Adults Sought for Study on Aging and Mobility

                                                               Walking stickman
The Biomechanics Laboratory in the kinesiology department is recruiting volunteers for a study about the effects of age and exercise on walking and muscle function. The researchers hope to learn about how changes in muscle function with age are related to the onset of disability.

The lab is looking for individuals who meet the following criteria: ages 55-70 with healthy body weight who participate in fewer than five 30-minute bouts of exercise per week (or less than a total of 150 minutes of planned exercise per week), no history of reconstructive surgery of the legs, no major health issues (heart disease, diabetes, neurological disease), able to walk for 30 minutes and no contraindications to MRI (metal implant, claustrophobia).

The study consists of two visits: a 1-hour visit to an MRI facility in Amherst and one 3-hour visit to the Biomechanics Lab on campus. During the lab visit researchers will collect data on how participants’ joints move as they walk over the ground and on a treadmill. The study will also collect data on the strength of the muscles in participants’ thighs. All procedures are non-invasive.

Source: UMass

New combination therapy developed for multiple myeloma

This is Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. Credit: VCU Massey Cancer Center

Each year, more than 25,000 Americans are diagnosed with multiple myeloma, a form of blood cancer that often develops resistance to therapies. However, researchers at Virginia Commonwealth University Massey Cancer Center are reporting promising results from laboratory experiments testing a new combination therapy that could potentially overcome the resistance hurdle.

While several drugs are effective against multiple myeloma, including the proteasome inhibitor bortezomib, multiple myeloma cells are often able to survive by increasing the production of a protein known as Mcl-1. Mcl-1 regulates a number of processes that promote cell survival and has been implicated in resistance to anti-myeloma drugs that were initially effective. However, a team of researchers led by Xin-Yan Pei, M.D., Ph.D., and Steven Grant, M.D., recently published the findings of a study in the journal PLoS ONE demonstrating that a novel drug combination both reduces Mcl-1 expression and disrupts its interactions with other proteins to effectively kill multiple myeloma cells. The therapy combines a type of drug known as a Chk1 inhibitor with another called a MEK inhibitor. Chk1 inhibitors prevent cells from arresting in stages of the cell cycle that facilitate the repair of DNA damage, while MEK inhibitors prevent cells from activating a variety of proteins that regulate DNA repair processes while promoting the accumulation of pro-death proteins.

"This research builds on our previous studies that showed exposing multiple myeloma and leukemia cells to Chk1 inhibitors activated a protective response through the Ras/MEK/ERK signaling pathway," says Pei, instructor in the Department of Internal Medicine at the VCU School of Medicine. "By combining a Chk1 inhibitor with a MEK inhibitor, we have developed one of only a limited number of strategies shown to circumvent therapeutic resistance caused by high expressions of Mcl-1."

In laboratory experiments, the scientists enforced overexpression of Mcl-1 in human multiple myeloma cells. They found that this caused the cells to become highly resistant to bortezomib, but it failed to protect them from the Chk1/MEK inhibitor regimen. 

Additionally, the combination therapy was able to completely overcome resistance due to microenvironmental factors associated with increased expression of Mcl-1. A cell's microenvironment consists of surrounding cells and the fluids in which they reside, and the communication between cancer cells and their surrounding cells can significantly impact resistance. Mcl-1 plays a key role in this communication by facilitating events that promote cancer cell survival.

"Not only was the combination therapy effective against multiple myeloma cells, it notably did not harm normal bone marrow cells, raising the possibility of therapeutic selectivity," says Grant, the study's lead investigator and Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. "We are hopeful that this research will lead to better therapies for multiple myeloma, and help make current therapies more effective by overcoming resistance caused by Mcl-1."

The researchers have started initial discussions with clinical investigators and drug manufacturers with hopes of developing a clinical trial testing a combination of Chk1 and MEK inhibitors in patients with refractory multiple myeloma. It is too early to estimate when the trial will open.

Source: Virginia Commonwealth University

Targeting fatty acids may be treatment strategy for arthritis, leukemia

The bone marrow of mice with normal ether lipid production (top) contains more white blood cells than are found in the bone marrow of mice with ether lipid deficiency (bottom).
Credit: Washington University School of Medicine

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, potentially opening up new avenues for treating these diverse diseases, according to new research at Washington University School of Medicine in St. Louis.

Working with genetically engineered mice, the researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of specialized white blood cells called neutrophils. Neutrophils are the most abundant type of white blood cell and a hallmark of inflammation, which is a key component of rheumatoid arthritis. Abnormally high levels of neutrophils also are common in patients with leukemia.

The study is published Jan. 6 in the journal Cell Metabolism.

"The link between these enzymes and neutrophils was a big surprise," said first author Irfan J. Lodhi, PhD, assistant professor of medicine. "We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking."

In the study, mice that couldn't make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

"This may be a pathway to limit inflammation," said senior investigator Clay F. Semenkovich, MD, the Herbert S. Gasser Professor of Medicine. "If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis."

Semenkovich, also a professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, said the enzymes specifically target neutrophils without affecting other immune cells.

"So ether lipids appear to be a very precise target," he said.

Working with Daniel Link, MD, the Alan A. and Edith L. Wolff Distinguished Professor of Medicine, the researchers learned that inactivating the enzymes didn't harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient's neutrophil count gradually would rise, allowing the immune system to return to normal.

Source: Washington University in St. Louis

Moderate consumption of sugary drinks has little impact on adolescents' metabolic health

Sugar-sweetened beverages, such as soft drinks, are the largest source of added sugar in the diets of adolescents in the United States. Credit: Image courtesy of University of Missouri-Columbia

Sugar-sweetened beverages are the largest source of added sugar in the diets of adolescents in the United States, and young adults ages 15-20 consume more of these drinks than any other age group, according to the Centers for Disease Control and Prevention. Adolescent obesity rates, which have quadrupled over the past thirty years, led to widespread scrutiny of added dietary sugars, especially those found in carbonated beverages. Now, MU researchers have found that short-term, moderate consumption of high-fructose and high-glucose beverages has little impact on the metabolic health of weight-stable, physically active adolescents.

"These beverages may not be as unhealthy for adolescents as previously thought, provided that kids stay active," said Jill Kanaley, professor and associate chair in the MU Department of Nutrition and Exercise Physiology. "That physical activity component is really critical in protecting against some of the negative effects of drinking large amounts of sugar-sweetened drinks demonstrated in previous studies."

Kanaley's study measured several aspects of metabolic health, including insulin sensitivity and cholesterol levels, after participants had consumed moderate amounts of either high-glucose or high-fructose beverages every day for two weeks. The high-glucose drink contained 50 grams of glucose and 15 grams of fructose; the high-fructose drink contained 50 grams of fructose and 15 grams of glucose. In comparison, two 12-ounce cans of white soda contain about 50 grams of fructose, although the amount of sugar found in soft drinks varies by brand and type. The researchers used armbands with electronic sensors to monitor physical activity of the participants, all of whom were healthy male and female adolescents ages 15-20.

Although some research has shown that consuming sugary drinks can have detrimental metabolic effects, Kanaley said that the results of these studies have been inconsistent. Previous research often has excluded adolescents and did not measure participants' levels of physical activity. In one of her previous studies, which recently was published in Medicine in Science and Sports, Kanaley found that increased physical activity diminished negative effects associated with high-fructose diets.

"Many parents of adolescents worry about their children's consumption of sweetened beverages," Kanaley said. "I certainly would recommend that they work to reduce their children's intake of sugary drinks, but it also is important for kids to remain active, especially if they are drinking a lot of sugary beverages. In our study, the female adolescents averaged around 8,000 steps per day, and the males averaged about 10,000 steps per day. 

These children weren't athletes, but they had active lifestyles."

Kanaley's article was published in the American Journal of Clinical Nutrition.

Source: University of Missouri-Columbia