Older Adults with Arthritis Need Just 45 Minutes of Activity Per Week

To remain functional, this population can do far less activity per week than recommended, study found

Newswise, February 15, 2017 - Older adults who suffer from arthritis need to keep moving to be functionally independent. But in an examination of a goal that is daunting for most of this aging population, a new Northwestern Medicine study found that performing even a third of the recommended activity is beneficial.

Federal guidelines suggest achieving 150 minutes of moderate activity per week to prevent premature death and serious illness, however only one in 10 older American adults with arthritis in their knees meet these guidelines. 

Northwestern Medicine researchers wanted to determine a less overwhelming activity goal to get this population up and moving, and 45 minutes per week was that magic number.

Approximately one third of participants improved or had high function after two years. But those participants who achieved this minimum of 45 minutes of moderate activity, such as brisk walking, per week were 80 percent more likely to improve or sustain high future function over two years compared with those doing less. This finding was true for both men and women. 

“Even a little activity is better than none,” said first author Dorothy Dunlop, professor of rheumatology and preventive medicine at Northwestern University Feinberg School of Medicine. 

“For those older people suffering from arthritis who are minimally active, a 45-minute minimum might feel more realistic.”

A rare examination of the type and intensity of physical activity older adults need to remain functional, the study was published online Dec. 28 in the journal Arthritis Care & Research.

10%Only one in 10 older adults with arthritis in their knees meet the federal guidelines of 150 minutes of moderate activity per week

“The federal guidelines are very important because the more you do, the better you’ll feel and the greater the health benefits you’ll receive,” Dunlop said. 

“But even achieving this less rigorous goal will promote the ability to function and may be a feasible starting point for older adults dealing with discomfort in their joints.”

Federal guidelines suggest achieving the 150 minutes of moderate activity done in sessions lasting at least 10 minutes to promote good cardiovascular health. But Dunlop and her team focused on simply keeping this population functioning over two years.

“We’re looking for an older population who can be functionally independent,” Dunlop said. 

“And we were interested in seeing what kind of physical activity might be beneficial to promote good function down the road. We found moderate-intensity activity rather than light activity, such as pushing a grocery cart, to be more valuable to promote future function.”

Even a little activity is better than none.”

Looking at the intensity of activity that older adults need to achieve to remain functional has not been systematically examined, Dunlop said.

Using sophisticated movement-monitoring accelerometers, the researchers measured the physical activity of 1,600 adults from the nationwide research study, Osteoarthritis Initiative, who had pain, aching or stiffness in their hips, knees or feet.

 “We found the most effective type of activity to maintain or improve your function two years later was moderate activity, and it did not need to be done in sessions lasting 10 minutes or more, as recommended by federal guidelines,” Dunlop said.

The research was supported in part by the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases under award numbers R01AR054155, P60AR064464, R21AR068500, and T32AR007611.

Investigational New Drug for Alzheimer’s Scheduled for First Study in Humans--Vanderbilt Scientists Take Investigational Drug Product From Bench To Clinical Trials in Humans

Newswise, February 13, 2017 — Vanderbilt University scientists have received notification from the U.S. Food and Drug Administration (FDA) that testing in humans may proceed for an investigational new drug after more than 10 years of research by scientists at Vanderbilt University and Vanderbilt University Medical Center.

It is relatively uncharted territory for an academic drug discovery group to take a molecule from the laboratory setting to the clinical trials stage.

“The movement to the clinical phase of the research is the result of tireless colleagues reaching across disciplines in pursuit of the shared goal of hoping to someday improve the lives of individuals with Alzheimer’s disease and possibly other brain disorders, such as schizophrenia,” Provost and Vice Chancellor for Academic Affairs Susan R. Wente, Ph.D. said.

“This work exactly illustrates the critical role that basic science conducted in partnership with a world-class medical center can play in advancing knowledge in an attempt to fight a devastating disease.”

For Alzheimer’s disease, the aim is for the investigational drug to target major pathologies of the disease and selectively activate a key receptor in the brain. The Vanderbilt researchers believe that the current standard of care for Alzheimer’s disease, cholinesterase inhibitors, has a different mechanism of action.

They are hoping to establish through future clinical testing that the molecule is broadly effective across a number of cognitive and neuropsychiatric disorders, including schizophrenia.

“This is the first instance I am aware of where an academic drug discovery group moved a molecule designed to hopefully treat a chronic brain disorder all the way from early discovery to human trials without there being, at some point along the way, a pharmaceutical partner,” said P. Jeffrey Conn, Ph.D., Lee E. Limbird Professor of Pharmacology in the Vanderbilt University School of Medicine and director of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). 

“And that really is crossing what people refer to all of the time as the ‘Valley of Death,’ where good research discoveries have a hard time moving into the clinical testing phase due to lack of funding,” he said.

“Importantly, at this early stage, the FDA has only granted permission to assess potential safety of this investigational new drug in healthy volunteers” said Conn.

“We cannot predict the outcome, but if these studies are successful in demonstrating that the investigational drug can be safely administered to humans, this would pave the way to allow filing of additional applications with the FDA to seek permission to advance to testing for efficacy in improving cognitive function in patients suffering from Alzheimer’s disease, and possibly schizophrenia or other brain disorders.

“While we cannot predict the outcome of any future safety or efficacy studies, this decision by FDA allowing clinical research to begin represents a major milestone in allowing us to hopefully provide answers to those critical questions in the future,” Conn said.

VCNDD Co-Director Craig W. Lindsley, Ph.D., director of Medicinal Chemistry and William K. Warren, Jr. Professor of Medicine, said phase I testing will assess drug safety and tolerability in healthy volunteer participants, a process that could take a year.

If successful, the phase II and III studies would include efficacy assessments in patients with Alzheimer’s disease and could take 3-5 years to complete.

“We are hoping to address what we see as an unmet medical need,” Lindsley said.

“For Alzheimer’s patients, the standard of care for symptomatic treatment remains cholinesterase inhibitors, which are 25 years old at this point. There hasn’t been any real scientific advancement in this field in a long time.”

Lindsley and Conn credit The William K. Warren Foundation for its philanthropic investments along the way to make clinical trials for this investigational drug a reality.

“One of the most challenging things about doing this in an academic environment is funding,” Lindsley said.

“Every step requires funding and if there is a delay or break in funding, then everything sits idle and potentially innovative approaches for patient care do not advance.”

“Being matched with the Warrens happened serendipitously. They have invested so much in our programs, and it is wonderful to show them progress on their investments,” he said.

“Without the financial support from the Warrens, this investigational drug would not be poised to enter human clinical trials.”

The William K. Warren Foundation Chief Executive Officer John-Kelly Warren said he is gratified that FDA has allowed for the investigational drug to proceed to testing in human beings.

“Although this is an important sequential milestone, the only milestone that matters to us is the hope that one day we will learn that this investigational new drug has positively and safely changed the life of a patient suffering from a brain disorder such as schizophrenia or Alzheimer’s disease,” Warren said. 

“That day will warrant a celebration felt in the heavens. Until then, we are prepared to support the VCNDD research team until they can deliver the necessary results,” he said.

A NIH National Cooperative Drug Discovery/Development grant funded the early basic science and discovery of this investigational drug and the Alzheimer’s Drug Discovery Foundation and Harrington Discovery Institute helped support some of the key toxicity studies that FDA required, Conn said.

“The investigational new drug has the potential to improve cognitive functions with fewer unwanted side effects.

“This could someday be an important advance for the treatment of cognitive deficits in psychiatric disorders and Alzheimer’s disease,” said Joshua Gordon, M.D., Ph.D., director of the National Institute of Mental Health, which co-funded the research. 

Conn and Lindsley said Vanderbilt’s “team science” approach included contributions from the director of Translational Pharmacology and Development for the VCNDD and Assistant Professor Carrie K. Jones, Ph.D., who coordinated the IND drafting, submission, and subsequent development into Phase I, director of Molecular Pharmacology for the VCNDD and Research Associate Professor of Pharmacology Colleen Niswender, Ph.D., for the molecular pharmacology; Research Assistant Professor of Pharmacology Jerri Rook, Ph.D., for the behavioral studies; and Research Assistant Professor of Pharmacology Thomas Bridges, Ph.D., and Research Assistant Professor of Pharmacology Anna Blobaum, Ph.D., for drug metabolism and pharmacokinetic profiling.

Paul Newhouse, M.D., director of the Center for Cognitive Medicine at VUMC and Jim Turner Professor in Cognitive Disorders, is expected to lead the upcoming clinical study funded in part by the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation.

Promising New Drug Stops Spread of Melanoma by 90 Percent

Newswise, February 13, 2017. – Michigan State University researchers have discovered that a chemical compound, and potential new drug, reduces the spread of melanoma cells by up to 90 percent.

The man-made, small-molecule drug compound goes after a gene’s ability to produce RNA molecules and certain proteins in melanoma tumors. This gene activity, or transcription process, causes the disease to spread but the compound can shut it down.

Up until now, few other compounds of this kind have been able to accomplish this.

“It’s been a challenge developing small-molecule drugs that can block this gene activity that works as a signaling mechanism known to be important in melanoma progression,” said Richard Neubig, a pharmacology professor and co-author of the study. “Our chemical compound is actually the same one that we’ve been working on to potentially treat the disease scleroderma, which now we’ve found works effectively on this type of cancer.”

Scleroderma is a rare and often fatal autoimmune disease that causes the hardening of skin tissue, as well as organs such as the lungs, heart and kidneys. The same mechanisms that produce fibrosis, or skin thickening, in scleroderma also contribute to the spread of cancer.

Small-molecule drugs make up over 90 percent of the drugs on the market today and Neubig’s co-author Kate Appleton, a postdoctoral student, said the findings are an early discovery that could be highly effective in battling the deadly skin cancer.

It’s estimated about 10,000 people die each year from the disease.

Their findings are published in the January issue of Molecular Cancer Therapeutics.

“Melanoma is the most dangerous form of skin cancer with around 76,000 new cases a year in the United States,” Appleton said.

“One reason the disease is so fatal is that it can spread throughout the body very quickly and attack distant organs such as the brain and lungs.”

Through their research, Neubig and Appleton, along with their collaborators, found that the compounds were able to stop proteins, known as Myocardin-related transcription factors, or MRTFs, from initiating the gene transcription process in melanoma cells.

These triggering proteins are initially turned on by another protein called RhoC, or Ras homology C, which is found in a signaling pathway that can cause the disease to aggressively spread in the body.

The compound reduced the migration of melanoma cells by 85 to 90 percent. The team also discovered that the potential drug greatly reduced tumors specifically in the lungs of mice that had been injected with human melanoma cells.

“We used intact melanoma cells to screen for our chemical inhibitors,” Neubig said. “This allowed us to find compounds that could block anywhere along this RhoC pathway.”

Being able to block along this entire path allowed the researchers to find the MRTF signaling protein as a new target.

Appleton said figuring out which patients have this pathway turned on is an important next step in the development of their compound because it would help them determine which patients would benefit the most.

“The effect of our compounds on turning off this melanoma cell growth and progression is much stronger when the pathway is activated,” she said.

“We could look for the activation of the MRTF proteins as a biomarker to determine risk, especially for those in early-stage melanoma.”

According to Neubig, if the disease is caught early, chance of death is only 2 percent. If caught late, that figure rises to 84 percent.

“The majority of people die from melanoma because of the disease spreading,” he said. “Our compounds can block cancer migration and potentially increase patient survival.”

The National Institutes of Health and MSU's annual Gran Fondo cycling event, which raises money for skin cancer research, funded the study. Additional researchers from MSU and the University of Michigan contributed to the project.

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Michigan State University has been working to advance the common good in uncommon ways for more than 150 years. One of the top research universities in the world, MSU focuses its vast resources on creating solutions to some of the world’s most pressing challenges, while providing life-changing opportunities to a diverse and inclusive academic community through more than 200 programs of study in 17 degree-granting colleges.

Vitamin D Deficiency Increases Risk of Chronic Headache

Newswise, February 10, 2017 — Vitamin D deficiency may increase the risk of chronic headache, according to a new study from the University of Eastern Finland. The findings were published in Scientific Reports.

The Kuopio Ischaemic Heart Disease Risk Factor Study, KIHD, analysed the serum vitamin D levels and occurrence of headache in approximately 2,600 men aged between 42 and 60 years in 1984-1989.

In 68% of these men, the serum vitamin D level was below 50 nmol/l, which is generally considered the threshold for vitamin D deficiency. Chronic headache occurring at least on a weekly basis was reported by 250 men, and men reporting chronic headache had lower serum vitamin D levels than others.

When the study population was divided into four groups based on their serum vitamin D levels, the group with the lowest levels had over a twofold risk of chronic headache in comparison to the group with the highest levels.

Chronic headache was also more frequently reported by men who were examined outside the summer months of June through September. Thanks to UVB radiation from the sun, the average serum vitamin D levels are higher during the summer months.

The study adds to the accumulating body of evidence linking a low intake of vitamin D to an increased risk of chronic diseases. Low vitamin D levels have been associated with the risk of headache also by some earlier, mainly considerably smaller studies.

In Finland and in other countries far from the Equator, UVB radiation from the sun is a sufficient source of vitamin D during the summer months, but outside the summer season, people need to make sure that they get sufficient vitamin D from food or from vitamin D supplements.

No scientific evidence relating to the benefits and possible adverse effects of long-term use in higher doses yet exists. The Finnish Vitamin D Trial, FIND, currently ongoing at the University of Eastern Finland will shed light on the question, as the five-year trial analyses the effects of high daily doses of vitamin D on the risk factors and development of diseases.

The trial participants are taking a vitamin D supplement of 40 or 80 micrograms per day. The trial also investigates the effects of vitamin D supplementation on various pain conditions.

Heart Surgery Is Excellent Option for Elderly Patients with Aortic Stenosis

Study surprises researchers in that surgical aortic valve replacement outcomes equal those of minimally invasive procedure

Newswise, February 3, 2017— Elderly patients with aortic stenosis (AS) and medium surgical risk experienced better than expected results after undergoing traditional surgical aortic valve replacement (SAVR), according to research presented at the 53rd Annual Meeting of The Society of Thoracic Surgeons.

“In an era that includes both SAVR and transcatheter aortic valve replacement (TAVR), it is clear that the treatment for aortic stenosis has changed,” said Vinod H. Thourani, MD, from Emory University in Atlanta, who led the study.

“But even with the availability of the relatively new TAVR procedure, SAVR remains a safe and effective way to treat aortic stenosis in intermediate-risk, elderly patients.”

Dr. Thourani and colleagues from 15 other institutions performed an in-depth analysis of SAVR outcomes in patients who participated in the Placement of Aortic Transcatheter Valves (PARTNER-IIA) trial.

In the PARTNER-IIA trial, conducted from December 2011 to November 2013, 1,011 severe aortic stenosis, intermediate-risk patients were randomized in 57 North American centers to SAVR. Of these, 937 patients had surgical valve implantation and ultimately composed the study group for this research. The mean age was 82 years old, and 55% were male.

In their analyses, researchers found that the operative mortality was 4.1%, somewhat lower than the STS predicted risk models—a tool for surgeons to predict the patient risk of death or illness following open aortic valve replacement.

“The outcomes in intermediate-risk patients who received SAVR were excellent, showing that mortality is non-inferior to TAVR,” said Dr. Thourani. “This was better than expected.”

According to Dr. Thourani, approximately 15% of all patients undergoing SAVR in the US are intermediate risk. SAVR is the replacement of the aortic valve, the main valve separating the heart from the rest of the body, through an incision in the chest.

During this procedure, the patient is placed on the heart-lung machine while the aorta (main blood vessel of the body) is opened and the defective valve is replaced with an artificial valve.

TAVR was approved in the United States in late 2011, providing an alternative therapy for high-risk patients with AS who previously were refused SAVR. Prior to TAVR, SAVR was the only effective long-term therapeutic option for patients.

Two Other Surprising Findings
In addition to a lower than expected mortality rate from SAVR, researchers were surprised to learn that prosthesis-patient mismatch was common, with 33% of patients receiving a surgical valve that was too small.

However, according to Dr. Thourani, this did not affect the mortality. The study also showed a greater risk of in-hospital stroke among SAVR.

“In the past, there were no formal neurological assessments, meaning that previous rates possibly were understated,” explained Dr. Thourani. “The PARTNER-IIA study was one of the first times that neurological evaluations following the SAVR procedure were conducted, so further research in this area is required.”

AS is the most common acquired valve disease in elderly patients and affects nearly 3% of those over the age of 75, according to the American Heart Association.

The ability to safely treat AS has become increasingly important; the US Census Bureau reports that the elderly population in the United States is projected to almost double, from the most current estimate of 43 million in 2012 to 80 million by the year 2050.

“Patients with aortic stenosis must realize how important it is that they are evaluated by a dedicated heart valve team that can help them understand the variety of options available and shepherd them into the most informed decision,” said Dr. Thourani.

Future research includes a randomized PARTNER-III study that will evaluate TAVR and SAVR in low-risk patients.

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The other authors of the study were Wilson Szeto, MD, Susheel Kodali, MD, Eugene Blackstone, MD, Ashley Lowry, MD, Raj Makkar, MD, Mathew Williams, MD, Joseph Bavaria, MD, Howard Herrmann, MD, Hersh Maniar, MD, Vasilis Babaliaros, MD, Craig Smith, MD, Alfredo Trento, MD, Paul Corso, MD, Augusto Pichard, MD, D. Craig Miller, MD, Lars Svensson, MD, Samir Kapadia, MD, Gorav Ailawadi, MD, Rakesh Suri, MD, Kevin Greason, MD, Rebecca Hahn, MD, Wael Jaber, MD, Jessica Forcillo, MD, Maria Alu, MD, Martin Leon, MD, and Michael Mack, MD.

Half of Breast Cancer Patients Experience Severe Side Effects

Study finds side effects cause extra burden for patients, health care system

Newswise, February 3, 2017— Nearly half of women treated for early stage breast cancer reported at least one side effect from their treatment that was severe or very severe, a new study finds.

While it might be expected for women undergoing chemotherapy, researchers found one-third of women who didn’t receive chemotherapy experienced severe side effects of treatment.

Side effects led to additional doctor’s appointments, trips to the emergency room, delays in treatment and reduced dosages.

“It's in patients’ best interest to receive their treatments on time and on schedule, whenever possible, to give them the best possible outcome. Unscheduled care for toxicities – including clinic visits, emergency department visits and hospital stays – are expensive, inconvenient and disruptive to both doctors and patients. We need to avoid them whenever possible,” says study author Steven J. Katz, M.D., MPH, professor of medicine and of health management and policy at the University of Michigan.

Researchers surveyed a diverse group of 1,945 women diagnosed with early stage breast cancer. Women were surveyed an average of seven months after diagnosis.

They were asked to rate the severity of seven common side effects of breast cancer treatment: nausea/vomiting, diarrhea, constipation, pain, arm swelling, shortness of breath and breast skin irritation.

The survey also asked patients what kind of help they sought for their side effects – from discussing it at a routine visit to scheduling additional appointments or seeking emergency care. The study is published in Cancer.

Overall, 93 percent of women said they experienced at least one of the seven side effects, with 45 percent rating it severe or very severe. Pain, skin irritation and constipation were most frequently severe or very severe.

Most patients sought help for side effects during routine doctor’s appointments, but 9 percent scheduled an additional appointment and 5 percent went to an emergency department or hospital.

Women who had both chemotherapy and radiation treatment were 30 percent more likely to report a severe side effect, compared to women who had only one of those treatments.

Women who had double mastectomy were twice as likely as those who had lumpectomy to report severe or very severe pain. Severe side effects were also more common to Latina women, who were 30 percent more likely than white women to report a severe or very severe side effect.

For the most part, side effects of cancer treatment are reported via clinical trials or cancer registries. Few studies have solicited input directly from a diverse group of patients.

“As an oncologist, I knew from my clinical practice that more women were suffering than is generally reported in clinical trials,” says Allison Kurian, M.D., M.Sc., associate professor of medicine and of health research and policy at Stanford University.

“Often, women suffer in silence, afraid to tell their providers about how bad things really are for fear that their treatments may be halted. We need to change that.”

She says it’s important for oncologists to share information about potential side effects with patients. By making patients aware, they can prepare what to do if nausea, constipation, pain or other side effects occur.

In addition, better data on the severity of side effects should be collected and then shared with patients to help with their treatment decision-making.

The researchers are developing tools to help women understand how side effects vary by treatment. Additional studies are examining how side effects vary across diverse chemotherapy practices, as well as the optimal way to manage side effects.

Additional authors: Christopher R. Friese, Ph.D.; Jordan M. Harrison, BSN; Nancy K. Janz, Ph.D.; Reshma Jagsi, M.D., D.Phil.; Monica Morrow, M.D.; Yun Li, Ph.D.; Ann S. Hamilton, Ph.D.; Kevin C. Ward, Ph.D.; Timothy P. Hofer, M.D.

Deep Brain Stimulation Studies in Alzheimer’s Disease Pose Ethical Challenges

Penn researchers propose guidelines to better protect patients in DBS clinical trials

Newswise, February 3, 2017--A—Promising, early studies of deep brain stimulation (DBS) for the treatment of Alzheimer’s disease have paved a path for future clinical trials, but there are unique ethical challenges with this vulnerable population regarding decision making and post-study treatment access that need to be addressed as they ramp up, Penn Medicine researchers argue in a new review in the Journal of Alzheimer’s Disease.

Does the patient still have the capacity to make an informed decision half way through the trial? Are there any misconceptions about its therapeutic benefit? Will the device remain after the trial ends, and who will pay for it?

These are the questions posed in an ethics review piece that also lays out guidelines for investigators to consider when enrolling Alzheimer’s patients in DBS trials.

The article is authored Andrew M. Siegel, MD, an assistant professor of Clinical Psychiatry in the Perelman School of Medicine at the University of Pennsylvania, Marna S. Barrett, PhD, an adjunct associate professor of Psychology in Psychiatry at Penn, and Mahendra T. Bhati, MD, a former assistant professor of Clinical Psychiatry at Penn, who is now at Stanford University, in an ethics review piece that also lays out guidelines for investigators to consider when enrolling Alzheimer’s patients in DBS trials.

Approved for the treatment of movement and neuropsychiatric disorders, such as Parkinson’s disease, DBS is an invasive, surgical procedure involving the implantation of a microstimulator that sends electrical impulses to specific targets in the brain.

Driven by the urgent need for effective therapies and the success of recent studies, DBS has now emerged as a possible treatment for Alzheimer’s.

“As the number of people affected by Alzheimer’s continues to grow, along with its substantial costs to individuals, their families, and society, novel therapies are urgently needed. DBS is one such treatment modality that has shown promising early results,” Siegel said.

“However, this enthusiasm should be tempered by prudent ethical considerations to help better protect the patients.”

The authors call out three ethical issues that should be addressed and recommendations.

Ensuring the trial subjects possess adequate decision-making capacity is important, the authors said, because such individuals have cognitive deficits that may reasonably limit that capacity and thereby compromise informed consent.

DBS for trials must have a robust mechanism for both detecting loss of decision-making capacity and protecting the interest of the patients during the trial, they wrote.

Suggestions include an Institutional Review Board (IRB)-mandated use of a validated decision-making capacity assessment, such as the MacCAT-CR interview, and an “auxiliary consenter,” someone not affiliated with the study to determine the patient’s knowledge about the procedures, risks, and the device.

Therapeutic misconception is another concern. Patients with Alzheimer’s, desperate for relief and without an effective alternative, may agree to DBS as a last resort.

Such desperation may alter their perception that the primary goal of the study is for health benefits and not knowledge about the efficacy of the device. Left unchecked, it could distort patients’ understanding of the risks and benefits of DBS.

“It may be necessary to directly inform patients during study consent that ‘scientific goals will have priority over therapeutic goals’,” the authors wrote. A “cooling off” period, where patients have adequate time to process all the information that has been given to them, may also prove effective.

Another question to be asked at the end of the trial is whether patients who have benefited from the device should continue to receive treatment.

This question is particularly salient considering the high cost of DBS and the fact that the device may be with the patient for many years after the trial ends.

The authors believe denying a patient access to the only intervention known to alleviate their suffering is tantamount to violating the sacrosanct principle of “do no harm.”

“Providing post-trial access to the subset of patients shown to benefit in a failed trial is not only ethically appropriate,” Siegel said, “but it would allow for the collection of longitudinal safety and efficacy data not captured in the original study.”

Once post-trial access is accepted by a research team, the challenge is financial responsibility. Patients, together with sponsors, investigators, health care systems, insurance, governments, and non-profit organizations must partner to share responsibility and negotiate continued access arrangements prior to study enrollment, the authors said.

This model has worked in the past – the HIV Netherlands, Australia, Thailand Research Collaboration is one example.

“We hope this review facilitates the development of study designs and IRB oversight procedures that best protect research subjects,” Siegel said.

“A reasonable next step is for research centers and hospitals to examine their current practice and policies guiding DBS in Alzheimer’s research. Our review could act as a guide in helping them ask the relevant questions about their current state of oversight and to consider changes as appropriate.”

Structure of Kidney Failure Patients’ Blood Clots May Increase Their Risk of Early Death

Highlights

• Hemodialysis patients tend to have denser blood clots than individuals without kidney disease.
• Dense blood clots were linked to an increased risk of premature death from cardiovascular and other causes.

Newswise,  February 3, 2017--Dialysis patients may have altered blood clots that increase their risk of dying prematurely, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN).

Kidney failure patients on dialysis have an elevated risk of dying early, especially from cardiovascular causes. Their blood also has altered coagulation properties, which increases their risk of both bleeding and thrombotic events such as stroke.

Because of these risks, a team led by Katharina Schütt, MD and Georg Schlieper, MD (RWTH University Aachen, in Germany) investigated the impact of clot structure on health outcomes in hemodialysis patients.

When the researchers analyzed the blood of 171 chronic hemodialysis patients, they found that the patients tended to have a denser clot structure than individuals without kidney disease.

In addition, patients with such compact clots had an increased risk of dying from cardiovascular causes as well as an increased risk of dying from other causes.

Finally, dialysis patients’ fibrinogen—a protein that is converted into fibrin during blood clot formation—exhibited certain modifications that were different from fibrinogen from patients without kidney disease.

“Whether better dialysis treatment or medication could improve clot structure needs to be investigated in future studies,” said Dr. Schütt.

Study co-authors include Anna Savvaidis, MD, Sebastian Maxeiner, Katharina Lysaja, Vera Jankowski, PhD, Stephan Schirmer, MD, Nada Dimkovic, MD, Peter Boor, MD, Nadine Kaesler, PhD, Friedo Dekker, MD, Jürgen Floege, MD, and Nikolaus Marx, MD.

Disclosures: The authors reported no financial disclosures.

The article, entitled “Clot structure – a potent mortality risk factor in hemodialysis patients,” will appear online at http://jasn.asnjournals.org/ on January 5, 2017, doi: 10.1681/ASN.2016030336. 

Study Unveils New Way to Starve Tumors to Death

Unlike a healthy cell, a sarcoma cell (above) relies on environmental sources of arginine, an important protein building block. Remove environmental arginine and the cell must begin a process called autophagy, or "self-eating," to survive. A second hit to its survival pathways then kills the cell, according to a new study at Washington University School of Medicine in St. Louis. Areas of autophagy are shown in green and the cell nucleus in blue.

Newswise, February 3, 2017 — For decades, scientists have tried to halt cancer by blocking nutrients from reaching tumor cells, in essence starving tumor cells of the fuel needed to grow and proliferate. Such attempts often have disappointed because cancer cells are nimble, relying on numerous backup routes to continue growing.

Now, scientists at Washington University School of Medicine in St. Louis have exploited a common weak point in cancer cell metabolism, forcing tumor cells to reveal the backup fuel supply routes they rely on when this weak point is compromised. Mapping these secondary routes, the researchers also identified drugs that block them. They now are planning a small clinical trial in cancer patients to evaluate this treatment strategy.

The research is published Jan. 24 in Cell Reports.

Studying human cancer cells and mice implanted with patients’ tumor samples, the researchers demonstrate that a double hit — knocking out the weak point and one of the tumor cells’ backup routes — shows promise against many hard-to-treat cancers.

Though present in multiple cancer types, the weak point is particularly common in sarcomas — rare cancers of fat, muscle, bone, cartilage and connective tissues. Doctors treat sarcomas primarily with traditional surgery, radiation and chemotherapy, but such treatments often are not effective.

“We have determined that this metabolic defect is present in 90 percent of sarcomas,” said senior author Brian A. Van Tine, MD, PhD, an associate professor of medicine.

“Healthy cells don’t have this weakness. We have been trying to create a therapy that takes advantage of the metabolic defect because, in theory, it should target only the tumor. Basically, the defect allows us to force the tumor cells to starve.”

To grow and proliferate, tumor cells must have basic building materials. The researchers’ strategy relies on the fact that the vast majority of sarcomas have lost the ability to manufacture their own arginine, a protein building block that cells need to make more of themselves.

Lacking this ability, the cells must harvest arginine from the surrounding environment. The supply of arginine in the blood is abundant, and cancer cells have no trouble scavenging it. But remove this environmental supply of arginine and the cells have a problem.

“When we use a drug to deplete arginine in the blood, the cancer cells panic because they’ve lost their fuel supply,” Van Tine said. “So they rewire themselves to try to survive. In this study, we used that rewiring to identify drugs that block the secondary routes.”

Unlike most cancer therapies, depleting arginine in the blood does not affect healthy cells. Normal cells don’t rely on external sources of arginine because they don’t have the cancer’s metabolic defect.

They continue to make their own arginine, so there is no induced starvation in normal cells even when there is no arginine in the blood. Van Tine said this strategy is based on the properties of a tumor — it shuts down tumor metabolism specifically and nothing else.

Unable to make or obtain external arginine, the tumor cells’ fuel supply routes are forced inward. The cells must begin to metabolize their internal supply of arginine in a process called autophagy, or “self-eating.”

In the case of sarcomas, this state slows or pauses cancer growth but does not kill the cell. During this period, tumor cells appear to be buying time to find yet another internal work-around.

“Cancer doesn’t die when you halt its primary fuel supply,” Van Tine said.

 “Instead, it turns on all these salvage pathways. In this paper, we identified the salvage pathways. Then we showed that when you drug them, too, you kill cells. Our study showed that tumors actually shrink under these conditions. This is the first time tumors have been shown to shrink using just metabolism drugs and no other anti-cancer strategies.”

The arginine-depleting drug is currently in clinical trials investigating its safety and effectiveness against liver, lung, pancreatic, breast and other cancers. But so far, it has been ineffective likely because it has activated the salvage pathways allowing cancer growth to continue. The researchers said the drug may yet become a vital metabolic therapy for cancer as long as it is used in combination with other drugs targeting the backup pathways.

Van Tine and the study’s first author, Jeff C. Kremer, a PhD student in Van Tine’s lab, explained that when cancer cells with this metabolic defect are deprived of environmental arginine, they are forced to shift from a system that burns glucose to a system that burns a different fuel called glutamine.

They showed that adding a glutamine inhibitor to the arginine-depleting drug is lethal to the cells. Eliminating arginine from the blood also rewires serine biology, another backup fuel, so adding serine inhibitors also causes cell death.

This strategy could be applied beyond rare sarcoma tumors because the metabolic defect is often present in other cancers, including certain types of breast, colon, lung, brain and bone tumors, the researchers said.

The new study includes data showing similar anti-tumor responses in cell lines from these cancer types. Van Tine also pointed out that all of the drugs used in the study are either already approved by the U.S. Food and Drug Administration for other conditions or in ongoing clinical trials investigating cancer drugs.

Based on this study and related research, Van Tine and his colleagues at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine are planning a clinical trial of the arginine-depleting drug in patients with sarcomas.

“We will start with a baseline trial testing the arginine-depleting drug against sarcomas with this defect, and then we can begin layering additional drugs on top of that therapy,” Van Tine said.

“Unlike breast cancer, for example, sarcomas currently have no targeted therapies. If this strategy is effective, it could transform the treatment of 90 percent of sarcoma tumors.”

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This work was supported by grants from CJ’s Journey; The Sarcoma Foundation of America; a Sarcoma Alliance for Research and Collaboration Career Development Award; and Polaris Pharmaceuticals. Polaris Pharmaceuticals provided funding and the arginine-depleting drug, ADI-PEG20 (pegylated arginine deiminase).

Kremer JC, Prudner BC, Lange SES, Bean GR, Schultze MB, Brashears CB, Radyk MD, Redlich N, Tzeng S, Kami K, Shelton L, Li A, Morgan Z, Bomalaski JS, Tsukamoto T, McConathy J, Michel LS, Held JM, Van Tine BA. Arginine deprivation inhibits the Warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS1-deficient cancers. Cell Reports. Jan. 24, 2017.

Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.