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Gene Identified That May Provide Potential Therapy for Cerebral Cavernous Malformations

Researchers at University of California San Diego School of Medicine, with national collaborators, have identified a series of molecular clues to understanding the formation of cerebral cavernous malformations (CCMs). The study offers the first genome-wide analysis of the transcriptome of brain microvascular endothelial cells after KRIT1 inactivation. Findings were published September 28 in the Journal of Experimental Medicine.

“These mouse studies reveal a critical mechanism in the pathogenesis of cerebral cavernous malformations and point to the possibility of using angiogenesis inhibitors, such as TSP1 for potential therapy,” said Mark H. Ginsberg, MD, professor of medicine, UC San Diego School of Medicine.

CCMs are collections of enlarged and irregular blood vessels in the central nervous system (CNS), for which there is no drug therapy. The vessels are prone to leakage causing headaches, seizures, paralysis, hearing or vision loss, or bleeding in the brain. There are two forms of the condition: familial and sporadic, affecting 1 in 200 patients in the U.S. The current treatment for CCMs involves invasive surgery, however, surgery is not possible for all patients due to location of vascular lesions within the CNS.

The most common cause of familial cavernous malformations is mutations of KRIT1. The protein produced from this gene is found in the junctions connecting neighboring blood vessel cells. Loss of function mutations in KRIT1 result in weakened contacts between blood vessel cells and CNS vascular abnormalities as seen in CCMs.

“Inactivation of KRIT1 in endothelial cells causes a cascade of changes in the expression of genes that regulate cardiovascular development,” said Ginsberg. “What we learned is that reduced expression of a protein encoded by one of these genes, TSP1, contributes to the growth of CCMs. Loss of one or two copies of THBS1, the gene that encodes TSP1, makes a mouse model of the disease much worse. Conversely, administration of 3TSR, a fragment of TSP1, reduces lesions in this mouse model. This means that replacement of TSP1 by 3TSR or other angiogenesis inhibitors may be a preventative for CCMs or treatment of the disease.”

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Stabilizing TREM2 — a potential strategy to combat Alzheimer’s disease

A gene called triggering receptor expressed on myeloid cells 2, or TREM2, has been associated with numerous neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease.

Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research, published today in EMBO Molecular Medicine, sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment.

Alzheimer’s disease, just like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually lose out and fail to rid all the damaging material.

TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage. They were led by Christian Haass at the German Center for Neurodegenerative Diseases at the Ludwig-Maximilians-University in Munich, Germany, and Damian Crowther of AstraZeneca’s IMED Neuroscience group in Cambridge, UK together with colleagues at the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto and the Cambridge Institute for Medical Research, University of Cambridge, UK.

Using different technological approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was no unknown. Only recently, researchers from China had uncovered that a mutation at this exact position, referred to as p.H157Y, increased the risk of Alzheimer’s disease. Together, these observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development.

As a next step, Haass and Crowther’s groups investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein. “Our results provide a detailed molecular mechanism for how this rare mutation alters the function of TREM2 and hence facilitates the progression of Alzheimer’s disease,” said Crowther.

While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. “The end result is the same. In both cases, there is too little full-length TREM protein on microglia,” said Haass. “This suggests that stabilizing TREM2, by making it less susceptible to cleavage, may be a viable therapeutic strategy.”

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How Prenatal Maternal Infections May Affect Genetic Factors in Autism Spectrum Disorder

Researchers find activation of maternal immune system during pregnancy disrupts expression of key genes and processes associated with autism and prenatal brain development

For some infections, such as Zika, the virus passes through the placenta and directly attacks the fetus. For others, such as the H1N1 influenza, the virus induces maternal immune activation (MIA) by triggering a woman’s immune system during pregnancy. Both Zika and MIA mechanisms may lead to potentially disastrous neurological repercussions for the unborn child, such as microcephaly (an undersized, underdeveloped brain and head) in the case of Zika or cortical abnormalities with excess numbers of neurons, patches of disorganized cortex, synapse mal-development and early brain overgrowth in some cases of MIA.

Large population-based studies suggest MIA caused by infection during pregnancy are also associated with small increases in risk for psychiatric disorders, including autism spectrum disorder (ASD). In a new study published today in Molecular Psychiatry, researchers at the University of California San Diego School of Medicine, University of Cyprus and Stanford University map the complex biological cascade caused by MIA: the expression of multiple genes involved in autism are turned up or down by MIA, affecting key aspects of prenatal brain development that may increase risk for atypical development later in life.

“We provide novel evidence that supports the link between prenatal infections and biology known to be important in the development of autism,” said senior author Tiziano Pramparo, PhD, associate research scientist at the Autism Center of Excellence at UC San Diego School of Medicine. “There are different routes of importance. We highlight a specific pathway that seems to be key in driving downstream early abnormal brain development.”

“Our work adds to growing evidence that prenatal development is an important window for understanding key biology of relevance to neurodevelopmental conditions like autism,” added lead author Michael Lombardo, PhD, at the University of Cyprus. “MIA is an environmental route of influence on fundamental biological processes important for brain development. The influence it exerts overlaps with key processes known to be important in how the brain in autism develops.”

Pramparo said the effects are not caused by the infectious agents themselves — virus or bacterium — but from the maternal immune response itself. “Although the mechanisms are not entirely known, it has to do with the cascade of altered events regulating production and function of neurons, their synapses and how they arrange themselves in the brain that are triggered when a mother’s immune system is activated.”

For example, increased levels of maternal cytokines (small signaling molecules driven by the immune response) may directly or indirectly alter gene expression in the fetus’ brain.

“These up- and down-regulated genes may lead to an excess or reduction in the normal amounts of proteins required for normal brain development,” Pramparo said. “Importantly, we have found that MIA-induced effects involve both single genes and pathways (many genes working in a coordinated way to serve some dedicated biological purpose) essential for early fetal neurodevelopment.” Among the large number of genes whose activity is altered by the maternal immune response, are a few that, when mutated, are thought to cause more genetic forms of autism in a small subset of all ASD toddlers.

Pramparo suggested the findings have multiple clinical implications.

“In general, the more we know and understand about a disrupted mechanism, the higher the chance of finding amenable targets for potential therapeutic intervention or for informing how to prevent such risk from occurring in the first place.”

Another implication, he said, is the potential to define the effects and clinical phenotypes based upon the underlying mechanisms: genetic, environmental or both.

“The MIA effects are transient but very potent during fetal development and perhaps even more potent than the effects induced by certain types of mutations in single gene forms of autism. Also, depending on when MIA occurs during gestation, the clinical characteristics may vary. The finding of MIA affecting the expression genes known to be important in autism supports the hypothesis that a genetic-by-environment interaction may lead to amplified effects at the clinical level. For example, more severe cases of autism.”

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Researchers Find Potential Therapy For Brain Swelling During Concussion

Biomedical engineering researchers pre-treated cells that swell after traumatic injury with an existing, FDA-approved drug.

A team of biomedical engineering researchers at the University of Arkansas have identified a cause of fluid swelling of the brain, or cellular edema, that occurs during a concussion.

The researchers discovered that pre-treating the cells with an existing, FDA-approved drug used for epilepsy and altitude sickness reduces the expression of a specific protein that causes swelling.

Their findings were published in a recent issue of Nature’s Scientific Reports.

“Our study found that mild traumatic brain injury resulted in increased expression of a protein called aquaporin-4, which caused a massive cellular influx of fluid, leading to increased astrocyte cell volume and injury,” said Kartik Balachandran, assistant professor of biomedical engineering. “We then worked with a drug called Acetazolamide. Our results showed that Acetazolamide minimized cell swelling and injury, suggesting a therapeutic role for this drug in reducing the detrimental effects of concussions.”

In addition to Balachandran, who led the study, the research was conducted by Nasya Sturdivant, biomedical-engineering doctoral candidate; Jeffrey Wolchok, assistant professor of biomedical engineering; and partners at the FDA’s National Center for Toxicological Research in Jefferson, Arkansas.

Mild traumatic brain injury, also known as a concussion, is a devastating condition that is commonly experienced in car accidents, full-contact sports and battlefield injuries. One of the main factors that leads to the high death rate in patients who experience mild traumatic brain injury is the swelling or edema of astrocytes, the most abundant cell type in the brain.

The researchers engineered a benchtop bioreactor to examine astrocyte cells. This device helped them see that mild traumatic brain injury led to an increased expression of aquaporin-4, the protein that causes a large cellular influx of fluid, which in turn leads to increased astrocyte cell volume.

“This study demonstrates the collaborative neuro-engineering efforts that are contributing to both diagnostic and therapeutic methods for addressing traumatic brain injury,” said Raj Rao, professor and chair of the Department of Biomedical Engineering at the University of Arkansas.

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Temple Attains $20 Million Award For Materials, Brain Injury Research

In one of the largest cooperative agreements for research in Temple University history, an interdisciplinary team of faculty is participating in a $20 million, two-year agreement with other universities and the U.S. Army Research Laboratory, or ARL.

Temple will be working with the ARL to perform research in three major areas: understanding and improving the performance of materials through the use of computational modeling; understanding the mechanisms and thresholds of traumatic brain injury by reviewing clinical, behavioral and biochemical changes related to traumatic brain injuries and concussions; and exploring new ways to improve protection against ballistics impacts.

“This pioneering research by some our most highly regarded faculty supports the protection of soldiers and also has potential for broader applications,” said Temple University President Richard M. Englert. “Temple’s research enterprise is clearly on the rise, and this is a tremendous example of what our expertise can do to improve lives.”

Other higher education collaborators include the University of Southern California, University of Southern Mississippi and the University of North Texas.

“ARL is creating a transformative global science and technology ecosystem by linking government, academia and business to share the best and brightest people, ideas and facilities in forward-reaching research areas of strategic importance to the Army,” said Philip Perconti, ARL acting director.

Under the leadership of Vice President for Research Michele M. Masucci, Temple’s research team features: College of Science and Technology Dean and Laura H. Carnell Professor of Science Michael L. Klein; Laura H. Carnell Professor of Physics and Chemistry John Perdew; Associate Professor of Neuroscience and Neurovirology T. Dianne Langford of Temple’s Lewis Katz School of Medicine; and Associate Professor of Kinesiology Ryan Tierney in the College of Public Health. Langford and Tierney’s project team includes additional Temple faculty from medicine, engineering, science and technology, and public health, as well as a representative from Temple Athletics.

“This award evidences that by working together across schools, colleges and universities, Temple’s faculty is able to provide national leadership in the design, development and measurement of advanced materials to protect army personnel as well as athletes,” Masucci said. “Through improving our knowledge of the protective effects of such materials by conducting clinical studies of their use, we hope to dramatically improve the safety of individuals at risk for traumatic brain injury.”

The research effort, which aims to create a new class of materials for use in personal protective equipment and decrease brain injuries, will leverage Temple’s Center for Computational Design of Functional Layered Materials and the Temple Materials Institute to develop and test new materials, as well as the university’s clinical, research and educational expertise in monitoring and understanding the consequences of head injuries.

“The project will also develop technologies that can be commercialized and brought to market, broadening the benefits of the program to society at large,” said Stephen Nappi, Temple’s associate vice president for technology commercialization and business development.

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Neighborhoods Important Factor In Risk Of Stroke For All Races

A higher neighborhood advantage, or socioeconomic status, of where a person lives contributes to a lower risk of having a stroke no matter the person’s race, according to findings published in the Oct. 14 online issue of Neurology®, the medical journal of the American Academy of Neurology.

The report from the University of Alabama at Birmingham REasons for Geographic And Racial Differences in Stroke study shows this effect is the same for black and white adults, both men and women.

“More blacks than whites in the United States have strokes and die from strokes,” saidVirginia Howard, Ph.D., lead author of the study and professor in the UAB School of Public Health Department of Epidemiology. “More people who live in the Southeastern area known as the stroke belt have stroke and die from stroke compared to those who live in the rest of the United States.”

This study showed that residents in more disadvantaged neighborhoods had greater stroke risk than those who lived in more advantaged neighborhoods. The neighborhood index is composed of six factors, including a higher value of housing units and higher proportion of residents employed in professional occupations. A higher score in all of these categories leads to a higher advantaged neighborhood.

The observation was true even after adjustment for age, race, sex and region of the country. But after adjustment for other stroke risk factors, there was no association between the level of the neighborhood advantage and stroke risk, suggesting that those living in more disadvantaged neighborhoods are more likely to develop risk factors including hypertension, diabetes and smoking. Because of being more likely to develop these risk factors, they are at higher risk of stroke.

“These results are consistent with other evidence showing that factors associated with living in more disadvantaged neighborhoods contribute to stroke risk. However, it is difficult to separate the influence of neighborhood characteristics from characteristics of the individuals living in the neighborhood,” Howard said. “Many social and behavioral risk factors, such as smoking and physical inactivity, are more prevalent in the less advantaged neighborhoods. Greater attention needs to be paid to risk factor management strategies in disadvantaged neighborhoods in order to make a difference in preventing stroke on an individual level.”

The current study looked at measures of the neighborhood advantage where people live to determine whether these factors contributed to future stroke risk. Data came from the REGARDS study, a national random sample of the general population with more people selected from the stroke belt and about half black, half white.

The study involved 24,875 people with an average age of 65 who had not had a stroke at the start of the study. The participants were divided into four neighborhood groups, ranging from lowest level of advantage to the highest. The participants were followed for an average of seven and a half years. During that time, 929 people had a stroke.

This study has advantages over other studies in that it includes individuals of low, middle, upper-middle and high individual wealth across 1,833 urban and rural counties in the United States, and a large number of both blacks and whites. Other stroke risk factors were measured prior to the stroke.

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New Hope For Recovery Of Hand Movement For Stroke Patients

Stroke patients are starting a trial of a new electronic device to recover movement and control of their hand.

Neuroscientists at Newcastle University have developed the device, the size of a mobile phone, which delivers a series of small electrical shocks followed by an audible click to strengthen brain and spinal connections.

The experts believe this could revolutionise treatment for patients, providing a wearable solution to the effects of stroke.

Following successful work in primates and healthy human subjects, the Newcastle University team are now working with colleagues at the prestigious Institute of Neurosciences, Kolkata, India, to start the clinical trial. Involving 150 stroke patients, the aim of the study is to see whether it leads to improved hand and arm control.

Stuart Baker, Professor of Movement Neuroscience at Newcastle University who has led the work said: “We were astonished to find that a small electric shock and the sound of a click had the potential to change the brain’s connections. However, our previous research in primates changed our thinking about how we could activate these pathways, leading to our study in humans.”

Recovering hand control

Publishing today in the Journal of Neuroscience, the team report on the development of the miniaturised device and its success in healthy patients at strengthening connections in the reticulospinal tract, one of the signal pathways between the brain and spinal cord.

This is important for patients as when people have a stroke they often lose the major pathway found in all mammals connecting the brain to spinal cord. The team’s previous work in primates showed that after a stroke they can adapt and use a different, more primitive pathway, the reticulospinal tract, to recover.

However, their recovery tends to be imbalanced with more connections made to flexors, the muscles that close the hand, than extensors, those that open the hand. This imbalance is also seen in stroke patients as typically, even after a period of recuperation, they find that they still have weakness of the extensor muscles preventing them opening their fist which leads to the distinctive curled hand.

Partial paralysis of the arms, typically on just one side, is common after stroke, and can affect someone’s ability to wash, dress or feed themselves. Only about 15% of stroke patients spontaneously recover the use of their hand and arm, with many people left facing the rest of their lives with a severe level of disability.

Senior author of the paper, Professor Baker added: “We have developed a miniaturised device which delivers an audible click followed by a weak electric shock to the arm muscle to strengthen the brain’s connections. This means the stroke patients in the trial are wearing an earpiece and a pad on the arm, each linked by wires to the device so that the click and shock can be continually delivered to them.

“We think that if they wear this for 4 hours a day we will be able to see a permanent improvement in their extensor muscle connections which will help them gain control on their hand.”

Improving connections

The techniques to strengthen brain connections using paired stimuli are well documented, but until now this has needed bulky equipment, with a mains electric supply.

The research published today is a proof of concept in human subjects and comes directly out of the team’s work on primates. In the paper they report how they pair a click in a headphone with an electric shock to a muscle to induce the changes in connections either strengthening or weakening reflexes depending on the sequence selected. They demonstrated that wearing the portable electronic device for seven hours strengthened the signal pathway in more than half of the subjects (15 out of 25).

Professor Stuart Baker added: “We would never have thought of using audible clicks unless we had the recordings from primates to show us that this might work. Furthermore, it is our earlier work in primates which shows that the connections we are changing are definitely involved in stroke recovery.”

The work has been funded through a Milstein Award from the Medical Research Council and the Wellcome Trust.

The clinical trial is just starting at the Institute of Neurosciences, Kolkata, India. The country has a higher rate of stroke than Western countries which can affect people at a younger age meaning there is a large number of patients. The Institute has strong collaborative links with Newcastle University enabling a carefully controlled clinical trial with results expected at the end of this year.

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Brain Cancer And Leukemia: New Molecular Mechanisms Decoded

Brain cancer and leukemia are two potentially fatal diseases that affect thousands of Canadians each year. But a joint study conducted by researchers Frederick Antoine Mallette, of the Maisonneuve-Rosemont Hospital Research Centre and the University of Montreal, and Marc-Étienne Huot, of Laval University, and published in the prestigious scientific journal Nature Communications has uncovered new molecular causes of brain cancer and leukemia.

We already knew the existence of a mutation phenomenon involving certain metabolic enzymes called isocitrate dehydrogenases 1 and 2 (IDH1/2) in various forms of brain cancer, including gliomas and glioblastomas, and in acute myeloid leukemia. Although the mutated forms of IDH1/2 appear to contribute to cancer formation, until now we had only limited understanding of the ways in which these metabolic defects caused cancer. Research conducted by Mélissa Carbonneau, a master’s student in Professor Mallette’s laboratory, has helped to better understand the effect of IDH1/2 mutations in cancer by demonstrating their role in activating the pathways involved in cell proliferation and survival.

“With the identification of the molecular modes of action that contribute to cancer in patients carrying IDH1/2 mutations, it is now possible to consider personalized treatment to potentially improve therapeutic response,” said Dr. Mallette.
Some statistics

It is estimated that in 2015, 3,000 Canadians were diagnosed with brain and spinal cord cancer, and 6,200 Canadians were diagnosed with leukemia.

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Dysfunction In Neuronal Transport Mechanism Linked To Alzheimer’s Disease

Researchers at University of California San Diego School of Medicine have confirmed that mutation-caused dysfunction in a process cells use to transport molecules within the cell plays a previously suspected but underappreciated role in promoting the heritable form of Alzheimer’s disease (AD), but also one that might be remedied with existing therapeutic enzyme inhibitors.

The findings published in the October 11 online issue of Cell Reports.

“Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD,” said the study’s senior author Larry Goldstein, PhD, Distinguished Professor in the Departments of Neuroscience and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of both the UC San Diego Stem Cell Program and Sanford Stem Cell Clinical Center at UC San Diego Health. “But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure.”

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. It affects more than 30 million people worldwide, including an estimated 5.4 million Americans. One in 10 persons over the age of 65 has AD; one in three over the age of 85. There are currently no treatments proven to cure or reduce the progression of AD.

Genetically, AD is divided into two groups: the much more common sporadic (sAD) form of the disease in which the underlying primary cause is not known and the rarer familial (fAD) form, produced by inherited genetic mutations. In both forms, the brains of AD patients feature accumulations of protein plaques and neurofibrillary tangles that lead to neuronal impairment and eventual cell death.

The prevailing “amyloid cascade hypothesis” posits that these plaques and tangles are comprised, respectively, of amyloid precursor protein (APP) fragments and tau proteins that fuel cellular stress, neurotoxicity, loss of function and cell death. There has been some evidence, however, of another disease-driver: defects in endocytic trafficking — the process by which cells package large, external molecules into vesicles or membrane-bound sacs for transport into the cell for a variety of reasons or uses.

But previous research focused on non-neuronal cells and did not examine the effects of normal expression levels of AD-related proteins, leaving it unclear to what degree decreased endocytosis and other molecular movement within cells played a causative role.

Goldstein and colleagues analyzed neurons created from induced pluripotent stem cells in which they generated PS1 and APP mutations characteristic of fAD using the emerging genome editing technologies CRISPR and TALEN. In this “disease-in-a-dish” approach, they found that the mutated neurons displayed altered distribution and trafficking of APP and internalized lipoproteins (proteins that combine with or transport fat and other lipids in blood plasma). Specifically, there were elevated levels of APP in the soma or cell body while levels were reduced in the neuronal axons.

In previous work, Goldstein’s team had demonstrated that PS1 and APP mutations impaired the activity of specific cellular enzymes. In the latest work, they found that treating mutated fAD neurons with a beta-secretase inhibitor rescued both endocytosis and transcytosis (molecule movement within a cell) functions.

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Closing In On Biomarkers For Suicidal Behavior

An enzyme called ACMSD—part of a chain of biochemical reactions called the kynurenine pathway, activated by inflammation—could become an important target for new drugs aimed at preventing suicide.

The enzyme shows reduced activity in people who have tried to kill themselves, according to astudy published online Aug. 2, 2016, in Translational Psychiatry. And downstream effects of the sluggish enzyme—namely, abnormal levels of two acids in the body—could potentially be measured in blood tests to help identify patients at high risk, say the researchers.

The study was conducted with Swedish patients but involved collaborators in three other countries, including in the U.S. at VA’s Rocky Mountain Mental Illness Research, Education, and Clinical Center (MIRECC) for Suicide Prevention in Denver, and at the Van Andel Research Institute in Michigan.

“We now want to find out if these changes are only seen in individuals with suicidal thoughts or if patients with severe depression also exhibit this. We also want to develop drugs that might activate the enzyme ACMSD and thus restore balance between quinolinic and picolinic acid,” said Dr. Sophie Erhardt of the Karolinska Institutet in Stockholm, one of the leaders of the study.

Senior author on the study was Dr. Lena Brundin at Van Andel. Representing VA was Dr. Teodor Postolache, a clinical and research psychiatrist with VA’s Rocky Mountain MIRECC for Suicide Prevention. Postolache is also an investigator with VA’s MIRECC in Baltimore, and a professor at the University of Maryland School of Medicine.

The immune system and mental health

An increasing body of evidence in recent years has implicated the immune system—particularly inflammation—as a possible contributing factor in both depression and suicidal behavior. Inflammation is one way the body responds to stress. But the link is complex, and researchers are still far from grasping exactly how the pieces fit together, and whether the findings can be used clinically to advance suicide prevention.

The new study, conducted in several phases, involved more than 300 Swedish patients and other volunteers. The researchers took samples of blood and cerebrospinal fluid from those who had attempted suicide, immediately after the suicidal episode and at intervals thereafter, and compared them with samples from healthy controls.

In the suicidal patients, the ratio between picolinic and quinolinic acid was out of whack—too little of the former, too much of the latter. Picolinic acid is protective, whereas quinolinic acid is toxic to the brain and nervous system.

The changes were most pronounced in the cerebrospinal fluid, the clear liquid that cushions the brain and spinal cord. The abnormal levels persisted at least two years in repeated tests of the fluid. The changes also showed up in blood tests, albeit less markedly. But blood tests are much easier to perform than spinal taps, so they could represent a more practical clinical option.

Gene tests confirm results

The researchers knew from past studies that ACSMD modulates the levels of the two acids. They confirmed the link in the current study though a genetic analysis. They found that a particular variant of the ACSMD gene was more prevalent in suicide attempters, and was associated with increased quinolinic acid.

Targeting ACSMD with a drug to boost its activity could, in theory, normalize the ratio between the two acids it affects, say the researchers.

But the study wasn’t designed to show a direct causal relationship between ACSMD activity and suicide risk. So it’s not clear that raising ACSMD activity and restoring the picolinic-quinolinic ratio would actually curb suicidal behavior.

The next step in exploring that, say the researchers, would be lab tests with an animal model of depression. Lab animals that exhibit traits typical of depression, such as lack of interest in normal activities, as well as traits such as impulsivity, are commonly studied by scientists looking at suicidal behavior.

Combating inflammation over long term may be best

Further research may also shed light on issues of timing. To the extent that inflammation does drive suicidal behavior, it could be a problem that is years in the making, and that demands long-range strategies.

Dr. John Krystal, a psychiatry researcher with VA and Yale School of Medicine, is the editor of the journal Biological Psychiatry. He was quoted in response to a study in the journal last year that showed increased levels of inflammation-causing immune chemicals called cytokines in suicidal patients:

“Inflammation affects every organ in the body,” noted Krystal. “It is increasingly evident that we need to take a long-term perspective on the effects of inflammation on the brain. The path to preventing suicide may be to intervene early in long-term processes that increase the risk for suicide, rather than to focus solely on the elusive short-term predictors of suicide.”

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Genetic ‘Switch’ Identified As Potential Target For Alzheimer’S Disease

A team at the MRC Clinical Sciences Centre (CSC), based at Imperial College London, has found an important part of the machinery that switches on a gene known to protect against Alzheimer’s Disease.

Working in collaboration with scientists at the Hong Kong University (HKU) and the Erasmus University in Rotterdam, CSC associate professor Richard Festenstein explored the steps by which this Neuroglobin gene is gradually switched on, or up-regulated.

Neuroglobin has previously been shown to protect against Alzheimer’s disease in mice in which it makes the protective Neuroglobin. It is thought that the gene might play a protective role early in the disease in patients, but appears to be down-regulated as the disease progresses. It may therefore prove useful in developing new ways to try to prevent or treat this common cause of dementia, for which there is currently no cure.

Professor Festenstein and Dr Tan-Un from HKU, with help from Professor Sjaak Phillipsen at the Erasmus University, examined how the Neuroglobin gene ‘folds up’ in the cell using a technique called chromosome conformation capture. In results published today in the journal Nucleic Acids Research, they showed that a particular region of DNA, outside the coding region of the Neuroglobin gene itself, loops round to make contact with the start of the gene.

They tested the ability of this newly-identified DNA region to switch on the Neuroglobin gene using two approaches. First, they linked the DNA region directly to another so-called ‘reporter’ gene, and demonstrated simply that it does indeed act as an up-regulator. Second, they used the new ‘Crispr’ technique of gene editing to completely remove this section of DNA from the cell, and showed that the Neuroglobin gene was no longer switched on.

Together, the results gave the team confidence that this newly-identified DNA region is indeed a powerful switching mechanism of the Neuroglobin gene.

As Neuroglobin is thought to be protective in Alzheimer’s, it may be possible in the future to use this ‘switch’ in developing new treatments, such as gene therapy. Such therapeutic approaches require a compact ‘chunk’ of DNA to be most efficient. Importantly, the team pinpointed the position of the new regulatory region, and found that it is some distance away from the Neuroglobin gene itself. It may now be possible to remove the less relevant sections of DNA in between the Neuroglobin gene and its regulator to create an efficient therapeutic gene therapy unit. It may be that this target may prove useful not only in Alzheimer’s but also in other neurodegenerative diseases.

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Computer Program Beats Physicians At Brain Cancer Diagnoses

Computer programs have defeated humans in Jeopardy!, chess and Go. Now a program developed at Case Western Reserve University has outperformed physicians on a more serious matter.

The program was nearly twice as accurate as two neuroradiologists in determining whether abnormal tissue seen on magnetic resonance images (MRI) were dead brain cells caused by radiation, called radiation necrosis, or if brain cancer had returned.

The direct comparison is part of a feasibility study published in the American Journal of Neuroradiology today.

“One of the biggest challenges with the evaluation of brain tumor treatment is distinguishing between the confounding effects of radiation and cancer recurrence,” said Pallavi Tiwari, assistant professor of biomedical engineering at Case Western Reserve and leader of the study. “On an MRI, they look very similar.”

But treatments for radiation necrosis and cancer recurrence are far different. Quick identification can help speed prognosis, therapy and improve patient outcomes, the researchers say.

With further confirmation of its accuracy, radiologists using their expertise and the program may eliminate unnecessary and costly biopsies Tiwari said. Brain biopsies are currently the only definitive test but are highly invasive and risky, causing considerable morbidity and mortality.

To develop the program, the researchers employed machine learning algorithms in conjunction with radiomics, the term used for features extracted from images using computer algorithms. The engineers, scientists and physicians trained the computer to identify radiomic features that discriminate between brain cancer and radiation necrosis, using routine follow-up MRI scans from 43 patients. The images were all from University Hospitals Case Medical Center.

The team then developed algorithms to find the most discriminating radiomic features, in this case, textures that can’t be seen by simply eyeballing the images.

“What the algorithms see that the radiologists don’t are the subtle differences in quantitative measurements of tumor heterogeneity and breakdown in microarchitecture on MRI, which are higher for tumor recurrence,” said Tiwari, who was appointed to the Department of Biomedical Engineering by the Case Western Reserve School of Medicine.

More specifically, while the physicians use the intensity of pixels on MRI scans as a guide, the computer looks at the edges of each pixel, explained Anant Madabhushi, F. Alex Nason professor II of biomedical engineering at Case Western Reserve, and study co-author.

“If the edges all point to the same direction, the architecture is preserved,” said Madabhushi, who also directs the Center of Computational Imaging and Personalized Diagnostics at CWRU. “If they point in different directions, the architecture is disrupted—the entropy, or disorder, and heterogeneity are higher. “

In the direct comparison, two physicians and the computer program analyzed MRI scans from 15 patients from University of Texas Southwest Medical Center. One neuroradiologist diagnosed seven patients correctly, and the second physician correctly diagnosed eight patients. The computer program was correct on 12 of the 15.

Tiwari and Madabhushi don’t expect the computer program would be used alone, but as a decision support to assist neuroradiologists in improving their confidence in identifying a suspicious lesion as radiation necrosis or cancer recurrence.

Next, the researchers are seeking to validate and the algorithms’ accuracy using a much larger collection of images from across different sites.

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Vesicles That Trap Amyloid Appear to Also Contribute to Alzheimer’s Disease

Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer’s, appear to also contribute to the disease, scientists report.

Reducing the production of these vesicles, called exosomes, could help reduce the amount of amyloid and lipid that accumulates, slow disease progression and help protect cognition, scientists at the Medical College of Georgia at Augusta University report in The Journal of Neuroscience.

When confronted with amyloid, astrocytes, plentiful brain cells that support neurons, start making exosomes, to capture and neutralize it, said Dr. Erhard Bieberich, neuroscientist in the MCG Department of Neuroscience and Regenerative Medicine and the study’s corresponding author.

“If you swarm astrocytes with amyloid, you trigger an aggressive response,” he said. Happy astrocytes, on the other hand, don’t make exosomes.

Not unlike a landfill, the real problems begin when the biological sacs get piled too high. In such volume and close proximity to neurons, exosomes begin to interfere with communication and nutrition, neurons stop functioning well and eventually begin to die, a scenario that fits with disease progression, Bieberich said.

MCG scientists followed the process in an animal model with several genetic mutations found in types of Alzheimer’s that tend to run in families and make brain plaques early in life. One mouse group also was genetically programmed to make a nonfunctional form of the enzyme neutral sphingomyelinase-2. Amyloid also activates this enzyme, which converts another lipid, called sphingomyelin, into ceramide, a component of the brain cell membrane known to be significantly elevated in Alzheimer’s. In fact, with disease, the brain has two to three times more of the lipid known for its skin-softening ability.

The MCG scientists found exosomes made by astrocytes accelerated the formation of beta amyloid and blocked its clearance in their animal model of Alzheimer’s. Male mice, which were also sphingomyelinase-deficient, developed fewer plaques and exosomes, produced less ceramide and performed better in cognitive testing.

For reasons that are unclear, female mice did not reap similar benefits, said Bieberich, noting that Alzheimer’s tends to be more aggressive in women. His earlier work has shown that female mice have higher levels of antibodies in response to the elevated ceramide levels that further contribute to the disease.

His new work is the first evidence that mice whose brain cells don’t make as many exosomes are somewhat protected from the excessive plaque accumulation that is the hallmark of Alzheimer’s. It is also an indicator that drugs that inhibit exosome secretion may be an effective Alzheimer’s therapy, Bieberich said. Current strategies to prevent plaque formation, have been unsuccessful, the researchers write.

“We show clearly that sphingomyelinase is causative here in making ceramide, making exosomes and in making plaques,” Bieberich said. He and his teams already are testing different drugs given to patients for reasons other than Alzheimer’s that may also inhibit sphingomyelinase and ultimately ceramide and exosome production.

Inside the brain, ceramide is an important component of the cell membrane, but too much starts collecting in the exosomes, combining with the amyloid to form a disruptive and eventually deadly aggregate. In fact, MCG scientists could see the ceramide and amyloid clustered together in the brains of mice without sphingomyelinase suppression, further implicating a close association.

In a scenario that seems to go full circle, Bieberich has mounting evidence that in Alzheimer’s, there is a shorter, “bad” form of ceramide coating the antennae of astrocytes. Normally, antennae help astrocytes focus on taking care of neurons. But the shorter version that he believes contributes to disease has astrocytes giving up their caretaker role, spending their energy on themselves and starting to divide.

Bieberich and his team already are looking for other exosome triggers such as inflammation-producing immune cells called cytokines as well as physical trauma. Ceramide levels have been proposed as an early Alzheimer’s biomarker as has evidence of amyloid-positive exosomes in the blood.

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Biomarkers May Help Better Predict Who Will Have a Stroke

People with high levels of four biomarkers in the blood may be more likely to develop a stroke than people with low levels of the biomarkers, according to a study published in the August 24, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Identifying people who are at risk for stroke can help us determine who would benefit most from existing or new therapies to prevent stroke,” said study author Ashkan Shoamanesh, MD, of McMaster University in Hamilton, Canada, and a member of the American Academy of Neurology. “Future research could also investigate whether lowering the levels of these biomarkers or blocking their action could be a way to prevent strokes. However, our study does not provide evidence that these markers are validated well enough to be implemented in clinical practice.”

For the study, researchers from the Boston University Schools of Medicine and Public Health measured the levels of 15 biomarkers associated with inflammation in the blood of people from the Framingham Heart Study Offspring Cohort who had never had a stroke. The 3,224 participants were an average age of 61 at the start of the study and were followed for an average of nine years. During that time, 98 people had a stroke.

Of the 15 biomarkers, four were associated with an increased risk of stroke. People with elevated homocysteine were 32 percent more likely to have a stroke. Those with high vascular endothelial growth factor were 25 percent more likely; those with high ln-C reactive protein were 28 percent more likely; and those with high ln-tumor necrosis factor receptor 2 were 33 percent more likely to have a stroke during the study.

Adding these four biomarkers to an existing method of predicting a person’s stroke risk based on factors such as age, sex, cholesterol and blood pressure, called the Framingham Stroke Risk Profile, improved the ability to predict who would develop a stroke.
Shoamanesh noted that the study was observational. It shows a relationship between high levels of the biomarkers and stroke; it does not establish that the high levels cause stroke. He also noted that the biomarkers were measured only once and researchers did not account for infections, chronic diseases or other conditions that could have affected the results. In addition, study participants are mainly of European ancestry and the results may not apply to other populations.

The study was supported by Framingham Heart Study’s National Heart, Lung, and Blood Institute contract, National Institute of Neurological Disorders and Stroke, National Institute on Aging and National Institutes of Health.

The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with 30,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

To learn more about stroke, please visit http://www.aan.com/patients.

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Changes Uncovered in the Gut Bacteria of Patients with Multiple Sclerosis

A connection between the bacteria living in the gut and immunological disorders such as multiple sclerosis have long been suspected, but for the first time, researchers have detected clear evidence of changes that tie the two together. Investigators from Brigham and Women’s Hospital (BWH) have found that people with multiple sclerosis have different patterns of gut microorganisms than those of their healthy counterparts. In addition, patients receiving treatment for MS have different patterns than untreated patients. The new research supports recent studies linking immunological disorders to the gut microbiome and may have implications for pursuing new therapies for MS.

“Our findings raise the possibility that by affecting the gut microbiome, one could come up with treatments for MS – treatments that affect the microbiome, and, in turn, the immune response,” said Howard L. Weiner, MD, director of the Partners MS Center and co-director of the Ann Romney Center for Neurologic Disease at Brigham Women’s Hospital, . “There are a number of ways that the microbiome could play a role in MS and this opens up a whole new world of looking at the disease in a way that it’s never been looked at before.”

Weiner and colleagues conducted their investigations using data and samples from subjects who are part of the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis) study at Brigham and Women’s Hospital. The team analyzed stool samples from 60 people with MS and 43 control subjects, performing gene sequencing to detect differences in the microbial communities of the subjects.

Samples from MS patients contained higher levels of certain bacterial species – including Methanobrevibacter and Akkermansia – and lower levels of others – such as Butyricimonas – when compared to healthy samples. Other studies have found that several of these microorganisms may drive inflammation or are associated with autoimmunity. Importantly, the team also found that microbial changes in the gut correlated with changes in the activity of genes that play a role in the immune system. The team also collected breath samples from subjects, finding that, as a result of increased levels of Methanobrevibacter, patients with MS had higher levels of methane in their breath samples.

The researchers also investigated the gut microbe communities of untreated MS patients, finding that MS disease-modifying therapy appeared to normalize the gut microbiomes of MS patients. The researchers note that further study will be required to determine the exact role that these microbes may be playing in the progression of disease and whether or not modifying the microbiome may be helpful in treating MS. They plan to continue to explore the connection between the gut and the immune system in a larger group of patients and follow changes over time to better understand disease progression and interventions.

“This work provides a window into how the gut can affect the immune system which can then affect the brain,” said Weiner, who is also a professor of Neurology at Harvard Medical School. “Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are at risk.”

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Genetic Variations that Boost PKC Enzyme Contribute to Alzheimer’s Disease

In Alzheimer’s disease, plaques of amyloid beta protein accumulate in the brain, damaging connections between neurons. Now, researchers at University of California San Diego School of Medicine and Harvard Medical School have found that the enzyme Protein Kinase C (PKC) alpha is necessary for amyloid beta to damage neuronal connections. They also identified genetic variations that enhance PKC alpha activity in patients with Alzheimer’s disease.

The study, published May 10 in Science Signaling, may present a new therapeutic target for the disease.

“Until recently, it was thought that PKC helped cells survive, and that too much PKC activity led to cancer. Based on that assumption, many companies tested PKC inhibitors as drugs to treat cancer, but they didn’t work,” said co-senior author Alexandra Newton, PhD, professor of pharmacology at UC San Diego School of Medicine.

“Instead, we recently found that the opposite is true. PKC serves as the brakes to cell growth and survival, so cancer cells benefit when PKC is inactivated. Now, our latest study reveals that too much PKC activity is also bad, driving neurodegeneration. This means that drugs that failed in clinical trials for cancer may provide a new therapeutic opportunity for Alzheimer’s disease.”

The study was a three-way collaboration between experts in PKC (Newton), neuroscience (Roberto Malinow, MD, PhD, Distinguished Professor of Neurosciences and Neurobiology and holder of the Shiley-Marcos Endowed Chair in Alzheimer’s Disease in Honor of Dr. Leon Thal at UC San Diego School of Medicine) and genomics (Rudolph Tanzi, PhD, professor of neurology at Harvard Medical School).

Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.

Enter the Tanzi team, which has a database of genetic information for 1,345 people in 410 families with late-onset Alzheimer’s disease. Tanzi and team use this database to look for rare variants — genetic mutations found only in family members with the disease. Here, the team found three variants in one form of the PKC enzyme, PKC alpha that were associated with the disease in five families.

The researchers replicated these three PKC alpha gene variants in laboratory cell lines. In each instance, PKC alpha activity was increased.

While this study surfaced only five families with these rare mutations in the PKC alpha gene, there are many ways to influence PKC alpha’s activity, Newton said. She believes there could be many other inherited genetic variations that indirectly boost or inhibit PKC activity, and therefore also influence a person’s likelihood of developing Alzheimer’s disease.

“Next we want to identify more molecules participating in the pathophysiology,” said Malinow. “The more steps in the mechanism we can understand, the more therapeutic targets we’ll find for Alzheimer’s disease.”

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Experimental Drug Cancels Effect From Key Intellectual Disability Gene in Mice

A University of Wisconsin-Madison researcher who studies the most common genetic intellectual disability has used an experimental drug to reverse — in mice — damage from the mutation that causes the syndrome.

The condition, called fragile X, has devastating effects on intellectual abilities.

Fragile X affects one boy in 4,000 and one girl in 7,000. It is caused by a mutation in a gene that fails to make the protein FMRP. In 2011, Xinyu Zhao, a professor of neuroscience, showed that deleting the gene that makes FMRP in a region of the brain that is essential to memory formation caused memory deficits in mice that mirror human fragile X.

The deletions specifically affected neural stem cells and the new neurons that they form in the hippocampus.

Tantalizingly, Zhao’s 2011 study showed that reactivating production of FMRP in new neurons could restore the formation of new memories in the mice. But what remained unclear was exactly how the absence of FMRP was blocking neuron formation, and whether there was any practical way to avert the resulting disability.

Now, in a study published on April 27 in Science Translational Medicine, Zhao and her colleagues at the Waisman Center at UW-Madison have detailed new steps in the complex chain reaction that starts with the loss of FMRP and ends up with mice that cannot remember what they had recently been sniffing.

This study’s newfound understanding of the biochemical chain of events became the basis for identifying an experimental cancer drug called Nutlin-3, which blocks the reaction.

In the new study, mice with the FMRP deletion took Nutlin-3 for two weeks. When tested four weeks later, they regained the ability to remember what they had seen — and smelled — in their first visit to a test chamber.

Statistically, the memory capacities of normal mice and fragile X models that were treated with Nutlin-3 were identical.

Still, many hurdles remain before the advance can be tested on human patients, Zhao says. “We are a long way from declaring a cure for fragile X, but these results are promising.”

Fragile X appears after birth, says Zhao. “Parents start to notice something is wrong, but even if they get an accurate diagnosis, there is no treatment at present. I’m encouraged because affecting this gene’s pathway does seem to reverse the memory impairment.”

The mouse memory test relied on curiosity. “We placed two objects in an enclosure and let the mice run around,” Zhao says. “Mice are naturally curious, so they explore and sniff each one. We take them out after 10 minutes, replace one object with a different one, wait 24 hours and put the mouse back in. If the mouse has normal learning ability, it will recognize the new object and spend more time with it. Mice without the FMRP gene don’t remember the old object, so they spend a similar amount of time on each one.”

The behavioral assessment was done by different people, says Zhao. “First author Yue Li, a postdoctoral researcher at Waisman, ran the test and sent the video to Michael Stockton, an undergraduate working on the project.” Stockton timed how and where each mouse was exploring, “but he had no idea which mouse was which,” Zhao says. “It was fantastic to see such clear data.”

Two other undergraduates, Jessica Miller and Ismat Bhuiyan (who is now in graduate school) and postdoctoral fellows Brian Eisinger and Yu Gao also worked on the study. The Wisconsin Alumni Research Foundation has applied for a patent on the discovery.

Nutlin-3, which can block the last stage of the chain reaction set off by a mutation in the FMRP gene, is in phase 1 trial for the treatment of the eye cancer retinoblastoma. Finding a new use for a drug that is approved, or that like Nutlin-3 and several derivatives, has entered the approval process, may shorten the lengthy FDA process, says Zhao.

The dose used in the trial — only 10 percent of the dose proposed for cancer chemotherapy — caused no apparent harm, she says. “We measured body weight and activity. So far, the mice look healthy and happy.”

Because more than one-third of fragile X patients are also diagnosed with autism, the study may shed light on that condition.

In any case, it’s far too soon to declare victory over fragile X, Zhao stresses. “There are many hurdles. Among the many questions that need to be answered is how often the treatment would be needed. Still, we’ve drawn back the curtain on fragile X a bit, and that makes me optimistic.”

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Cell Transplant Treats Parkinson’s in Mice Under Control of Designer Drug

A University of Wisconsin-Madison neuroscientist has inserted a genetic switch into nerve cells so a patient can alter their activity by taking designer drugs that would not affect any other cell. The cells in question are neurons and make the neurotransmitter dopamine, whose deficiency is the culprit in the widespread movement disorder Parkinson’s disease.

Dopamine is a brain chemical essential for coordinated movement. Dopamine replacement, a standard therapy for Parkinson’s disease, usually loses its effect with time and, with the advent of stem cell technology, biomedical researchers have explored the notion of making dopamine-producing cells in the lab for transplant. And while doctors have tested dopamine cell transplants, the therapy often fails when the transplanted cells make either too much or too little of the essential neurotransmitter.

In a study published April 28 in the journal Cell Stem Cell, Su-Chun Zhang, a professor of neuroscience at the UW-Madison Waisman Center, created two related cell types. When they detect the designer drug, one type ramps up production of dopamine; the other chokes it off.

Zhang and co-first authors Yuejun Chen and Man Xiong grew the specialized nerve cells from human embryonic stem cells, which are able to form any of the 220 cell types in the human body. Their behavioral tests, designed to show when the Parkinson’s symptoms abated in the mice, confirmed that both the “up” and “down” switches performed as anticipated. The results suggest that it may one day be possible to resume dopamine neuron transplants to assist Parkinson’s disease patients.

But the ability to transplant cells that respond to regulatory drugs could have much wider application, says Zhang, who pioneered the transformation of embryonic stem cells into neural cells. “I’m a neuro guy, and the Parkinson’s disease model is very well established in mice — you can measure the outcome in their behavior. If the animal recovers, it must be due to the secretion of dopamine from the transplanted cell.”

Cells tend to have quite specific actions, and the ability to control them with benign drugs could find other uses, Zhang says. In diabetes, for example, “perhaps the beta cells that secrete insulin could be transplanted, and the patients could control insulin secretion with a designer drug.”

The current advance was built with a new, highly precise form of “gene editing” called CRISPR. The new technique replaces the scattershot method of moving genes with something that resembles the “find and replace” command in a word processor that puts the insertion only at the desired location.

Cell therapy was one of the most touted potential benefits of embryonic stem cells and the stem cells that were later derived from adult tissue (both technologies pioneered at UW-Madison), but few applications have reached the clinic as the technology continues to be refined and made safer. Control is part of the problem, Zhang says: “If we are going to use cell therapy, we need to know what the transplanted cell will do. If its activity is not right, we may want to activate it, or we may need to slow or stop it.”

The mouse study showed both abilities, says Zhang, who anticipates that cells will also be engineered to contain switches that work in both directions.

Several major steps will be needed before the first clinical trial can be started. These include:
—Proving the safety of the genetically engineered stem cells, and of the drugs used for control purposes.
—Choosing transplants with maximum potential for natural, neural control of dopamine secretion.
—Ensuring that the neurons reach the brain location where dopamine is needed to control movement.
—Passing nonhuman primate studies. “We need to prove that this is not just a mouse phenomenon,” Zhang says, “that this really works to alleviate the symptoms of Parkinson’s disease.”
Such studies are already underway, he adds.

Despite those hurdles, Zhang considers the discovery one the most exciting in his substantial record of scientific firsts. After the engineered cells are transplanted into the mouse brain, he says, “we can turn them on or off, up or down, using a designer drug that can only act on cells that express the designer receptor. The drug does not affect any host cell because they don’t have that specialized receptor. It’s a very clean system.”

The study shows, for the first time with a human stem cell transplant, that because of this new technology of gene editing, you can remotely regulate the function of the transplanted cell, one that is reversible. If you take away the drug, it comes back.

Many other conditions could benefit from this approach, Zhang says. “This is the first proof of principle, using Parkinson’s disease as the model, but it may apply to many other diseases, and not just neurological diseases.”

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Inhibition of β2-Adrenergic Receptor Reduces Triple-Negative Breast Cancer Brain Metastases: The Potential Benefit of Perioperative β-Blockade.

While we look to invent new medicines to treat cancer, a parallel approach to repurpose existing medicines may be highly effective. Stress, mediated by adrenaline, has been suspected to promote cancer growth and this research study shows that by blocking adrenaline receptors in breast cancers, they are less successful in spreading to and growing in the brain.

Background: Cancer cells are under the relentless drive to spread, this metastasis is responsible for a majority of cancer-related deaths. The most ominous part of the body to which cancer can spread is the brain leading to what is called brain metastasis. Because the brain is highly unique in its anatomy and biology, breast cancer cells circulating in the blood would need to exhibit unique features to exploit the brain’s native nutrient sources – neurochemicals. Interestingly, adrenaline is a major neurochemical that is abundant during stress and also narrows blood vessels resulting in elevated blood pressure. Since many people are on regular blood pressure medicine, we investigated with bioinformatics whether patients on beta blockers (a specific blood pressure medicine that blocks the adrenaline receptor) had fewer metastases using a City of Hope patient database. In parallel, we looked at the cancer biology of triple negative breast cancers and adrenaline in the laboratory.

How the Study Was Conducted and Results: This study was initiated by a retrospective study of the metastatic breast cancer patient population at City of Hope, comparing patients who were on beta-blockers versus patients who were not taking beta-blockers. The clinical analysis suggested that there was decreased metastasis in patients taking beta-blockers.

We further investigated the effects of beta-blockers in the laboratory, and found high receptor expression in both Triple Negative (TN) breast cancer and brain metastasis tissues but not in Her2+ breast cancer and brain metastasis tissues. We then applied a variety of beta-blockers used in the clinic to the breast cancer and brain metastasis cells in the laboratory in order to observe three traits of metastasis- proliferation, migration, and invasion. We found that brain metastases cells were more sensitive than primary breast cancer cells to select beta-blocker treatments. There was a decrease in proliferation, migration, and invasion in brain metastasis cells when treated with beta-blockers. Finally, addition to using the beta-blockers alone, we added beta-blockers to cells treated with drugs that would activate the receptor. Although activating the receptor increased metastatic traits, beta-blockers decreased those effects.