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Personal DNA sequencing once promised to up the ante for individualized medicine. Perhaps no one believed that more than human genomics pioneer J. Craig Venter, who in 2014 co-founded a company called Human Longevity to predict and prevent disease by sequencing a million human genomes. But Venter is no longer content with your DNA. His latest venture—a subsidiary called Health Nucleus based in San Diego, California—says it can detect undiagnosed health problems by combining DNA analyses with a $25,000 workup including a whole-body MRI scan, metabolomics screening, 2 weeks of constant heart monitoring, pedigree analysis, microbiome sequencing, and a glut of standard laboratory tests. Enthusiasts of “precision medicine” say this kind of screening—similar to the U.S. National Institutes of Health’s (NIH’s) Precision Medicine Initiative—is the way of the future. But many other clinicians and researchers are leery or even downright outraged by the program’s potential for over diagnosis and what they see as lack of evidence for its benefits. Late last week, Venter and co-workers quietly published a paper on the preprint server bioRxiv—which does not use peer review—that appears to present data from the new project. According to the study, screening detected “age-related chronic diseases requiring prompt (<30 days) medical attention” in 8 % of the 209 participants, and MRIs found early-stage cancer in 2%. However, Health Nucleus did not confirm that the data were from its $25,000 medical exam, although descriptions of the diagnostics were nearly identical. “It’s a classic Craig Venter study that pushes the envelope of what is considered reasonable,” says Olivier Elemento, associate director at the Institute for Computational Biomedicine at Weill Cornell Medicine in Ithaca, New York. Meanwhile, Venter has been making the media rounds to promote the screening. On Fox Business, he said the exam finds “something seriously wrong” in 40% of participants (though that claim is left unexplained). CBS News reports that Venter’s group can predict Alzheimer’s disease 20 years in advance by scanning the 20 regions of the brain. And STAT news reports that the exams detect tumors early enough that every participant with cancer so far has been able to treat it, even the notoriously unforgiving pancreatic cancer. A spokesperson for Human Longevity said they would not comment on the contents of the paper until it is published in a peer-reviewed journal. Critics aren’t buying it. “If I wanted to write a Swiftian parody illustrating the insanity of this extreme version of [precision medicine], I could not have written a better paper,” says Nigel Paneth, a pediatrician and epidemiologist from Michigan State University in East Lansing, who cites a litany of problems that could result from the study including psychological damage, high medical costs, unnecessary tests, and “the absence of the slightest shred of evidence that any benefit will accrue to anyone.” Eric Topol, director of Scripps Translational Science Institute in San Diego says this is “kind of the most extensive diagnostic evaluation of people that has ever been done,” but he takes issue with billing the study as a precision medicine screening. “Is this precise or is this promiscuous?” he asks. “That term ‘precision medicine screening’ is very difficult to accept unless you prove that you are actually helping people. That hypothesis is still unproven after this paper was published,” Topol says. “What if it helps one and harms 10?” He’s particularly concerned  about running tests on people without a sound rationale. “Don’t do a bunch of tests unless there is a good reason; otherwise you get a bunch of false positives.” The study included twice as many men as women, and participants ranged in age from 20 to 98, with an average age of 55. A whopping 78% had “evidence of age-related chronic disease or risk factors,” which for the majority translated to diabetes or risk of atherosclerotic disease. Michael Joyner, a medical doctor and integrative physiology researcher at the Mayo Clinic in Rochester, Minnesota, also notes that over 70% of the participants are currently taking prescribed medication for high LDL cholesterol and hypertension. “To tell me that a bunch of 60-year-old men with prolonged EKG monitoring had some funny heartbeats … is news, give me a break,” he says. “The whole thing is an example of technology run amok from a belief that if you can measure it, it must be meaningful.” But the amped up testing has its proponents. “The over-diagnosis concern is completely over-exaggerated,” says Michael Snyder, the director of the Stanford Center for Genomics and Personalized Medicine in Palo Alto, California, who made news 5 years ago when he detected his own diabetes by intensively studying his body. “Some of the stuff they found seems pretty serious, so I think it is a good thing to catch that early,” he says, predicting that in the future, “we will be measuring thousands of things much more routinely.” Despite Venter’s personalized genomics evangelism, the study’s results pointedly indicate that “the genome alone doesn’t tell you the whole story,” says Elemento of Cornell. Only 25% of patients had probable links between gene variants and disease phenotypes. “But when you can combine genes with an additional readout that tells you the gene is doing something, your ability to predict disease increases dramatically.” Some see the early data from Health Nucleus as the potential start of another Venter-versus-the government scenario. “What Venter has done here is pretty much the goal of NIH’s Precision Medicine Initiative, and I imagine Craig envisions immediate scale-up to compete with that particular government project,” says Robert W. West Jr., who previously taught a course on precision medicine at SUNY Upstate Medical University. “If this is really Craig’s goal, then he would likely beat NIH to the punch again.” Health Nucleus says 570 people have participated in the full $25,000 panoramic medical workups thus far, but this week they launched a $7500 pared-down version that focuses on the full genome sequencing and full-body scan. “This is a study that is going to remain controversial,” Topol says. “And maybe it is futuristic, but I think most people in medicine who understand the history of this will know that this is potentially engendering trouble and doing all sorts of tests that don’t have any basis.”


News Article | May 19, 2017
Site: www.techtimes.com

Scientists and researchers from the Weill Cornell Medicine made a breakthrough discovery. They stumbled on a unique way to produce limitless blood supply from readily-available stem cells, which line the blood vessels. This is the first time that a research team is successful in generating such blood forming stem cells. Senior author of the study Shahin Rafii shares that this discovery brings doctors and scientist a step closer to treating blood disorders effectively. The discovery also enables them to gain insight into the complex biology of stem cell self-renewal machinery. HSCs or Hematopoietic stem cells are long lasting cells that can transform into all blood cells types such as White Blood Cells or WBC, Red Blood Cell or RBC, and blood platelets. RBC do not survive for long and, therefore, need to be continuously replenished. If the RBC amount in the blood supply goes down, diseases such as anemia and other life-endangering infections can occur. One of the unique abilities of the HSCs is that it can "self-renew" to form more of its kind. This special characteristic permits just a few thousand HSCs to generate all the blood cells an individual requires for survive in their lifetime. Researchers have been persevering to emulate the process through which our bodies produce HSCs to treat and cure diseases for a long time. Their previous attempts were unsuccessful as the researchers were unable to create a nurturing environment in which the stems cells would be able to convert into long-lasting new cells. However, Rafii and team were successful in effectively converting vascular endothelial cells into completely functioning HSCs. These HSCs can be used to produce a limitless blood supply for a lifetime. Vascular endothelial cells are generally found in our body's blood vessel lining. To achieve this feat, the team based their current study on a previous research, which it conducted in 2014. In the previous study, the researchers were able to prove that adult human vascular endothelial cells can be converted into healthy HSCs. However, they were unable to deduce whether the HSC they generated were true human HSCs or not. To validate the HSC's authenticity, the team applied their previously-developed conversion process to mouse blood marrow transplant models. These models were not only capable of normal immune functions, but also ultimate proof for HSC's potential, which can be rigorously tested. Extraordinarily, the conversion process produced a huge number of transplantable HSCs that can supply mice with blood for their entire lifespan. This phenomenon is known as engraftment in medical circles. Rafii and team — in collaboration with Jenny Xiang from Genomics Services and Olivier Elemento from HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine —demonstrated that all progeny of HSCs were gifted with the same genetic characteristics found in normal adult stem cells. The study's key findings were published in the journal Nature on Wednesday, May 17. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


Researchers at Weill Cornell Medicine have discovered an innovative method to make an unlimited supply of healthy blood cells from the readily available cells that line blood vessels. This achievement marks the first time that any research group has generated such blood-forming stem cells. "This is a game-changing breakthrough that brings us closer not only to treat blood disorders, but also deciphering the complex biology of stem-cell self-renewal machinery," said senior author Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, chief of the Division of Regenerative Medicine and the Arthur B. Belfer Professor at Weill Cornell Medicine. "This is exciting because it provides us with a path towards generating clinically useful quantities of normal stem cells for transplantation that may help us cure patients with genetic and acquired blood diseases," added co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director of the Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine. Hematopoietic stem cells (HSCs) are long-lasting cells that mature into all types of blood cells: white blood cells, red blood cells and platelets. Billions of circulating blood cells do not survive long in the body and must be continuously replenished. When this does not happen, severe blood diseases, such as anemia, bleeding or life-threatening infections, can occur. A special property of HSCs is that they can also "self-renew" to form more HSCs. This property allows just a few thousand HSCs to produce all of the blood cells a person has throughout one's life. Researchers have long hoped to find a way to make the body produce healthy HSCs in order to cure these diseases. But this has never been accomplished, in part because scientists have been unable to engineer a nurturing environment within which stem cells can convert into new, long-lasting cells--until now. In a paper published May 17 in Nature, Dr. Rafii and his colleagues demonstrate a way to efficiently convert cells that line all blood vessels, called vascular endothelial cells, into abundant, fully functioning HSCs that can be transplanted to yield a lifetime supply of new, healthy blood cells. The research team also discovered that specialized types of endothelial cells serve as that nurturing environment, known as vascular niche cells, and they choreograph the new converted HSCs' self-renewal. This finding may solve one of the most longstanding questions in regenerative and reproductive medicine: How do stem cells constantly replenish their supply? The research team showed in a 2014 study that converting adult human vascular endothelial cells into hematopoietic cells was feasible. However, the team was unable to prove that they had generated true HSCs because human HSCs' function and regenerative potential can only be approximated by transplanting the cells into mice, which don't truly mimic human biology. To address this issue, the team applied their conversion approach to mouse blood marrow transplant models that are endowed with normal immune function and where definitive evidence for HSC potential could rigorously tested. The researchers took vascular endothelial cells isolated from readily accessible adult mice organs and instructed them to overproduce certain proteins associated with blood stem-cell function. These reprogrammed cells were grown and multiplied in co-culture with the engineered vascular niche. The reprogrammed HSCs were then transplanted as single cells with their progenies into mice that had been irradiated to destroy all of their blood forming and immune systems, and then monitored to see whether or not they would self-renew and produce healthy blood cells. Remarkably, the conversion procedure yielded a plethora of transplantable HSCs that regenerated the entire blood system in mice for the duration of their lifespans, a phenomenon known as engraftment. "We developed a fully-functioning and long-lasting blood system," said lead author Dr. Raphael Lis, an instructor in medicine and reproductive medicine at Weill Cornell Medicine. In addition, the HSC-engrafted mice developed all of the working components of the immune systems. "This is clinically important because the reprogrammed cells could be transplanted to allow patients to fight infections after marrow transplants," Dr. Lis said. The mice in the study went on to live normal-length lives and die natural deaths, with no sign of leukemia or any other blood disorders. In collaboration with Dr. Olivier Elemento, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, and Dr. Jenny Xiang, the director of Genomics Services, Dr. Rafii and his team also showed that the reprogrammed HSCs and their differentiated progenies -- including white and red bloods cells, as well as the immune cells -- were endowed with the same genetic attributes to that of normal adult stem cells. These findings suggest that the reprogramming process results in the generation of true HSCs that have genetic signature that are very similar to normal adult HSCs The Weill Cornell Medicine team is the first to achieve cellular reprogramming to create engraftable and authentic HSCs, which have been considered the holy grail of stem cell research. "We think the difference is the vascular niche," said contributing author Dr. Jason Butler, an assistant professor of regenerative medicine at Weill Cornell Medicine. "Growing stem cells in the vascular niche puts them back into context, where they come from and multiply. We think this is why we were able to get stem cells capable of self-renewing." If this method can be scaled up and applied to humans, it could have wide-ranging clinical implications. "It might allow us to provide healthy stem cells to patients who need bone marrow donors but have no genetic match," Dr. Scandura said. "It could lead to new ways to cure leukemia, and may help us correct genetic defects that cause blood diseases like sickle-cell anemia." "More importantly, our vascular niche-stem-cell expansion model may be employed to clone the key unknown growth factors produced by this niche that are essential for self-perpetuation of stem cells," Dr. Rafii said. "Identification of those factors could be important for unraveling the secrets of stem cells' longevity and translating the potential of stem cell therapy to the clinical setting." Additional study co-authors include Charles Karrasch, Dr. Michael Poulos, Balvir Kunar, David Redmond, Jose-Gabriel Barcia-Duran, Chaitanya Badwe, and Koji Shido of Weill Cornell Medicine; Dr. Will Schachterle, formerly of Weill Cornell Medicine, Dr. Arash Rafii of Weill Cornell Medicine-Qatar; Dr. Michael Ginsberg of Angiocrine Bioscience; and Dr. Nancy Speck of the Abramson Family Cancer Research Institute in the Perelman School of Medicine at the University of Pennsylvania. Various study authors have relationships with Angiocrine Bioscience that are independent of Weill Cornell Medicine. This study was funded in part by the National Institutes of Health, grants NIH-R01 DK095039, HL119872, HL128158, HL115128, HL099997, CA204308, HL133021, HL119872, HL128158 and HL091724; U54 CA163167; and NIH-T32 HD060600.


News Article | May 18, 2017
Site: www.sciencedaily.com

Researchers at Weill Cornell Medicine have discovered an innovative method to make an unlimited supply of healthy blood cells from the readily available cells that line blood vessels. This achievement marks the first time that any research group has generated such blood-forming stem cells. "This is a game-changing breakthrough that brings us closer not only to treat blood disorders, but also deciphering the complex biology of stem-cell self-renewal machinery," said senior author Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, chief of the Division of Regenerative Medicine and the Arthur B. Belfer Professor at Weill Cornell Medicine. "This is exciting because it provides us with a path towards generating clinically useful quantities of normal stem cells for transplantation that may help us cure patients with genetic and acquired blood diseases," added co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director of the Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine. Hematopoietic stem cells (HSCs) are long-lasting cells that mature into all types of blood cells: white blood cells, red blood cells and platelets. Billions of circulating blood cells do not survive long in the body and must be continuously replenished. When this does not happen, severe blood diseases, such as anemia, bleeding or life-threatening infections, can occur. A special property of HSCs is that they can also "self-renew" to form more HSCs. This property allows just a few thousand HSCs to produce all of the blood cells a person has throughout one's life. Researchers have long hoped to find a way to make the body produce healthy HSCs in order to cure these diseases. But this has never been accomplished, in part because scientists have been unable to engineer a nurturing environment within which stem cells can convert into new, long-lasting cells -- until now. In a paper published May 17 in Nature, Dr. Rafii and his colleagues demonstrate a way to efficiently convert cells that line all blood vessels, called vascular endothelial cells, into abundant, fully functioning HSCs that can be transplanted to yield a lifetime supply of new, healthy blood cells. The research team also discovered that specialized types of endothelial cells serve as that nurturing environment, known as vascular niche cells, and they choreograph the new converted HSCs' self-renewal. This finding may solve one of the most longstanding questions in regenerative and reproductive medicine: How do stem cells constantly replenish their supply? The research team showed in a 2014 Nature study that converting adult human vascular endothelial cells into hematopoietic cells was feasible. However, the team was unable to prove that they had generated true HSCs because human HSCs' function and regenerative potential can only be approximated by transplanting the cells into mice, which don't truly mimic human biology. To address this issue, the team applied their conversion approach to mouse blood marrow transplant models that are endowed with normal immune function and where definitive evidence for HSC potential could rigorously tested. The researchers took vascular endothelial cells isolated from readily accessible adult mice organs and instructed them to overproduce certain proteins associated with blood stem-cell function. These reprogrammed cells were grown and multiplied in co-culture with the engineered vascular niche. The reprogrammed HSCs were then transplanted as single cells with their progenies into mice that had been irradiated to destroy all of their blood forming and immune systems, and then monitored to see whether or not they would self-renew and produce healthy blood cells. Remarkably, the conversion procedure yielded a plethora of transplantable HSCs that regenerated the entire blood system in mice for the duration of their lifespans, a phenomenon known as engraftment. "We developed a fully-functioning and long-lasting blood system," said lead author Dr. Raphael Lis, an instructor in medicine and reproductive medicine at Weill Cornell Medicine. In addition, the HSC-engrafted mice developed all of the working components of the immune systems. "This is clinically important because the reprogrammed cells could be transplanted to allow patients to fight infections after marrow transplants," Dr. Lis said. The mice in the study went on to live normal-length lives and die natural deaths, with no sign of leukemia or any other blood disorders. In collaboration with Dr. Olivier Elemento, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, and Dr. Jenny Xiang, the director of Genomics Services, Dr. Rafii and his team also showed that the reprogrammed HSCs and their differentiated progenies -- including white and red bloods cells, as well as the immune cells -- were endowed with the same genetic attributes to that of normal adult stem cells. These findings suggest that the reprogramming process results in the generation of true HSCs that have genetic signature that are very similar to normal adult HSCs The Weill Cornell Medicine team is the first to achieve cellular reprogramming to create engraftable and authentic HSCs, which have been considered the holy grail of stem cell research. "We think the difference is the vascular niche," said contributing author Dr. Jason Butler, an assistant professor of regenerative medicine at Weill Cornell Medicine. "Growing stem cells in the vascular niche puts them back into context, where they come from and multiply. We think this is why we were able to get stem cells capable of self-renewing." If this method can be scaled up and applied to humans, it could have wide-ranging clinical implications. "It might allow us to provide healthy stem cells to patients who need bone marrow donors but have no genetic match," Dr. Scandura said. "It could lead to new ways to cure leukemia, and may help us correct genetic defects that cause blood diseases like sickle-cell anemia." "More importantly, our vascular niche-stem-cell expansion model may be employed to clone the key unknown growth factors produced by this niche that are essential for self-perpetuation of stem cells," Dr. Rafii said. "Identification of those factors could be important for unraveling the secrets of stem cells' longevity and translating the potential of stem cell therapy to the clinical setting."


News Article | April 28, 2017
Site: www.businesswire.com

NEW YORK--(BUSINESS WIRE)--Weill Cornell Medicine today announced a gift made by WorldQuant, LLC (“WorldQuant”) and Igor Tulchinsky that will further realize the promise of precision medicine. The $5 million gift establishes a new initiative that will use predictive tools to enhance Weill Cornell Medicine’s capability to diagnose and treat a variety of illnesses, with the goal of improving outcomes for patients. The WorldQuant Initiative for Quantitative Prediction brings together financial and medical experts whose collaboration strives to enhance biomedical research. Weill Cornell Medicine’s scientists, working closely with researchers and technologists from WorldQuant, will deploy predictive tools and quantitative methods to deepen the understanding of genetic factors that drive disease in individual patients. Using sophisticated algorithms, the new initiative will enable the research team to analyze genomic data to identify patterns and trends that may predict patients’ future risk of developing disease, as well as potential outcomes. These insights may be used to improve the diagnosis and treatment of a variety of illnesses, including cancer, neurological disorders, cardiovascular diseases and infections. Weill Cornell Medicine researchers Dr. Christopher Mason, the WorldQuant Research Scholar, and Dr. Olivier Elemento, the Walter B. Wriston Research Scholar, will lead the initiative, which will involve joint work with physician-scientists at the Caryl and Israel Englander Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “This outstanding gift will accelerate and expand Weill Cornell Medicine’s approach to precision medicine, providing new predictive tools that will lead to even better outcomes for patients,” said Jessica Bibliowicz, chairman of the Weill Cornell Medicine Board of Overseers. “We are very grateful to Igor Tulchinsky and WorldQuant, LLC for making this initiative possible.” “The use of quantitative prediction for patients represents an important new tool at Weill Cornell Medicine,” said Dr. Augustine M.K. Choi, the Stephen and Suzanne Weiss Dean at Weill Cornell Medicine. “We appreciate Mr. Tulchinsky’s generosity, which will help us achieve new goals in the rapidly evolving field of precision medicine.” For WorldQuant, an international quantitative investment management firm founded by Mr. Tulchinsky, who is chairman and CEO, applying predictive algorithms to medical research is a natural progression. “There is a great opportunity to leverage the technology and proprietary algorithms we’ve developed for use outside of the financial markets, particularly around predictive medicine and cancer research, where the stakes are so high,” said Mr. Tulchinsky, a member of the Board of Overseers at Weill Cornell Medicine. “This initiative has tremendous possibilities, and I am proud to help drive advances in the field.” Drs. Mason and Elemento, as co-directors of the initiative, will leverage new technologies to analyze clinical samples and visualize various diseased tissues at single-cell resolution. These methods will be combined with a supercomputing infrastructure, which includes developing new software to crunch data using advanced pattern-recognition algorithms to model disease progression. One of the initiative’s ultimate goals is to give researchers the ability to examine a blood draw or urine sample from one patient and predict his or her future risk for developing a specific type of cancer. The same technology could also give researchers the ability to rapidly diagnose patients and predict which treatments might work, which treatments may encounter resistance and how the disease is likely to progress. In the future, this framework may enable investigators to analyze single cells and molecules from blood, tumor biopsies, saliva or other clinical samples collected from patients seeking care at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, and then use analytical algorithms to create personalized predictive models based on findings from longitudinal healthcare data collected from thousands of patients. To accomplish this, Drs. Mason and Elemento will work closely with WorldQuant’s research team and intend to recruit software engineers and experts in artificial intelligence who can develop innovative quantitative prediction tools and analyze findings. They will continue to provide advanced training in quantitative biology and modeling to Weill Cornell Medicine’s physician-scientists to support this effort. “We are looking forward to using the tools and methods that will result from this philanthropic investment to tease apart disease cells’ secrets and create predictive models of health for patients,” said Dr. Mason, who is also an associate professor of physiology and biophysics, an associate professor of computational genomics at the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, and an associate professor of neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. “Not only does this gift enable new science and predictive models in medicine, it also creates an unprecedented collaboration between two big-data groups at Weill Cornell Medicine and WorldQuant.” “This incredibly generous gift will likely spur a whole new generation of biomedical discoveries by helping bring predictive disease analytics to precision medicine,” said Dr. Elemento, who is also associate director of the Institute for Computational Biomedicine and an associate professor of physiology and biophysics at Weill Cornell Medicine. “We’re profoundly thankful to Igor for his support, and grateful to have WorldQuant as a partner in pioneering new approaches to understanding cancer, infections and neurological diseases.” Weill Cornell Medicine is committed to excellence in patient care, scientific discovery and the education of future physicians in New York City and around the world. The doctors and scientists of Weill Cornell Medicine — faculty from Weill Cornell Medical College, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Physician Organization — are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. Located in the heart of the Upper East Side's scientific corridor, Weill Cornell Medicine's powerful network of collaborators extends to its parent university Cornell University; to Qatar, where an international campus offers a U.S. medical degree; and to programs in Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell Medicine faculty provide comprehensive patient care at NewYork-Presbyterian Weill Cornell Medical Center, NewYork-Presbyterian Lower Manhattan Hospital and NewYork-Presbyterian Queens. Weill Cornell Medicine is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu. WorldQuant, LLC is a global quantitative investment firm that was founded in 2007 by Igor Tulchinsky and now has more than $5 billion in assets under management. The firm has more than 20 offices in 15 countries and over 600 employees and 500 consultants. WorldQuant develops and deploys systematic investment strategies across a variety of asset classes in global markets, utilizing a proprietary research platform and investment process. For more information on WorldQuant’s culture and philosophy, please visit www.WeAreWorldQuant.com.


Popovic R.,Northwestern University | Teater M.,Institute for Computational Biomedicine | Jiang Y.,Institute for Computational Biomedicine | Ezponda T.,Northwestern University | And 25 more authors.
Cancer Cell | Year: 2013

The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting. © 2013 Elsevier Inc.


PubMed | Institute for Computational Biomedicine, Cornell College and Cornell University
Type: | Journal: Journal of visualized experiments : JoVE | Year: 2016

Understanding tumor clonality is critical to understanding the mechanisms involved in tumorigenesis and disease progression. In addition, understanding the clonal composition changes that occur within a tumor in response to certain micro-environment or treatments may lead to the design of more sophisticated and effective approaches to eradicate tumor cells. However, tracking tumor clonal sub-populations has been challenging due to the lack of distinguishable markers. To address this problem, a VDJ-seq protocol was created to trace the clonal evolution patterns of diffuse large B cell lymphoma (DLBCL) relapse by exploiting VDJ recombination and somatic hypermutation (SHM), two unique features of B cell lymphomas. In this protocol, Next-Generation sequencing (NGS) libraries with indexing potential were constructed from amplified rearranged immunoglobulin heavy chain (IgH) VDJ region from pairs of primary diagnosis and relapse DLBCL samples. On average more than half million VDJ sequences per sample were obtained after sequencing, which contain both VDJ rearrangement and SHM information. In addition, customized bioinformatics pipelines were developed to fully utilize sequence information for the characterization of IgH-VDJ repertoire within these samples. Furthermore, the pipeline allows the reconstruction and comparison of the clonal architecture of individual tumors, which enables the examination of the clonal heterogeneity within the diagnosis tumors and deduction of clonal evolution patterns between diagnosis and relapse tumor pairs. When applying this analysis to several diagnosis-relapse pairs, we uncovered key evidence that multiple distinctive tumor evolutionary patterns could lead to DLBCL relapse. Additionally, this approach can be expanded into other clinical aspects, such as identification of minimal residual disease, monitoring relapse progress and treatment response, and investigation of immune repertoires in non-lymphoma contexts.


News Article | February 3, 2016
Site: news.yahoo.com

FILE - In this March 30, 2011, file photo, a bedbug is displayed at the Smithsonian Museum in Washington. Researchers from Weill Cornell and scientists at the American Museum of Natural History have traced the nefarious pest through the New York City subway system and discovered a genetic diversity among the bloodsucking creatures. (AP Photo/Carolyn Kaster, File) More NEW YORK (AP) — Scientists have mapped the genome of bedbugs in New York City, then traced fragments of the nefarious pests' DNA through the subway system. In the grubby recesses of hundreds of stations, they discovered surprising genetic diversity among the bloodsucking creatures. The next step is to figure out how the information can be put to good use, such as to develop better insecticides or blood thinners. But these goals will take further medical research. For now, the focus is on two main players in New York life: the subway and bedbugs. Scientists already have found that genetic traces of bedbugs in northern Manhattan are more closely related to those in the island's southern part, while there are bigger variations between the Upper East Side and Upper West Side. Geneticist Christopher Mason, who worked on the project, says the reason for that can be found simply by looking at a subway map: In Manhattan, for instance, subway lines run the length of the island north to south, while there's no subway link through Central Park between the East Side and the West Side. Not that bedbugs are riding the subway, noted George Amato, an evolutionary biologist at the American Museum of Natural History who also worked on bedbug project. He says New York's bedbugs "move around with people, dogs, and people's items — and they probably move most easily the way people move most easily." Amato collaborated with Mason, who works at Weill Cornell Medicine's Institute for Computational Biomedicine. A bedbug colony at the famed museum was used for the genome map. A similar map was assembled by an international research team at 36 institutions, including the University of Cincinnati. The New York team's resulting scientific paper on the subject was published Tuesday in Nature Communications. A second paper on bedbug genetics, from the University of Cincinnati, also appeared Tuesday in the same publication. To learn how the bedbug has evolved and spread, the New York team took DNA sample swabs from 1,400 city locations including subway cars, turnstiles, ticket vending kiosks, and above ground places like parks. Amato said there are many ways small fragments of the critters' DNA, or DNA of a related species, could get into the subway — clinging to the clothes of some of the 6 million daily riders and their belongings, or washed down into the stations. Amato said the first rough bedbug genetic sequence emerged about a year ago, but it took months to refine the model into an accurate genome. "Before this, people were just feeling their way through in the dark; this genome turns the light on for various areas of other research," said Amato. "Our team is now moving on to the genetics of cockroaches and other living fossils." This story has been corrected to show that fragments of bedbugs' DNA or related species' DNA were collected at subways, not whole bedbugs.


News Article | February 3, 2016
Site: www.biosciencetechnology.com

Scientists have mapped the genome of bedbugs in New York City, then traced fragments of the nefarious pests' DNA through the subway system. In the grubby recesses of hundreds of stations, they discovered surprising genetic diversity among the bloodsucking creatures. The next step is to figure out how the information can be put to good use, such as to develop better insecticides or blood thinners. But these goals will take further medical research. For now, the focus is on two main players in New York life: the subway and bedbugs. Scientists already have found that genetic traces of bedbugs in northern Manhattan are more closely related to those in the island's southern part, while there are bigger variations between the Upper East Side and Upper West Side. Geneticist Christopher Mason, who worked on the project, says the reason for that can be found simply by looking at a subway map: In Manhattan, for instance, subway lines run the length of the island north to south, while there's no subway link through Central Park between the East Side and the West Side. Not that bedbugs are riding the subway, noted George Amato, an evolutionary biologist at the American Museum of Natural History who also worked on bedbug project. He says New York's bedbugs "move around with people, dogs, and people's items - and they probably move most easily the way people move most easily." Amato collaborated with Mason, who works at Weill Cornell Medicine's Institute for Computational Biomedicine. A bedbug colony at the famed museum was used for the genome map. A similar map was assembled by an international research team at 36 institutions, including the University of Cincinnati. The New York team's resulting scientific paper on the subject was published Tuesday in Nature Communications. A second paper on bedbug genetics, from the University of Cincinnati, also appeared Tuesday in the same publication. To learn how the bedbug has evolved and spread, the New York team took DNA sample swabs from 1,400 city locations including subway cars, turnstiles, ticket vending kiosks, and above ground places like parks. Amato said there are many ways small fragments of the critters' DNA, or DNA of a related species, could get into the subway - clinging to the clothes of some of the 6 million daily riders and their belongings, or washed down into the stations. Amato said the first rough bedbug genetic sequence emerged about a year ago, but it took months to refine the model into an accurate genome. "Before this, people were just feeling their way through in the dark; this genome turns the light on for various areas of other research," said Amato. "Our team is now moving on to the genetics of cockroaches and other living fossils."

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