Time filter

Source Type

"Over one-third of Ferring's research and development investment goes towards finding breakthrough treatments that help mothers and babies, from conception to birth, with the goal of contributing to safe pregnancies and deliveries," says Per Falk, Chief Scientific Officer and Executive Vice President, Ferring Pharmaceuticals. "This collaboration reinforces our commitment to improving maternal care through scientific innovation and complements our active research programmes in preeclampsia and preterm birth as well as our recent investments in microbiome research to better understand these conditions." "The high rate of preterm birth in the U.S. and around the world is an avoidable human tragedy," says Stacey D. Stewart, President of the March of Dimes. "We must do more to save families from the trauma caused by prematurity and the pain of losing a baby born too soon. March of Dimes staff and volunteers are grateful to Ferring Pharmaceuticals for supporting cutting-edge research to help us fulfill our goal to give every baby a chance to be born healthy." The March of Dimes Prematurity Research Centers3 encompass approximately 200 scientists in numerous fields, including obstetrics, neonatology, genetics and genomics, immunology, engineering, informatics, and social sciences. These Centers work together at multiple levels, sharing findings and data to expedite findings on the underlying causes of preterm birth. David K. Stevenson, M.D., Senior Associate Dean for Maternal and Child Health and Co-Director of the Child Health Research Institute at Stanford University School of Medicine, is the principal Investigator of the first March of Dimes Prematurity Research Center. "My colleagues and I in the current Prematurity Research Centers are very excited by the opportunities this new funding provides and the collaboration with top researchers in Europe," he says. "European countries have some of the lowest rates of preterm birth in the world, and we would love to share in the wealth of data and experience of our colleagues there." "We don't just want to solve the knowledge gap on prematurity," says Joe Leigh Simpson, MD, Senior Vice President for Research and Global Programs at the March of Dimes. "We want to find new clinical and policy-based solutions for families and societies around the world to prevent preterm birth." Preterm birth (before 37 weeks of pregnancy) and its consequences are the leading cause of death among babies in the U.S. and worldwide among children under age five (see infographic here). Babies who survive an early birth often face serious and lifelong health problems, including chronic lung disease, vision and hearing impairment, cerebral palsy, and neurodevelopmental disabilities.2 Headquartered in Saint-Prex, Switzerland, Ferring Pharmaceuticals is a research-driven, specialty biopharmaceutical group active in global markets. A leader in reproductive and maternal health, Ferring has been developing treatments for mothers and babies for over 50 years. Today, over one third of the company's research and development investment goes towards finding innovative treatments to help mothers and babies, from conception to birth. The company also identifies, develops and markets innovative products in the areas of urology, gastroenterology, endocrinology and orthopedics. Ferring has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries. For further information on Ferring or its products, visit www.ferring.com.   For more information on preterm birth and Ferring's work in this area, view our infographic Preterm birth: A global issue. The March of Dimes is the leading nonprofit organization for pregnancy and baby health. For more than 75 years, moms and babies have benefited from March of Dimes research, education, vaccines, and breakthroughs. For the latest resources and health information, visit our websites marchofdimes.org and nacersano.org. If you have been affected by prematurity or birth defects, visit our shareyourstory.org community to find comfort and support. For detailed national, state and local perinatal statistics, visit peristats.org. You can also find us on Facebook or follow us on Instagram and Twitter. 1,2 Born Too Soon: The Global Action Report on Preterm Birth. (WHO, March of Dimes) 2012.  3 Current March of Dimes Prematurity Research Centers are located at (with date of launch): To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/ferring-commits-10-million-to-march-of-dimes-to-expand-research-needed-to-end-preterm-birth-300460419.html


Saint-Prex, Switzerland and White Plains, N.Y., USA, May 23, 2017 - Ferring Pharmaceuticals and the March of Dimes Foundation announced today that Ferring has committed $10 million to support the network of March of Dimes Prematurity Research Centers that are discovering the biological causes of preterm birth. Included in Ferring's contribution is funding for a new European-based Prematurity Center, which will become a partner of the existing five U.S.-based centers. Both Ferring and March of Dimes are committed to advancing research to help prevent the 15 million annual preterm births recorded globally, including about 380,000 in the United States. Preterm birth is the leading cause of death in babies in the U.S. and of children under age 5 around the world, and is responsible for 1.1 million infant deaths each year. "Over one-third of Ferring's research and development investment goes towards finding breakthrough treatments that help mothers and babies, from conception to birth, with the goal of contributing to safe pregnancies and deliveries," says Per Falk, chief scientific officer and executive vice president, Ferring Pharmaceuticals. "This collaboration reinforces our commitment to improving maternal care through scientific innovation and complements our active research programmes in preeclampsia and preterm birth as well as our recent investments in microbiome research to better understand these conditions." "The high rate of preterm birth in the U.S. and around the world is an avoidable human tragedy," says Stacey D. Stewart, president of the March of Dimes. "We must do more to save families from the trauma caused by prematurity and the pain of losing a baby born too soon. March of Dimes staff and volunteers are grateful to Ferring Pharmaceuticals for supporting cutting-edge research to help us fulfill our goal to give every baby a chance to be born healthy." The March of Dimes Prematurity Research Centers encompass approximately 200 scientists in numerous fields, including obstetrics, neonatology, genetics and genomics, immunology, engineering, informatics, and social sciences. These Centers work together at multiple levels, sharing findings and data to expedite findings on the underlying causes of preterm birth. David K. Stevenson, M.D.,senior associate dean for Maternal and Child Health and co-director of the Child Health Research Institute at Stanford University School of Medicine, is the principal Investigator of the first March of Dimes Prematurity Research Center. "My colleagues and I in the current Prematurity Research Centers are very excited by the opportunities this new funding provides and the collaboration with top researchers in Europe," he says. "European countries have some of the lowest rates of preterm birth in the world, and we would love to share in the wealth of data and experience of our colleagues there." "We don't just want to solve the knowledge gap on prematurity," says Joe Leigh Simpson, MD, Senior Vice President for Research and Global Programs at the March of Dimes. "We want to find new clinical and policy-based solutions for families and societies around the world to prevent preterm birth." Preterm birth (before 37 weeks of pregnancy) and its consequences are the leading cause of death among babies in the U.S. and worldwide among children under age five. Babies who survive an early birth often face serious and lifelong health problems, including chronic lung disease, vision and hearing impairment, cerebral palsy, and neurodevelopmental disabilities. Headquartered in Saint-Prex, Switzerland, Ferring Pharmaceuticals is a research-driven, specialty biopharmaceutical group active in global markets. A leader in reproductive and maternal health, Ferring has been developing treatments for mothers and babies for over 50 years. Today, over one third of the company's research and development investment goes towards finding innovative treatments to help mothers and babies, from conception to birth. The company also identifies, develops and markets innovative products in the areas of urology, gastroenterology, endocrinology and orthopedics. Ferring has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries. For further information on Ferring or its products, visit www.ferring.com. For more information on preterm birth and Ferring's work in this area, view our infographic Preterm birth: A global issue. The March of Dimes is the leading nonprofit organization for pregnancy and baby health. For more than 75 years, moms and babies have benefited from March of Dimes research, education, vaccines, and breakthroughs. For the latest resources and health information, visit our websites marchofdimes.org and nacersano.org. If you have been affected by prematurity or birth defects, visit our shareyourstory.org community to find comfort and support. For detailed national, state and local perinatal statistics, visit peristats.org. You can also find us on Facebook or follow us on Instagram and Twitter. Current March of Dimes Prematurity Research Centers are located at (with date of launch):


Millions of people wear some kind of wristband activity tracker and use the device to monitor their own exercise and health, often sharing the data with their physician. But is the data accurate? Such people can take heart in knowing that if the device measures heart rate, it's probably doing a good job, a team of researchers at the Stanford University School of Medicine reports. But if it measures energy expenditure, it's probably off by a significant amount. An evaluation of seven devices in a diverse group of 60 volunteers showed that six of the devices measured heart rate with an error rate of less than 5 percent. The team evaluated the Apple Watch, Basis Peak, Fitbit Surge, Microsoft Band, Mio Alpha 2, PulseOn and the Samsung Gear S2. Some devices were more accurate than others, and factors such as skin color and body mass index affected the measurements. In contrast, none of the seven devices measured energy expenditure accurately, the study found. Even the most accurate device was off by an average of 27 percent. And the least accurate was off by 93 percent. "People are basing life decisions on the data provided by these devices," said Euan Ashley, DPhil, FRCP, professor of cardiovascular medicine, of genetics and of biomedical data science at Stanford. But consumer devices aren't held to the same standards as medical-grade devices, and it's hard for doctors to know what to make of heart-rate data and other data from a patient's wearable device, he said. A paper reporting the researchers' findings will be published online May 24 in the Journal of Personalized Medicine. Ashley is the senior author. Lead authorship is shared by graduate student Anna Shcherbina, visiting assistant professor Mikael Mattsson, PhD, and senior research scientist Daryl Waggott. Hard for consumers to know device accuracy Manufacturers may test the accuracy of activity devices extensively, said Ashley, but it's hard for consumers to know how accurate such information is or the process that the manufacturers used in testing the devices. So Ashley and his colleagues set out to independently evaluate activity trackers that met criteria such as measuring both heart rate and energy expenditure and being commercially available. "For a lay user, in a non-medical setting, we want to keep that error under 10 percent," Shcherbina said. Sixty volunteers, including 31 women and 29 men, wore the seven devices while walking or running on treadmills or using stationary bicycles. Each volunteer's heart was measured with a medical-grade electrocardiograph. Metabolic rate was estimated with an instrument for measuring the oxygen and carbon dioxide in breath -- a good proxy for metabolism and energy expenditure. Results from the wearable devices were then compared to the measurements from the two "gold standard" instruments. "The heart rate measurements performed far better than we expected," said Ashley, "but the energy expenditure measures were way off the mark. The magnitude of just how bad they were surprised me." The take-home message, he said, is that a user can pretty much rely on a fitness tracker's heart rate measurements. But basing the number of doughnuts you eat on how many calories your device says you burned is a really bad idea, he said. Neither Ashley nor Shcherbina could be sure why energy-expenditure measures were so far off. Each device uses its own proprietary algorithm for calculating energy expenditure, they said. It's likely the algorithms are making assumptions that don't fit individuals very well, said Shcherbina. "All we can do is see how the devices perform against the gold-standard clinical measures," she said. "My take on this is that it's very hard to train an algorithm that would be accurate across a wide variety of people because energy expenditure is variable based on someone's fitness level, height and weight, etc." Heart rate, she said, is measured directly, whereas energy expenditure must be measured indirectly through proxy calculations. Ashley's team saw a need to make their evaluations of wearable devices open to the research community, so they created a website that shows their own data. They welcome others to upload data related to device performance at http://precision. . The team is already working on the next iteration of their study, in which they are evaluating the devices while volunteers wear them as they go about a normal day, including exercising in the open, instead of walking or running on a laboratory treadmill. "In phase two," said Shcherbina, "we actually want a fully portable study. So volunteers' ECG will be portable and their energy calculation will also be done with a portable machine." The work is an example of Stanford Medicine's focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill. Other Stanford co-authors are clinical nurse specialist Heidi Salisbury, RN, MSN; clinical exercise physiologist Jeffrey Christle, PhD; Trevor Hastie, PhD, professor of statistics and of biomedical data science; and Matthew Wheeler, MD, PhD, clinical assistant professor of cardiovascular medicine. Ashley is also a member of the Stanford Cardiovascular Institute, the Stanford Child Health Research Institute and Stanford Bio-X. Hastie is a member of CHRI, Bio-X, the Stanford Cancer Institute and the Stanford Neurosciences Institute. Stanford's departments of Medicine, of Genetics and of Biomedical Data Science supported the work. The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med. . The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med. .


News Article | February 17, 2017
Site: www.futurity.org

Chemists and gene therapy experts have a new way to insert the code for modified proteins into the cells of mice. They’ve used firefly proteins to make a glow-in-the-dark mouse and, if the technique also works in humans, it could be useful for vaccines or cancer therapies. Not only did the mouse glow, recalls Timothy Blake, a postdoctoral fellow in the Waymouth lab at Stanford University, but it also later woke up and ran around, completely unaware of the complex series of events that had just taken place within its body. Blake says it was the most exciting day of his life. This success, the topic of a recent paper in Proceedings of the National Academy of Sciences, could mark a significant step forward for gene therapy. It’s hard enough getting these protein instructions, called messenger RNA (mRNA), physically into a cell. It’s another hurdle altogether for the cell to actually use them to make a protein. If the technique works in people, it could provide a new way of inserting therapeutic proteins into diseased cells. “It’s almost a childlike enthusiasm we have for this,” says chemistry professor Robert Waymouth. “The code for an insect protein is put into an animal and that protein is not only synthesized in the cells but it’s folded and it becomes fully functional, capable of emitting light.” Although the results are impressive, this technique is remarkably simple and fast. And unlike traditional gene therapy that permanently alters the genetic makeup of the cell, mRNA is short-lived and its effects are temporary. The transient nature of mRNA transmission opens up special opportunities, such as using these compounds for vaccination or cancer immunotherapy. Gene therapy is a decades-old field of research that usually focuses on modifying DNA, the fundamental genetic code. That modified DNA then produces a modified mRNA, which directs the creation of a modified protein. The current work skips the DNA and instead just delivers the protein’s instructions. Previous work has been successful at delivering a different form of RNA—called short interfering RNA, or siRNA—but sending mRNA through a cell membrane is a much bigger problem. While both siRNA and mRNA have many negative charges—so-called polyanions—mRNA is considerably more negatively charged, and therefore more difficult to sneak through the positively charged cell membrane. What the researchers needed was a positively charged delivery method—a polycation—to complex, protect, and shuttle the polyanions. However, this alone would only assure that the mRNA made it through the cell membrane. Once inside, the mRNA needed to detach from the transporter compound in order to make proteins. The researchers addressed this twofold challenge with a novel, deceptively straightforward creation, which they call charge-altering releasable transporters (CARTs). “What distinguishes this polycation approach from the others, which often fail, is the others don’t change from polycations to anything else,” says chemistry professor Paul Wender, coauthor of the paper. “Whereas, the ones that we’re working with will change from polycations to neutral small molecules. That mechanism is really unprecedented.” As part of their change from polycations to polyneutrals, CARTs biodegrade and are eventually excreted from the body. The researchers say CARTs could move the field of gene therapy forward dramatically in several directions. “Gene therapy has been held up as a silver bullet because the idea that you could pick any gene you want is so alluring,” says Jessica Vargas, co-lead author of the study, who was a PhD student in the Wender lab during this research. “With mRNA, there are more limitations because the protein expression is transient, but that opens up other applications where you wouldn’t use other types of gene therapy.” One especially appropriate application of this technology is vaccination. At present, vaccines require introducing part of a virus or an inactive virus into the body in order to elicit an immune response. CARTs could potentially cut out the middleman, directly instructing the body to produce its own antigens. Once the CART dissolves, the immunity remains without any leftover foreign material present. The team is also working on applying their technique to another genetic messenger that would produce permanent effects, making it a complementary option to the temporary mRNA therapies. With the progress already made using mRNA and the potential of their ongoing research, they and others could be closer than ever to making individualized therapeutics using a person’s own cells. “Creating a firefly protein in a mouse is amazing but, more than that, this research is part of a new era in medicine,” says Wender. Funding came from the Department of Energy, the National Science Foundation, the National Institutes of Health, the Chambers Family Foundation for Excellence in Pediatric Research, the Child Health Research Institute, the Stanford Center for Molecular Analysis and Design, and the National Center for Research Resources.


News Article | February 16, 2017
Site: www.eurekalert.org

Timothy Blake, a postdoctoral fellow in the Waymouth lab, was hard at work on a fantastical interdisciplinary experiment. He and his fellow researchers were refining compounds that would carry instructions for assembling the protein that makes fireflies light up and deliver them into the cells of an anesthetized mouse. If their technique worked, the mouse would glow in the dark. Not only did the mouse glow, but it also later woke up and ran around, completely unaware of the complex series of events that had just taken place within its body. Blake said it was the most exciting day of his life. This success, the topic of a recent paper in Proceedings of the National Academy of Sciences, could mark a significant step forward for gene therapy. It's hard enough getting these protein instructions, called messenger RNA (mRNA), physically into a cell. It's another hurdle altogether for the cell to actually use them to make a protein. If the technique works in people, it could provide a new way of inserting therapeutic proteins into diseased cells. "It's almost a childlike enthusiasm we have for this," said chemistry Professor Robert Waymouth. "The code for an insect protein is put into an animal and that protein is not only synthesized in the cells but it's folded and it becomes fully functional, capable of emitting light." Although the results are impressive, this technique is remarkably simple and fast. And unlike traditional gene therapy that permanently alters the genetic makeup of the cell, mRNA is short-lived and its effects are temporary. The transient nature of mRNA transmission opens up special opportunities, such as using these compounds for vaccination or cancer immunotherapy. Gene therapy is a decades-old field of research that usually focuses on modifying DNA, the fundamental genetic code. That modified DNA then produces a modified mRNA, which directs the creation of a modified protein. The current work skips the DNA and instead just delivers the protein's instructions. Previous work has been successful at delivering a different form of RNA - called short interfering RNA, or siRNA - but sending mRNA through a cell membrane is a much bigger problem. While both siRNA and mRNA have many negative charges - so-called polyanions - mRNA is considerably more negatively charged, and therefore more difficult to sneak through the positively charged cell membrane. What the researchers needed was a positively charged delivery method - a polycation - to complex, protect and shuttle the polyanions. However, this alone would only assure that the mRNA made it through the cell membrane. Once inside, the mRNA needed to detach from the transporter compound in order to make proteins. The researchers addressed this twofold challenge with a novel, deceptively straightforward creation, which they call charge-altering releasable transporters (CARTs). "What distinguishes this polycation approach from the others, which often fail, is the others don't change from polycations to anything else," said chemistry Professor Paul Wender, co-author of the paper. "Whereas, the ones that we're working with will change from polycations to neutral small molecules. That mechanism is really unprecedented." As part of their change from polycations to polyneutrals, CARTs biodegrade and are eventually excreted from the body. This research was made possible through coordination between the chemists and experts in imaging molecules in live animals, who rarely work together directly. With this partnership, the synthesis, characterization and testing of compounds could take as little as a week. "We are so fortunate to engage in this kind of collaborative project between chemistry and our clinical colleagues. It allowed us to see our compounds go from very basic building blocks - all the way from chemicals we buy in a bottle - to putting a firefly gene into a mouse," said Colin McKinlay, a graduate student in the Wender lab and co-lead author of the study. Not only did this enhanced ability to test and re-test new molecules lead to the discovery of their charge-altering behavior, it allowed for quick optimization of their properties and applications. As different challenges arise in the future, the researchers believe they will be able to respond with the same rapid flexibility. After showing that the CARTs could deliver a glowing jellyfish protein to cells in a lab dish, the group wanted to find out if they worked in living mice, which was made possible through the expertise of the Contag lab, run by Christopher Contag, professor of pediatrics and of microbiology and immunology. Together, the multidisciplinary team showed that the CARTs could effectively deliver mRNA that produced glowing proteins in the thigh muscle or in the spleen and liver, depending on where the injection was made. The researchers said CARTs could move the field of gene therapy forward dramatically in several directions. "Gene therapy has been held up as a silver bullet because the idea that you could pick any gene you want is so alluring," said Jessica Vargas, co-lead author of the study, who was a PhD student in the Wender lab during this research. "With mRNA, there are more limitations because the protein expression is transient, but that opens up other applications where you wouldn't use other types of gene therapy." One especially appropriate application of this technology is vaccination. At present, vaccines require introducing part of a virus or an inactive virus into the body in order to elicit an immune response. CARTs could potentially cut out the middleman, directly instructing the body to produce its own antigens. Once the CART dissolves, the immunity remains without any leftover foreign material present. The team is also working on applying their technique to another genetic messenger that would produce permanent effects, making it a complementary option to the temporary mRNA therapies. With the progress already made using mRNA and the potential of their ongoing research, they and others could be closer than ever to making individualized therapeutics using a person's own cells. "Creating a firefly protein in a mouse is amazing but, more than that, this research is part of a new era in medicine," said Wender. Additional co-authors of this study, "Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals," include Timothy Blake, Jonathan Hardy, Masamitsu Kanada and Christopher Contag. Waymouth is also a professor, by courtesy, of chemical engineering, a member of Stanford Bio-X, a faculty fellow of Stanford ChEM-H and an affiliate of the Stanford Woods Institute for the Environment. Wender is also a professor, by courtesy, of chemical and systems biology, a member of Stanford Bio-X, a member of the Stanford Cancer Institute and a faculty fellow of Stanford ChEM-H. Contag is also a professor, by courtesy, of radiology and of bioengineering, a member of Stanford Bio-X, a member of the Child Health Research Institute and a member of the Stanford Cancer Institute. This work was funded by the Department of Energy, the National Science Foundation, the National Institutes of Health, the Chambers Family Foundation for Excellence in Pediatric Research, the Child Health Research Institute, the Stanford Center for Molecular Analysis and Design and the National Center for Research Resources.


News Article | February 15, 2017
Site: www.eurekalert.org

Researchers at the Stanford University School of Medicine used heart muscle cells made from stem cells to rank commonly used chemotherapy drugs based on their likelihood of causing lasting heart damage in patients. Drugs known as tyrosine kinase inhibitors can be an effective treatment for many types of cancers, but they also have severe and sometimes fatal side effects. Using lab-grown heart cells, Stanford researchers were able to assess the drugs' various effects on heart muscle cells, including whether the cells survived, were able to beat rhythmically and effectively, responded appropriately to electrophysiological signals and communicated with one another. The researchers found that their assay can accurately identify those tyrosine kinase inhibitors already known to be the most dangerous in patients. In the future, they believe their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity. "This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients," said Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute and a professor of cardiovascular medicine and of radiology. "It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects." A paper describing the research will be published Feb. 15 in Science Translational Medicine. Wu, who holds the Simon H. Stertzer Professorship, is the senior author. Former graduate student Arun Sharma, PhD, is the lead author. "We used multiple measurements to accurately predict which of the tyrosine kinase inhibitors were the most cardiotoxic," said Sharma. "The drugs with the lowest safety indices in our study were also those identified by the Food and Drug Administration as the most cardiotoxic to patients. Other drugs that are not as cardiotoxic performed much better in our assays." Validating the researchers' cardiac-safety test on drugs with extensive clinical track records is necessary before the assay can be used to predict with confidence the likely clinical outcomes of drugs still under development. Sharma, Wu and their colleagues created heart muscle cells called cardiomyocytes from induced pluripotent stem cells, or iPS cells, from 11 healthy people and two people with kidney cancer. They grew the lab-made cardiomyocytes in a dish and tested the effects of 21 commonly used tyrosine kinase inhibitors on the cells. They found that treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction. The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that those drugs known to be particularly dangerous to heart function, such as nilotinib, which is approved for the treatment of chronic myelogenous leukemia, and vandetanib, which is approved for the treatment of some types of thyroid cancer, also had the lowest safety indices based on the assay; conversely, those known to be better tolerated by patients ranked higher on their safety index. Prescribing information for both nilotinib and vandetanib contains warnings from the FDA about the drugs' potential cardiotoxicity. An activity increase in an insulin responsive pathway Six of the 21 tyrosine kinase inhibitors tested were assigned cardiac safety indices at or below 0.1 -- the threshold limit at which the researchers designated a drug highly cardiotoxic. Three of these six are known to inhibit the same two signaling pathways: VEGFR2 and PDGFR. The researchers noticed that cells treated with these three drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulinlike growth factor. This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further. They found that exposing the cells to insulin or IGF1 made it less likely they would die due to tyrosine kinase inhibitors blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these chemotherapies. The current study mirrors another by Wu's lab that was published in April 2016 in Nature Medicine. That research focused on the toxic effect of a chemotherapy drug called doxorubicin on iPS cell-derived cardiomyocytes. Doxorubicin, which indiscriminately kills any replicating cells, is increasingly being replaced by more targeted, cancer-specific therapies such as the tyrosine kinase inhibitors tested in the current study. "The switch from doxorubicin is a result of the paradigm shift in cancer treatment to personalized, precise treatment as emphasized by President Obama's 2015 Precision Medicine Initiative," said Wu. "Moving even further, we're discovering that many tyrosine kinase inhibitors are themselves significantly cardiotoxic, and some have been withdrawn from the market. There is a critical need for a way to 'safety test' all drugs earlier in development before they are administered to patients. Our drug safety index is a step in that direction." Other Stanford co-authors are Paul Burridge, PhD, a former instructor at the Cardiovascular Institute; graduate student Wesley McKeithan; postdoctoral scholars Praveen Shukla, PhD, Tomoya Kitani, MD, Haodi Wu, PhD, and Alexandra Holmström, PhD; instructors Nazish Sayed, MD, PhD, Elena Matsa, PhD, and Jared Churko, PhD; medical student Anusha Kumar; undergraduate student Yuan Zhang; assistant professor of medicine Alice Fan, MD; associate professor of medicine Sean Wu, MD, PhD; and professor of medicine Mark Mercola, PhD. The research was funded by the American Heart Association, the National Science Foundation, the National Institutes of Health (a Director's Pioneer Award and grants R01HL113006, R01HL130020, R01HL128170, R01HL123968 and R24HL117756), the Lucile Packard Foundation for Children's Health, the Stanford Child Health Research Institute and the Burroughs Wellcome Foundation. Wu is a member of the Stanford Cancer Institute, Bio-X and the Child Health Research Institute. Mercola is on the scientific advisory board for Vala Sciences, a company offering high-content screening services, and Wu is on the scientific advisory board of Stem Cell Theranostics, a company using patient-specific iPS cells for drug discovery. The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med. . The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med. .


News Article | February 23, 2017
Site: www.futurity.org

Cells within our bodies divide and change over time, with thousands of chemical reactions occurring within each cell daily. This makes it difficult for scientists to understand what’s happening inside. New nanostraws offer a non-disruptive way to find out. A problem with the current method of cell sampling, called lysing, is that it ruptures the cell. Once the cell is destroyed, it can’t be sampled from again. This new sampling system relies on tiny tubes 600 times smaller than a strand of hair that allow researchers to sample a single cell at a time. The nanostraws penetrate a cell’s outer membrane, without damaging it, and draw out proteins and genetic material from the cell’s salty interior. “It’s like a blood draw for the cell,” says Nicholas Melosh, an associate professor of materials science and engineering at Stanford University and senior author of a paper describing the work in the Proceedings of the National Academy of Sciences. The nanostraw sampling technique, according to Melosh, will significantly impact our understanding of cell development and could lead to much safer and effective medical therapies because the technique allows for long term, non-destructive monitoring. “What we hope to do, using this technology, is to watch as these cells change over time and be able to infer how different environmental conditions and ‘chemical cocktails’ influence their development—to help optimize the therapy process,” Melosh says. If researchers can fully understand how a cell works, then they can develop treatments that will address those processes directly. For example, in the case of stem cells, researchers are uncovering ways of growing entire, patient-specific organs. The trick is, scientists don’t really know how stem cells develop. “For stem cells, we know that they can turn into many other cell types, but we do not know the evolution—how do they go from stem cells to, say, cardiac cells? There is always a mystery. This sampling technique will give us a clearer idea of how it’s done,” says Yuhong Cao, a graduate student and first author on the paper. The sampling technique could also inform cancer treatments and answer questions about why some cancer cells are resistant to chemotherapy while others are not. “With chemotherapy, there are always cells that are resistant,” says Cao. “If we can follow the intercellular mechanism of the surviving cells, we can know, genetically, its response to the drug.” The sampling platform on which the nanostraws are grown is tiny—about the size of a gumball. It’s called the Nanostraw Extraction (NEX) sampling system, and it was designed to mimic biology itself. In our bodies, cells are connected by a system of “gates” through which they send each other nutrients and molecules, like rooms in a house connected by doorways. These intercellular gates, called gap junctions, are what inspired Melosh six years ago, when he was trying to determine a non-destructive way of delivering substances, like DNA or medicines, inside cells. The new NEX sampling system is the reverse, observing what’s happening within rather than delivering something new. “It’s a super exciting time for nanotechnology,” Melosh says. “We’re really getting to a scale where what we can make controllably is the same size as biological systems.” Building the NEX sampling system took years to perfect. Not only did Melosh and his team need to ensure cell sampling with this method was possible, they needed to see that the samples were actually a reliable measure of the cell content, and that samples, when taken over time, remained consistent. When the team compared their cell samples from the NEX with cell samples taken by breaking the cells open, they found that 90 percent of the samples were congruous. Melosh’s team also found that when they sampled from a group of cells day after day, certain molecules that should be present at constant levels remained the same, indicating that their sampling accurately reflected the cell’s interior. With help from collaborators Sergiu P. Pasca, assistant professor of psychiatry and behavioral sciences, and Joseph Wu, professor of radiology, Melosh and coworkers tested the NEX sampling method not only with generic cell lines, but also with human heart tissue and brain cells grown from stem cells. In each case, the nanostraw sampling reflected the same cellular contents as lysing the cells. The goal of developing this technology, according to Melosh, was to make an impact in medical biology by providing a platform that any lab could build. Only a few labs across the globe, so far, are employing nanostraws in cellular research, but Melosh expects that number to grow dramatically. “We want as many people to use this technology as possible,” he says. Funding for the work came from the National Institute of Standards and Technology, the Knut and Alice Wallenberg Foundation, the National Institutes of Health, Stanford Bio-X, the Progenitor Cell Biology Consortium, the National Institute of Mental Health, an MQ Fellow award, the Donald E. and Delia B. Baxter Foundation, and the Child Health Research Institute.


News Article | February 27, 2017
Site: www.eurekalert.org

A combination of two cancer drugs inhibited both dengue and Ebola virus infections in mice in a study led by Stanford University School of Medicine researchers, despite the fact that these two viruses are vastly different from each other. In laboratory-dish experiments, the drug combination, which has previously shown efficacy against the hepatitis C virus, also was effective against West Nile and Zika viruses, both of which are relatives of the hepatitis C virus, and multiple other unrelated viruses. The multi-institution study, to be published online Feb. 27 in the Journal of Clinical Investigation, also pinpointed the specific molecular mechanism by which these drugs derail a variety of RNA viruses, whose genetic material consists not of DNA but of its close relative, RNA. "We've shown that a single combination of drugs can be effective across a broad range of viruses -- even when those viruses hail from widely separated branches of the evolutionary tree," said the study's senior author, Shirit Einav, MD, assistant professor of infectious diseases and of microbiology and immunology. The study's lead authors are former Stanford postdoctoral scholars Elena Bekerman, PhD, now at Gilead Sciences Inc., and Gregory Neveu, PhD, now at the University of Lyon and French National Institute of Health and Medical Research. The reason the drugs used in the study are able to combat infections by such different viruses is that their disabling action is directed not at the virus but at proteins of the host cell it's trying to infect, Einav said. Einav and her team are investigating strategies for combatting RNA viruses, such as dengue and Ebola. These viruses have a faulty replication process that results in frequent errors as their genetic material is copied, rendering them especially prone to mutations. Consequently, they swiftly acquire resistance to a typical antiviral drug that targets a specific viral enzyme, Einav said. "The 'one drug, one bug' approach can be quite successful, as in the case of hepatitis C virus," for which a concerted effort has generated several approved antiviral treatments, she said. But it took more than 10 years of research, she noted, and drug development costs typically exceed $2 billion. Making matters worse, Einav added, is the impossibility of predicting what the next emerging viral threat will look like. "We're always getting blindsided," she said. The deadly Ebola epidemic of a few years ago has subsided but could return at any time. Dengue infects an estimated 390 million people annually in over 100 countries. Four distinct strains of the dengue virus exist, hampering the development of a vaccine and boosting the chances of a once-infected person's re-infection by a different strain against which that person hasn't achieved sufficient immunity. Secondary infections can become life-threatening. While an Ebola vaccine has shown promise, it's not yet approved. A recently approved dengue vaccine has only limited efficacy. No viable antiviral drugs are currently available for either virus. Viruses are cut-rate brigands: They produce nothing on their own, but rather hijack the machinery of our cells. Hepatitis C, dengue, Ebola and other viruses hop onto molecular "buses" that whisk cargo between cell compartments. These buses shuttle the viruses around inside of cells. The buses' routes and fares are regulated by numerous cellular enzymes. Two such enzymes, which go by the acronyms AAK1 and GAK, essentially lower the fares charged by the molecular buses by tweaking them so they bind more strongly to their cargo. The standard antiviral approach aims to disable a specific viral enzyme. Einav and her associates' alternative approach took advantage of viruses' total dependence on infected cells' molecular machinery. The two-drug drug combination Einav's team put to work against dengue and Ebola impedes AAK1's and GAK's activity, effectively pricing bus fares beyond the viral budget. Erlotinib and sunitinib, each approved by the Food and Drug Administration more than a decade ago, are prescribed for various cancer indications. Neither AAK1 nor GAK are the primary targets of these drugs in their cancer-fighting roles. But Einav's group discovered, by accessing publicly available databases, that the two drugs impair AAK1 and GAK activity, too. Einav and her colleagues previously demonstrated that erlotinib and sunitinib inhibit hepatitis C virus infection in cells. In the new study, the investigators conducted experiments in lab dishes to show that both drugs inhibit viral infection by impeding the activity of AAK1 and GAK. Next, they tested the combination in lab dishes against the dengue and Ebola viruses, and observed that viral activity was strongly inhibited in both. While the dengue virus is a relatively close cousin of hepatitis C, it is quite different from the Ebola virus. The same drug combination also showed efficacy against a variety of other RNA viruses related to hepatitis C, including the Zika and West Nile viruses, and even against several unrelated viruses. In a prevention experiment in mice, the investigators administered the erlotinib-sunitinib combination once daily starting on the day of dengue-virus infection, employing the two drugs for five days at doses comparable to those approved for use against cancer in humans. All the control mice died between days four and eight. But of those treated with the drug combination, 65 to 100 percent, depending on the individual experiment, survived and regained their pre-infection weight and mobility. Given individually, the drugs provided substantially less protection, Einav said. In another experiment designed to test the drugs as a therapy, the combination retained substantial antiviral efficacy as long as it was given less than 48 hours after infection. In a similar prevention experiment with the Ebola virus, the scientists administered the drug daily for 10 days starting at six hours before infection. Some 90 percent of the control mice died within a week or two. But half the mice receiving the drug combination survived. Again, the drugs were substantially less effective when given individually. Additional lab experiments showed that the combination profoundly inhibited the dengue virus's ability to develop drug resistance. There's no possible way for viral mutations to alter the proteins of the cells it infects, Einav said, and no easy way for the virus to mutate around its dependence on those proteins. Stanford's Office of Technology Licensing has filed for patents on intellectual property associated with the findings. Other Stanford study co-authors are Claude Nagamine, DVM, PhD, assistant professor of comparative medicine; and research scientist Robert Mateo, PhD. The study was carried out in collaboration with researchers from the University of Chicago, the U.S. Army Medical Research Institute of Infectious Diseases in Maryland, the Washington University School of Medicine in St. Louis and the University of Leuven in Belgium. The study was funded by the National Institute of Health (grants IU19AI10966201 and U19A1083019); the American Cancer Society; the Doris Duke Charitable Foundation; the Department of Defense; Stanford Bio-X; the Stanford Spark program; the Stanford Translational Research and Applied Medicine program; Spectrum, which administers Stanford's Clinical and Translational Science Award (grant UL1TR001085) from the NIH; the Stanford Child Health Research Institute; and the Taiwan Ministry of Science and Technology. Stanford's departments of Medicine and of Microbiology and Immunology also supported the work. The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med. . The medical school is part of Stanford Medicine, which includes Stanford Health Care and Lucile Packard Children's Hospital Stanford. For information about all three, please visit http://med. .


News Article | February 22, 2017
Site: www.eurekalert.org

Cells within our bodies divide and change over time, with thousands of chemical reactions occurring within each cell daily. This makes it difficult for scientists to understand what's happening inside. Now, tiny nanostraws developed by Stanford researchers offer a method of sampling cell contents without disrupting its natural processes. A problem with the current method of cell sampling, called lysing, is that it ruptures the cell. Once the cell is destroyed, it can't be sampled from again. This new sampling system relies on tiny tubes 600 times smaller than a strand of hair that allow researchers to sample a single cell at a time. The nanostraws penetrate a cell's outer membrane, without damaging it, and draw out proteins and genetic material from the cell's salty interior. "It's like a blood draw for the cell," said Nicholas Melosh, an associate professor of materials science and engineering and senior author on a paper describing the work published recently in Proceedings of the National Academy of Sciences. The nanostraw sampling technique, according to Melosh, will significantly impact our understanding of cell development and could lead to much safer and effective medical therapies because the technique allows for long term, non-destructive monitoring. "What we hope to do, using this technology, is to watch as these cells change over time and be able to infer how different environmental conditions and 'chemical cocktails' influence their development - to help optimize the therapy process," Melosh said. If researchers can fully understand how a cell works, then they can develop treatments that will address those processes directly. For example, in the case of stem cells, researchers are uncovering ways of growing entire, patient-specific organs. The trick is, scientists don't really know how stem cells develop. "For stem cells, we know that they can turn into many other cell types, but we do not know the evolution - how do they go from stem cells to, say, cardiac cells? There is always a mystery. This sampling technique will give us a clearer idea of how it's done," said Yuhong Cao, a graduate student and first author on the paper. The sampling technique could also inform cancer treatments and answer questions about why some cancer cells are resistant to chemotherapy while others are not. "With chemotherapy, there are always cells that are resistant," said Cao. "If we can follow the intercellular mechanism of the surviving cells, we can know, genetically, its response to the drug." The sampling platform on which the nanostraws are grown is tiny - about the size of a gumball. It's called the Nanostraw Extraction (NEX) sampling system, and it was designed to mimic biology itself. In our bodies, cells are connected by a system of "gates" through which they send each other nutrients and molecules, like rooms in a house connected by doorways. These intercellular gates, called gap junctions, are what inspired Melosh six years ago, when he was trying to determine a non-destructive way of delivering substances, like DNA or medicines, inside cells. The new NEX sampling system is the reverse, observing what's happening within rather than delivering something new. "It's a super exciting time for nanotechnology," Melosh said. "We're really getting to a scale where what we can make controllably is the same size as biological systems." Building the NEX sampling system took years to perfect. Not only did Melosh and his team need to ensure cell sampling with this method was possible, they needed to see that the samples were actually a reliable measure of the cell content, and that samples, when taken over time, remained consistent. When the team compared their cell samples from the NEX with cell samples taken by breaking the cells open, they found that 90 percent of the samples were congruous. Melosh's team also found that when they sampled from a group of cells day after day, certain molecules that should be present at constant levels remained the same, indicating that their sampling accurately reflected the cell's interior. With help from collaborators Sergiu P. Pasca, assistant professor of psychiatry and behavioral sciences, and Joseph Wu, professor of radiology, Melosh and co-workers tested the NEX sampling method not only with generic cell lines, but also with human heart tissue and brain cells grown from stem cells. In each case, the nanostraw sampling reflected the same cellular contents as lysing the cells. The goal of developing this technology, according to Melosh, was to make an impact in medical biology by providing a platform that any lab could build. Only a few labs across the globe, so far, are employing nanostraws in cellular research, but Melosh expects that number to grow dramatically. "We want as many people to use this technology as possible," he said. "We're trying to help advance science and technology to benefit mankind." Melosh is also a professor in the photon science directorate at SLAC National Accelerator Laboratory, a member of Stanford Bio-X, the Child Health Research Institute, the Stanford Neurosciences Institute, Stanford ChEM-H and the Precourt Institute for Energy. Wu is also the Simon H. Stertzer, MD, Professor; he is director of the Stanford Cardiovascular Institute and a member of Stanford Bio-X, the Child Health Research Institute, Stanford ChEM-H and the Stanford Cancer Institute. Pasca is also a member of Stanford Bio-X, the Child Health Research Institute, the Stanford Neurosciences Institute and Stanford ChEM-H. The work was funded by the National Institute of Standards and Technology, the Knut and Alice Wallenberg Foundation, the National Institutes of Health, Stanford Bio-X, the Progenitor Cell Biology Consortium, the National Institute of Mental Health, an MQ Fellow award, the Donald E. and Delia B. Baxter Foundation and the Child Health Research Institute.


News Article | February 16, 2017
Site: www.eurekalert.org

Alpha cells in the pancreas can be induced in living mice to quickly and efficiently become insulin-producing beta cells when the expression of just two genes is blocked, according to a study led by researchers at the Stanford University School of Medicine. Studies of human pancreases from diabetic cadaver donors suggest that the alpha cells' "career change" also occurs naturally in diabetic humans, but on a much smaller and slower scale. The research suggests that scientists may one day be able to take advantage of this natural flexibility in cell fate to coax alpha cells to convert to beta cells in humans to alleviate the symptoms of diabetes. "It is important to carefully evaluate any and all potential sources of new beta cells for people with diabetes," said Seung Kim, MD, PhD, professor of developmental biology and of medicine. "Now we've discovered what keeps an alpha cell as an alpha cell, and found a way to efficiently convert them in living animals into cells that are nearly indistinguishable from beta cells. It's very exciting." Kim is the senior author of the study, which will be published online Feb. 16 in Cell Metabolism. Postdoctoral scholar Harini Chakravarthy, PhD, is the lead author. "Transdifferentiation of alpha cells into insulin-producing beta cells is a very attractive therapeutic approach for restoring beta cell function in established Type 1 diabetes," said Andrew Rakeman, PhD, the director of discovery research at JDRF, an organization that funds research into Type 1 diabetes. "By identifying the pathways regulating alpha to beta cell conversion and showing that these same mechanisms are active in human islets from patients with Type 1 diabetes, Chakravarthy and her colleagues have made an important step toward realizing the therapeutic potential of alpha cell transdifferentiation." Rakeman was not involved in the study. Cells in the pancreas called beta cells and alpha cells are responsible for modulating the body's response to the rise and fall of blood glucose levels after a meal. When glucose levels rise, beta cells release insulin to cue cells throughout the body to squirrel away the sugar for later use. When levels fall, alpha cells release glucagon to stimulate the release of stored glucose. Although both Type 1 and Type 2 diabetes are primarily linked to reductions in the number of insulin-producing beta cells, there are signs that alpha cells may also be dysfunctional in these disorders. "In some cases, alpha cells may actually be secreting too much glucagon," said Kim. "When there is already not enough insulin, excess glucagon is like adding gas to a fire." Because humans have a large reservoir of alpha cells, and because the alpha cells sometimes secrete too much glucagon, converting some alpha cells to beta cells should be well-tolerated, the researchers believe. The researchers built on a previous study in mice several years ago that was conducted in a Swiss laboratory, which also collaborated on the current study. It showed that when beta cells are destroyed, about 1 percent of alpha cells in the pancreas begin to look and act like beta cells. But this happened very slowly. "What was lacking in that initial index study was any sort of understanding of the mechanism of this conversion," said Kim. "But we had some ideas based on our own work as to what the master regulators might be." Chakravarthy and her colleagues targeted two main candidates: a protein called Arx known to be important during the development of alpha cells and another called DNMT1 that may help alpha cells "remember" how to be alpha cells by maintaining chemical tags on its DNA. The researchers painstakingly generated a strain of laboratory mice unable to make either Arx or DNMT1 in pancreatic alpha cells when the animals were administered a certain chemical compound in their drinking water. They observed a rapid conversion of alpha cells into what appeared to be beta cells in the mice within seven weeks of blocking the production of both these proteins. To confirm the change, the researchers collaborated with colleagues in the laboratory of Stephen Quake, PhD, a co-author and professor of bioengineering and of applied physics at Stanford, to study the gene expression patterns of the former alpha cells. They also shipped the cells to collaborators in Alberta, Canada, and at the University of Illinois to test the electrophysiological characteristics of the cells and whether and how they responded to glucose. "Through these rigorous studies by our colleagues and collaborators, we found that these former alpha cells were -- in every way -- remarkably similar to native beta cells," said Kim. The researchers then turned their attention to human pancreatic tissue from diabetic and nondiabetic cadaver donors. They found that samples of tissue from children with Type 1 diabetes diagnosed within a year or two of their death include a proportion of bi-hormonal cells -- individual cells that produce both glucagon and insulin. Kim and his colleagues believe they may have caught the cells in the act of converting from alpha cells to beta cells in response to the development of diabetes. They also saw that the human alpha cell samples from the diabetic donors had lost the expression of the very genes -- ARX and DNMT1 -- they had blocked in the mice to convert alpha cells into beta cells. "So the same basic changes may be happening in humans with Type 1 diabetes," said Kim. "This indicates that it might be possible to use targeted methods to block these genes or the signals controlling them in the pancreatic islets of people with diabetes to enhance the proportion of alpha cells that convert into beta cells." Kim is a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Stanford Cancer Institute and the Stanford Child Health Research Institute. Researchers from the University of Alberta, the University of Illinois, the University of Geneva and the University of Bergen are also co-authors of the study. The research was supported by the National Institutes of Health (grants U01HL099999, U01HL099995, UO1DK089532, UO1DK089572 and UC4DK104211), the California Institute for Regenerative Medicine, the Juvenile Diabetes Research Foundation, the Center of Excellence for Stem Cell Genomics, the Wallenberg Foundation, the Swiss National Science Foundation, the NIH Beta-Cell Biology Consortium, the European Union, the Howard Hughes Medical Institute, the H.L. Snyder Foundation, the Elser Trust and the NIH Human Islet Resource Network. Stanford's Department of Developmental Biology also supported the work. The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med. . The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med. .

Loading Child Health Research Institute collaborators
Loading Child Health Research Institute collaborators