Past News Items - July 2016
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Protein Found to Bolster Growth of Damaged Muscle Tissue
Johns Hopkins University biologists have found that a protein that plays a key role in the lives of stem cells can bolster the growth of damaged muscle tissue, a step that could potentially contribute to treatments for muscle degeneration caused by old age and diseases such as muscular dystrophy.
The results, published online by the journal Nature Medicine, show that a particular type of protein called integrin is present on the stem cell surface and used by stem cells to interact with, or “sense” their surroundings. How stem cells sense their surroundings, also known as the stem cell “niche,” affects how they live and last for regeneration. The presence of the protein β1-integrin was shown to help promote the transformation of those undifferentiated stem cells into muscle after the tissue has degraded, and improve regenerated muscle fiber growth as much as 50 percent.
While the presence of β1-integrin in adult stem cells is apparent, “its role in these cells has not been examined,” especially its influence on the biochemical signals promoting stem cell growth, wrote the three authors, Chen-Ming Fan, an adjunct biology professor; Michelle Rozo, who completed her doctorate in biology at Johns Hopkins this year; and doctoral student Liangji Li.
The experiment shows that β1-integrin—one of 28 types of integrin—maintains a link between the stem cell and its environment, and interacts biochemically with a growth factor called fibroblast growth factor [FGF] to promote stem cell growth and restoration after muscle tissue injury. Aged stem cells do not respond to FGF, and the results also show that β1-integrin restores aged stem cell’s ability to respond to FGF to grow and improve muscle regeneration.
By tracking an array of proteins inside the stem cells, the researchers tested the effects of removing β1-integrin from the stem cell. This is based on the understanding that the activities of stem cells—undifferentiated cells that can become specialized—are dependent on their environment and supported by the proteins found there.
“If we take out β1-integrin, all these other (proteins) are gone,” said Fan, the study’s senior author and a staff member at the Carnegie Institution for Science in Washington and Baltimore.
Why that is the case is not clear, but the experiment showed that without β1-integrin, stem cells could not sustain growth after muscle tissue injury.
By examining β1-integrin molecules and the array of proteins that they used to track stem cell activity in aged muscles, the authors found that all of these proteins looked like they had been removed from aged stem cells. They injected an antibody to boost β1-integrin function into aged muscles to test whether this treatment would enhance muscle regeneration. Measurements of muscle fiber growth with and without boosting the function of β1-integrin showed that the protein led to as much as 50-percent more regeneration in cases of injury in aged mice.
When the same β1-integrin function-boosting strategy was applied to mice with muscular dystrophy, the muscle was able to increase strength by about 35 percent.
Fan said the team’s research will next try to determine what is happening inside the stem cells as they react with their immediate environment, as a step to understanding more about the interaction of the two. That, in turn, could help refine the application of integrin as a therapy for muscular dystrophy and other diseases, and for age-related muscle degeneration.
“We provide here a proof-of-principle study that may be broadly applicable to muscle diseases that involve SC (stem cell) niche dysfunction,” the authors wrote. “But further refinement is needed for this method to become a viable treatment.”
Funding for this work was provided by the Carnegie Institution for Science and the National Institutes of Health (AR060042 and HD075345).
SOURCE Johns Hopkins University
What Are Gut Bacteria Doing in Critically Ill Lungs? New Discovery Could Change ICU Care
No one knows for sure how they got there. But the discovery that bacteria that normally live in the gut can be detected in the lungs of critically ill people and animals could mean a lot for intensive care patients.
Today, scientists are reporting that they found gut bacteria in the deepest reaches of failing lungs—an environment where they normally aren’t found and can’t survive. The more severe the patients’ critical illness, the more their usual lung bacteria were outnumbered by the misplaced gut bugs.
The findings, published in Nature Microbiology, were made by a team at the University of Michigan Medical School.
Their conclusion: critical illness involving the lungs has more to do with disruptions to the body’s natural population of microbes, or microbiome, than previously thought.
The researchers saw the effect both in rodents with the dangerous whole-body inflammation known as sepsis, and in 68 human patients with the serious and sudden lung failure known as the Acute Respiratory Distress Syndrome or ARDS. Using special genetic tools and bacterial culture techniques, they were able to study the lung microbiome of humans with ARDS for the first time and compare them to samples from healthy volunteers.
More than 200,000 Americans develop ARDS each year; many of them are among the million Americans who develop sepsis. Nearly half of ARDS and sepsis patients die from those conditions.
“Our results suggest that in our past attempts to find treatments for sepsis and ARDS, we may have been overlooking a major part of the story,” says lead author Robert P. Dickson, MD, a critical care physician and laboratory scientist. “Virtually all of our attempts to treat these critical illnesses have been aimed at fixing the disordered inflammation and tissue injury we can see in our patients. But our study raises the possibility that this inflammation and injury may actually be downstream consequences of an upstream source: disordered bacterial communities in the gut and lung.”
A Vicious Cycle
Dickson and his colleagues believe that patients with these conditions may actually be stuck in a vicious cycle caused by dysbiosis—an out-of-whack microbiome.
Based on their findings, they suggest that the insult that caused the patient’s or animal’s illness in the first place triggers a “chicken and the egg” feedback loop.
Changes in the microbiome lead to inflammation, as the body’s immune system tries to fend off what it sees as invaders. And that inflammation in turn injures the delicate lung tissue. But then that injury and inflammation change the environment within the lung, allowing microbes that don’t normally grow there to invade, or to “bloom” if they were already present in low levels.
Improving survival of critically ill patients, then, would require breaking that cycle—which means figuring out how to keep the microbiome relatively normal.
To do that, the researchers know they’ll have to show where the gut bacteria in the lung originally came from. However, in the animals with sepsis, they did rule out the usual route by which microbes get into the lung every day—through the upper respiratory tract of the mouth, nose, and throat.
One possible explanation (one that researchers have speculated about since the 1950s) is that in patients with critical illness, the walls of the intestines get “leaky,” and bacteria escape and travel upward into the lungs. Another potential explanation is that small numbers of these gut bacteria were present in the lungs all along, but couldn’t grow for lack of the proper environmental conditions.
“We’ve only recently started thinking of the lungs as an ecosystem,” says Dickson. “So we’re just now sorting out the rules for how these bacterial communities get established, both in health and in critical illness.”
Continuing the Sleuth Work
Dickson notes that the new findings help explain something that critical care teams have known for decades: that the gut microbiome is somehow linked to a person’s chances of surviving a critical illness.
Animal studies have shown since the 1950s that pre-treatment of the gut with antibiotics before trauma or other critical illness can protect against lung injury and death. Dickson published a review of what’s known about the microbiome and critical illness in Lancet Respiratory Medicine in January.
In other countries, he notes, doctors even treat uninfected ICU patients with antibiotics to suppress their microbiomes, and decrease their rates of organ failure and death. They call the practice selective decontamination of the digestive tract. But such prophylactic tactics aren’t commonly used in the U.S. because of concerns that antibiotic use could accelerate the rise of “superbugs” resistant to modern antibiotics.
To get to the bottom of the lung-gut microbiome mystery, Dickson and colleagues have already begun capturing samples from more patients at risk for ARDS in the intensive care units of U-M’s University Hospital. U-M is part of the National Institutes of Health’s ARDS clinical trials network called Prevention and Early Treatment of Acute Lung Injury, or PETAL. Dickson is also an associate director of U-M’s Center for Integrative Research in Critical Care, which brings scientists, engineers and clinicians together to advance understanding of diseases like ARDS.
The team will also leverage the resources of the Medical School’s Host Microbiome Initiative, which gives researchers access to oxygen-free growth chambers, germ-free animal facilities,
and advanced genetic sequencing and cultivation tools. Such tools were important to showing, in the new paper, that the gut bacteria were alive in the lungs, not just detectable as DNA from dead bacteria.
“In the long run, we need to start thinking of the microbiome as an organ that can fail in critically ill patients,” says Dickson. “We're studying how it gets disordered, how it impacts other organs, and how we can fix it. The importance of the microbiome in the ICU has been clear for decades, but with these new tools we're finally able to ask and answer the right questions. It's a really exciting time.”
The research was funded by the NIH (TR000433, HL130641, HL00774921, HL123515,
HL123031, HL098961 and HL114447) and by the Michigan Institute for Clinical & Health Research, the Medical School’s Host Microbiome Initiative and MCIRCC. In addition to Dickson, the study’s authors include senior author Gary Huffnagle, M.D., and co-authors Benjamin H. Singer, M.D., Ph.D., Michael W. Newstead, Nicole R. Falkowski, John R. Erb-Downward, Ph.D., and Theodore J. Standiford, M.D. All are members of the Division of Pulmonary and Critical Care Medicine in the Department of Internal Medicine; Huffnagle is also a member of the Department of Microbiology and Immunology. Reference: Nature Microbiology, 10.1038/nmicrobiol.2016.113
SOURCE Univeristy of Michigan Health System
Stem Cells Engineered to Grow Cartilage, Fight Inflammation
With a goal of treating worn, arthritic hips without extensive surgery to replace them, scientists have programmed stem cells to grow new cartilage on a 3-D template shaped like the ball of a hip joint. What’s more, using gene therapy, they have activated the new cartilage to release anti-inflammatory molecules to fend off a return of arthritis.
The technique, demonstrated in a collaborative effort between Washington University School of Medicine in St. Louis and Cytex Therapeutics Inc. in Durham, N.C., is described July 18 in Proceedings of the National Academy of Sciences.
The discovery one day may provide an alternative to hip-replacement surgery, particularly in younger patients. Doctors are reluctant to perform such operations in patients under age 50 because prosthetic joints typically last for less than 20 years. A second joint-replacement surgery to remove a worn prosthetic can destroy bone and put patients at risk for infection.
“Replacing a failed prosthetic joint is a difficult surgery,” said Farshid Guilak, PhD, a professor of orthopedic surgery at Washington University. “We’ve developed a way to resurface an arthritic joint using a patient’s own stem cells to grow new cartilage, combined with gene therapy to release anti-inflammatory molecules to keep arthritis at bay. Our hope is to prevent, or at least delay, a standard metal and plastic prosthetic joint replacement.”
The technique uses a 3-D, biodegradable synthetic scaffold that Guilak and his team developed. The scaffold, molded into the precise shape of a patient’s joint, is covered with cartilage made from the patient’s own stem cells taken from fat beneath the skin. The scaffold then can be implanted onto the surface of an arthritic hip, for example. Resurfacing the hip joint with “living” tissue is designed to ease arthritis pain, and delay or even eliminate the need for joint-replacement surgery in some patients.
Additionally, by inserting a gene into the newly grown cartilage and activating it with a drug, the gene can orchestrate the release of anti-inflammatory molecules to fight a return of arthritis, which usually is what triggers such joint problems in the first place.
“When there is inflammation, we can give a patient a simple drug, which activates the gene we’ve implanted, to lower inflammation in the joint,” said Guilak, also a professor of developmental biology and of biomedical engineering. “We can stop giving the drug at any time, which turns off the gene.”
That gene therapy is important, he explained, because when levels of inflammatory molecules rise in a joint, the cartilage is destroyed and pain increases. By adding gene therapy to the stem cell and scaffold technique, Guilak and his colleagues believe it will be possible to coax patients’ joints to fend off arthritis and function better for a longer time.
The 3-D scaffold is built using a weaving pattern that gives the device the structure and properties of normal cartilage. Franklin Moutos, PhD, vice president of technology development at Cytex, explained that the unique structure is the result of approximately 600 biodegradable fiber bundles woven together to create a high-performance fabric that can function like normal cartilage.
“As evidence of this, the woven implants are strong enough to withstand loads up to 10 times a patient’s body weight, which is typically what our joints must bear when we exercise,” Moutos said.
Currently, there are about 30 million Americans who have diagnoses of osteoarthritis, and data suggest that the incidence of osteoarthritis is on the rise. That number includes many younger patients—ages 40 to 65—who have limited treatment options because conservative approaches haven’t worked and they are not yet candidates for total joint replacement because of their ages.
Bradley Estes, PhD, vice president of research and development at Cytex, noted, “We envision in the future that this population of younger patients may be ideal candidates for this type of biological joint replacement.”
Guilak, who also is the director of research at Shriners Hospitals for Children - St. Louis, and co-director of the Washington University Center of Regenerative Medicine, has been collaborating with Cytex on this research. The scientists have tested various aspects of the tissue engineering in cell culture, and some customized implants already are being tested in laboratory animals. He said if all goes well, such devices could be ready for safety testing in humans in three to five years.
Moutos FT, Glass KA, Compton SA, Ross AK, Gersbach CA, Guilak F, Estes BT. Anatomically shaped tissue-engineered cartilage with tunable and inducible anti-cytokine delivery for biological joint resurfacing. Proceedings of the National Academy of Sciences. July 18, 2016.
This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging of the National Institutes of Health (NIH), grant numbers AR55042, AR50245, AR48852, AG15768, AR48182, AG46927 and AR067467. Additional funding provided by the Collaborative Research Center; the AO Foundation, Davos, Switzerland; the Arthritis Foundation; the Nancy Taylor Foundation for Chronic Diseases; and the National Science Foundation (NSF).
Authors Farshid Guilak, Bradley T. Estes, Franklin Moutos and Sarah Compton have a financial interest in Cytex Therapeutics of Durham, N.C., which holds patents for the development of these devices. They could realize financial gain if the devices eventually are approved for clinical use.
Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
SOURCE Washington University in St. Louis
Wellness Coaching Can Produce Significant and Long-Term Improvements in Health Behaviors
Making a lifestyle change can be a daunting task, as an overwhelming amount of popular health trends seem unsustainable at best and, at worst, could be dangerous. However, promising results of a study conducted by Mayo Clinic experts suggest that one of these latest trends—wellness coaching—can produce substantial lifestyle improvements that align with an individual’s personal values and foster confidence to sustain these changes after the program has concluded.
Wellness coaches are trained professionals who help individuals identify values and make customized changes to manage stress, begin or maintain healthy habits, and improve their overall quality of life. One of the reasons wellness coaching can be successful is that the focus isn’t necessarily on weight management or fitness. People usually begin wellness programs to lose weight, but, according to Matthew Clark, PhD, LP, the study’s lead author and medical expert at the Mayo Clinic Healthy Living Program, what often begins as a short-term goal evolves into clinically meaningful improvements, such as stress reduction, sleep improvement, increased spiritual connection and quality of life that is sustained long after the wellness program has been completed.
This study, which is published in the American Journal of Health Promotion, examines data from three main areas of wellness coaching: health behaviors, eating self-efficacy, and goal-setting skills. Researchers asked 100 participants to evaluate themselves based on these criteria at the beginning of the program, after the standard 12 weeks were completed, and three months following the last appointment. In all three areas, individuals reported statistically significant improvement and maintained self-perception of these improvements during the three-month period following.
The research from the study, conducted at the Dan Abraham Healthy Living Center on Mayo Clinic’s campus in Rochester, is being used for ongoing program planning at the clinic’s own Healthy Living Program—a comprehensive wellness program led by certified wellness experts. Dr. Clark offers this advice for people looking to make a lifestyle change: “If you’re looking to improve your quality of life—if you’re trying to make healthier changes—and it’s been difficult to do that on your own, be receptive to working with a wellness coach. That person can provide you with guidance, look at your strengths, and help you build confidence and skills for long-term change.”
To contact the Mayo Clinic Healthy Living Program for more information, go to https://healthyliving.mayoclinic.org/.
SOURCE Mayo Clinic
HIFU – Taking the Fight to Prostate Cancer
Dr. Tracy Gapin continues to establish the benchmark for treating prostate cancer in Florida and around the world. His utilization of the revolutionary HIFU treatment has been successful in applying the latest technology to ablate the prostate tissue. The state of the art medical advancement is building significant momentum after recent clearance by the Food and Drug Administration.
Dr. Gapin recognizes the new procedure as a breakthrough for patients in the early and middle stages of prostate cancer. The technique, which centers around the usage of "high intensity focused ultrasound"(thus the acronym), was responsible for leading to the eradication of cancer tissue in ninety-four percent of early stage prostate cancer patients, according to a recent study. Dr. Gapin is the Founder and Director of Sarasota Prostate Care of Florida. The center is recognized for excellence in minimally invasive prostate cancer treatment options.
Dr. Gapin was quoted in a recent interview where he explained, "If we are going to continue to lead in this fight against prostate cancer we must utilize every technological advancement along with compassionate care." Dr. Gapin, who completed his residency at the University of Florida and is recognized as a Fellow of the American College of Surgeons (FACS), is considered to be among the most prestigious group of medical professionals and continues his leadership role with the latest of recent successes. Among many firsts, Dr. Gapin is one of the pioneers in his field of urology to conduct a robot-guided surgery using the Da Vinci prostatectomy. He has since performed more than 300 successful surgeries implementing the one of a kind technique.
Dr. Gapin recognized the potential for HIFU as a major and successful player in the field of prostate cancer treatment even prior to the most famous study, which involved 101 patients. The study, which involved an incredible amount of recorded data, examined 87 of the group who had experienced cancer removal in the lobes that were treated. Additionally, 68 members of that same test group showed no cancer throughout the entire prostate, which included areas that were not directly treated. After a two-year follow-up study, 89 percent of the test group were living without the need for radical therapy.
More than 40,000 men worldwide were treated with HIFU techniques and recovered. Reviews by top professionals of the treatment consider it to be an excellent option that provides extraordinary results with negligible side effects. In addition to the success rate, the recovery time is noted to be exceptionally quick. Over 7,000 United States citizens had traveled outside the country for treatment prior to the FDA approval.
Dr. Gapin continues to break new ground by combining state of the art technology treatments for prostate cancer with compassionate care in the post-modern Sarasota Prostate Care facility. Through their concerted efforts to remain ahead of the disease, the facility continues to lead the way in Florida as well as the rest of the world in the treatment of prostate cancer. For more information on HIFU, please visit http://www.sarasotaprostate.com.
SOURCE Sarasota Prostate Care
Antibiotics Weaken Alzheimer's Disease Progression through Changes in the Gut Microbiome
Long-term treatment with broad spectrum antibiotics decreased levels of amyloid plaques, a hallmark of Alzheimer’s disease, and activated inflammatory microglial cells in the brains of mice in a new study by neuroscientists from the University of Chicago.
The study, published July 21, 2016, in Scientific Reports, also showed significant changes in the gut microbiome after antibiotic treatment, suggesting the composition and diversity of bacteria in the gut play an important role in regulating immune system activity that impacts progression of Alzheimer’s disease.
“We're exploring very new territory in how the gut influences brain health,” said Sangram Sisodia, PhD, Thomas Reynolds Sr. Family Professor of Neurosciences at the University of Chicago and senior author of the study. “This is an area that people who work with neurodegenerative diseases are going to be increasingly interested in, because it could have an influence down the road on treatments.”
Two of the key features of Alzheimer’s disease are the development of amyloidosis, accumulation of amyloid-ß (Aß) peptides in the brain, and inflammation of the microglia, brain cells that perform immune system functions in the central nervous system. Buildup of Aß into plaques plays a central role in the onset of Alzheimer’s, while the severity of neuro-inflammation is believed to influence the rate of cognitive decline from the disease.
For this study, Sisodia and his team administered high doses of broad-spectrum antibiotics to mice over five to six months. At the end of this period, genetic analysis of gut bacteria from the antibiotic-treated mice showed that while the total mass of microbes present was roughly the same as in controls, the diversity of the community changed dramatically. The antibiotic-treated mice also showed more than a two-fold decrease in Aß plaques compared to controls, and a significant elevation in the inflammatory state of microglia in the brain. Levels of important signaling chemicals circulating in the blood were also elevated in the treated mice.
While the mechanisms linking these changes is unclear, the study points to the potential in further research on the gut microbiome’s influence on the brain and nervous system.
“We don’t propose that a long-term course of antibiotics is going to be a treatment—that’s just absurd for a whole number of reasons,” said Myles Minter, PhD, a postdoctoral scholar in the Department of Neurobiology at UChicago and lead author of the study. “But what this study does is allow us to explore further, now that we’re clearly changing the gut microbial population and have new bugs that are more prevalent in mice with altered amyloid deposition after antibiotics.”
The study is the result of one the first collaborations from the Microbiome Center, a joint effort by the University of Chicago, the Marine Biological Laboratory and Argonne National Laboratory to support scientists at all three institutions who are developing new applications and tools to understand and harness the capabilities of microbial systems across different fields. Sisodia, Minter, and their team worked with Eugene B. Chang, Martin Boyer Professor of Medicine at UChicago, and Vanessa Leone, PhD, a postdoctoral scholar in Chang’s lab, to analyze the gut microbes of the mice in this study.
Minter said the collaboration was enabling, and highlighted the cross-disciplinary thinking necessary to tackle a seemingly intractable disease like Alzheimer’s. “Once you put ideas together from different fields that have largely long been believed to be segregated from one another, the possibilities are really amazing,” he said.
Sisodia cautioned that while the current study opens new possibilities for understanding the role of the gut microbiome in Alzheimer’s disease, it’s just a beginning step.
“There’s probably not going to be a cure for Alzheimer’s disease for several generations, because we know there are changes occurring in the brain and central nervous system 15 to 20 years before clinical onset,” he said. “We have to find ways to intervene when a patient starts showing clinical signs, and if we learn how changes in gut bacteria affect onset or progression, or how the molecules they produce interact with the nervous system, we could use that to create a new kind of personalized medicine.”
The study, “Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease,” was supported by the Cure Alzheimer’s Fund and the National Institute of Diabetes and Digestive and Kidney Diseases. Additional authors include Daina Ringus, Xiaoqiong Zhang, Paul Oyler-Castrillo, and Mark Musch from the University of Chicago; Can Zhang, Joseph Ward, and Rudolph Tanzi from Massachusetts General Hospital; and Fan Liao and David Holtzman from Washington University.
SOURCE University of Chicago Medical Center
Novel Approach Reveals More Diversity in the Human Brain
A collaborative effort from the University of California San Diego, The Scripps Research Institute (TSRI), and Illumina has led to the classification of neuronal single-nuclei transcriptomes from the cerebral cortex of the human brain. The new findings were published June 23 in the Journal of Science.
Classification of single neurons into subtypes has often posed a challenge because of the lower signal-to-noise ratio in cell subtypes than other typical single-cell datasets. Dr. Rizi Ai (Wang Lab at University of California, San Diego), the leading researcher and co-first author in the new Journal of Science paper, developed a new bioinformatics algorithm to iteratively classify 3,227 single-cell transcriptome datasets across the six brain regions. Dr. Ai's algorithm called "Clustering-and-Classification" is able to sensitively measure the most variant gene expressions at each splitting level and determine the cell subtypes based on the active/inactive genes iteratively. The algorithm successfully revealed a lot more diversity in human brain than previously thought by dividing 3,227 individual neurons into 16 neuronal subtypes that are correlated with functions. Besides, Dr. Ai also developed an automatic analysis pipeline to automatically process and analyze large volumes of high-throughput sequencing data such as RNA sequencing data of neuronal cells.
Dr. Rizi Ai had this to say when contacted through email:
"Our research is beyond classifying cells into cell types, we wanted to look more deeply and classify single neurons into cell subtypes. This process is important in further understanding how different brain regions could function differently. With the shortfalls of traditional clustering methods I worked around the clock to create the novel bioinformatics algorithm, Clustering-and-Classification. This new algorithm is sensitive enough to reveal heterogeneity in cell subtypes and capturing transcription variation signals from different neuronal subtypes. "
The Journal of Science article that Dr. Rizi Ai co-first authored is a huge step forward in understanding neuronal subtypes in the human cerebral cortex and provides a framework for comparing individual neurons. This data can also be useful for further research into neurological disorders like dementia, Alzheimer's, Parkinson's, schizophrenia, and depression, as well as seeing if changes in heterogeneity of neuronal subtypes plays a role in these diseases.
SOURCE Wei Wang's Lab
Study Finds Potential Treatment for Non-Alcoholic Fatty Liver Disease
Researchers report in the journal Cell Reports a targeted molecular therapy that dramatically reduces the initial development of Non-Alcoholic Fatty Liver Disease (NAFLD) in laboratory mouse models of the disease.
The study, published online June 30, found increased levels of an enzyme called cdk4 in patients with NAFLD and in mouse models. Researchers at Cincinnati Children's Hospital Medical Center report that when they used two drugs that inhibit cdk4 in mouse models of NAFLD (flavopiridol, PD-0332991), this significantly reduced development of hepatic steatosis—the first stage of the disease.
"This is the first study to show that cdk4 triggers development of NAFLD and that inhibiting this enzyme can both prevent and reverse the first step of the disease," said Nikolai Timchenko, PhD, senior author and head of the Liver Tumor Biology Program at Cincinnati Children's. "Both of the cdk4 inhibitors we tested are approved by the FDA and in clinical trials for liver cancer, so it should be possible to initiate clinical trials for NAFLD with these drugs soon."
NAFLD is an abnormal buildup of extra fat in liver cells that is not caused by alcohol. The disease—which affects up to 25 percent of the US population—usually develops in people who are overweight, obese, or have diabetes and high cholesterol. The first stage of the disease, hepatic steatosis, can progress to a condition called NASH (non-alcoholic steatohepatitis) and ultimately cirrhosis or liver cancer.
Timchenko said new therapies for NAFLD are needed because, short of weight loss and lifestyle changes, there currently are no safe or effective treatments. There are new treatments being tested in clinical trials with promising results, but these studies have revealed evidence of serious side effects.
Unraveling a Mystery
Despite technology advancements in molecular analysis, study authors said that very little has been known about key biological events that cause NAFLD. In people, the disease is usually linked to age and an inappropriate, high-fat diet that initially leads to the disease's first stage.
Timchenko and his colleagues turned to what they say is one of the best biologically relevant animal models for the disease—mice put on a high-fat diet that researchers have learned mimic the main steps of NAFLD development in people.
The researchers started making progress in unraveling the molecular progression of NAFLD when they bred genetically engineered mice that developed first-stage disease much faster than normal wild-type mice. The genetically bred mice had elevated levels of a complex of enzymes, suggesting to the researchers a particular enzyme might trigger the disease.
After repeated testing—including analysis of donated liver tissues from human patients—the researchers found an association between elevated levels of cdk4 and NAFLD in humans and mouse models. Mice that were bred to not express high levels of cdk4 did not develop the initial stage of NAFLD, according to the authors.
Because NAFLD is a progressive disease with several stages, the researchers are now conducting tests to see if using drugs to inhibit cdk4 not only stops or reverses the progression of hepatic steatosis, but also the later disease stages of NAFLD.
Funding support for the study came in part from the National Institutes of Health (R01DK102597, R01CA159942, AR052791, AR064488) and from Cincinnati Children's.
About Cincinnati Children's
Cincinnati Children's, a non-profit, pediatric, academic medical center established in 1883, is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education, and innovation. A destination for children with complex medical conditions, it also served patients from all 50 states and nearly 70 countries during the past year. Additional information can be found at www.cincinnatichildrens.org.
SOURCE Cincinnati Children's Hospital Medical Center
GD Biosciences Announces PULS Cardiac Test Distribution Partnership With Cleveland HeartLab, Inc.
Irvine, California-based Global Discovery Biosciences (GD Biosciences), a biotechnology company dedicated to research and development of innovative solutions to some of the biggest challenges in healthcare, announced that it will partner exclusively with Cleveland HeartLab, Inc. to distribute the PULS Cardiac Test to physicians in the United States. Formed in 2009 as a spin-off from the Cleveland Clinic, Cleveland HeartLab, Inc. offers its testing to thousands of leading clinicians focused on health and wellness as well as corporate wellness plans through its CAP accredited and CLIA-certified clinical lab, and shares Global Discovery Biosciences’ commitment to preventing heart disease.
Heart disease remains the leading cause of death and disability worldwide, but is 80-percent preventable with early detection and lifestyle modifications. Most patients present with no signs or symptoms before a fatal or debilitating heart attack. Nearly half of all heart attacks are silent according to a study published on May 16th, 2016 in the American Heart Association Journal Circulation. The ability to identify these individuals before they have a heart attack has high clinical value.
The PULS (Protein Unstable Lesion Signature) Cardiac Test is an affordable, non-invasive blood test that has the ability to find these individuals before they experience a heart attack. The PULS Cardiac Test quantifies endothelial damage, measures the body’s immune response to the damage, and predicts risk of an acute coronary syndrome (ACS). The PULS Cardiac Test incorporates the most significant predictive markers and risk factors to provide a powerful indication of coronary artery endothelial damage and a risk for potential ACS. Measured and validated against the current gold standards in cardiology, the PULS Cardiac Test is a potential game changer in uncovering asymptomatic patients at real risk of heart attacks who are missed by current conventional methods.
Already being used by select physicians in the US, United Kingdom, Canada, and countries with growing heart disease problems such as Indonesia, China, Middle East, and India, the PULS Cardiac Test is a diagnostic and predictive blood test that detects the body’s immune response to early coronary artery endothelial damage, often in patients with no symptoms of heart disease (the Vulnerable Patient). The immune response frequently causes formation of unstable cardiac lesions that are like blisters or pimples in the coronary artery wall. These lesions can become unstable and rupture, forming a blood clot. This process blocks blood flow to the heart muscle and is the most common cause of heart attacks (75 percent).
“The PULS Cardiac Test is becoming a critical tool for physicians to identify apparently healthy patients with silent disease who are at risk of heart attack. We tend to focus too much on cholesterol and the structural defects in heart disease, and not enough on the functional defects,’” said Douglas S. Harrington, MD, CEO of GD Biosciences. “Free radicals, including oxidized cholesterol, cause damage to the coronary arteries. The body has the ability to repair this damage. In order to do so, it receives a signal from the injury to activate the immune response and repair the damage. We detect the body’s immune response to this injury with the PULS Cardiac Test and predict the likelihood of a heart attack in a 5 year timeline. This allows physicians to implement potentially life-saving prevention plans and improve patient care.”
Jake Orville, CEO of Cleveland HeartLab, Inc. commented “Numerous studies have shown that 50 percent of heart attack victims have normal cholesterol levels. Recently, the American Heart Association’s “Get with the Guidelines” revealed that over 70 percent of patients hospitalized with a first Acute Coronary Syndrome (Heart Attack) event were well within guideline targets for lipids. Cleveland HeartLab is focused on providing breakthrough innovations to the market and the PULS Cardiac Test complements our industry leading menu of cardiac tests and enhances our ability to provide Doctors and patients with actionable results.”
About GD Biosciences
Global Discovery Biosciences (GD Biosciences) is a pioneer in the field of diagnostic medicine and focuses on turning academic discoveries into innovative clinical products for global clinical applications. Its CLIA-certified and GMP laboratory performs a menu of clinically effective tests targeting key health issues. Our goal is to equip physicians with the tools they need to transform health care—one patient at a time.
About Cleveland HeartLab
Cleveland HeartLab Inc. (CHL) is the premier cardiovascular disease (CVD) Management Company with a comprehensive array of propriety tests focused on improving the early identification of those with CVD risk. In addition to its industry leading approach to inflammation testing, CHL manages a robust R&D program to accelerate the clinical use of scientifically proven and medically relevant biomarkers. CHL’s biomarkers have been validated in more than 100 peer-review studies published in leading medical and scientific journals. For more information about CHL visit us at www.clevelandheartlab.com. For more information on CVD visit www.knowyourrisk.com.
SOURCE GD Biosciences
NIH Funds Zika Virus Study Involving US Olympic Team
Researchers supported by the National Institutes of Health will monitor potential Zika virus exposure among a subset of athletes, coaches, and other US Olympic Committee (USOC) staff attending the 2016 Summer Olympics and Paralympics in Brazil. The study, funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and led by Carrie L. Byington, MD, from the University of Utah, Salt Lake City, aims to improve understanding of how the virus persists in the body and to identify potential factors that influence the course of infection.
“Zika virus infection poses many unknown risks, especially to those of reproductive age,” said Catherine Y. Spong, MD, acting director of NICHD. “Monitoring the health and reproductive outcomes of members of the US Olympic team offers a unique opportunity to answer important questions and help address an ongoing public health emergency.”
USOC established an Infectious Disease Advisory Group (IDAG), chaired by Dr. Byington, to help prepare the US Olympic team for travel to Brazil, which is the epicenter of the Zika virus outbreak in the Americas. Dr. Byington proposed the project, which aims to enroll at least 1,000 men and women, in response to an NIH announcement designed to expedite review and funding for Zika-related research projects.
“We partnered with the USOC to improve knowledge of the dynamics of Zika infection, so that we can better protect the health of athletes and staff who will participate in the 2016 Games,” said Dr. Byington. “This ongoing relationship also opens avenues for long-term research that promises to benefit not only the Americas, but also other regions facing the emergence of the virus.”
The current study seeks to determine the incidence of Zika virus infection, identify potential risk factors for infection, detect where the virus persists in the body (blood, semen, vaginal secretions, or saliva), evaluate how long the virus remains in these fluids, and study the reproductive outcomes of Zika-infected participants for up to one year.
To prepare, USOC and the University of Utah conducted a pilot study in March and April 2016. The study was fully enrolled in two days and included 150 participants. Notably, one-third of the pilot group indicated that they or their partner planned to become pregnant within 12 months of the Olympic Games.
Participants in the current study will complete health surveys and provide samples of bodily fluids for the detection of Zika and similar flaviviruses, such as dengue. Zika virus infection typically does not cause symptoms in adults, so routine sampling will detect asymptomatic infections and help shed light on symptomatic versus asymptomatic infections. Zika virus testing kits and training on how to use the tests will be provided by the US Centers for Disease Control and Prevention.
Before traveling to Brazil, all USOC staff, including athletes and coaches, will be briefed on a number of items, including the Zika outbreak. IDAG will provide educational materials to athletes and staff and answer questions. During this time, the NIH-funded researchers will present the study and enroll as well as consent USOC staff who are interested in participating. Approximately 3,000 USOC staff members are expected to travel to Brazil. In addition, spouses or sexual partners who are traveling to Brazil may be eligible to participate.
The 2016 Summer Olympics will take place in Rio de Janeiro, from August 5-21, 2016, and the Paralympic Games are scheduled for September 7-18, 2016.
About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NICHD conducts and supports research in the United States and throughout the world on fetal, infant and child development; maternal, child and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit NICHD’s website.
About the National Institutes of Health (NIH)
NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.