Category Archives: Gene Medicine

A new technique adds a spatial dimension to studies of gene expression

Neuron pathways from the motor cortex connect multiple regions throughout the mouse brain. Credit: Allen Mouse Brain Connectivity Atlas

Scientists can now take snapshots of where and how thousands of genes are expressed in intact tissue samples, ranging from a slice of a human brain to the embryo of a fly.

The technique, reported today inScience, can turn a microscope slide into a tool for creating data-rich, three-dimensional maps of how cells interact with one another a key to understanding the origins of diseases such as cancer. The methodology also has broader applications, enabling researchers to create, for instance, unique molecular barcodes to trace connections between cells in the brain, a stated goal of the US National Institutes of Health'sHuman Connectome Project.

Previously, molecular biologists had a limited spatial view of gene expression, the process by which a stretch of double-stranded DNA is turned into single-stranded RNAs, which can in turn be translated into protein products. Researchers could either grind up a hunk of tissue and catalogue all the RNAs they found there, or use fluorescent markers to track the expression of up to 30 RNAs inside each cell of a tissue sample. The latest technique maps up to thousands of RNAs.

Mapping the matrix In a proof-of-principle study,molecular biologist George Churchof Harvard Medical School in Boston, Massachusetts, and his colleagues scratched a layer of cultured connective-tissue cells and sequenced the RNA of cells that migrated to the wound during the healing process. Out of 6,880 genes sequenced, the researchers identified 12 that showed changes in gene expression, including eight that were known to be involved in cell migration but had not been studied in wound healing, the researchers say.

This verifies that the technique could be used to do rapidly what has taken scientists years of looking at gene products one by one, says Robert Singer, a molecular cell biologist at Albert Einstein College of Medicine in New York, who was not involved in the study.

The method hinges on fossilizing the RNA in place in the cell and sequencing it. First, the researchers affix a slice of tissue on a surface and wash away the cellular membranes, keeping the cells' scaffolding, RNA and proteins in place. Next, the researchers add chemicals to 'reverse-transcribe' each short segment of RNA, converting it into circular fragments of single-stranded DNA. Then they add more chemicals to make hundreds of copies of each DNA circle, which form clusters called nanoballs. These nanoballs are chemically linked together to form a durable, transparent matrix that approximates the original layout of the cell, and then analyzed by SOLiD sequencing, a method that uses digital imaging to capture the colors and locations of fluorescent probes as they interrogate the DNA.

The technique has applications beyond understanding gene-expression patterns, says Jay Lee, a medical doctor and biologist in Churchs lab. At present, the most advanced technology for labelling and mapping neurons,Brainbow, is limited to 100 simultaneous hues. Lee says that its now possible to create 1 trillion different molecular barcodes from small strands of RNA. He is also working on techniques to add barcodes to proteins inside the cell.

Lee says that the technique reminds him of a scene from the science-fiction filmThe Matrix, in which the character Neo sees the binary source code underlying his environment. This sounds a little corny, he concedes, but he adds, I want biology to be like that.

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Gene Activity Can Now Be Mapped Spatially across Intact Tissue

By Steven Reinberg HealthDay Reporter

MONDAY, Feb. 24, 2014 (HealthDay News) -- Women who carry a BRCA1 gene mutation and have their ovaries removed by age 35 appear to dramatically reduce their odds of developing ovarian cancer and dying, a new international study finds.

Having this procedure, called oophorectomy, may reduce the odds of dying by age 70 by about 77 percent, researchers say. Women who have BRCA1 or BRCA2 gene mutations are at greater risk of developing breast and/or ovarian cancer.

"We have a strong basis to recommend that women who have a BRCA1 mutation really benefit from having an oophorectomy, and they should have it by age 35," said lead researcher Dr. Steven Narod, a professor of medicine at the University of Toronto, in Canada.

Women with BRCA2 mutations can delay surgery until they're 40, since their risk of ovarian cancer is not as strong, he added.

The procedure made news last year when film star Angelina Jolie, a carrier of the BRCA1 mutation, announced plans to have her ovaries removed. Previously, she had undergone a preventive double mastectomy. Jolie's mother, actress Marcheline Bertrand, died of ovarian cancer at the age of 56.

Study author Narod noted that the benefits of the surgery outweigh the side effects. Those side effects include menopause symptoms, such as hot flashes and sleep disturbances, which can be managed by hormone replacement therapy, he said.

Other side effects may include a small increase in the risk for heart disease and possibly memory and thinking problems. Of course, removing the ovaries means not having children, but by 35 the women could have already started a family, Narod said.

The real challenge, Narod added, is getting women screened for BRCA mutations. Most women who have these mutations don't know they have them. "Probably only one in 300 women carry these mutations," he said.

"If we are going to get the full impact, it's important that more women get tested," Narod said. But making genetic testing more available means lowering the cost from around $1,000 to $100, he added.

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Ovarian Cancer Gene May Point to Early Removal of Ovaries: Study

After a heart attack, there is often permanent damage to a portion of the heart. This happens, in part, because cardiac muscle cells are terminally differentiated and cannot proliferate after blood flow is blocked off to the heart. This partial healing can be attributed to heart disease being one of the leading causes of death. What if the cells could be stimulated to divide and the heart could be induced to repair itself? This was the question posed by George Washington University (GW) researcher Scott Shapiro, M.D., Ph.D., and his co-authors, who found that cardiac regeneration may be a possibility with gene therapy.

The research, published yesterday in Science Translational Medicine, found that gene therapy can elicit a regenerative response in pig hearts. Shapiro and his research team first looked to small animals such as the zebrafish, which are able to regenerate heart tissue after a heart attack. This animal has a key protein at play, Cyclin A2 (Ccna2).

After seeing the effects of CCna2 in small animals, we began looking at the effects of the gene in larger animals, such as pigs, said Shapiro, assistant professor of medicine at the GW School of Medicine and Health Sciences. We delivered Ccna2 directly into the heart and found that pigs not only had improved cardiac function, but also found evidence of cellular regeneration.

Ccna2 is a prenatal gene normally turned off in humans after birth. Shapiro believes using gene therapy as a tool for cardiac regeneration, optimized for humans, could lead to a viable treatment option for patients who suffer from myocardial infarction, or heart attack.

Story Source:

The above story is based on materials provided by George Washington University. Note: Materials may be edited for content and length.

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Gene therapy a promising tool for cardiac regeneration

Rochester, NY (PRWEB) February 23, 2014

Is it possible that the medical community focuses too much on fatigue and ignores other relevant symptoms of Chronic Fatigue Syndrome? polyDNA has learned that The Institute of Medicine (the health arm of the National Academy of Sciences) is reviewing how chronic fatigue syndrome is diagnosed... Core to the diagnosis, patients and doctors who specialize in the disorder say, is a physical and mental crash of extreme exhaustion and ill feeling after even mild exercise, requiring days to weeks of recovery (1). polyDNA recommends that individuals who suffer from fatigue take Gene-Eden-VIR. This natural product was clinically proven to reduce physical and mental fatigue in a study that followed FDA guidelines.

Some people believe that the name Chronic Fatigue Syndrome trivializes the condition and puts a chilling effect on high quality research into its cause (1). Dr. Nancy Lee said There are many people - scientists, clinicians, advocates - who believe the name 'chronic fatigue syndrome' does harm to patients (1).

The Institute of Medicine panel is being asked to review evidence on the best way to diagnose the disorder. It will also consider whether the name should be changed (1). This is because long-standing fatigue is just one of many debilitating symptoms of CFS. Sleep disturbance also affects nearly all patients, who typically wake up unrefreshed no matter how long they sleep. Muscle and joint pain and problems with thinking, concentration and memory are also nearly universal. Other common symptoms include gastrointestinal problems, dizziness, heat or cold intolerance, sore throat and swollen lymph nodes (1).

The CDC says that Chronic fatigue syndrome, or CFS, is a devastating and complex disorder. People with CFS have overwhelming fatigue and a host of other symptoms that are not improved by bed rest and that can get worse after physical activity or mental exertion. They often function at a substantially lower level of activity than they were capable of before they became ill. (See the CDCs web page on CFS, last reviewed on May 13, 2012) (3).

The syndrome often follows a viral illness, such as with the Epstein Barr Virus (EBV).

Interestingly, abnormalities in the immune system have been reported in CFS patients and study authors specifically noted that Almost all patients reported a previous infection as the onset of fatigue symptom. (See the International Journal of Pediatrics, from 2013) (2). Moreover, Almost all patients reported themselves to be previously healthy prior to their fatigue and also ascribed the onset due to an infection (2).

Gene-Eden-VIR is a natural antiviral remedy. Moreover, in forthcoming post-marketing clinical study, Gene-Eden-VIR was shown to reduce fatigue associated with a viral infection.

For those who believe CFS might be a result of a viral infection, we recommend Gene-Eden-VIR. Mike Evans, polyDNA

polyDNA points out that there are no FDA approved drugs that specifically treat fatigue.

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NPR: Chronic Fatigue Syndrome (CFS) or Myalgic Encephalomyelitis? polyDNA Recommends Gene-Eden-VIR to Reduce Fatigue ...

PUBLIC RELEASE DATE:

20-Feb-2014

Contact: Lisa Anderson lisama2@gwu.edu 202-994-3121 George Washington University

WASHINGTON (Feb. 20, 2014) After a heart attack, there is often permanent damage to a portion of the heart. This happens, in part, because cardiac muscle cells are terminally differentiated and cannot proliferate after blood flow is blocked off to the heart. This partial healing can be attributed to heart disease being one of the leading causes of death. What if the cells could be stimulated to divide and the heart could be induced to repair itself? This was the question posed by George Washington University (GW) researcher Scott Shapiro, M.D., Ph.D., and his co-authors, who found that cardiac regeneration may be a possibility with gene therapy.

The research, published yesterday in Science Translational Medicine, found that gene therapy can elicit a regenerative response in pig hearts. Shapiro and his research team first looked to small animals such as the zebrafish, which are able to regenerate heart tissue after a heart attack. This animal has a key protein at play, Cyclin A2 (Ccna2).

"After seeing the effects of CCna2 in small animals, we began looking at the effects of the gene in larger animals, such as pigs," said Shapiro, assistant professor of medicine at the GW School of Medicine and Health Sciences. "We delivered Ccna2 directly into the heart and found that pigs not only had improved cardiac function, but also found evidence of cellular regeneration."

Ccna2 is a prenatal gene normally turned off in humans after birth. Shapiro believes using gene therapy as a tool for cardiac regeneration, optimized for humans, could lead to a viable treatment option for patients who suffer from myocardial infarction, or heart attack.

###

The study, titled "Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction Through Cytokinesis of Adult Cardiomyocytes," is available at http://stm.sciencemag.org/content/6/224/224ra27.short.

Additional authors of the study include researchers from the Cardiovascular Institute at the Mount Sinai School of Medicine, the Centro Nacional de Investigaciones Cardiovasculares at the Hospital Universitario La Paz, and the Division of Cardiology at the Albert Einstein College of Medicine.

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GW researcher finds gene therapy a promising tool for cardiac regeneration

Injections of a normally silent gene sparked recovery in pigs induced to have heart attacks

Thinkstock/iStock

When a heart attack brings blood flow to a screeching halt, thats only the first assault on our fist-size organ. Among survivors, the recovery itself fuels more permanent damage to the heart. Scar tissue can harden once-flexible heart muscle, making it less elastic. And as tentacles of this tissue creep over the aorta the heart muscle can no longer fully contract. This long-term damage can minimize the amount of oxygen-rich blood sent throughout the body, which can send patients spiraling into heart failure. Heart transplants are one way to circumvent these scar tissue issues, but donor hearts are always in short supply. Devising other truly effective solutions has long eluded researchers. A form of gene therapy, however, is now showing promise in pigs. It turns out that a normally silent gene called Cyclin A2, or CCNA2, can be coaxed into action to combat the formation of scar tissue in pigs that suffer a heart attack. This treatment sparked regeneration of heart muscle cells in pigs as well as improvements in the volume of blood pushed out with every beat. The finding is published in the February 19 issue of Science Translational Medicine. Gene therapy, the authors hope, may one day join stem cell treatments as a contender for transforming the way doctors treat heart failure. Stem cellbased therapies have already resulted in more healthy tissue and decreased scar mass in human clinical trials as well as small improvements in how much blood the heart can pump from one chamber to another. But as Scientific American reported in April 2013, many questions remain about which stem cells to use and how to prepare them. For this study, researchers randomly assigned 18 pigs recovering from heart attacks to either receive injections of the gene expressed under a promoter (which would force it to be expressed) or the same solution without the gene. Pigs treated with the gene had greater success pushing out blood with each heartbeat, but also produced a greater number of heart muscle cells. These findings echo the teams earlier heart regeneration successes in mice and rats. The researchers replicated their findings in a petri dish and watched adult porcine heart muscle cells treated with the same regimen of gene therapy undergo complete cell division in the dishdemonstrating under a microscope how the heart cells were dividing and thriving with the gene therapy. This new approach mimics the kind of regeneration we see in the newt and zebra fish, says lead author Hina Chaudhry, the director of cardiovascular regenerative medicine at The Mount Sinai Hospital in New York City. If the technique proves successful in humans, it could boost patient recovery rates by helping strengthen heart muscles and improving blood flow, all while giving a needed lift to gene therapy research, which has been slow to gain momentum in the U.S. In 1999 Jesse Gelsinger, 18, died after a gene therapy experiment cost him his life. The virus used to deliver a gene that would potentially control his rare digestive disorder fueled a massive and fatal immune reaction. That highly publicized case, along with other gene therapy missteps, put a pall on the field. Chaudhry says that her team is proceeding with caution and plans to be careful when administering this treatment to patient populations. For patients who have a large heart attack who are at risk of heart failure, I think the therapy is going to be very beneficial, she says. If you have a small heart attack, it probably wont make as much of a difference in overall survival because of advances with todays medicines. As more researchers look to gene therapy for previously intractable human conditions, a success with heart attack treatments could send ripples throughout the field.

2014 Scientific American, a Division of Nature America, Inc.

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Gene Therapy Shows Promise for Treating Heart Attack Victims

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Newswise WASHINGTON (Feb. 20, 2014) After a heart attack, there is often permanent damage to a portion of the heart. This happens, in part, because cardiac muscle cells are terminally differentiated and cannot proliferate after blood flow is blocked off to the heart. This partial healing can be attributed to heart disease being one of the leading causes of death. What if the cells could be stimulated to divide and the heart could be induced to repair itself? This was the question posed by George Washington University (GW) researcher Scott Shapiro, M.D., Ph.D., and his co-authors, who found that cardiac regeneration may be a possibility with gene therapy.

The research, published yesterday in Science Translational Medicine, found that gene therapy can elicit a regenerative response in pig hearts. Shapiro and his research team first looked to small animals such as the zebrafish, which are able to regenerate heart tissue after a heart attack. This animal has a key protein at play, Cyclin A2 (Ccna2).

After seeing the effects of CCna2 in small animals, we began looking at the effects of the gene in larger animals, such as pigs, said Shapiro, assistant professor of medicine at the GW School of Medicine and Health Sciences. We delivered Ccna2 directly into the heart and found that pigs not only had improved cardiac function, but also found evidence of cellular regeneration.

Ccna2 is a prenatal gene normally turned off in humans after birth. Shapiro believes using gene therapy as a tool for cardiac regeneration, optimized for humans, could lead to a viable treatment option for patients who suffer from myocardial infarction, or heart attack.

The study, titled Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction Through Cytokinesis of Adult Cardiomyocytes, is available at http://stm.sciencemag.org/content/6/224/224ra27.short.

Additional authors of the study include researchers from the Cardiovascular Institute at the Mount Sinai School of Medicine, the Centro Nacional de Investigaciones Cardiovasculares at the Hospital Universitario La Paz, and the Division of Cardiology at the Albert Einstein College of Medicine.

Media: To interview Dr. Shapiro about this study, please contact Lisa Anderson at lisama2@gwu.edu or 202-994-3121.

###

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Researcher Finds Gene Therapy a Promising Tool for Cardiac Regeneration

Next-generation sequencing defines new pathway for blood vessel disease

National Institutes of Health researchers have identified gene variants that cause a rare syndrome of sporadic fevers, skin rashes and recurring strokes, beginning early in childhood. The teams discovery coincides with findings by an Israeli research group that identified an overlapping set of variants of the same gene in patients with a similar type of blood vessel inflammation.

A variation in the gene that makes a key blood vessel enzyme makes children prone to fevers, rash and strokes.

The NIH group first encountered a patient with the syndrome approximately 10 years ago. The patient, then 3 years old, experienced fevers, skin rash and strokes that left her severely disabled. Because there was no history of a similar illness in the family, the NIH group did not at first suspect a genetic cause, and treated the patient with immunosuppressive medication. However, when the NIH team evaluated a second patient with similar symptoms two years ago a child who had experienced recurrent fevers and six strokes by her sixth birthday they began to suspect a common genetic cause and embarked on a medical odyssey that has led not only to a diagnosis, but to fundamental new insights into blood vessel disease.

In their study, which appears in the Feb. 19, 2014, advance online edition of the New England Journal of Medicine, the researchers describe how next-generation genome sequencing, only recently available, facilitated a molecular diagnosis for patients in their study. The researchers found that harmful variants in the CECR1 gene impede production of a protein vital to the integrity of healthy blood vessel walls.

This discovery is another example of genome sequencing playing a central role in revealing the genomic basis for an important rare disease, said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), where the lead members of the research team are based. Such studies illustrate how genomics is paving the way to improved human health.

The researchers showed that faulty variants in their patients DNA that encode the CECR1 gene cause a loss of function of the genes ability to produce of an enzyme called adenosine deaminase 2 (ADA2). Without it, abnormalities and inflammation in blood vessel walls result. The researchers call the new syndrome, deficiency of ADA2, or DADA2. The enzyme ADA2 is chemically similar to the enzyme ADA1, whose deficiency results in severe combined immunodeficiency disease.

NHGRI Scientific Director Daniel Kastner, M.D., Ph.D., led the team of collaborators from NIH and beyond in mounting the study of nine patients. It has been incredibly fantastic to see this kind of progress being made within the last decade, he said. Our study raises the possibility that the ADA2 pathway may contribute to susceptibility to stroke in the more general population.

For children, as with adults, stroke can affect physical, cognitive and emotional functioning. Some outcomes, such as blindness and deafness, can be lasting; others, such as the ability to walk, can be relearned.

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News & Events

PUBLIC RELEASE DATE:

19-Feb-2014

Contact: Raymond MacDougall macdougallr@mail.nih.gov 301-443-3523 NIH/National Human Genome Research Institute

National Institutes of Health researchers have identified gene variants that cause a rare syndrome of sporadic fevers, skin rashes and recurring strokes, beginning early in childhood. The team's discovery coincides with findings by an Israeli research group that identified an overlapping set of variants of the same gene in patients with a similar type of blood vessel inflammation.

The NIH group first encountered a patient with the syndrome approximately 10 years ago. The patient, then 3 years old, experienced fevers, skin rash and strokes that left her severely disabled. Because there was no history of a similar illness in the family, the NIH group did not at first suspect a genetic cause, and treated the patient with immunosuppressive medication. However, when the NIH team evaluated a second patient with similar symptoms two years agoa child who had experienced recurrent fevers and six strokes by her sixth birthdaythey began to suspect a common genetic cause and embarked on a medical odyssey that has led not only to a diagnosis, but to fundamental new insights into blood vessel disease.

In their study, which appears in the Feb. 19, 2014, advance online edition of the New England Journal of Medicine, the researchers describe how next-generation genome sequencing, only recently available, facilitated a molecular diagnosis for patients in their study. The researchers found that harmful variants in the CECR1 gene impede production of a protein vital to the integrity of healthy blood vessel walls.

"This discovery is another example of genome sequencing playing a central role in revealing the genomic basis for an important rare disease," said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), where the lead members of the research team are based. "Such studies illustrate how genomics is paving the way to improved human health."

The researchers showed that faulty variants in their patients' DNA that encode the CECR1 gene cause a loss of function of the gene's ability to produce of an enzyme called adenosine deaminase 2 (ADA2). Without it, abnormalities and inflammation in blood vessel walls result. The researchers call the new syndrome, deficiency of ADA2, or DADA2. The enzyme ADA2 is chemically similar to the enzyme ADA1, whose deficiency results in severe combined immunodeficiency disease.

NHGRI Scientific Director Daniel Kastner, M.D., Ph.D., led the team of collaborators from NIH and beyond in mounting the study of nine patients. "It has been incredibly fantastic to see this kind of progress being made within the last decade," he said. "Our study raises the possibility that the ADA2 pathway may contribute to susceptibility to stroke in the more general population."

For children, as with adults, stroke can affect physical, cognitive and emotional functioning. Some outcomes, such as blindness and deafness, can be lasting; others, such as the ability to walk, can be relearned.

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NIH team discovers genetic disorder causing strokes and vascular inflammation in children

A molecular diagnosis gives doctors and patients better treatment options when suspicious lumps are found in the neck.

Genetic biopsy: A Veracyte technician tests 142 genes from patients with suspicious nodules in their thyroid glands.

Later this year, doctors in the U.S. will be able to use a gene test to guide thyroid cancer surgery. The test helps determine when patients harbor a particularly dangerous form of the disease, which can require surgeons to do a second operation on top of the initial diagnostic procedure. Knowing that a patient has this particular form of thyroid cancer could enable surgeons to instead do a single, more extensive surgery.

The company behind the test, Veracyte, already sells a unique genetic assay that helps doctors decide whether to perform surgery on thyroid cancer patients at all. Thyroids that are not cancerous are often removed, which means unnecessary surgery and lifelong hormone replacement therapy for some patients.

Both tests are part of a broader movement in recent years to bring genetic tests into medical care, with oncology leading the way. One test, from Myriad Genetics, looks for mutations linked to increased risk of cancer; others, such as one offered by Foundation Medicine, help doctors prescribe drugs tailored to a particular tumor (see Foundation Medicine: Personalizing Cancer Drugs).

Veracytes first test is the only one that rules out cancer. A lump, or nodule, is caused by growths of cells in the thyroid gland, which is located in the base of the neck. Most often these growths are not cancers. To figure out whether they are, doctors will first take a small needle to extract cells from the lump and then look at the cells under the microscope. And up to 30 percent of the time in U.S. clinics, that test is inconclusive. Because cancer cant be ruled out, typically the next step is to remove the thyroid. The gland normally produces important hormones that regulate metabolism and other body functions, so patients usually then have to take hormone replacement therapy for the rest of their lives.

Between 60 and 80 percent of the time, the nodule in the removed thyroid turns out to be benign. You have unnecessarily put a patient through surgery, says Kishore Lakshman, director of a community thyroid care center in Fall River, Massachusetts. This puts patients at risk for complications such as infection, and creates dependence on hormone therapy. Since 2011, Lakshman has been using Veracytes gene test to assess the risk of cancer in patients whose initial thyroid screen was inconclusive. When I found out that there was a very efficient way of knowing the benign potential of a nodule without exposing a patient to surgery, I was quick to jump on it, says Lakshman.

Veracyte analyzed gene expression levels in hundreds of patients with thyroid nodules, some cancerous, some not, and identified 142 genes that can reliably separate benign from malignant samples. Measuring every gene in the human genome, our scientific team was able to extract genomic information and interpret it with machine-learning algorithms taught to recognize patients with benign nodules, says Bonnie Anderson, CEO and cofounder of the South San Francisco-based company.

The performance of the test was evaluated and published in the New England Journal of Medicine in 2012. That trial showed that Veracytes test can reclassify a nodule from indeterminate to benign 95 percent of the time.

In addition to saving patients from unnecessary surgeries, the test could save significant health-care dollars. A health economics study by Johns Hopkins University School of Medicine researchers found that if the test were used universally in the U.S. for patients whose needle assay was inconclusive, then approximately $122 million in medical costs would be saved each year, primarily because of the significant reduction in surgeries.

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Gene Test Helps Patients Avoid Thyroid Surgery