Category Archives: Transhuman News

UT Southwestern Medical Center researchers have demonstrated in both cancer cell lines and in mice that blocking critical DNA repair mechanisms could improve the effectiveness of radiation therapy for highly fatal brain tumors called glioblastomas.

Radiation therapy causes double-strand breaks in DNA that must be repaired for tumors to keep growing. Scientists have long theorized that if they could find a way to block repairs from being made, they could prevent tumors from growing or at least slow down the growth, thereby extending patients' survival. Blocking DNA repair is a particularly attractive strategy for treating glioblastomas, as these tumors are highly resistant to radiation therapy. In a study, UT Southwestern researchers demonstrated that the theory actually works in the context of glioblastomas.

"This work is informative because the findings show that blocking the repair of DNA double-strand breaks could be a viable option for improving radiation therapy of glioblastomas," said Dr. Sandeep Burma, Associate Professor of Radiation Oncology in the division of Molecular Radiation Biology at UT Southwestern.

His lab works on understanding basic mechanisms by which DNA breaks are repaired, with the translational objective of improving cancer therapy with DNA damaging agents. Recent research from his lab has demonstrated how a cell makes the choice between two major pathways that are used to repair DNA breaks -- non-homologous end joining (NHEJ) and homologous recombination (HR). His lab found that enzymes involved in cell division called cyclin-dependent kinases (CDKs) activate HR by phosphorylating a key protein, EXO1. In this manner, the use of HR is coupled to the cell division cycle, and this has important implications for cancer therapeutics. These findings were published April 7 in Nature Communications.

While the above basic study describes how the cell chooses between NHEJ and HR, a translational study from the Burma lab demonstrates how blocking both repair pathways can improve radiotherapy of glioblastomas. Researchers in the lab first were able to show in glioblastoma cell lines that a drug called NVP-BEZ235, which is in clinical trials for other solid tumors, can also inhibit two key DNA repair enzymes, DNA-PKcs and ATM, which are crucial for NHEJ and HR, respectively. While the drug alone had limited effect, when combined with radiation therapy, the tumor cells could not quickly repair their DNA, stalling their growth.

While excited by the initial findings in cell lines, researchers remained cautious because previous efforts to identify DNA repair inhibitors had not succeded when used in living models -- mice with glioblastomas. Drugs developed to treat brain tumors also must cross what's known as the blood-brain-barrier in living models.

But the NVP-BEZ235 drug could successfully cross the blood-brain-barrier, and when administered to mice with glioblastomas and combined with radiation, the tumor growth in mice was slowed and the mice survived far longer -- up to 60 days compared to approximately 10 days with the drug or radiation therapy alone. These findings were published in the March 1 issue of Clinical Cancer Research.

"The consequence is striking," said Dr. Burma. "If you irradiate the tumors, nothing much happens because they grow right through radiation. Give the drug alone, and again, nothing much happens. But when you give the two together, tumor growth is delayed significantly. The drug has a very striking synergistic effect when given with radiation."

The combination effect is important because the standard therapy for glioblastomas in humans is radiation therapy, so finding a drug that improves the effectiveness of radiation therapy could have profound clinical importance eventually. For example, such drugs may permit lower doses of X-rays and gamma rays to be used for traditional therapies, thereby causing fewer side effects.

"Radiation is still the mainstay of therapy, so we have to have something that will work with the mainstay of therapy," Dr. Burma said.

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Blocking DNA repair mechanisms could improve radiation therapy for deadly brain cancer

James P. Eaton (AP Photo/Racine County Sheriff)

Authorities tailed a man for several days and used DNA from a cigarette he tossed away at a train station to connect him to the cold-case slaying of a teenage runaway whose body was found in a marsh in 1997, a sheriff in southeastern Wisconsin said Tuesday.

James Eaton, 36, of Palatine, Ill., was arrested Saturday in Chicago, Racine County Sheriff Chris Schmaling said. Eaton has been charged with first-degree intentional homicide and hiding a corpse. He was being held at the Racine County Jail on Tuesday on $1 million bail.

"This is a day that we have been waiting more than 17 years to arrive," Schmaling said at a news conference.

Eaton is suspected in connection with the slaying of Amber Creek, a 14-year-old from Palatine, Ill.

Amber Gail Creek on her 13th birthday. (AP Photo/Racine County Sheriff via the Racine Journal Times)

Two weeks later, a pair of hunters found Creek's corpse in a marsh in the Town of Burlington. She'd been beaten, sexually assaulted and suffocated with a plastic bag. She had a human bite mark on her neck, and her body was posed with an upraised hand that had the word "Hi" written on her palm.

Investigators referred to her as Jane Doe for 16 months until they could determine her name.

Schmaling said there was no indication that Eaton, who would have been 19 at the time of her disappearance, knew Creek. "Eaton had not previously been a suspect or mentioned during the course of this investigation," he said.

Investigators recovered DNA from Creek's body and fingerprints from the bag used to suffocate her. The evidence was sent to the FBI and crime labs in other states, but no matches turned up.

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DNA ties Illinois man to Wisconsin runaway found dead in 1997

Johns Hopkins researchers say they have confirmed suspicions that DNA modifications found in the blood of mice exposed to high levels of stress hormone -- and showing signs of anxiety -- are directly related to changes found in their brain tissues.

The proof-of-concept study, reported online ahead of print in the June issue of Psychoneuroendocrinology, offers what the research team calls the first evidence that epigenetic changes that alter the way genes function without changing their underlying DNA sequence -- and are detectable in blood -- mirror alterations in brain tissue linked to underlying psychiatric diseases.

The new study reports only on so-called epigenetic changes to a single stress response gene called FKBP5, which has been implicated in depression, bipolar disorder and post-traumatic stress disorder. But the researchers say they have discovered the same blood and brain matches in dozens more genes, which regulate many important processes in the brain.

"Many human studies rely on the assumption that disease-relevant epigenetic changes that occur in the brain -- which is largely inaccessible and difficult to test -- also occur in the blood, which is easily accessible," says study leader Richard S. Lee, Ph.D., an instructor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. "This research on mice suggests that the blood can legitimately tell us what is going on in the brain, which is something we were just assuming before, and could lead us to better detection and treatment of mental disorders and for a more empirical way to test whether medications are working."

For the study, the Johns Hopkins team worked with mice with a rodent version of Cushing's disease, which is marked by the overproduction and release of cortisol, the primary stress hormone also called glucocorticoid. For four weeks, the mice were given different doses of stress hormones in their drinking water to assess epigenetic changes to FKBP5. The researchers took blood samples weekly to measure the changes and then dissected the brains at the end of the month to study what changes were occurring in the hippocampus as a result of glucocorticoid exposure. The hippocampus, in both mice and humans, is vital to memory formation, information storage and organizational abilities.

The measurements showed that the more stress hormones the mice got, the greater the epigenetic changes in the blood and brain tissue, although the scientists say the brain changes occurred in a different part of the gene than expected. This was what made finding the blood-brain connection very challenging, Lee says.

Also, the more stress hormone, the more RNA from the FKBP5 gene was expressed in the blood and brain, and the greater the association with depression. However, it was the underlying epigenetic changes that proved to be more robust. This is important, because while RNA levels may return to normal after stress hormone levels decrease or change due to small fluctuations in hormone levels, epigenetic changes persist, reflect overall stress hormone exposure and predict how much RNA will be made when stress hormone levels increase.

The team of researchers used an epigenetic assay previously developed in their laboratory that requires just one drop of blood to accurately assess overall exposure to stress hormone over 30 days. Elevated levels of stress hormone exposure are considered a risk factor for mental illness in humans and other mammals.

Other Johns Hopkins researchers involved in the study include Erin R. Ewald; Gary S. Wand, M.D.; Fayaz Seifuddin, M.S.; Xiaoju Yang, M.D.; Kellie L. Tamashiro, Ph.D.; and Peter Zandi, Ph.D. James B. Potash, M.D., M.P.H., formerly of Johns Hopkins, also contributed to this research.

The study was funded by grants from the National Institutes of Health's National Institute on Alcohol Abuse and Alcoholism (UO1 AA020890) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD055030), the Kenneth A. Lattman Foundation, a NARSAD Young Investigator Grant, the Margaret Ann Price Investigator Fund and the James Wah Fund for Mood Disorders via the Charles T. Bauer Foundation.

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DNA modifications measured in blood signal related changes in the brain