Monthly Archives: December 2011

Fish Oil May Hold Key to Leukemia Cure

A compound produced from fish oil that appears to target leukemia stem cells could lead to a cure for the disease, according to Penn State researchers. The compound — delta-12-protaglandin J3, or D12-PGJ3 — targeted and killed the stem cells of chronic myelogenous leukemia, or CML, in mice, said Sandeep Prabhu, associate professor of immunology and molecular toxicology in the Department of Veterinary and Medical Sciences. The compound is produced from EPA — Eicosapentaenoic Acid — an Omega-3 fatty acid found in fish and in fish oil, he said. 

“Research in the past on fatty acids has shown the health benefits of fatty acids on cardiovascular system and brain development, particularly in infants, but we have shown that some metabolites of Omega-3 have the ability to selectively kill the leukemia-causing stem cells in mice,” said Prabhu. “The important thing is that the mice were completely cured of leukemia with no relapse.”

The researchers, who released their findings in the current issue of Blood, said the compound kills cancer-causing stem cells in the mice’s spleen and bone marrow. Specifically, it activates a gene — p53 — in the leukemia stem cell that programs the cell’s own death. “p53 is a tumor suppressor gene that regulates the response to DNA damage and maintains genomic stability,” Prabhu said.

The current therapy for CML extends the patient’s life by keeping the number of leukemia cells low, but the drugs fail to completely cure the disease because they do not target leukemia stem cells, said Robert Paulson, associate professor of veterinary and biomedical sciences, who co-directed this research with Prabhu.Killing the stem cells in leukemia, a cancer of the white blood cells, is important because stem cells can divide and produce more cancer cells, as well as create more stem cells, Prabhu said.

“The patients must take the drugs continuously,” said Paulson. “If they stop, the disease relapses because the leukemia stem cells are resistant to the drugs.”

Current treatments are unable to kill the leukemia stem cells, Paulson noted. “These stem cells can hide from the treatment, and a small population of stem cells give rise to more leukemia cells,” said Paulson. “So, targeting the stem cells is essential if you want to cure leukemia.”

In previous experiments, the compound also killed the stem cells of Friend Virus-induced leukemia, an experimental model for human leukemia.During the experiments, the researchers injected each mouse with about 600 nanograms of D12-PGJ3 each day for a week. Tests showed that the mice were completely cured of the disease. The blood count was normal, and the spleen returned to normal size. The disease did not relapse.

The researchers focused on D12-PGJ3 because it killed the leukemia stem cells, but had the least number of side effects. The researchers currently are working to determine whether the compound can be used to treat the terminal stage of CML, referred to as Blast Crisis. There are currently no drugs available that can treat the disease when it progresses to this stage.

Sourced: Penn State, Matt Swayne

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Stem Cells “Can Treat Diabetes”

A US-Brazilian project with 23 patients found most were able to produce their own insulin after a transplant of stem cells from their own bone marrow.

Even those who relapsed needed less insulin than before. 

But writing in the journal JAMA, the team warned the treatment may only work in those very recently diagnosed.

The treatment is designed to stop the immune systems of those with type 1 diabetes, a condition which usually develops in childhood, from mistakenly destroying the cells which create insulin.

To measure its effectiveness, team from Northwestern University in the US and the Regional Blood Centre in Brazil, looked at levels of C-peptides, which show how well the body is producing insulin.

Twenty of the 23 patients who received the treatment became insulin-free – one for as long as four years. Eight had to return to insulin injections, but at reduced levels.

The treatment did not work in three of the patients, and it was also unlikely to work in patients more than three months after diagnosis of diabetes, said Dr Richard Burt of Northwestern. This was because by this stage, the immune system had destroyed the body’s islet cells.

It was also unlikely to be have any therapeutic benefits for those with type 2 diabetes, mainly associated with obesity, as these patients still make insulin.

Dr Iain Frame, director of research at Diabetes UK, said: “although this remains an interesting area of research, the importance of a limited extension to this study should not be overstated – this is not a cure for Type 1 diabetes.”

He added: “we would like to see this experiment carried out with a control group for comparison of results and a longer-term follow up in a greater number of people.

“It is important that the researchers look at the causes of the apparent improvement in insulin production and C-peptide levels in some participants. In particular, it is crucial to find out whether this is associated with the timing of the treatment or possible side effects of it rather than the stem cell transplant itself.

“It would be wrong to unnecessarily raise the hopes of people living with diabetes about a new treatment for the condition on the back of the evidence provided in this study.”

 Source: BBC News

Scientists use animal-free reagents to create clinical-grade neurons from skin cells

 Using a specially designed facility, UCLA stem cell scientists have taken human skin cells, reprogrammed them into cells with the same unlimited property as embryonic stem cells, and then differentiated them into neurons while completely avoiding the use of animal-based reagents and feeder conditions throughout the process.
Generally, stem cells are grown using mouse “feeder” cells, which help the stem cells flourish and grow. But such animal-based products can lead to unwanted variations and contamination, and the cells must be thoroughly tested before they can be deemed safe for use in humans.
The UCLA study represents the first time scientists have derived induced pluripotent stem (iPS) cells with the potential for clinical use and differentiated them into neurons in animal origin–free conditions using commercially available reagents to facilitate broad application, said Saravanan Karumbayaram, the first author of the study and an associate researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
The Broad Center researchers also developed a set of standard operating procedures for the process so that other scientists can benefit from the derivation and differentiation techniques. The process was performed under good manufacturing practices (GMP) protocols, which are tightly controlled and regulated, so the cells created meet all the standards required for use in humans.
“Developments in stem cell research show that pluripotent stem cells ultimately will be translated into therapies, so we are working to develop the methods and systems needed to make the cells safe for human use,” Karumbayaram said. 
The study was published Dec. 7 in the early online edition of the inaugural issue of the peer-reviewed journal Stem Cells Translational Medicine, a new journal that seeks to bridge stem cell research and clinical trials.
           
Karumbayaram tested six different animal-free media formulations before arriving at a composition that generated the most robust pluripotent stem cells. He combined two commercial media solutions to create his own mix and tried different concentrations of an important growth factor.
“The colonies we get are of very good quality and are quite stable,” said Karumbayaram, who compared his animal-free colonies to those created conventionally using mouse feeder cells.
Efficiency did suffer. Fewer colonies were created using the animal-free feeders, but the colonies did remain stable for at least 20 passages.
The neurons that resulted from the process started life as a small skin-punch biopsy from a volunteer. The skin cells were then reprogrammed to become pluripotent stem cells with the ability to make any cell in the human body. These iPS cells were grown in colonies and were later coaxed into becoming neural precursor cells and, finally, neurons.
The animal-free cells were compared at every step in the process to cells produced by typical animal-based methods, Karumbayaram said, and were found to be of very similar quality.
“We were very excited when we saw the first colonies growing, because we were not sure it would be possible to derive and grow cells completely animal-free,” he said.
Because the cells were grown in a special facility designed to culture animal-free cells, the testing and examination required to make clinical-grade cells should be much simpler, said William Lowry, senior author of the study and an assistant professor of molecular, cell and developmental biology in the UCLA Division of Life Sciences.
To date, at least 15 animal-free iPS cell lines have been created at the Broad Stem Cell Research Center.
“It’s critical to note that we are nowhere near ready to use these cells in the clinic,” Lowry said. “We are working to develop methods to make sure these cells are genetically stable and will be as safe as possible for human use. The main goal of this project was to generate a platform that will one day allow translation of stem cells to the clinic.”
The study was supported by the California Institute of Regenerative Medicine, the National Institutes of Health, the U.S. Department of Defense, the Foundation to Eradicate Duchenne, the UCLA Muscular Dystrophy Core Center and the Broad Stem Cell Research Center.
Source: Kim Irwin, UCLA Newsroom

Blood Stem Cells Engineered to Fight Melanoma

Researchers from UCLA’s cancer and stem cell centers have demonstrated for the first time that blood stem cells can be engineered to create cancer-killing T-cells that seek out and attack a human melanoma. The researchers believe the approach could be useful in about 40 percent of Caucasians with this malignancy. 

Done in mouse models, the study serves as the first proof-of-principle that blood stem cells, which make every type of cell found in the blood, can be genetically altered in a living organism to create an army of melanoma-fighting T-cells, said Jerome Zack, the study’s senior author and a scientist with UCLA’s Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

“We knew from previous studies that we could generate engineered T-cells. But would they work to fight cancer in a relevant model of human disease, such as melanoma?” asked Zack, a professor of medicine and microbiology, immunology and molecular genetics in the UCLA Life Sciences Division. “We found with this study that they do work in a human model to fight cancer, and it’s a pretty exciting finding.”

The study appeared Monday (Nov. 28) in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.

Researchers used a T-cell receptor — cloned by other scientists from a cancer patient — that seeks out an antigen expressed by a certain type of melanoma. They then genetically engineered the human blood stem-cells by importing genes for the T-cell receptor into the stem cell nucleus using a viral vehicle. The genes integrate with the cell DNA and are permanently incorporated into the blood stem cells, theoretically enabling them to produce melanoma-fighting cells indefinitely and when needed, said Dimitrios N. Vatakis, the study’s first author and an assistant researcher in Zack’s lab.

“The nice thing about this approach is a few engineered stem cells can turn into an army of T-cells that will respond to the presence of this melanoma antigen,” Vatakis said. “These cells can exist in the periphery of the blood, and if they detect the melanoma antigen, they can replicate to fight the cancer.”

In the study, the engineered blood stem cells were placed into human thymus tissue that had been implanted in the mice, allowing Zack and his team to study the human immune system reaction to melanoma in a living organism. Over about six weeks, the engineered blood stem cells developed into a large population of mature, melanoma-specific T-cells that were able to target the right cancer cells.

The mice were then implanted with two types of melanoma tumors, one that expressed the antigen complex that attracts the engineered T-cells and one that did not. The engineered cells specifically went after the antigen-expressing melanoma, leaving the control tumor alone, Zack said.

The study included nine mice. In four animals, the antigen-expressing melanomas were completely eliminated, while in the other five, these melanomas decreased in size, Zack said — an impressive finding.

Response was assessed not only by measuring physical tumor size but by monitoring the cancer’s metabolic activity using positron emission tomography (PET), which measures how much energy the cancer is “eating” to drive its growth.

“We were very happy to see that four tumors were completely gone and the rest had regressed, both by measuring their size and actually seeing their metabolic activity through PET,” Zack said.

This approach to immune system engineering has intriguing implications, Zack said. T-cells can be engineered to fight disease, but their function is not long-lasting in most cases, and more engineered T-cells ultimately are needed to sustain a response. This new approach engineers the cells that give rise to the T-cells so that “fresh” cancer-killing cells could be generated when needed, perhaps protecting against cancer recurrence later.

Going forward, the team would like to test this approach in clinical trials. One possible approach would be to engineer both the peripheral T-cells and the blood stem cells that give rise to T-cells. The peripheral T-cells would serve as the front-line cancer fighters, while the blood stem cells are creating a second wave of warriors to take up the battle as the front line T-cells are losing function.

Zack said he hopes this engineered immunity approach will translate to other cancers as well, including breast and prostate cancers.

The four-year study was funded in part by the National Institutes of Health, the California Institute for Regenerative Medicine, the Caltech-UCLA Joint Center for Translational Medicine, the UCLA Center for AIDS Research and the UCLA AIDS Institute.

Source: Kim Irwin, University of California


First Artificial Windpipe Made With Stem Cells Seems Successful

WEDNESDAY, Nov. 23 (HealthDay News) — A 36-year-old husband and father of two children with an inoperable tumor in his trachea (windpipe) has received the world’s first artificial trachea made with stem cells.

A report published online Nov. 23 in The Lancet described the transplant surgery, which was performed in June at the Karolinska University Hospital in Stockholm, Sweden.

Without the transplant, the authors of the report explained, the man from Reykjavik, Iceland would have died. A golf ball-sized tumor on his trachea had begun to restrict his breathing. In a 12-hour procedure, doctors completely removed the affected area of his trachea and replaced it with an artificial one.

The artificial trachea was custom-made using three-dimensional imaging. First, a glass model was built to help shape an artificial scaffold. Stem cells were then inserted into the scaffold to create a functioning airway, the authors explained in a journal news release.

The scientists said their technique is an improvement over other methods because they used the patient’s own cells to create the airway so there is no risk of rejection and the patient does not have to take immunosuppressive drugs.

In addition, they noted, because the trachea was custom-made it would be an ideal fit for the patient’s body size and shape, and would eliminate the need to remain on a waiting list for a human donor.

“The patient has been doing great for the last four months and has been able to live a normal life. After arriving in Iceland at the start of July, he was one month in hospital and another month in a rehabilitation center,” a co-author of the study and the physician who referred the patient for the procedure, Tomas Gudbjartsson, of Landspitali University Hospital and University of Iceland, Reykjavik, said in the news release.

The transplant team has since performed another transplant on a second patient from Maryland with cancer of the airway. This patient’s bioartificial scaffold, however, was made from nanofibers. They now hope to treat a 13-month-old South Korean infant also using this method.

“We will continue to improve the regenerative medicine approaches for transplanting the windpipe and extend it to the lungs, heart and esophagus. And investigate whether cell therapy could be applied to irreversible diseases of the major airways and lungs,” said Gudbjartsson.

Although the technique shows promise, Dr. Harald C. Ott and Dr. Douglas J. Mathisen, from Massachusetts General Hospital and Harvard Medical School in Boston, cautioned that more research must to be done to fully evaluate its safety and effectiveness.

“To be adjudged successful, bioartificial organs must function over a long time — short-term clinical function is an important achievement, but is only one measure of success. Choice of ideal scaffold material, optimum cell source, well-defined tissue culture conditions, and perioperative management pose several questions to be answered before the line to broader clinical application of any bioartificial graft can be crossed safely and confidently,” Ott and Mathisen concluded in the news release.

SOURCE: The Lancet, news release, Nov. 23, 2011

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