Embryonic Signal Drives Pancreatic Cancer and Offers a Way to Kill It

Pancreatic cancer is a particularly challenging one to beat; it has a tendency to spread and harbors cancer stem cells that stubbornly resist conventional approaches to therapy. Now, researchers reporting in the November issue of Cell Stem Cell, a Cell Press publication, have evidence to suggest there is a way to kill off those cancer stem cells. The target is a self-renewal pathway known for its role not in cancer but in embryonic stem cells.

"I don't think the cancer stem cells have any direct link to embryonic development, rather they are using this developmental pathway for their uncontrolled self-renewal capacity," said Christopher Heeschen of the Spanish National Cancer Research Centre in Madrid. "This pathway is completely inactive in adult tissue. We've checked many tissues and there is zero -- no detectable expression at all."

The so-called Nodal/Activin pathway's embryonic ties and absence from other tissues present a real opportunity. It suggests you could target the molecular pathway without harming other adult cells. Heeschen's team has now shown that approach to therapy does seem to work in mice.

They first demonstrated the important role of the Nodal/Activin pathway in cancer stem cells derived from human pancreatic cancer. When that signal was blocked, normally resistant pancreatic cancer stem cells became sensitive to chemotherapy.

The researchers then moved on to experiments in mice with established tumors seeded from human cancer cells. Treatment of those animals with the pathway inhibitor plus standard chemotherapy eliminated those stem cells.

"The dual combination therapy worked strikingly well," Heeschen said. "The mice responded with 100 percent survival after 100 days." That's compared to mice not receiving the therapy, which bore large tumors and died within 40 days of implantation.

That two-part treatment wasn't enough to tackle pancreatic cancer when intact tumor tissue was implanted into mice as opposed to just cancer cells, the researchers found. Heeschen says that's because those cells were nestled within a supportive "stroma." That protective tissue delivered the Activin signal and prevented the drug combination from reaching the cells.

To get around that, Heeschen and his colleagues added a third ingredient to therapy, an inhibitor intended to target the stroma. The three-pronged approach translated into long-term, progression-free survival for the mice.

Interestingly, Heeschen says the animals' tumors didn't show signs of shrinking even as they were defeated. "They were more or less dead tissue. They were senescent with no cancer stem cells -- just sitting there," he said.

Those tissues apparently had no ability to form new tumors. The findings suggest that tumor regression isn't always the key thing to look for. It also shows that drugs designed to target cancer stem cells alone are promising, but only in combination with other drugs.

"The concept that you can hit cancer stem cells and tumors will melt away must be abandoned," Heeschen said. "You have to treat the entire cancer -- the stroma, cancer stem cells and differentiated cells -- as a complex. "

Heeschen says there are hints that this embryonic pathway might have important roles in other forms of cancer, including breast, lung and colorectal cancers. That's something they will now test in further studies.

Journal Reference:

1. Enza Lonardo, Patrick C. Hermann, Maria-Theresa Mueller, Stephan Huber, Anamaria Balic, Irene Miranda-Lorenzo, Sladjana Zagorac, Sonia Alcala, Iker Rodriguez-Arabaolaza, Juan Carlos Ramirez, Raul Torres-Ruíz, Elena Garcia, Manuel Hidalgo, David Álvaro Cebrián, Rainer Heuchel, Matthias Löhr, Frank Berger, Peter Bartenstein, Alexandra Aicher, Christopher Heeschen. Nodal/Activin Signaling Drives Self-Renewal and Tumorigenicity of Pancreatic Cancer Stem Cells and Provides a Target for Combined Drug Therapy. Cell Stem Cell, 2011; 9 (5): 433 DOI: 10.1016/j.stem.2011.10.001

Courtesy: ScienceDaily

Advance Toward an Imaging Agent for Diagnosing Alzheimer's Disease

Scientists are reporting development and initial laboratory tests of an imaging agent that shows promise for detecting the tell-tale signs of Alzheimer's disease (AD) in the brain -- signs that now can't confirm a diagnosis until after patients have died. Their report appears in the journal ACS Medicinal Chemistry Letters.

Masahiro Ono and colleagues explain that no proven laboratory test or medical scan now exists for AD, which is claiming an increasingly heavy toll with the graying of the world's population. Patients now get a diagnosis of AD based on their medical history and symptoms, and symptoms like memory loss often are identical to those of normal aging. Currently, the only definitive way to diagnose AD involves an autopsy with examination of brain samples for the presence of the clumps and tangles of abnormal protein that occur in the disease.

The scientists describe the synthesis and lab testing of a new imaging agent (called FPPDB), which bound tightly to ß-amyloid plaques and neurofibrillary tangles -- signs of AD -- in human brain samples. In normal laboratory mice, which served as stand-ins for humans, FPPDB stayed in the body long enough for a PET scan (a sophisticated medical imaging technique). With further development, the imaging agent may allow early AD diagnosis in humans, the scientists indicate.

The authors acknowledge funding from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Journal Reference:

1. Kenji Matsumura, Masahiro Ono, Hiroyuki Kimura, Masashi Ueda, Yuji Nakamoto, Kaori Togashi, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hideo Saji. 18F-Labeled Phenyldiazenyl Benzothiazole for in Vivo Imaging of Neurofibrillary Tangles in Alzheimer's Disease Brains. ACS Medicinal Chemistry Letters, 2012; 3 (1): 58 DOI: 10.1021/ml200230e

Courtesy: ScienceDaily

Genetic Mechanism Linked to Congenital Heart Disease Identified

Scientists at the Gladstone Institutes have identified a finely tuned mechanism by which fetal heart muscle develops into a healthy and fully formed beating heart -- offering new insight into the genetic causes of congenital heart disease and opening the door to one day developing therapies to fight this chronic and potentially fatal disorder.

In a paper being published online in Nature Genetics, researchers in the laboratory of Gladstone Senior Investigator Benoit Bruneau, PhD, describe the roles that two genes -- Ezh2 and Six1 -- play in embryonic heart development, while also uncovering how the genetic basis of embryonic heart formation can have profound health consequences later in life.

This research highlights the emerging importance of a biological process called "epigenetics," in which a genetic change that is inherited by a cell or organism early during development has long-term consequences. Epigenetics is of particular interest in heart development, as the incorrect activation of genes in fetal development can lead to congenital heart disease into adulthood.

"Approximately 1.3 million children and adults in the United States live with congenital heart disease -- requiring daily medications, surgeries and for some, heart transplants," said Dr. Bruneau, who is also a professor of Pediatrics at the University of California, San Francisco, with which Gladstone is affiliated. "An understanding of the epigenetic regulation of heart development could someday bring us closer to improving the lives of these individuals."

At specific times during healthy heart development, Ezh2 acts as a "master regulator," shutting off genes that are no longer needed or that need to be kept off. In the past, the focus has been on which genes get switched on during normal heart development. But in this paper, Dr. Bruneau, along with Gladstone Postdoctoral Scholar Paul Delgado-Olguin, PhD, investigated which genes must remain off to ensure the development of a healthy heart.

In laboratory experiments, Drs. Bruneau and Delgado-Olguin removed Ezh2 from mice at various developmental stages, monitoring any ensuing genetic or physical changes and comparing them to mice whose Ezh2 remained intact. Surprisingly, mice without Ezh2 developed normally in the uterus. It wasn't until after birth that they began to show problems. Their hearts became enlarged and weakened and were unable to pump blood efficiently. An enlarged heart is a hallmark feature of cardiomyopathy, a form of congenital heart disease that afflicts thousands of children each year and for which the only manifestation may be sudden death.

Further analysis revealed that Six1 is normally on only for a brief period during heart development, after which Ezh2 shuts it off for good. But without Ezh2 to act as a regulator, Six1 remains on -- leading to heart problems later in life.

"When Six1 remains active for too long in Ezh2-deficient mice, it boosts the activity of other genes that shouldn't be activated in heart-muscle cells -- such as genes that make skeletal muscle," said Dr. Delgado-Olguin. "The enlargement and thickening of the mice's hearts over time eventually led to heart failure."

This breakthrough may help researchers improve their understanding of the genetic causes of congenital heart disease while also pointing the way to potential therapies. For example, a type of congenital heart disease called dilated cardiomyopathy is caused by mutations in Eya4, a gene that is also regulated by Ezh2 in the heart.

"Six1 is just one of many Ezh2-regulated genes that are vital for heart development," said Dr. Bruneau. "Our next goal is to find out exactly how Ezh2 regulates these other genes, so that we can begin to develop a complete genomic blueprint of how a heart becomes a heart."

Senior Research Technologist Yu Huang, MD, PhD, also participated in this research at Gladstone, which received funding from the National Institutes of Health, the California Institute for Regenerative Medicine, the DeGeorge Charitable Trust, the American Heart Association and William H. Younger.

Journal Reference:

1. Paul Delgado-Olguín, Yu Huang, Xue Li, Danos Christodoulou, Christine E Seidman, J G Seidman, Alexander Tarakhovsky, Benoit G Bruneau. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nature Genetics, 2012; DOI: 10.1038/ng.1068

Courtesy: ScienceDaily

Brain Glia Cells Increase Their DNA Content to Preserve Vital Blood-Brain Barrier

The blood-brain barrier is essential for maintaining the brain's stable environment -- preventing entry of harmful viruses and bacteria and isolating the brain's specific hormonal and neurotransmitter activity from that in the rest of the body.

In addition to nerve cells, the brain contains glia cells that support and protect the neurons. In the fruit fly, the blood-brain boundary is made by glia joined into an envelope sealed around the nerve cells. As the brain rapidly expands during development, the glial envelope must grow correspondingly to remain intact. However, little has been known about how the blood-brain barrier maintains its integrity as the brain it protects develops.

Now Whitehead Institute scientists report that as the developing larval fruit fly brain grows by cell division, it instructs subperineurial glia (SPG) cells that form the blood-brain barrier to enlarge by creating multiple copies of their genomes in a process known as polyploidization. The researchers report their work this month in the journal Genes and Development.

"We think that this may be the same developmental strategy that's used in other contexts, where you need an outer layer of cells to maintain a seal, yet you also need the organ to grow during development," says Whitehead Member Terry Orr-Weaver.

Like the larval fruit fly's blood-brain barrier, cell layers in the human placenta and skin may employ polyploidization to respond to the need to expand while maintaining a sound boundary between the fetus and its surroundings, and the body and the outside world, respectively.

For preserving such barriers, polyploidy is ideal, as the cells forming the boundary enlarge without undergoing full cell division, a process that would break the tight junctions between cells.

In the larval fruit fly, polyploid SPG are necessary for maintaining the blood-brain barrier. When Yingdee Unhavaithaya, a postdoctoral researcher in Orr-Weaver's lab and first author of the Genes and Development article, prevented the SPG from making additional genome copies and becoming polyploid, the blood-brain barrier shattered as the brain continued to expand and the SPG was unable to accommodate its growth.

When allowed to progress naturally, polyploidy is flexible enough to accommodate even unusual brain expansion. After Unhavaithaya enlarged the brain by inducing a brain tumor, the SPG responded by increasing their ploidy and the blood-brain barrier remained unbroken.

This experiment also indicates that somehow the expanding brain mass is telling the SPG to increase their ploidy, but only as much as necessary to maintain the tight junctions between the SPG.

"It's a glimpse of communication between tissues during organogenesis," says Unhavaithaya. "We see different tissues trying to make a properly sized organ together. And one of the ways is by receiving instruction from the growing tissue so the other tissue can scale its size to properly conform to this tissue ratio for the organism."

For Orr-Weaver, Unhavaithaya's work could lead to additional exciting research.

"It has really opened up a whole new area to look at, so we can understand the mechanistic basis by which this communication happens," says Orr-Weaver, who is also an American Cancer Society professor of biology at MIT. "Does it happen at the organ level, or does it happen locally? There's really a lot to sort out."

This work was supported the Harold and Leila Mathers Charitable Foundation and the American Cancer Society.

Journal Reference:

1. Y. Unhavaithaya, T. L. Orr-Weaver. Polyploidization of glia in neural development links tissue growth to blood-brain barrier integrity. Genes & Development, 2012; 26 (1): 31 DOI: 10.1101/gad.177436.111

Courtesy: ScienceDaily

The Microbiome and Disease: Gut Bacteria Influence the Severity of Heart Attacks in Rats

New research published online in the FASEB Journal suggests that the types and levels of bacteria in the intestines may be used to predict a person's likelihood of having a heart attack, and that manipulating these organisms may help reduce heart attack risk. This discovery may lead to new diagnostic tests and therapies that physicians use to prevent and treat heart attacks. In addition, this research suggests that probiotics may be able to protect the heart in patients undergoing heart surgery and angioplasty.

"Our discovery is a revolutionary milestone in the prevention and treatment of heart attacks," said John E. Baker, Ph.D., study author from the Division of Cardiothoracic Surgery at the Medical College of Wisconsin in Milwaukee. "The biochemical link between intestinal bacteria, their metabolites, and injury to the heart will reduce the risk of death from a heart attack and, coupled with the use of probiotics, will ultimately be able to improve the overall cardiovascular health of the human population."

To make this discovery, Baker and colleagues conducted experiments involving three groups of rats. The first group was fed a standard diet. The second group was treated orally with the antibiotic vancomycin in the drinking water. The third group was fed a probiotic supplement that contains Lactobacillus plantarum, a bacterium that suppresses the production of leptin.

The group treated with the antibiotic had decreased levels of leptin (a protein hormone that plays a key role in appetite and metabolism), which resulted in smaller heart attacks, and improved recovery of mechanical function as compared to the group fed a standard diet. The antibiotic reduced total bacterial numbers in the intestines and altered the abundance of specific types of bacteria and fungi that live in the gut. Treating these rats with leptin was shown to offset the protection produced by the antibiotic treatment. The third group was fed a probiotic that also altered the numbers and types of bacteria and fungi living in the gut. Like those fed the antibiotic, these rats also had decreased leptin levels, resulting in smaller heart attacks and greater recovery of mechanical function as compared to the first group. Treating these rats with leptin also was shown to offset the protection produced by the probiotic.

"We may not be ready to prescribe yogurt to prevent heart attacks, but this research does gives us a much better understanding of how the microbiome affects our response to injury," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. "Just as physicians use cholesterol levels, blood pressure, and overall body composition as measures of heart disease risk, we may soon evaluate our body's susceptibility to disease by looking at the microbes that inhabit the gut."

Journal Reference:

1. Vy Lam, Jidong Su, Stacy Koprowski, Anna Hsu, James S. Tweddell, Parvaneh Rafiee, Garrett J. Gross, Nita H. Salzman, and John E. Baker. Intestinal microbiota determine severity of myocardial infarction in rats. FASEB J., 2012 DOI: 10.1096/fj.11-197921

Courtesy: ScienceDaily

New Method Keeps Normal Cells and Tumor Cells Taken from an Individual Cancer Patient Alive

In a major step that could revolutionize biomedical research, scientists have discovered a way to keep normal cells as well as tumor cells taken from an individual cancer patient alive in the laboratory -- which previously had not been possible. Normal cells usually die in the lab after dividing only a few times, and many common cancers will not grow, unaltered, outside of the body.

This new technique, described December 29 online in the American Journal of Pathology, could be the critical advance that ushers in a new era of personalized cancer medicine, and has potential application in regenerative medicine, says the study's senior investigator, Richard Schlegel, M.D., Ph.D., chairman of the department of pathology at Georgetown Lombardi Comprehensive Cancer Center, a part of Georgetown University Medical Center.

"Because every tumor is unique, this advance will make it possible for an oncologist to find the right therapies that both kills a patient's cancer and spares normal cells from toxicity," he says. "We can test resistance as well chemosensitivity to single or combination therapies directly on the cancer cell itself."

The research team, which also includes several scientists from the National Institutes of Health, found that adding two different substances to cancer and normal cells in a laboratory pushes them to morph into stem-like cells -- adult cells from which other cells are made.

The two substances are a Rho kinase (ROCK) inhibitor and fibroblast feeder cells. ROCK inhibitors help stop cell movement, but it is unclear why this agent turns on stem cell attributes, Schlegel says. His co-investigator Alison McBride, Ph.D., of the National Institute of Allergy and Infectious Diseases, had discovered that a ROCK inhibitor allowed skin cells (keratinocytes) to reproduce in the laboratory while feeder cells kept them alive.

The Georgetown researchers -- 13 investigators in the departments of pathology and oncology -- tried ROCK inhibitors and fibroblast feeder cells on the non-keratinocyte epithelial cells that line glands and organs to see if they had any effect. They found that both were needed to produce a dramatic effect in which the cells visibly changed their shape as they reverted to a stem-like state.

"We tried breast cells and they grew well. We tried prostate cells and their growth was fantastic, which is amazing because it is normally impossible to grow these cells in the lab," Schlegel says. "We found the same thing with lung and colon cells that have always been difficult to grow."

"In short, we discovered we can grow normal and tumor cells from the same patient forever, and nobody has been able to do that," he says. "Normal cell cultures for most organ systems can't be established in the lab, so it wasn't possible previously to compare normal and tumor cells directly."

The ability to immortalize cancer cells will also make biobanking both viable and relevant, Schlegel says. The researchers further discovered that the stem-like behavior in these cells is reversible. Withdrawing the ROCK inhibitor forces the cells to differentiate into the adult cells that they were initially. This "conditional immortalization" could help advance the field of regenerative medicine, Schlegel says.

However, the most immediate change in medical practice from these findings is the potential they have in "revolutionizing what pathology departments do," Schlegel says.

"Today, pathologists don't work with living tissue. They make a diagnosis from biopsies that are either frozen or fixed and embedded in wax," he says. "In the future, pathologists will be able to establish live cultures of normal and cancerous cells from patients, and use this to diagnose tumors and screen treatments. That has fantastic potential."

This research was funded by grants from the National Institutes of Health, Department of Defense fellowship funding, and an internal grant from Georgetown Lombardi's Cancer Center Support Grant from the National Cancer Institute.

Georgetown University and the National Institutes of Health have filed two patent applications on technologies described in this paper. The inventors for the patent application related to immortalization of non-keratinocyte technology described in this paper which is jointly owned by Georgetown and NIH include Schlegel, Xuefeng Liu and Alison McBride. Sandra Chapman and McBride are co-inventors on a separate patent application filed by the National Institutes of Health related to keratinocyte technology described in this paper.

Journal Reference:

1. Xuefeng Liu, Virginie Ory, Sandra Chapman, Hang Yuan, Chris Albanese, Bhaskar Kallakury, Olga A. Timofeeva, Caitlin Nealon, Aleksandra Dakic, Vera Simic, Bassem R. Haddad, Johng S. Rhim, Anatoly Dritschilo, Anna Riegel, Alison McBride, Richard Schlegel. ROCK Inhibitor and Feeder Cells Induce the Conditional Reprogramming of Epithelial Cells. The American Journal of Pathology, 2011; DOI: 10.1016/j.ajpath.2011.10.036

Courtesy: ScienceDaily

Changes Seen in Cerebrospinal Fluid Levels Before Onset of Alzheimer's Disease

Cerebrospinal fluid levels of Aβ42 appear to be decreased at least five to 10 years before some patients with mild cognitive impairment develop Alzheimer disease (AD) dementia whereas other spinal fluid levels seem to be later markers of disease, according to a report in the January issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

The researchers note as background in the study that disease-modifying therapies, such as immunotherapy, are more likely to be successful if started in the early stages of the disease so there is a need to identify patients with Alzheimer disease before neurodegeneration is not too severe.

Peder Buchhave, M.D., Ph.D, who is affiliated with Lund University and Skane University, Sweden, and colleagues conducted an extended follow-up of the cohort from a previous study of 137 patients with mild cognitive impairment (MCI) at baseline. The median follow-up was 9.2 years.

During the follow-up, 72 patients (53.7 percent) developed AD and 21 (15.7 percent) progressed to other forms of dementia. At the baseline, cerebrospinal fluid Aβ42 levels were reduced and other biomarkers T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with levels in patients who did not develop AD.

The study indicates baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within five years (the early converters) compared to those who converted later between five and 10 years. However, T-tau and P-tau levels were significantly higher in early converters compared to later ones.

Researchers suggest that "approximately 90 percent of patients with MCI and pathologic CSF biomarkers at baseline will develop AD within 9.2 years."

"Therefore, these markers can identify individuals at high risk for future AD least five to 10 years before conversion to dementia. Hopefully, new therapies that can retard or even halt progression of the disease will soon be available. Together with an early and accurate diagnosis, such therapies could be initiated before neuronal degeneration is too widespread and patients are already demented," the authors conclude.

Journal Reference:

1. P. Buchhave, L. Minthon, H. Zetterberg, A. K. Wallin, K. Blennow, O. Hansson. Cerebrospinal Fluid Levels of β-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia. Archives of General Psychiatry, 2012; 69 (1): 98 DOI: 10.1001/archgenpsychiatry.2011.155

Courtesy: ScienceDaily

Anti-Sense Might Make Sense for Treating Liver Cancer

A new study shows that it is possible to selectively target and block a particular microRNA that is important in liver cancer. The finding might offer a new therapy for this malignancy, which kills an estimated 549,000 people worldwide annually.

The animal study, by researchers at The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James) and at Mayo Clinic, focused on microRNA-221 (miR-221), a molecule that is consistently present at abnormally high levels in liver cancer.

To control the problem molecule, the researchers designed a second molecule as a kind of mirror image of the first. That mirror molecule is called an antisense oligonucleotide, and it selectively bound to and blocked the action of miR-221 in human liver cancer transplanted into mice. The treatment significantly prolonged the animals' lives and promoted the activity of important tumor-suppressor genes.

"This study is significant because hepatocellular carcinoma, or liver cancer, generally has a poor prognosis, so we badly need new treatment strategies," says principal investigator Thomas Schmittgen, associate professor and chair of pharmaceutics at Ohio State's College of Pharmacy and a member of the OSUCCC -- James Experimental Therapeutics program.

The findings are published in the journal Cancer Research.

For the study, Schmittgen and his colleagues injected liver cancer cells labeled with the luminescent lighting-bug protein luciferase into the livers of mice. The researchers used bioluminescence imaging to monitor tumor growth.

When the tumors reached the appropriate size, they gave one group of animals the molecule designed to block miR-221; the other group received a control molecule.

Key findings include the following:

• After treatment with the antisense oligonucleotide, half the treated animals were alive at 10 weeks versus none of the controls.
• The antisense oligonucleotide significantly reduced levels of miR-221 in both tumor and normal liver samples.
• Treatment with the antisense oligonucleotide caused a three-fold increase in the activity of three important tumor-suppressor genes that are blocked by miR-221 in liver cancer. (The tumor suppressors were p27, p57 and PTEN.)

"Overall, this study provides proof-of-principle for further development of microRNA-targeted therapies for hepatocellular carcinomas," Schmittgen says.

Funding from the National Cancer Institute and from the National Institute of Diabetes and Digestive and Kidney Diseases supported this research.

Other researchers involved in this study were Jong-Kook Park, Jinmai Jiang, Lei He, Ji Hye Kim, Mitch A. Phelps, Tracey L. Papenfuss and Carlo M. Croce of Ohio State; Takayuki Kogure and Tushar Patel of Mayo Clinic, Jacksonville, Florida; and Gerard J. Nuovo.

Journal Reference:

1. J.-K. Park, T. Kogure, G. J. Nuovo, J. Jiang, L. He, J. H. Kim, M. A. Phelps, T. L. Papenfuss, C. M. Croce, T. Patel, T. D. Schmittgen. miR-221 Silencing Blocks Hepatocellular Carcinoma and Promotes Survival. Cancer Research, 2011; 71 (24): 7608 DOI: 10.1158/0008-5472.CAN-11-1144

Courtesy: ScienceDaily

World’s First Primate Chimeric Offspring Produced: Research Demonstrates Not All Embryonic Stem Cells Are Equal

Newly published research by scientists at Oregon Health & Science University provides significant new information about how early embryonic stem cells develop and take part in formation of the primate species. The research, which took place at OHSU's Oregon National Primate Research Center, has also resulted in the first successful birth of chimeric monkeys -- monkeys developed from stem cells taken from two separate embryos.

The research is being published this week in the online edition of the journal Cell and will be published in a future printed copy of the journal.

The research was conducted to gain a better understanding of the differences between natural stem cells residing in early embryos and their cultured counterparts called embryonic stem cells. This study also determined that stem cell functions and abilities are different between primates and rodents.

Here's more information about the early primate stem cells that were studied: The first cell type was totipotent cells -- cells from the early embryo that have the ability to divide and produce all of the differentiated cells in the placenta and the body of organism. These were compared with pluripotent cells -- cells derived from the later stage embryo that have only the ability to become the body but not placenta.

In mice, either totipotent or pluripotent cells from two different animals can be combined to transform into an embryo that later becomes a chimeric animal. However, the current research demonstrated that for reasons yet unknown, chimeric animals can only develop from totipotent cells in a higher animal model: the rhesus macaque. OHSU showed this to be the case by successfully producing the world's first primate chimeric offspring, three baby rhesus macaques named Roku, Hex and Chimero.

"This is an important development -- not because anyone would develop human chimeras -- but because it points out a key distinction between species and between different kind of stem cells that will impact our understanding of stem cells and their future potential in regenerative medicine," explained Shoukhrat Mitalipov, Ph.D., an associate scientist in the Division of Reproductive and Developmental Sciences at ONPRC.

"Stem cell therapies hold great promise for replacing damaged nerve cells in those who have been paralyzed due to a spinal cord injury or for example, in replacing dopamine-producing cells in Parkinson's patients who lose these brain cells resulting in disease. As we move stem cell therapies from the lab to clinics and from the mouse to humans, we need to understand what these cells do and what they can't do and also how cell function can differ in species."

The OHSU Oregon National Primate Research Center and the National Institutes of Health funded the research.

Journal Reference:

1. Masahito Tachibana, Michelle Sparman, Cathy Ramsey, Hong Ma, Hyo-Sang Lee, Maria Cecilia T. Penedo, Shoukhrat Mitalipov. Generation of Chimeric Rhesus Monkeys. Cell, 2012; DOI: 10.1016/j.cell.2011.12.007

Courtesy: ScienceDaily

Computer Assisted Design (CAD) for RNA: Researchers Develop CAD-Type Tools for Engineering RNA Control Systems

The computer assisted design (CAD) tools that made it possible to fabricate integrated circuits with millions of transistors may soon be coming to the biological sciences. Researchers at the U.S. Department of Energy (DOE)'s Joint BioEnergy Institute (JBEI) have developed CAD-type models and simulations for RNA molecules that make it possible to engineer biological components or "RNA devices" for controlling genetic expression in microbes. This holds enormous potential for microbial-based sustainable production of advanced biofuels, biodegradable plastics, therapeutic drugs and a host of other goods now derived from petrochemicals.

"Because biological systems exhibit functional complexity at multiple scales, a big question has been whether effective design tools can be created to increase the sizes and complexities of the microbial systems we engineer to meet specific needs," says Jay Keasling, director of JBEI and a world authority on synthetic biology and metabolic engineering. "Our work establishes a foundation for developing CAD platforms to engineer complex RNA-based control systems that can process cellular information and program the expression of very large numbers of genes. Perhaps even more importantly, we have provided a framework for studying RNA functions and demonstrated the potential of using biochemical and biophysical modeling to develop rigorous design-driven engineering strategies for biology."

Keasling, who also holds appointments with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkley, is the corresponding author of a paper in the journal Science that describes this work. The paper is titled "Model-driven engineering of RNA devices to quantitatively-program gene expression." Other co-authors are James Carothers, Jonathan Goler and Darmawi Juminaga.

Synthetic biology is an emerging scientific field in which novel biological devices, such as molecules, genetic circuits or cells, are designed and constructed, or existing biological systems, such as microbes, are re-designed and engineered. A major goal is to produce valuable chemical products from simple, inexpensive and renewable starting materials in a sustainable manner. As with other engineering disciplines, CAD tools for simulating and designing global functions based upon local component behaviors are essential for constructing complex biological devices and systems. However, until this work, CAD-type models and simulation tools for biology have been very limited.

Identifying the relevant design parameters and defining the domains over which expected component behaviors are exerted have been key steps in the development of CAD tools for other engineering disciplines," says Carothers, a bioengineer and lead author of the Science paper who is a member of Keasling's research groups with both JBEI and the California Institute for Quantitative Biosciences. "We've applied generalizable engineering strategies for managing functional complexity to develop CAD-type simulation and modeling tools for designing RNA-based genetic control systems. Ultimately we'd like to develop CAD platforms for synthetic biology that rival the tools found in more established engineering disciplines, and we see this work as an important technical and conceptual step in that direction."

Keasling, Carothers and their co-authors focused their design-driven approach on RNA sequences that can fold into complicated three dimensional shapes, called ribozymes and aptazymes. Like proteins, ribozymes and aptazymes can bind metabolites, catalyze reactions and act to control gene expression in bacteria, yeast and mammalian cells. Using mechanistic models of biochemical function and kinetic biophysical simulations of RNA folding, ribozyme and aptazyme devices with quantitatively predictable functions were assembled from components that were characterized in vitro, in vivo and in silico. The models and design strategy were then verified by constructing 28 genetic expression devices for the Escherichia coli bacterium. When tested, these devices showed excellent agreement -- 94-percent correlation -- between predicted and measured gene expression levels.

"We needed to formulate models that would be sophisticated enough to capture the details required for simulating system functions, but simple enough to be framed in terms of measurable and tunable component characteristics or design variables," Carothers says. "We think of design variables as the parts of the system that can be predictably modified, in the same way that a chemical engineer might tune the operation of a chemical plant by turning knobs that control fluid flow through valves. In our case, knob-turns are represented by specific kinetic terms for RNA folding and ribozyme catalysis, and our models are needed to tell us how a combination of these knob-turns will affect overall system function."

JBEI researchers are now using their RNA CAD-type models and simulations as well as the ribozyme and aptazyme devices they constructed to help them engineer metabolic pathways that will increase microbial fuel production. JBEI is one of three DOE Bioenergy Research Centers established by DOE's Office of Science to advance the technology for the commercial production of clean, green and renewable biofuels. A key to JBEI's success will be the engineering of microbes that can digest lignocellulosic biomass and synthesize from the sugars transportation fuels that can replace gasoline, diesel and jet fuels in today's engines.

"In addition to advanced biofuels, we're also looking into engineering microbes to produce chemicals from renewable feedstocks that are difficult to produce cheaply and in high yield using traditional organic chemistry technology," Carothers says.

While the RNA models and simulations developed at JBEI to date fall short of being a full-fledged RNA CAD platform, Keasling, Carothers and their coauthors are moving towards that goal.

"We are also actively trying to make our models and simulations more accessible to researchers who may not want to become RNA control system experts but would nonetheless like to use our approach and RNA devices in their own work," Carothers says.

While the work at JBEI focused on E. coli and the microbial production of advanced biofuels, the authors of the Science paper believe that their concepts could also be used for programming function into mammalian systems and cells.

"We recently initiated a research project to investigate how we can use our approach to engineer RNA-based genetic control systems that will increase the safety and efficacy of regenerative medicine therapies that use cultured stem cells to treat diseases such as diabetes and Parkinson's," Carothers says.

This research was supported in part by grants from the DOE Office of Science through JBEI, and the National Science Foundation through the Synthetic Biology Engineering Research Center (SynBERC).

Journal Reference:

1. James M. Carothers, Jonathan A. Goler, Darmawi Juminaga, Jay D. Keasling. Model-Driven Engineering of RNA Devices to Quantitatively Program Gene Expression. Science, December 2011: Vol. 334 no. 6063 pp. 1716-1719 DOI: 10.1126/science.1212209

Courtesy: ScienceDaily

Self-Regulation of the Immune System Suppresses Defense Against Cancer

Regulatory T cells (Tregs), which are part of the body's immune system, downregulate the activity of other immune cells, thus preventing the development of autoimmune diseases or allergies. Scientists at the German Cancer Research Center (DKFZ) have now found the activation steps that are blocked by Tregs in immune cells. Since Tregs can also suppress the body's immune defense against cancer, the findings obtained by the DKFZ researchers are important for developing more efficient cancer treatments.

It is vital that the body's own immune system does not overreact. If its key players, the helper T cells, get out of control, this can lead to autoimmune diseases or allergies. An immune system overreaction against infectious agents may even directly damage organs and tissues.

Immune cells called regulatory T cells ("Tregs") ensure that immune responses take place in a coordinated manner: They downregulate the dividing activity of helper T cells and reduce their production of immune mediators. "This happens through direct contact between regulatory cell and helper cell," says Prof. Peter Krammer of DKFZ. "But we didn't know yet what this contact actually causes in helper cells." The researchers' hypothesis was that the contact with the Tregs affects certain steps in the complex signaling cascade that leads to the activation of the helper T cells.

If the T cell receptor, a sensor molecule on the surface of helper cells, senses foreign or damaged protein molecules, this will trigger a cascade of biochemical activation reactions. At the end of this signaling cascade, genes that are required for an immune attack will be read in the nucleus of helper cells.

Jointly with colleagues from several German research institutes, Peter Krammer, Angelika Schmidt and co-workers have now compared the signaling cascades in helper cells with and without contact to Tregs. The immunologists found out that a short contact of the two types of cells in the culture dish is sufficient to suppress the helper cells. Following Treg contact, the typical release of calcium ions into the plasma of helper cells does not occur. As a result, two important transcription factors, NFkappaB and NFAT, do no longer function. They normally activate genes for immune mediators, thus alerting the immune system.

"The mode of action of Tregs is of great importance for cancer medicine. Many of our colleagues have shown in various types of cancer that Tregs can downregulate the immune response against tumors so that transformed cells escape the immune defense. This can contribute to the development and spread of cancer. We are therefore searching for ways to reactivate such suppressed helper cells," said Krammer, explaining the goals of his work. For developing immune therapies against cancer it is also crucial to understand how Tregs work. The researchers are trying to prevent that immune cells which have been painstakingly activated against cancer in the culture dish are immediately suppressed again by Tregs.

Journal Reference:

1. A. Schmidt, N. Oberle, E.-M. Weiss, D. Vobis, S. Frischbutter, R. Baumgrass, C. S. Falk, M. Haag, B. Brugger, H. Lin, G. W. Mayr, P. Reichardt, M. Gunzer, E. Suri-Payer, P. H. Krammer. Human Regulatory T Cells Rapidly Suppress T Cell Receptor-Induced Ca2 , NF- B, and NFAT Signaling in Conventional T Cells. Science Signaling, 2011; 4 (204): ra90 DOI: 10.1126/scisignal.2002179

Courtesy: ScienceDaily

Alzheimer's: Diet Patterns May Keep Brain from Shrinking

People with diets high in several vitamins or in omega 3 fatty acids are less likely to have the brain shrinkage associated with Alzheimer's disease than people whose diets are not high in those nutrients, according to a new study published in the December 28, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Those with diets high in omega 3 fatty acids and in vitamins C, D, E and the B vitamins also had higher scores on mental thinking tests than people with diets low in those nutrients. These omega 3 fatty acids and vitamin D are primarily found in fish. The B vitamins and antioxidants C and E are primarily found in fruits and vegetables.

In another finding, the study showed that people with diets high in trans fats were more likely to have brain shrinkage and lower scores on the thinking and memory tests than people with diets low in trans fats. Trans fats are primarily found in packaged, fast, fried and frozen food, baked goods and margarine spreads.

The study involved 104 people with an average age of 87 and very few risk factors for memory and thinking problems. Blood tests were used to determine the levels of various nutrients present in the blood of each participant. All of the participants also took tests of their memory and thinking skills. A total of 42 of the participants had MRI scans to measure their brain volume.

Overall, the participants had good nutritional status, but seven percent were deficient in vitamin B12 and 25 percent were deficient in vitamin D.

Study author Gene Bowman, ND, MPH, of Oregon Health & Science University in Portland and a member of the American Academy of Neurology, said that the nutrient biomarkers in the blood accounted for a significant amount of the variation in both brain volume and thinking and memory scores. For the thinking and memory scores, the nutrient biomarkers accounted for 17 percent of the variation in the scores. Other factors such as age, number of years of education and high blood pressure accounted for 46 percent of the variation. For brain volume, the nutrient biomarkers accounted for 37 percent of the variation.

"These results need to be confirmed, but obviously it is very exciting to think that people could potentially stop their brains from shrinking and keep them sharp by adjusting their diet," Bowman said.

The study was the first to use nutrient biomarkers in the blood to analyze the effect of diet on memory and thinking skills and brain volume. Previous studies have looked at only one or a few nutrients at a time or have used questionnaires to assess people's diet. But questionnaires rely on people's memory of their diet, and they also do not account for how much of the nutrients are absorbed by the body, which can be an issue in the elderly.

The study was supported by the National Institutes of Health, the National Institute on Aging and National Center for Complementary and Alternative Medicine and the U.S. Department of Veteran Affairs, Portland VA Medical Center.

Story Source:

The above story is reprinted from materials provided by American Academy of Neurology.

Courtesy: ScienceDaily