INDIANAPOLIS – Melanoma tumors switch to an alternative energy system when they develop resistance to chemotherapy, making that alternative system an attractive target for new treatments, according to researchers at Indiana University School of Medicine.

Malignant melanoma is one of the most lethal forms of cancer, responsible for 95 percent of skin cancer-related deaths. When the cancer has not spread, surgery is an effective treatment option. If it has spread, drugs that block the activity of the mutated gene successfully shrink the tumors, but the tumors eventually develop resistance to the drugs, leaving physicians without effective treatment options.

The research, recently published in the Journal of Biological Chemistry, focused on the subtype of malignant melanoma that contains a particular genetic mutation found in nearly 50 percent of such tumors.

Like most cells in the body, cancer cells process glucose to provide the energy needed for cellular activities and proliferation. However, previous research with PET scans has shown that glucose levels drop significantly in melanoma tumor cells as they develop resistance to drugs.

In the new study, researchers led by Samisubbu R. Naidu, PhD, research assistant professor of microbiology and immunology, determined that more than half of malignant melanomas, those carrying the mutant gene, shifted from using glucose to acetate as a main source of energy. The researchers also identified the enzyme responsible for conversion of acetate into energy.

These findings highlight the potential of this enzyme as a novel target for a new anti-melanoma therapy, Dr. Naidu said.

"If we can develop a drug that can effectively inhibit this enzyme, we could extend the life of melanoma patients from months to years," he said.

The study focused on melanoma cells containing a mutant BRAF protein, which directs the cells to proliferate and survive in nutrient-limited environments.

In a series of experiments, the researchers grew melanoma cells in various combinations of nutritional media and found that supplementing the media with acetate enabled the cells to survive and proliferate in the absence of glucose.

Subsequently, it was found that in the absence of glucose, mitochondria, the cellular organelles commonly known as the “powerhouse of the cell,” were increasingly active in the energy production, using acetate as a fuel. One particular enzyme enabled the use of this alternative source of energy. Importantly, by deleting this gene in melanoma cells, the authors showed that melanoma tumor growth in mice was blunted.

Dr. Naidu noted that mutations in the BRAF gene are found in many other types of cancer. Therefore, he said, "The benefits of this discovery may well go beyond melanoma."

Financial support for this research was provided in part by the Indiana Clinical and Translational Sciences Institute Independent Scientist Award, Indiana CTSI Core awards, the Ralph W. and Grace M. Showalter Research Trust as well as funds from Hal E. Broxmeyer, PhD, Distinguished Professor and professor of microbiology and immunology.

In addition to Dr. Naidu and Dr. Broxmeyer, investigators contributing to the work were Alexander J. Lakhter, James Hamilton, Raymond L Konger and Nickolay Brustovetsky, all of IU School of Medicine.

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INDIANAPOLIS and Bar Harbor, Maine — With the goal of breaking the bottleneck in developing new drugs to treat Alzheimer’s disease, the National Institute of Aging will provide $25 million over five years to establish and fund the Alzheimer’s Disease Precision Models Center at Indiana University School of Medicine and The Jackson Laboratory (JAX). The center will be jointly led by Drs. Bruce Lamb and Paul Territo at IU School of Medicine and Drs. Gareth Howell and Greg Carter at JAX.

An age-related neurodegenerative disease, Alzheimer's disease is the leading cause of dementia among people age 65 and older. An estimated 5 million Americans have the disease, and it ranks among the top six causes of death. The center will focus on creating dozens of new models of Alzheimer’s disease; study their physiology, behavior and genomes for disease relevance; and discover and test potential Alzheimer’s disease treatments.

To date, success rates in clinical trials of Alzheimer's disease drugs after testing in animal models have been disappointing. Howell noted, "Existing mouse models for Alzheimer's disease have provided important insights into aspects of Alzheimer's disease biology, but have not been great preclinical models as they do not sufficiently model the disease. The combination of new gene editing technologies such as CRISPR/Cas9, large-scale genomic data resources, and advanced computational methods is enabling the rapid and precise development of mouse models of disease, even in complex diseases such as Alzheimer's disease that involve multiple gene mutations.

"Our aim is to develop animal models that more closely mimic human Alzheimer's disease and a preclinical testing pipeline through which novel therapies can be tested to greatly accelerate the process by which therapies are successfully moved forward to human Alzheimer's disease clinical trials," Howell said.

Bruce Lamb, PhD, executive director of the Stark Neurosciences Research Institute at IU School of Medicine, noted that in the past decade researchers have identified many genetic variants that appear to be linked to Alzheimer's disease but whose roles are unknown.

"I would argue that those results indicate that we do not, even today, have a very good understanding of the biology of late-onset Alzheimer's disease," said Dr. Lamb, Roberts Family Professor of Alzheimer's Disease Research.

"Developing these new animal models will be key to ultimately translating those research discoveries into new Alzheimer's therapies," Dr. Lamb said.

"The goal of this partnership is to create animal models that will, on a national level, accelerate the development of effective therapies for Alzheimer’s disease," said Jay L. Hess, MD, PhD, MHSA, dean of the IU School of Medicine and vice president for university clinical affairs.

The Alzheimer’s Disease Precision Models Center will build on the unique expertise of both institutions. IU’s strengths in neurodegenerative research include 25 years as home to the NIA-supported Indiana Alzheimer Disease Center, expertise in clinical drug testing and a leadership role in the national Alzheimer's Disease Neuroimaging Initiative.

JAX, which has the NIA-supported Nathan A. Shock Center of Excellence in the Basic Biology of Aging, has more than eight decades of expertise in mammalian genetics and disease modeling, as well as a special role in providing mouse and data resources to the international biomedical research community.

Recently JAX broke ground on a Center for Biometric Analysis, a world-class imaging suite that will enable high-throughput analysis and assessment of the new Alzheimer's disease mouse models developed in the new Alzheimer’s center.

JAX Associate Professor Greg Carter, PhD, will lead the center’s bioinformatics core; Howell and Michael Sasner, PhD, a JAX expert in neurodegenerative disease mouse models, will co-direct the disease modeling core; Paul Territo, PhD, of IU will direct the center’s preclinical testing core with support from Stacey Rizzo, PhD, of JAX. Sage Bionetworks will distribute Center results to the clinical and basic research communities through their Synapse web system.

The NIA will provide $5 million per year in funding for five years, split between IU and JAX. The JAX Director’s Innovation Fund provided an additional $280,000 to support preliminary studies that contributed to the application.

About Stark Neurosciences Research Institute
The mission of the Stark Neurosciences Research Institute at Indiana University School of Medicine is to advance knowledge and understanding of the brain and behavior through research and training programs that apply the latest innovations in biomedical discovery with the central goal of informing ongoing and future treatment of neurological and mental disorders through outstanding science.

About The Jackson Laboratory
The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a National Cancer Institute-designated Cancer Center, a facility in Sacramento, Calif., and a genomic medicine institute in Farmington, Conn. It employs 1,800 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.

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INDIANAPOLIS – The OPTIMISTIC study, an innovative program developed and implemented by clinician-researchers from the Indiana University Center for Aging Research and the Regenstrief Institute to prevent unnecessary hospitalizations of long stay nursing home residents has been recognized by the Journal of the American Geriatrics Society as one of 20 articles published from 2000 to 2015 that have shaped the field of geriatrics — the medical care of older adults.

The aim of OPTIMISTIC — an acronym for Optimizing Patient Transfers, Impacting Medical quality and Improving Symptoms: Transforming Institutional Care — is to improve care and communication within nursing facilities and between these facilities and acute-care institutions so problems can be caught and solved, improving quality of care and reducing unnecessary hospital transfers.

Earlier detection and prevention are key to OPTIMISTIC. If not addressed and prevented, problems such as medication errors, lack of advance care planning and delayed recognition of changes in medical status could result in health decline and hospitalization of the nursing facility resident.

The article honored by the journal, "The Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care Approach: Preliminary Data from the Implementation of a Centers for Medicare and Medicaid Services Nursing Facility Demonstration Project," was published in January 2015 and focuses on the first years of the initial phase of OPTIMISTIC.

Throughout the initial phase, nurses stationed at the 19 participating nursing facilities in central Indiana provided direct support to long-stay residents and their families as well as education and training to the facility staff. OPTIMISTIC nurses led care management reviews to optimize chronic disease management, reduce unnecessary medications and clarify goals of care.

"OPTIMISTIC is about systems change," noted first author Kathleen T. Unroe, M.D., MHA, Regenstrief Institute investigator, IU Center for Aging Research center scientist and IU School of Medicine assistant professor of medicine. Dr. Unroe is co-director of Phase 1 and director of Phase 2 of OPTIMISTIC. "The recognition of our 2015 OPTIMISTIC study by the leading geriatrics journal is a testament to the hope of leaders in the field that our model will lead to real impact on improving care for nursing home residents."

The IU Center for Aging Research and Regenstrief Institute clinician-researchers chose the acronym OPTIMISTIC to set a tone for how they feel about the potential to improve care for frail older adults. Working with their colleagues and community partners, they are providing education and training in real-world environments, developing a new model of care, and putting increased resources into nursing homes, which they hope will result in system change regionally and across the nation.

"Long-stay nursing facility residents are high-need and high-risk individuals who, before OPTIMISTIC, received insufficient attention in the research arena and have been overlooked to a great extent by health care reform," said Greg A. Sachs, M.D., project co-director of the first phase of OPTIMISTIC and director of the IU School of Medicine's Division of General Internal Medicine and Geriatrics. Dr. Sachs is also a professor of medicine, an IU Center for Aging Research center scientist, a Regenstrief Institute investigator and senior author of the commended study. "With OPTIMISTIC, we work with the residents in the nursing homes where they live to improve many aspects of their lives including chronic disease management — especially for dementia, which affects about half of long-stay residents — as well as ensure that the medical care they receive matches the goals of the residents and their families."

In addition to Dr. Unroe and Dr. Sachs, co-authors of the honored study included Laura R. Holtz, B.S. of the IU Center for Aging Research and the Regenstrief Institute; Ellen Miller, Ph.D. of University of Indianapolis; Susan E. Hickman, Ph.D., of the IU School of Nursing; and Greg Arling, Ph.D., formerly with the IU Center for Aging Research and the Regenstrief Institute and now with Purdue University School of Nursing. All continue with OPTIMISTIC.

OPTIMISTIC is expected to receive more than $30 million of Centers for Medicare and Medicaid Services funding from the start of the project in 2012 through its projected conclusion in 2020. This includes $16.9 million awarded earlier this year for the second phase of OPTIMISTIC commencing in October.

At that time, the 19 central Indiana nursing homes that participated in the project's initial phase will be joined by 25 additional nursing homes from across Indiana. Phase 2 will continue phase 1 clinical interventions in the existing facilities and, additionally, test a new CMS payment model that incentivizes nursing facilities and their medical staffs to provide higher levels of care on site rather than sending residents to the hospital. OPTIMISTIC's goal remains the improvement of the health and health care of long-term nursing home residents and ultimately reduction of potentially avoidable hospital admissions of older adults.

OPTIMISTIC is one of 7 demonstration projects nationwide funded by the CMS Innovations Center through the Initiative to Reduce Avoidable Hospitalizations among Nursing Facility Residents.

The authors of "Influence of Studies Published by the Journal of the American Geriatrics Society: Top 20 Articles from 2000–2015" wrote that selection of a study as one of the top 20 articles was based on study objective, relevance of the findings, and effect on current practice.

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INDIANAPOLIS – If you really want a drink right now, the source of your craving may be a pea-sized structure deep inside the right side of your brain, according to scientists at the Indiana University School of Medicine.

Using two different kinds of advanced brain imaging techniques (PET and fMRI), the researchers compared the results of giving beer drinkers a taste of their favorite beer versus a sports drink. After tasting the beer the participants reported increased desire to drink beer, whereas the sports drink did not provoke as much desire for beer. The brain scans also showed that the beer flavor induced more activity in both frontal lobes and in the right ventral striatum of the subjects’ brains than did the sports drink.

More specifically, both methods of brain imaging showed increased activity in the right ventral striatum, a deep structure inside the brain that is linked to motivated behavior and reward. The researchers previously showed that beer flavor triggered dopamine release; the addition of fMRI showed that craving for alcohol correlated with frontal as well as right ventral striatum activation. The study was published recently in the journal Alcoholism: Clinical and Experimental Research.

In an earlier study of 49 men , the research team, led by David A. Kareken, Ph.D., professor of neurology at the IU School of Medicine and the deputy director of the Indiana Alcohol Research Center, found that just the taste of beer, without any intoxicating effects of alcohol, was enough to cause the release of dopamine, a brain neurotransmitter. Much research has linked dopamine to consumption of drugs of abuse.

The new study was conducted with 28 beer drinkers who had participated in the first study, who then underwent functional magnetic resonance imaging – fMRI scans – during the separate beer and Gatorade tastings.

"We believe this is the first study to use multiple brain imaging modalities to reveal both increased blood oxygen levels and dopamine activity in response to the taste of an alcoholic beverage," said Brandon G. Oberlin, Ph.D., assistant research professor of neurology and first author of the paper. "The combination of these two techniques in the same subjects strengthens the evidence that these effects may be strongest in the right ventral striatum.

"Our results indicate that the right ventral striatum may be an especially important area for addiction research," Dr. Oberlin said.

In addition to Drs. Oberlin and Kareken, investigators contributing to the research were Mario Dzemidzic, Jaroslaw Harezlak, Maria A. Kudela, Stella M. Tran, Christina M. Soeurt and Karmen K. Yoder of the IU School of Medicine.

The research was supported by grants from the National Institutes of Health, R01AA017661-01A1S1, T32AA007462 and K99AA023296, as well as the Indiana Alcohol Research Center (P60AA07611), the Indiana Clinical and Translational Sciences Institute Clinical Research Center, UL1TR001108, NIH, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award.

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