Researchers, led by Anthony Firulli, Ph.D., associate professor of pediatrics and of medical and molecular genetics at the Indiana University School of Medicine, investigated the interaction of proteins responsible for Saethre-Chotzen Syndrome, a rare genetic disorder associated with limb abnormalities including webbed fingers and other developmental defects.

In the study, Dr. Firulli and colleagues studied how two proteins, Twist1 and Hand2, which are antagonists, couple to determine the number of digits on a hand, paw or wing, and whether these digits are webbed or not. In addition to limb abnormalities, these proteins are associated with cardiac and placental tissue defects. Twist1 mutations are encountered at high frequency in patients with Saethre-Chotzen Syndrome.

"By studying a disease in which things go wrong at the cellular level, we gain insight into how to correct these errors," said Dr. Firulli, who also is a molecular biologist at the medical school's Herman B Wells Center for Pediatric Research.

"From a pediatrics perspective -- there are many congenital defects - holes in the heart, cleft pallet, webbed hands -- which are outcomes of inappropriate molecular programs due to miscommunication at the cellular level. If we can understand what is going wrong, we may be able to correct these problems before birth," said Dr. Firulli.

Co-authors of the study are IU School of Medicine investigators Beth A. Firulli, Dayana Krawchuk, Victoria E. Centonze, Neil Vargesson, David M. Virshup, Simon J. Conway, Peter Cserjesi and Columbia University's Ed Laufer.

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The NF Kappa B protein is well known to researchers as a transcription factor that regulates many genes. In cancer cells, NF Kappa B regulates genes involved in cancer cell survival, proliferation and blood vessel formation (angiogenesis). NF Kappa B is hyperactive in many human cancers including pancreatic. The Mayo Clinic study shows that in pancreatic cancer, the activity of NF Kappa B is regulated by GSK-3 Beta. Researchers determined this by showing that if they could decrease GSK-3 Beta protein or inactivate it using small molecular inhibitors, they could likewise decrease NF Kappa B - and deprive the pancreatic cancer cells of a means to grow and survive.

Notably, in pancreatic cancer, NF Kappa B activity is high - which can cause resistance to chemotherapy drugs used to treat the disease. This new information suggests a potential means of treating pancreatic cancer by a two-pronged attack of administering the gemcitabine in combination with a drug to block GSK-3 Beta.

Despite recent advances in understanding how cancers work at the molecular level, pancreatic cancer lacks an effective treatment. Approximately 30,000 Americans are diagnosed with pancreatic cancer annually, and the disease kills the same number each year. Ninety percent of these cancers are pancreatic ductular adenocarcinoma, the fourth leading cause of cancer deaths in the United States. Pancreatic cancer patients have one of the poorest prognoses - the five-year survival rate is 3 percent. Because pancreatic cancer is aggressive, spreads rapidly and few treatment options are available, researchers welcome any promising leads for improving diagnosis and therapy.

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