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Newswise January 13, 2015 New York, NY Peter S. Kim has been named the Virginia and D.K. Ludwig Professor of Biochemistry at Stanford University School of Medicine. Established in 1994, Ludwig professorships have since been awarded to a total of 15 leading scientists at academic institutions affiliated with the six U.S.-based Ludwig Centers. With this appointment Kim also becomes a member of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford.

Kims lab focuses on the mechanisms by which viral membranes fuse with cell membranes, which has to happen for the virus to invade its target cell. His team also studies how that process might be disrupted by small molecules and antibodies. Kims lab is, for example, using such studies to engineer antigens for a vaccine that might elicit antibodies that block a key step in HIVs invasion of its target cell. The strategies that he is developing could be applied to design new preventive and therapeutic vaccines for cancers. His lab is also developing methods to identify small molecules that bind tightly and very specifically to proteins that have so far proved resistant to targeting by typical drug-like molecules.

Kim joined Stanford University in February 2014 after a ten-year tenure as president of Merck Research Laboratories, Merck & Co., Inc. During this time he oversaw the development and FDA approval of Gardasil, the worlds first vaccine against HPV, the causative agent of cervical cancer. Kim began his academic career as a professor in the biology department at MIT, where he ultimately served as associate head. During his 16 years at MIT Kim was also an investigator of the Howard Hughes Medical Institute and a member of the Whitehead Institute for Biomedical Research.

We are very happy, and fortunate, to have Peter Kim back here at Stanford, where he began his graduate training, said Irv Weissman, director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. Peter brings with him rare experience and new strategies for developing preventive tools and therapiesincluding immunotherapiesfor viral infections that cause, allow and/or infect cancers. His goals are in line with our mission, and his approaches complement our own efforts to recruit the immune system to attack cancer cells.

Kim has received numerous awards for his research and holds leadership positions at several academic and scientific institutions. He is a member of the National Academy of Sciences and the Institute of Medicine and a fellow of the American Academy of Arts and Sciences. He serves on the Scientific Review Board of the Howard Hughes Medical Institute, the External Scientific Advisory Board of the Harvard Program in Therapeutic Science, the Board of Scientific Governors of the Scripps Research Institute and the Scientific Advisory Working Group of the Vaccine Research Center, NIAID, NIH.

Kim joins four other Virginia and D.K. Ludwig Professors at Stanford: Lucy Shapiro, Irving Weissman, Sanjiv Sam Gambhir and Roeland Nusse.

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About Ludwig Cancer Research Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer discoveries for more than 40 years. Ludwig combines basic research with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested more than $2.5 billion in life-changing cancer research through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers.

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Peter S. Kim Named the Virginia and D.K. Ludwig Professor of Biochemistry at Stanford

IMAGE:This is the cover for Stem Cells, Tissue Engineering and Regenerative Medicine. view more

Credit: World Scientific, 2015

In his latest book published by World Scientific, Professor David Warburton from The Saban Research Institute of Children's Hospital Los Angeles and the University of Southern California presents a collection of essays on the current state of the regenerative medicine and stem cell research field.

Entitled Stem Cells, Tissue Engineering and Regenerative Medicine, this up-to-date compendium surveys current issues in stem cell biology and regenerative medicine. Topics range from key concepts in regenerative medicine to the newest progenitor cell therapies for organ systems, to advice on how to set up a pluripotent stem cell laboratory.

Overviews of the most recent progress in stem cell research describe work that is in the pre-clinical pipeline from scientists working at The Saban Research Institute of Children's Hospital Los Angeles and colleagues around the world.

"The book addresses some of the big questions faced by researchers in the field of stem cell biology and regenerative medicine," said Professor Warburton. "Those of us working in this field in California are positively impacted by the critical funding provided by the citizens of the state through the California Institute for Regenerative Medicine. I believe this book shows that the hope behind CIRM - the hope that stem cells can really revolutionize medicine and human health - is fully justified."

A global collection of essays from collaborating investigators in Australia, Brazil, Iran, Taiwan and the United Kingdom, as well as across the United States. This book will describe diverse regenerative medicine solutions for airways, cancer, craniofacial structures, intestine, heart, kidney, liver, lung and nervous system. These advances are placed in the context of the overall field, providing an investigator-level overview which will be accessible to the educated scientific generalist as well as a college-educated readership, scientific writers, educators and professionals of all kinds.

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Professor Warburton's research is supported by the California Institute for Regenerative Medicine, the National Institutes of Health: National Heart, Lung and Blood Institute, National Institute of Environmental Health Sciences, Fogarty International Center, National Institute of General Medical Sciences, The Pasadena Guild of Children's Hospital Los Angeles, The Santa Anita Foundation, The Webb Foundation, The Garland Foundation and anonymous venture philanthropy.

The book retails for US$155/ 102 (hardcover). More information on the book can be found at http://www.worldscientific.com/worldscibooks/10.1142/9212.

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Renowned professor's book addresses stem cell biology & regenerative medicine

UC Irvine scientists studying the role of circadian rhythms in skin stem cells found that this clock plays a key role in coordinating daily metabolic cycles and cell division.

Their research, which appears Jan. 6 in Cell Reports, shows for the first time how the body's intrinsic day-night cycles protect and nurture stem cell differentiation. Furthermore, this work offers novel insights into a mechanism whereby an out of synch circadian clock can contribute to accelerated skin aging and cancers.

Bogi Andersen, professor of biological chemistry and medicine, and Enrico Gratton, professor of biomedical engineering, focused their efforts on the epidermis, the outermost protective layer of the skin that is maintained and healed by long-lived stem cells.

While the role of the circadian clock in processes such as sleep, feeding behavior and metabolism linked to feeding and fasting are well known, much less is known about whether the circadian clock also regulates stem cell function.

The researchers used novel two-photon excitation and fluorescence lifetime imaging microscopy in Laboratory of Fluorescence Dynamics in UCI's Department of Biomedical Engineering to make sensitive and quantitative measurements of the metabolic state of single cells within the native microenvironment of living tissue.

They discovered that the circadian clock regulates one form of intermediary metabolism in these stem cells, referred to as oxidative phosphorylation. This type of metabolism creates oxygen radicals that can damage DNA and other components of the cell. In fact, one theory of aging posits that aging is caused by the accumulative damage from metabolism-generated oxygen radicals in stem cells.

The Andersen-Gratton study also revealed that the circadian clock within stem cells shifts the timing of cell division such that the stages of the cell division cycle that are most sensitive to DNA damage are avoided during times of maximum oxidative phosphorylation.

Other studies in animals have linked aging to disruption of circadian rhythms, and Andersen said that accelerated aging could be caused by asynchrony in the metabolism and cell proliferation cycles in stem cells.

"Our studies were conducted in mice, but the greater implication of the work relates to the fact that circadian disruption is very common in modern society, and one consequence of such disruption could be abnormal function of stem cells and accelerated aging," he said.

Andersen adds that it is possible that future studies could advance therapeutic insights from this research.

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Circadian rhythms regulate skin stem cell metabolism and expansion, study finds

Body clock protects cells from metabolism-generated oxygen radical damage during division

Irvine, Calif., Jan. 6, 2015 -- UC Irvine scientists studying the role of circadian rhythms in skin stem cells found that this clock plays a key role in coordinating daily metabolic cycles and cell division.

Their research, which appears Jan. 6 in Cell Reports, shows for the first time how the body's intrinsic day-night cycles protect and nurture stem cell differentiation. Furthermore, this work offers novel insights into a mechanism whereby an out of synch circadian clock can contribute to accelerated skin aging and cancers.

Bogi Andersen, professor of biological chemistry and medicine, and Enrico Gratton, professor of biomedical engineering, focused their efforts on the epidermis, the outermost protective layer of the skin that is maintained and healed by long-lived stem cells.

While the role of the circadian clock in processes such as sleep, feeding behavior and metabolism linked to feeding and fasting are well known, much less is known about whether the circadian clock also regulates stem cell function.

The researchers used novel two-photon excitation and fluorescence lifetime imaging microscopy in Laboratory of Fluorescence Dynamics in UCI's Department of Biomedical Engineering to make sensitive and quantitative measurements of the metabolic state of single cells within the native microenvironment of living tissue.

They discovered that the circadian clock regulates one form of intermediary metabolism in these stem cells, referred to as oxidative phosphorylation. This type of metabolism creates oxygen radicals that can damage DNA and other components of the cell. In fact, one theory of aging posits that aging is caused by the accumulative damage from metabolism-generated oxygen radicals in stem cells.

The Andersen-Gratton study also revealed that the circadian clock within stem cells shifts the timing of cell division such that the stages of the cell division cycle that are most sensitive to DNA damage are avoided during times of maximum oxidative phosphorylation.

Other studies in animals have linked aging to disruption of circadian rhythms, and Andersen said that accelerated aging could be caused by asynchrony in the metabolism and cell proliferation cycles in stem cells.

"Our studies were conducted in mice, but the greater implication of the work relates to the fact that circadian disruption is very common in modern society, and one consequence of such disruption could be abnormal function of stem cells and accelerated aging," he said.

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Circadian rhythms regulate skin stem cell metabolism and expansion, UCI study finds

Seal Beach, Laguna Hills, and Lake Forest, California (PRWEB) January 05, 2015

The Irvine Stem Cell Treatment Center announces a series of free public seminars on the use of adult stem cells for various degenerative and inflammatory conditions. They will be provided by Dr. Thomas A. Gionis, Surgeon-in-Chief.

The seminars will be held on Sunday, January 11, 2015, at 2:30pm and 4:30pm at Marie Callenders Grill, 12489 Seal Beach Blvd., Seal Beach, CA 90740; Tuesday, January 13, 2015, at 2:00pm and 4:00pm at Pollys Pies, 23701 Moulton Parkway, Laguna Hills, CA 92653; Friday, January 16, 2015, at 1:30pm and 3:30pm at Marie Callenders Grill, 12489 Seal Beach Blvd., Seal Beach, CA 90740; Saturday, January 17, 2015, at 2:30pm and 4:30pm at Dennys Restaurant, 23515 El Toro Road, Lake Forest, CA 92630. Please RSVP at (949) 679-3889.

The Irvine Stem Cell Treatment Center, along with sister affiliates, the Miami Stem Cell Treatment Center and the Manhattan Regenerative Medicine Medical Group, abide by investigational protocols using adult adipose derived stem cells (ADSCs) which can be deployed to improve patients quality of life for a number of chronic, degenerative and inflammatory conditions and diseases. ADSCs are taken from the patients own adipose (fat) tissue (found within a cellular mixture called stromal vascular fraction (SVF)). ADSCs are exceptionally abundant in adipose tissue. The adipose tissue is obtained from the patient during a 15 minute mini-liposuction performed under local anesthesia in the doctors office. SVF is a protein-rich solution containing mononuclear cell lines (predominantly adult autologous mesenchymal stem cells), macrophage cells, endothelial cells, red blood cells, and important Growth Factors that facilitate the stem cell process and promote their activity.

ADSCs are the body's natural healing cells - they are recruited by chemical signals emitted by damaged tissues to repair and regenerate the bodys injured cells. The Irvine Stem Cell Treatment Center only uses Adult Autologous Stem Cells from a persons own fat No embryonic stem cells are used. Current areas of study include: Emphysema, COPD, Asthma, Heart Failure, Parkinsons Disease, Stroke, Multiple Sclerosis, Lupus, Rheumatoid Arthritis, Crohns Disease, and degenerative orthopedic joint conditions. For more information, or if someone thinks they may be a candidate for one of the adult stem cell protocols offered by the Irvine Stem Cell Treatment Center, they may contact Dr. Gionis directly at (949) 679-3889, or see a complete list of the Centers study areas at: http://www.IrvineStemCellsUSA.com.

About the Irvine Stem Cell Treatment Center: The Irvine Stem Cell Treatment Center, along with sister affiliates, the Miami Stem Cell Treatment Center and the Manhattan Regenerative Medicine Medical Group, is an affiliate of the Cell Surgical Network (CSN); we are located in Irvine and Westlake, California. We provide care for people suffering from diseases that may be alleviated by access to adult stem cell based regenerative treatment. We utilize a fat transfer surgical technology to isolate and implant the patients own stem cells from a small quantity of fat harvested by a mini-liposuction on the same day. The investigational protocols utilized by the Irvine Stem Cell Treatment Center have been reviewed and approved by an IRB (Institutional Review Board) which is registered with the U.S. Department of Health, Office of Human Research Protection; and the study is registered with Clinicaltrials.gov, a service of the U.S. National Institutes of Health (NIH). For more information, visit our websites: http://www.IrvineStemCellsUSA.com, http://www.MiamiStemCellsUSA.com or http://www.NYStemCellsUSA.com.

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The Irvine Stem Cell Treatment Center Announces Adult Stem Cell Public Seminars in Orange County, California

Released: 30-Dec-2014 1:50 PM EST Embargo expired: 1-Jan-2015 2:00 PM EST Source Newsroom: Johns Hopkins Medicine Contact Information

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Newswise Scientists from the Johns Hopkins Kimmel Cancer Center have created a statistical model that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide. By their measure, two-thirds of adult cancer incidence across tissues can be explained primarily by bad luck, when these random mutations occur in genes that can drive cancer growth, while the remaining third are due to environmental factors and inherited genes.

All cancers are caused by a combination of bad luck, the environment and heredity, and weve created a model that may help quantify how much of these three factors contribute to cancer development, says Bert Vogelstein, M.D., the Clayton Professor of Oncology at the Johns Hopkins University School of Medicine, co-director of the Ludwig Center at Johns Hopkins and an investigator at the Howard Hughes Medical Institute.

Cancer-free longevity in people exposed to cancer-causing agents, such as tobacco, is often attributed to their good genes, but the truth is that most of them simply had good luck, adds Vogelstein, who cautions that poor lifestyles can add to the bad luck factor in the development of cancer.

The implications of their model range from altering public perception about cancer risk factors to the funding of cancer research, they say. If two-thirds of cancer incidence across tissues is explained by random DNA mutations that occur when stem cells divide, then changing our lifestyle and habits will be a huge help in preventing certain cancers, but this may not be as effective for a variety of others, says biomathematician Cristian Tomasetti, Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. We should focus more resources on finding ways to detect such cancers at early, curable stages, he adds.

In a report on the statistical findings, published Jan. 2 in Science, Tomasetti and Vogelstein say they came to their conclusions by searching the scientific literature for information on the cumulative total number of divisions of stem cells among 31 tissue types during an average individuals lifetime. Stem cells self-renew, thus repopulating cells that die off in a specific organ.

It was well-known, Vogelstein notes, that cancer arises when tissue-specific stem cells make random mistakes, or mutations, when one chemical letter in DNA is incorrectly swapped for another during the replication process in cell division. The more these mutations accumulate, the higher the risk that cells will grow unchecked, a hallmark of cancer. The actual contribution of these random mistakes to cancer incidence, in comparison to the contribution of hereditary or environmental factors, was not previously known, says Vogelstein.

To sort out the role of such random mutations in cancer risk, the Johns Hopkins scientists charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans. From this so-called data scatterplot, Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to one, the more stem cell divisions and cancer risk are correlated.

Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue, says Vogelstein. One example, he says, is in colon tissue, which undergoes four times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.

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'Bad Luck' of Random Mutations Plays Predominant Role in Cancer, Study Shows

Chuck Bednar for redOrbit.com Your Universe Online

Two-thirds of all adult cancer cases are primarily the result of bad luck, according to the authors of a new study appearing in Fridays edition of the journal Science.

Dr. Bert Vogelstein, the Clayton Professor of Oncology at the Johns Hopkins University School of Medicine, and Dr. Cristian Tomasetti, an assistant professor of oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, developed a statistical model that measured the proportion of cancer incidence across many different tissue types.

They found that two-thirds of adult cancer incidence across tissues occur when the random mutations that take place during stem cell division drive cancer through, while the remaining one-third of cases are the result of environmental factors and inherited genes.

All cancers are caused by a combination of bad luck, the environment and heredity, and weve created a model that may help quantify how much of these three factors contribute to cancer development, explained Dr. Vogelstein, who is also co-director of the Ludwig Center at Johns Hopkins and an investigator at the Howard Hughes Medical Institute.

Cancer-free longevity in people exposed to cancer-causing agents, such as tobacco, is often attributed to their good genes, but the truth is that most of them simply had good luck, he said, adding that that poor lifestyle choices can also contribute to this so-called bad luck factor.

The authors said that the implications of their model could alter the public perception about cancer risk factors, as well as impact the funding of research related to the disease.

If most cancer cases can be explained by random DNA mutations that occur as stem cells divide, explained Dr. Tomasetti, it means that lifestyle changes will be a tremendous help when it comes to preventing some forms of the disease, but will be less effective against other types.

As a result, the medical community should should focus more resources on finding ways to detect such cancers at early, curable stages, he added. He and Vogelstein said that they reached their conclusion by searching scientific literature for data on the cumulative number of total stem cell divisions among 31 tissue types that take place during a persons lifetime.

Stem cells renew themselves, repopulating cells that die off in specific organs, the researchers said. Cancer arises when tissue-specific stem cells experience mutations in which one chemical letter in DNA is erroneously swapped for another during the replication process.

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Two-thirds of cancer cases are "bad luck," study says

Abstract: Adipose tissue is an abundant source of mesenchymal stem cells, which have shown promise in the field of regenerative medicine. Furthermore, these cells can be readily harvested in large numbers with low donor-site morbidity. During the past decade, numerous studies have provided preclinical data on the safety and efficacy of adipose-derived stem cells, supporting the use of these cells in future clinical applications. Various clinical trials have shown the regenerative capability of adipose-derived stem cells in subspecialties of medical fields such as plastic surgery, orthopedic surgery, oral and maxillofacial surgery, and cardiac surgery. In addition, a great deal of knowledge concerning the harvesting, characterization, and culture of adipose-derived stem cells has been reported. This review will summarize data from in vitro studies, pre-clinical animal models, and recent clinical trials concerning the use of adipose-derived stem cells in regenerative medicine.

Introduction

In the field of regenerative medicine, basic research and preclinical studies have been conducted to overcome clinical shortcomings with the use of mesenchymal stem cells (MSCs). MSCs are present in adult tissues, including bone marrow and adipose tissue. For many years, bone marrow-derived stem cells (BSCs) were the primary source of stem cells for tissue engineering applications (Caplan, 1991; Pittenger et al., 1999; Caplan, 2007). However, recent studies have shown that subcutaneous adipose tissue provides a clear advantage over other stem cell sources due to the ease with which adipose tissue can be accessed as well as the ease of isolating stem cells from harvested tissue (Schffler et al., 2007). Initial enzymatic digestion of adipose tissue yields a mixture of stromal and vascular cells referred to as the stromal-vascular fraction (SVF) (Traktuev et al., 2008). A putative stem cell population within this SVF was first identified by Zuk et al. and named processed lipoaspirate (PLA) cells (Zuk et al., 2001; Zuk et al., 2002).

There is no consensus when it comes to the nomenclature used to describe progenitor cells from adipose tissue-derived stroma, which can sometimes lead to confusion. The term PLA refers to adipose-derived stromal cells and adipose-derived stem cells (ASCs) and describes cells obtained immediately after collagenase digestion. Accordingly, the term ASC will be used throughout this review.

ASCs exhibit stable growth and proliferation kinetics and can differentiate toward osteogenic, chondrogenic, adipogenic, myogenic, or neurogenic lineages in vitro (Zuk et al., 2002; Izadpanah et al., 2006; Romanov et al., 2005). Furthermore, a group has recently described the isolation and culture of ASCs with multipotent differentiation capacity at the single-cell level (Rodriguez, et al., 2005).

Using these attractive cell populations, recent studies have explored the safety and efficacy of implanted/administrated ASCs in various animal models. Furthermore, clinical trials using ASCs have been initiated in some medical subspecialties. This review summarizes the current preclinical data and ongoing clinical trials and their outcomes in a variety of medical fields.

Characterization and Localization

ASCs express the mesenchymal stem cell markers CD10, CD13, CD29, CD34, CD44, CD54, CD71, CD90, CD105, CD106, CD117, and STRO-1. They are negative for the hematopoietic lineage markers CD45, CD14, CD16, CD56, CD61, CD62E, CD104, and CD106 and for the endothelial cell (EC) markers CD31, CD144, and von Willebrand factor (Zuk et al., 2002; Musina et al., 2005; Romanov et al., 2005). Morphologically, they are fibroblast-like and preserve their shape after expansion in vitro (Zuk et al., 2002; Arrigoni et al., 2009; Zannettino et al., 2008).

The similarities between ASCs and BSCs may indicate that ASCs are derived from circulating BSCs, which infiltrate into the adipose compartment through vessel walls (Zuk et al., 2002; Zannettino et al., 2008; Brighton et al., 1992; Canfield et al., 2000; Bianco et al., 2001). On the other hand, according to a recent theory, these stem cells are actually pericytes (Traktuev et al., 2008; Chen et al., 2009; Crisan et al., 2008; Zannettino et al., 2008; Tintut et al., 2003; Abedin et al., 2004; Amos et al., 2008). Pericytes around microvessels express alpha-smooth muscle actin (-SMA) as well as certain MSC markers (CD44, CD73, CD90, CD105); however, they do not express endothelial or hematopoietic cell markers (Chen et al., 2009). Pericytes adhere, proliferate in culture, sustain their initial antigenic profile, and can differentiate into bone, cartilage and fat cells (Chen et al., 2009). Moreover, injected MSCs migrate to the blood vessels in vivo and become pericytes (Chen et al., 2009). Considering the above-mentioned data, it can be speculated that pericytes are the ancestors of MSCs, but this does not mean that all MSCs are descendants of pericytes (Chen et al., 2009) or that all pericytes are necessarily stem cells (Lin et al., 2008; Traktuev et al., 2008; da Silva et al., 2008; Abedin et al., 2004; Tintut et al., 2003; Zannettino et al., 2008; Amos et al., 2008).

Traktuev et al. (2008) defined a periendothelial pericyte-like subpopulation of ASCs. These cells were CD34+, CD31-, CD45-, and CD144- and expressed mesenchymal cell markers, smooth muscle antigens, and pericytic markers, including chondroitin sulfate proteoglycan (NG2), CD140a, and CD140b (PDGF receptor and , respectively) (Traktuev et al., 2008; Amos et al., 2008). However, Lin et al. (2008) could not co-localize CD34 and CD104b, and thus concluded that CD34+/CD31- cells of adipose vasculature are not pericytes.

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Adipose-derived Stem Cells: Current Findings and Future ...

The body has evolved ways to get rid of faulty stem cells. A University of Colorado Cancer Center study published in the journal Stem Cells shows that one of these ways is a "program" that makes stem cells damaged by radiation differentiate into other cells that can no longer survive forever. Radiation makes a stem cell lose its "stemness." That makes sense: you don't want damaged stem cells sticking around to crank out damaged cells.

The study also shows that this same safeguard of "programmed mediocrity" that weeds out stem cells damaged by radiation allows blood cancers to grow in cases when the full body is irradiated. And by reprogramming this safeguard, we may be able to prevent cancer in the aftermath of full body radiation.

"The body didn't evolve to deal with leaking nuclear reactors and CT scans. It evolved to deal with only a few cells at a time receiving dangerous doses of radiation or other insults to their DNA," says James DeGregori, PhD, investigator at the CU Cancer Center, professor of Biochemistry and Molecular Genetics at the CU School of Medicine, and the paper's senior author.

DeGregori, doctoral student Courtney Fleenor, and colleagues explored the effects of full body radiation on the blood stem cells of mice. In this case, radiation increased the probability that cells in the hematopoietic stem cell system would differentiate. Only, while most followed this instruction, a few did not. Stem cells with a very specific mutation were able to disobey the instruction to differentiate and retain their "stemness." Genetic inhibition of the gene C/EBPA allowed a few stem cells to keep the ability to act as stem cells. With competition from other, healthy stem cells removed, the stem cells with reduced C/EBPA were able to dominate the blood cell production system. In this way, the blood system transitioned from C/EBPA+ cells to primarily C/EBPA- cells.

Mutations and other genetic alterations resulting in inhibition of the C/EBPA gene are associated with acute myeloid leukemia in humans. Thus, it's not mutations caused by radiation but a blood system reengineered by faulty stem cells that creates cancer risk in people who have experienced radiation.

"It's about evolution driven by natural selection," DeGregori says. "In a healthy blood system, healthy stem cells out-compete stem cells that happen to have the C/EBPA mutation. But when radiation reduces the heath and robustness (what we call 'fitness') of the stem cell population, the mutated cells that have been there all along are suddenly given the opportunity to take over."

Think about it in terms of chipmunks and squirrels: reducing an ecosystem's population of chipmunks may allow squirrels to flourish -- especially if the way in which chipmunks are reduced changes the ecosystem to favor squirrels, similar to how radiation changes the body in a way that favors C/EBPA-mutant stem cells).

These studies don't just tell us why radiation makes hematopoietic stem cells (HSCs) differentiate; they also show that by activating a stem cell maintenance pathway, we can keep it from happening. Even months after irradiation, artificially activating the NOTCH signaling pathway of irradiated HSCs lets them act "stemmy" again -- restarting the blood cell assembly line in these HSCs that would have otherwise differentiated in response to radiation.

When DeGregori, Fleenor and colleagues activated NOTCH in previously irradiated HSCs, it kept the population of dangerous, C/EBPA cells at bay. Competition from non-C/EBPA-mutant stem cells, with their fitness restored by NOTCH activation, meant that there was no evolutionary space for C/EBPA-mutant stem cells.

"If I were working in a situation in which I was likely to experience full-body radiation, I would freeze a bunch of my HSCs," DeGregori says, explaining that an infusion of healthy HSCs after radiation exposure would likely allow the healthy blood system to out-compete the radiation-exposed HSC with their "programmed mediocrity" (increased differentiation) and even HSC with cancer-causing mutations. "But there's also hope that in the future, we could offer drugs that would restore the fitness of stem cells left over after radiation."

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Reprogramming stem cells may prevent cancer after radiation

The competition for Maryland's stem cell research grants will be stiffer than ever as applications flood in next month, forcing officials to be more selective even as scientists worry that the state's fiscal problems and a new administration in Annapolis may mean smaller budgets in the future.

The Maryland Stem Cell Research Commission received a record 240 letters declaring intent to apply for $10.4 million in grants, officials said this month. While the majority came from researchers, more than a dozen came from startups and other companies and half a dozen for work testing therapies on humans proof that the 8-year-old program is boosting the state's biotechnology industry, officials said.

But that also means the state likely will reject more applications for the grants than in previous years. And with no funding promises from Gov.-elect Larry Hogan and state budget cuts looming, researchers worry there will be less to go around in 2016 and beyond.

The uncertainty comes just as advancements in stem cell science are making more research possible, threatening progress in Maryland even as other states surge forward, researchers said.

"In California, they have $3 billion. Here, we have $10 million a year. It is very hard," said Ricardo Feldman, an associate professor of microbiology and immunology at the University of Maryland School of Medicine. "Not all of us who have exciting results are going to get it, and some of us who do not get funding will not be able to continue what we started, and that will be very sad."

At an annual symposium on state-funded stem cell research this month, state stem cell commission officials said they received letters of intent from a record 16 companies as well as seven proposals for clinical work and 144 proposals for "translational" work research that aims to turn basic science into viable therapies. Applications are due Jan. 15.

Historically, the awards have gone more for university research and projects that are still at least a few steps away from being used in hospitals, but the surge in commercial and clinical work is a product of the state's long-term commitment to the grants, said Dan Gincel, the stem cell research fund's executive director.

The grants help research projects advance to a stage where they can attract backers like drug companies or other for-profit investors, who are more discriminating in the projects they support since many end up going nowhere.

"A long-term commitment is extra important for something so high-risk," Gincel said. "You gain trust that this is going somewhere."

There aren't many investors for researchers to turn to early on, said Jennifer Elisseeff, a professor of biomedical engineering at the Johns Hopkins University who has been part of teams receiving $920,000 in state grants over the past two years. She and colleagues are exploring how to stimulate stem cells to regrow tissues, a project she called "kind of basic science-y but also very applied."

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Record competition for stem cell grants means tough choices for state officials