Biomarker Autotaxin, related to diabetes predicts Alzheimer’s disease outcome

An enzyme found in the fluid around the brain and spine is giving researchers a snapshot of what happens inside the minds of Alzheimer’s patients and how that relates to cognitive decline.

Iowa State University researchers say higher levels of the enzyme, autotaxin, significantly predict memory impairment and Type 2 diabetes.  Autotaxin often studied in cancer research, is an even stronger indicator of Type 2 diabetes. A single point increase reflects a 300 percent greater likelihood of having the disease or pre-diabetes. The results are published in the Journal of Alzheimer’s Disease. Willette and Kelsey McLimans, a graduate research assistant, say the discovery is important because of autotaxin’s proximity to the brain.

“We’ve been looking for metabolic biomarkers which are closer to the brain. We’re also looking for markers that reliably scale up with the disease and have consistently higher levels across the Alzheimer’s spectrum,” said Auriel Willette, an assistant professor of food science and human nutrition at Iowa State. “This is as directly inside of the brain as we can get without taking a tissue biopsy.”

Willette’s previous research found a strong association between insulin resistance and memory decline and detrimental brain outcomes, increasing the risk for Alzheimer’s disease. Insulin resistance is a good indicator, but Willette says it has limitations because what happens in the body does not consistently translate to what happens in the brain. That is why the correlation with this new enzyme found in the cerebrospinal fluid is so important.

“It has a higher predictive rate for having Alzheimer’s disease,” McLimans said. “We also found correlations with worse memory function, brain volume loss and the brain using less blood sugar, which has also been shown with insulin resistance, but autotaxin has a higher predictive value.”

The fact that autotaxin is a strong predictor of Type 2 diabetes and memory decline emphasizes the importance of good physical health. Researchers say people with higher levels of autotaxin are more likely to be obese, which often causes an increase in insulin resistance. Willette says autotaxin levels can determine the amount of energy the brain is using in areas affected by Alzheimer’s disease. People with higher autotaxin levels had fewer and smaller brain cells in the frontal and temporal lobes, areas of the brain associated with memory and executive function. As a result, they had lower scores for memory and tests related to reasoning and multitasking.

Researchers analyzed data from 287 adults collected through the Alzheimer’s Disease Neuroimaging Initiative, a public-private partnership working to determine whether MRI and PET scans as well as biological markers can measure the progression of cognitive impairment and Alzheimer’s disease. The data came from adults ranging in age from 56 to 89 years old. Study participants completed various tests to measure cognitive function. This included repeating a list of words over various time increments.

Citation: McLimans, Kelsey E. and Auriel A. Willette. “Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes”. Journal of Alzheimer’s Disease Volume 56, Number 1.
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Research funding: Iowa State Presidential Initiative for Interdisciplinary Research and National Institutes of Health.
Adapted from press release by Iowa State University.

Multiple sclerosis pathogenesis: association between amount of leaked hemoglobin and severity of brain shrinkage

A leak of a protein called hemoglobin from damaged red blood cells may be associated with brain shrinkage in multiple sclerosis. This is the conclusion of a team from Imperial College London, whose early-stage findings suggest treatments that lower levels of hemoglobin could slow progression of the disease. Haemoglobin carries iron and oxygen around the body in red blood cells.

The research, which involved 140 patients with an advanced form of the disease, called secondary progressive multiple sclerosis, has just passed peer review on a new publishing platform, Wellcome Open Research.

Professor Charles Bangham, the lead author of the study from the Department of Medicine at Imperial, said: “These are exciting but early results. If further studies confirm them, they may suggest new avenues of treatment and hopefully more options to offer patients in the future.”

Multiple sclerosis (MS) affects around 100,000 people in the UK. The lifelong condition affects the brain and spinal cord, and results in nerves being destroyed. The symptoms and the severity of the illness vary widely from person to person but often include fatigue, vision problems, muscle spasms and impaired mobility. At first, patients tend to experience repeated episodes of the condition, but symptoms improve between each period of illness. However around 65 percent of patients eventually develop a more severe form of the disease, called secondary progressive multiple sclerosis. In this phase, which generally starts around 15 years after the initial MS diagnosis, the symptoms become steadily worse, with no periods of improvement.

The condition also causes brain cells to die, and on average the brain shrinks by about 0.3 per cent a year in secondary progressive MS. Previous research has found high amounts of iron deposited around blood vessels in the brain. Although the mineral is crucial for our bodies to function, it is toxic at high levels – and scientists have suggested this may trigger the death of brain cells in MS. In the new study, the team suggests that hemoglobin, which carries iron and oxygen around the body may cause these high iron levels.

Haemoglobin is usually contained within the red blood cells. However, previous research suggests red blood cells in MS patients are, for unknown reasons, more fragile than normal and break apart easily.

When red blood cells break down they release hemoglobin into the bloodstream. Normally, the protein would then be prevented from entering the brain by a ‘checkpoint’ between the bloodstream and the brain. However, in MS patients this checkpoint – called the blood-brain barrier – is weakened, allowing hemoglobin to sail through.

The team suggests that once hemoglobin enters the brain it is broken down by an enzyme called haem oxygenase I, which has been found at high levels in the brains of MS patients. The destruction of hemoglobin causes iron to be released into the brain.

Professor Bangham explained: “The iron escapes from the hemoglobin, and may then result in the cell damage and brain shrinkage we see in secondary progressive MS.”

The researchers stress that there are no dietary methods for reducing hemoglobin levels, and people should not remove iron from their diet. “Iron eaten in foods has no effect on the levels of iron that accumulate in the brain. It is the hemoglobin levels, rather than iron that needs to be tackled. Iron is vital for the body, and should not be reduced in the diet,” said Professor Bangham.

In the study, the team found that the MS patients had high levels of a compound called serum lactate dehydrogenase, which is released when red blood cells disintegrate. In the research, the scientists analyzed blood samples of 140 patients with secondary progressive MS, taken over a two-year period, and looked for any proteins raised above normal levels. The team also analyzed brain scans of the patients, as well as blood samples from 20 healthy controls, and 40 patients with other medical conditions apart from MS. They found that blood levels of “free” hemoglobin – hemoglobin that has escaped from the red blood cells – were significantly higher in MS patients with the greatest amount of brain shrinkage. The researchers calculated that a 30 percent increase in free hemoglobin levels resulted in an increased rate of brain shrinkage by 0.1 per cent. This could make a significant difference to a patient’s symptoms.

Professor Bangham explained that the findings were unexpected: “We were amazed by the results, and we were surprised by the size of the apparent effect of hemoglobin on brain shrinkage. Over a number of years, it could significantly impact a patient’s symptoms.” He added that high hemoglobin levels are not the only factor leading to brain shrinkage, but could be a significant contributor.

Existing trials are testing potential MS treatments that mop up excess iron. Professor Bangham questions whether this is the best approach. “It may be more effective to look at ways of removing excess hemoglobin from the blood, rather than iron. There are a number of drugs that do this, although none have been used for multiple sclerosis.”

Furthermore, testing hemoglobin in the blood would not be helpful. This would only show that brain shrinkage is occurring – which would already be detectable on a scan.

The study was performed on patients who had been taking part in a clinical trial, examining the effect of statins on secondary progressive MS. The trial showed statins may have a beneficial effect on brain shrinkage, although this doesn’t seem to be linked to hemoglobin levels said Professor Bangham. “We are still unsure how the statins work, but it seems to be completely separate from the way hemoglobin triggers brain shrinkage.”

The team is now working on further studies to confirm the findings and explore what treatments may tackle high levels of hemoglobin in the blood.

Citation: Alex Lewin, Shea Hamilton, Aviva Witkover, Paul Langford, Richard Nicholas, Jeremy Chataway, Charles R.M. Bangham.  “Free serum hemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis”. Wellcome Open Research 2016 vol: 1 pp: 10.
DOI: 10.12688/wellcomeopenres.9967.1
Research funding: Wellcome trust, Medical Research Council
Adapted from press release by Imperial College London.

Trastuzumab biosimilar (MYL-14010) shown effective in breast cancer clinical trial

Among women with metastatic breast cancer, treatment with a drug that is biosimilar to the breast cancer drug trastuzumab resulted in an equivalent overall response rate at 24 weeks compared with trastuzumab, according to a study published online by JAMA.

Trstuzumab Biosimilars
Biological agents, including monoclonal antibodies, have increased the treatment options and greatly improved outcomes for a number of cancers. However, patient access to these biologics is limited in many countries. With impending patent expiration of some biological agents, development of biosimilars has become a high priority for drug developers and health authorities throughout the world to provide access to high-quality alternatives. A biosimilar drug is a biological product that is highly similar to a licensed biological product, with no clinically meaningful differences in terms of safety or potency.

Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves progression-free and overall survival in patients with ERBB2 (HER2)-positive metastatic breast cancer. In this multicenter, phase 3 study, Hope S. Rugo, M.D., of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and colleagues randomly assigned patients with ERBB2-positive metastatic breast cancer to receive a proposed trastuzumab biosimilar (MYL-14010) (n = 230) or trastuzumab (n = 228) with a taxane (a chemotherapy agent) to compare the overall response rate and safety after 24 weeks. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. Tumor was assessed every 6 weeks. The primary outcome was week 24 overall response rate defined as complete or partial response.

The overall response rate was 70 percent for the proposed biosimilar vs 64 percent for trastuzumab. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41 percent vs 43 percent), progression-free survival (44 percent vs 45 percent), or overall survival (89 percent vs 85 percent). In the proposed biosimilar and trastuzumab groups, 99 percent and 95 percent of patients had at least 1 adverse event.

“Trastuzumab is not widely available around the world,” the authors write. “A biosimilar treatment option may increase global access to biologic cancer therapies, provided, among other issues, that the price of the biosimilar is sufficiently inexpensive to enable women in non-high-income countries to access this therapy.”

The researchers note that further study is needed to assess safety as well as long-term clinical outcome.

Additional Comments
With trastuzumab coming towards end of its patent life we should expect arrival of new biosimilar drugs that will mimic transtuzumab in action and potency. It is a good news to see some of them in action such as above. There is a new hope with arrival of these biosimilar drugs that it will be widely available around the world at reasonable price level.

1.“Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)–Positive Metastatic Breast Cancer: A Randomized Clinical Trial”. Hope S. Rugo, Abhijit Barve, Cornelius F. Waller, Miguel Hernandez-Bronchud, Jay Herson, Jinyu Yuan, Rajiv Sharma, Mark Baczkowski, Mudgal Kothekar, Subramanian Loganathan, Alexey Manikhas, Igor Bondarenko, Guzel Mukhametshina, Gia Nemsadze, Joseph D. Parra, Maria Luisa T. Abesamis-Tiambeng, Kakhaber Baramidze, Charuwan Akewanlop, Ihor Vynnychenko, Virote Sriuranpong, Gopichand Mamillapalli, Sirshendu Ray, Eduardo P. Yanez Ruiz, Eduardo Pennella. JAMA vol: 56 (4) pp: 226-243.
DOI: 10.1001/jama.2016.18305
Research funding: Mylan Inc., Biocon Research Limited.
Adapted from press release by The JAMA Network.

Walnut consumption is key to better mood and happiness in college students

Professor Pribis recommends a handful of walnuts, 1 to 3 ounces,
daily for increased health benefits. The benefits from the tree nut
 not only positively affect mood but also the cardiovascular
system and can be used as a support for weight loss.
Credit: California Walnut Commission
College can be a stressful time for young adults as they figure out how to manage intense daily routines that include work, study, and play. Eat well, exercise and get plenty of sleep is a familiar mantra to alleviate this stress, but now with the results of his latest study, UNM Nutrition Professor Peter Pribis is able to tell college students that walnuts could be a key to a happier state-of-mind. 
In this first intervention study in humans, Pribis measured the effect of walnut consumption on mood. “In the past, studies on walnuts have shown beneficial effects on many health outcomes like heart disease, diabetes, and obesity,” said Pribis. “Our study was different because we focused on cognition, and in this controlled randomized trial (CRT) we measured mood outcomes in males and females.”

The participants of the study were 64 students between the ages of 18-25. They represented most ethnic groups: Caucasian, African American, Hispanic and Asian. The participants were asked to eat three slices of banana bread every day for sixteen weeks–eight weeks of banana bread with walnuts and eight weeks of banana bread without walnuts. The nuts were finely ground into the dough so the two banana breads were similar in taste and appearance. While eating banana bread with walnuts the participants consumed half a cup of walnuts daily. The mood of the students was measured at the end of each eight-week period.

“We used a validated questionnaire called Profiles of Mood States (POMS),” says Pribis. “It is one of the most widely used and accepted mood scales in studies on cognition. The test has six mood domains: tension, depression, anger, fatigue, vigor, confusion and also provides a Total Mood Disturbance score (TMD). The lower the TMD score the better the mood.”

In this double-blind, randomized, placebo-controlled, cross-over feeding trial with walnuts for eight weeks, Pribis observed a significant improvement in mood in young, healthy males. “There was a meaningful, 28 percent improvement of mood in young men,” said Pribis. “However we did not observe any improvement of mood in females. Why this is we do not know.”

There are several nutrients in walnuts that could be responsible for the improved mood like alpha-Linolenic acid, vitamin E, folate, polyphenols or melatonin. However, this was a whole food study, so in the end, it was the synergy and interaction of all the nutrients in the walnuts combined.

For Pribis, the lesson learned from this food study is clear, “Eat more walnuts. This is an easy intervention. They’re not only good for your mood but overall health as well. The recommended amount is one handful per day.” With this knowledge in hand–and hopefully, walnuts in the other–young men can happily tackle life’s daily stress.

Citation: Pribis, Peter. “Effects of Walnut Consumption on Mood in Young Adults—A Randomized Controlled Trial.” Nutrients 8, no. 11 (2016): 668.
Research funding: California Walnut Commission 

Adapted from press release by University of New Mexico.

Virtual clinical trials use mathematical modelling to predict melanoma response

Researchers from Moffitt Cancer Center’s Integrated Mathematical Oncology (IMO) Department are overcoming the limitations of common preclinical experiments and clinical trials by studying cancer through mathematical modeling. A study led by Alexander “Sandy” Anderson, Ph.D., chair of IMO, and Eunjung Kim, Ph.D., an applied research scientist, shows how mathematical modeling can accurately predict patient responses to cancer drugs in a virtual clinical trial. This study was recently published in the November issue of the European Journal of Cancer.

Cancer is a complicated process based on evolutionary principals and develops as a result of changes in both tumor cells and the surrounding tumor environment. Similar to how animals can change and adapt to their surroundings, tumor cells can also change and adapt to their surroundings and to cancer treatments. Those tumor cells that adapt to their environment or treatment will survive, while tumor cells that are unable to adapt will die.

Preclinical studies with tumor cell models cannot accurately measure these changes and adaptations in a context that accurately reflects what occurs in patients. “Purely experimental approaches are unpractical given the complexity of interactions and timescales involved in cancer. Mathematical modeling can capture the fine mechanistic details of a process and integrate these components to extract fundamental behaviors of cells and between cells and their environment,” said Anderson.

The research team wanted to demonstrate the power of mathematical modeling by developing a model that predicts the responses of melanoma to different drug treatments: no treatment, chemotherapy alone, AKT inhibitors, and AKT inhibitors plus chemotherapy in sequence and in combination. They then tested the model predictions in laboratory experiments with Keiran Smalley, Ph.D., director of the Donald A. Adam Comprehensive Melanoma and Skin Cancer Research Center of Excellence at Moffitt, to confirm that their model was accurate.

To determine the long-term outcome of therapy in different patients, the researchers developed a virtual clinical trial that tested different combinations of AKT inhibitors and chemotherapy in virtual patients. The researchers show that this Phase i trial (i for in silico, and representing the imaginary number) or virtual clinical trial was able to reproduce patient responses to those observed in the published results of an actual clinical trial. Importantly, their approach was able to stratify patient responses and predict a better treatment schedule for AKT inhibitors in melanoma patients that improves patient outcomes and reduces toxicities.

“By using a range of mathematical modeling approaches targeted at specific types of cancer, Moffitt’s IMO Department is aiding in the development and testing of new treatment strategies, as well as facilitating a deeper understanding of why they fail. This multi-model, multi-scale approach has led to a diverse and rich interdisciplinary environment within our institution, one that is creating many novel approaches for the treatment and understanding cancer,” Anderson said.

Citation: Kim, Eunjung, Vito W. Rebecca, Keiran SM Smalley, and Alexander RA Anderson. “Phase i trials in melanoma: A framework to translate preclinical findings to the clinic.” bioRxiv (2015): 015925. European journal of cancer 2016 vol: 67 pp: 213-222.
Adapted from press release by Moffitt Cancer Center

Protein biomarkers to screen early type 1 diabetes mellitus

Certain proteins in the blood of children can predict incipient type 1 diabetes, even before the first symptoms appear. A team of scientists at the Helmholtz Zentrum München, partners in the German Center for Diabetes Research (DZD), reported these findings in the ‘Diabetologia’ journal.

The work was based on two large studies that are intended to explain the mechanisms behind the development of type 1 diabetes (BABYDIAB and BABYDIET*). The study participants are children who have a first-degree relative with type 1 diabetes and who consequently have an increased risk of developing the disease due to the familial predisposition. Type 1 Diabetes is an autoimmune disease and often young children go through asymptomatic phase characterized by presence of auto antibodies in the blood.

A team of scientists, led by Dr. Stefanie Hauck, head of the Research Unit Protein Science and the Core Facility Proteomics, and Prof. Dr. Anette-G. Ziegler, Director of the Institute of Diabetes Research (IDF) at the Helmholtz Zentrum München, analyzed blood samples from 30 children with autoantibodies who had developed type 1 diabetes either very rapidly or with a very long delay. The researchers compared the data with data on children who displayed neither autoantibodies nor diabetes symptoms. In a second step with samples from another 140 children, the researchers confirmed the protein composition differences that they found in this approach.

“Altogether, we were able to identify 41 peptides from 26 proteins that distinguish children with autoantibodies from those without,” reports Dr. Christine von Toerne. Striking in their evaluations: A large number of these proteins are associated with lipid metabolism. “Two peptides – from the proteins apolipoprotein M and apolipoprotein C-IV – were particularly conspicuous and were especially differently expressed in the two groups,” von Toerne adds. In autoantibody-positive children, it was furthermore possible to reach a better estimate of the speed of the diabetes development using the peptide concentrations of three proteins (hepatocyte growth factor activator, complement factor H and ceruloplasmin) in combination with the age of the particular child.

The researchers are confident that the protein signatures they have discovered will be helpful as biomarkers for future diagnostics.

Citation: Christine von Toerne, Michael Laimighofer, Peter Achenbach, Andreas Beyerlein, Tonia de las Heras Gala, Jan Krumsiek, Fabian J. Theis, Anette G. Ziegler, Stefanie M. Hauck. “Peptide serum markers in islet autoantibody-positive children”. Diabetologia (2016).
Adapted from press release by Helmholtz Zentrum München

Bone marrow derived stem cell therapy shown to reduce inflammation in traumatic brain injury

Results of a cellular therapy clinical trial for traumatic brain injury (TBI) using a patient’s own stem cells showed that the therapy appears to dampen the body’s neuroinflammatory response to trauma and preserve brain tissue, according to researchers at The University of Texas Health Science Center at Houston (UTHealth). The results, which also confirmed safety and feasibility as cited in earlier studies, were published online Nov. 1 in the journal STEM CELLS.

According to the Centers for Disease Control, 1.7 million Americans sustain a traumatic brain injury annually. Of those, 275,000 are hospitalized and 52,000 die. TBI is a contributing factor to a third of all injury-related deaths in the country. According to published research cited in the paper, more than 6.5 million patients are burdened by the physical, cognitive and psychosocial deficits associated with TBI, leading to an economic impact of approximately $60 billion.

There are few current therapies to treat TBI. Critical care teams work to stabilize patients and surgery is sometimes necessary to remove or repair damaged blood vessels or tissue, as well as provide relief from swelling.

To potentially open a new avenue of treatment, Cox has been researching cell therapy for neurological disease in pre-clinical and clinical trials for more than two decades. The new study builds on his previously published research showing that autologous stem cell therapy after TBI is safe and reduces the therapeutic intensity requirements of neurocritical care. The theory is that the stem cells work in the brain to alleviate the body’s inflammatory response to the trauma.

Researchers enrolled 25 patients in a dose-escalation format with five controls followed by five patients in each of three different doses followed by five more controls for a total of 25. Bone marrow harvesting, cell processing and re-infusion occurred within 48 hours after injury. Cellular processing was done at The Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory at McGovern Medical School.

Functional and neurocognitive outcomes were measured and correlated with imaging data including magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) of white brain matter.

According to the authors, despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes and key inflammatory cytokines were down-regulated after bone marrow cell infusion.

Citation: Cox, Charles S., Robert A. Hetz, George P. Liao, Benjamin M. Aertker, Linda Ewing‐Cobbs, Jenifer Juranek, Sean I. Savitz et al. “Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.” STEM CELLS.
DOI: 10.1002/stem.2538
Research funding:US Department of Defense, National Institutes of Health, Glassell Foundation Stem Cell Research Program, The Brown Foundation, Inc.
Adapted from press release by The University of Texas Health Science Center at Houston