which the receptor In a paper published January 28 in emerges from the membrane into the cell’s Proceedings of the National Academy of Sciences, cytoplasm. In contrast, this study showed a team led by Ludwig researcher Stefan that it prevents close pairing of upstream Constantinescu in Brussels and colleagues membrane domains and receptor showed how a mutation that alters a activation. Stefan and his colleagues have single amino acid in the thrombopoietin begun bioinformatics studies to test this receptor turns it on permanently. They new hypothesis—and determine whether explained how this leads to the blood similar mutations on other receptors are Stefan Constantinescu malignancies essential thrombocythemia also associated with cancer.

5 Ask a scientist What do you think has been the biggest achievement of the war on cancer?

As a medical oncologist, I’m impressed A cancer diagnosis is no longer We are just beginning to understand by how the FDA approval of a death sentence. Early detection how complex cancer really is, with ipilimumab has changed the landscape and advances in tumor biology and genetic heterogeneity found within in the ‘war on cancer’: transforming the genetics shifted it from being an single tumor biopsies. The dawn of standard of care for melanoma and enigmatic killer to a familiar enemy. inexpensive and fast whole-genome acting as a catalyst for the broader Moving forward, we need to diversify sequencing will enable individualized development and clinical testing of research and treatment strategy to fully diagnosis and treatment, providing the immunotherapies in melanoma and unmask this heterogeneous and devious unique opportunity to unify all aspects beyond. disease. of cancer research into comprehensive —Maggie Callahan, —Ciro Zanca, cancer systems biology. Ludwig New York Ludwig San Diego —Rasmus Freter, Ludwig Oxford

COMPANY NEWS Grand alliance The research and clinical development first candidate will enter clinical trials in partnership will focus on generating and early 2015. Tumors have an uncanny ability to evade developing three antibody therapeutics immune responses. that target regulatory checkpoints of the “We have seen tremendous progress immune system. These checkpoints act in the development of treatments that But Ludwig is fighting back on several as on- or off-switches for the T cells of harness the power of the immune system fronts. In January, the Ludwig Institute the immune system, and are important to better detect and treat cancer. This and 4-Antibody, a Swiss antibody in anticancer therapy. The only FDA- expanded collaboration will provide technology company, signed a multitarget approved immune checkpoint antibody to Ludwig scientists with access to important research and clinical development date is ipilimumab (Yervoy); it is currently clinical agents and enable us to identify collaboration with Recepta Biopharma, the highest grossing melanoma drug in the and evaluate new combinations of a company founded by Ludwig and a US and the five major European Union treatments to facilitate the development group of Brazilian investors. Recepta is the markets. of the next generation of more potent leading developer in Brazil of therapeutic immunotherapy drugs,” said Jonathan antibodies, which can block the growth 4-Antibody will generate panels of fully Skipper, head of Ludwig’s technology of a tumor and/or recruit the body’s human therapeutic antibodies against development program. immune system to attack it. The new deal these targets. The Institute has developed extends a collaboration between Ludwig a novel assay platform that it will use to Once these antibodies have been validated, and 4-Antibody that began in 2011, and select candidate antibodies for further the Institute will use them in clinical trials expands Recepta’s antibody pipeline. evaluation. The parties anticipate that the that Recepta will conduct in Brazil.

6 Q&A WITH ANDY SHIAU AND TIM GAHMAN

Three years ago, biochemist Andy Shiau (program director) and chemist Tim Gahman (director of medicinal chemistry) came to Ludwig to help our scientists perform cutting-edge research and take their ideas from concept to clinical testing. We recently had a chance to sit down with our San Diego- based ‘drug hunters’ and learn more about their unique group.

What are small Small molecules are chemical compounds. molecules? They can be substances you find in nature or things chemists make in the lab. Table sugar is a small molecule. Vitamin C is a small molecule. So are drugs, including pain relievers like aspirin and antibiotics such as penicillin. Right now, small molecules make up about 90 percent of the drug market.

Why was the Small Targeted small molecule therapies hold Molecule Discovery great promise for the battle against Andy Shiau Program started? cancer. They block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. In fact, today there are several small molecules that are targeted cancer therapies, for example Gleevec, which is approved to treat gastrointestinal stromal tumor, a rare cancer of the gastrointestinal tract.

The small molecule lab provides the Ludwig community around the world access to small molecule tools for research and helps them move basic scientific findings from the lab to a clinical setting.

How do you go Making any kind of drug is a technically about creating a exacting process. And making small small molecule? molecule drugs is no exception. Once Tim Gahman we’ve identified a target, we create molecules from scratch by using sophisticated computer modeling. At the interaction or role of a particular other times we apply a process called biochemical process in biology, an high-throughput screening, which can important early step in drug development. be used to quickly conduct millions of The chemical hits we get from our initial chemical tests on cells or proteins. Both screening or design process are then of these approaches help us to determine optimized, or altered to make them more what type of molecule controls the activity effective and safer. For example, we can of a specific protein that tells cancer cells modify a compound to make it less likely to to grow and multiply out of control. We’re interact with certain pathways in the body looking to slow or block these types of and reduce the potential for side effects, biochemical signals and cause cancer cells, such as toxicity to a healthy organ. but not normal ones, to die. We test hundreds or even thousands of The results of these experiments provide compounds against a target to identify any starting points for understanding continued on next page

7 that might be promising. And based on the results, we might select several lead compounds for further study. We’ve used these types of approaches to identify inhibitors of many proteins, such as Working with the enzymes and receptors that Ludwig small-molecule team scientists are interested in. Paul Mischel of Ludwig San Diego talks about his collaboration with the small- Can you give us We are working with Karen Oegema’s molecule development team. an example? and Arshad Desai’s labs to use our polo- like kinase 4 (PLK4) inhibitors to figure Working with the group, we’re able to use small molecules out how normal and cancer cells divide. to better understand the biology of our targets and to then This is a pretty basic concept that we develop drugs that could potentially have a major impact in still have a lot to learn about. PLK4 is the care of patients. For example, we’ve identified a novel an important cell cycle regulator that’s mechanism by which brain cancer cells regulate cholesterol involved in the regulation of centrosome levels and might turn out to be a powerful therapeutically duplication. Centrosomes help regulate targetable opportunity. The group has been developing and the cell’s progression through the refining compounds that target this mechanism, causing cell cycle. Errors in the centrosome tumor cells to die in well-controlled pre-clinical models. duplication cycle may be an important These results are very exciting and may lead to a clinical cause of aneuploidy, a chromosome trial. Without their expertise, we wouldn’t have been able problem caused by an extra or missing to do it because in the traditional academic model, we’d be chromosome, which may contribute to compelled to try and convince a pharmaceutical company cancer formation. that the target is of interest.

We’ve screened multiple small molecules against PLK4 and identified one that potently and specifically inhibits the Why is it important Biological systems are very complicated, enzyme in both biochemical and cellular that Ludwig so it’s virtually impossible to foresee what assays. If we find differences between the undertakes drug projects will ultimately pay off. This makes dependence of normal and cancer cells discovery research? it very expensive and risky. Many people on PLK4 and centrosomes, we can use think discovering and making drugs is like this information to make a totally new manufacturing cars or electronics. It’s a class of drugs targeting tumors in which lot less predictable than that. Maybe one PLK4 regulation is disrupted. Small out of a thousand or even ten thousand molecules that target PLK4 could hold projects will lead to a drug. So, the drug great promise as anticancer drugs. industry is more like Hollywood—it’s very hit driven. Pharmaceutical companies are reluctant to undertake early-stage What excites you The incredible wealth of knowledge research, and it’s getting harder to fund about your work? that has been generated with the biotech startups as venture capitalists sequencing of the human genome realize how much work and time goes into has really revolutionized the discovery developing a drug. That’s why Ludwig is and development of small molecule important. It’s willing to invest in research cancer drugs over the last decade. We’re today to develop the drugs of tomorrow. moving from a one-size-fits-all approach that emphasized chemotherapy to a personalized medicine strategy that What is the biggest Our biggest challenge is that we’re focuses on the discovery and development challenge the group starting at the very beginning of the drug of molecularly targeted drugs that exploit faces? discovery process. We’re talking to people the vulnerabilities of cancer cells. Because about ideas. We’re talking about results of of its vision and resources, Ludwig an experiment that researchers have seen is uniquely positioned to help in this for the very first time. But we’re in the transition. continued on next page

8 ideal place to take this approach because we have great colleagues who do fantastic science, the support of Ludwig, and a mission to deliver therapeutics. Working with the small-molecule team What gets you up Finding a small molecule drug that will in the morning? drive cancer cells to suicide. Walking the Benoît Van den Eynde of Ludwig Brussels halls and interacting with some of the talks about his collaboration with the small- world’s leading scientists. Working in an molecule development team. environment where people are constantly looking for answers and challenging Immunotherapy – boosting the body’s natural immune themselves to do incredibly novel things. system to fight cancerous tumors – is the next frontier in life-extending cancer treatment. We’ve identified two Kick-starting the body’s own tumor- targets whose inhibition with a drug could enhance the destroying systems to trigger cell death ability of the immune system to reject cancer cells. We’ve in cancerous but not healthy tissue is a chosen to push the development of these drugs through project we’re working on with Benoît Van the creation of a start-up company, iTeos Therapeutics. den Eynde. Understanding cholesterol Andy and Tim have been involved in this project from the metabolism in brain tumors and uncovering very beginning, by accelerating the medicinal chemistry new biology are part of an exciting programs, helping to vet medicinal staff candidates and collaboration with Paul Mischel. selecting the most efficient subcontractors for chemical synthesis. They’re also providing ongoing guidance during Bottom line: Driving the science forward the development program, and directly participating in the gets us up in the morning. research effort through the development of a new assay to screen for compounds inhibiting one of our targets. Their And figuring out how to do that keeps us input has been invaluable. awake at night.

REQUIRED READING

Ludwig Brussels Eshleman JR, Carvalho JP, Marie SK, Thiem S, Pierce TP, Palmieri M, Proceedings of the National Academy of Sciences Papadopoulos N, Kinzler KW, Putoczki TL, Buchert M, Preaudet A, USA 2013 January 28 Vogelstein B, Diaz LA Jr. Farid RO, Love C, Catimel B, Lei Z, Tryptophan at the transmembrane-cytosolic Rozen S, Gopalakrishnan V, Schaper F, junction modulates thrombopoietin receptor Hallek M, Boussioutas A, Tan P, dimerization and activation LICR/UNIL Center Lausanne Jarnicki A, Ernst M. Defour JP, Itaya M, Gryshkova V, Nature Nanotechnology 2013 February 8 Brett IC, Pecquet C, Sato T, Smith SO, Direct detection of a BRAF mutation in total Constantinescu SN. RNA from melanoma cells using cantilever arrays Ludwig Center at MSKCC Huber F, Lang HP, Backmann N, Molecular Cell 2012 December 14 Rimoldi D,* Gerber Ch.* Transcriptome-wide miR-155 binding map Ludwig Center at Johns Hopkins *These authors contributed equally to this work reveals widespread noncanonical microRNA Science Translational Medicine targeting 2013 January 9 Loeb GB,* Khan AA,* Canner D, Evaluation of DNA from the Papanicolaou test Ludwig Melbourne Hiatt JB, Shendure J, Darnell RB, to detect ovarian and endometrial cancers Journal of Clinical Investigation Leslie CS, Rudensky AY. Kinde I, Bettegowda C, Wang Y, Wu J, 2013 January 16 (Epub ahead of print) *These authors contributed equally to this work Agrawal N, Shih IeM, Kurman R, mTORC1 inhibition restricts inflammation- Dao F, Levine DA, Giuntoli R, Roden R, associated gastrointestinal tumorigenesis in mice continued on next page

9 REQUIRED READING

Ludwig Oxford Ludwig São Paulo Cell 2012 December 21 PLoS Genetics 2013 January 24 MeCP2 binds to 5hmC enriched within active Gene copy-number polymorphism caused by genes and accessible chromatin in the nervous retrotransposition in humans system Schrider DR, Navarro FC, Galante PA, Mellén M, Ayata P, Dewell S, Parmigiani RB, Camargo AA, Kriaucionis S, Heintz N. Hahn MW, de Souza SJ.

Ludwig San Diego Ludwig Center Proceedings of the National Academy of Sciences at Stanford University USA 2013 February 4 (Epub ahead of Proceedings of the National Academy of Sciences print) USA 2013 February 4 (Epub ahead of ALS-linked TDP-43 mutations produce aberrant print) RNA splicing and adult-onset motor neuron Anti-KIT monoclonal antibody inhibits imatinib- disease without aggregation or loss of nuclear resistant gastrointestinal stromal tumor growth TDP-43 Edris B, Willingham SB, Weiskopf K, Arnold ES, Ling SC, Huelga SC, Volkmer AK, Volkmer JP, Lagier-Tourenne C, Polymenidou M, Mühlenberg T, Montgomery KD, Ditsworth D, Kordasiewicz HB, Contreras-Trujillo H, Czechowicz A, McAlonis-Downes M, Platoshyn O, Fletcher JA, West RB, Weissman IL, Parone PA, Da Cruz S, Clutario KM, van de Rijn M. Swing D, Tessarollo L, Marsala M, Shaw CE, Yeo GW, Cleveland DW.