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In the 90s, Alzheimers researchers were full of optimism. New genetic studies all pointed to one culprithard clumps of protein, called amyloid, that litter the brains of people with the disease.

With the emergence of the first tangible target, pharmaceutical companies jumped in to develop drugs to clear amyloid from the brain. In animals, the drugs appeared to improve memory. But the results of human clinical trials that followed were disheartening: One after one, these drugsall designed to target amyloidhave failed to slow the disease.

The onslaught of news about these failures has left the public wondering whether amyloid has anything to do with Alzheimersand whether a new approach is needed.

The field has already begun to redirect its focus, says Scott Small, MD, director of Columbias Alzheimers Disease Research Center and theBoris and Rose Katz Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons.

Theres now reason to be cautiously optimismistic, he says, because we have uncovered new pathways that lead to the disease, and we know that they truly make a difference.

The CUIMC Newsroom spoke with Small about the current state of research into Alzheimers treatments and prevention.

In retrospect, the idea that reducing amyloid in the brainwhich all the failed drugs dois based on an incomplete picture of the disease.

To treat a disease, we need to treat whats broken. But its very difficult to find whats broken in these slowly progressive brain disorders.

One way to find whats broken is through genetics, but the first wave of genetic studies in the 80s and 90s only had the technical capabilities to investigate Alzheimers cases that run in families, those caused by a single gene.

The results of these studies all seemed to converge on one biological process: amyloid.

But these single-gene forms of Alzheimers are rareand account for maybe 2% to 3% of cases. Most cases of Alzheimers are caused by a complex interplay of many genes and the environment.

The field made the assumption that amyloid is the primary culprit in all forms of Alzheimers. It made perfect sense, because we see amyloid in all patients with Alzheimers, whether their disease is caused by a single gene or not.The amyloid finding was extremely exciting, and there was a sense that we were on the cusp of curing this devastating, horrible disease.

The amyloid hypothesis is that amyloid is the trigger of everything in Alzheimers. That seems now to be wrong.

New studies from the past decade tell us that amyloid is part of the story of Alzheimers disease, but its the smoke, not the fire. Weve learned that the single-gene and more common, complex forms of Alzheimers are not identical, though they do overlap.

Theres been a lot of backlash against the amyloid hypothesis lately, but in the 90s, it was the right idea. The pharmaceutical industry was right to jump on the amyloid bandwagon. And theyre now right to give it up, I think.

Back in the 80s and 90s, genetic tools weren't quite developed enough to address the real question we had: What genes are involved in most cases of Alzheimers disease?

Techniques have advanced and we can now answer this question. New studiesmany led by Richard Mayeux, MD[chair of neurology at Columbia]have been pointing to other processes in the brain. We also have better biological tools that can reveal the basic problem inside neurons.

Based on this research, the new consensus in the field is that there are two other pathways that cause the disease.

One involves protein trafficking, which is how proteins are shipped to different sites within a single cell. The health of neurons, more so than other cells, depends on protein trafficking in and out of one particular site: the endosome.

In Alzheimers, the flow of proteins out of the endosome is blocked, and we think that causes the other problems we see in the disease: the amyloid, the tau tangles also common in the Alzheimers brain, and the neurodegeneration. Essentially it's a plumbing problem.

Our research here at Columbia provided some early evidence for an endosomal trafficking problem in Alzheimers. And genetic studiesincluding those led by Dr.Mayeuxhave now found that some endosomal genes are linked to Alzheimers, which provides more support.

The second pathway involves microglia, which are cells in the brain that help maintain the health of neurons and help keep the spaces between neurons clear of pathogens, protein aggregates, and other cellular debris.

Recently discovered genesby Phil De Jager, MD, PhD, in our center and otherspoint us to these cells. But what exactly is wrong with the microglia is still hotly debated. We dont know if theyre working too well or not well enough, but we do know theyre not working properly.

We now, I believe, have evidence to help us understand why the first hypothesis was wrong. Scientifically, we have very good justification to argue why our new hypotheses are correct.

Were now seeing that companies are getting back into drug development because these new pathways are so compelling.

In the coming years, our biggest focus at the Alzheimers Disease Research Center at Columbia will be accelerating drug discovery. One of the most important goals is to develop new biomarkersfor the new Alzheimers pathways. These biomarkers are crucial for developing the new generation of theraputic agents.These biomarkers will be useful for enrolling patients into new anticipated clinical trials, following the logic of precision medicine.Also, just as biomarkers of amyloid were important for testing assumptions about the primacyof amyloid in the disease, these biomarkers are important for testingor potentially refutingthe new pathways.

Were also testing gene therapies and other ways to restore endosomal traffickingto see if that prevents neurodegeneration in animal models.

Frank Provenzano and Adam Brickman are developing new techniques, with imaging and cognitive testing, to detect patients with endosomal defects as early as possible. We think the sooner we can treat people, the better. Sabrina Simoes, one of our newest members, is developing new ways to use spinal fluid and blood to remotely monitor endosomal trafficking. Thats a critical step in measuring a drugs effectiveness when the drug moves to clinical testing.

In science, though, you never can be sure.The only way well know were right is by developing drugs and testing the hypothesis in clinical trials in patients, like we did with the amyloid hypothesis.

In my practice, I encounter many people who have family members with Alzheimer's and theyre worried about that their genes. But in most cases, just because your mother has it, doesnt mean youre going to get it.

In a complex disease, each gene and each environmental factor is like putting a pebble on a scale. None of them by themselves can prevent or cause Alzheimers.So if your parent has Alzheimers, that puts one pebble on the scale. But if you went to college, if you exercise, those are pebbles on the other side of the scale.

Many of the things that we thought historically cause Alzheimer's have been debunkedfor example, the idea that itwas caused by various heavy metals. But we do know that maintaining cardiac health is good: Exercise is good; smoking is bad; developing diabetes or obesity increases the risk.These recommendations, as most people know, are true for any disease.

People often ask me this question, hoping I know something that no one else does. I dont have any other answers at the moment, but everyone in the field is doing their best to find new ways to forestall this disease.

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Will a Treatment for Alzheimer's Ever Be Found? - Columbia University Irving Medical Center

At the start of this decade, the federal government called out consumer DNA testing as a burgeoning scam industry. Little did we know how it would explode in popularity.

In 2010, the U.S. Government Accountability Office (GAO) published an investigative report that bashed consumer DNA test companies for misleading the public. It accused them of deceptively claiming their products could predict the odds of developing more than a dozen medical conditions; some even went as far to offer equally dubious dietary supplements. The report had followed a similar lambasting of the industry by the GAO in 2006.

Also in 2010, the FDA publicly warned 23andMe and other companies that genetic health tests were considered medical devices and needed to be cleared by the FDA before they could be sold to the public. Three years later, following a lack of response from 23andMe, the agency took the harsh step of temporarily banning 23andMe from selling its health-related tests at all.

Despite these hurdles, the DNA testing industry has nonetheless exploded. According to a report by MIT Technology Review this February, more than 26 million people have had their DNA tested by the biggest names in the industry, with AncestryDNA, 23andMe, and MyHeritage being the top three.

Consumer DNA testing is undoubtedly now mainstreambut its not much less scammy than it was when the decade started.

The industry has existed since the late 1990s. But in 2007, the new kid on the block, 23andMe, became the first company to offer a particular kind of at-home DNA test that was cheap, easy to use, and promised to track back your origins further back than ever before.

23andMes testsand eventually those of its competitorssearch for and analyze the most common genetic variations, called single nucleotide polymorphisms (SNPs), in our autosomal DNA, the 22 of 23 pairs of chromosomes not used to determine sex. For as little as $99 and a spit sample, these SNP-based tests are advertised to determine a persons ancestry or genetic health risks. But much of this realm of consumer DNA testing, as the GAO report showed, can uncharitably be described as complete bullshit.

The crux of the problem is that our genetics are only a piece of the puzzle that influences our health. Sure, you can sometimes point to a specific gene mutation that always makes someone sick in a specific way if they carry it. But much more often, its a complex, barely understood mix of gene variants that predispose us to develop cancer or heart diseaseand that risk can be amplified or muted by our environment (including the crucial months we spend in the womb).

In the earliest days, companies didnt much care for this complexity, using weak evidence to make sweeping health claims about which genes ought to make you more of a fish eater or develop diabetes.

Following the FDAs ban in 2013, 23andMe spent the next two years devising genetic health tests that wouldnt overpromise. In 2015, it was allowed to sell tests that told people if they carried a recessive mutation for genetic conditions like Bloom syndrome and sickle-cell disease. A positive test meant their children would have a 25 percent chance of having the condition if both parents were carriers. Two years later, it became the first company with FDA-approved tests that were allowed to tell people about their risk of developing one of 10 diseases or conditions, such as late-onset Alzheimers or celiac disease.

23andMes return to the health side of things wasnt the only fuse that lit a fire under the consumer DNA industrythe tens of millions in annual advertising now being spent by companies like MyAncestry certainly helped, too. But regardless, the FDAs approval of these tests signaled a new opening in the industry. And unsurprisingly, the industry as a whole has ballooned, as has the glut of scammy services on offer.

Many of these companies now steer clear of making blanket health claims, but it doesnt make them any less laughable. Your DNA results can apparently tell you whether youve found your romantic match, how to be good at soccer, and, like a decade ago, how to find the perfect diet and avoid bloating. Just dont pay attention to the studies showing that theres no consistent link between genes seemingly tied to our nutrition and any actual diet-related conditions.

Its not only the tests vaguely connected to our health that are the problem. As Gizmodo once illustrated, even relying on these DNA tests to figure out your ancestry is a dicey proposition. At best, youre roughly estimating where your recent ancestors lived, but that estimate can vary widely depending on which company does the testing, thanks to the different algorithms they use. And the farther away your lineage is from Europe, the less accurate these tests will be for you, thanks to the fact that the algorithmsas well as the research linking genes to our healthare largely based on the DNA of white Americans and Europeans.

Health and ancestry aside, sharing your DNA with the outside world can have unintended consequences. Law enforcement agencies are now using genealogy databases to solve criminal cases, by connecting anonymous crime scene DNA to DNA submitted to these family tree companies, working backward through distant relatives to identify their suspect. And while some people may be fine with this genetic sleuthing, there are no clear rules on how this data can be used by law enforcementtheres merely the promise by private companies that they will share responsibly. This November, police in Florida obtained a warrant to search through a third-party genealogy database, months after the service had enforced a new opt-in policy meant to let users decide if they wanted their data to be searchable by police in these cases.

At a certain point, it wont even matter whether youve decided to share your DNA. A study last October estimated that once enough peoples DNA is in a databasea scant 2 to 3 percent of any given populationanyone could conceivably track the identity of every person in that population using the same techniques genetic detectives are using now. And researchers have already demonstrated how less scrupulous forces, including hackers, could actively manipulate these databases.

None of this is meant to diminish the real potential of genetics as a field of research and medicine, nor the progress that has been made over the past decade.

Companies like 23andMe rely on detecting thousands of genetic markers still only a tiny slice of our DNA. But the technology that allows a persons entire genome to be sequenced has vastly improved, scaling down its costs and upkeep over the past decade. These techniques can scan a persons whole genome as well as the smaller part of the genome that codes for the proteins our bodys cells make, called the exome.

In 2010, for instance, the company Illumina initially offered its whole genome sequencing at $50,000 a person; this year, Veritas dropped the price of its service to only $600 and says it may soon charge as little as $100.

These innovations have led to large-scale research projects that collect genetic data from hundreds of thousands of people at once. Scientists can scour through these large datasets to find new links between our genes, traits, and medical conditions. This research has helped us better understand longstanding questions about our biology and health. Someday soon, genetic sequencing may also help us optimize the existing medical treatments people get, particularly for conditions like cancer.

Right now, though, its still up in the air how useful this info dump really is to the average person looking to stay healthy.

In March, 23andMe debuted (or more accurately, reintroduced) a service that tells people about their genetic risk of type 2 diabetes. Unlike the tests approved by the FDA, it relies on whats known as a polygenic risk score. This adds up the very small contribution of many genetic markers to a particular condition, which combined might be enough to nudge your overall risk upwards.

The trouble is that these markers have little to do with why you get type 2 diabetesyour age or weight play a much bigger role. And even if the test does consider you genetically unlucky (an average risk difference of 5 percent from a typical person), the advice youll get is the same that anyone hoping for a long, healthy life would get: eat more vegetables and exercise more. This test, as well as many of those offered by the hundreds of big and small DNA testing companies on the market, illustrates the uncertainty of personalized consumer genetics.

The bet that companies like 23andMe are making is that they can untangle this mess and translate their results back to people in a way that wont cross the line into deceptive marketing while still convincing their customers they truly matter. Other companies have teamed up with outside labs and doctors to look over customers genes and have hired genetic counselors to go over their results, which might place them on safer legal and medical ground. But it still raises the question of whether people will benefit from the information they get. And because our knowledge of the relationship between genes and health is constantly changing, its very much possible the DNA test you take in 2020 will tell you a totally different story by 2030.

Given how popular at-home DNA testing has become, theres really no sealing the genie back in the bottle. So if you want to get your genetic horoscope read this holiday, dont let me stop you. But its a big decision you should sleep on. After all, once your DNA is out there, theres no going back.

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Consumer DNA Testing May Be the Biggest Health Scam of the Decade - Gizmodo

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Personality genes strongly linked to learning, memory

Researchers at Washington University School of Medicine in St. Louis and the University of Granada, Spain, used artificial intelligence techniques to identify gene networks that appear to play a major role in the development of and variation in personality.

Using artificial intelligence techniques, researchers studying the role of genes and the environment in shaping our personalities have identified gene networks largely responsible for the development of and variation in personality.

Those networks include 972 individual genes linked to aspects of personality, such as self-awareness, intentionality which has to do with a person being deliberate or purposeful and creative thinking relating to the purpose and meaning a person hopes to achieve. The findings also suggest that, regardless of genes and environmental factors, individuals still possess the capacity to make choices that also can influence personality and that those choices can result in personality changes over time.

The new research, led by a group at Washington University School of Medicine in St. Louis and the University of Granada, Spain, is published Nov. 21 in the journal Molecular Psychiatry.

Personality is an individuals unique pattern of behaviors, feelings and thoughts, and those factors are strong predictors of physical, mental and social health, said the studys senior investigator, C. Robert Cloninger, MD, a professor emeritus in psychiatry at Washington University. A better understanding of how those factors work together could contribute to improvements in psychiatric and general health for people around the world.

Cloninger

Using computer algorithms, they identified three distinct gene networks connected to personality. The networks are related to learning and memory, but the computer algorithms also found that most of the genes in the three personality networks are not only associated with brain activity but also function in many other organs. As a result, development of a healthy, well-integrated personality may influence a persons physical health as well as his or her mental and social health and well-being, Cloninger said.

In addition to genes, a persons environment which might include home life, family income level, education, exposure to violence or poverty, rural or urban life, and other factors also influences personality, he said. Our personalities develop from the actions of both genetic and environmental factors, as well as interactions between genes, and between genes and environment. Although there are many combinations of genetic and environmental influences, as human beings we still have the capacity to freely choose some aspects of how our personalities develop.

The researchers studied gene-environment relationships in more than 2,100 healthy people in Finland who were part of whats called the Young Finns Study. The scientists then replicated those findings in people from other cultures and backgrounds, studying similar genetic data from more than 900 healthy adults in Germany and more than 1,000 adults in South Korea.

We were able to replicate associations between genetic markers and personality traits in all three groups, said co-investigator Igor Zwir, PhD, an assistant professor in psychiatry and an associate professor in computer science and artificial intelligence at the University of Granada, Spain. In all three populations, we found the same associations between personality traits and genetic markers. However, in people within each country, the same gene networks didnt always lead to the same personality traits.

Zwir

Even with the influence of genes and environmental factors, Cloninger noted that an individuals free will also is involved in how his or her personality develops, as well as how it might change over time.

For a long time, mental health professionals felt that personality traits were fixed early in life and that a persons personality didnt really change much, but weve found that personality can and does change and evolve, he said. Some gene networks influence habit learning, which is the gradual acquisition of associations between stimuli and responses that help us learn to make one choice rather than another. Others influence our capacity to set goals and accomplish them intentionally. But when we change our goals and intentions, or the things we value, we actually also modify the ways that these genes work to influence personality. In other words, our character allows us to regulate the way some of these genes function.

The researchers divided personality into two parts: temperament, representing habits and automatic emotional reactions; and character, representing qualities such as cooperativeness, self-directedness and self-transcendence. The way a person develops his or her character shapes the ability to regulate desires and to satisfy goals and values.

Computer algorithms allowed the researchers to identify clusters of genes related to character that regulate temperament through pathways that involve learning. But in addition to their effects on the brain, those genes also may influence overall health and vulnerability to illness. It turned out the healthiest people were able to create healthy ways of living, using their self-awareness and insight.

The researchers also found that some of both temperament and character were passed on from ones parents. About 50% of a persons temperament and character were heritable. In addition, they found that what was inherited involved three distinct ways of learning that are crucial to being healthy and feeling satisfied with life.

Nature and nurture cannot be separated, Cloninger said. We inherit how we learn, and that means we are then able to deliberately and creatively shape how we adapt to lifes challenges and opportunities.

Added Zwir: Although we inherit some of our personality, that still leaves a great deal of room for change. We are uncovering a dynamic system of relationships between gene networks and environmental factors. If you measure personality with our tools and then come back and do it again six months or a year later, you might see changes because personality seems to develop and evolve. Very little of this is fixed. It can be changed in both positive and negative ways.

Zwir I, et al. Three genetic-environmental networks for human personality. Molecular Psychiatry, published online Nov. 21, 2019. https://doi.org/10.1038/s41380-019-0579-x

Also see Cloninger CR, et al. The complex genetics and biology of human temperament: A review of traditional concepts in relation to new molecular findings. Translational Psychiatry, published online Nov. 11, 2019. https://doi.org/10.1038/s41398-019-0621-4

The Young Finns Study was financially supported by the Academy of Finland; the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals, the Juho Vainio Foundation; the Paavo Nurmi Foundation, the Finnish Foundation for Cardiovascular Research; the Finnish Cultural Foundation; the Tampere Tuberculosis Foundation; the Emil Aaltonen Foundation; the Yrjo Jahnsson Foundation; the Signe and Ane Gyllenberg Foundation; the Diabetes Research Foundation of the Finnish Diabetes Association; an EU Horizon 2020 grant; and the Tampere University Hospital Supporting Foundation. The American Foundation for Suicide Prevention supported the study of healthy Germans. The national Healthy Twin Family Register of Korea supported the study of healthy Koreans. In addition, the Anthropedia Foundation and the Spanish Ministry of Science and Technology supported the collaboration.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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AI helps identify gene, environment networks that shape personality - Washington University School of Medicine in St. Louis

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School of Medicine leading multicenter study aimed at understanding brain development in babies with the condition

Kelly N. Botteron, MD, a professor of psychiatry and of radiology at Washington University School of Medicine in St. Louis, is leading a multicenter brain-imaging study focused on infants with Down syndrome. The five-year, $11.5 million grant from the National Institutes of Health (NIH) will focus on brain development in babies with the genetic syndrome.

Researchers at Washington University School of Medicine in St. Louis have received a five-year, $11.5 million grant to lead a multicenter effort to understand how brain development in babies with Down syndrome differs from that in other babies. The effort, which involves scanning the babies brains using MRI, will provide a foundation that may lead to therapies to counter developmental delays in children with the condition.

The grant, from the National Institutes of Health (NIH), is part of a $77 million initiative that began in 2018 to bolster basic and clinical research focused on infants and children with Down syndrome. Most people with the genetic condition have mild to severe developmental delays, learning disabilities, and distinct facial and physical features. Some also experience heart and gastrointestinal disorders.

Each year, about 6,000 babies in the U.S. are born with the condition.

It is astounding how sparse the research is involving neuroimaging characterization of neurodevelopment in Down syndrome, especially given that the condition is rather common, said the studys lead investigator, Kelly N. Botteron, MD, a Washington University professor of psychiatry and of radiology. Brain-imaging studies in children with Down syndrome are almost nonexistent. Before we can develop and assess therapies to improve cognitive outcomes, we need to understand more about the alterations in early brain development in these children.

Researchers will conduct behavioral and developmental testing, as well as MRI brain imaging, to examine the brain structure and cognitive function of 140 infants with Down syndrome and 70 babies without the condition. The children will be studied when they are 6 months old and, again, when they are 1 year old and then 2 years old.

The researchers also will compare the brain scans of the two groups of children with scans of autistic infants and toddlers. Such scans in autistic children have been part of a separate multicenter study co-led by Washington University.

This will give us a large set of data to detect differences in neurodevelopmental patterns, Botteron said. It will be eye-opening because there are some developmental characteristics that are unique to children with Down syndrome. They tend to have more motor and coordination delays, in addition to language delays. This information is critical to developing potential innovative treatment trials including additional physical therapy, applied behavior analyses, novel drugs and potential genetic editing techniques to improve both the quality of life and overall health of people with Down syndrome.

The infants will undergo MRI scans, generally in the evening after they fall asleep naturally, nixing the need for anesthesia. The researchers have developed strategies for scanning the brains of babies, based on MRI, without disturbing infants sleep.

Over the past 10 to 15 years, weve learned a lot about conducting brain imaging on infants and children with autism and healthy comparison controls, Botteron said.

One tactic is to introduce the babies beforehand to noise they can expect to hear from the MRI machine. Its important to prepare the babies and toddlers, she said. This means making them comfortable and scanning them at night while theyre naturally sleeping.

The studys other participants include researchers from the University of Washington in Seattle; Childrens Hospital of Philadelphia; University of North Carolina; University of Minnesota; New York University; and the Montreal Neurological Institute in Canada.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Brain imaging of babies with Down syndrome focus of $11.5 million grant - Washington University School of Medicine in St. Louis

Matthew Breen, a professor of genomics at NCState, says his 25-year career has roots in childhood heartbreak.

When I was young, my family had two dogs die from cancer and there was very little we could do to help them, says Breen. There were great strides being made with human cancer research, so why were we unable to help our animal companions more?

We are committed to making that change happen at NCState, he adds.

Today, the internationally recognized researcher specializes in molecular cytogenetics: the study of the structure and function of cells and chromosomes. His work in the College of Veterinary Medicine is helping our pets live longer, healthier lives and unlocking new insights about human cancers along the way.

Since joining NCStates faculty in 2002, Breen has focused on exploring the genetics and genomics of animal diseases, including how they initiate and respond to treatment.

He was a member of the team that sequenced the canine genome 14 years ago. The project sparked a new area of focus in his field: comparing the canine and human genomes to accelerate discoveries for both.

Humans and their furry friends actually share a very similar genetic makeup. And they share certain types of cancers, too. Many cancers diagnosed in humans and dogs have a similar pathology and clinical presentation, says Breen.

But when it comes to canines, its often easier to pinpoint the genetic abnormalities that lead to those cancers. This is especially the case for purebreds. Dogs of the same breed have less genetic variation among them than humans or mixed-breed dogs, making them an ideal genetic model.

Now, Breens lab works extensively in the area and hes become a pioneer in comparative oncology.

By working with human and animal cancers side by side, we are able to find shared features that may help identify the drivers of these cancers and provide opportunities to highlight targets for new therapies, says Breen.

Take, for example, Breens work with the BRAF gene.

Six years ago, his team discovered that a single mutation in the gene was found in 85% of dogs with transitional cell carcinoma (TCC) also called urothelial carcinoma (UC) which is the most common form of bladder cancer in canines. More than 80,000 dogs in the United States will be affected this year alone.

This particular BRAF mutation was already known to exist in some human cancers, but Breens discovery helped unlock its significance for both species. It also revealed an opportunity to create a much-needed tool to aid diagnosis.

By working with human and animal cancers side by side, we are able to find shared features.

In most cases, canine bladder cancer isnt diagnosed until it has reached an advanced stage. Thats because the cancer shares many clinical signs with other, more common urinary tract conditions.

Treatments for the common alternatives may alleviate symptoms temporarily, but they mask the larger problem and buy the cancer more time to progress. In fact, upon diagnosis, more than half of canine bladder cancer cases have already spread.

Identifying the BRAF mutation as a genetic signature of canine bladder cancer was a powerful insight. From there, Breens team began developing a molecular diagnostics test that could identify the mutation and detect the cancer earlier than ever.

That molecular test called CADET BRAF was developed in Breens research laboratory in 2014. Using a urine sample, the system detects cells that possess the BRAF mutation and can monitor changes in the number of mutated cells being shed during treatment of canine TCC and UC.

CADET BRAF represents the worlds first liquid biopsy for the detection of cancer in veterinary medicine, says Breen.

It offers several improvements over current alternatives. Requiring only a simple free-catch urine sample, CADET BRAF is the only non-invasive approach. Other methods often involve costly procedures, such as sedation or anesthesia, that carry additional risks.

The test can also detect bladder cancer in the early stages of the disease, potentially leading to improved outcomes.

CADET BRAF represents the worlds first liquid biopsy for the detection of cancer in veterinary medicine.

We can detect the cancer in dogs that have already presented with clinical signs and avoid repeated attempts to treat solely the signs, says Breen. That allows more time for the veterinarian and owner to develop a plan to treat the root cause. In addition, we have been able to detect the presence of very early disease, several months before the dog has any clinical signs.

Now we have to determine how to manage these preclinical patients, and that is part of ongoing work by our team at NCStates College of Veterinary Medicine, he adds.

The test is also dependable. After rigorous validation of thousands of dogs, Breen says hes found that the presence of the BRAF mutation in canine urine is a highly reliable indicator of the presence of TCC/UC. Weve shown the BRAF mutation isnt found in the urine of healthy dogs or dogs that have other common conditions such as bladder polyps, inflammation or chronic cystitis, he says.

In the two years following the development of CADET BRAF, Breen focused on developing a strong proof of concept. Teaming up with the American Kennel Club, he recruited urine samples from hundreds of dogs to show that the approach could work with real patients.

His next step was commercialization. Breens startup, Sentinel Biomedical, was formed in 2015. Located right on NCStates campus, the company works to develop and scale diagnostic tests for the health care industry.

Since its formation, theyve developed another product called CADET BRAF-PLUS. The test is designed for dogs who dont have the BRAF mutation but do show clinical signs of TCC/UC. It can detect over two-thirds of bladder cancer cases not identified by CADET BRAF, increasing the overall detection sensitivity of the tests to over 95%.

Headquartered right on NCStates campus, Sentinel Biomedical seeks to improve diagnosis and treatment for dogs and their owners.

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Whats next for Sentinel Biomedical? It recently announced a joint venture with Antech Diagnostics, part of MARS. Together theyve formed Antech Molecular Innovations, also based on NCStates Centennial Campus, and work to broaden access to CADET BRAF and CADET BRAF-PLUS.

With the distribution channels of one of the worlds largest animal health providers, we are providing veterinarians with easy access to the tests we develop and enhancing our ability to become a global leader in innovation for veterinary molecular diagnostics, says Breen. And because our work is translational, we also have greater potential to translate our findings to humans.

This will bring the innovations developed at NCState to a whole new level.

Today, the National Cancer Institute spends $6 billion on cancer research annually, and its estimated that less than 0.5% is directed toward veterinary oncology. But Breen sees his innovations and those of his colleagues across the nation as promising steps in the right direction.

Currently, hes involved in a clinical study in the College of Veterinary Medicine that will evaluate the timeline between when a BRAF mutation is detected in a dogs urine and when that dog begins to show clinical signs of TCC/UC. Breen hopes this knowledge will lead to earlier intervention, improved quality of life and increased survival rates.

This will bring the innovations developed at NCState to a whole new level.

Recent collaborations with colleagues at Duke Cancer Institute are also exploring the genetic and environmental factors shared between canine and human bladder cancers. A study proposed by this multidisciplinary team was awarded funding from the V Foundation for Cancer Research in 2019. Such comparative oncology studies, Breen says, have the potential to realize the true value that dogs can bring to our fight against cancer.

Through Antech Molecular Innovations, Sentinel Biomedical has begun pursuing more projects to provide rapid, accessible molecular diagnostics for a variety of cancers that impact our pets and ourselves.

For now, Breen is excited to see his work take on a wider reach. These cancer detection tests will help a new generation of canine companions and their human friends (maybe even kids who are experiencing what Breen did as a child). Whats more, the increased volumes of data theyll collect may unlock insights that lead to the development of new treatment opportunities for cancers in both species.

Although we may not be able to help all dogs with cancer today, we are driven to learn from their cancers to help the dogs of tomorrow, and the families who care for them, says Breen.

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Sniffing Out Cancer in Canines And Humans, Too - NC State News

Delirium is the most common post-surgical complication in older adults. Marked by acute temporary confusion, disorientation and/or agitation, it strikes as many as half of adults over 65 who undergo high-risk procedures such as cardiac surgery and hip replacements.

Postoperative delirium is also tightly linked to Alzheimers disease. Although each can occur independently, Alzheimers is a leading risk factor for delirium, and an episode of delirium puts patients at increased risk for cognitive decline and Alzheimers.

However, the physiological mechanisms that link delirium and Alzheimers disease remain largely unknown.

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Now, in a paper published Nov. 22 in Alzheimers & Dementia: The Journal of the Alzheimers Association, researchers at Harvard Medical School and Beth Israel Deaconess Medical Center shed light on a genetic risk factor for Alzheimers disease that may indirectly influence patients risk of postoperative delirium.

In a study of older adults without dementia undergoing major noncardiac surgery, researchers observed that patients carrying a specific variant of a gene appeared to be much more vulnerable to delirium under certain conditions than people without the variant.

The teams findings could open the door to future interventions to prevent or mitigate postoperative delirium in at-risk patients.

Our findings confirmed our hypothesis that patients risk of postoperative delirium differs by genetic predisposition, said Sarinnapha Vasunilashorn, assistant professor of medicine at HMS and Beth Israel Deaconess and first author of the study. We observed a strong and significant association between high postoperative inflammation and delirium incidence, duration and severity among patients carrying a variant of the gene considered to be risky, while the association was weaker and nonsignificant among noncarriers.

Vasunilashorn and colleagues focused on a gene called APOE, short for apolipoprotein E. The risky version of the gene, notated as APOE 4, is the strongest known genetic risk factor for late-onset Alzheimers disease and a widely studied genetic risk marker for delirium.

While recent studies have shown no direct relationship between APOE 4 and delirium, Vasunilashorns team hypothesized that the gene variant might indirectly influence risk of delirium by modifying the bodys response to inflammationpart of the immune systems natural defense systemindicated by the presence of an inflammatory marker in the blood called C-reactive protein, or CRP.

Using data from the Successful Aging after Elective Surgery (SAGES) study, an ongoing prospective cohort study investigating risk factors and long-term outcomes of delirium, the scientists looked at the incidence, severity and duration of delirium in 560 patients who were at least 70 years old and who underwent major noncardiac surgeries under general or spinal anesthesia. Patients were monitored for delirium, assessed by daily cognitive assessments of attention, memory and orientation throughout their hospital stay.

Analyzing data from patients blood drawn before surgery, immediately after surgery, two days after and one month after revealed that, among carriers of the APOE 4 gene variant, patients with high levels of inflammation had an increased risk of postoperative delirium. However, among noncarriers of the APOE 4 gene variant, the scientists found no such association.

Our findings suggest that APOE 4 may be an indicator of brain vulnerability, said Vasunilashorn. This work may inform the targeting of future interventions, such as anti-inflammatory treatments, for prevention of postoperative delirium and its associated adverse long-term cognitive outcomes in patients with this genetic susceptibility.

Edward Marcantonio, professor of medicine at HMS and Beth Israel Deaconess, is senior author of the study.

This work was supported by the National Institute of Aging of the National Institutes of Health (grants K01AG057836, R03AG061582, P01AG031720, R24AG054259, K07AG041835, R21AG057955, R01AG041274, R21AG048600, R01AG051658 and K24AG035075); the Charles A. King Trust Postdoctoral Research Fellowship Program; Bank of America, N.A., Co-Trustee, and the Alzheimers Association (AARF-18-560786).

Adapted from a Beth Israel Deaconess news release.

Image: kemalbas/Getty Images

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Gene linked to Alzheimers disease plays indirect role in risk for... - ScienceBlog.com

Dr Sadaf Farooqi

BRIGHTON, UK The obesity epidemic is not simply the result of changes in the lived environment but a complex interplay between genes and surroundings that has driven people who would have been genetically susceptible but remained thin in previous eras to become obese, says one expert.

This was the argument put forward as part of a debate on whether an individual's body weight is determined by "nature or nurture" at the recent Society for Endocrinology BES Conference 2019 in Brighton, UK.

Before the debate began, Rob Semple, MD, University of Edinburgh, UK, introduced the speakers and polled the audience on their "baseline" views onthe statement: "This house believes that nature not nurture determines our body weight."

The response was 36% "for" the statement (ie, nature) and 64% "against,"which Semple noted suggested that the first speaker, Sadaf Farooqi, MBChB, PhD, "will have her work cut out" to convince the audience that nature is the main driver of obesity.

Farooqui is professor of metabolism and medicine at the University of Cambridge, UK, and was the winner of the 2019 American Diabetes Association Outstanding Scientific Achievement Award.

Farooqi's adversary in the debate was John Wilding, DM, of the University of Liverpool, UK, who Semple described as "similarly formidable."

Farooqi began by saying that the question before the audience is "fundamentally important," and noted that there is plenty of evidence to suggest there is a biological system for regulating body weight.

Experiments have shown that animals and humans maintain a set point for weight that they return to after periods of limited food intake, regardless of how much weight they lose.

Initially, the hypothalamus was found to play a key role in weight regulation, but it was the discovery of leptin that allowed the whole system, with its links to adipose tissue, the pancreas, and the intestines, to be elucidated, she explained.

Work with children then revealed the influence of genetic factors on the body weight "set point."

Identical twins reared apart were found to have a very similar body weight, and adoptive children were shown to have a similar weight to their biologic, rather than adoptive, parents.

Tying these observations to individual or small numbers of genetic variants has, however, proven difficult, beyond the known variants associated with thinness and the rare variants in 15 genes linked to severe obesity.

That is, Farooqi said, until the publication of US research earlier this year testing a polygenic risk predictor involving 2.1 million common variants in more than 300,000 individuals.

The research showed that, across polygenic score deciles, there was a 13-kg gradient in weight and a 25-fold gradient in the risk of severe obesity.

Moreover, another 2019 study, this time by Farooqi's team, revealed some loss of function variants in the melanocortin 4 receptor gene are linked to an increased risk of obesity, type 2 diabetes, and coronary artery disease, and some gain in function variants are linked to a lower risk of obesity and cardiometabolic disorders.

Farooqi believes the reason there is an obesity epidemic is that the physiological system for regulating weight "evolved to stop us starving" but is now faced with "an abundance of food."

The impact of this is all the greater because we live in a "complex food environment," with high sugar and high fat foods that are seen as "very rewarding," as demonstrated on brain scans of people shown pictures of such foods.

Individuals also engage in stress-related eating, which is played out via neural circuits linking the hypothalamus to the limbic system.

She characterized such eating as a "biologically appropriate thing to do because it gives you a rewarding, pleasurable feeling."

She said that, together, this underlines that the "biology of appetite" is a mixture of both innate and learned behaviors.

Farooqi concluded: "I hope I've made the case for you that there is clear, strong, compelling evidence" that weight is regulated by a homeostatic system centered on the hypothalamus, and genetic disorders, tumors, surgery, radiotherapy, and medications can all "perturb" weight regulation.

"In some people, that promotes obesity, in some people it protects them against obesity," she said.

Dr John Wilding

Taking to the podium, Wilding proceeded to present the case for the notion that body weight is determined "by nurture."

He pointed to data from the World Obesity Federation on adult obesity showing that, between the 1960s and 1990s, the prevalence of obesity topped more than 15% in only a few developed countries and no developing nations.

But from 2000 onwards, the situation has completely reversed. At least 15% of the population is obese in most developed countries, rising to over 25% in the United States, Canada, Australia, and the UK, among others. The prevalence of obesity is also rising rapidly in many middle-income countries.

Yet, Wilding pointed out, humanity cannot have evolved genetically to a sufficient extent over that period to account for the change.

He turned to the UK Government's obesity system map, which is a visual representation of the different factors that influence obesity levels.

Although it places physiological energy balance at the heart of the map, and a large part of that is devoted to biologic processes, Wilding highlighted that the visual also places a great degree of emphasis on food production and consumption, societal influences, individual psychology and movement, and the "activity environment."

He also showed data suggesting it is not so much energy and fat intake that is associated with obesity trends as the increase in the number of cars per household and hours spent watching television.

For example, it is estimated that, compared with the 1950s, the average adult now walks, on average, a marathon (approximately 26 miles) less per week, he said.

The Cuban economic crisis of the 1990s also provides an illuminating example, Wilding added.

The sudden end of Soviet subsidies to Cuba led to food shortages, the loss of public and private transport, and the importof 1.5 million bicycles from China.

The subsequent drop in the prevalence of obesity was associated with a reduction in the incidence of diabetes and diabetes-related mortality, with all three increasing substantially once food and transport levels were restored.

Taking a more recent example, Wilding showed longitudinal findings from the HUNT study, which involved almost 119,000 individuals with repeated body mass index (BMI) measurements from 1963, and over 67,000 who were tested for 96 known obesity genes.

The HUNT authors concluded that, although "genetically predisposed people are at greater risk for higher BMI and that genetic predisposition interacts with the obesogenic environment resulting in higher BMI...BMI has increased for both genetically predisposed and nonpredisposed people, implying that the environment remains the main contributor."

Wilding said that, taken together, obesity is "common and increasing almost everywhere," and that the epidemic "is driven by societal change," despite the underlying biology determining an individual's susceptibility.

He ended his pitch to much laughter with a quote by Farooqi from a 2014 review that supports his argument: "Evidence clearly shows that both increases in energy intake and reductions in energy expenditure during physical activity have driven increases in the mean BMI seen in many countries over the past 30years."

Both speakers were then invited back to the podium, allowing Farooqi to respond that, although she did indeed pen that statement in a 2014 review, if one were to look "carefully," the article discussed the last 30 years, and indeed, "our genes haven't changed in that time, but the environment has."

"We agree on that point, and hence my quote," she said, "but what our environment has done is it has unmasked the genetic susceptibility of some individuals, so what we see when we look at the pattern of BMI in the population is that the mean BMI has increased...but also the proportion of people with severe obesity has increased."

She clarified that what this suggests is that, within any population, there are some people who are genetically more susceptible to obesity, so some of those who may not have been obese 30 years ago now are because of the environment.

"It is the environment acting on genetic susceptibility that is contributing to the distribution of BMI," she emphasized.

Wilding again pointed to the HUNT study, which showed that, even in individuals with "thin genes," there has been a rise in mean BMI.

Farooqi said this, in fact, underlines a limitation of that study, which is they only used 96 well-known genetic variants associated with obesity, but the polygenic risk study she highlighted earlier used 2.1 million genetic variants.

Consequently, data from the HUNT study "captures some of the variation but not all," she stressed.

The debate continued, with questions from the floor covering many aspects of obesity.

The final question was directed at Farooqi: "What proportion of somebody's weight is considered to be genetic...as opposed to the nurtured weight?"

She replied this is a "hugely important" question, because "if we don't recognize that theres a biological role for the regulation of weight, how on earth can politicians, with their somewhat different capacity for taking on new information, do that?"

The "evidence suggests around 40% of a person's weight is influenced by genetic factors," she said.

"In some people it's higher, where there are penetrant genes having an effect, in other people it's about 40% with a combination of genes which, added together, influence their risk of either gaining weight or staying thin."

In response, Wilding was keen to stress: "No matter which side of the argument you're on, the point is that this is not the individual's fault."

"It's either a response to their environment...or it's something that they've inherited and don't have individual control over," he noted.

"Sadaf [Farooqi] said it herself, 40% of our body weight is genetic, that means that 60% is environmental, and I rest my case," Wilding said.

However, that did not hold sway with the audience, who, when they voted again at the end of the debate, indicated they had changed their minds: 53% agreed with the statement that nature, not nurture, determines body weight, and 47% disagreed.

A win for the lady, it would seem.

Society for Endocrinology BES 2019. Presented November 11, 2019.

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Nature vs Nurture: What's Fueling the Obesity Epidemic? - Medscape

Posted By: Staff WriterNovember 18, 2019

With artificial intelligence and genetic engineeringcontinuing to shape the future of scientific innovation and discovery,questions about the ethical implications only seem to get more complicated.

Additionally, CRISPR a tool for DNA sequencing and geneediting is bringing new technological changes and advancements in a rapidlyshifting landscape.

A panel discussion at Stanford University later thisweek, moderated by Russ Altman a professor of Bioengineering, Genetics,Medicine, Biomedical Data Science and Computer Science at the university, seeksto discuss how AI and CRISPR are influencing these ethical quandaries and howthey might influence the evolutionary process.

The two panelists for the free, sold-out event areleaders in the field. Jennifer Doudna, a professor of chemistry and molecularand cell biology at UC Berkeley, helped discover CRISPR-Cas9. Fei-Fei Li is acomputer science professor at Stanford in the universitys Institute forHuman-Centered Artificial Intelligence. She previously worked at the schoolsAI Lab and at Google.

The Institute for Human-Centered Artificial Intelligenceis hosting for forum at Stanfords CEMEX Auditorium, 655 Knight Way. It is setfor Tuesday, November 19, from 7 to 8:30 p.m.

While the event has sold out of pre-registration tickets,limited general admission will be available at the site. It will also belivestreamed.

To see more details, click here.

To watch the livestream, click here.

Originally posted here:
Examining the ethics of scientific discovery - Cupertino Today

News Release

Wednesday, November 20, 2019

Studies in cell and animal models reveal insights into cancer cells vulnerability that could lead to new strategies against brain cancers.

Researchers have devised a new plan of attack against a group of deadly childhood brain cancers collectively called diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma. Scientists at the National Institutes of Health, Stanford University, California, and Dana-Farber Cancer Institute, Boston, identified a drug pair that worked together to both kill cancer cells and counter the effects of a genetic mutation that causes the diseases.

The researchers showed that combining the two drugs panobinostat and marizomib was more effective than either drug by itself in killing DMG patient cells grown in the laboratory and in animal models. Their studies also uncovered a previously unrecognized vulnerability in the cancer cells that scientists may be able to exploit to develop new strategies against the cancer and related diseases. The results were published Nov. 20 in Science Translational Medicine.

DMGs are aggressive, hard-to-treat tumors that represent the leading cause of brain cancer-related death among U.S. children. DMGs typically affect a few hundred children a year between ages 4 to 12; most children die within a year of diagnosis. Most cases of DMG are caused by a specific mutation in histone genes. Histones are protein complexes in the cell nucleus. DNA wraps around histones to form chromatin, which packages DNA in the nucleus. How DNA winds and unwinds around histones is influenced by enzymes, including histone deacetylases. These enzymes add or remove chemical tags, which indirectly controls if genes are turned on or off.

In an earlier study, Stanford neuro-oncologist Michelle Monje. M.D., Ph.D., and her colleagues showed that panobinostat, which blocks key histone deacetylase enzymes, could restore the DIPG histone function to a more normal state. While panobinostat is already in early clinical testing in DIPG patients, its usefulness may be limited because cancer cells can learn to evade its effects. So Monjes team wanted to identify other possible drugs and combinations of them that could affect the cancer.

Very few cancers can be treated by a single drug, said Monje, a senior author of the study who treats children with DIPG and other diffuse midline gliomas. Weve known for a long time that we would need more than one treatment option for DIPG. The challenge is prioritizing the right ones when there are thousands of potential options. Were hopeful that this combination will help these children.

Monje and the National Cancer Institutes Katherine Warren, M.D., now at Dana-Farber Cancer Institute and Boston Childrens Hospital, collaborated with Craig Thomas, Ph.D., and his colleagues at the NIHs National Center for Advancing Translational Sciences (NCATS). Thomas and his team used NCATS drug screening expertise and matrix screening technology to examine drugs and drug combinations to see which ones were toxic to DIPG patient cells.

NCATS robotics-enabled, high-throughput screening technologies enable scientists to rapidly test thousands of different drugs and drug combinations in a variety of ways. Scientists can examine the most promising single drugs and combinations, determine the most effective doses of each drug and learn more about the possible mechanisms by which these drugs act.

The NCATS researchers first studied the effects of single approved drugs and investigative compounds on DIPG cell models grown in the laboratory from patient cells. They focused on agents that could both kill DIPG cells and cross the brains protective blood-brain barrier, a necessity for a drug to be effective against DIPG in patients. The team then tested the most effective single agents in various combinations.

Such large, complex drug screens take a tremendous collaborative effort, said Thomas, also a senior study author. NCATS was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.

While there were multiple, promising outcomes from these screens, the team focused on the combination of histone deacetylase inhibitors (like panobinostat) with drugs called proteasome inhibitors (such as marizomib). Proteasome inhibitors block cells normal protein recycling processes. The panobinostat-marizomib combination was highly toxic to DIPG cells in several models, including DIPG tumor cell cultures that represented the main genetic subtypes of the disease and mice with cells transplanted from patient tumors. The combination also reduced tumor size in mice and increased their survival. A similar response was found in spinal cord and thalamic DMG models developed from cells grown in culture from patient cells.

The screening studies also provided important clues to the ways the drugs were working. Building on these data, the collaborative team subsequently conducted a series of experiments that showed the DIPG cells responded to these drugs by turning off a biochemical process in the cells mitochondria that is partly responsible for creating ATP, which provides energy to cells. The drug combination essentially shuts down tumor cell ATP production.

The panobinostat-marizomib drug combination exposed an unknown metabolic vulnerability in DIPG cells, said first author Grant Lin, Ph.D., at Stanford University School of Medicine. We didnt expect to find this, and it represents an exciting new avenue to explore in the development of future treatment strategies for diffuse midline gliomas.

Plans are underway for clinical trials of the drug combination and of marizomib alone.

Many drugs that we test have multiple effects on DIPG cells, said Warren, a senior study author. Panobinostat, for example, inhibits a specific enzyme, but it has other mechanisms working in tumor cells that may contribute to its effectiveness. Were still trying to understand the various Achilles heels in these cancer cells. This work is an important step in translating our preclinical data into patients.

Monje stressed the panobinostat-marizomib combination might be an important component of a multitherapy strategy, including approaches that harness the immune system and those that disrupt factors in the tumor microenvironment that the glioma cells depend on to grow. Like Warren, Monje emphasized the need to better understand how drugs target and impact the DIPG cells vulnerabilities.

Our work with NCATS showed the need to gather more preclinical data in a systematic, high-throughput way to understand and prioritize the strategies and agents to combine, Monje said. Otherwise were testing things one or two drugs at a time and designing clinical trials without preclinical data based on hypothesized mechanisms of action. We want to move past this guesswork and provide preclinical evidence to guide clinical decisions and research directions.

Lin added, The idea is to get as many effective tools as possible to work with that can have an impact on patients.

The research was funded by Alexs Lemonade Stand Foundation, Izzys Infantry Foundation, McKenna Claire Foundation, Unravel Pediatric Cancer, Defeat DIPG Foundation, ChadTough Foundation, N8 Foundation, Kortney Rose Foundation, Cure Starts Now Foundation and the DIPG Collaborative, Sam Jeffers Foundation, Lyla Nsouli Foundation, Abbies Army Foundation, Waxman Family Research Fund, Virginia and D.K. Ludwig Fund for Cancer Research, National Institute for Neurological Disorders and Stroke (R01NS092597) and NIH Directors Common Fund (DP1NS111132), Maternal and Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, The DIPG All-In Initiative and the NCATS and NCI intramural programs.

Reference:GL Lin et al. Therapeutic Strategies for Diffuse Midline Glioma from High-Throughput Combination Drug Screening. Science Translational Medicine. DOI: 10.1126/scitranslmed.aaw0064

About the National Center for Advancing Translational Sciences (NCATS):NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visithttps://ncats.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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Scientists find promising drug combination against lethal childhood brain cancers - National Institutes of Health

Mila Makovec has high pigtails in her dark hair and a cloth doll tucked under her arm as she wakes up in a hospital bed, where shes just been injected with a one-of-a-kind drug intended to save her life.

The drug works for only one person in the world this 9-year-old girl from Boulder.

In a spectacular example of what the future might hold for precision medicine, the drug was made only for her in a quest to save Mila from a neurological disease that is destroying her brain. Her DNA is in the formula. The 22-letter genome sequence in the drugs recipe matches the one in Milas cells that is broken.

It is the first time the FDA has approved a drug for a single person.

The drug appropriately called milasen might not have come soon enough to save Mila, as it can only slow the process of degeneration, not replace the brain cells that have already died.

But this story is no longer just about Mila; it never actually was.

This is not just for my daughter anymore, said Julia Vitarello, who took to social media to fundraise and find a researcher and drug manufacturer who would help her. This is for something much bigger.

Milas case catapulted specialized drug development at least a decade into the future, her doctors say, opening a new path for other children with rare genetic diseases that have no cure.

Childrens Hospital Colorado, where Mila was diagnosed three years ago and now receives her treatment, and Boston Childrens, where her drug was designed, are leading the way in creating a model in which academic researchers could help perhaps a handful of children each year by crafting one-of-a-kind medicines. Next year, Childrens Colorado will begin whole-genome sequencing with a new machine called a Novaseq, a major step in the process of finding mutations in DNA.

The whole concept raises ethical questions for sure: How safe is it to initiate a clinical trial for a single child? Who makes sure the children who could benefit most not just those whose families have money or the ability to raise money get the specialized treatment?

Vitarello, who created Milas Miracle Foundation and raised $3 million while trying to save her daughter, wants to establish funding for children who need drugs tailored to their own cellular biology. She suggests an admissions process where the researchers deciding whether to help a child do not know that childs name, face or ability to pay.

There are going to be parents who are going to do anything for their kid, Vitarello said. They are going to come with money. Thats totally fine, no judgment. I would do the same thing. But in an ideal world, there would be patients coming through a funnel with no names or faces or money attached. Whoever is at the table makes the best decision.

The path forward is likely in the academic, nonprofit space, Vitraello said. She is initiating talks with the National Institutes of Health, the largest public funder of biomedical research, as well as research institutions, the FDA and the pharmaceutical industry. An estimated 1.3 million people with rare genetic diseases could potentially benefit from a treatment like Milas, she said.

There are 1.3 million kids that are dying that have no other treatment, no pharma company is going to help them, there is nothing that we can do, and now suddenly, weve opened up a pathway for that, she said Tuesday at the hospital in Aurora, as Mila rested following her injection. The only way to get it is to have more academic institutions treat more kids one, two, five, 10. Open it up.

The goal is that kids with flaws in their DNA could receive precision medicine sooner, halting neurological diseases before they steal the ability to walk, talk, eat or see.

Mila was a perfectly healthy child the first three years of her life. She was learning to ski, went hiking with her parents and had a vocabulary advanced beyond her years.

Her mom noticed the subtle changes before anyone the way she pulled books close to her face because she couldnt see, how her feet turned inward, that she began bumping into things and fell for no reason, how she stuttered sometimes but it wasnt like typical stuttering.

Vitarello brought her to 100 doctors and therapists from the East Coast to the West and in Canada, many of whom told her to calm down and that her daughter seemed fine. I had doctors tell me I was pretty much crazy. Very top level doctors told me to chill out, she said. Well, I wasnt going to chill out. I just kept going.

By age 7, Mila was having trouble walking and eating and was going blind. Her body was wracked with multiple seizures each day.

I spent three years trying to figure out what was wrong with her, Vitarello said. I basically gave up and brought her to the ER at Childrens Colorado.

Mila was admitted and her case assigned to Dr. Austin Larson, a geneticist whose main job at the hospital is to figure out whats wrong with patients who have an undiagnosed disease. An MRI found that the part of Milas brain that is responsible for balance, the cerebellum, was smaller than expected. But it was a genetic test that for the first time gave Vitarello a name for Milas illness: Batten disease, and a specific type of Batten that is so rare, just 25 people in the world are known to have it.

The disease occurs when both of a childs two CNL7 genes are mutated one mutation from each parent.

Larson was able to identify the defective gene from Milas father, but could not find one from her mother. At the time, Childrens Colorado along with most places didnt have the technology to search that deeply into Milas DNA through whole-genome sequencing, and Larson warned Milas family that it was likely impossible to find a clinical lab that could. She would need a researcher.

Vitarello turned to Facebook, begging for help for Mila but also so she could find out if her son, who was 2 at the time and completely healthy, had the same devastating disease that was taking away her daughter.

I was going to get nowhere with Mila unless I just opened up my story fully, to everyone, her mom said.

Dr. Larson had given her enough information and the right words to make a plea. A Boston physician saw her message and connected her with Dr. Timothy Yu, a neurogeneticist at Boston Childrens.

At the same time, the FDA had just approved a new drug called Spinraza, the first drug to treat a separate genetic condition called spinal muscular atrophy. The drug, injected into the fluid around the spinal cord, helped babies in clinical trials improve head control, sitting and standing.

The way Spinraza was designed was a game-changer for medicine and key in helping Mila. Yu and his team in Boston wondered if they could make a similar drug for the Colorado girl.

The Boston team spent days staring at screens of Milas DNA sequences until they discovered the other piece of the genetic puzzle in addition to the gene mutation from her father, Mila had inherited extra genetic material from her mother. The combination meant that, in the most basic terms, Mila had a sequence of broken DNA in her cells.

The drug created only for Mila contains little pieces of synthetic genetic material that search for a specific 22-letter sequence and cover it up so that her cells cannot read it. We are taking a Band-Aid and sticking it onto that part, said Dr. Scott Demarest, a pediatric neurologist at Childrens Colorado and a specialist in rare genetic epilepsies. That is literally what is happening. It is sticking to that spot so that the cell skips over that and goes to the next part that is correct.

The only difference between Spinraza and milasen is the genetic sequence inside the drugs send Band-Aids to different addresses.

After discovering the genetic flaw, Yu in Boston and Larson in Colorado called Milas mom together to give her the news. Her son did not have either of the recessive genes, and her daughter had both.

It was a huge mix of extreme happiness and, within the same second, just extreme falling-to-the-floor sadness for Mila, Vitarello recalled. My daughter had gotten both of the bad mutations and my son had gotten both of the good ones.

Next, Vitarello had to persuade a drugmaker to make a drug for one, and the FDA to allow doctors to inject it in her daughters spinal fluid.

The stars aligned, she says, still in disbelief.

Milas team made it happen by emphasizing that although this drug had the potential to work only on one person, the process could become a blueprint for other patients. Only the DNA sequence in the medicine would change.

They persuaded a drug manufacturer in California, TriLink Biotechnologies, to make Milas drug. And the FDA agreed to speed up the clinical trial process by allowing Yu to test the drug on rats at the same time Mila was receiving her first dose. The doctor had first tested it on Milas skin cells.

Milasen is technically now in clinical trial a trial of one patient involving two childrens hospitals.

The night before Milas first injection in January 2018, as Vitarello went for a run in subzero Boston, she told herself she was OK with whatever happened. Mila was out of time. Vitarello had seen the descriptions online and knew where Mila was headed.

My daughters trajectory of not treating her was so black and white, Vitarello said. Everyone always wonders what is going to happen to your life. When you have a rare disease, you can see exactly what is going to happen to your child ahead of time and its not a good thing.

I figured the worst-case scenario was not her dying, it was her being in pain, Vitarello said, recalling that she asked Yu to tell the FDA that she thought the drugs potential benefits outweighed the risk. I said, If my daughter dies on the spot, Im OK with that.

Instead, the injections that first year seemed to stop the diseases progression. Mila quit eating through a g-tube and started eating her moms pureed food again. She could hold up her head and her upper body, and her walking improved. Her seizures decreased from 30 a day to two or three.

Quality of life, those are huge, Vitarello said.

Now in the second year of treatment, some of Milas symptoms have declined, but not as steeply as other children with her disease. Milas team has upped her doses and started injecting them every two months instead of every three, but they have no precedent to follow.

They could find out years from now that they were giving Mila 1,000 times too little, her mother said.

I honestly dont know if it was in time for Mila, Vitarello said. She was really progressed when she received her treatment. There is still hope.

The key to saving more children from rare genetic diseases is diagnosing them earlier ideally at birth.

What if we found this three years sooner? Larson asked. I think about that a lot. What would it have taken to have found this the first time that (Vitarello) took Mila to a physician and said, I am concerned about the subtle difference in the way she walks?

The answer is it takes having a very broad test and being very good at interpreting that very broad swath of information.

Science is a ways off from being able to detect diseases as rare as Milas in newborns. But breakthroughs are coming for other genetic diseases.

Starting in January, spinal muscular atrophy will become one of 38 genetic diseases newborn babies are screened for via blood tests, said Raphe Schwartz, chief strategy officer for Childrens.

Childrens intends to take what it has learned through Milas case, partner with other institutions and use it to help more children, Schwartz said. What we learn reveals the roadmap for the future, he said. The future ones we do are more effective and less expensive over time.

There is a sense of urgency, but also caution.

We want to make sure we are doing it right, we are doing it safely, we are doing it for kids who are going to benefit the most, Demarest said. There are ethical challenges around it. We need to be very thoughtful and careful that we are doing this the right way, but were also doing it in a way that allows this to be a reality for kids as soon as possible and for as many as possible.

For now, Vitarello is grateful that Mila can receive her treatments in Colorado. Until September, they were traveling to Boston every other month for 10 days, but now they can leave home after breakfast on treatment days and return by dinner.

On Tuesday, Vitarello recited Goldilocks and the Three Bears and sang camp songs while Mila, bundled in blankets, received the 10-minute injection in her lower back, which Vitarello said doesnt seem to hurt Mila. They celebrated Milas 9th birthday last week, and her little brother, now 5, picked out a squishy toy and a sequined mermaid for her birthday presents.

Im faced with a huge amount of sadness around this, but at the same time, its making such a huge difference that it gives a lot of purpose to her life and it gives a lot of purpose to my life, Vitarello said. We are still fighting hard for Mila. But I can see this making a much bigger impact.

This reporting is made possible by our members. You can directly support independent watchdog journalism in Colorado for as little as $5 a month. Start here: coloradosun.com/join

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This miracle drug was designed and manufactured for just one person a 9-year-old Boulder girl - The Colorado Sun

Autoimmune diseases are immune system disorders where the bodys immune system attacks its own tissues. Examples of common autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, multiple sclerosis (MS) and others.

A peculiarity of autoimmune diseases is that they have many genes in common, but they develop differently. For example, why does a patient with an autoimmune disease become a type 1 diabetic rather than have rheumatoid arthritis?

Decio L. Eizirik, a researcher at Universit Libre de Bruxelles Centre for Diabetes Research in Belgium, who is also a senior research fellow at the Indiana Biosciences Research Institute, recently published research in the journal Nature Genetics that found significant insight into this question. Eizirik took time to speak with BioSpace about the research and how a researcher in Belgium came to collaborate with researchers in Indiana, Spain, the UK and the U.S. National Institutes of Health.

Several autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, etc., have as much as 30 to 50% of their candidates genes in common, said Eizirik, raising the question on why in some individuals the immune system attacks, for instance, the insulin-producing beta cells, causing type 1 diabetes, while in others it targets joint tissues, leading to rheumatoid arthritis. Most of the research in the field has focused on the role for these candidate genes on the immune system, but our work indicated that many of these candidates genes affect the function and survival of pancreatic beta cells, leading to a misguided dialogue between them and the immune system that culminates in diabetes.

The early stages of type 1 diabetes, for example, show local autoimmune inflammation and progressive loss of the pancreatic beta cells that produce insulin. How these genetic transcription factors, or cytokines, interact with the beta-cell regulatory environment, and the changes that occur, suggest a key role in how the immune system gets triggered to attack the beta cells.

The research was conducted by Eizirik, Lorenzo Pasquali from the Institucio Catalana de Recerca I Estudis Avancats (ICREA) in Barcelona, Spain, and colleagues from Oxford, UK; Pisa, Italy, and the NIH. For about 20 years, Eizirik has run a diabetes-focused laboratory in Brussels. In August 2019, he launched a new laboratory at the IBRI, where, he said, three top scientists and assistants, Donalyn Scheuner, senior staff scientist at IBRI, Bill Carter, research analyst at IBRI, and Annie Rocio Pineros Alvarez, postdoctoral fellow in medicine at Indiana University, are already working. These two laboratories are working closely togetherfor instance, we have weekly meetings by videoconference, and besides my regular visits to the IBRI, scientists are moving between our European and USA labs on a temporary or permanent basis.

The IBIR was created by the State of Indiana and the states leading life science companies, academic research universities and medical school, as well as philanthropic organizations. The focus is on metabolic disease, including diabetes, cardiovascular disease obesity and poor nutrition. Its laboratories and offices are housed in about 20,000 square feet of space in Indian University School of Medicines Biotechnology Research and Training Center in Indianapolis. It expects to move into a new 68,000-square-feet site in mid-2020.

Eizirik said, The IBRI offers a unique opportunity to translate our basic research findings to the clinic, and we are working closely together with colleagues at Indiana University, particularly Carmella Evans-Molina, director of the Indiana Diabetes Research Center (IDRC) and the IDRC Islet and Physiology Core, to confirm our basic research findings in patients samples, and to eventually bring them to the clinic.

The specific research study looked at the binding of tissue-specific transcription factors. Transcription factors are basically proteins whose job it is to turn genes on or off by binding to DNA. So, for example, there are specific transcription factors whose job it is to regulate insulin production in pancreatic beta cells. In the case of this research, Eizirik and his team studied tissue-specific transcription factors that open the chromatin. Chromatin is a complex of DNA and protein found in the nucleus of the cell. It allows long DNA molecules to be packaged, typically in the form of chromosomes.

For gene transcription to occur, Eizirik said, chromatin must open and provide access to transcription factors. This allows binding of pro-inflammatory transcription factors induced in the beta cells by local inflammation.

For certain people who are genetically predisposed to type 1 diabetes, this leads to the generation of signals by the beta cells, Eizirik said, that contribute to attract and activate immune cells, rendering beta cells a potential target to the immune system.

Eizirik said, These observations have clarified the role for pancreatic beta cells in type 1 diabetes and provided an explanation for the reasons behind the immune system targeting beta cells.

The amplifying loop mechanism observed potentially explains other autoimmune diseases. Eizirik notes, Binding of tissue-specific transcription factors, within an inflammatory context and in genetically predisposed individuals, could generate signals that would attract and activate immune cells against specific target tissues.

Testing the theory in other autoimmune diseases will be required to verify it, but potentially could open up new therapies or preventive treatments for type 1 diabetes and other autoimmune diseases.

Type 1 diabetes has a strong genetic component, Eizirik said. At least 50% of the disease risk is due to genetic causesand understanding the role for candidate genes in the disease may point to novel therapies. For instance, up to now, nearly all therapeutic approaches to prevent type 1 diabetes have targeted the immune system, with little success. Our findings suggest that we must also take steps to directly boost beta cell survival.

He compared targeting the immune system only in type 1 diabetes to trying to fly a plane with only one wing. Our present and previous data suggest that we need two wings: first, to re-educate the immune system to stop its attack on the beta cells, and second, to increase the beta cell resistance to the immune attack, and to find means to restore the lost beta cell mass. Unfortunately, to achieve these goals in both type 1 diabetes and other autoimmune diseases is not easy, and we must redouble our efforts.

The next stages of the research will be to study the function of two novel candidate genes for type 1 diabetes that were discovered in the research. They both act at the beta cell level. He expects to conduct that research with Pasquali. The second stage is to evaluate the impact of other immune mediators that act earlier in the disease course at the beta cell level. And the third stage is to test their hypothesis regarding the role for the target tissue in other autoimmune diseases.

In addition to that ambitious agenda, Eizirik and his group are establishing an Inducible Pluripotential Cell Core at the IBRI.

Eizirik said, This will allow us to de-differentiate, for instance, skin cells from patients into pluripotential cells, and then to differentiate them into pancreatic beta cells. This will allow us to study the impact of the novel candidate genes we are discovering on beta cell function and survival, again in collaboration with Lorenzo Pasquali and Carmella Evans-Molina. This will also provide an excellent model to test new drugs to protect the beta cells in early type 1 diabetes.

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Researchers Working to Understand Why Some Patients with Autoimmune Diseases Develop Diabetes Instead of Arthritis - BioSpace

For most patients,sudden cardiac death iscompletely unexpected, according toDr. Amit Khera, a cardiologist at Massachusetts General Hospital.

Its always particularly devastating because many dont have prior symptoms. Their first symptom is actually dropping dead, Khera said. The question is can we find these people before something really bad happens?

Many scientists, including Khera, theorizedthat one way to find people who might suffer these sudden cardiac deaths fatal events related to an abrupt cardiovascular failure could betheir genetics.

We always had a hunch that maybe there was something in their DNA that predisposed them to this tragedy, he said.

Now, he and his colleagues believe theyve found 14 different gene variants, spread across seven genes that may put their carriers at greater risk for sudden heart death.

The researchers made this discovery by sequencingthe genes of 600 people who died from sudden cardiac death and600 people of the same age whowere healthy. Khera said they focused on 49 genesalreadyknown to be important for cardiovascular disease.

These genes contribute to any of the four major causes [for sudden cardiac death], he said. Sometimes its a weak heart and the pumping function is not quite right. The second is a heart attack. The third is a problem with the hearts rhythm. The last is a tear in a major blood vessel.

After a geneticist on the team analyzed the genetic data, Khera said 14 different versions of 7 genes stood out.

These 14 variants were found in 15 people. Whats really striking is that all 15 people were sudden cardiac death cases and zero were [healthy], he explained.

The team reported their findings Saturday in the Journal of the American College of Cardiology.

After identifying the specific gene variants, theresearchers looked ata larger database of 4,000 individuals. They found that about 1% of the population without a history of heart disease carries them.

Its a really small percent of people, but an important percent," said Khera. "These people are predisposed to sudden cardiac death, and if we can find them then we have tools to prevent disease onset.

Carrying one of these gene variants doesn't mean a person is certain to suffer from sudden cardiac death. But over a period of 15 years, Kherasaid, peoplewho carry at least one of the 14 gene variantsare three times more likely to succumb tosudden cardiac death.

In most cases, doctors saysudden cardiac death arises from preventable causes.

Most of the gene variations underlying [sudden cardiac death] are related to the electrical rhythm of the heart going chaotic or haywire," said Dr. Eric Topol, vice president of Scripps Research and a cardiologist who did not work on the study.

"There are many ways you can prevent this occurrence if you know a person has a high risk mutation, Topol said. Medications or a device like a defibrillator or pacemaker can fix the underlying problem.

There are likely many more mutations that increase the risk for sudden cardiac death.

The more we find of these, the more confident we are that they are the real deal, the better we will, in the future, be at preventing these catastrophes, Topol said. So, I think this is really important work.

And not every sudden cardiac death strikes healthy individuals with no previous history of heart disease, Khera added.

Of course, important lifestyle factors play a role, like smoking over the course of a lifetime or not well controlled blood pressure, he said.

But often, families and friends of those who die from sudden cardiac death dont get a reason for why it happened.

The DNA can provide an explanation as to why this happened, Khera said. And even more importantly, this persons family members may also have the gene variant, and if they know about it then they can take preventative measures.

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Knowing If You Have One Of These 14 Genetic Mutations May Help Prevent Sudden Cardiac Death - WBUR

Mining the rich uncharted territory of the genome, or genetic material of a cancer cell, has yielded gold for Princess Margaret Cancer Centre scientists: new protein targets for drug development against prostate cancer.

Using state-of-the-art, whole-genome sequencing technologies on prostate tumour samples, researchers at the Princess Margaret focused on the often overlooked noncoding regions of the genome: vast stretches of DNA that are free of genes (i.e. that do not code for proteins), but nonetheless harbour important regulatory elements that determine if genes are turned on or off.

Previously dismissed as "junk" DNA, noncoding regions were once thought to have little to offer for a cure against cancer.

But this never dissuaded Dr. Mathieu Lupien, Senior Scientist, Princess Margaret Cancer Centre, to commit his research program to the study of the noncoding genome.

"We are exploring uncharted territory," says Dr. Lupien, who is also an Associate Professor in the Department of Medical Biophysics, University of Toronto, whose lab's tagline is "Decoding cancer through epigenetics."

"Our goal is to conquer cancer in our lifetime. We have to look everywhere including the 'darkest' parts of the genome of cancer cells for that hidden 'gold,'" he says.

In his latest paper, entitled "Cistrome-partitioning reveals convergence of somatic mutations and risk-variants on master transcription regulators in primary prostate tumors," published inCancer Cellon Thursday, Dr. Lupien and a 21-member team of national and international clinicians, scientists, pathologists and computational scientists assessed the role of more than 270,000 mutations found in primary prostate tumours.

They found that these accumulate in specific noncoding regions bound by a specific set of proteins that control the on/off state of genes. Inhibiting these proteins, which Dr. Lupien refers to as "the maestro of the cell," blocks growth of prostate cancer cells, showing their value for drug development.

This represents a new approach that exploits the rich information from all mutations found in tumours, from both coding and noncoding sources. It allows us to prioritize targets for therapy, he explains.

"Just imagine the possibilities the noncoding genome opens up," he adds.

Understanding the non-coding or dark genome is an area of increasing focus for scientists.

In 2003, the Human Genome Project mapped and sequenced the human genome, consisting of all the genes necessary to grow a human being.

It found that about 21,000 protein-coding genes make up about only two per cent of our entire genome the blueprint of life or the human genetic instruction booklet.

And the other 98 per cent of the genome the non-coding (for proteins) portion what role does it play?

Scientists have come to realize that hidden amongst this noncoding DNA are crucial elements that not only control the activity of thousands of genes, but also play a major role in many diseases. Mining this area could provide important sequencing clues for potential cures.

The human genome is incredibly complicated, says Dr. Lupien. He explains that the dark, or as yet undiscovered, portion of the genome contains millions of gene switches, affecting all the cells in our bodies, at various points throughout our lives.

"Now we can start connecting these genetic switches to cancer development to get a more precise understanding of how disease begins and how we can treat it," he says.

Precision medicine currently relies on a few hundred biomarker-drug combination, and we need to expand our list of biomarkers and drugs if we want to deliver on the promise of precision medicine, adds Dr. Lupien. "The inclusion of the noncoding genome in our analysis is a leap in the right direction to achieve our goal," he says.

Reference:Mazrooei, et al. (2019) Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors. Cancer Cell DOI:https://doi.org/10.1016/j.ccell.2019.10.005

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Mining the Genome: Exploring Uncharted Territory To Discover New Drug Targets - Technology Networks

By Stephanie Miceli | Nov. 13, 2019

When Sara Altschule took a 23andMe ancestry test, the results confirmed what she already suspected: She is 77 percent Ashkenazi Jewish. However, months later, after opting into add-on health tests, she received life-changing news: She had a BRCA2 gene mutation, which is particularly prevalent among Ashkenazi Jewish women. Altschules BRCA2 mutation meant her lifetime risk of developing breast cancer is about 69 percent; for ovarian cancer, it is about 17 percent.

As at-home genetic tests grow in popularity, some individuals have expressed concern about the complexities of the results. Speaking about her experience with at-home genetic testing at a recent workshop of the Roundtable on Genomics and Precision Health of the National Academies of Sciences, Engineering, and Medicine, Altschule told attendees, The results not only probably saved my life, but may have also saved the lives of people in my family who now know they are also BRCA2 positive. While empowering for her, she also wishes she had received the results from a genetic counselor not via email.

Traditionally, there have been two main types of genetic testing: traditional tests initiated by a doctor, and direct-to-consumer (at-home) tests. Most people do a combination of both, said keynote speaker Robert Nussbaum, chief medical officer of Invitae. About one-third of people who take an at-home test share the results with a provider, who can make appropriate referrals based on the results, he said.

Knowledge Is Power

After seeing a genetic counselor and getting a more comprehensive blood test, Altschule decided to undergo a preventive double mastectomy at the age of 31. I felt powerless during this process, and I wanted to take my power back. This was the easiest and toughest decision of my life, said Altschule.

Panelist Dorothy Pomerantz, who also received news of her BRCA status via 23andMe, said online test results are not a replacement for a one-to-one conversation with a trusted provider. Pomerantz considers herself lucky to have received actionable information, though she still has complicated feelings about how that information was delivered.

This information is complicated and nuanced. We need someone to walk us through the dark, said Pomerantz. When my genetic counselor confirmed my results, she asked me what I needed in that moment. Did I need to vent? Did I want information? Did I need to be alone or cry?

Affordability Is Part of Accessibility

Aside from having access to genetic testing in the first place, Altschule and Pomerantz acknowledged they had the resources to get immediate follow-up testing and surgery.

What about those who cant get their doctors on the phone? What about those who dont have doctors at all? asked Pomerantz.

Without insurance, someone with a risk of cancer may not have those options, said Sadie Hutson, director of the Cancer Genetics Program at Pikeville Medical Center in Kentucky. In the Appalachian communities where she works, coal mining, the dominant industry, has been linked to high incidences of lung cancer. However, many people have to live with the knowledge of that risk and the inability to act on it.

Affordability of genetic testing is a very real problem, said Hutson.

There is also a dire shortage of genetic counselors in the region, she added. Hutson has partnered with mobile clinics and faith-based organizations that provide genetic testing and counseling free of charge, particularly to the regions Medicaid population. Hutson also noted the importance of offering free follow-up testing to family members.

Panelists discussed the accessibility of direct-to-consumer genetic tests for underserved and rural populations and ways to increase engagement, literacy, and reduce disparities.

Steps Toward Including All of Us

We have a skewed evidence base in human genomics research, said Malia Fullerton, professor of bioethics and humanities at the University of Washington School of Medicine. Because certain populations are underrepresented in research, when they do receive genetic testing, there is a lack of data that they can act on. Joyce Tung, 23andMes vice president of research, acknowledged most of the companys customers are white people of European descent and it wants to change that.

We cant provide information that we dont have, she said. A lack of data can halt progress and new discoveries in diseases that primarily affect diverse communities such as sickle cell disease, which is prevalent in people of African descent. Tung highlighted several initiatives at 23andMe that aim to improve diversity, including the African American Sequencing Project, Global Genetics Project, and the Latino Sequencing Project.

In addition, underrepresented populations are more likely to receive uncertain test results, often because their genetic variants have not been well-studied. As a result, they may experience unnecessary testing or lifestyle changes, or false reassurance, and the psychological burden that comes with it, Fullerton said.

To address the lack of diversity in genetic databases, last year, the National Institutes of Health launched its All of Us research initiative. It aims to collect data from 1 million Americans from various population groups.

The vast majority of 23andMe consumers 80 percent agree to share their data in the hopes of contributing to science and new insights about health and disease. However, the current lack of diversity in genetic databases risks hindering the science.

There is a critical opportunity for multiple sectors to come together to ensure proper inclusion of all individuals in genetic and genomic testing, said Hutson.

Integrating Consumer Genomics into Health Care

Speakers throughout the day acknowledged the challenges around integrating consumer genomics data into clinical care. Consumers often want information fast, but health systems may not be able to quickly provide the confirmation genetic testing following a positive DTC result.

This continuum of care has a lot of access points and a lot of people trying to find pathways, but really it is reflective of the overall health system, said Siobhan Dolan, a professor and vice chair for research at Albert Einstein College of Medicine. Maybe genetics has given people an opportunity to find alternative routes and maybe we could continue to learn from that try to put something together that is continuous.

Visit http://nationalacademies.org/hmd/Activities/Research/GenomicBasedResearch/2019-OCT-29.aspx to view speaker presentations and other information about the Workshop on Exploring the Current Landscape of Consumer Genomics.

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At-Home DNA Tests Still Need the 'Human Touch,' Say Panelists at Genomics Roundtable Workshop - National Academies of Sciences, Engineering, and...

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Researcher Tom Cappola tells us about the latest clinical trials and medical breakthroughs to be announced during Scientific Sessions.

Chief of the cardiovascular medicine division in the Perelman School of Medicine at the University of Pennsylvania, Tom Cappola.

For the first time in its near 100-year history, the American Heart Association (AHA)will host its annual meeting in Philadelphia. AHAs Scientific Sessions is the largest cardiovascular meeting in the United States. On November 16-18, the meeting will attract nearly 18,000 attendees from more than 100 countries to the Pennsylvania Convention Center, and an additional two million medical professionals who will participate virtually in lectures and discussions about basic, translational, clinical and population science innovations aimed at reducing disability and deaths caused by cardiovascular disease and stroke.

The American Heart Association is excited to be in Philadelphia, said Michelle Kirkwood, director of National Science Media Relations for AHA. It has been on our wish list for some time, especially since the renovations at the Pennsylvania Convention Center and the citys landmark, robust nonsmoking laws that align directly with the American Heart Associations health and wellness goals. We are excited for our thousands of attendees to visit Philadelphia.

More than 610,000 people die of heart disease in the United States every year, according to the CDC. While heart disease is a leading cause of death for both men and women, it claims the lives of over 400,000 American women each year, or one death every 80 seconds. During the three-day meeting, more than 12,000 leading physicians, scientists, cardiologists and healthcare professionals in the global cardiovascular health community will host 850 educational sessions and more than 4,100 original research presentations to unveil the late-breaking science, clinical trials, and novel therapeutics and pathways that are shaping the future of cardiovascular care.

Its very fitting for Scientific Sessions to be here, chief of the cardiovascular medicine division in the Perelman School of Medicine at the University of Pennsylvania Tom Cappola said. We have the first medical school in the country and the first teaching hospital in the country. It makes sense that these new innovations would be presented in a place where theres already been so much innovation.

Cappola will be one of several Penn researchers leading the Cardiovascular Expert Theater, Innovations in Cardiovascular Therapies session during the meeting. Here are just a few big trends in heart care that Cappola says we can expect to learn more about during this weekends meeting:

Using artificial intelligence to monitor heart health

Artificial intelligence (AI) is having a big impact on cardiovascular care. Results from two preliminary studies to be presented this weekend will show AI can be used to accurately examine electrocardiogram (ECG) test results to possibly predict irregular heartbeat and risk of death. There will also be a presentation on the Apple Heart Study, which found that the Apple Watch and other wearable remote monitoring devices may be capable of detecting atrial fibrillation (aFib), an irregular and often rapid heartbeat that can lead to blood clots, stroke, heart failure and other complications.

Identifying new risk factors for aFib and stroke

George Mason University researchers will present results from two studies that found young people who smoke marijuana regularly have an increased risk of stroke. According to the study findings, young adults between the ages 18 and 44 who reported frequent use of marijuana, cigarettes and e-cigarettes were three times more likely to suffer stroke than young adults who did not smoke marijuana at all. The study also found that African-American males between the ages of 15 and 24 faced the highest risk of being hospitalized for arrhythmia.

In one Penn study to be presented this weekend, researchers found women who are diagnosed with peripartum cardiomyopathy (PPCM) during late pregnancy or within a month following delivery are more likely to experience restored cardiac function and improved outcomes compared to those who are diagnosed later in the postpartum period. The findings underscore the need for increased awareness and monitoring of heart failure symptoms, particularly among black women, who, on average, are diagnosed significantly later than white patients, according to study results.

Making advances in genetics and genomics

Another big trend at this years meeting will be the continued advancement in genetics and genomics, and how thats impacting cardiovascular care.

I think that genomic medicine has arrived and its arriving in waves, but it will ultimately affect all aspects of cardiovascular care, Cappola said. We have lots of people getting their 23andMe for sort of recreational purposes and they dont know what to do with it. But were starting to figure out what to do with that genetic information to improve care.

Another Penn Medicine study to be presented during the meeting will show why taller people may have an increased risk of developing atrial aFib. The research found a strong link between the genetic variants associated with height and ones risk for AFib, for the first time demonstrating that height may be a causal not correlated risk factor for the condition. Researchers hope insight from human genetics in large studies like this one will help them better understand causal risk factors for common disease.

It takes expertise to find links like this. Thats why researchers go to the American Heart Association meetings. You get all the experts together, they share their knowledge and this helps us to actually figure out what to do with this genetic information, Cappola said. Thats true across the board, but its particularly important for genomic medicine as it continues to advance.

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The American Heart Association's Annual Conference Comes to Philly This Weekend - Philadelphia magazine

A new study led by researchers at Baylor College of Medicine revealed how in utero Zika virus infection can lead to microcephaly in newborns. The team discovered that the Zika virus protein NS4A disrupts brain growth by hijacking a pathway that regulates the generation of new neurons. The findings point at the possibility of developing therapeutic strategies to prevent microcephaly linked to Zika virus infection. The study appeared Thursday in the journal Developmental Cell.

Patients with rare genetic mutations shed light on how Zika virus causes microcephaly

The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG), a center directed by Dr. Jim Lupski, professor of pediatrics, molecular and human genetics at Baylor College of Medicine and attending physician at Texas Childrens Hospital, said Dr. Hugo J. Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital.

This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition. Interestingly, a few years back the Bellen lab had discovered in the fruit fly model that ANKLE2 gene was associated with neurodevelopmental disorders. Knowing that Zika virus infection in utero can cause microcephaly in newborns, the team explored the possibility that Zika virus was mediating its effects in the brain via ANKLE2.

In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein.

Since very little is known about the role of ANKLE2 or VRK1 in brain development, Bellen and his colleagues applied a multidisciplinary approach to tease apart the exact mechanism underlying ANKLE2-associated microcephaly.

The fruit fly helps clarify the mystery

The team found that fruit fly larvae with mutations in ANKLE2 gene had small brains with dramatically fewer neuroblasts brain cell precursors and could not survive into adulthood. Experimental expression of the normal human version of ANKLE2 gene in mutant larvae restored all the defects, establishing the loss of Ankle2 function as the underlying cause.

To understand why ANKLE2 mutants have fewer neuroblasts and significantly smaller brains, we probed deeper into asymmetric cell divisions, a fundamental process that produces and maintains neuroblasts, also called neural stem cells, in the developing brains of flies and humans, said first author Dr. Nichole Link, postdoctoral associate in the Bellen lab.

Asymmetric cell division is an exquisitely regulated process by which neuroblasts produce two different cell types. One is a copy of the neuroblast and the other is a cell programmed to become a different type of cell, such as a neuron or glia.

Proper asymmetric distribution and division of these cells is crucial to normal brain development, as they need to generate a correct number of neurons, produce diverse neuronal lineages and replenish the pool of neuroblasts for further rounds of division.

When flies had reduced levels of Ankle2, key proteins, such as Par complex proteins and Miranda, were misplaced in the neuroblasts of Ankle2 larvae. Moreover, live imaging analysis of these neuroblasts showed many obvious signs of defective or incomplete cell divisions. These observations indicated that Ankle2 is a critical regulator of asymmetric cell divisions, said Link.

Further analyses revealed more details about how Ankle2 regulates asymmetric neuroblast division. They found that Ankle2 protein interacts with VRK1 kinases, and that Ankle2 mutants alter this interaction in ways that disrupt asymmetric cell division.

The Zika connection

Linking our findings to Zika virus-associated microcephaly, we found that expressing Zika virus protein NS4A in flies caused microcephaly by hijacking the Ankle2/VRK1 regulation of asymmetric neuroblast divisions. This offers an explanation to why the severe microcephaly observed in patients with defects in the ANKLE2 and VRK1 genes is strikingly similar to that of infants with in utero Zika virus infection, Link said.

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For decades, researchers have been unsuccessful in finding experimental evidence between defects in asymmetric cell divisions and microcephaly in vertebrate models. The current work makes a giant leap in that direction and provides strong evidence that links a single evolutionarily conserved Ankle2/VRK1 pathway as a regulator of asymmetric division of neuroblasts and microcephaly, Bellen said.

Moreover, it shows that irrespective of the nature of the initial triggering event, whether it is a Zika virus infection or congenital mutations, the microcephaly converges on the disruption of Ankle2 and VRK1, making them promising drug targets.

Another important takeaway from this work is that studying a rare disorder (which refers to those resulting from rare disease-causing variations in ANKLE2 or VRK1 genes) originally observed in a single patient can lead to valuable mechanistic insights and open up exciting therapeutic possibilities to solve common human genetic disorders and viral infections.

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How in utero Zika virus infection can lead to microcephaly in newborns: Baylor research - Outbreak News Today

Scholars are divided on how to regulate heritable genome editing.

Heritable genome editing refers to changing human reproductive cells so that the resulting fetus has genetic changes that its future offspring may inherit.

Proponents of heritable gene-editing champion the possibility of editing out incurable heritable diseases, but others caution that gene editing may have unintended effects. For example, an edit to prevent a child from inheriting a disease might also reduce that childs immunity to other diseases, a concern that is amplified by the fact that any changes to immunity would be heritable.

The debate is no longer theoretical. Shortly after reports of the first live births of gene-edited babies surfaced in 2018, a number of prominent scientists called for a ban on any further experimentation that would result in live births, at least until regulatory schemes were put in place.

This weeks Saturday Seminar explores scholarly works on current and proposed regulatory approaches to heritable gene-editing, as well as the unique challenges to effective regulation given factors like the medical tourism industry.

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The Next Generation's Genes - The Regulatory Review

The taller you are, the higher your risk of developing developing atrial fibrillation, a new study by Penn Medicine says.

The study found a strong association between the genetic variants of height and an increased risk of atrial fibrillation (AFib) a heart condition that causes an irregular and rapid heartbeat. The link appears to be causal, meaning it's more than a correlation.

The studywill be presented on Saturday at the American Heart Association's 2019 Scientific Sessions in Philadelphia.

Researchers analyzed the association by examining data from Genetic Investigation of Anthropometric Trials, a consortium that studied genetic height variants, and Atrial Fibrillation Genetics, a consortium that studied associations between genetic variants and AFib.

They found that the risk of developing AFib increased by 3% for every one-inch increase in height when compared to those who are considered average in height 5 feet, 7 inches.

This association remained strong even after the data was adjusted for additional risk factors, including heart disease and diabetes.

Researchers thenanalyzed more than 7,000 patients enrolled in the Penn Medicine Biobank to study the association on an individual level. They again found again that height and its genetic variants are strongly linked to an increased risk of developing AFib.

Atrial fibrillationcan lead to severe complications such as stroke, blood clots, and heart failure, according to the Mayo Clinic. Patients with AFib do not always exhibit symptoms, but when symptoms do occur they can includepalpitations, shortness of breath and fatigue.

AFib affects more than 33 million people across the world.

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While the rate of death from cancer has been declining since the 1990s, an estimated 9.6 million people died from cancer in 2018, making it the second-leading cause of death worldwide [1]. According to the NCI Cancer Trends Progress Report, in the United States, the incidence and death rates of some cancer types have also been increasing. Together, these facts indicate that despite tremendous recent progress, the research community unfortunately still has a long list of tasks to complete to end global suffering from cancer.

The clinical management of cancer has long been rooted in morphological and histopathological analyses for diagnosis, and the triad of surgery, chemotherapy, and radiation for treatment. However, we are quickly moving towards a pervasive reliance on high resolution, high throughput, molecular marker-based diagnostic as well as precision-targeted therapeutic modalities. The progressive development of the paradigm that defined molecular drivers of cancer has exposed therapeutic vulnerabilities; for example, the BCR-ABL1 gene fusion in chronic myeloid leukemia, KIT mutations in gastrointestinal stromal tumors, ERBB2 amplification in a subset of breast cancers, or EGFR mutations and ALK/ ROS/ RET gene fusions in lung cancers to name a few. Fueled by advances in high-throughput sequencing, it is increasingly practical (and arguably affordable) to systematically pursue Targeted Anticancer Therapies and Precision Medicine in Cancer.

PLOS ONE, together with PLOS Computational Biology, launched a Call for Papers earlier this year to increase understanding of this clinically important area. The scope of this call encompassed four areas: identification and classification of driver genes and somatic alterations; target and drug discovery; mechanisms of drug resistance; and early detection and screening.

Today, we are very happy to announce the launch of the resulting Collection. Featuring an initial set of nearly two dozen papers, with more to be added as they are published, these articles represent diverse facets of ongoing efforts in this area, where general knowledge of cancers serves to inform individual patients care, and at the same time particulars from individual cancer cases contribute to improved resolution of our general knowledge pool.

Somatic aberrations that are critical to the development, growth and progression of cancer are defined as drivers that are typically accompanied by large numbers of incidental aberrations referred to as passengers, acquired in the tumors due to the general chromosomal instability characteristic of advanced cancers. Distinguishing driver aberrations from passengers in individual tumors represents an active area of research that involves development of smarter analytical algorithms, as well as definitive functional characterization of candidate aberrations.

Emilie A. Chapeau et al. developed a conditional inducible transgenic JAK2V617F mouse model that recapitulates aspects of human myeloproliferative neoplasms, including splenomegaly, erythroid expansion and hyperproliferation of bone marrow, with some intriguing differences seen between male and female mice. Importantly, the disease phenotype was reversible when transgene expression was switched off. This work underscores the key role for JAK2V617F in the initiation and maintenance of myeloproliferative neoplasms, and suggests that inhibitors specific to this JAK2 mutation might be efficacious in this disease [2].

Using targeted exon sequencing and array comparative genomic hybridization (CGH), Gayle Pageau Pouliot et al. identified monoallelic mutations in Fanconi-BRCA pathway genes in samples collected from children with T cell acute lymphoblastic leukemia (T-ALL). These mutations appeared to arise in early stages of tumorigenesis, suggesting a potential role for Fanconi-BRCA pathway insufficiency in the initiation of T-ALL. Although PARP inhibitors did not affect viability of isolated T-ALL cells with monoallelic Fanconi-BRCA mutations, these cells were hypersensitive to UV irradiation in vitro or ATR inhibition in vivo, suggesting that ATR inhibitors might have therapeutic value in T-ALL [3].

Three papers in this Collection examine links between genetic alterations and prognosis. Sumadi Lukman Anwar et al. report that LINE-1 hypomethylation in human hepatocellular carcinoma samples correlates with malignant transformation, decreased overall survival and increased tumor size [4]. Investigating HER2-positive breast cancer specimens, Arsalan Amirfallah et al. found that high levels of vacuole membrane protein 1 (VMP1) could potentially contribute to cancer progression and might be a marker of poor prognosis [5]. Finally, in their systematic review and meta-analysis, Chia Ching Lee et al. identified low discordance rates in EGFR mutations between primary lung tumors and distant metastases, although they note some differences depending on metastatic site. Notably, discordance rates appear to be higher in bone metastases compared to central nervous system or lung metastases [6]. These studies provide much-needed leads for the potential development of new diagnostic tests or targeted therapies.

Precision therapy of cancers is premised on the identification of tumor-specific driver aberrations that are necessary for tumor growth and survival. These aberrations represent potential therapeutic targets. While matching therapeutics have been developed for some of the tumor-specific targets, particularly many oncogenic kinases, a large number of defined driver aberrations remain in search of effective therapies. Drug discovery efforts to match defined targets represent a vigorous area of ongoing research with implications for survival and quality of lives of cancer patients worldwide. The development of drugs to treat cancers driven by transcription factors, chromatin modifiers, and epigenetic modulators has proved particularly challenging. On the other hand, recent development of novel immunotherapeutic approaches has spurred research to identify potential targets and matching drug discovery efforts.

This Collection highlights several interesting new strategies to identify potential lead compounds for cancer treatment. Thomas W. Miller et al. describe the development of a biochemical quantitative high-throughput screen for small molecules that disrupt the interaction between CD47 and SIRP. Preclinical studies have shown that disrupting this interaction may provide a new approach for cancer immunotherapy. Small molecular inhibitors that specifically target the interaction between CD47 and SIRP are potentially advantageous over biologics that target CD47, because they might have less on target toxicologic issues and greater tissue penetrance [7].

Work from Gabrielle Choonoo, Aurora S. Blucher et al. examines the feasibility of repurposing existing cancer drugs for new indications. The authors compiled information about somatic mutations and copy-number alterations in over 500 cases of head and neck squamous cell carcinoma (HNSCC) and mapped these data to potential drugs listed in the Cancer Targetome [8]. This approach uncovered pathways that are routinely dysregulated in HNSCC and for which potential anti-cancer therapies are already available, as well as those for which no therapies exist. The work opens new therapeutic avenues in the treatment of this disease and also illuminates which pathways could be prioritized for the development of therapies [9].

Another important approach in extending the clinical utility of existing anti-cancer drugs is to determine whether they are effective in other settings. Indeed, Kirti Kandhwal Chahal et al. have demonstrated that the multi-tyrosine kinase inhibitor nilotinib, which is approved for use in chronic myeloid leukemia, binds the Smoothened receptor and inhibits Hedgehog pathway signaling. Nilotinib decreased viability of hedgehog-dependent medulloblastoma cell lines in vitro and in patient-derived xenografts in vivo, suggesting that nilotinib might be an effective therapy in Hedgehog-dependent cancer [10]. (Check out the authors preprint of this article on bioRxiv.) Darcy Welch, Elliot Kahen et al. took a different approach to identify new tricks for old drugs. By testing two-drug combinations of five established (doxorubicin, cyclophosphamide, vincristine, etoposide, irinotecan) and two experimental chemotherapeutics (the lysine-specific demethylase 1 (LSD1) inhibitor SP2509 and the HDAC inhibitor romidepsin), they found that combining SP2509 with topoisomerase inhibitors or romidepsin synergistically decreased the viability of Ewing sarcoma cell lines in vitro [11].

Two papers in this collection describe potential new therapeutic approaches in cancer. Vagisha Ravi et al. developed a liposome-based delivery mechanism for a small interfering RNA targeting ferritin heavy chain 1 (FTH1) and showed that this increased radiosensitivity and decreased viability in a subpopulation of glioma initiating cells (GICs) [12]. Yongli Li et al. identified 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate podophyllotoxin ester, a podophyllotoxin derivative that inhibits matrix metalloproteinases and Topoisomerase II. Treatment with this compound decreased the migration and invasion of human liver cancer cell lines in vitro, as well as growth of HepG2-derived tumors in mouse xenografts [13].

The success of precision cancer therapy targeting defined somatic aberrations is hampered by an almost inevitable, eventual treatment failure due to the emergence of drug resistance. Resistance often involves new mutations in the therapeutic target itself, or it may result due to activation of alternative pathways. Identification and therapeutic targeting of drug resistant clones represents an ongoing research problem with important practical implications for the clinical management of cancer.

Afatinib is a pan-human epidermal growth factor receptor (HER) inhibitor under investigation as a potential therapeutic option for people with gastric cancer; however, preclinical studies have found that some gastric cancer cell lines are resistant to afatinib treatment. Karolin Ebert et al. identify a potential mechanism behind this lack of response, demonstrating that siRNA-mediated knockdown of the receptor tyrosine kinase MET increases afatinib sensitivity of a gastric cancer cell line containing a MET amplification. As upregulation of MET has been linked to resistance to anti-HER therapies in other cancers, these findings support a role for MET in afatinib resistance in gastric cancer and suggest that combined afatinib and anti-MET therapy might be clinically beneficial for gastric cancer patients [14].

Identifying mechanisms to circumvent drug resistance is critically important to improve response and extend survival, but it is equally important to identify individuals who could be at risk of not responding to anti-cancer therapeutics. Lucas Maahs, Bertha E. Sanchez et al. report progress towards this end, showing that high expression of class III -tubulin in metastatic castration-resistant prostate cancer (CRPC) correlated with decreased overall survival and worse response rate (as measured by changes in prostate-specific antigen (PSA) levels) in CRPC patients who received docetaxel therapy. The development of a biomarker indicating potential treatment resistance to docetaxel could help develop treatment plans with the best chance of success [15].

The converse approach identifying biomarkers that correlate with drug sensitivity could help distinguish subsets of patients who would benefit most from a certain anti-cancer therapy. Kevin Shee et al. mined publicly available datasets to identify genes whose expression correlate with sensitivity and response to chemotherapeutics and found that expression of Schlafen Family Member 11 (SLFN11) correlates with better response to a variety of DNA-damaging chemotherapeutics in several types of solid tumors [16]. Separately, Jason C. Poole et al. validated the use of the Target Selector ctDNA assay, a technology developed by their group that allows the specific amplification of very low frequency mutant alleles in circulating tumor DNA (ctDNA). Testing for EGFR, BRAF and KRAS mutations yielded a very high, >99% analytical sensitivity and specificity with the capability of single mutant copy detection, indicating that accurate molecular disease management over time is possible with this minimally invasive method [17].

Work from Georgios Kaissis, Sebastian Ziegelmayer, Fabian Lohfe et al. uses a machine learning algorithm to differentiate subtypes of pancreatic ductal adenocarcinoma based on 1,606 different radiomic features. Intriguingly, the subtypes identified in their analysis correlated with response to chemotherapeutic regimens and overall survival [18]. An imaging approach taken by Seo Young Kang et al. demonstrates the potential power of fluorodeoxyglucose (FDG) PET/CT scans in determining the response of people with metastatic differentiated thyroid cancer to radioactive iodine treatment [19].

Since cancer growth and development accrues progressive accumulation of somatic aberrations, early detection holds the promise of more effective interventions. Similarly, screening of at risk demographics has been found effective in preventing or better managing cancer care, as exemplified by the significant reduction in cases of cervical cancer after the introduction of the Pap smear as well as human papillomavirus (HPV) testing.

Biomarker development is also critically important for the early detection of cancer and metastatic disease; moreover, biomarkers are being identified that can provide insight into patient prognosis. Several papers in this Collection report interesting findings in the area of biomarker development. A report from Lingyun Xu et al. describes a magneto-nanosensor-based multiplex assay that measures circulating levels of PSA and four proteins associated with prostate cancer. This approach segregates people with prostate cancer from those with benign prostate hyperplasia with high sensitivity and specificity [20].

Two articles provide new insight into markers of disease progression and survival. Vidya Balagopal et al. report the development of a 22-gene hybrid-capture next generation sequencing panel to identify measurable residual disease in patients with acute myeloid leukemia (AML). In their retrospective study, the panel was effective at detecting evidence for residual disease. Importantly, it correctly identified patients who had never relapsed in that no evidence of residual disease was detected in any of these respective samples. Once validated, this approach could potentially be useful in monitoring patients with AML to ensure that recurrence or relapse is identified as soon as possible [21]. Separately, Yoon-Sim Yap et al. use a label-free microfluidic platform to capture circulating tumor cells (CTCs) from people with breast cancer and show that absolute numbers of CTCs predict progression-free survival with higher levels of CTCs correlating with a worse prognosis [22].

Finally, Lucia Suzuki et al. report findings into a potential role for the intestinal stem cell marker olfactomedin 4 (OLFM4) as a biomarker for metastasis in esophageal adenocarcinoma. The authors found that OLFM4 expression was not significantly associated with disease-free or overall survival; however, low OLFM4 expression was detected in poorly differentiated early and advanced-stage esophageal adenocarcinoma and was an independent prognostic variable for lymph node metastasis [23].

This collection of studies encompassing the range of research topics under the banner of targeted anticancer therapies highlights the diversity, complexity and inter-disciplinary nature of research efforts actively contributing to our collective knowledge base with the hope to positively impact the lives of all cancer patients.

We would like to thank all Academic Editors and reviewers for their expert evaluation of the articles in this Collection as well as the authors for their contributions to this field. Special thanks to Senior Editor, Team Manager Emily Chenette for her invaluable help and guidance in publishing this Collection.

Andrew Cherniack

Andrew Cherniack is a group leader in the Cancer Program at the Broad Institute of MIT and Harvard and in the Department of Medical Oncology at the Dana Farber Cancer Institute. He led the Broad Institutes effort to analyze somatic DNA copy number alterations for The Cancer Genome Atlas (TCGA) and is now co-principal investigator of the Broad Institutes copy number Genome Data Analysis Center for the National Cancer Institutes Genomic Data Analysis Network (GDAN). He also leads the oncoming effort to identify new cancer therapeutic targets for the partnership with Bayer. Prior to joining the Broad Institute in 2010, Dr. Cherniack worked in both academia and industry, with a 9-year tenure at the Abbott Bioresearch Center following a similar time period in the Program in Molecular Medicine at UMass Medical School, where he was a postdoctoral researcher and a research assistant professor. Dr. Cherniack holds a Ph.D. in molecular genetics from Ohio State University and a B.A. in biology from the University of Pennsylvania.

Anette Duensing

Anette Duensing is an Assistant Professor of Pathology at the University of Pittsburgh School of Medicine and a Member of the Cancer Therapeutics Program at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center. Dr. Duensings research focuses on bone and soft tissue sarcomas with the goal of identifying novel therapeutic approaches that target the underlying molecular biology of these malignancies. Her special interest and expertise are in gastrointestinal stromal tumors (GISTs), a sarcoma characterized by mutations in the KIT or PDGFRA receptor tyrosine kinases and the first solid tumor entity that was successfully treated with small molecule kinase inhibitors. Dr. Duensing holds an M.D. degree from the University of Hannover School of Medicine, Germany, and was a research scholar of the Dr. Mildred Scheel Stiftung fr Krebsforschung (German Cancer Aid/Deutsche Krebshilfe) at Brigham and Womens Hospital, Harvard Medical School. She is the recipient of an AACR Scholar-in-Training Award (AACR-AstraZeneca), a Young Investigator Award from The Liddy Shriver Sarcoma Initiative, a UPCI Junior Scholar Award, a Jeroen Pit Science Award, a Research Award from the GIST Group Switzerland and was named Hillman Fellow for Innovative Cancer Research. Dr. Duensing is co-founder and leader of the Pittsburgh Sarcoma Research Collaborative (PSaRC), a highly translational, interdisciplinary sarcoma research program. She is also affiliated with the Department of Urology at the University of Heidelberg, Germany. Dr. Duensing is an Academic Editor for PLOS ONE and author of nearly 70 original articles, reviews and book chapters.

Steven G. Gray

Steven Gray graduated from Trinity College Dublin in 1992. He joined the laboratory of Tomas J. Ekstrm at the Karolinska Institute (Sweden) in 1996 and received his PhD in 2000. He moved to the Van Andel Research Institute in Michigan, USA where he continued his studies on the therapeutic potential of histone deacetylase inhibitors in the treatment of cancer. He also spent time as a visiting fellow at Harvard Medical School, Boston working on epigenetic therapies for neurodegenerative disease. Returning to Europe, Dr. Gray spent some time at the German Cancer Research Centre (DKFZ Heidelberg), and subsequently moved to Copenhagen to work for Novo Nordisk as part of the research team of Prof Pierre De Meyts at the Hagedorn Research Institute working on epigenetic mechanisms underpinning diabetes pathogenesis. Dr. Gray is currently a senior clinical scientist at St Jamess Hospital at the Thoracic Oncology Research Group at St. Jamess Hospital. He holds adjunct positions at both Trinity College Dublin (senior clinical lecturer with the Dept. of Clinical Medicine), and at Technical University Dublin (adjunct senior lecturer, School of Biology DIT). Dr. Gray has published over 100 peer-reviewed articles, 15 book chapters and has edited 1 book. Research in Dr Grays laboratory focuses on Receptor Tyrosine Kinases as potential therapeutic targets for the treatment of mesothelioma; epigenetic mechanisms underpinning drug resistance in lung cancer; targeting epigenetic readers, writers and erasers for the treatment of mesothelioma and thoracic malignancy; circulating tumour cells; and non-coding RNA repertoires in mesothelioma and thoracic malignancy.

Sunil Krishnan

Sunil Krishnan is the Director of the Center for Radiation Oncology Research and the John E. and Dorothy J. Harris Professor of Gastrointestinal Cancer in the department of Radiation Oncology at MD Anderson Cancer Center. He received his medical degree from Christian Medical College, Vellore, India and completed a radiation oncology residency at Mayo Clinic, Rochester, Minnesota. In the clinic, he treats patients with hepatobiliary, pancreatic and rectal tumors with radiation therapy. His laboratory has developed new strategies and tools to define the roles and mechanisms of radiation sensitization with gold nanoparticles, chemotherapeutics, biologics and botanicals. Dr. Krishnan serves as the co-chair of the gastrointestinal scientific program committee of ASTRO, co-chair of the gastrointestinal translational research program of RTOG, consultant to the IAEA for rectal and liver cancers, chair of the NCI pancreatic cancer radiotherapy working group, and Fellow of the American College of Physicians. He has co-authored over 200 peer-reviewed scientific publications, co-authored 17 book chapters, and co-edited 3 books.

Chandan Kumar-Sinha

Chandan Kumar-Sinha is a Research Associate Scientist in the Department of Pathology at the University of Michigan. He obtained Masters in Biotechnology from Madurai Kamraj University, and PhD in Plant Molecular Biology from Indian Institute of Science. He completed a Postdoctoral Fellowship at the Department of Pathology, University of Michigan, where he worked on genomic profiling of cancers. Thereafter, he joined the Advanced Center for Treatment, Research and Education in Cancer in India as a faculty member. After establishing a cancer genomics group there, he moved back to the University of Michigan to pursue translational cancer research. Dr. Kumar-Sinhas current research involves integrative clinical sequencing using high-throughput genome and transcriptome analyses to inform precision oncology. He has authored over 50 peer-reviewed publications, two book chapters, and is named co-inventor on a patent on prostate cancer biomarkers.

Gayle E. Woloschak

Gayle Woloschak is Professor of Radiation Oncology, Radiology, and Cell and Molecular Biology in the Feinberg School of Medicine, Northwestern University. Dr. Woloschak received her Ph.D. in Medical Sciences from the University of Toledo (Medical College of Ohio). She did her postdoctoral training at the Mayo Clinic, and then moved to Argonne National Laboratory until 2001. Her scientific interests are predominantly in the areas of molecular biology, radiation biology, and nanotechnology studies, and she has authored over 200 papers. She is a member of the National Council on Radiation Protection, the International Commission on Radiation Protection and numerous other committees and also serves on the US delegation to the United National Scientific Committee on the Effects of Atomic Radiation.

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Introducing the Targeted Anticancer Therapies and Precision Medicine in Cancer Collection - PLoS Blogs

Innovation in the health care industry is seen by many as a way to address rising health care costs by improving technology, managing Big Data to develop best clinical practices, reducing pain and suffering or maybe even curing diseases.

Recent innovative developments in Michigan include a statewide telestroke program at the University of Michigan, a precision medicine program at Barbara Ann Karmanos Cancer Institute and a device that can identify pathogens developed by Seraph Biosciences Inc., a Detroit-based spinoff company of Wayne State University.

At Crain's 12th annual Health Care Leadership Summit, moderator David Ellis, a futurist and also head of the Detroit International Research and Education Foundation, led a three-member panel on a discussion about how innovation has changed medicine and patient care.

"I like to think that my colleagues here (on the panel) are representative of the people who are moving towards the speed of light, if not at the speed of light" to develop innovative clinical solutions, Ellis said. "Innovation is not just happening, but it is happening faster and faster."

Ellis asked the panel Mollie McDermott, M.D., a neurologist and stroke specialist with Michigan Medicine; Elisabeth Heath, M.D., a medical oncologist at Karmanos; and Greg Auner, a medical engineer at Wayne State University School of Medicine to describe the biggest innovation to happen in their field in the past five years and to project the next five years.

McDermott, who is the director of the telestroke program at Michigan Medicine, said the biggest innovation in her field is the widespread use of a special type of imaging called "perfusion imaging in acute stroke." This advancement can identify tissue that could be saved through the use of thrombolytic therapy, or "clot buster" drugs, in clogged arteries.

"When I started medical school, there were interventions available for stroke out to three hours from last known normal. And now that time has expanded to 24 hours with the idea that we're selecting patients who may benefit based on this specialized imaging. Stroke call has gotten very complicated," McDermott said. "It used to be, three hours and then you're done. Now we're getting called out to 24 hours. Decision-making is very complicated and there is a lack of vascular neurology expertise in our country."

McDermott said Michigan Medicine uses its telestroke program to pass along this vascular neurology expertise to small and rural hospitals where they don't have specialists trained in perfusion imaging.

Heath, who is Karmanos' associate center director of translational sciences, said the field of genomics and precision medicine more specifically precision oncology has grown tremendously over the past five years.

"Explosion would be a small word to characterize (the pace of change) because there's no meeting that you go to now in the world of oncology where that concept (using an individual's DNA to customize cancer treatment) is not discussed," she said.

Heath said Karmanos' partnership with McLaren Healthcare Corp., a 14-hospital system based in Grand Blanc, has been especially helpful in spreading knowledge of precision oncology throughout Michigan.

McDermott said the next five years for telemedicine will bring even more specialists closer to patients in helping to diagnose complex problems. "Patients (are) at home and trying to figure out, do I need to go to the emergency room? Do I need to go to urgent care? Do I need to set up an appointment with my primary care physician? Do I need to call 911? These kinds of decisions (influenced by telemedicine or virtual care) ... seems to be the next place we're headed."

Auner, one of the co-founders of Seraph, said individualized genetic analysis will transform cancer treatment. But the massive amount of data available will challenge researchers and clinicians going forward.

"Something that is quite interesting is deep learning (or) artificial intelligence that can gather through data from different sources, images, diagnostic signals ... and put that together and provide that as a tool," Auner said. "I see that probably is the biggest future breakthrough."

Heath said the next five years will challenge medical researchers because of all the clinical data on patients. "There's a fine line between a hoarder and a collector (of clinical data)," she said. "I would really like to be a collector, not a hoarder. And at this moment we're all hoarders of data and it's wonderful ... but really understanding what it means, especially if on a patient level, that's (another) discussion."

Ellis said one of the problems hospitals, doctors and health insurers have is trusting each other to share claims data and other medical records on patients to deliver appropriate care.

"One of the reasons for that of course, is purely technical. Not every system (electronic health record) is as good as the next and data breaches do occur," Ellis said. "That's got pretty severe implications."

But he said innovations occurring now to share "Big Data" using artificial intelligence and other systems could overcome trust and technical issues.

"I always see a solution. That's why I'm the perpetual optimist," Heath said. "As an oncologist, there's always a solution. I'm not saying it's right, but I think you have to have a plan" to share and use data.

McDermott said changing provider and hospital behavior is difficult. "We're taught basically from day one of medical school not to trust anybody. You have to verify for yourself, don't trust other people's exams," she said. "I don't trust research unless I have read the methods' section. So overcoming that is a cultural, not just a pragmatic phenomenon."

Auner said there is a "scary" aspect as clinical research becomes more individualized to patients "from the standpoint of what is known about a particular patient (and) knowing everything about you genetically."

For example, what if your genetic data and predisposition to disease or illness finds its way to your health insurance company? "(They) may then predict what's going to happen to you and how that may" affect your health and premium dollars charged to you or your employer.

"The knowledge of that can be unnerving," Auner said.

Heath said the big unanswered question out there is who owns the data. She wondered if patients own their data or does the health system, the university, the researcher?

"When you say it's in my medical record, that has a lot of implications when you're talking about genomic data," she said. "Is it just knowing that its the breast cancer gene itself? Is it knowing down to the nucleotide? Are you looking at things that exist only in the webspace because we can't house it in the computer? What is that sort of ownership from a patient level?"

Ellis said the reality is right now there are companies out there like Mark Zuckerberg's Facebook that contends if there is data out there "it's mine, I'll grab it. ... It's a free for all. It's the first come, first served."

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