Fresno Bee | The Board Room for July 3 Fresno Bee He completed medical school and his residency at the Tehran University of Medical Sciences, followed by research at the Institute of Genetic Medicine at USC and his residency at the Department of Internal Medicine at USC. Realty Concepts added Parvis ... |
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In brief
Cancer has long been defined by where it starts to growthe lungs, the colon, the breasts. But the recent approval of a cancer immunotherapy for anyone harboring a specific genetic profile, regardless of the tissue in which it is found, signals a shift in how researchers think about cancer. Read on to learn more about how technology and drug development are converging to realize the promise of personalized medicine.
When Adrienne Skinner was diagnosed with ampullary cancer, a rare gastrointestinal tumor, in early 2013, it didnt come as a complete surprise. For nearly a decade, she had known her genes were not in her favor. What she didnt know was that her genes would also point the way to a cure.
Skinner has Lynch syndrome, an inherited disorder caused by a defect in mismatch repair (MMR) genes, which encode for proteins that spot and fix mistakes occurring during DNA replication. People with Lynch syndrome have an up to 70% risk of developing colon cancer. Women with the disorder have similarly high chances of developing endometrial cancer at an early age.
The first time Skinner heard about the syndrome was in late 2004, after her sister was diagnosed with colon, ovarian, and endometrial cancers, the telltale trifecta associated with Lynch syndrome. It turned out that Skinner, her sister, and their mother were all carriers of deficient MMR genes.
After Skinner spent a year responding toand then not responding totwo types of chemotherapy, her oncologist suggested she look into a novel trial under way at Johns Hopkins Kimmel Cancer Center. Clinicians there were testing a drug called Keytruda in cancer patients who have gene defects like hers.
Keytruda, developed by Merck & Co., is part of a wave of new treatments called checkpoint inhibitors that help the immune system recognize and attack cancer cells.
Although remarkably successful at treating skin and lung cancers, checkpoint inhibitors werent eliciting the same results with colon cancer. The team at Hopkins had a theory about why only a handful of colon cancer patients benefited: Like Skinner, they harbor defects in MMR genes. The researchers convinced Merck to give them the drug and found a nonprofit to support a study to test their hypothesis.
Once every two weeks, Skinner took a train from her home in Larchmont, N.Y., to Baltimore, where she was given an infusion of Keytruda.
Less than three months into the study, she went in for a biopsy to gauge whether the drug was kicking her immune system into gear. The surgeon who walked in after the procedure delivered incredible news. Skinner recalls he looked at her and said, You know, if somebody hadnt told me you had ampullary cancer, I wouldnt have known, because theres nothing in there.
Skinner isnt the only patient to experience that kind of dramatic response. Clinicians later reported that the immunotherapy works in people with all sorts of cancers that are characterized by MMR deficiency or a related condition known as microsatellite instability.
In a trial of 149 patients who had not responded to more conventional cancer drugs, tumors shrank in roughly 40% of those with colon cancer and 48% of those with other types of cancer.
The results were unbelievable, says Luis Diaz, who conceived the trial while at Hopkins and is now head of the solid tumor oncology division at Memorial Sloan Kettering Cancer Center. Things never happen this way. I mean, 80% of the ideas one has fail.
In May, swayed by the Keytruda data, the U.S. Food & Drug Administration granted its first-ever approval of a cancer therapy for patients harboring a specific molecular profile. The tissue-agnostic approval is perhaps the most public example of an ongoing redefinition of how cancer patients are treated.
Cancer care has always centered on the organ where a tumor is bornthe lungs, the breasts, the colon. Even in this much-heralded era of personalized medicine, drugs that target genetic aberrations are still approved for use in specific organs. Moreover, companies still largely need to run separate trials to prove a drugs efficacy in each organ.
Now, thanks to cheaper and faster genetic sequencing, researchers are thinking differently about cancer. With the technology, they can more easily match targeted treatments or cancer immunotherapies to the patients who have the molecular makeup to benefit from them.
More and more early- and midphase clinical trials, known as basket studies, are looking beyond the organ of origin and welcoming anyone with a specific genetic profile. Now that FDA appears open to a genetics-focused development approach, experts expect the oncology field to shift from its preoccupation with a tumors location.
The overarching goal of the tissue-agnostic approach is to make cancer drug development more efficient. Looking beyond the location of a tumor promises to speed up treatment options for people such as Skinner, who otherwise might not have known they would benefit from a drug.
Mercks tissue-agnostic approval is a watershed event, says Razelle Kurzrock, head of the Center for Personalized Cancer Therapy at the University of California, San Diegos Moores Cancer Center.
Kurzrock explains that oncology has for decades defined cancer cells by how they look under a microscope, leading to todays organ-centered categories. Now, instead of looking at the surface of the cell, she says, oncologists are more often looking inside the cell to identify what is making it abnormal.
Scientifically, that makes so much sense, Kurzrock says. Youre hitting the fundamental alteration that is driving cancer rather than the superficial appearance of the cancer.
Still, the focus on the organ of origin persists, even as companies turn to designing drugs that block cancer-causing genetic mutations found in many tumor types. The idea of precision medicine actually does work, but up until now, it has been largely tumor restricted, says Roy Baynes, Mercks senior vice president for global clinical development. The real hope is this mechanism-based approach will translate more broadly.
But challenges abound. Although oncologists laud the tissue-agnostic approval of Keytruda, they also caution against overselling genetics as a panacea.
Its definitely a step forward but not a definitive solution to all cancers, says Igor Puzanov, director of early-phase clinical trials at Roswell Park Cancer Institute.
Among cancer researchers such as Puzanov, the BRAF gene is the fly in the ointment of tissue-agnostic drug development. BRAF mutations are ubiquitous in cancer but most commonly found in melanoma, colon cancer, and thyroid cancer. When the BRAF inhibitor vemurafenib was discovered, researchers hoped the molecule would destroy cancer cells in people with any of these three cancers.
Skinners ampullary cancer immediately responded to treatment with Keytruda.
Credit: Courtesy of Adrienne Skinner
It didnt. Vemurafenib, which specifically blocks the BRAF V600E mutation, works remarkably well against skin cancerRoche won approval for the drug to treat melanoma in 2011but hardly any colon cancer patients respond to it. Researchers have spent several years trying to understand the discrepancy. Even as they come up with plausible theories, the failure of BRAF inhibitors to work in both kinds of tumor has dogged the field.
UCSDs Kurzrock argues that dismissing tissue-agnostic approaches based on the BRAF story is shortsighted. No cancer drug works in every person. Even vemurafenib elicits a response in only half of melanoma patients with BRAF mutations. The other half have additional mutations that also need to be blocked.
Colon cancer is no different, Kurzrock says. The key is figuring out the other pathways involved so appropriate treatment combinations can be pursued. For example, adding an EGFR inhibitor to a BRAF inhibitor elicits a response in colon cancer patients.
Shifting how the medical establishment thinks about cancer means overcoming a mind-set that has persisted for decades.
While we live in a research world where we sequence 600 genes for every tumor, youre going to be worked up in a diagnostic setting that is different if you have breast cancer versus lung cancer, says Wendy Winckler, head of next-generation diagnostics at the Novartis Institutes for BioMedical Research. Thus, a patient with, for example, breast cancer typically isnt tested for EGFR mutation, which is commonly found in lung cancer.
Moreover, for drug companies it was simply easier to seek an approval for melanoma patients, 3045% of whom have BRAF V600E mutations, than for non-small cell lung cancer patients, just 12% of whom have the mutation. To run a clinical trial in lung cancer, 100 patients would need to be screened to find just one to enroll. That wasnt happening before, Winckler says.
Credit: Yang H. Ku/C&EN/Shutterstock
But the availability of broad screening panels is changing that paradigm. Historically, the world has been rate limited from doing this kind of drug development largely because of diagnostics, says Joshua Bilenker, chief executive officer of Loxo Oncology. Just five years ago, he notes, the next-generation gene sequencers that can test for a large swath of molecular drivers of cancer didnt even exist.
Broad testing is how you find things you never even knew you were looking for, Bilenker says. This was the case for the rare mutations targeted by Loxos most advanced drug candidate, larotrectinib.
Loxo is developing larotrectinib as a treatment for any cancer patient harboring TRK gene fusions, which occur when chromosomes break apart and then rejoin in the wrong place. Between 1,500 and 5,000 patients who are newly diagnosed with advanced cancer each year have a TRK fusion, Loxo estimates, meaning the genetic error appears in less than 1% of all cancers.
Larotrectinib, which inhibits the fusions, stole the spotlight at last months annual meeting of the American Society of Clinical Oncology in Chicago. Researchers presented a study that tested the drug in 50 children and adults who had TRK fusions across 17 cancer types, ranging from rare tumors to common cancers, such as colon and lung. An astounding 76% saw their tumors shrink, and the drug continued to work for those responders a year into the trial.
The truly tumor-agnostic activity weve seen is a bit surprising, even to us, Bilenker says. Loxo plans to apply by early 2018 for FDA approval of the drug for anyone with TRK fusions.
Last month, the biotech firm also began a trial of its next-generation TRK inhibitor, LOXO-195. Although many patients have seen sustained responses to larotrectinib, cancer cells inevitably develop resistance to targeted agents. LOXO-195 was designed to lock the conformation of TRK into place, overcoming resistance.
Another company, Ignyta, will also seek approval next year of a drug for people with TRK fusions.
Ignyta is taking a slightly different approach for its lead compound, entrectinib, which blocks fusions in TRKs, ROS1, and ALK. It plans in 2018 to seek a tissue-agnostic approval in people with TRK fusions and an approval in lung cancer for people with ROS1 mutations.
The tissue-agnostic development pathways that Loxo and Ignyta chose are outliers. Although several other large basket trials are under way, most are geared toward finding signals of efficacy before companies move on to trials in specific organs or tissues. Still, researchers hope that some of those studies will reveal drugs with broad efficacy.
The National Cancer Institute (NCI) recently announced that it has sequenced the tumors of 6,000 people as part of its Molecular Analysis for Therapy Choice, or NCI-MATCH, trial. The study started enrolling patients in August 2015 with the goal of pairing anyone whose tumor has a particular molecular makeup with one of 21 drugs or drug combinations.
So far, about 19% of the people recruited have been matched with a drug or drug combination, and more than half of them have rare cancers, says Barbara Conley, the associate director of NCIs Cancer Diagnosis Program. Conley is responsible for overseeing the NCI-MATCH study.
The trial is designed to find signals that the targeted treatments are effective. Still to be seen is whether the signals point to broad use in patients who share mutations or suggest efficacy in specific organs. There are going to be some drivers that are so strong that they will drive a response and benefit across tumors, Conley says, but she expects responses limited to individual organs to be more common.
Novartis, meanwhile, has for several years been running what it calls Signature trials, which similarly match patients to one of its targeted therapies.
Since the program launched in 2013, Novartis has studied more than 600 patients who have 15 types of cancer and were given a range of experimental compounds, says Richard Woodman, Novartiss head of North American oncology clinical development.
Looking ahead, researchers see several opportunities for tissue-agnostic drug approvals. Everyone points out that high tumor mutational burden, a measure of the number of gene mutations in cancer cells, anecdotally correlates with positive response to checkpoint inhibitors such as Keytruda.
Researchers are also interested in exploring whether PARP inhibitorscompounds that block an enzyme that helps patch up tumor DNA and are already approved to treat BRCA-mutated ovarian cancercould be broadly effective against all BRCA-mutated cancers. And ongoing studies are testing whether HER2-targeted breast cancer treatments could be effective in other HER2-mutated tumors.
The futuristic world is broad sequencing assays are used in nearly all routine cancer workups to find whatever it is that leads to the right therapeutic option for the patient, Loxos Bilenker says.
FDA seems invested in clearing the path for developing drugs based on genetics. Last month, in testimony to a Senate subcommittee, FDA Commissioner Scott Gottlieb said the agency will this year release a new policy that will address the issue of targeted drugs and how we simplify the development of drugs targeted to rare disorders that are driven by genetic variations, and where diseases all have a similar genetic fingerprint, even if they have a slightly different clinical expression.
Regardless of what comes next, patients such as Skinner who have rare mutations are thankful for the recent advances. Skinner stopped treatment with Keytruda in April 2016 and more than a year later remains tumor-free. Given her genetic makeup, she knows her cancer could return. But she is relieved to have access to an approved drug that could address whatever comes next.
That relief isnt just about her own future. Skinner has four daughters, three of whom have tested positive for Lynch syndrome. I can face near-certain deathand I didand Ill tell you that I was ready for it, she says. But the fact that my kids are at risk was the worst. That now makes this drug trial and fabulous result that much more meaningful for me.
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At Jacobs Island Dog Park on Wednesday afternoon, Laura Tonnessen threw a stick into the river for her dog Thor. He barked enthusiastically, retrieving and dropping the stick at her feet. But in a few days, on the Fourth of July, Tonnessen knows Thors demeanor will change. The loud fireworks frighten him.
Hell hide behind furniture and act weird and whine, Tonnessen said.
Last year, Tonnessens friends pitbull, Cracker, ran away and was lost for three days because he was spooked by loud fireworks. It was traumatic to lose him for so long, Tonnessen said, and she makes sure to keep Thor inside on the holiday to prevent him from running away, too.
Michael Edwards, a student at the University of Montana, said his 130-pound great Pyrenees, Snowy, climbs into the bathtub, pulls the shower curtain closed with her mouth, and howls until the thunder storm or fireworks end.
If shes outside, she runs. They once found her about seven miles from their house, trying to escape the source of the noise. Animal shelters report that July 4-5 are their busiest days of the year.
When dogs bark, flee or cower on the Fourth of July, they are exhibiting symptoms of a panic disorder called noise phobia.
Fireworks and other loud noises terrify a fraction of all dogs, and their reactions sometimes endanger their health. Dogs may jump through windows, climb fences or run away for days to try to escape the sounds of patriotic celebration.
This phobia, which is a symptom of underlying anxiety issues, has recently been linked to a certain gene in dogs, says Dr. Leticia Fanucchi, a veterinary behaviorist at Washington State University's College of Veterinary Medicine.
Some dogs are more genetically predisposed to anxiety disorders, Fanucchi said, just like humans.
The area that is activated in our brain for fear is the amygdala, and the amygdala can be triggered long before the prefrontal cortex can process information, Fanucchi said.
Its like people who suffer from arachnophobia even if you explain that the spider won't hurt them, it activates the amygdala and makes them panic.
The amygdala is where irrational fears trigger a fight, flight or freeze response, while the prefrontal cortex controls reason and rational decision-making. Dogs panic at the sound of fireworks because they think their lives are at risk, even if they are safe at home.
Fanucchi said not all breeds of dogs carry this anxiety gene, and some are more prone to it than others. Within one breed, a dog could have the anxiety gene while another might not. This explains why some dogs dont react at all to loud noises. Those that do are typically anxious about other things, as well.
What we do know is that a good chunk of the dogs that have noise phobia do have generalized anxiety as an underlying disease, Fanucchi said. About 40 percent of the dogs that have generalized anxiety have noise phobia. So noise phobia is a big red flag that something else is going on with that dog, and it needs to be diagnosed and treated appropriately.
For this Fourth of July, its too late to start a long-term medication regimen to treat anxiety because medications typically take a few weeks to become effective, Fanucchi said. But there are other, short-term practices that can minimize dogs anxiety and keep them safe.
Creating a quiet and distracting setting for dogs can help them stay calm, said Emily Adamson, director of Organizational Advancement at the Humane Society of Western Montana. Scent therapy, like lavender spray, is popular for calming dogs, Adamson said.
Food toys and soft music (they play classical at the shelter) help distract the dogs from the source of their fear. For people who do take their dogs outside, Adamson recommends double-checking their ID tags to make sure the information is current, in case the dogs run away.
And then, theres the Thundershirt.
Dr. Lindsey Rewinkel at Pruyn Veterinary Hospital in Missoula said Thundershirts are available at pet stores and some veterinary hospitals, and serve as a dog anxiety vest.
Its a heavy fabric fashioned into a shirt that you wrap them in, Rewinkel said. Its not quite as severe as a swaddle, but the goal is to make them feel comforted. That has helped an incredible amount of dogs cope with noise phobias if they're not as severe.
Finally, there are medications vets can prescribe that sedate dogs and minimize their anxiety symptoms on the Fourth of July if none of these other practices work. Rewinkel said she always urges people to also treat the underlying anxiety issue with long-term behavioral therapy, and not just resort to medication, which can serve as a Band-Aid solution to a larger problem.
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Why does your dog hate Fourth of July fireworks? It's genetic - The Missoulian
June 30, 2017
Uncovering rare susceptibility variants that contribute to the causes of complex diseases requires large sample sizes and massively parallel sequencing technologies. These sample sizes, often made up of exome and genome data from tens to hundreds of thousands of individuals, are often too large for current analytical tools to process. A team at Baylor College of Medicine, led by Dr. Suzanne Leal, professor of molecular and human genetics, has developed new software called SEQSpark to overcome this processing obstacle. A study on the new technology appears in The American Journal of Human Genetics.
"To handle these large data sets, we built the SEQSpark tool based on the commonly used Spark program, which allows SEQSpark to utilize multiple processing platforms to increase the speed and efficiency of performing data quality control, annotation and rare variant association analysis," Leal said.
To test and validate the versatility and speed of SEQSpark, Leal and her team analyzed benchmarks from the whole genome sequence data from the UK10K, testing specifically for waist-to-hip ratios.
"The analysis and related tasks took about one and a half hours to complete, in total. This includes loading the data, annotation, principal components analysis and single and rare variant aggregate association analysis for the more than 9 million variants present in this sample set," explained Di Zhang, a postdoctoral associate in the Leal lab at Baylor and first author on the paper.
To evaluate SEQSpark's performance in a larger data set, Leal and the research team generated 50,000 simulated exomes. The SEQSprak program ran the analysis for a quantitative trait using several variant aggregate association methods in an hour and forty-five minutes.
When compared to other variant association tools, SEQSpark was consistently faster, reducing computation to a hundredth of the time in some cases.
"What is unique about SEQSpark is that it is scalable, and smaller labs can run it without super specific hardware, and it can also be run in a multi-server environment to increase its speed and capacity for large genetic data sets," Zhang said. "It is ideal for large-scale genetic epidemiological studies and is highly efficient from a computational standpoint."
"We see this software as being very useful as the demand for the analysis of massively parallel sequence data grows. SEQSpark is highly versatile, and as we analyze increasingly large sets of rare variant data, it has the potential to play a key role in furthering personalized medicine," Leal said.
In the future, Leal and her team will continue to test and increase SEQSpark's capabilities and will be analyzing soon data sets that have 500,000 samples or more.
Explore further: Genetic test for familial data improves detection genes causing complex diseases such as Alzheimer's
More information: Di Zhang et al. SEQSpark: A Complete Analysis Tool for Large-Scale Rare Variant Association Studies using Whole-Genome and Exome Sequence Data, The American Journal of Human Genetics (2017). DOI: 10.1016/j.ajhg.2017.05.017
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Researchers build SEQSpark to analyze massive genetic data sets - Medical Xpress
June 29, 2017 Micrograph showing prostatic acinar adenocarcinoma (the most common form of prostate cancer) Credit: Wikipedia
Scientists have had limited success at identifying specific inherited genes associated with prostate cancer, despite the fact that it is one of the most common non-skin cancers among men. Researchers at University of Utah Health studied prostate cancer patients with multiple cancer diagnoses, many who would not be recommended for genetic tests following current guidelines, to identify genetic mutations that may influence cancer treatment and cancer risk assessment for family members. Their findings are reported in the June issue of the journal Cancer.
"We commonly use a combination of a patient's personal and family cancer histories to identify those individuals who may have a mutation in a gene that predisposes that individual to developing cancers," said Patrick Pili, M.D., medical oncology fellow at the University of Texas MD Anderson Cancer Center. "Testing for hereditary cancers impacts not only the patient with cancer but also potentially the cancer screening and health outcomes of their entire family, but many prostate cancer patients do not meet the current guidelines to test for genetic cancer heritability."
Pili was part of a research team led by Kathleen Cooney, M.D., chair of the Department of Internal Medicine at U of U Health and a Huntsman Cancer Institute investigator, who proposed a strategy to identify germline mutations in men selected for the study based on their clinical history not their family history.
The study was highly selective, including 102 patients who had been diagnosed with prostate cancer and at least one additional primary cancer, like melanoma, pancreatic cancer, testicular cancer, or Hodgkin lymphoma.
The researchers examined the frequency of harmful germline mutations in this group of men. These mutations originate on either the egg or sperm and become incorporated into the DNA of every cell in the body of the resulting offspring.
Using next generation sequencing, the researchers found that 11 percent of the patients had a disease-causing mutation in at least one cancer-predisposing gene, which suggests these genetic variations contributed to their prostate cancer. Cooney found no difference in cancer aggressiveness or age of diagnosis compared to patients without these mutations.
In addition, a certified genetic counselor and co-investigator Elena Stoffel, M.D., University of Michigan Comprehensive Cancer Center, reviewed personal and family histories from each patient to determine whether they would meet clinical genetic testing guidelines. The majority of the men in the study, 64 percent, did not meet current criteria to test for hereditary cancer based on personal and/or family history.
The findings suggest that there are men with heritable prostate cancer-predisposing mutations that are not eligible for genetic screening under current guidelines.
"This is the first paper in which we can show the potential of using a clinical history of multiple cancers, including prostate cancer, in a single individual to identify inherited germline mutations," Cooney said.
The majority of harmful mutations identified were in genes involved in DNA repair.
"These mutations prevent the DNA from healing itself, which can lead to a predisposition for cancer," Cooney said.
This result is also beneficial because drugs like PARP [poly ADP ribose polymerase] inhibitors have a better success rate in treating cancers with the underlying gene mutation associated with DNA repair.
Cooney cautions that this is a small pilot study rather than a broader epidemiological survey, and it consists of a highly specific subset of patients.
"We cannot generalize these findings to the broader population, because we used highly selective criteria to tip us off to patients that may have mutations outside typical hereditary genetic patterns," she said.
The 102 patients included in the study were identified from the University of Michigan's Prostate Cancer Genetics Project, which registers patients who are diagnosed with prostate cancer before age 55 or who have a first- or second-degree relative with prostate cancer. In addition, the research team identified patients from the University of Michigan's Cancer Genetics Registry, which includes individuals with personal or family history suggestive of a hereditary risk of cancer.
"Our findings are in line with those of other studies, suggesting that approximately 1 in 10 men with advanced prostate cancer harbors a genetic variant associated with increased cancer risk," said Stoffel. "While family history is an important tool, there may be better ways to identify patients with genetic risk."
Future studies with larger sample sizes will include sequencing of tumors that will allow investigators to more carefully explore the different features associated with tumors that arise in individuals with germline mutations.
"This approach will help us identify patients at greater risk for aggressive prostate cancer so they can seek earlier screening while pre-symptomatic," Cooney said.
Explore further: Are men with a family history of prostate cancer eligible for active surveillance?
More information: Patrick G. Pili et al. Germline genetic variants in men with prostate cancer and one or more additional cancers, Cancer (2017). DOI: 10.1002/cncr.30817
Journal reference: Cancer
Provided by: University of Utah
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MSUToday | Research offers new clues to rare genetic disease MSUToday Tuberous sclerosis complex, or TSC, is considered a rare genetic disease, yet for the estimated 50,000 patients in the United States and almost 2 million individuals worldwide, dealing with its symptoms can be overwhelming. It's a devastating disease ... |
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Patients who underwent genetic screenings now fear that documentation of the results in their medical records could lead to problems if a new health law is enacted. Sam Edwards/Caiaimage/Getty Images hide caption
Patients who underwent genetic screenings now fear that documentation of the results in their medical records could lead to problems if a new health law is enacted.
Two years ago, Cheasanee Huette, a 20-year-old college student in Northern California, decided to find out if she was a carrier of the genetic mutation that gave rise to a disease that killed her mother. She took comfort in knowing that whatever the result, she'd be protected by the Affordable Care Act's guarantees of insurance coverage for pre-existing conditions.
Her results came back positive. Like her mother, she's a carrier of one of the mutations known as Lynch syndrome. The term refers to a cluster of mutations that can boost the risk of a wide range of cancers, particularly colon and rectal.
As Republican lawmakers advance proposals to overhaul the ACA's consumer protections, Huette frets that her future health coverage and employment options will be defined by that test.
She even wonders if documentation of the mutation in her medical records and related screenings could rule out individual insurance plans. She's currently covered under her father's policy. "Once I move to my own health care plan, I'm concerned about who is going to be willing to cover me, and how much will that cost," she says.
In recent years, doctors have urged patients to be screened for a variety of diseases and predisposition to illness, confident it would not affect their future insurability. Being predisposed to an illness such as carrying the BRCA gene mutations associated with breast and ovarian cancer does not mean a patient will come down with the illness. But knowing they could be at risk may allow patients to take steps to prevent its development.
Under the current health law, many screening tests for widespread conditions such as prediabetes are covered in full by insurance. The Centers for Disease Control and Prevention and the American Medical Association have urged primary care doctors to test patients at risk for prediabetes. But doctors, genetic counselors and patient advocacy groups now worry that people will shy away from testing as the ACA's future becomes more uncertain.
Dr. Kenneth Lin, a family physician at Georgetown University School of Medicine in Washington, D.C., says if the changes proposed by the GOP become law, "you can bet that I'll be even more reluctant to test patients or record the diagnosis of prediabetes in their charts." He thinks such a notation could mean hundreds of dollars a month more in premiums for individuals in some states under the new bill.
Huette says she's sharing her story publicly since her genetic mutation is already on her medical record.
But elsewhere, there have been "panicked expressions of concern," says Lisa Schlager of the patient advocacy group Facing Our Risk of Cancer Empowered (FORCE). "Somebody who had cancer even saying, 'I don't want my daughter to test now.' Or 'I'm going to be dropped from my insurance because I have the BRCA mutation.' There's a lot of fear."
Those fears, which come in an era of accelerating genetics-driven medicine, rest upon whether a gap that was closed by the ACA will be reopened. That remains unclear.
A law passed in 2008, the Genetic Information Nondiscrimination Act, bans health insurance discrimination if someone tests positive for a mutation. But that protection stops once the mutation causes "manifest disease" essentially, a diagnosable health condition.
That means "when you become symptomatic," although it's not clear how severe the symptoms must be to constitute having the disease, says Mark Rothstein, an attorney and bioethicist at the University of Louisville School of Medicine in Kentucky, who has written extensively about GINA.
The ACA, passed two years after GINA, closed that gap by barring health insurance discrimination based on pre-existing conditions, Rothstein says.
On paper, the legislation unveiled by Senate Majority Leader Mitch McConnell last week wouldn't let insurers set higher rates for people with pre-existing conditions, but it could effectively exclude such patients from coverage by allowing states to offer insurance plans that don't cover certain maladies, health analysts say. Meanwhile, the bill that passed the House last month does have a provision that allows states to waive protections for people with pre-existing conditions, if they have a gap in coverage of 63 days or longer in the prior year.
When members of a Lynch Syndrome social media group were asked for their views on genetic testing amid the current health care debate, about two dozen men and women responded. Nearly all said they were delaying action for themselves or suggesting that family members, particularly children, hold off.
Huette was the only one who agreed to speak for attribution. She says before the ACA was enacted, she witnessed the impact that fears about insurance coverage had on patients. Her mother, a veterinarian, had wanted to run her own practice but instead took a federal government job for the guarantee of health insurance. She died at the age of 57 of pancreatic cancer, one of six malignancies she had been diagnosed with over the years.
Huette says she doesn't regret getting tested. Without the result, Huette points out, how would she have persuaded a doctor to give her a colonoscopy in her 20s?
"Ultimately, my health is more important than my bank account," she says.
Kaiser Health News, a nonprofit health newsroom whose stories appear in news outlets nationwide, is an editorially independent part of the Kaiser Family Foundation.
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Patients Who Tested Positive For Genetic Mutations Fear Bias ... - NPR - NPR
June 27, 2017
Alzheimer's disease patients are increasing with the aging of the world's population, becoming a huge health care and social burden. To find the cause of various diseases, in recent years, scientists have focused within the human genome on copy number variations (CNVs), which are changes in the number of genes within a population.
Likewise, a group of genes responsible for a gene number change has also been reported for Alzheimer's disease, but to date, it has not been easy to identify a causative gene from multiple genes within the pathogenic CNV region.
Now, a new approach to finding Alzheimer's disease (AD) causative genes was estimated by paying attention to special duplicated genes called "ohnologs" included in the genomic region specific to AD patients. Human ohnologs, which are vulnerable to change in number, were generated by whole genome duplications 500 million years ago.
In a new study published in the advanced online edition of Molecular Biology and Evolution, Mizuka Sekine and Takashi Makino investigated the gene expression and knockout mouse phenotype for ohnologs, and succeeded in narrowing down the genetic culprits. The narrowed gene group had a function related to the nervous system and a high expression level in the brain which were similar to characteristics of known AD causative genes.
Their findings suggest that the identification of causative genes using ohnologs is a promising and effective approach in diseases caused by dosage change.
Explore further: Characterizing the mouse genome reveals new gene functions and their role in human disease
More information: Molecular Biology And Evolution (2017). DOI: 10.1093/molbev/msx183
The first results from a functional genetic catalogue of the laboratory mouse has been shared with the biomedical research community, revealing new insights into a range of rare diseases and the possibility of accelerating ...
An algorithm developed by Saudi Arabia's King Abdullah University of Science and Technology (KAUST) scientists has the potential to help patients with mysterious ailments find genetic causes for their undiagnosed diseases.
Geneticists from Trinity College Dublin have used our evolutionary history to shine light on a plethora of neurodevelopmental disorders and diseases. Their findings isolate a relatively short list of genes as candidates for ...
Although a family history of Alzheimer's disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes the amyloid precursor protein and presenilins 1 and 2 have been established ...
Using a new and powerful approach to understand the origins of neurodegenerative disorders such as Alzheimer's disease, researchers at Mayo Clinic in Florida are building the case that these diseases are primarily caused ...
Alzheimer's disease and frontotemporal lobar degeneration (FTLD) are two of the most prevalent forms of neurodegenerative disorders. In a study published online today in Genome Research, researchers have analyzed changes ...
(Medical Xpress)Via genetic analysis, a large international team of researchers has found rare, damaging gene variants that they believe contribute to the risk of a person developing schizophrenia. In their paper published ...
Using a new skin cell model, researchers have overcome a barrier that previously prevented the study of living tissue from people at risk for early heart disease and stroke. This research could lead to a new understanding ...
Whole genome sequencing involves the analysis of all three billion pairs of letters in an individual's DNA and has been hailed as a technology that will usher in a new era of predicting and preventing disease. However, the ...
Researchers have found that genes for coronary heart disease (CAD) also influence reproduction, so in order to reproduce successfully, the genes for heart disease will also be inherited.
When Ricky Ramon was 7, he went for a routine checkup. The pediatrician, who lingered over his heartbeat, sent him for a chest X-ray, which revealed a benign tumor in the top-left chamber of his heart. For Ramon, it was the ...
Gene mutations accumulating in cells are typical of the development of cancer. Finnish researchers have found that a similar accumulation of mutations occurs also in some patients with rheumatoid arthritis.
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Alzheimer's is triggered by pheromone insult. Anger closes erectile tissues in the upper and middle meati, explaining this behavior among sufferers as defensive. Lesions progress rostro-centrally along the olfactory and accessory olfactory nerves. Healthy adult male facial skin surface lipid liquid pheromone by mouth diminishes symptoms, laughing usually returns for instance. (N=2, so this is obviously just anecdotal, but the partial recovery was welcome.)
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Estimating Alzheimer's disease causative genes by an evolutionary ... - Medical Xpress
June 28, 2017 Micrograph showing inflammation of the large bowel in a case of inflammatory bowel disease. Colonic biopsy. Credit: Wikipedia/CC BY-SA 3.0
Scientists have closed in on specific genes responsible for Inflammatory Bowel Disease (IBD) from a list of over 600 genes that were suspects for the disease. The team from the Wellcome Trust Sanger Institute and their collaborators at the Broad Institute of MIT and Harvard and the GIGA Institute of the University of Lige combined efforts to produce a high resolution map to investigate which genetic variants have a causal role in the disease.
In the new study, published today (28 June) in Nature, scientists examined the genome of 67,852 individuals and applied three statistical methods to zoom in on which genetic variants were actively implicated in the disease. Of the regions of the genome associated with IBD that were studied, 18 could be pin-pointed to a single genetic variant with more than 95 per cent certainty. The results form a basis for more effective prescription of current treatments for the disease as well as the discovery of new drug targets.
More than 300,000 people suffer from IBD in the UK. IBD is a debilitating disease in which the body's own immune system attacks parts of the digestive tract. The exact causes of this disease are unclear, and there currently is no cure.
To understand more about the genetics underlying IBD, researchers have conducted genome wide association studies and previously found hundreds of genetic variants linked to the disease. However, it was not certain which specific genes were actually implicated by those variants.
Dr Jeffrey Barrett, joint lead author from the Wellcome Trust Sanger Institute said: "We have taken the biggest ever data set for IBD and applied careful statistics to narrow down to the individual genetic variants involved. Now we have a clearer picture of which genes do and do not play a role in the disease. We are zooming in on the genetic culprits of IBD."
The high resolution map of the disease enabled scientists to see which variants directly influence disease, and to separate them from other variants which happen to be located near each other in the genome.
Dr Hailiang Huang, first author from the Massachusetts General Hospital and Broad Institute said: "An issue with studying complex diseases is that it can be hard to move from genetic associations, usually including many genetic variants of similar evidence, to knowing exactly which variants are involved. We need to be careful in deciding when we are sure we have the right variant. This new technique helps us to pinpoint which genetic variants are implicated in IBD with greater confidence."
Professor Michel Georges, joint lead author from the GIGA Institute of the University of Lige said: "These results will help towards rational drug discovery for complex human diseases like IBD, and possibly for the development of personalised medicine by finding biomarkers for more effective prescription of existing drugs."
Explore further: Isolated Greek villages reveal genetic secrets that protect against heart disease
More information: Hailiang Huang et al. (2017) Fine-mapping inflammatory bowel disease loci to single variant resolution. Nature. DOI: 10.1038/nature22969
A genetic variant that protects the heart against cardiovascular disease has been discovered by researchers at the Wellcome Trust Sanger Institute and their collaborators. Reported today in Nature Communications, the cardioprotective ...
Genetic variants linked to higher body mass index (BMI) are associated with lower risk of Parkinson disease, according to a study published by Nicholas Wood and colleagues from the University College London, UK, in PLOS Medicine.
In two studies published today (30 January) in Nature Genetics, researchers from the Wellcome Trust Sanger Institute and their collaborators have identified a genetic variant that doubles an individual's risk of developing ...
Scientists from the Welcome Trust Sanger Institute and their collaborators have discovered 17 rare human genetic variations associated with risk factors for diseases such as heart disease and diabetes.
Genetic diagnosis of disease and personalization of treatment have the potential to dramatically improve strategies for diagnosis and therapy. Around 80% or rare diseases are thought to have a genetic component, but currently ...
Genome wide association studies (GWAS) scan the entire genome in order to pinpoint genetic variants associated with a particular disease. The technique is employed to identify biological pathways - the series of actions and ...
Scientists have closed in on specific genes responsible for Inflammatory Bowel Disease (IBD) from a list of over 600 genes that were suspects for the disease. The team from the Wellcome Trust Sanger Institute and their collaborators ...
A study led by scientists at Monash University has shown that a new therapy developed through stem cell technology holds promise as a treatment for chronic asthma.
Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with ...
Superficially, psoriasis and atopic dermatitis may appear similar but their commonalities are only skin deep. Atopic dermatitis, also known as eczema, is primarily driven by an allergic reaction, while psoriasis is considered ...
Mast cells, a type of white blood cell, are present in the airways of severe asthmatics even in the face of aggressive treatment, and their presence is associated with key indicators of severe asthma. It has long been thought ...
Research into the mechanism behind asthma attacks has discovered potential new ways to treat - and possibly prevent - this life-threatening condition.
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Inflammatory bowel disease: Scientists zoom in on genetic culprits - Medical Xpress
New Delhi: Calling for better health research in India, health experts, including those from the All India of Institute of Medical Sciences (AIIMS), on Wednesday said that innovations in medicine alone can help cure rare diseases.
Considering India's population, doctors said that the number of patients suffering from rare diseases was quite significant now.
The diseases are usually severe and chronic and it is often difficult to diagnose and treat them due to their complexity, according to them.
Although significant progress has been made in new therapies, unfortunately, treatment is available only for five per cent of rare diseases and much work needs to be done in this regard, they felt.
"Tremendous progress has been made towards developing new therapies, which has drastically improved patients' quality of life. A greater understanding of the underlying biology of the disease would enable researchers to develop more targeted therapies," said I.C. Verma, Head of Genetic Medicine, Sir Ganga Ram Hospital.
According to Verma, need of the hour is continued research for newer drugs and treatment methods that can provide greater relief to patients with rare diseases.
Mentioning new therapies that have helped patients, Verma said Enzyme Replacement Therapy (ERT) had proved to be very successful for the treatment of a missing enzyme in the body that causes diseases like Gaucher, Pompe, Fabry, etc.
"More recently, a therapy called Substrate Reduction Therapy (SRT) is being used which helps the body produce less substrates so that less is accumulated in the cells. More therapies like this are needed which can enable patients to more effectively manage rare diseases," he said.
Madhulika Kabra, Additional Professor at Pediatrics Department's Genetics unit of AIIMS, said that rare diseases were complex and their underlying biological mechanisms were not adequately understood by many.
Stating that a small patient population made it difficult to conduct clinical studies and thereby establish efficacy and safety of a particular treatment, Kabra said: "Going beyond symptom management and combating the root cause of a rare disease is essential."
Considering the high cost of new therapies, Sudeep Singh Sachdev, Nephrologist at Max Smart Super Speciality Hospital, called for innovations in existing and new treatment options as they would result in better management of rare diseases.
"The development of therapeutic options for rare diseases is challenging. Policy and regulatory interventions for furthering research will play a critical role in overcoming the many challenges in drug development for rare diseases and would provide a ray of hope to the patients and their families."
Prasanna Shirol, co-founder, Organisation for Rare Diseases India, said that developing therapy options for more and more rare diseases would provide relief to a lot of patients and families.
"At present, treatment is available only for a handful of rare diseases and hence, it is important that research is done in the area of other such diseases so that patients suffering from them have an option of leading healthier and active lives," Shirol said.
The government also needed to extend its support for a future where drugs and therapies would become more accessible for different rare disease patients, he added.
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Innovations in medicine needed to cure rare diseases: Doctors - Zee News
Two new studies suggest that one in five seemingly healthy people hasDNA mutations that puts him or herat increased risk for genetic disease.
BlackJack3D/iStockPhoto
By Ryan CrossJun. 26, 2017 , 6:15 PM
Some doctors dream of diagnosing diseasesor at least predicting disease riskwith a simple DNA scan. But others have said the practice, which could soon be the foundation of preventative medicine, isnt worth the economic or emotional cost. Now, a new pair of studies puts numbers to the debate, and one is the first ever randomized clinical trial evaluating whole genome sequencing in healthy people. Together, they suggest that sequencing the genomes of otherwise healthy adults can for about one in five people turn up risk markers for rare diseases or genetic mutations associated with cancers.
What that means for those people and any health care system considering genome screening remains uncertain, but some watching for these studies welcomed the results nonetheless. It's terrific that we are studying implementation of this new technology rather than ringing our hands and fretting about it without evidence, says Barbara Biesecker, a social and behavioral researcher at the National Human Genome Research Institute in Bethesda, Maryland.
The first genome screening study looked at 100 healthy adults who initially reported their family history to their own primary care physician. Then half were randomly assigned to undergo an additional full genomic workup, which cost about $5000 each and examined some 5 million subtle DNA sequence changes, known as single-nucleotide variants, across 4600 genessuch genome screening goes far beyond that currently recommended by the American College of Medical Genetics and Genomics (ACMG), which suggests informing people of results forjust 59 genes known or strongly expected to cause disease.
Of the 50 participants whose genomes were sequenced, 11 had alterations in at least one letter of DNA suspected to causeusually rarediseases, researchers report today in The Annals of Internal Medicine. But only two exhibited clear symptoms. One was a patient with extreme sensitivity to the sun. Their DNA revealed a skin condition called variegate porphyria. Now that patient knows they will be much less likely to get bad sunburns or rashes if they avoid the sun and certain medications, says Jason Vassy, a primary care clinician-investigator at Veteran Affairs Boston Healthcare System and lead author of the study.
The team also found that every sequenced patient carried at least one recessive mutation linked to a diseasea single copy of a mutant gene that could cause an illness if two copies are present. That knowledge can be used to make reproductive decisionsa partner may get tested to see if they have a matching mutationand prompt family members to test themselves for carrier status. And in what Vassy calls a slightly more controversial result, the team examined participants chances of developing eight polygenic diseases, conditions that are rarely attributed to a single genetic mutation. Here, they compiled the collective effects of multiple genesup to 70 for type II diabetes and 60 for coronary heart diseaseto predict a patients relative risk of developing the disease.
Just 16% of study volunteers who only reported their family history were referred to genetic counselors or got follow-up laboratory tests. In the genome sequencing group, the number was 34%.
Some researchers have expressed concern that such whole genome screening will skyrocket medical costs or cause undue psychological harm. Aside from the initial cost of sequencing (which was covered by the study), patients who underwent the genomic screen paid an average of $350 additional in healthcare costs over the next 6 months, Vassy and colleagues reported. But contrary to fears of emotional trauma, neither the sequencing group nor the control group showed any changes in anxiety or depression 6 months after the study.
Vassy stresses that their study was small and needs follow-up, but it still impressed Christa Martin, a geneticist at Geisinger Health System, in Danville, Pennsylvania, who worked on the ACMGs recommendations for genome sequencing. I almost feel like the authors undersold themselves, she says. Many of their patients are making health behavioral changes, so they are using the information in a positive way.
The study was extremely well designed and very appropriately run, adds Barbara Koenig, a medical anthropologist who directs the University of CaliforniaSan Francisco Bioethics Program. But she still questions the assumption by many physicians, ethicists, and patient advocates that more information is always beneficial. It is just hard to know how all this information is going to be brought together in our pretty dysfunctional healthcare system.
Another paper published last week on the preprint server bioRxiv, which has not yet undergone peer review, yields similar results. Using whole-exome sequencing, which looks only at the protein-coding regions of the genome, Michael Snyder, director of the Stanford Center for Genomics and Personalized Medicine in Palo Alto, California, and colleagues found that 12 out of 70 healthy adults, or 17%, unknowingly had one or more DNA mutations that increased the risk for genetic diseases for which there are treatment or preventative options.
Both studies suggest that physicians should look at genes beyond the ACMGs 59 top priorities, Snyder says. He argues that whole-genome sequencing should be automatically incorporated into primary care. You may have some super-worriers, but I would argue that the information is still useful for a physician to have. Vassy, however, says that there isnt yet enough evidence to ask insurance companies to reimburse whole genome sequencing of healthy patients.
We like a quick fix and the gene is an important cultural icon right now, so we probably give it more power than it really has, Koenig says. But these are still really early days for these technologies to be useful in the clinic.
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One in five 'healthy' adults may carry disease-related genetic mutations - Science Magazine
From Mission Health:
Mission Healths Personalized Medicine program focuses on response to drugs in a way that will increase the likelihood that a drug will work effectively while decreasing the likelihood that it will result in a bad side effect for our patients. Personalized medicine testing utilizes the genetic make-up of the individual, or in cancer, the genetic makeup of the patients tumor to predict which drug might be the best match for an individual patient. Mission Health is one of the few community health systems in the nation to offer this vital program for both cancer patients and non-cancer patients.
Important initiatives that are fueling the study and practice of personalized medicine at Mission Health are the 2013 recruitment of nationally known personalized medicine expert Lynn Dressler, PhD to develop and direct the Mission Personalized Medicine Program, the opening of Missions Personalized Medicine Clinic in the Fullerton Genetics Center and a grant from the North Carolina Biotechnology Center (NCBC) to help bring this testing to primary care providers in western North Carolina (the grant helps cover the cost of testing). The NCBC is a private nonprofit organization devoted to building long-term societal and economic benefits to North Carolina by supporting biotechnology research, business, and education across the state.
The NCBC funded pilot study focuses on how testing for drug response can be used effectively in a primary care setting. The pilot study evaluates the barriers that might prevent primary care practices from adopting this testing and how those barriers could be addressed, including opportunities for economic development and job growth. The Mission Personalized Medicine team provides education and training for providers to use and interpret test results.
Dr. Dresslers interest in pursuing solutions to obstacles that currently exist for primary care practices to adopt personalized medicine testing for drug response is the opportunity to enhance care and reduce costs with minimal disruption to the primary care practice current work flow. Patients can only benefit if their providers adopt testing, says Dressler. This study will provide free testing and free education and training to providers, so at least those main barriers are off the table. By giving clinicians and patients an opportunity to try out this testing within a safe environment, it may identify and address other barriers that we have not yet realized.
One year into the NCBC funded study, Dressler and the PM team has successfully recruited 10 clinicians from four primary care practices and tested 41 patients. Recommendations for changes in medication management were suggested in more than one third of patients. The study has already identified additional barriers to be addressed to make this testing more efficient and available to more patients and providers. Future plans for the study include recruitment of several additional practices, with a goal of recruiting approximately 80 total patients from the region. Mission Health plans to conduct other pilot studies to enhance drug management in areas such as behavioral health and supportive care for cancer patients.
Ronald A. Paulus, M.D., President and CEO of Mission Health, who will be speaking at the 13th Annual Personalized Medicine Conference at Harvard Medical School in November declares that personalized medicine offers extraordinary medical possibilities. If we can harness the power of this transformational biomedical technology successfully and we are already beginning to we can improve outcomes for our patients and increase the effectiveness of our dedicated clinicians skillful and compassionate care. At the same time, this technology empowers our patients to be informed, shared decision-makers with their physicians. It is truly an exciting time, he says.
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Mission Health Takes National Leadership Role in Personalized Medicine - Mountain Xpress (blog)
Born in August, Charlie Gard has a rare genetic disorder known as mitochondrial DNA depletion syndrome. Caused by a genetic mutation, it leads to weakened muscles and organ dysfunction, among other symptoms, with a poor prognosis for most patients.
Charlie is on life support and has been in the intensive care unit at the Great Ormond Street Hospital for Children in London since October. His doctors wish to take him off life support, but his parents disagree.
"The domestic courts concluded that it would be lawful for the hospital to withdraw life sustaining treatment because it was likely that Charlie would suffer significant harm if his present suffering was prolonged without any realistic prospect of improvement, and the experimental therapy would be of no effective benefit," a press release from the court announcing the decision said.
Charlie's parents appealed to the UK Supreme Court to decide the best interests of their child. After they lost that appeal, the 10-month-old was due to have his life support switched off at the end of the day June 13.
Gard and Yates then filed a request with the European Court of Human Rights, an international court based in Strasbourg, France, to consider the case.
The original ruling to provide life support until June 13 was extended by European Court of Human Rights initially for one week, until June 19. Rather than making a decision then, the court granted a three week-extension, until July 10, to allow for a more informed decision by the court. That extension ended Tuesday with the courts decision.
However, parental rights are not absolute, and in cases in which doctors and parents disagree, the courts may exercise objective judgment in a child's best interest.
In April, a judge tasked with ruling on the impasse between doctors and parents decided in favor of the Great Ormond Street Hospital doctors. In his decision, Justice Francis said life support treatment should end so Charlie could die with dignity.
The boy's parents challenged this ruling in May, yet it was upheld by a Court of Appeal. Three Supreme Court justices later dismissed another challenge from the couple.
Since Charlie's birth, "his condition has deteriorated seriously," the UK Supreme Court stated in a decision June 8; his brain is severely affected, and "he cannot move his arms or legs or breathe unaided."
On this basis, the court ruled that the child's life support should be switched off June 13, but the family appealed to the European court.
Charlie's parents argued that the UK courts gave insufficient weight to their own human rights, and some of Charlie's human rights, in their decision-making, Wilson said.
After the European court's ruling to extend the deadline while judges considered the case further, the Supreme Court told doctors it "would not be unlawful" to continue to provide life support.
After the extension, a Supreme Court hearing was requested by the government and the Great Ormond Street Hospital for Children, which did not know whether the Strasbourg court order was legally binding in the UK, Wilson explained.
"There was also a secondary issue, which was that (Great Ormond Street Hospital's) legal representatives were concerned that at present, doctors did not have sufficient legal clarity about what they can and can't do if Charlie's condition deteriorates," Wilson said. "So this court was also invited to consider whether any UK court, and if so which court, should handle that matter."
In fact, it has never been used to treat this form of mitochondrial DNA depletion syndrome, according to the British ruling, though it has proved beneficial to patients with a different form of the disease.
"He literally has nothing to lose but potentially a healthier, happier life to gain," they said.
Parents are rightly at the "heart" of decisions made about life-sustaining treatment for critically ill children, noted Dominic Wilkinson, director of medical ethics at the Oxford Uehiro Centre.
"Sadly, reluctantly, doctors and judges do sometimes conclude -- and are justified in concluding -- that slim chances of life are not always better than dying." Sometimes, the "best that medicine can do" -- and the most ethical decision -- is to provide comfort and to avoid painful and unhelpful medical treatments, he wrote.
The court said the decision was meticulous, noting that they spoke with Charlie's health care providers, independent experts, experts recommended by the family, and Charlie's parents to inform the ruling. In the end, the press released said they determined, "it was most likely Charlie was being exposed to continued pain, suffering and distress and that undergoing experimental treatment with no prospects of success would offer no benefit, and continue to cause him significant harm."
CNN's Stephanie Halasz, Debra Goldschmidt and Judith Vonberg contributed to this report.
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Court rules hospital can withdraw life support for sick baby Charlie Gard - CNN
GETTY
People with Lynch syndrome have an increased risk of bowel cancer and cancer of the womb.
The condition is also known as hereditary non-polyposis colorectal cancer (HNPCC).
The syndrome also increases the risk of the disease reoccurring, but hospitals can screen patients to check if they are at risk.
Bowel Cancer UK said that a lack of systematic testing means that 95 per cent of the 175,000 people with Lynch syndrome are unaware that they have the condition.
GETTY
An estimated 1,100 cases of bowel cancer can be attributed to Lynch syndrome each year, with many of those affected under the age of 50, according to the charity.
The children and siblings of those with Lynch syndrome have a 50 per cent chance of having the condition themselves.
Those with the condition can benefit from regular monitoring and better awareness of symptoms of cancers that they are at increased risk of being diagnosed with.
There are no symptoms of Lynch syndrome, and sometime the first sign a person has Lynch syndrome is when the symptoms of bowel or womb cancer develop.
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Bowel cancer risk factors
This will generally happen a a younger age than people whose cancers are not caused by inherited faulty genes.
Bowel cancer that doesnt run in families usually develops in people over the age of fifth, however people with Lynch syndrome can be affected at the age of 40 or even younger.
Macmillan Cancer Support urged people to be particularly aware of symptoms including
- Blood in stools - Diarrhoea or constipation - Unexplained weight loss - Pain in the tummy
If a person has a suspected cancer believed to be caused by Lynch Syndrome, genetic tests can be done.
Those who do carry the gene might need regular bowel cancer screening from a younger age - such as 25 - and women might need to be screened for womb or ovarian cancer.
GETTY
Professor Nicoline Hoogerbrugge, head of the Radboud university medical centre expert centre on hereditary cancers, Nijmegen, The Netherlands, has said there is an urgent need to find families carrying a mutation for Lynch syndrome in order to decrease mortality from the disease.
The expert has spoken out in favour of raising the age limit for testing.
By implementing appropriate prevention measures, deaths from Lynch syndrome in affected families can be reduced by more than 60 percent over 15 years.
Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle, United Kingdom, said: It is very important to recognise whether a person suffers from sporadic or familiar cancer, as this identifies family members at risk who can take preventative measures.
For this, genetic tests need to be done in cancer patients."
This study shows that we should extend these genetic tests to older colorectal cancer patients of whom a significant number suffer from familiar cancer.
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Do YOU have Lynch syndrome? Genetic condition is common cause of killer bowel cancer - Express.co.uk
Thirty-six percent of Hispanic families in the U.S. with a common form of retinitis pigmentosa got the disease because they carry a mutation of the arrestin-1 gene, according to a new study from researchers at The University of Texas Health Science Center at Houston (UTHealth) School of Public Health.
Retinitis pigmentosa is a group of rare, genetic eye disorders in which the retina of the eye slowly degenerates. The disease causes night blindness and progressive loss of peripheral vision, sometimes leading to complete blindness. According to Stephen P. Daiger, Ph.D., senior author of the study, an estimated 300,000 people in the U.S. suffer from the disease, which gets passed down through families.
In the study published recently in Investigative Ophthalmology & Visual Science, UTHealth researchers found that in a U.S. cohort of 300 families with retinitis pigmentosa, 3 percent exhibited a mutation of the arrestin-1 gene. However, more than 36 percent of Hispanic families from the cohort exhibited the arestin-1 mutation and they all came from areas in the Southwestern U.S., such as Texas, Arizona and Southern California.
When I started studying retinitis pigmentosa in 1985, we set out to find the one gene that causes the disease. Thirty-three years later, weve found that more than 70 genes are linked to retinitis pigmentosa, said Daiger, a professor in the Human Genetics Center and holder of the Thomas Stull Matney, Ph.D. Professorship in Environmental and Genetic Sciences at UTHealth School of Public Health.
Some of the genes that cause retinitis pigmentosa are recessive, which means two mutations are required, and some are dominant, which means you only need one mutation. Arrestin-1 piqued Daigers interest because that particular mutation is dominant while all previously found mutations in the gene are recessive. This unexpected finding shows that even a single mutation in the gene is sufficient to cause the disease.
Daiger and his team have identified the genetic cause of retinitis pigmentosa for 75 percent of families in their cohort. Possible treatments for some forms of retinitis pigmentosa are being tested but are still limited. However, the speed at which companies are developing gene therapies and small molecule therapies gives reason to hope, he said. Daiger and his collaborators have begun to connect some of the patients in the retinitis pigmentosa cohort to clinical trials that treat specific genes.
I want our cohort families to know that even if there is not an immediate cure for their specific gene mutation, at this rate it wont be long until a therapy becomes available, said Daiger, who also holds the Mary Farish Johnston Distinguished Chair in Ophthalmology at McGovern Medical School at UTHealth.
UTHealth coauthors include Lori S. Sullivan, Ph.D.; Sara J. Browne, Ph.D.; Elizabeth L. Cadena; Richard S. Ruiz, M.D., and Hope Northrup, M.D. Additional co-authors are from Nationwide Childrens Hospital; Kellogg Eye Center at the University of Michigan; Retina Foundation of the Southwest; Casey Eye Institute at Oregon Health and Science University; Vanderbilt University and the Department of Molecular and Human Genetics at Baylor College of Medicine.
Support for the study, titled A novel dominant mutation in SAG, the arrestin-1 gene, is a common cause of retinitis pigmentosa in Hispanic families in the Southwestern United States, was provided by the William Stamps Farish Fund and the Hermann Eye Fund.
Additional support was provided by the National Institutes of Health (EY007142, EY009076, EY011500, EY010572 and K08-EY026650), a Wynn-Gund TRAP Award, the Foundation Fighting Blindness, the Max and Minnie Voelker Foundation and a grant to the Casey Eye Institute from Research to Prevent Blindness.
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June 26, 2017 Credit: CC0 Public Domain
Between 15 and 20 percent of black people carry a genetic mutation that puts them at risk for certain chronic kidney disease, but only about half of them develop the illness - a variance that long has puzzled researchers. Now a study has found that the gene mutation's toxic effects require higher than normal levels of a protein called suPAR to trigger the onset and progression of the disease.
The results of the study, published in a research article in the journal Nature Medicine today, could lead soon to new treatments for chronic kidney disease that target these risk factors, according to Dr. Jochen Reiser, the senior author of the paper. Reiser is the chairperson of the Department of Internal Medicine and Ralph C. Brown MD Professor of Medicine at Rush University Medical Center, Chicago.
Chronic kidney disease - or CKD for short - is a progressive failure of function that prevents kidneys from fulfilling their role filtering waste from the blood stream. Nearly 17 percent of people in the U.S. have chronic kidney disease, and approximately 4 percent require dialysis and/or a kidney transplant due to kidney failure. Currently, there are no drugs that can treat CKD in an effective way.
Study analyzed samples from more than 1,000 people with genetic risk for CKD
For the study recounted in the Nature Medicine paper, Reiser worked with a team that included researchers at Emory University, Harvard University, Johns Hopkins University, the National Institute of Health, Ruprecht Karls University of Heidelberg, the Israel Institute of Technology and others. Together, they looked at two well-known genetic risk factors for CKD in black people, the mutated G1 or G2 variations in the gene known as apolipoprotein L1 (APOL1). To be at risk for developing CKD, an individual must have inherited two of these gene variants, one from each parent.
The study analyzed blood samples for suPAR levels, screened for APOL1 gene mutations and measured kidney function from two separate cohorts of black patients - 487 people from the Emory Cardiovascular Biobank, 15 percent of whom had a high-risk APOL1 genotype; and 607 from the multi-center African American Study of Kidney Disease and Hypertension, including 24 percent with the high-risk mutation.
Using these two large, unrelated cohorts, the researchers found that plasma suPAR levelsindependently predict renal function decline in individuals with two copies of APOL1 risk variants. APOL1-related risk is reduced by lower levels of plasma suPAR and strengthened by higher levels.
The team then went on and used purified proteins to study if suPAR and APOL1 bind to each other. They found that the mutated G1 and G2 variant did so particularly well on what's known as a receptor on the surface of kidney cells, in this case the suPAR activated receptor alphavbeta3 integrin. "This binding appears to be a key step in the disease onset" adds Dr. Kwi Hye Ko, a scientist at Rush and the study's co-first author.
This binding causes kidney cells to change their structure and function, permitting disease onset. Using cell models and genetically engineered mice, the authors then could reproduce kidney disease changes upon expression of APOL1 gene variants, but the disease required the presence suPAR.
Without elevated suPAR levels, genetic mutation much less likely to trigger disease
Everybody has suPAR, which is produced by bone marrow cells, in their blood, with normal levels around 2400 picogram per milliliter (pg/ml). As levels of suPAR rise, risk for kidney disease rises in turn.
Patients with levels above 3000 picogram per milliliter carry a much higher risk for kidney disease in the general population. Black people are particularly at risk, given the study's finding that suPAR activates its receptor on kidney cells that then attract the APOL1 risk proteins. Over time, these assaults can damage and eventually destroy the kidney.
On the other hand, without high levels of suPAR, the ability of the genetic mutation of APOL1 to exert its damaging effects is impaired, which helps identify patients in most need of suPAR lowering or future anti-suPAR therapy.
"Patients with APOL1 mutations who don't get kidney disease have more commonly low suPAR levels," said Dr. Salim Hayek, co-first author of the paper and a cardiologist at Emory University School of Medicine. "The suPAR level needs to be high to activate the mechanism in the kidney that enables APOL1 proteins" and set off the chain of events the genetic mutation can trigger.
suPAR 'is to the kidneys as cholesterol is to the heart'
Like some other pathological gene mutations, the APOL1 variations may have persisted in the population, in this case in Africa, because they could protect people from infection with the parasites known as trypanosome. explained Sanja Sever, PhD, co-correspondent author of the paper and associate professor of medicine at Harvard Medical School. In the United States, however, fighting parasitic trypanosomes isn't a significant concern, while lifestyle and environmental pressures such as obesity promote the rise in suPAR levels. This scenario sets up people for high risk of kidney disease.
Reiser has spent his career studying a scarring type of chronic kidney disease, focal segmental glomerulosclerosis. In past studies, he discovered that suPAR not only is a marker for kidney disease, but also a likely cause.
"What we are learning today is that suPAR in a general way is to kidneys what cholesterol is to the heart, a substance that can cause damage if levels rise too high, or a substance that can likely make many forms of kidney disease worse," Reiser says. "Based on these fundamental insights, suPAR level testing may become a routine test at many institutions around the world."
Like cholesterol, suPAR levels vary from person to person. Some environmental factors can contribute significantly to elevated suPAR levels. "Lifestyle is a big factor, bigger than we thought," Reiser says.
Smoking, weight gain and even frequent infections can add up and send suPAR to dangerous heights. Weight loss and smoking cessation can help bring levels down, but once elevated, suPAR may not recede to a healthy level again, said Dr. Melissa Tracy, co-author of the study and an associate professor of cardiology at Rush. People at genetic risk for kidney disease should aim to live a healthy life to keep suPAR levels low.
Explore further: Circulating blood factor linked with a leading cause of kidney failure
More information: A tripartite complex of suPAR, APOL1 risk variants and v3 integrin on podocytes mediates chronic kidney disease, Nature Medicine (2017). DOI: 10.1038/nm.4362
Patients with a disease that is a leading cause of kidney failure tend to have high levels of a particular factor circulating in their blood, according to a study appearing in an upcoming issue of the Journal of the American ...
A protein known as suPAR has been identified in recent years as both a reliable marker for chronic kidney disease and a pathogen of the often deadly condition. Its place of origin in the human body, however, has been a mysteryuntil ...
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African Americans have a heightened risk of developing chronic and end-stage kidney disease. This association has been attributed to two common genetic variants - named G1 and G2in APOL1, a gene that codes for a human-specific ...
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Catalyst for genetic kidney disease in black people identified - Medical Xpress
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Fast, Precise Cancer Care Is Coming to a Hospital Near You - WIRED
June 26, 2017 New DNA-based LASSO molecule probe can bind target genome regions for functional cloning and analysis. Credit: Jennifer E. Fairman/Johns Hopkins University
Discovering the function of a gene requires cloning a DNA sequence and expressing it. Until now, this was performed on a one-gene-at-a-time basis, causing a bottleneck. Scientists at Rutgers University-New Brunswick in collaboration with Johns Hopkins University and Harvard Medical School have invented a technology to clone thousands of genes simultaneously and create massive libraries of proteins from DNA samples, potentially ushering in a new era of functional genomics.
"We think that the rapid, affordable, and high-throughput cloning of proteins and other genetic elements will greatly accelerate biological research to discover functions of molecules encoded by genomes and match the pace at which new genome sequencing data is coming out," said Biju Parekkadan, an associate professor in the Department of Biomedical Engineering at Rutgers University-New Brunswick.
In a study published online today in the journal Nature Biomedical Engineering, the researchers showed that their technologyLASSO (long-adapter single-strand oligonucleotide) probescan capture and clone thousands of long DNA fragments at once.
As a proof-of-concept, the researchers cloned more than 3,000 DNA fragments from E. coli bacteria, commonly used as a model organism with a catalogued genome sequence available.
"We captured about 95 percent of the gene targets we set out to capture, many of which were very large in DNA length, which has been challenging in the past," Parekkadan said. "I think there will certainly be more improvements over time."
They can now take a genome sequence (or many of them) and make a protein library for screening with unprecedented speed, cost-effectiveness and precision, allowing rapid discovery of potentially beneficial biomolecules from a genome.
In conducting their research, they coincidentally solved a longstanding problem in the genome sequencing field. When it comes to genetic sequencing of individual genomes, today's gold standard is to sequence small pieces of DNA one by one and overlay them to map out the full genome code. But short reads can be hard to interpret during the overlaying process and there hasn't been a way to sequence long fragments of DNA in a targeted and more efficient way. LASSO probes can do just this, capturing DNA targets of more than 1,000 base pairs in length where the current format captures about 100 base pairs.
The team also reported the capture and cloning of the first protein library, or suite of proteins, from a human microbiome sample. Shedding light on the human microbiome at a molecular level is a first step toward improving precision medicine efforts that affect the microbial communities that colonize our gut, skin and lungs, Parekkadan added. Precision medicine requires a deep and functional understanding, at a molecular level, of the drivers of healthy and disease-forming microbiota.
Today, the pharmaceutical industry screens synthetic chemical libraries of thousands of molecules to find one that may have a medicinal effect, said Parekkadan, who joined Rutgers' School of Engineering in January.
"Our vision is to apply the same approach but rapidly screen non-synthetic, biological or 'natural' molecules cloned from human or other genomes, including those of plants, animals and microbes," he said. "This could transform pharmaceutical drug discovery into biopharmaceutical drug discovery with much more effort."
The next phase, which is underway, is to improve the cloning process, build libraries and discover therapeutic proteins found in our genomes, Parekkadan said.
Explore further: Technical advances in reading long DNA sequences have ramifications in understanding primate evolution, human disease
More information: Long-adapter single-strand oligonucleotide probes for the massively multiplexed cloning of kilobase genome regions, Nature Biomedical Engineering (2017). DOI: 10.1038/s41551-017-0092
Technical advances in reading long DNA sequences have ramifications in understanding primate evolution and human disease.
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When Mark Martindale decided to trace the evolutionary origin of muscle cells, like the ones that form our hearts, he looked in an unlikely place: the genes of animals without hearts or muscles.
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Cloning thousands of genes for massive protein libraries - Phys.Org
June 26, 2017 Credit: CC0 Public Domain
The first results from a functional genetic catalogue of the laboratory mouse has been shared with the biomedical research community, revealing new insights into a range of rare diseases and the possibility of accelerating development of new treatments and precision medicine.
The research, which generated over 20 million pieces of data, has found 360 new disease models and provides 28,406 new descriptions of the genes' effects on mouse biology and disease. The new disease models are being made available to the biomedical community to aid their research.
The International Mouse Phenotyping Consortium (IMPC) is aiming to produce a complete catalogue of mammalian gene function across all genes. Their initial results, now published in Nature Genetics, is based on an analysis of the first 3,328 genes (15 per cent of the mouse genome coding for proteins).
Lead author Dr Damian Smedley from Queen Mary University of London (QMUL) and a Monarch Initiative Principal Investigator, said: "Although next generation sequencing has revolutionised the identification of new disease genes, there is still a lack of understanding of how these genes actually cause disease.
"These 360 new disease models that we've identified in mice represent the first steps of a hugely important international project. We hope researchers will be able to use this knowledge to develop new therapies for patients, which is ultimately what we're all striving to achieve."
With its similarity to human biology and ease of genetic modification, the laboratory mouse is arguably the preferred model organism for studying human genetic disease. However, the vast majority of the mouse genome remains poorly understood, as scientists tend to focus their research on a few specific areas of the genome linked to the most common inherited diseases.
Development of therapies for rare disease lags far behind, with over half of diagnosed rare diseases still having no known causative gene. This is why the IMPC is aiming to build a complete database that systematically details the functions of all areas of the mouse genome, including neurological, metabolic, cardiovascular, respiratory and immunological systems.
Terry Meehan, IMPC Project Coordinator at European Bioinformatics Institute (EMBL-EBI) said: "Mouse models allow us to speed up patient diagnosis and develop new therapies. But before that can work, we need to understand exactly what each gene does, and what diseases it is associated with. This is a significant effort in data collection and curation that goes well beyond the capabilities of individual labs. IMPC is creating a data resource that will benefit the entire biomedical community."
The project involves going through the mouse genome systematically and knocking out a particular gene, one by one, in different mice. By looking at the mouse's resulting characteristics in a variety of standardised tests, the team then see if and how the gene knockout manifests itself as a disease, and link their findings to what is already known about the human version of the disease. The 'one by one' knockout approach lends itself to rare gene discovery, as often these diseases are caused by variants of a single gene.
More than half of the 3,328 genes characterised have never been investigated in a mouse before, and for 1,092 genes, no molecular function or biological process were previously known from direct experimental evidence. These include genes that have now been found to be involved in the formation of blood components (potentially involved in a type of anaemia), cell proliferation and stem cell maintenance.
For the first time, human disease traits were seen in mouse models for forms of Bernard-Soulier syndrome (a blood clotting disorder), Bardet-Biedl syndrome (causing vision loss, obesity and extra fingers or toes) and Gordon Holmes syndrome (a neurodegenerative disorder with delayed puberty and lack of secondary sex characteristics).
The team also identified new candidate genes for diseases with an unknown molecular mechanism, including an inherited heart disease called 'Arrhythmogenic Right Ventricular Dysplasia' that affects the heart muscle, and Charcot-Marie-Tooth disease, which is characterised by nerve damage leading to muscle weakness and an awkward way of walking.
Dr Smedley added: "In addition to a better understanding of the disease mechanism and new treatments for rare disease patients, many of the lessons we learn here will also be of value to precision medicine, where the goal is to improve treatment through the customisation of healthcare based on a patient's genomic information."
Explore further: Major mouse study reveals the role of genes in disease
More information: 'Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium' by Meehan et al., Nature Genetics. DOI: 10.1038/ng.3901
The functions of around 150 genes have been discovered by scientists across Europe in a major initiative to try to understand the part they play in disease and biology.
Roughly a third of all genes in the mammalian genome are essential for life. A new article in Nature, from an international, multi-institutional research team, including Baylor College of Medicine, describes the large-scale ...
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Whole genome sequencing involves the analysis of all three billion pairs of letters in an individual's DNA and has been hailed as a technology that will usher in a new era of predicting and preventing disease. However, the ...
The first results from a functional genetic catalogue of the laboratory mouse has been shared with the biomedical research community, revealing new insights into a range of rare diseases and the possibility of accelerating ...
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