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News Article | May 22, 2017
Site: www.eurekalert.org

Many things go wrong in cells during the development of cancer. At the heart of the chaos are often genetic switches that control the production of new cells. In a particularly aggressive form of leukemia, called acute myeloid leukemia, a genetic switch that regulates the maturation of blood stem cells into red and white blood cells goes awry. Normally, this switch leads to appropriate numbers of white and red blood cells. But patients with acute myeloid leukemia end up with a dangerous accumulation of blood stem cells and a lack of red and white blood cells -- cells that are needed to supply the body with oxygen and fight infections. Now, researchers at Caltech and the Sylvester Comprehensive Cancer Center at the University of Miami are narrowing in on a protein that helps control this genetic switch. In healthy individuals, the protein, called DPF2, stops the production of red and white blood cells when they do not need to be replaced. That is, it turns the switch off. But the protein can be overproduced in acute myeloid leukemia patients. The protein basically sits on the switch, preventing it from turning back on to make the blood cells as needed. Patients who overproduce DPF2 have a particularly poor prognosis. In a new study, to be published the week of May 22, 2017, in the journal Proceedings of the National Academy of Sciences, the researchers demonstrate new ways to impede DPF2, potentially rendering acute myeloid leukemia more treatable. They report new structural and functional details about a fragment of DPF2. This new information reveals targets for the development of drugs that would block the protein's function. "Many human diseases, including cancers, arise because of malfunctioning genetic switches," says André Hoelz, the corresponding author of the study. Hoelz is a professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and a Howard Hughes Medical Institute (HHMI) Faculty Scholar. "Elucidating how they work at atomic detail allows us to begin the process of custom tailoring drugs to inactivate them and in many cases that is a significant step towards a cure." Red and white blood cells are constantly regenerated from blood stem cells, which reside in our bone marrow. Like other stem cells, blood stem cells can live forever. It is only when they become differentiated into specific cell types, such as red and white blood cells, that they then become mortal, or acquire the ability to die after a certain period of time. "Our bodies use a complex series of genetic switches to differentiate a blood stem cell into many different cell types. These differentiated cells then circulate in the blood and serve a variety of different functions. When these cells reach the end of their lifespan they need to be replaced," says Hoelz. "This is somewhat like replacing used tires on a car." To investigate the role of DPF2 and learn more about how it controls the genetic switch for making blood cells, the Hoelz group partnered with Stephen D. Nimer, co-corresponding author of the paper and director of the Sylvester Comprehensive Cancer Center, and his team. First, Ferdinand Huber and Andrew Davenport -- both graduate students at Caltech in the Hoelz group and co-first-authors of the new study--obtained crystals of a portion of the DPF2 protein containing a domain known as a PHD finger, which stands for planet homeodomain. They then used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the PHD finger domain. The technique was performed at the Stanford Synchrotron Radiation Lightsource, using a dedicated beamline of Caltech's Molecular Observatory. The results revealed how DPF2 binds to a DNA-protein complex, called the nucleosome, to block the production of red and white blood cells. The protein "reads" various signals displayed on the nucleosome surface by adopting a shape that fits various modifications on the nucleosome complex, like the different shaped pieces of a jigsaw puzzle. Once the protein binds to this DNA locus, DPF2 turns off the switch that regulates blood cell differentiation. The next step was to see if DPF2 could be blocked in human blood stem cells in the lab. Sarah Greenblatt, a postdoctoral associate in Nimer's group and co-first author of the study, used the structural information from Hoelz's group to create a mutated version of the protein. The Nimer group then introduced the mutated protein in blood stem cells, and found that the mutated DPF2 could no longer bind to the nucleosome. In other words, DPF2 could no longer inactivate the switch for making blood cells. "The mutated DPF2 was unable to bind to specific regions in the genome and could not halt blood stem cell differentiation," says Huber. "Whether DPF2 can also be blocked in the cancer patients themselves remains to be seen." The researchers say a structural socket in DPF2, one of the puzzle-piece-like regions identified in the new study, is a good target for candidate drugs. The study, titled "Histone-Binding of DPF2 Mediates Its Repressive Role in Myeloid Differentiation," was funded by a PhD fellowship of the Boehringer Ingelheim Fonds, a National Institutes of Health Research Service Award, the National Cancer Institute of the National Institutes of Health, a Faculty Scholar Award of the Howard Hughes Medical Research Institute, the Heritage Medical Research Institute, Caltech startup funds, the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, and a Teacher-Scholar Award of the Camille & Henry Dreyfus Foundation. Other authors are Concepcion Martinez and Ye Xu of the University of Miami and Ly P. Vu of the Memorial Sloan Kettering Cancer Center.


News Article | May 22, 2017
Site: phys.org

A crystal structure of a portion of human DPF2, a protein that controls a genetic switch that tells blood stem cells when to become red and white blood cells. Orange and yellow regions illustrate the DPF2 'reader' domain, which is stabilized by zinc ions, represented as red and grey spheres. Credit: Hoelz Lab/Caltech Many things go wrong in cells during the development of cancer. At the heart of the chaos are often genetic switches that control the production of new cells. In a particularly aggressive form of leukemia, called acute myeloid leukemia, a genetic switch that regulates the maturation of blood stem cells into red and white blood cells goes awry. Normally, this switch leads to appropriate numbers of white and red blood cells. But patients with acute myeloid leukemia end up with a dangerous accumulation of blood stem cells and a lack of red and white blood cells—cells that are needed to supply the body with oxygen and fight infections. Now, researchers at Caltech and the Sylvester Comprehensive Cancer Center at the University of Miami are narrowing in on a protein that helps control this genetic switch. In healthy individuals, the protein, called DPF2, stops the production of red and white blood cells when they do not need to be replaced. That is, it turns the switch off. But the protein can be overproduced in acute myeloid leukemia patients. The protein basically sits on the switch, preventing it from turning back on to make the blood cells as needed. Patients who overproduce DPF2 have a particularly poor prognosis. In a new study, to be published the week of May 22, 2017, in the journal Proceedings of the National Academy of Sciences, the researchers demonstrate new ways to impede DPF2, potentially rendering acute myeloid leukemia more treatable. They report new structural and functional details about a fragment of DPF2. This new information reveals targets for the development of drugs that would block the protein's function. "Many human diseases, including cancers, arise because of malfunctioning genetic switches," says André Hoelz, the corresponding author of the study. Hoelz is a professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and a Howard Hughes Medical Institute (HHMI) Faculty Scholar. "Elucidating how they work at atomic detail allows us to begin the process of custom tailoring drugs to inactivate them and in many cases that is a significant step towards a cure." Red and white blood cells are constantly regenerated from blood stem cells, which reside in our bone marrow. Like other stem cells, blood stem cells can live forever. It is only when they become differentiated into specific cell types, such as red and white blood cells, that they then become mortal, or acquire the ability to die after a certain period of time. "Our bodies use a complex series of genetic switches to differentiate a blood stem cell into many different cell types. These differentiated cells then circulate in the blood and serve a variety of different functions. When these cells reach the end of their lifespan they need to be replaced," says Hoelz. "This is somewhat like replacing used tires on a car." To investigate the role of DPF2 and learn more about how it controls the genetic switch for making blood cells, the Hoelz group partnered with Stephen D. Nimer, co-corresponding author of the paper and director of the Sylvester Comprehensive Cancer Center, and his team. First, Ferdinand Huber and Andrew Davenport—both graduate students at Caltech in the Hoelz group and co-first-authors of the new study—obtained crystals of a portion of the DPF2 protein containing a domain known as a PHD finger, which stands for planet homeodomain. They then used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the PHD finger domain. The technique was performed at the Stanford Synchrotron Radiation Lightsource, using a dedicated beamline of Caltech's Molecular Observatory. The results revealed how DPF2 binds to a DNA-protein complex, called the nucleosome, to block the production of red and white blood cells. The protein "reads" various signals displayed on the nucleosome surface by adopting a shape that fits various modifications on the nucleosome complex, like the different shaped pieces of a jigsaw puzzle. Once the protein binds to this DNA locus, DPF2 turns off the switch that regulates blood cell differentiation. The next step was to see if DPF2 could be blocked in human blood stem cells in the lab. Sarah Greenblatt, a postdoctoral associate in Nimer's group and co-first author of the study, used the structural information from Hoelz's group to create a mutated version of the protein. The Nimer group then introduced the mutated protein in blood stem cells, and found that the mutated DPF2 could no longer bind to the nucleosome. In other words, DPF2 could no longer inactivate the switch for making blood cells. "The mutated DPF2 was unable to bind to specific regions in the genome and could not halt blood stem cell differentiation," says Huber. "Whether DPF2 can also be blocked in the cancer patients themselves remains to be seen." The researchers say a structural socket in DPF2, one of the puzzle-piece-like regions identified in the new study, is a good target for candidate drugs. Explore further: Researchers show p300 protein may suppress leukemia in MDS patients More information: Ferdinand M. Huber el al., "Histone-binding of DPF2 mediates its repressive role in myeloid differentiation," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1700328114


PASADENA, CA, November 09, 2016 /24-7PressRelease/ -- Huntington Medical Research Institutes (HMRI), an independent, leading biomedical research institute based in Pasadena, California, has announced the appointment of Allyson Simpson as Vice President of Philanthropy and Susie Silk Berry as Director of Philanthropy. Prior to joining HMRI, Allyson Simpson was the Senior Director of Gift Planning at California Institute of Technology (Caltech) in Pasadena for six years. Simpson also served as associate director of gift planning at Cedars-Sinai Medical Center in Los Angeles. Before she transitioned into development with a focus on planned, major and leadership giving, Simpson practiced corporate and regulatory law in Los Angeles for 25 years. She is a member of the Partnership for Philanthropic Planning - Los Angeles, where she has been appointed as President-Elect in 2016-2017 and will serve as President in 2017-2018. Simpson is currently Chair of the South Central Los Angeles Ministry Project Development Committee and is a member of the Mayfield Junior School Development Committee. Susie Berry will bring more than a decade of development experience to HMRI as the new Director of Philanthropy. Her new duties will include raising funds to further support the organization's biomedical research and development of new diagnostics and therapies. Prior to joining HMRI, Berry was the Director of Development at the YMCA in Los Angeles where she established goals, objectives and strategies to achieve annual revenue targets through major gifts, annual giving and foundation grants. Berry wrote grant proposals and managed the operations of the Chairman's Round Table annual funding driving sponsorships among other responsibilities. During her time with the YMCA, she successfully created the South Pasadena San Marino 5K/10K YRUN fundraiser through securing sponsors and exceeding the revenue goal by 20% through raising awareness of the Y's work in the community. "With their specialized skill sets and experience, both Simpson and Berry's work will make a tremendous impact in supporting our audacious scientific goals. They maintain strong ties in the philanthropic community and industry trade associations, and are well-respected in our community. They are true professionals who fit so well into the vision of HMRI," says Dr. Marie Csete, HMRI's President & Chief Scientist. "Simpson and Berry are exceptional, passionate individuals who will certainly make HMRI better known and better supported in our mission of changing lives through multidisciplinary, patient-focused research. I could not be happier with these new leaders of HMRI at this critical time in the organization's history with reinvigorated research programs and new labs under construction." About Huntington Medical Research Institutes Huntington Medical Research Institutes (HMRI) is a tax-exempt 501(c)(3) nonprofit, public-benefit organization based in Pasadena, California, dedicated to studying and enhancing knowledge of diseases in order to improve health and save lives. HMRI's mission is to change lives through multidisciplinary, patient-focused research. For six decades, it has been making biomedical discoveries and developments that have set new precedents in medical knowledge across the nation and around the world. HMRI is Pasadena's only independent, dedicated biomedical research organization with more than 47,000 square feet of research facilities focused on neurosciences (Alzheimer's, traumatic brain injury, migraine), cardiovascular, cell and tissue biology, advanced imaging, and liver, GI and GU research. For more information, visit: http://www.hmri.org


Shon Y.E.,HMRI | Chang B.J.,HMRI | You J.M.,HMRI | Han B.W.,HMRI
Naval Architect | Year: 2016

CFD analysis was used to study the hydrodynamic characteristics of the twin skeg type LNG carrier, and to design the new twisted rudder. To validate the computational method used, the CFD results of the original wake field analysis were compared with the experimental results of the same subject vessel via the use of stereoscopic particle image velocimetry system during model testing at HMRI's towing tank. The axial velocity of the left side (inboard) was faster than the right side (outboard). Armed with a better understanding of the propeller wake field flow, it was possible to design a twisted rudder using the CFD results. This design was compared with a symmetrical rudder during a model test using a three-dimensional method of interpretation in consideration of the form factor, which established the clear benefit of the twisted design.


Whalley R.H.,HMRI
IET Seminar Digest | Year: 2010

The paper outlines the development and requirements of relevant legislation. It shows how the systems to meet the requirements have developed and how they are met with current technology. It explores different braking systems and the interfaces between braking and traction control systems. Finally it looks at the implications of such control systems on track capacity and the slippery topic of adhesion in the evolving world of ERTMS.


Huntington Medical Research Institutes (HMRI), an independent, leading biomedical research institute based in Pasadena, California, has announced the appointment of Allyson Simpson as Vice President of Philanthropy and  Susie Silk Berry as Director..

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