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Newswise —
A simple blood test can rapidly and accurately detect mutations in two key genes in non-small cell lung tumors, researchers at Dana-Farber Cancer Institute and other institutions report in a new study – demonstrating the test’s potential as a clinical tool for identifying patients who can benefit from drugs targeting those mutations.
The test, known as a liquid biopsy, proved so reliable in the study that the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) this week became the first medical facility in the country to offer it to all patients with non-small cell lung cancer (NSCLC), either at the time of first diagnosis or of relapse following previous treatment.
NSCLC is the most common form of lung cancer, diagnosed in more than 200,000 people in the United States each year, according to the American Cancer Society. An estimated 30 percent of NSCLC patients have mutations in either of the genes included in the study, and can often be treated with targeted therapies. The study is being published online today by the journal JAMA Oncology.
The liquid biopsy tested in the study – technically known as rapid plasma genotyping – involves taking a test tube-full of blood, which contains free-floating DNA from cancer cells, and analyzing that DNA for mutations or other abnormalities. (When tumor cells die, their DNA spills into the bloodstream, where it’s known as cell-free DNA.) The technique, which provides a “snapshot” of key genetic irregularities in a tumor, is a common tool in research for probing the molecular make-up of different kinds of cancers.
“We see plasma genotyping as having enormous potential as a clinical test, or assay – a rapid, noninvasive way of screening a cancer for common genetic fingerprints, while avoiding the challenges of traditional invasive biopsies,” said the senior author of the study, Geoffrey Oxnard, MD, thoracic oncologist and lung cancer researcher at Dana-Farber and Brigham and Women’s Hospital. “Our study was the first to demonstrate prospectively that a liquid biopsy technique can be a practical tool for making treatment decisions in cancer patients. The trial was such a success that we are transitioning the assay into a clinical test for lung cancer patients at DF/BWCC.”
The study involved 180 patients with NSCLC, 120 of whom were newly diagnosed, and 60 of whom had become resistant to a previous treatment, allowing the disease to recur. Participants’ cell-free DNA was tested for mutations in the EGFR and KRAS genes, and for a separate mutation in EGFR that allows tumor cells to become resistant to front-line targeted drugs. The test was performed with a technique known as droplet digital polymerase chain reaction (ddPCR), which counts the individual letters of the genetic code in cell-free DNA to determine if specific mutations are present. Each participant also underwent a conventional tissue biopsy to test for the same mutations. The results of the liquid biopsies were then compared to those of the tissue biopsies.
The data showed that liquid biopsies returned results much more quickly. The median turnaround time for liquid biopsies was three days, compared to 12 days for tissue biopsies in newly diagnosed patients and 27 days in drug-resistant patients.
Liquid biopsy was also found to be highly accurate. In newly diagnosed patients, the “predictive value” of plasma ddPCR was 100 percent for the primary EGFR mutation and the KRAS mutation – meaning that a patient who tested positive for either mutation was certain to have that mutation in his or her tumor. For patients with the EGFR resistance mutation, the predictive value of the ddPCR test was 79 percent, suggesting the blood test was able to find additional cases with the mutation that were missed using standard biopsies.
“In some patients with the EGFR resistance mutation, ddPCR detected mutations missed by standard tissue biopsy,” Oxnard remarked. “A resistant tumor is inherently made up of multiple subsets of cells, some of which carry different patterns of genetic mutations. A single biopsy is only analyzing a single part of the tumor, and may miss a mutation present elsewhere in the body. A liquid biopsy, in contrast, may better reflect the distribution of mutations in the tumor as a whole.”
When ddPCR failed to detect these mutations, the cause was less clear-cut, Oxnard says. It could indicate that the tumor cells don’t carry the mutations or, alternatively, that the tumor isn’t shedding its DNA into the bloodstream. This discrepancy between the test results and the presence of mutations was less common in patients whose cancer had metastasized to multiple sites in the body, researchers found.
The ddPCR-based test, or assay, was piloted and optimized for patients at the Translational Resarch lab of the Belfer Center for Applied Cancer Science at Dana-Farber. It was then validated for clinical use at Dana-Farber’s Lowe Center for Thoracic Oncology.
An advantage of this form of liquid biopsy is that it can help doctors quickly determine whether a patient is responding to therapy. Fifty participants in the study had repeat testing done after starting treatment for their cancer. “Those whose blood tests showed a disappearance of the mutations within two weeks were more likely to stay on the treatment than patients who didn’t see such a reduction,” said the study’s lead author, Adrian Sacher, MD, of Dana-Farber and Brigham and Women’s Hospital.
And because tumors are constantly evolving and acquiring additional mutations, repeated liquid biopsies can provide early detection of a new mutation – such as the EGFR resistance mutation – that can potentially be treated with targeted agents.
“The study data are compelling,” said DF/BWCC pathologist Lynette Sholl, MD, explaining the center’s decision to begin offering ddPCR-based liquid biopsy to all lung cancer patients. “We validated the authors’ findings by cross-comparing results from liquid and tissue biopsies in 34 NSCLC patients. To work as a real-world clinical test, liquid biopsy needs to provide reliable, accurate data and be logistically practical. That’s what we’ve seen with the ddPCR-based blood test.
“The test has great utility both for patients newly diagnosed with NSCLC and for those with a recurrence of the disease,” she continued. “It’s fast, it’s quantitative (it indicates the amount of mutant DNA in a sample), and it can be readily employed at a cancer treatment center.”
The co-authors of the study are Cloud Paweletz, PhD, Allison O’Connell, BSc, and Nora Feeney, BSc, of the Belfer Center for Applied Cancer Science at Dana-Farber; Ryan S. Alden BSc, and Stacy L. Mach BA, of Dana-Farber; Suzanne E. Dahlberg, PhD, of Dana-Farber and Harvard T.H. Chan School of Public Health; and Pasi A. Jänne, MD, PhD, of Dana-Farber, the Belfer Center, and Brigham and Women’s Hospital.
Newswise —
For most people, the culmination of a good life is a “good death,” though what that means exactly is a matter of considerable consternation. Researchers at the University of California, San Diego School of Medicine surveyed published, English-language, peer-reviewed reports of qualitative and quantitative studies defining a “good death,” ultimately identifying 11 core themes associated with dying well.
The findings are published in the April 2016 issue of the American Journal of Geriatric Psychiatry.
The research team, headed by senior author Dilip Jeste, MD, Distinguished Professor of Psychiatry and Neurosciences and director of the Sam and Rose Stein Institute for Research on Aging at UC San Diego School of Medicine, focused on three groups of stakeholders: patients, family members (before or during bereavement) and health care providers.
“This is the first time that data from all of the involved parties have been put together,” said Jeste, who is also associate dean for healthy aging and senior care at UC San Diego School of Medicine. “Death is obviously a controversial topic. People don’t like to talk about it in detail, but we should. It’s important to speak honestly and transparently about what kind of death each of us would prefer.”
The literature search culled through 32 qualifying studies. It identified 11 core themes of good death: preferences for a specific dying process, pain-free status, religiosity/spirituality, emotional well-being, life completion, treatment preferences, dignity, family, quality of life, relationship with the health care provider and “other.”
The top three themes across all stakeholder groups were preferences for specific dying process, pain-free status and emotional well-being. For other themes, however, different stakeholders put somewhat different levels of emphasis. For example, patients more often cited religiosity/spirituality as important than did family members, who believed dignity and life completion were more critical to a good death. Health care providers tended to represent a middle ground between patients and family members.
“Clinically, we often see a difference between what patients, family members and health care providers value as most important near the end of life”, said first author Emily Meier, PhD, a psychologist at Moores Cancer Center at UC San Diego Health. “Ultimately, existential and other psychosocial concerns may be prevalent among patients, and this serves as a reminder that we must ask about all facets of care that are essential at the end of life.”
The bottom line, said Jeste, is “ask the patient.”
“Usually, patients know what they want or need and there is relief in talking about it. It gives them a sense of control. I hope these findings spur greater conversation across the spectrum. It may be possible to develop formal rating scales and protocols that will prompt greater discussion and better outcomes. You can make it possible to have a good death by talking about it sometime before.”
Newswise —
A diet rich in vitamin C could cut risk of cataract progression by a third, suggests a study being published online today in Ophthalmology, the journal of the American Academy of Ophthalmology. The research is also the first to show that diet and lifestyle may play a greater role than genetics in cataract development and severity.
Cataracts occur naturally with age and cloud the eye’s lens, turning it opaque. Despite the advent of modern cataract removal surgery, cataracts remain the leading cause of blindness globally.1 Researchers at King’s College London looked at whether certain nutrients from food or supplements could help prevent cataract progression. They also tried to find out how much environmental factors such as diet mattered versus genetics.
The team examined data from more than 1,000 pairs of female twins from the United Kingdom. Participants answered a food questionnaire to track the intake of vitamin C and other nutrients, including vitamins A, B, D, E, copper, manganese and zinc. To measure the progression of cataracts, digital imaging was used to check the opacity of their lenses at around age 60. They performed a follow-up measurement on 324 pairs of the twins about 10 years later.
During the baseline measurement, diets rich in vitamin C were associated with a 20 percent risk reduction for cataract. After 10 years, researchers found that women who reported consuming more vitamin C-rich foods had a 33 percent risk reduction of cataract progression.
Genetic factors accounted for 35 percent of the difference in cataract progression. Environmental factors, such as diet, accounted for 65 percent. These results make the study the first to suggest that genetic factors may be less important in progression of cataract than previously thought.How vitamin C inhibits cataract progression may have to do with its strength as an antioxidant. The fluid inside the eye is normally high in vitamin C, which helps prevents oxidation that clouds the lens. More vitamin C in the diet may increase the amount present in the fluid around the lens, providing extra protection. Researchers noted that the findings only pertain to consuming the nutrient through food and not vitamin supplements.
“The most important finding was that vitamin C intake from food seemed to protect against cataract progression,” said study author Christopher Hammond, M.D., FRCOphth, professor of ophthalmology at King’s College London. “While we cannot totally avoid developing cataracts, we may be able to delay their onset and keep them from worsening significantly by eating a diet rich in vitamin C.”
Newswise —
Obese young people can still turn their chances of developing life threatening illness around if they change before middle age, says new research.
The study looked at the body mass index (BMI) of people when they were young and compared it to when they were middle aged to see whether it affected their risk of heart attack, stroke or diabetes.
Men who had high BMI levels at 21, but had lowered their BMI by the time they were 50, had similar or lower rates of diabetes as people who were normal weight when younger, the results showed.
In a unique approach, the study used the records of men’s military service, which recorded their BMI at 21, as well as participant recall and followed up with them 30 years later.
Lead research Professor Christopher Owen from St George’s University of London said the effects of high BMI early in life may be reversible.
“Even in men who carried out UK National Service and were relatively thin in early life compared to more recent men, higher levels of fatness in early adult life appear to be associated with later diabetes,” he said.
“However, effects of early body mass appear to be reversible by subsequent weight loss. These findings have important implications for Type 2 diabetes prevention, especially in more recent adults with high levels of obesity.”
But the study, which examined almost 5000 men, found that a higher BMI earlier in life did not impact on the risk of heart attack or stroke.
However, men who were obese when they were 50 had increased chances of suffering a heart attack, stroke or diabetes.
Obesity is the biggest risk factor for type 2 diabetes and over 4 million people in the UK are at high risk of developing the condition.
Newswise —
UC Berkeley biologists have discovered the switch that triggers the power kick sperm use to penetrate and fertilize a human egg, uncovering a possible source of male infertility but also a potential target for contraceptives that work in both men and women.
The switch is a protein receptor that responds to the female sex hormone progesterone, which is released by the egg or oocyte, the ultimate goal toward which sperm swim. Thousands of these receptors sit on the surface of a sperm’s tail and when the sperm gets close to the egg, the hormone activates the receptor and triggers a cascade of changes that make the tail snap like a whip, powering the sperm into and hopefully through the cells protecting the egg.
“If the receptor protein doesn’t recognize progesterone, you would be infertile,” said Melissa Miller, a postdoctoral fellow at both UC Berkeley and UC San Francisco and the first author of a paper reporting the discovery. “This gives us an understanding of another pathway that is involved in human sperm activity.”
A drug that inactivates this newly discovered receptor, however, might make a good “unisex” contraceptive – one that could be used by either sexual partner.
“What’s really cool is that we have an actual target for unisex contraceptive development,” Miller said. “If you can stop progesterone from inducing a power stroke, sperm are not going to be able to reach or penetrate the oocyte.”
While there are other possible targets for a contraceptive that would prevent the initiation of the power stroke, called hyperactivation, or the simultaneous release of enzymes that cut through the protective layer around the egg, “this is one of the better options we have for a unisex contraceptive,” she said.
Senior author Polina Lishko, a UC Berkeley assistant professor of molecular and cell biology, noted that many tissues – the brain, the lungs, smooth muscle – contain related progesterone or steroid receptors that may work in a similar manner to trigger major changes in tissues.
“Now that we know the players, the next step is to look in other tissues that express these proteins to see whether progesterone acts on them in a similar manner to affect pain threshold adjustment in pain sensing neurons, surfactant production in the lungs or the excessive smooth muscle contractions found in asthma,” she said. “This may be a universal pathway in all cells.”
Miller, Lishko and their colleagues will publish their findings in the March 17 “Fast Release” issue of the journalScience.
Few known causes of male infertility
Today, doctors are unable to determine the cause of nearly 80 percent of all cases of male infertility, in part because little is known about the many molecular steps involved in the production of sperm and its interactions with the egg. Sperm may be to blame in half of all cases of infertile couples.
Yet because the U.S. government forbids the use of federal funds for research that brings eggs and sperm together in the same dish, little research has been done on how egg-sperm interactions lead to infertility. And until five years ago, it was very difficult to study the inner workings of sperm – the body’s smallest cell – with ordinary lab techniques.
The new discovery comes thanks to techniques that Lishko and her colleague Yuriy Kirichok developed over the past five years at UCSF and UC Berkeley. The techniques allow them to stick electrodes on a sperm’s tail and record its reactions to hormones, key to probing the molecular cascades that govern sperm behavior.
That technique led to their discovery that a large receptor on sperm tails – a calcium channel dubbed CatSper – is activated by progesterone from the egg. Progesterone unlocks the channel gate, letting electrically charged calcium atoms flood into the cell. This leads to a biochemical cascade that readies the sperm cell for its last-ditch effort to fertilize the oocyte.
Miller and Lishko suspected, however, that progesterone was not acting directly on the calcium channel, but on some other receptor that, in turn, activated the calcium channel.
That proved to be the case. They showed that progesterone actually binds to a previously mysterious enzyme called ABHD2, which is found at high levels in sperm. Once progesterone binds to the enzyme, which sits on the surface of the sperm, it removes a lipid (2AG) that has been inhibiting the calcium channel. Released of inhibition, CatSper opens the gate to calcium ions and eventual sperm activation.
The inhibitor of the calcium channel CatSper is probably there for a good reason: to prevent sperm from prematurely sprinting toward the egg and using up their limited supply of energy, Miller said.
Marathon or team sport?
“People tend to think of fertilization as like a marathon, where the fastest, most powerful sperm is going to win,” Miller said. “We think of it like the Tour de France, where the riders in front are blocking the wind for the actual winner. Fertilization is a team sport, where the first sperm clear the way, expending their energy to break through the barrier cells, so that the slow and steady guy can get into the oocyte.”
The study also sheds light on a long-standing mystery about steroids like progesterone: why they appear to act in two distinctly different ways. As a sex hormone, progesterone usually triggers a cascade of events in the cell that alter the expression of genes in the nucleus, a process that can take days. But sometimes progesterone causes immediate changes in the cell – something called non-genomic steroid signaling – that evidently use a quicker process than gene expression.
Lishko, who studies the sperm of rats, mice, bulls and boars as well as human to understand how fertilization works across different species, says that sperm are a perfect system in which to study non-genomic steroid signaling, since the genes in sperm are silenced and the normal type of steroid signaling is not present. As she and her colleagues uncover the basics of steroid signaling in sperm, the same process can then be studied in many other types of cells, she said.
The research was supported by the National Institutes of Health and by Pew Scholars and Alfred P. Sloan Awards to Lishko. Lishko, Miller and Kirichok have filed a patent on usage of ABHD2.
Aside from Miller, Lishko and Kirichok, other authors of the paper are Nadja Mannowetz, Anthony Iavarone, Rojin Safavi, Rose Hill and Diana Bautista of UC Berkeley, Elena Gracheva of Yale University and James Smith of UCSF.
Healthy sperm employ a regular sinusoidal tail motion when swimming, unlike the whiplike motion they use when they reach the egg.
Newswise —
A University of California, Irvine scientific team led by infectious diseases researchers Philip Felgner and Aaron Esser-Kahn has received $8 million from the U.S. Department of Defense’s Defense Threat Reduction Agency to help develop a new vaccine for Q fever.
Caused by the Coxiella burnetii bacterium, Q fever is a highly infectious agent common among livestock. It has a history of being aerosolized for use in biological warfare and is considered a potential bioterrorism weapon.
Q fever is also a public health threat; a 2007-10 outbreak in the Netherlands affected thousands of people. Symptoms include high fever, nausea, severe headache and abdominal pain. It is rarely fatal.
“The current vaccine for Q fever is effective but has severe side effects that limit its widespread use,” said Felgner, an adjunct professor of medicine at UCI. “It’s a high priority that this vaccine be administered to members of the armed forces. Consequently, the military is interested in developing an alternative protective vaccine that’s safer and does not cause adverse reactions.”
Felgner will use an approach he pioneered at UCI to create whole proteome microarrays to discover immune response-activating antigen proteins that may be effective as a vaccine. Additionally, he’ll collaborate with Esser-Kahn, assistant professor of chemistry, whose group will develop synthetic agents that can boost and control the immune response to these proteins.
Felgner said this dual method may be applicable in creating more vaccines important to the military and general public health, adding that this is an opportunity for the Department of Defense to test these methods for their potential use against other infectious diseases.
After identifying the target proteins, Felgner will work with the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick in Maryland on next-stage animal studies of a candidate vaccine.
The project is a successful outgrowth of the Pacific Southwest Regional Center of Excellence, one of only 11 National Institutes of Health-funded research sites dedicated to countering threats from bioterrorism agents and emerging infectious diseases. UCI received $85 million for this effort, which was led by Dr. Alan Barbour, professor of microbiology & molecular genetics. The federal program ended in 2015.
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UCLA researchers have found that space-mapping neurons – the GPS system in the brain - have a strong dependence on what is being looked at when triangulating location, a finding that resolves a neurological mystery that has vexed scientists for more than four decades.
This also expands on an earlier finding that neurons responsible for creating spatial maps react differently in virtual reality than they do in the real-world environments. Researchers again used rats in a virtual reality environment to test the long-debated theory of whether landmarks are necessary or whether that region of the brain is also counting steps or directional movement to determine location, said Mayank Mehta, a UCLA professor of neurology, physics and astronomy, and neurobiology in the UCLA College and the study’s senior author.
The study, which appears today in the peer-reviewed journal Cell, showed that many neurons were firing selectively only when rats were looking at certain landmarks on screens, either in the real or in the virtual reality environment.
“This part of the brain, the hippocampus, has neurons that fire in specific places. If I’m walking around a room, some neurons fire near the door, others around the middle of the room, and they all form a map of space in the brain,” said Mehta, who also is director of a W.M. Keck Foundation neurophysics center. “Where does this map come from? The classic idea was there are two possible mechanisms. One hypothesis is that neurons triangulate distances with respect to visual landmarks. However, it was commonly believed that hippocampal neural responses do not depend on which landmark the rat was looking at, a long standing paradox. The other idea is that neurons are keeping track of the distances traveled by the subject, through the so called path-integration, though not directly tested.”
Surprisingly, the team found that the neurons did signal for what landmark the rat was looking at, thus removing the 45 year old paradox about whether the landmarks exert a causal influence on hippocampal directional responses. Further, careful experiments using virtual reality showed that the neural responses were neither abstract representations of space, as commonly thought, nor vestibular input driven path-integration signals. Instead, these responses were causally and predictably governed by visual landmarks.
This study is a part of series of studies undertaken by the Mehta laboratory to understand how the brain rapidly makes memories, including spatial maps, on the fly. They have been using Virtual Reality to manipulate the perception of space and time. Using this technique they have recently shown that in more than half of the neurons in hippocampus shut down in virtual reality. They also showed that the brain in the virtual world does not create a spatial map like it does in the real world environment, a finding that was replicated in this study, that could have implications for people who use virtual reality for gaming, military, commercial, scientific or other purposes.The scientists were studying the hippocampus, a region of the brain that is critical for learning and memory and involved in diseases such as Alzheimer’s, stroke, schizophrenia, depression, epilepsy and post-traumatic stress disorder. The hippocampus also plays an important role in forming new memories and creating mental maps of space.
Researchers created a sophisticated virtual reality environment for rats that cost nearly $1 million to develop. They placed a small harness around rats and put them on a treadmill-like device surrounded by a “virtual world” on large video screens in an otherwise dark, quiet room.
The rats walk in the virtual room in a similar way as they would in a real room, Mehta said.
Because no mental map was being made, part of the brain was not working in virtual reality. Could there be long-term implications for that as more and more people use virtual reality?
“This could have important implications. This part of the brain that makes maps of space is also involved in making memories, like what did I have for lunch, what was I doing on 9/11? It is, in that sense, what makes us human,” Mehta said. “If people are spending time in virtual reality, could that alter the way the brain works? If it’s not making maps, will the making of memories be affected? Everything in the brain influences what the brain will do later on. It’s the reason we are different at age 40 than we were at age four. The brain remembered everything that happened and modified itself because of it. Now what will happen when people’s neural responses become different in virtual reality?”Mehta said the findings, although found in rodents, are equally applicable to humans.
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A physician-researcher at The Children’s Hospital of Philadelphia (CHOP) has received a $1 million Hyundai Quantum Grant from Hyundai Hope on Wheels to advance treatment for a high-risk form of childhood leukemia. The research focuses on immunotherapy—an approach that utilizes a patient’s immune system to better fight off cancer.
“This Hyundai Quantum Grant gives us substantial resources to make progress against the most life-threatening form of leukemia,” said CHOP pediatric oncologist Richard Aplenc, M.D., Ph.D. “I’m constantly inspired by the resilience of my patients, and the grace and tenderness of their families, and this grant support is very helpful in advancing new cancer treatments.”
The Hyundai Quantum Grant, a new category in Hyundai’s pediatric cancer grant program, provides each research center $250,000 per year for four years. Focusing on pediatric cancers with the lowest survival rates, the program announced competitive awards to CHOP and three other institutions participating in the Children’s Oncology Group. Hyundai Hope on Wheels is the nonprofit organization of Hyundai Motor America, and is in its 18th year of supporting childhood cancer research. This year’s awards are Hyundai’s largest individual research grants ever for pediatric cancer research.
“We are proud to fund Dr. Aplenc, one of this year’s Hyundai Quantum winners, and his innovative work in AML,” said Dave Zuchowski, president and CEO, Hyundai Motor America. “We are hopeful for the discoveries to come from his important work in the coming years. No child should ever have to hear the words, ‘You have cancer,’ and we will continue to support the efforts fighting for that day to come.”
Overall survival rates for children’s cancer have reached 80 percent, but some high-risk forms of cancer have stubbornly resisted this progress. One such example isacute myeloid leukemia (AML), which has a complicated variety of difficult-to-treat subtypes. Even among survivors of AML, intensive chemotherapy may cause lifelong side effects.
Immunotherapy, which is currently being studied in other types of leukemia, may provide a more effective treatment for AML, with fewer long-term side effects. The new grant, said Aplenc, will enable his team to identify specific proteins on the outside surface of AML cells that could be the most appropriate targets for immune cells programmed to attack cancers.
“New technologies have dramatically altered the research landscape, by allowing scientists to better identify proteins and to make use of DNA sequencing data from AML patients,” said Aplenc. “This research grant will enable us to discover more about these specific biological molecules, offering data with great potential to help us design innovative treatments.”
Stephen Hunger, M.D., chief of the Division of Oncology and director of the Center for Childhood Cancer Researchat CHOP, added, “This award will help CHOP physicians and their collaborators develop new therapies for children with AML that has not responded to current therapies, or has relapsed despite those therapies.”
About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit www.chop.edu.
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Could there be a vegetarian gene?
Cornell University researchers have found evidence of a genetic variation – called an allele – that has evolved in populations that have historically favored vegetarian diets, such as in India, Africa and parts of East Asia. They also discovered a different version of this gene adapted to a marine diet discovered among the Inuit in Greenland, who mainly consume seafood.
The vegetarian allele evolved in populations that have eaten a plant-based diet over hundreds of generations. The adaptation allows these people to efficiently process omega-3 and omega-6 fatty acids and convert them into compounds essential for early brain development and if they stray from a balanced omega-6 to omega-3 diet, it may make people more susceptible to inflammation, and by association, increased risk of heart disease and colon cancer.
In Inuit populations of Greenland, the researchers uncovered that a previously identified adaptation is opposite to the one found in long-standing vegetarian populations: While the vegetarian allele has an insertion of 22 bases (a base is a building block of DNA) within the gene, this insertion was found to be deleted in the seafood allele.
“The opposite allele is likely driving adaptation in Inuit,” said Kaixiong Ye, co-lead author of the paper appearing March 29 in the journal Molecular Biology and Evolution. Ye is a postdoctoral researcher in the lab of Alon Keinan, associate professor of biological statistics and computational biology, and the paper’s co-senior author.
“Our study is the first to connect an insertion allele with vegetarian diets, and the deletion allele with a marine diet,” Ye said.
“It is the most interesting example of local adaptation that I have been fortunate to help study,” said Keinan. “Several studies have pointed to adaptation in this region of the genome. Our analyses combine to show that the adaptation is driven by an insertion of a small piece of DNA that we know its function. Moreover, when it reached the Greenlandic Inuit, with their marine-based diet rich in omega-3, it might have become detrimental.”
FADS1 and FADS2 are enzymes that are essential for converting omega-3 and omega-6 fatty acids into downstream products needed for brain development and controlling inflammation. Meat and seafood eaters have less need for increased FADS1 and FADS2 enzymes to get proper nutrition because their omega-3 and omega-6 fatty acid conversion process is simpler and requires fewer steps.
This study is based on previous work by co-senior author Tom Brenna, professor of human nutrition and of chemistry at Cornell University, who showed the insertion can regulate the expression of FADS1 and FADS2 and hypothesized it could be an adaptation in vegetarian populations.
Ye, Keinan and colleagues analyzed frequencies of the vegetarian allele in 234 primarily vegetarian Indians and 311 U.S. individuals and found the vegetarian allele in 68 percent of the Indians and in just 18 percent of Americans. Analysis using data from the 1,000 Genomes Project similarly found the vegetarian allele in 70 percent of South Asians, 53 percent of Africans, 29 percent of East Asians and 17 percent of Europeans.
“Northern Europeans have a long history of drinking milk and they absorbed enough end products from milk for long-chain fatty acid metabolism so they don’t have to increase capacity to synthesize those fatty acids from precursors,” said Ye.
“One implication from our study is that we can use this genomic information to try to tailor our diet so it is matched to our genome, which is called personalized nutrition,” he added.
The researchers are not sure yet when the adaptation first occurred, as analyses of chimpanzee or orangutan genomes did not uncover the vegetarian allele. But there is evidence for the allele in early hominid Neanderthal and Denisovan genomes.
“It is possible that in the history of human evolution, when people migrated to different environments, sometimes they ate a plant-based diet and sometimes they ate a marine-based diet, and in different time periods these different alleles were adaptive,” meaning the alleles have a tendency to evolve under dietary pressures, Ye said.
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Ever see something that isn't really there? Could your mind be playing tricks on you? The "tricks" might be your brain reacting to feedback between neurons in different parts of the visual system, according to a study published in the Journal of Neuroscience by Carnegie Mellon University Assistant Professor of Biological Sciences Sandra J. Kuhlman and colleagues.
Understanding this feedback system could provide new insight into the visual system's neuronal circuitry and could have further implications for understanding how the brain interprets and understands sensory stimuli.
Many optical illusions make you see something that's not there. Take the Kanizsa triangle: when you place three Pac-Man-like wedges in the right spot, you see a triangle, even though the edges of the triangle aren't drawn.
"We see with both our brain and our eyes. Your brain is making inferences that allow you to see the triangle. It's connecting the dots between the corners of the wedges," said Kuhlman, who is a member of Carnegie Mellon's BrainHub neuroscience initiative and the joint Carnegie Mellon/University of Pittsburgh Center for the Neural Basis of Cognition (CNBC). "Optical illusions illustrate some of the amazing things our visual system can do."
When we look at an object, information about what we see travels through circuits of neurons beginning in the retina, through the thalamus and into the brain's visual cortex. In the visual cortex, the information gets processed in multiple stages and is ultimately sent to the prefrontal cortex -- the area of the brain that makes decisions, including how to respond to a given stimulus.
However, not all information stays on this forward moving path. At the secondary stage of processing in the visual cortex some neurons reverse course and send information back to the first stage of processing. Researchers at Carnegie Mellon wondered if this feedback could change how the neurons in the visual cortex respond to a stimulus and alter the messages being sent to the prefrontal cortex.
While there has been a good deal of research studying how information moves forward through the visual system, less has been done to study the impact of the information that moves backward. To find out if the information traveling from the secondary stage of processing back to the first stage impacted how information is encoded in the visual system, the researchers needed to quantify the magnitude of information that was being sent from the second stage back to the first stage. Using a mouse model, they recorded normal neuronal firing in the first stage of the visual cortex as the mouse looked at moving patterns that represented edges. They then silenced the neurons in the second stage using modified optogenetic technology. This halted the feedback of information from the second stage back to the first stage, and allowed the researchers to determine how much of the neuronal activity in the first stage of visual processing was the result of feedback.
Twenty percent of the neuronal activity in the visual cortex was the result of feedback, a concept Kuhlman calls reciprocal connectivity. This indicates that some of the information coming from the visual cortex is not a direct response to a visual stimuli, but is a response to how the stimuli was perceived by higher cortical areas.
The feedback, she says, might be what causes our brain to complete the undrawn lines in the Kanizsa triangle. But more importantly, it signifies that studying neuronal feedback is important to our understanding of how the brain works to process stimuli.
"This represents a new way to study visual perception and neural computation. If we want to truly understand the visual pathway, and cortical function in general, we have to understand these reciprocal connection," Kuhlman said.