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Many genetic changes can occur early in human development Science Daily "The diagnostics lab Baylor Genetics is one of the pioneers in this new era of clinical genomics-supported medical practice and disease gene discovery research," Lupski said. "They are developing the clinical genomics necessary to foster and support ...

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Many genetic changes can occur early in human development - Science Daily

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Scientists Favor Gene Editing, But Only For 'Fixing Diseases' ValueWalk An international body of scientific experts has stated, with caution, that gene editing technologies should be allowed for treating diseases or disabilities. The US National Academy of Sciences and the National Academy of Medicine said in a 200-page ... Gene Editing Could Make You SmarterFuturism all 8 news articles »

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Scientists Favor Gene Editing, But Only For 'Fixing Diseases' - ValueWalk

Trying to mimic the early stages of reproduction, Cambridge University researchers cultivated two types of mouse stem cells in a Petri dish and watched an embryo emerge one that closely resembled a natural mouse embryo in its architecture, its development process and its ability to assemble itself.

The artificial structure shows promise as a tool for medical research, though it cannot develop into an actual baby.

I not only want to understand the basic biology of development but also why it goes awry in the early stages of up to 70% of human pregnancies, said Magdalena Zernicka-Goetz, senior author of the research, which was published Thursday in the journal Science.

Natures way

After an egg is fertilized by a sperm, it begins to divide multiple times. This process generates a small, free-floating ball of stem cells: a blastocyst.

Within a mammalian blastocyst, the cells that will become the body of the embryo (embryonic stem cells) begin to cluster at one end. Two other types of cells, the extra-embryonic trophoblast stem cells and the endoderm stem cells, begin to form patterns that will eventually become a placenta and a yolk sac, respectively.

To develop further, the blastocyst has to implant in the womb, where it transforms into a more complex architecture. However, implantation hides the embryo from view and from experimentation.

In the study, Zernicka-Goetz wanted to replicate developing embryonic events using stem cells.

Other scientists who have attempted the same thing have used only embryonic stem cells, but these experiments, though they have yielded embryoid bodies, have not been entirely successful. The artificial bodies never follow the same chain of events found in nature, and they lack the structure of a natural embryo.

Zernicka-Goetz, a professor in Cambridges Department of Physiology, Development and Neuroscience, hypothesized that the trophoblast stem cells communicate with the embryonic stem cells and guide their development.

She and her colleagues placed embryonic and trophoblast stem cells within an extra-cellular matrix: the non-cell component found in all tissues and organs that provides biochemical support to cells. This formed a scaffold on which the two stem cell types could co-develop.

The embryonic stem cells sent chemical messages to the trophoblast stem cells and vice versa, said Zernicka-Goetz. Essentially, the different stem cells began to talk to each other, and this helped the embryonic stem cells, she explained.

They respond by turning on particular developmental gene circuits or by physically changing shape to accomplish some architectural remodeling, she wrote in an email. This happens in normal embryogenesis and it is what we are trying to recreate in the culture dish.

Ultimately, the cells organized themselves into a structure that not only looked like an embryo, it behaved like one, with anatomically correct regions developing at the right time and in the right place.

The results were spectacular they formed structures that developed in a way strongly resembling embryos in their architecture and expressing specific genes in the right place and at the right time, Zernicka-Goetz wrote.

Despite its resemblance to a real embryo, this artificial embryo will not develop into a healthy fetus, the researchers said. That would require the endoderm stem cells, which does other things that are most likely necessary for further development, said Zernicka-Goetz.

Whether adding these to the system would be enough to achieve further development, I dont know, she said.

Correct placental development is essential for proper implantation into either the womb or a substitute for the womb, she said. To achieve this will be some time off.

Therapeutic applications

Robin Lovell-Badge, an embryologist and head of the Division of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute, found the new research to be interesting on a number of counts.

He wrote in a commentary published with the study on the website of the journal Science that past research suggests that the cells fated to become support structures (placenta and yolk sac) for the embryo in fact organize the cell types within the embryo. Meanwhile, the new research suggests that it is the combination of the two cell types (embryonic and trophectoderm) that is important while the third cell type, endoderm, may not be essential.

According to Dr. Christos Coutifaris, president-elect of the American Society for Reproductive Medicine and a professor at the University of Pennsylvania, the new study is significant because it shows how the cells that are extra-embryonic the ones that are going to give rise to the placenta actually play a role in the development of cells that eventually become the fetus.

Its not two completely separate entities, Coutifaris said, referring to the embryo and its support structure. Understanding how the two types of cells interact and the chemical signals they exchange is really, really critical.

Zernicka-Goetzs model has practical applications in research, where it can be used to better understand the conversation between embryonic stem cells and trophoblast stem cells, he said. You can manipulate these cells molecularly to try to understand these interactions and how early development occurs pre-implantation.

According to Kyle E. Orwig, an associate professor of obstetrics, gynecology and reproductive sciences, and molecular genetics and biochemistry at the University of Pittsburgh, Zernicka-Goetzs model will enable investigators to investigate the effects of genetic manipulations, environmental toxins, therapeutics and factors on embryo development. Artificial embryos represent a powerful tool for research that might reduce (but not eliminate) the need for human embryos, Orwig said.

Dr. David Adamson, a reproductive endocrinologist, an adjunct clinical professor at Stanford University and chairman of the International Committee Monitoring Assisted Reproductive Technologies, believes that its very important to continue to do basic science research in reproductive medicine.

How our species reproduces is very important to know, Adamson said. When you learn about reproduction and learn how cells reproduce and how cells differentiate and what makes things happen normally and what makes thing happen abnormally, then there clearly are a lot of potential therapeutic applications.

Past advances in reproductive medicine have helped scientists prevent genetic-based diseases, he said. Specifically, in vitro fertilization techniques have allowed doctors to biopsy and conduct genetic tests on embryos to prevent inherited illnesses, including Huntingtons.

In vitro fertilization is fundamentally transformative, said Adamson, who sees the new research as adding to the wealth of knowledge about this procedure.

In fact, Zernicka-Goetz works in the same nondescript brick building on the Cambridge campus where Robert Edwards, a reproductive medicine pioneer, once toiled. Edwards developed the Nobel Prize-winning technique of in vitro fertilization, which eventually resulted in the birth of the first test tube baby, Louise Brown.

Helping families have babies is the most obvious contribution of in vitro fertilization. Today, Adamson said, there have been approximately 6.5 million babies born using in vitro fertilization since the procedure was first developed. An exact number is not known because many countries, including China, do not have registries to count them, explained Adamson.

Meanwhile, Zernicka-Goetz said she will continue her work on embryonic development as she and the members of her lab are totally driven by a curiosity to understand these fundamental aspects of life.

She plans to use human stem cells to create a similar embryonic model. Then she plans to use that model to learn more about normal embryonic development and understand when it goes wrong without needing to experiment on an actual human embryo.

The work also continually teaches us about the properties of stem cells, Zernicka-Goetz said. She added that this knowledge is useful for developing therapies to replace faulty tissues in so-called regenerative medicine.

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Artificial embryo shows early potential for medical therapies, not babies - Gant Daily

When Nisa Leung was pregnant with her first child in 2012, her doctor in Hong Kong offered her a choice. She could take a prenatal test that would require inserting a needle into her uterus, or pay $130 more for an exam that would draw a little blood from her arm.

Leung opted for the simpler and less risky test, which analyzed bits of the babys DNA that had made its way into her bloodstream. Then, Leung went on to do what she often does when she recognizes a good product: look around for companies to invest in.

The managing partner at Qiming Venture Partners decided to put money into Chinese genetic testing firm Berry Genomics, which eventually entered into a partnership with the Hong Kong-based inventor of the blood test. Over the next few months, Berry is expected to be absorbed into a Chinese developer in a 4.3 billion yuan ($625 million) reverse merger. And Leungs venture capital firm would be the latest to benefit from a boom in so-called precision medicine, an emerging field that includes everything from genetic prenatal tests to customizing treatments for cancer patients.

Source: Qiming Venture Partners

China has made the precision medicine field a focus of its 13th five-year plan, and its companies have been embarking on ambitious efforts to collect a vast trove of genetic and health data, researching how to identify cancer markers in blood, and launching consumer technologies that aim to tap potentially life-saving information. The push offers insight into Chinas growing ambitions in science and biotechnology, areas where it has traditionally lagged developed nations like the U.S.

Investing in precision medicine is definitely the trend, said Leung,whos led investments in more than 60 Chinese health-care companies in the past decade. As China eyes becoming a biotechnology powerhouse globally, this is an area we will venture into for sure and hopefully be at the forefront globally.

New Chinese firms like iCarbonX and WuXi NextCode that offer consumers ways to learn more about their bodies through clues from their genetic make up are gaining popularity. Chinese entrepreneurs and scientists are also aiming to dominate the market for complex new procedures like liquid biopsy tests, which would allow for cancer testing through key indicators in the blood.

iCarbonX founder Wang Jun.

Photographer: Calvin Sit/Bloomberg

Such research efforts are still in early stages worldwide. But doctors see a future beyond basic commercial applications, aiming instead for drugs and treatment plans tailored to a persons unique genetic code and environmental exposure, such as diet and infections.

Isaac Kohane, a bioinformatics professor at Harvard University, says when it comes to precision medicine, the science community has Google maps envy. Just as the search engine has transformed the notion of geography by adding restaurants, weather and other locators,more details on patients can give doctors a better picture on how to treat diseases.

For cancer patients, for example, precision medicine might allow oncologists to spot specific mutations in a tumor. For many people with rare ailments like muscle diseases or those that cause seizures, it allows for earlier diagnosis. Pregnant women, using the kind of tests that Leung used, could also learn more about the potential for a child to inherit a genetic disease.

The global interest in the field comes as the cost of sequencing DNA, or analyzing genetic information, is falling sharply. But a number of hurdles remain. Relying on just genes isnt enough, and there must also be background information on a patients lifestyle and medication history.

Precision medicine applications also require heavy investment to store large amounts of information. A whole genome is over 100 gigabytes, according toan e-mailed response to questions from Edward Farmer, WuXi NextCodes vice-president of communications and new ventures. So you can imagine that analyzing thousands or hundreds of thousands of genomes is a true big data challenge."

WuXi NextCode was formed after Shanghai-based contract research giant WuXi AppTec Inc. acquired genomic analysis firm NextCode Health, a spin-off from Reykjavik, Iceland-based Decode Genetics, which has databases on the islands population. Wuxi NextCode continues to have an office in Iceland, where the population is relatively homogenous and therefore good for gene discovery.

Source: WuXi NextCODE

"Genomics today is like the computer industry in the 70s," said Hannes Smarason, WuXi NextCodes co-founder and chief operating officer. "Weve made great progress but theres still a long way to go.

In China, Wuxi NextCode now offers consumers genetic tests that cost between about 2,500 yuan and 8,000 yuan, providing more details on rare conditions a child might be suffering from or even the risk of passing on an inherited disease.

China is diverse and with 1.4 billion people, the planets most populous nation. WuXi NextCode announced a partnership with Huawei Technologies Co.,Chinas largest telecommunications equipment maker, in May to enable different institutions and researchers to store their data.

The goal is to use that deep pool of information -- which ranges from genome sequences to treatment regimens -- to find more clues on tackling diseases. WuXi says that this will in many instances enable the largest studies ever undertaken in many diseases.

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The global precision medicine market was estimated to be worth $56 billion in revenue at the end of 2016,with China holding about 4 to 8 percent of the global market, according to a December report from Persistence Market Research.

Encouraging interventions for some patients too early, even before they have life-threatening diseases, comes with risks and ethical questions, Laura Nelson Carney,an analyst at Sanford C Bernstein, wrote in a Jan. 6 note. Still, precision medicine research has many benefits, and some in China see the countrys push as a significant opportunity "to scientifically leapfrog the West, she said.

In the U.S., universities, the National Institutes of Health and American drugmakers are part of a broad march into precision medicine.

Amgen Inc. bought Icelandic biotechnology company DeCode Genetics for $415 million in 2012, to acquire its massive database on Icelands population. U.S.-based Genentech Inc. is collaborating with Silicon Valley startup 23andMe to study the genetic underpinnings of Parkinsons disease.

Humans are computable," saidWang Jun, the chief executive officer of ChinasiCarbonX. "So we need a computable model that we can use to intervene and change peoples status, thats the whole point.

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China Turns to Precision Medicine in Fight Against Cancer ... - Bloomberg

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Youre one of a kind. Its not just your eyes, smile, and personality. Your health, risk for disease, and the ways you respond to medicines are also unique. Medicines that work well for some people may not help you at all. They might even cause problems. Wouldnt it be nice if treatments and preventive care could be designed just for you?

The careful matching of your biology to your medical care is known as personalized medicine. Its already being used by health care providers nationwide.

The story of personalized medicine begins with the unique set of genes you inherited from your parents. Genes are stretches of DNA that serve as a sort of instruction manual telling your body how to make the proteins and perform the other tasks that your body needs. These genetic instructions are written in varying patterns of only 4 different chemical letters, or bases.

The same genes often differ slightly between people. Bases may be switched, missing, or added here and there. Most of these variations have no effect on your health. But some can create unusual proteins that might boost your risk for certain diseases. Some variants can affect how well a medicine works in your body. Or they might cause a medicine to have different side effects in you than in someone else.

The study of how genes affect the way medicines work in your body is called pharmacogenomics.

If doctors know your genes, they can predict drug response and incorporate this information into the medical decisions they make, says Dr. Rochelle Long, a pharmacogenomics expert at NIH.

Its becoming more common for doctors to test for gene variants before prescribing certain drugs. For example, children with leukemia might get the TPMT gene test to help doctors choose the right dosage of medicine to prevent toxic side effects. Some HIV-infected patients are severely allergic to treatment drugs, and genetic tests can help identify who can safely take the medicines.

By screening to know who shouldnt get certain drugs, we can prevent life-threatening side effects, Long says.

Pharmacogenomics is also being used for cancer treatment. Some breast cancer drugs only work in women with particular genetic variations. If testing shows patients with advanced melanoma (skin cancer) have certain variants, 2 new approved drugs can treat them.

Even one of the oldest and most common drugs, aspirin, can have varying effects based on your genes. Millions of people take a daily aspirin to lower their risk for heart attack and stroke. Aspirin helps by preventing blood clots that could clog arteries. But aspirin doesnt reduce heart disease risk in everyone.

NIH-funded researchers recently identified a set of genes with unique activity patterns that can help assess whether someone will benefit from taking aspirin for heart health. Scientists are now working to develop a standardized test for use in daily practice. If doctors can tell that aspirin wont work in certain patients, they can try different treatments.

One NIH-funded research team studied a different clot-fighting drug known as clopidogrel (Plavix). Its often prescribed for people at risk for heart attack or stroke. Led by Dr. Alan Shuldiner at the University of Maryland School of Medicine, the team examined people in an Amish community. Isolated communities like this have less genetic diversity than the general population, which can make it easier to study the effects of genes. But as in the general population, some Amish people have risk factors, such as eating a high-fat diet, that raise their risk for heart disease.

Many of the Amish people studied had a particular gene variant that made them less responsive to clopidogrel, the scientists found. Further research revealed that up to one-third of the general population may have similar variations in this gene, meaning they too probably need a different medicine to reduce heart disease risks.

The findings prompted the U.S. Food and Drug Administration (FDA) to change the label for this common drug to alert doctors that it may not be appropriate for patients who have certain gene variations. Two alternative drugs have since been developed. If people have these gene variants, they know they have options, says Shuldiner. This is a great example of how study results made it onto a drug label and are beginning to be implemented into patient care.

Getting a genetic test usually isnt difficult. Doctors generally take a sample of body fluid or tissue, such as blood, saliva or skin, and send it to a lab. Most genetic tests used today analyze just one or a few genes, often to help diagnose disease. Newborns, for example, are routinely screened for several genetic disorders by taking a few drops of blood from their heels. When life-threatening conditions are caught early, infants can be treated right away to prevent problems.

The decision about whether to get a particular genetic test can be complicated. Genetic tests are now available for about 2,500 diseases, and that number keeps growing. Your doctor might advise you to get tested for specific genetic diseases if they tend to run in your family or if you have certain symptoms.

While there are many genetic tests, they vary as to how well they predict risk, says Dr. Lawrence Brody, a genetic testing expert at NIH.

For some diseases, such as sickle cell anemia or cystic fibrosis, inheriting 2 copies of abnormal genes means a person will get that disease. But for other diseases and conditions, the picture is more complex. For type 2 diabetes, testing positive for some specific gene variants may help predict risk, but no better than other factorssuch as obesity, high blood pressure and having a close relative with the disease.

The latest approach to personalized medicine is to get your whole sequenced. Thats still expensive, but the cost has dropped dramatically over the past decade and will likely continue to fall. Since your genome essentially stays the same over time, this information might one day become part of your medical record, so doctors could consult it as needed.

You can start to get a sense of your genetic risks by putting together your familys health history. A free online tool called My Family Health Portrait from the U.S. Surgeon General can help you and your doctor spot early warning signs of conditions that run in your family.

But personalized medicine isnt just about genes. You can learn a lot about your health risks by taking a close look at your current health and habits. Smoking, a poor diet, and lack of exercise can raise your risks for life-threatening health problems, such as heart disease and cancer. Talk to your health care provider about the steps you can take to understand and reduce your unique health risks.

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Personalized Medicine - NIH News in Health, December 2013

8 October 2007

The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2007 jointly to

Mario R. Capecchi, Martin J. Evans and Oliver Smithies

for their discoveries of "principles for introducing specific gene modifications in mice by the use of embryonic stem cells"

This year's Nobel Laureates have made a series of ground-breaking discoveries concerning embryonic stem cells and DNA recombination in mammals. Their discoveries led to the creation of an immensely powerful technology referred to as gene targeting in mice. It is now being applied to virtually all areas of biomedicine from basic research to the development of new therapies.

Gene targeting is often used to inactivate single genes. Such gene "knockout" experiments have elucidated the roles of numerous genes in embryonic development, adult physiology, aging and disease. To date, more than ten thousand mouse genes (approximately half of the genes in the mammalian genome) have been knocked out. Ongoing international efforts will make "knockout mice" for all genes available within the near future.

With gene targeting it is now possible to produce almost any type of DNA modification in the mouse genome, allowing scientists to establish the roles of individual genes in health and disease. Gene targeting has already produced more than five hundred different mouse models of human disorders, including cardiovascular and neuro-degenerative diseases, diabetes and cancer.

Information about the development and function of our bodies throughout life is carried within the DNA. Our DNA is packaged in chromosomes, which occur in pairs one inherited from the father and one from the mother. Exchange of DNA sequences within such chromosome pairs increases genetic variation in the population and occurs by a process called homologous recombination. This process is conserved throughout evolution and was demonstrated in bacteria more than 50 years ago by the 1958 Nobel Laureate Joshua Lederberg.

Mario Capecchi and Oliver Smithies both had the vision that homologous recombination could be used to specifically modify genes in mammalian cells and they worked consistently towards this goal.

Capecchi demonstrated that homologous recombination could take place between introduced DNA and the chromosomes in mammalian cells. He showed that defective genes could be repaired by homologous recombination with the incoming DNA. Smithies initially tried to repair mutated genes in human cells. He thought that certain inherited blood diseases could be treated by correcting the disease-causing mutations in bone marrow stem cells. In these attempts Smithies discovered that endogenous genes could be targeted irrespective of their activity. This suggested that all genes may be accessible to modification by homologous recombination.

The cell types initially studied by Capecchi and Smithies could not be used to create gene-targeted animals. This required another type of cell, one which could give rise to germ cells. Only then could the DNA modifications be inherited.

Martin Evans had worked with mouse embryonal carcinoma (EC) cells, which although they came from tumors could give rise to almost any cell type. He had the vision to use EC cells as vehicles to introduce genetic material into the mouse germ line. His attempts were initially unsuccessful because EC cells carried abnormal chromosomes and could not therefore contribute to germ cell formation. Looking for alternatives Evans discovered that chromosomally normal cell cultures could be established directly from early mouse embryos. These cells are now referred to as embryonic stem (ES) cells.

The next step was to show that ES cells could contribute to the germ line (see Figure). Embryos from one mouse strain were injected with ES cells from another mouse strain. These mosaic embryos (i.e. composed of cells from both strains) were then carried to term by surrogate mothers. The mosaic offspring was subsequently mated, and the presence of ES cell-derived genes detected in the pups. These genes would now be inherited according to Mendels laws.

Evans now began to modify the ES cells genetically and for this purpose chose retroviruses, which integrate their genes into the chromosomes. He demonstrated transfer of such retroviral DNA from ES cells, through mosaic mice, into the mouse germ line. Evans had used the ES cells to generate mice that carried new genetic material.

By 1986 all the pieces were at hand to begin generating the first gene targeted ES cells. Capecchi and Smithies had demonstrated that genes could be targeted by homologous recombination in cultured cells, and Evans had contributed the necessary vehicle to the mouse germ line the ES-cells. The next step was to combine the two.

For their initial experiments both Smithies and Capecchi chose a gene (hprt) that was easily identified. This gene is involved in a rare inherited human disease (Lesch-Nyhan syndrome). Capecchi refined the strategies for targeting genes and developed a new method (positive-negative selection, see Figure) that could be generally applied.

The first reports in which homologous recombination in ES cells was used to generate gene-targeted mice were published in 1989. Since then, the number of reported knockout mouse strains has risen exponentially. Gene targeting has developed into a highly versatile technology. It is now possible to introduce mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal.

Almost every aspect of mammalian physiology can be studied by gene targeting. We have consequently witnessed an explosion of research activities applying the technology. Gene targeting has now been used by so many research groups and in so many contexts that it is impossible to make a brief summary of the results. Some of the later contributions of this year's Nobel Laureates are presented below.

Gene targeting has helped us understand the roles of many hundreds of genes in mammalian fetal development. Capecchis research has uncovered the roles of genes involved in mammalian organ development and in the establishment of the body plan. His work has shed light on the causes of several human inborn malformations.

Evans applied gene targeting to develop mouse models for human diseases. He developed several models for the inherited human disease cystic fibrosis and has used these models to study disease mechanisms and to test the effects of gene therapy.

Smithies also used gene targeting to develop mouse models for inherited diseases such as cystic fibrosis and the blood disease thalassemia. He has also developed numerous mouse models for common human diseases such as hypertension and atherosclerosis.

In summary, gene targeting in mice has pervaded all fields of biomedicine. Its impact on the understanding of gene function and its benefits to mankind will continue to increase over many years to come.

Mario R. Capecchi, born 1937 in Italy, US citizen, PhD in Biophysics 1967, Harvard University, Cambridge, MA, USA. Howard Hughes Medical Institute Investigator and Distinguished Professor of Human Genetics and Biology at the University of Utah, Salt Lake City, UT, USA.

Sir Martin J. Evans, born 1941 in Great Britain, British citizen, PhD in Anatomy and Embryology 1969, University College, London, UK. Director of the School of Biosciences and Professor of Mammalian Genetics, Cardiff University, UK.

Oliver Smithies, born 1925 in Great Britain, US citizen, PhD in Biochemistry 1951, Oxford University, UK. Excellence Professor of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA.

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The 2007 Nobel Prize in Physiology or Medicine - Press Release

The right drug at the right dose at the right time. Those goals drive pharmacogenomics how genetics influence a person's response to medications.

Chemotherapy drugs are more effective when treating certain types of cancers. Codeine offers no pain relief in some patients and in others causes life-threatening reactions, such as respiratory depression. Other individuals experience harmful side effects from statin drugs designed to lower cholesterol levels. Finding the right dose of blood-thinning agents, such as warfarin, can involve a long process of trial and error.

Some Food and Drug Administration-approved drug labels contain warnings or information about potential adverse event risks, variable responses, drug-action mechanisms or genotype-based drug dosing. Recommendations are based on genomic information about the drug.

Pharmacogenomics drives greater drug effectiveness, with increased safety and reduced side effects. At Mayo Clinic, drug-gene alerts are part of the electronic medical record system, assisting providers in delivering safer, more effective care.

Each day, research uncovers new gene variants or novel drug-gene interactions that influence whether a patient may be harmed or helped by a medication. Keeping up to date with complex, new genomic information is a challenging task for clinicians, but decision-support tools and online education helps.

The Center for Individualized Medicine at Mayo Clinic is adding drug-gene interactions to the patient electronic medical record to alert physicians and pharmacists at the point of care as part of the clinical decision-support system.

If genomic information exists for a drug-gene interaction, alerts are triggered in the patient's electronic medical record to guide the clinician regarding prescription choices and dosing recommendations.

A team of physicians, pharmacists, genetic counselors and medical educators provides just-in-time education linked to these pop-up alerts. Online resources provide information about:

Ongoing discovery and validation of new drug-gene pairs at Mayo Clinic and elsewhere will result in additional alerts being added to the electronic medical record.

Applied pharmacogenomics resolves patient's lifelong anxiety and depression.

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Drug-Gene Alerts - Mayo Clinic Center for Individualized ...

Welcome to the website of the Oxford University Gene Medicine Research Group. We are a University of Oxford research group based in the Radcliffe Department of Medicine at the John Radcliffe Hospital.

We are focused on the development of clinical gene therapies for the treatment of lung diseases. Our primary focus has been Cystic Fibrosis (CF) lung disease.

Together with colleagues at the University of Edinburgh and Imperial College London we form the UK Cystic Fibrosis Gene Therapy Consortium, funded by the Medical Research Council, the National Institute for Health Research and the UK Cystic Fibrosis Trust.

The Consortium is currently undertaking one of the world's largest ever gene therapy clinical trials in CF patients based on our gene therapy research.

Patient Recruitment for the Muti-Dose Clinical Trial

We are pleased to announce the launch of new charity Just Gene Therapy with the specific aim of raising funds for gene therapy research for CF. The charity has been established by Rosie Barnes in conjunction with Professor Eric Alton, and is the only way in which donations can directly support the work of the Consortium.

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UK Cystic Fibrosis Gene Therapy Consortium : Oxford ...

Study of twins discovers gene mutation linked to short sleep duration American Academy of Sleep Medicine Thursday, July 31, 2014

FOR IMMEDIATE RELEASE CONTACT: Lynn Celmer, 630-737-9700, ext. 9364, lcelmer@aasmnet.org

DARIEN, IL Researchers who studied 100 twin pairs have identified a gene mutation that may allow the carrier to function normally on less than six hours of sleep per night. The genetic variant also appears to provide greater resistance to the effects of sleep deprivation.

Results show that a participant with p.Tyr362His a variant of the BHLHE41 gene had an average nightly sleep duration of only five hours, which was more than one hour shorter than the non-carrier twin, who slept for about six hours and five minutes per night. The twin with the gene mutation also had 40 percent fewer average lapses of performance during 38 hours without sleep and required less recovery sleep afterward sleeping only eight hours after the period of extended sleep deprivation compared with his twin brother, who slept for 9.5 hours.

According to the authors, this is only the second study to link a mutation of the BHLHE41 gene also known as DEC2 - to short sleep duration. The study provides new insights into the genetic basis of short sleep in humans and the molecular mechanisms involved in setting the duration of sleep that individuals need.

This work provides an important second gene variant associated with sleep deprivation and for the first time shows the role of BHLHE41 in resistance to sleep deprivation in humans, said lead author Renata Pellegrino, PhD, senior research associate in the Center for Applied Genomics at The Childrens Hospital of Philadelphia. The mutation was associated with resistance to the neurobehavioral effects of sleep deprivation.

Study results are published in the Aug. 1 issue of the journal Sleep.

Pellegrino, along with co-author Ibrahim Halil Kavakli, from Koc University in Istanbul, Turkey, studied 100 twin pairs 59 monozygotic pairs and 41 dizygotic pairs who were recruited at the University of Pennsylvania. All twin pairs were the same sex and were healthy with no chronic conditions. Nightly sleep duration was measured at home by actigraphy for seven to eight nights. Response to 38 hours of sleep deprivation and length of recovery sleep were assessed in a sleep lab. During sleep deprivation, cognitive performance was measured every two hours using the Psychomotor Vigilance Test.

Although individual sleep needs vary, the American Academy of Sleep Medicine recommends that adults get about seven to nine hours of nightly sleep. However, a small percentage of adults are normal short sleepers who routinely obtain less than six hours of sleep per night without any complaints of sleep difficulties and no obvious daytime dysfunction.

This study emphasizes that our need for sleep is a biological requirement, not a personal preference, said American Academy of Sleep Medicine President Dr. Timothy Morgenthaler. Most adults appear to need at least seven hours of quality sleep each night for optimal health, productivity and daytime alertness.

According to the AASM, most people who regularly get six hours of sleep or less are restricting their sleep and suffer from insufficient sleep syndrome, which occurs when an individual persistently fails to obtain the amount of sleep required to maintain normal levels of alertness and wakefulness. Data from the Centers for Disease Control and Prevention indicate that 28 percent of U.S. adults report sleeping six hours or less in a 24-hour period. Insufficient sleep results in increased daytime sleepiness, concentration problems and lowered energy level, and it increases the risk of depression, drowsy driving, and workplace accidents.

The study involved a collaboration between researchers from The Childrens Hospital of Philadelphia; Universidade Federal de So Paulo (UNIFESP) in So Paulo, Brazil; Koc University in Istanbul, Turkey; the University of Pennsylvania Perelman School of Medicine; the Philadelphia Veterans Affairs Medical Center; and Washington State University. The research was supported in part by grants from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), and the Institutional Development Fund from the Center for Applied Genomics at The Childrens Hospital of Philadelphia.

To request a copy of the study, A Novel BHLHE41Variant is Associated with Short Sleep and Resistance to Sleep Deprivation in Humans, or to arrange an interview with the study author or an AASM spokesperson, please contact Communications Coordinator Lynn Celmer at 630-737-9700, ext. 9364, or lcelmer@aasmnet.org.

The monthly, peer-reviewed, scientific journal Sleep is published online by the Associated Professional Sleep Societies LLC, a joint venture of the American Academy of Sleep Medicine and the Sleep Research Society. The AASM is a professional membership society that improves sleep health and promotes high quality patient centered care through advocacy, education, strategic research, and practice standards (www.aasmnet.org). A searchable directory of AASM accredited sleep centers is available at http://www.sleepeducation.org.

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AASM News Archive - American Academy of Sleep Medicine

Gene therapy is a novel approach to treat, cure, or ultimately prevent disease by changing the expression of a persons genes. Gene therapy is in its infancy, and current therapies are primarily experimental, with most human clinical trials still in the research stages.

How does gene therapy work? Genes are composed of DNA that carries information needed to make proteins the building blocks of our bodies. Variations in the DNA sequence or code of a gene are called mutations, which often are harmless but sometimes can lead to serious disease. Gene therapy treats disease by repairing dysfunctional genes or by providing copies of missing genes.

To reverse disease caused by genetic damage, researchers isolate normal DNA and package it into a vehicle known as a vector, which acts as a molecular delivery truck. Vectors composed of viral DNA sequences have been used successfully in human gene therapy trials. Doctors infect a target cell usually from a tissue affected by the illness, such as liver or lung cellswith the vector. The vector unloads its DNA cargo, which then begins producing the proper proteins and restores the cell to normal. Problems can arise if the DNA is inserted into the wrong place in the genome. For example, in rare instances the DNA may be inserted into a regulatory gene, improperly turning it on or off, leading to cancer.

Researchers continue to optimize viral vectors as well as develop non-viral vectors that may have fewer unexpected side effects. Nonviral gene delivery involves complexing DNA with an agent that allows it to enter a cell nonspecifically. DNA delivered in this manner is usually expressed for only a limited time because it rarely integrates into the host cell genome.

Initial efforts in gene therapy focused on delivering a normal copy of a missing or defective gene, but current programs are applying gene delivery technology across a broader spectrum of conditions. Researchers are now utilizing gene therapy to :

What diseases could be treated with gene therapy? About 4,000 diseases have been traced to gene disorders. Current and possible candidates for gene therapy include cancer, AIDS, cystic fibrosis, Parkinsons and Alzheimers diseases, amyotrophic lateral sclerosis (Lou Gehrig's disease), cardiovascular disease and arthritis.

In cases such as cystic fibrosis or hemophilia, disease results from a mutation in a single gene. In other scenarios like hypertension or high cholesterol, certain genetic variations may interact with environmental stimuli to cause disease.

Has gene therapy been successfully used in humans? Gene therapy is likely to be most successful with diseases caused by single gene defects. The first successful gene therapy on humans was performed in 1990 by researchers at the National Institutes of Health. The therapy treated a four-year-old child for adenosine deaminase (ADA) deficiency, a rare genetic disease in which children are born with severe immunodeficiency and are prone to repeated serious infections.

Since 1990, gene therapy had been tested in human clinical trials for treating such diseases as severe combined immunodeficiency disease (SCID), cystic fibrosis, Canavan's disease, and Gaucher's disease. In 2003, more than 600 gene therapy clinical trials were under way in the United States but only a handful of these are in advanced stages. SCID, in which children lack natural defenses against infection and can only survive in isolated environments, remains the only disease cured by gene therapy.

Are genetic alterations from gene therapy passed on to children? Gene therapy can be targeted to somatic (body) or germ (egg and sperm) cells. In somatic gene therapy, the patients genome is changed, but the change is not passed along to the next generation. In germline gene therapy, the patients egg or sperm cells are changed with the goal of passing on changes to their offspring. Existing gene therapy treatments and experiments are all somatic.

Germline gene therapy is not being actively investigated in larger animals and humans for safety and ethical reasons. In September 2000, the American Association for the Advancement of Science (AAAS) called for a moratorium on attempts to cure genetic diseases through human germline gene therapy. While its report supported expanded basic research in the field of clinical gene therapy, AAAS concluded that neither science nor society is ready for germline gene therapy research.

Learn more about federal policies and regulations protecting those who volunteer to participate in biomedical research.

Sources U.S. Department of Energy Office of Science, Office of Biological and Environmental Research, Human Genome Program American Society of Gene Therapy Gene-Cell, Inc. Targeted Genetics Corp.

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Gene Therapy - American Medical Association

Cancer Gene: Medicines Next Big Thing?
This year alone, 16000 children under the age of 19 will be diagnosed with cancer.

By: NewsChannel 5

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Cancer Gene: Medicines Next Big Thing? - Video

PARP inhibitors interfere with cancers ability to repair damage to its DNA. They are becoming increasingly useful in treating ovarian cancer.

Valencia Halls oncologist wanted to give her the best possible chance of staying in remission, so in June 2017, she prescribed Zejula (niraparib), a once-daily oral treatment thats part of an emerging class of medicines known as poly (ADP-ribose) polymerase (PARP) inhibitors. Just a few months before Valencia Halls disease returned, Zejula had become the first PARP inhibitor approved by the Food and Drug Administration (FDA) to treat women with recurrent ovarian cancer who do not have a genetic abnormality but previously responded well to platinum-based chemotherapy. Valencia Hall was a perfect candidate for the drug, which is referred to as a maintenance treatment because its prescribed with the goal of preventing ovarian cancer from returning.

She has been free of the disease since starting Zejula and has experienced no side effects, aside from a temporary drop in platelet counts that her oncologist corrected by dialing down Valencia Halls daily dose. Zejula has allowed me to live my life as I see fit, says Valencia Hall, 51, a freelance graphic artist in Phoenix. Its an oral medication, so I dont have to go in for infusions. The opportunity to have this as a maintenance therapy is exciting its hope.

Zejula is one of three PARP inhibitors that are taking an increasingly prominent role in ovarian cancer treatment and improving patients prognosis. With dozens of clinical trials underway, including some that seek to combine PARP inhibitors with other cancer treatments, that role could expand even more.

Drugs in this class work by inhibiting the PARP enzyme, which normally helps damaged DNA repair itself. Preventing this repair causes cancer cells to die, especially those that already have DNA repair defects due to a mutated BRCA 1 or 2 gene or other abnormalities. So far, clinical trials have shown that these drugs can lengthen the time until the disease progresses; their impact on the length of life is still being investigated. For women using a PARP inhibitor for maintenance, the drugs can help increase the time between courses of chemotherapy for recurrent disease.

In the past, we would take patients who had a high risk of recurrence and just watch them until cancer came back because we didnt have maintenance therapies that were effective, tolerable or convenient, says Dr. Bradley Monk, a professor and director of the division of gynecologic oncology at Creighton University School of Medicine at St. Josephs Hospital and Medical Center in Phoenix, Arizona, and also medical director of gynecologic oncology research for the U.S. Oncology Research Network. PARP inhibitors have been significant because theyre expanding the treatment opportunity for many patients, he adds.

Each year, more than 22,000 women in the U.S., about half of whom are over age 63, receive a diagnosis of ovarian cancer, according to the American Cancer Society. A small proportion of women have inherited mutations in BRCA1, BRCA2 or other cancer-related genes that raise their risk of ovarian cancer and can take steps to fend off the disease, including surgery to remove their ovaries. But most cases occur out of the blue, and because the symptoms can be vague and easily overlooked, like bloating or stomach pain, many women do not receive a diagnosis until the disease has advanced to the point where it can be hard to treat. The disease will recur in about 85% of women who initially respond to chemotherapy.

For women with ovarian cancer, PARP inhibitors have been an option since 2014, when the FDA approved Lynparza (olaparib) as a maintenance therapy for patients with BRCA mutations who had received three or more chemotherapy treatments. Rubraca (rucaparib) followed in 2016 and Zejula in 2017.

PARP INHIBITORS REACH MORE PATIENTS

Over the past two years, the FDA approved more uses of PARP inhibitors so that many more patients can benefit from these medicines and access the drugs earlier in treatment. In April 2018, Rubraca was approved as a maintenance therapy to treat recurrent ovarian cancer in women who responded at least partially to platinum-based chemotherapy, whether or not they had a genetic mutation. That December, Lynparza was approved as a first-line maintenance treatment for BRCA-mutated ovarian cancer, meaning patients can be given the drug after successfully completing just one round of platinum-based chemotherapy.

That was based on a clinical trial showing the drug reduced the rate of disease progression or death by 70%.

Most recently, in October 2019, the FDA approved Zejula for use in patients with advanced ovarian cancer associated with a cellular abnormality called homologous recombination deficiency. BRCA1 and BRCA2 are two of these types, but in ovarian cancer, about 17 other such genetic abnormalities can drive the disease. Between 41% and 50% of ovarian tumors are thought to have homologous recombination deficiency, which can be detected with a tumor test, Myriad myChoice CDx, that the FDA also approved last October.

In a clinical trial leading to the approval, 24% of participants with homologous recombination deficiency-positive ovarian cancer responded well to Zejula, experiencing some tumor shrinkage. That may not sound like a high response rate, but it surpasses the overall response rate to PARP inhibitors among all patients with ovarian cancer either with or without mutations, says lead clinical trial investigator Dr. Kathleen Moore, associate professor of gynecologic oncology at Stephenson Cancer Center at the University of Oklahoma.

These are heavily pretreated patients in which the response rate has typically been 12%, so this was double what we normally see, Moore says. The clinical benefit here was quite high. She adds that patients with BRCA mutations did particularly well: Nearly 40% of those who previously responded well to platinum-based chemotherapy responded to Zejula. The most common side effects include gastric upset, mouth sores, rash, headache and dizziness. The drug can also cause anemia and abnormal blood counts, which, in rare cases, can lead to myelodysplastic syndrome, a bone marrow problem, or the blood cancer acute myeloid leukemia.

As PARP inhibitors continue to help a widening population of patients with ovarian cancer, a push is underway to use them earlier in the treatment process. Several trials presented at the 2019 European Society for Medical Oncology conference demonstrated the potential value of that strategy.

One study found an 84% survival rate among patients who took Zejula for two years following chemotherapy, regardless of their homologous recombination deficiency status, compared with 77% who got a placebo. The median progression-free survival period (time from treatment to disease progression) for patients taking the drug was 14 months compared with eight months for those on placebo.

Another study evaluated an investigational PARP inhibitor, veliparib, combined with chemotherapy as a first-line treatment followed by veliparib alone for maintenance. Median progression-free survival among patients on that regimen was 23.5 months versus 17.3 months for those taking a placebo.

The third trial presented at the conference involved Avastin (bevacizumab), a drug that cuts off the blood supply to tumors. The FDA approved Avastin in 2018 to treat advanced ovarian cancer in conjunction with chemotherapy.

During the more recent trial, patients with newly diagnosed advanced ovarian cancer took Avastin plus chemotherapy, followed by Avastin with Lynparza for maintenance. Those who took Lynparza along with Avastin had a median progression-free survival of 22 months compared with 17 months for those who received Avastin and a placebo.

In all three studies, progression-free survival rates were the highest among homologous recombination deficiency-positive patients, but the fact that PARP inhibitors extended survival even among those without those mutations was encouraging to oncologists who treat ovarian cancer.

These were all positive studies that undoubtedly show that PARP inhibitor maintenance following chemotherapy will extend beyond BRCA-associated ovarian cancer, Moore says. Its highly likely that a much larger proportion of women with ovarian cancer who are diagnosed in 2020 will receive a PARP inhibitor (than in previous years). Women will be able to live longer with their cancer because were developing effective therapies that push out progression-free survival.

COMBINATIONS GAIN STEAM

A clinical trial investigating a novel PARP combination proved a lifesaver for Diane Sarver, who first received a diagnosis of ovarian cancer in 2010. Chemotherapy put her cancer in remission three times, but when she relapsed again in 2015, she decided to search for a novel treatment strategy and traveled from her home in Lake Oswego, Oregon, to The University of Texas MD Anderson Cancer Center in Houston.

Sarver was entered into an early-phase trial combining Lynparza with the investigational drug AZD2014, which interferes with a cellular pathway (called phosphatidylino-sitol-3 [PI3] kinase) that drives resistance to PARP inhibitors. Within seven weeks of starting the combination therapy which consists of two oral drugs taken twice a day , Sarvers ovarian cancer came under control. As part of the ongoing trial, she continues to take the two drugs, which, she says, have caused no side effects and shes still disease-free.

Whats notable about Sarvers case is that she didnt inherit any genetic mutations that would predict such a long-lasting response to PARP inhibitors. Although her tumor tested positive for a rare BRCA mutation, it was considered nonactionable scientists did not yet know whether or not the mutation produced an aberrant protein that would make it likely to respond to the drug combination being studied. The theory behind the trial is that blocking PI3 kinase may transform tumors that would not normally respond to PARP inhibition into responders.

Im amazed that Ive had such a good outcome, says Sarver, 69, a retired clinical technologist and mother of two grown children. Her only limitation is that she has to fast two hours before and after taking the drugs, she says, but the lack of side effects has given her the freedom to travel, speak to medical students about her experiences and spend time with her family.

Ive seen both children through their college graduations, Sarver says. I feel completely functional and am grateful to have never experienced any fatigue or other physical restriction.

MD Anderson is now planning several midstage clinical trials combining PARP and PI3 kinase inhibition, including one that pairs Lynparza with Piqray (alpelisib), a drug currently used to treat some patients with breast cancer. In an early trial of the combination that was reported in April 2019, 36% of patients had a partial response of some tumor shrinkage and half achieved stable disease, meaning their cancer didnt get worse. That was impressive, considering the bulk of the patients had become resistant to platinum chemotherapy, says Dr. Shannon Westin, a clinical investigator in the department of gynecologic oncology and reproductive medicine at MD Anderson. And there was a similar response rate regardless of mutation status, which was very exciting.

RESEARCHERS PURSUE MORE USES

Pairing PARP inhibitors with drugs that boost the immune systems ability to fight cancer is another idea being investigated in the treatment of ovarian cancer, because tumors with unstable DNA repair abilities might also be easier for the immune system to recognize. For example, Keytruda (pembrolizumab) inhibits programmed cell death protein 1 (PD-1), an immune checkpoint responsible for keeping the immune system under control.

The drug essentially takes the brakes off the immune system so it can better recognize and attack cancer. In an early trial combining Keytruda with Zejula, 65% of patients with ovarian cancer saw their disease come under control, either with total or partial tumor shrinkage or with stable disease.

Several other ongoing studies are combining PARP inhibition with immunotherapy, including a trial of Zejula with Tecentriq (atezolizumab), an inhibitor of a protein called programmed death-ligand 1 (PD-L1), and Cotellic (cobimetinib), which inhibits the cancer-associated mitogen-activated (MEK) protein. Another study combines Zejula with TSR-042, an investigational PD-1 blocker.

Could PARP inhibitors be useful for some women even earlier in the treatment process? MD Anderson recently started a small trial designed to investigate the potential of using the agents in place of chemotherapy in women with newly diagnosed cancer who have BRCA mutations. During the trial, patients will receive Lynparza for up to three months before moving on to surgery and chemotherapy. A similar trial is ongoing using the PARP inhibitor Talzenna (talazoparib) for BRCA-mutated breast cancer.

There could be many advantages of starting treatment with a PARP inhibitor rather than chemotherapy, Westin says. Patients can take the drugs at home instead of going to a facility for chemotherapy infusions. And PARP inhibitors dont cause many of the uncomfortable side effects common with chemotherapy, like neuropathy (numbness and tingling in the extremities) and hair loss. Some patients could potentially avoid that toxicity, Westin says.

The question is: Do we even need chemotherapy? Westin adds. Can we utilize a more targeted therapy to get better results? This is the next step.

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An Expanding Role For PARP Inhibitors Shows Promise In Treating Ovarian Cancer - Curetoday.com

Gene therapy, or the use of genetic manipulation for disease treatment, is derived from advances in genetics, molecular biology, clinical medicine, and human genomics. Molecular medicine, the application of molecular biological techniques to disease treatment and diagnosis, is derived from the development of human organ transplantation, pharmacotherapy, and elucidation of the human genome. An Introduction to Molecular Medicine and Gene Therapy provides a basis for interpreting new clinical and basic research findings in the areas of cloning, gene transfer, and targeting; the applications of genetic medicine to clinical conditions; ethics and governmental regulations; and the burgeoning fields of genomics, biotechnology, and bioinformatics. By dividing the material into three sections - an introduction to basic science, a review of clinical applications, and a discussion of the evolving issues related to gene therapy and molecular medicine-this comprehensive manual describes the basic approaches to the broad range of actual and potential genetic-based therapies.

In addition, An Introduction to Molecular Medicine and Gene Therapy:

This textbook offers a clear, concise writing style, drawing upon the expertise of the authors, all renowned researchers in their respective specialties of molecular medicine. Researchers in genetics and molecular medicine will all find An Introduction to Molecular Medicine and Gene Therapy to be an essential guide to the rapidly evolving field of gene therapy and its applications in molecular medicine.

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An Introduction to Molecular Medicine and Gene Therapy ...

GERMANTOWN, Md. & HILDEN, Germany--(BUSINESS WIRE)--QIAGEN N.V. (NYSE: QGEN; Frankfurt Prime Standard: QIA) today announced the CE-marking and launch of its therascreen PIK3CA RGQ PCR Kit in Europe as an aid in identifying breast cancer patients with a PIK3CA mutation. Last year the therascreen PIK3CA test was approved by the FDA and launched as a companion diagnostic test for Piqray (alpelisib) in the US.

The therascreen PIK3CA test is a new diagnostic assay for detection of activating mutations in the phosphatidyl 3-kinase catalytic subunit alpha (PIK3CA) gene, and the first to enable testing of both DNA from FFPE tissue or plasma specimens. All QIAGEN therascreen PIK3CA tests leverage QIAGENs worldwide co-exclusive license from Johns Hopkins University for PCR-based companion diagnostics based on detection of mutations in the PIK3CA gene.

1 in 8 women in Europe will develop breast cancer before the age of 85, making it the most common form of cancer in female patients. The therascreen assay detects 11 clinically actionable PIK3CA mutations, which are estimated to be present in approximately 40% of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+ HER2-) advanced breast cancer cases.

This launch in Europe further underscores our commitment to support patients with breast cancer, the most common cancer in female cancer patients, with an estimated incidence of 562,500 in Europe in 2018 according to the WHO said Jonathan Arnold, Vice President, Head of Oncology and Precision Diagnostics. We are convinced that our therascreen PIK3CA Kit, which expands our market-leading therascreen portfolio of companion diagnostics, will provide a valuable testing option for those seeking new ways to combat advanced breast cancer. We are committed to making the therascreen PIK3CA Kit available immediately so that leading laboratories in Europe can provide patients with the test as soon as possible.

Please find the full press release here

Additional information can be found at http://www.qiagen.com/cmp/mdx/pik3ca-rgq-pcr-kit-row/

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QIAGEN Launches FFPE and Liquid Biopsy PIK3CA Diagnostics in Europe to Enhance Precision Medicine in Advanced Breast Cancer - Business Wire

Nisha Kurian,1 Taylor S Cohen,2 Lisa berg,3 Erica De Zan,3 Gabriel Skogberg,4 Stefan Vollmer,3 Engin Baturcam,3 Petter Svanberg,5 Britta Bonn,5 Paul D Smith,6 Outi Vaarala,3 Danen M Cunoosamy3

1Respiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca, Gothenburg, Sweden; 2Microbial Sciences, Medimmune, Gaithersburg, MD, USA; 3Translational Science and Experimental Medicine, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 4Bioscience, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 5Drug Metabolism and Pharmacokinetics, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 6Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK

Correspondence: Nisha KurianRespiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca, Gothenburg, SwedenTel +46 72 197 9662Email Nisha.e.kurian@astrazeneca.com

Background: Unlike p38 mitogen-activated protein Kinases (MAPK) that has been extensively studied in the context of lung-associated pathologies in COPD, the role of the dual-specificity mitogen-activated protein kinase kinase (MEK1/2) or its downstream signaling molecule extracellular signal-regulated kinases 1/2 (ERK1/2) in COPD is poorly understood.Objectives: The aim of this study was to address whether MEK1/2 pathway activation is linked to COPD and that targeting this pathway can improve lung inflammation through decreased immune-mediated inflammatory responses without compromising bacterial clearance.Methods: Association of MEK1/2 pathway activation to COPD was investigated by immunohistochemistry using lung tissue biopsies from COPD and healthy individuals and through analysis of sputum gene expression data from COPD patients. The anti-inflammatory effect of MEK1/2 inhibition was assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages. The effect of MEK1/2 inhibition on bacterial clearance was assessed using Staphylococcus aureus killing assays with RAW 264.7 macrophage cell line and human neutrophils.Results: We report here MEK1/2 pathway activation demonstrated by increased pERK1/2 staining in bronchial epithelium and by the presence of MEK gene activation signature in sputum samples from COPD patients. Inhibition of MEK1/2 resulted in a superior anti-inflammatory effect in human alveolar macrophages in comparison to a p38 inhibitor. Furthermore, MEK1/2 inhibition led to an increase in bacterial killing in human neutrophils and RAW 264.7 cells that was not observed with the p38 inhibitor.Conclusion: Our data demonstrate the activation of MEK1/2 pathway in COPD and highlight a dual function of MEK1/2 inhibition in improving host defense responses whilst also controlling inflammation.

Keywords: exacerbation, infection, alveolar macrophage, p38 MAPK, steroid, transcriptomics, sputum

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host | COPD - Dove Medical Press

June 8, 2017 Hair thinning in a human patient and mouse with inherited loss of function mutations in WNT10A is shown. Credit: Michael Passanante and Mingang Xu, PhD

It is almost axiomatic in medicine that the study of rare disorders informs the understanding of more common, widespread ailments. Researchers from the Perelman School of Medicine at the University of Pennsylvania who study an inherited disorder of skin, hair follicles, nails, sweat glands, and teeth called hypohidrotic ectodermal dysplasia (HED) have identified a mechanism that may also be disrupted in male pattern baldness, a more common condition. They published their findings this week in Nature Communications.

About one in 5,000 to 10,000 people are thought to have HED, although this may be an underestimate of its actual prevalence as this condition is not always diagnosed correctly. HED is most frequently caused by mutations in the EDA, EDAR, EDARRAD and WNT10A genes. In addition to its association with HED, mutations in WNT10A are the most common genetic defect observed in people who are born missing one or more teeth, but do not display other characteristics of the disease. These milder WNT10A mutations occur surprisingly frequently, in about 1 to 2 percent of the population. Interestingly, a variant of the WNT10A gene associated with lower levels of its protein's expression has been linked to a greater likelihood of male pattern baldness, according to a recent genome-wide association study.

"By analyzing mice with the WNT10A mutation, as well as tissues from human patients with WNT10A mutations, we found that WNT10A regulates the proliferation, but not the maintenance, of stem cells in hair follicles," said Sarah Millar, PhD, vice chair for Basic Research in the Department of Dermatology. "Together with a previously published genome-wide association study, our findings suggest that lower levels of WNT10A may contribute to male pattern baldness in some individuals."

The team made mouse models for WNT10A-associated HED by deleting the Wnt10a gene. The mutant mice displayed the same symptoms as HED patients with severe loss of function mutations in the WNT10A gene. Long-term absence of WNT10A leads to miniaturization of hair follicle structures and enlargement of the associated sebaceous glands, a phenomenon that is also observed in male pattern baldness.

Millar's group and her clinical collaborators, including Emily Chu, MD, PhD, an assistant professor of Dermatology and John McGrath, MD, from King's College, London, also discovered that cracking and scaling of palm and foot sole skin in WNT10A patients is due to decreased expression of a structural protein called Keratin 9, which is specifically expressed in these regions of skin and contributes to its mechanical integrity.

"Our studies took us back and forth between human patients and our mouse model," said Millar. "Our goal was to find what happened to cellular components affected by the WNT10A mutation to make better treatments."

Millar's group showed that decreased proliferation and Keratin 9 expression in the absence of WNT10A resulted from failure of signaling through a well-characterized pathway that stabilizes a protein called beta-catenin, allowing it to enter the cell nucleus and activate gene transcription.

These findings indicate that small molecule drugs that activate the beta-catenin pathway downstream of WNT10A could potentially be used to treat hair thinning and palm and sole skin defects in WNT10A patients. These agents may also be useful for preventing hair loss in a subgroup of people with male pattern baldness.

Explore further: Study of 52,000 men uncovers the genetics underlying male pattern baldness

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UT Southwestern Medical Center researchers have identified the cells that directly give rise to hair as well as the mechanism that causes hair to turn gray findings that could one day help identify possible treatments ...

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By the time they turn 50, half of European men have some degree of hair loss. For many, it will begin far earlier than that, and yet male pattern baldness is poorly understood.

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It is almost axiomatic in medicine that the study of rare disorders informs the understanding of more common, widespread ailments. Researchers from the Perelman School of Medicine at the University of Pennsylvania who study ...

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Inherited, rare skin disease informs treatment of common hair disorders, study finds - Medical Xpress

At a ceremony at Yale Center for Clinical Investigation on September 4, Yale School of Medicine and Yale New Haven Health System officially launched Generations, one of the largest DNA sequencing projects of its kind in the United States. The aim is to enroll more than 100,000 patients in and near Connecticut, whose DNA will then be analyzed by Yale scientists to develop useful data for predicting, preventing, and treating what may eventually be hundreds of gene-related conditions.

The process starts with a simple blood sample, with the patients identity hidden from the research teams to ensure personal privacy. As genetic trends related to specific diseases are found, Yale clinicians will put their findings into practice for patients of Yale Medicine and the Yale New Haven Health System. We learn from every patient whom we treat within the health center, said Brian R. Smith, MD, professor and chair of laboratory medicine, deputy dean for scientific affairs, co-director of the Yale Center for Clinical Investigation, and co-principal investigator of the Yale Clinical and Translational Science Award Program. As a consequence of that, we do a better job with the next patient we treat, and on and on.

In fact, patients receiving that improved treatment will include actual study volunteers, because Generations will provide those who give blood samples with the relevant personal genetic information that it finds. Theres a possibility that you will learn something about your own health and disease risks that could benefit you, said Michael F. Murray, MD, professor of genetics and director for clinical operations in Yales Center for Genomic Health. In just a couple of months, we give that information back to you and then guide you to get preventive care. Murray said that in about 3% of participants, risks of cancer or heart disease will turn up that they probably didnt know about. Once they know, they and their doctors can take steps to lower their risk or prevent disease. And that two to three percent will grow over time as we learn more about genetics.

It is a program exclusive to Yale. Nobody else has it. Nobody else will develop it and implement it the way we are, said Richard DAquila, president of Yale New Haven Hospital and Yale New Haven Health System, which is comprised of five hospitals, more than 150 ambulatory facilities, numerous physician practices, and other affiliated centers. It really defines what our hopes and aspirations are for an academically connected health system across the state of Connecticut and beyond.

Generations builds on a heritage of genetics-related firsts at Yale School of Medicine. Robert J. Alpern, MD, dean and Ensign Professor of Medicine noted that Yale actually had the foresight decades and decades ago to form the first department of genetics in the country. Now, with advances both in knowledge and in available technology, he said, we have the ability to tie it all together, and really participate in what is going to be a revolution in health care, and were really looking forward to being a part of it.

Potential participants can contact Generations at helpusdiscover@yale.edu or 1-877-978-8343.

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Yale Launches Comprehensive DNA ... - medicine.yale.edu

A. aegypti mosquitos play a leading role in spreading diseases such as Zika and dengue viruses. (Photo from the Centers for Disease Control)

Next time you slap a mosquito consider this Tulane researchers are testing a strategy to alter the genes of female Aedes aegypti mosquitos so they die soon after a blood meal. A. aegypti mosquitos play a leading role in spreading diseases such as Zika and dengue viruses. The results of this research were published in the June 2017 issue of The FASEB Journal, the journal of the Federation of American Societies for Experimental Biology.

The research team, led by Patricia Y. Scaraffia, assistant professor in the Department of Tropical Medicine and member of the Vector-Borne Infectious Disease Center at the School of Public Health and Tropical Medicine at Tulane University, found that they increased mosquito deaths and decreased egg laying by altering the way female mosquitoes use a crucial protein called xanthine dehydrogenase 1 (XDH1).

XDH1 plays an essential role in blood-fed Aedes aegypti mosquitoes and that silencing of XDH1 gene promotes a blood feeding-induced adulticidal activity, explains Scaraffia. By blocking this gene, the female mosquito cant produce uric acid after a blood meal, which means the mosquitos body cant remove waste. As a result, mosquitos lay fewer eggs and die early.

This novel finding can help researchers to design metabolism-based strategies to control populations of A. aegypti mosquitoes, vectors of diseases of public health significance, says Scaraffia, adding that the teams research has shown that either reducing the amount of XDH1 or blocking it entirely are effective ways to target mosquitos.

Co-authors include Jun Isoe, research scientist at the University of Arizona; Tulane post-doctoral fellow Natthida Petchampai; University of Arizona undergraduate Yurika E. Isoe; Tulane laboratory research scientist Katrina Co; and Stacy Mazzalupo, assistant scientific investigator at The University of Arizona. Financial support came from the Corine Adams Baines Professorship Award and a grant from the U.S. National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant (NIH/NIAID).

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Silencing mosquito gene could slow spread of disease - News from Tulane

In 2012, Madurai-based Avinash Shetty, then 30, was busy making arrangements for his wedding. But festivities were not the only thing on his familys mind. With serious health scares on both sides, his fiance and he were aware they had the odds stacked against them in the genetic department. My mother-in-law had succumbed to leukaemia and my mother was suffering from lung carcinoma and diabetes. Plus, I was (and still am) a smoker, says Shetty. My mother, a nurse, insisted that my future bride and I get genetic testing done, he says. Blood and tissue samples were sent for testing. Fortunately, there was nothing amiss. The couple married and now have two daughters.

The 46 chromosomes or genetic material that we inherit from our parents are responsible for more than just shaping our physical characteristics. They can give us insight into the kind of diseases we could be exposed to. With a single blood test, doctors are now able to analyse our risk to disease at the DNA level and tell in advance the kind of illness you might possibly develop, says Mumbai-based Priyanka Raina, genetic counsellor at Positive Bioscience, a clinical genomics company, and consultant at Saifee Hospital.

The study of a persons DNA to identify various mutations is called genetic testing. Genomic medicine is the broad disciplinebasically medical care attuned to the bodys unique genetic make-up. So, when you get tested for disease based on your genetic coding, it is called genetic testing. The medical care that results is genomic medicine.

Advances in genomic medicine are the results of ground-breaking research. We expect it to transform the very fabric of healthcare, says Samarth Jain, founder and chief executive officer of Positive Bioscience, which offers genetic testing and evaluation of ones risk for disease.

Perhaps the most famous example of genetic diagnosis is Angelina Jolies preventive breast surgeries in 2013. A simple blood test showed the actor carried the BRCA1 gene, which meant she had an 87% risk of contracting breast cancer and a 50% risk of ovarian cancer. She knew she had a strong family risk for both diseases, since her mother and aunts had succumbed to them. Jolie removed her breasts, uterus and fallopian tubes in successive operations.

Shortly afterwards, there were reports of a steady rise in demand for pre-emptive surgeries by women. Doctors still advise caution, however; they say pre-emptive surgery necessitates a thorough assessment of risk factors, age and family history.

While pre-emptive surgery isnt the norm in India yet, there is a growing awareness about genetic diagnosis, especially in the area of cancer prediction and treatment, says Vikas Goswami, senior oncologist at the Fortis Hospital in Noida, near Delhi. But in many cases, even as were able to assess our risk to cancer, we wont always have the medicine to treat it. And that is a very real vulnerability.

To be able to diagnose whether we may be at risk of the disease is only part of the story. We need to be able to answer questions such as what the nature of this disease would be, what drugs would be effective, can we predict whether the cancer would spread or recur. We hope that genetic research can provide answers to these in the days ahead, says Dr Goswami.

In addition to cancer, genomic testing has opened up our world to many other diseases that could possibly be diagnosed or predicted, such as cardiovascular diseases, diabetes, autism spectrum diseases and neurological disorders, says Radhika Vaishnav, a Vadodara-based genetic scientist and executive editor of the International Journal Of Molecular ImmunoOncology. Being able to treat previously untreatable conditions is becoming a reality today, she adds. However, though far more accessible (with costs half of what they were in 2011), genetic testing is still in its infancy in India. This is because genomic medicine relies on Big Data (comparing the genetic data of millions of people) for its accuracy in the prediction of disease. There are concerns that there is not enough Indian population-specific data to compare and accurately predict disease risk.

Prenatal care

Since the 1970s, blood tests have been conducted routinely during pregnancy in India to rule out genetic diseases such as Downs Syndrome. Today, were able to catch rare genetic disorders earlier, says Seema Thakur, senior consultant, genetics and foetal diagnosis, at the Indraprastha Apollo Hospitals in New Delhi. Diseases like thalassemia (an inherited blood disorder requiring frequent blood transfusion), dwarfism and Gauchers (an inherited disorder in which the bodys ability to store fats is compromised, accumulating it in the bodys tissues, cells and organs) are now being identified early.

Great strides have also been made in the treatment of muscular dystrophy (MD), a genetic disorder which causes progressive muscular degeneration and weakness. Of the nine kinds of muscular dystrophy, Duchenne Muscular Dystrophy (DMD) the most common oneis treatable after prenatal genetic testing. DMD can begin as early as the age of 3. By the time a child reaches his/her teens, their muscles progressively waste away and they will find themselves in a wheelchair. By the age of 21, the disease can prove fatal, says Berty Ashley, senior research associate at the Dystrophy Annihilation Research Trust, a non-profit in Bengaluru. DMD occurs because a certain gene in our bodies (incidentally the largest gene we have) called the dystrophin gene is not copied in its entirety when it is passed on to the child in the womb. The gene is made of 79 exons, structures that fit like a jigsaw puzzle. When the gene is transferred to the child, exon 51 is missing or deleted, says Ashley.

In September, the US food and drug administration approved the use of new medication (dystrophy eteplirsen) for this. Taking this drug during pregnancy will introduce the missing genetic strand in the child. It wont cure the disease but it could effectively hamper its progression, says Ashley. A child will still have weak limbs, but s/he will be spared a life in a wheelchair or premature death.

Dr Thakur, however, believes that genetic testing without sustained counselling both before and afterwards could lead to greater stress for patients.

Genetic testing is extremely expensive (ranging from Rs12,000 to Rs1.5 lakh) and not all (diagnostic) labs offer standardized results. If you are faced with an incurable disease, there is little you can do. It could cause great anxiety, she says.

It is disturbing that people are requesting tests on their own because emotionally, they may not be equipped to handle the results. Adequate counselling and follow-up on treatment/medication are important, Dr Thakur explains, adding, There is no doubt that our knowledge of genetic diagnosis will bring with it greater responsibility.

Where to go

Places that provide prenatal diagnostic services and genetic diagnosis

The Indian Council of Medical Research in Mumbai provides prenatal diagnostic services (www.icmr.nic.in)

The genetics unit, department of paediatrics, All India Institute of Medical Sciences, New Delhi (a World Health Organization collaborating centre) offers genetic diagnosis, prenatal diagnosis and counselling (www.aiims.edu)

Genetic blood tests and counselling are offered at hospitals across the country such as Apollo (Madurai, Chennai), Saifee (Mumbai), Kokilaben Dhirubhai Ambani Hospital, Breach Candy (Mumbai) and MedantaThe Medicity (Gurugram).

First Published: Mon, Feb 27 2017. 05 44 PM IST

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Taking the gene test - Livemint