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Street Closures for Annual Pride Celebration

Several area streets will be closed for the 41st Annual LA Pride Festival scheduled for June 10-12 in West Hollywood.

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2 Minutes with ... Robert J. Siegel, M.D.

Dr. Siegel is director of the Cardiac Noninvasive Laboratory at the Cedars-Sinai Heart Institute and cardiology director of the Cedars-Sinai Marfan Center. He holds the Rexford S. Kennamer, M.D., Chair in Cardiac Ultrasound.

He took a few minutes away from the ultrasound machine to answer our questions.

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Zebrafish Earn Their Stripes in Cushing's Research

Researchers at Cedars-Sinai have a petite, yet productive new model to use in testing drugs to treat Cushing's disease.

The tiny, black striped zebrafish – already known for regularly contributing to health research due to its biological similarities to humans – have recently shown promise in the identification of potential treatments for Cushing's disease in the laboratory of Shlomo Melmed, M.D., senior vice president of Academic Affairs and dean of the medical faculty at Cedars-Sinai.

The research, currently being led by Ning-Ai Liu, M.D., Ph.D., consists of introducing a "pituitary tumor transforming gene," which was discovered in Melmed's lab in 1997 into a zebrafish.

Researchers then identify whether or not the zebrafish exhibit symptoms associated with Cushing's disease which, in this case, they did. These symptoms included high levels of cortisol; and signs of diabetes and heart disease. The zebrafish are then bred with fish that have green fluorescent markers, facilitating visual identification.

Zebrafish eggs grow outside the female's body allowing researchers an opportunity to view development of a newly-formed fish, including its pituitary gland.

"In this case, because the embryos are transparent, we can mark the pituitary gland with a fluorescent marker and then use a fluorescent microscope to see the pituitary light up in the living embryo," Liu said. "This is an ideal model to test drugs and, the fish don't have to be sacrificed, which also allows us to watch the pituitary's progression."

Cushing's disease is often caused by a pituitary tumor that triggers overproduction of a hormone, which, in turn, stimulates the adrenal gland to overproduce cortisol. Cortisol overproduction affects nearly every body tissue, including the regulation of blood pressure and metabolism. This leads to serious health problems, including diabetes, hypertension, osteoporosis, obesity (especially with a distinctive moon-shaped face and fatty tissue deposits in the midsection, upper back and between the shoulders) and cardiovascular disease.

During this phase of the research, Liu's team used five drugs they reasoned would cause some effect on the tumor. One of those drugs, R-roscovitine, a drug in phase two trials to treat esophageal and non-small cell lung cancer, showed promise because it effectively suppressed levels of the hormone secreted by the pituitary tumor, as well as the level of cortisol, Liu said.

The drugs were dissolved into the water that the embryos were growing in, and the research team was able to identify what impact the drugs have on overall development of the fish, such as whether or not the drug's toxicity might inhibit growth.
"If a drug is high in toxicity, it wouldn't be a good candidate for a human," Liu said. "When you screen for a drug, you want the drug to specifically target the tumor, but be benign to the rest of the body."

Besides sharing biological similarities to humans, zebrafish are helpful in research because they reproduce prolifically, hatching up to 500 eggs at a time, Liu said. Additionally, the zebrafish offspring are fully-grown within two to four days of hatching so researchers can get immediate results.

As far as this particular research, Liu said the next phase is to expand testing to a much larger pool of molecules. This means more drugs will be tested using the zebrafish and their offspring.

"This new model for Cushing's disease implies that we can more rapidly and effectively identify drugs that could be successful in fighting these tumors," Melmed said. "With no current drug therapies and limited medical options available to Cushing's patients, it is our hope that our research will enable medical advances that will revolutionize how this disease is treated."

The model was recently published in the Proceedings of the National Academy of Sciences.

The study is supported by a National Institutes of Health Grant and the Doris Factor Molecular Endocrinology Laboratory.