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IU, Paradigm Team Up to Test Genomic Sequencing for Women with Aggressive Form of Breast Cancer

Indiana University cancer researchers are testing whether therapy incorporating advanced genomic technology will provide better outcomes than current treatments for those with an aggressive form of breast cancer.

Researchers Identify Biomarkers for Possible Blood Test to Predict Suicide Risk

Indiana University School of Medicine researchers have found a series of RNA biomarkers in blood that may help identify who is at risk for committing suicide.

In a study reported Aug. 20 in the advance online edition of the Nature Publishing Group journal Molecular Psychiatry, the researchers said the biomarkers were found at significantly higher levels in the blood of both bipolar disorder patients with thoughts of suicide as well in a group of people who had committed suicide.

Principal investigator Alexander B. Niculescu III, M.D., Ph.D., associate professor of psychiatry and medical neuroscience at the IU School of Medicine and attending psychiatrist and research and development investigator at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, said he believes the results provide a first “proof of principle” for a test that could provide an early warning of somebody being at higher risk for an impulsive suicide act.

“Suicide is a big problem in psychiatry. It’s a big problem in the civilian realm, it’s a big problem in the military realm and there are no objective markers,” said Dr. Niculescu, director of the Laboratory of Neurophenomics at the Institute of Psychiatric Research at the IU School of Medicine.

“There are people who will not reveal they are having suicidal thoughts when you ask them, who then commit it and there’s nothing you can do about it. We need better ways to identify, intervene and prevent these tragic cases,” he said.

Over a three-year period, Niculescu and his colleagues followed a large group of patients diagnosed with bipolar disorder, completing interviews and taking blood samples every three to six months. The researchers conducted a variety of analyses of the blood of a subset of participants who reported a dramatic shift from no suicidal thoughts to strong suicidal ideation. They identified differences in gene expression between the “low” and “high” states of suicidal thoughts and subjected those findings to a system of genetic and genomic analysis called Convergent Functional Genomics that identified and prioritized the best markers by cross-validation with other lines of evidence.

The researchers found that the marker SAT1 and a series of other markers provided the strongest biological “signal” associated with suicidal thoughts.

Next, to validate their findings, working with the local coroner’s office, they analyzed blood samples from suicide victims and found that some of same top markers were significantly elevated.

Finally, the researchers analyzed blood test results from two additional groups of patients and found that high blood levels of the biomarkers were correlated with future suicide-related hospitalizations, as well as hospitalizations that had occurred before the blood tests.

“This suggests that these markers reflect more than just a current state of high risk, but could be trait markers that correlate with long term risk,” said Dr. Niculescu.

Although confident in the biomarkers validity, Dr. Niculescu noted that a limitation is that the research subjects were all male.
“There could be gender differences,” he said. “We would also like to conduct more extensive, normative studies, in the population at large.”

In addition to extending the research to females to see if the same or other markers come into play, Dr. Niculescu and colleagues plan to conduct research among other groups, such as persons who have less impulsive, more deliberate and planned subtypes of suicide.

Nonetheless, Dr. Niculescu said, “These seem to be good markers for suicidal behavior in males who have bipolar mood disorders or males in the general population who commit impulsive violent suicide. In the future we want to study and assemble clinical and socio-demographic risk factors, along with our blood tests, to increase our ability to predict risk.

“Suicide is complex: in addition to psychiatric and addiction issues that make people more vulnerable, there are existential issues related to lack of satisfaction with one’s life, lack of hope for the future, not feeling needed, and cultural factors that make suicide seem like an option.”

He said he hopes such biomarkers, along with other tools, including neuropsychological tests and socio-demographic checklists currently in development by his group, ultimately can help identify people who are at risk, leading to pre-emptive intervention, counseling, and saved lives.

“Over a million people each year world-wide die from suicide and this is a preventable tragedy”.

Study: Discovery and validation of blood biomarkers for suicidality [Molecular Psychiatry]

Source: Indiana University School of Medicine

Scientists Identify Biomarker to Predict Immune Response Risk After Stem Cell Transplants

Researchers from Indiana University, the University of Michigan, the Fred Hutchinson Cancer Research Center and the Dana-Farber Cancer Institute have identified and validated a biomarker accessible in blood tests that could be used to predict which stem cell transplant patients are at highest risk for a potentially fatal immune response called graft-versus-host disease.

Although transplant specialists have been able to reduce its impact, graft-versus-host disease remains a leading cause of death among patients who receive a stem cell transplant from another person, known as an allogeneic transplant. Such transplants are used to treat blood and bone marrow cancers such as leukemia and multiple myeloma, often as a last resort. Graft-versus-host disease occurs when immune cells from the transplant see the patient’s body as foreign and attack it.

Approximately 20,000 allogeneic stem cell transplants were performed worldwide in 2012. Thirty to 40 percent of stem cell transplant recipients whose donor is related will experience graft-versus-host disease. The percentage could rise to 60 to 80 percent if the patient and donor are not related.

The researchers found that patients with a high level of a protein named ST2 were more than twice as likely to have graft-versus-host disease that resisted standard treatment with steroids; and nearly four times as likely to die within six months of the transplant. Their findings were reported in the Aug. 8 edition of the New England Journal of Medicine.

“What we found particularly significant was that this marker was a better predictor than the clinical severity of the disease when it was diagnosed,” said Sophie Paczesny, M.D., Ph.D., associate professor of medicine at the IU School of Medicine and senior author of the study.

Thus, patients with low ST2 levels were more likely to respond to treatment regardless of how serious their graft-versus-host disease was graded, while patients with high ST2 levels were less likely to respond to treatment, whether their disease was graded less serious or more serious.

“This blood test, which is currently available to clinicians, will make informed treatment possible as the clinicians will now be able to adjust therapy to the degree of risk rather than treating every patient the same way,” Dr. Paczesny said.

In addition, while the disease most commonly appears about 30 days after the transplant, higher ST2 levels in blood samples taken as early as 14 days after transplant — far before the clinical signs of graft-versus-host disease are apparent — were associated with an increased risk of death from the toxicity of the transplant.

Therefore, the authors noted, early identification of patients who likely won’t respond to standard treatments is important and would allow physicians to consider additional therapies and early intervention. On the other hand, patients with low risk will not need to have additional medicine further suppressing their immune system. But, they cautioned, additional large prospective studies are needed to better define the levels of risk predicted by the ST2 marker.

Study: ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. [New England Journal of Medicine]

Source: Indiana University School of Medicine

Big Data From Alzheimer’s Disease Whole Genome Sequencing Will Be Available to Researchers Due to Novel Global Research Database

The Alzheimer’s Association and the Brin Wojcicki Foundation announced recently that massive amounts of new data have been generated by the first “Big Data” project for Alzheimer’s disease. The data will be made freely available to researchers worldwide to quickly advance Alzheimer’s science.

Discussed recently at the Alzheimer’s Association International Conference (AAIC) 2013 in Boston, the project obtained whole genome sequences on the largest cohort of individuals related to a single disease – more than 800 people enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

The genome sequencing data – estimated to be 200 terabytes – will be housed in and available through the Global Alzheimer’s Association Interactive Network (GAAIN), a planned massive network of Alzheimer’s disease research data made available by the world’s foremost Alzheimer’s researchers from their own laboratories, and which also is being publicly announced today at AAIC 2013. GAAIN is funded by an initial $5 million dollar investment by the Alzheimer’s Association, made possible due to the generous support of donors.

“The Alzheimer’s Association is committed to creating open access to research data, and we believe GAAIN will transform how neuroscience data is shared and accessed by scientists throughout the world,” said Maria Carrillo, Ph.D., Alzheimer’s Association vice president of Medical and Scientific Relations. “By fostering a higher level of global data sharing, GAAIN will accelerate investigation and discovery in Alzheimer’s through a system comparable to a search engine like Google or Bing for relevant data.”

“With the addition of more than 800 whole genomes on ADNI subjects that can be linked to the current rich dataset, ADNI data will be even more useful to scientists who are seeking new approaches to treatment and prevention of Alzheimer’s disease,” said Robert C. Green, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, who led the ADNI sequencing project. “ADNI is a leader in open data sharing, having provided clinical, imaging and biomarker data to over 4,000 qualified scientists around the world, which has generated over 700 scientific manuscripts.

First, Massive Whole Genome Sequencing Project in Alzheimer’s Disease

Whole genome sequencing determines all six billion letters in an individual’s DNA in one comprehensive analysis. The raw data from the ADNI project is being made available to qualified scientists around the globe to mine for novel targets for risk assessment, new therapies, and much-needed insight into the causes of the fatal brain disease. The new data may enable scientists to better understand how our genes cause and are affected by bodily changes associated with Alzheimer’s disease.

ADNI enrolls people with Alzheimer’s disease, mild cognitive impairment, and normal cognition who have agreed to be studied in great detail over time. The goal is to identify and understand markers of the disease in body fluids, structural changes in the brain, and measures of memory; the hope is to improve early diagnosis and accelerate the discovery of new treatments. ADNI is led by Principal Investigator Michael W. Weiner, M.D., of the University of California San Francisco and the San Francisco VA Medical Center. Dr. Green collaborated on managing the sequencing efforts with Arthur Toga, Ph.D., of UCLA and Andrew J. Saykin, Psy.D., of Indiana University. The actual genome sequencing was performed at Illumina, Inc.

ADNI is a public-private research project led by the National Institutes of Health (NIH) with private sector support through the Foundation for NIH. Launched in 2004, ADNI’s public-private funding consortium includes pharmaceutical companies, science-related businesses, and nonprofit organizations including the Alzheimer’s Association and the Northern California Institute for Research and Education.

The Global Alzheimer’s Association Interactive Network (GAAIN)

Data-sharing has already greatly benefitted scientific disciplines such as genetics, molecular biology, and the physical sciences. Data-sharing in genetics has led to dramatic advances in understanding the risk factors underlying complex diseases. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a compelling example of dozens of geographically-dispersed researchers working together to share their data while making it freely available to others for analysis and publication.

“GAAIN is similar in spirit and goals to other ‘big data’ initiatives that seek to greatly improve the tools and techniques needed to access, organize, and make discoveries from huge volumes of digital data,” Carrillo said. “The advent of cloud computing makes it possible to link databases throughout the world and expand their data processing capability significantly to benefit the research community.”

Carrillo will supervise the development of GAAIN in conjunction with co-principal investigators Art Toga, Ph.D., of the Laboratory of Neuro Imaging (LONI) at the University of Southern California and Giovanni Frisoni, M.D., of the National Center for Alzheimer’s Disease Research and Care and the Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fatebenefratelli Hospital, Italy. Enrique Castro-Leon, Ph.D., who will serve as a consultant, is an enterprise and data center architect for strategic partner Intel Digital Enterprise Group.

GAAIN is built on an international database framework already in use by thousands of scientists and local computational facilities in North America and Europe. The network makes research data available free-of-charge for searching, downloading, and processing across a cloud-based, grid-network infrastructure accessible anywhere through Internet access.

The key to GAAIN’s innovation is its federation of data, which is unprecedented for such a system. GAAIN leadership will invite scientists conducting qualified studies to become partners by permitting GAAIN to link directly to their databases. This will enable researchers to add continually to their data sets and keep all data in GAAIN current and dynamic. It also will enable the scientists to retain control over access to their data, which the Association believes will be important to encouraging participation.

“This is unprecedented and of the utmost importance in brain research, where sometimes thousands of examples are required to observe even the smallest change in the brain,” said Giovanni Frisoni, M.D., neurologist and deputy scientific director at the National Center for Alzheimer’s Disease Research and Care at the IRCCS. He will lead the work of GAAIN in Europe.

“Through GAAIN we envision combining massive amounts of data from multiple sources across many subjects participating in numerous studies,” said Art Toga, Ph.D., professor of neurology at UCLA and director of LONI. “This will provide more statistical power than ever before.”

Source: Alzheimer’s Association

EntreMed Announces Initiation Of Second Site For Phase 2 Trial In Triple-Negative Breast Cancer

EntreMed, Inc. (ENMD), a clinical-stage pharmaceutical company, recently announced the initiation of a second site for its Phase 2 study of ENMD-2076 in triple-negative breast cancer (TNBC). Kathy Miller, MD, Associate Professor at the Melvin and Bren Simon Cancer Center at Indiana University serves as the investigator for the study. Indiana University joins the University of Colorado Cancer Center where the Phase 2 study is already underway. This study is sponsored by EntreMed and is supported by a grant from the National Cancer Institute. More information about the clinical trial can be found at www.ClinicalTrials.gov.