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samedi 24 septembre 2016
vendredi 12 août 2016
Molecular Flexibility Shown to Help Pharmaceutical Drugs Bind to Their Targets
Breakthrough could open up new directon when designing pharmaceutical drugs
By Sean Nealon
RIVERSIDE, Calif. (www.ucr.edu) — Scientists have discovered an alternative way to create a stronger binding between pharmaceutical drugs and the part of the body they are targeting – a development that can be used to fight a variety of diseases, including breast cancer.
The study published in the journal PLOS Computational Biology shows that flexible molecules, instead of rigid ones, as previously thought, can bind more effectively to the proteins causing the disease.
Being a tight binder is important for a molecule to be a good pharmaceutical drug. When designing a pharmaceutical drug, scientists typically make molecules – which are naturally flexible – rigid so that they can strongly bind, like a lock and key, with the disease causing protein in the body.
When molecules bind to their partners they usually decrease their flexibility which leads to the so-called entropy penalty. Having a large entropy penalty has been shown to be bad for creating a tight bindings. Scientists aim to reduce it so that the drug can stay on the target protein and alter its functional behavior for good. However, one key problem to this approach is that scientists are reaching the limit of how much rigidity can be produced in order to reduce entropy penalty and result in tighter binders.
Researchers, led by Wanli You, a graduate student at the University of California, Riverside, found that keeping the molecules flexible, as opposed to making them rigid, both reduced the entropy penalty and created a stronger binding.
One of the authors, Chia-en A. Chang, an associate professor of chemistry at UC Riverside, notes that: “This was really unexpected and opens up a new direction for designing pharmaceutical drugs”.
In order to discover this, the researchers examined the thermodynamic properties of different ligands binding to a promiscuous modular protein, Breast-cancer-gene 1 (BRCA1) C-terminal (BRCT). The authors used molecular dynamics simulations and a rigorous free energy calculation method to study ligands binding to BRCT, understand promiscuous molecular recognition and guide inhibitor design. Flexible ligands, the researchers found, may utilize multiple conformations in their bound states to keep good attractions with BRCT whilst also reducing entropy cost.
The research focused on breast cancer drugs, but the principles could be applied in drug development targeting other diseases and also in basic cell biology studies.
Molecular Flexibility Shown to Help Pharmaceutical Drugs Bind to Their TargetsNeedles that hit the right mark
New sensor could help anesthesiologists place needles for epidurals and other medical procedures.
Anne Trafton | MIT News Office
More than 13 million pain-blocking epidural procedures are performed every year in the United States. Although epidurals are generally regarded as safe, there are complications in up to 10 percent of cases, in which the needles are inserted too far or placed in the wrong tissue.
A team of researchers from MIT and Massachusetts General Hospital hopes to improve those numbers with a new sensor that can be embedded into an epidural needle, helping anesthesia doctors guide the needle to the correct location.
Currently, anesthesiologists must guide a four- to six-inch needle through multiple layers of tissue to reach the epidural space surrounding the spinal cord. They know when the needle has reached the right spot based on how the tissue’s resistance changes. However, some patients’ tissues vary from the usual pattern, which can make it more difficult to determine whether the needle is in the right place.
“The needle is placed essentially blindly,” says T. Anthony Anderson, an anesthesiologist at MGH and an assistant professor at Harvard Medical School. “The needle can go too far or into the wrong tissue, which means the patient doesn’t get the positive effect that you want or is injured.”
In most cases, these complications lead to reduced effectiveness of the pain-killing drug, or an excruciating post-procedure headache. In rare cases in which the needle goes too far or into a blood vessel, a stroke or spinal cord injury can occur.
Distinguishing tissues
To improve the accuracy of epidural needle placement, Anderson teamed up with researchers at MIT’s Laser Biomedical Research Center, headed by Peter So, a professor of mechanical engineering and biological engineering.
So and MIT research scientist Jeon Woong Kang designed and tested several types of optical sensors that could be placed at the tip of an epidural needle and determined that the best is one that relies on Raman spectroscopy. This technique, which uses light to measure energy shifts in molecular vibrations, offers detailed information about the chemical composition of tissue. In this case, the researchers measured the concentrations of albumin, actin, collagen, triolein, and phosphatidylcholine to accurately identify different tissue layers.
This sensor, which the researchers described in the journal Anesthesiology, provides immediate feedback telling the anesthesiologist which tissue the needle is in. As an epidural needle is inserted, it passes through five layers — skin, fat, supraspinous ligament, interspinous ligament, and ligamentum flavum — before reaching the epidural space, which is the target. Beyond that space lies the dura mater, a stiff membrane that surrounds the spinal cord and cerebrospinal fluid.
“The sensor is continuously measuring Raman spectroscopy signals, which tells you the chemical composition of the tissue. From the chemical composition you can identify all tissue layers, from skin to spinal cord,” Kang says.
The team found that Raman spectroscopy could distinguish each of the eight tissue layers around the epidural space with 100 percent accuracy. Two other techniques that they tested, fluorescence and reflectance spectroscopy, could distinguish some layers but not all eight.
“Blind procedures”
The researchers have tested the sensor in pig tissue and now plan to do further animal studies before testing it in human patients. They also plan to reduce the diameter of the sensor slightly, from 2 millimeters, which is too large to fit in the most commonly used epidural needles, to 0.5 mm.
Jeanine Wiener-Kronish, chief of anesthesia and critical care at MGH, says this type of sensor could greatly improve safety for epidurals, as well as other procedures involving needles.
“The era of blind procedures is one we need to move away from, because we’re very interested in improving safety and quality,” says Wiener-Kronish, who was not involved in the research. “This sensor could allow us to take a fairly blind procedure and be able to get more information about where the needle is.”
The researchers have started a company, Medisight Corp., to continue developing the technology, which they believe could also be applied to medical procedures, such as cancer biopsies or injecting drugs into the joints, which can be difficult to do accurately. This commercialization effort is supported by MIT entrepreneurship programs, including the MIT Translational Fellows Program, MIT Venture Mentoring Service, and MIT Innovation Initiative. The team also received support from the National Science Foundation in the form of a Small Business Technology Transfer program grant.
In addition to So, Kang, and Anderson, authors of the paper include Tatyana Gubin, an MIT undergraduate, and Ramachandra Dasari, a principal research scientist in MIT’s Department of Chemistry.
MIT
Needles that hit the right markMillions deprived of life saving antifungal medicines, report finds
Actor and GAFFI celebrity patron Rupert Everett declared that: “We have known for over 25 years that many people with AIDS and cancer do die of fungal complications. And death is avoidable with treatment. Why on earth are commonly used antifungal medicines not provided to everyone who needs them?”
Dr Glenda Gray, President and CEO of the African Medical Research Council and Professor of Pediatrics, Faculty of Health Sciences, at University of Witwatersrand, said: “In South Africa we are addressing the HIV epidemic squarely on with greatly increased provision of anti-retroviral drugs and expanding testing.
“Fungal diseases in AIDS have not received the priority they should have, although this is now changing with our national screening program for Cryptococci meningitis. Clearly ensuring antifungal agents are available to all is an key component in reducing deaths and illness across southern Africa."
Key findings:
- One of the critical drugs for fungal meningitis in AIDS (amphotericin B) is not available in 42 countries. The other key drug for fungal meningitis, flucytosine, is unavailable in at least 95 countries. Yet both have been available in Europe and the US for over 40 years. The World Health Organization recommends they be used together to bring down mortality from 100% to 25%. Fungal meningitis is the commonest form of meningitis in sub-Saharan Africa because of AIDS.
- The 25 -year old drug, fluconazole is available in all countries and itraconazole is unavailable in just five countries. However, being available is not enough – price also matters as patients pay for their care in many countries. The daily cost of fluconazole varied from <$1 to $31 and itraconazole from <$1 to $102. In South Africa, which has the largest AIDS burden in the world and a massive TB problem, itraconazole costs about £11.60 per day – unaffordable for most people there.
*Kneale M, Bartholomew JS, Davies E, Denning DW. Global Access to Antifungal Therapy and its Variable Cost. J Antimicrob Chemother. In press.
Millions deprived of life saving antifungal medicines, report findsjeudi 11 août 2016
New imaging platform tracks cancer progression
A new rapid fluorescent 3-D imaging system developed by UCL and Imperial College London scientists offers a non-invasive approach to accurately monitor tumour development in adult zebrafish.
Animal testing is an essential step in developing new drugs for diseases; however, the process usually involves invasive procedures with animals that must be euthanized. The new method, adapted from an imaging method called optical projection tomography (OPT), repeatedly images the same organisms, reducing the number of animals used in testing.
The MRC-funded scientists can now image and measure the growth of cancerous tumours and the associated development of growth-enabling blood vessels in live zebrafish which develop cancer in a way similar to humans. UCL is a world leader in zebrafish research with the largest and most comprehensive fish facility in the UK.
Dr Paul Frankel, UCL Division of Medicine, who led the cancer biology aspects of the project, said: “Zebrafish serve as animal models of liver and other cancers, developing a form of the disease genetically similar to human tumours. This, as well as their small size, quick reproduction and transparency – which is necessary for OPT imaging – makes zebrafish an ideal organism to study using this technique.”
Being able to track the stages of disease progression in a living organism means the team could also use the technique to monitor the effects of new anti-cancer drugs that aim to reduce tumour size.
Co-first author, Nicola Lockwood, also UCL Division of Medicine, said: “With the zebrafish model, we were able to directly visualise live progression of tumours within the context of a fully formed blood supply and immune system. This will be extremely important as we proceed to development of novel anti-cancer drugs.”
Essential to tumour development is angiogenesis, the process by which tumours generate their own blood vessels to deliver the nutrients that enable growth. This process also facilitates the spread of tumours to other parts of the body, usually resulting in poor patient prognosis and death.
In a preliminary study, the OPT system was used to image zebrafish over time during tumour progression, allowing the researchers to measure tumour size and the amount of blood vessels within the tumour.
The approach uses genetic fluorescence labelling techniques, which allow internal organs to be visualised through their emission of different colour light. In the study, zebrafish whose blood vessels were labelled with a red fluorescent protein were bred with zebrafish that grew liver tumours labelled with a green fluorescent protein when given a chemical compound called doxycycline.
As the offspring of these fish have both genes, when imaged, their blood vessels fluoresce red and the liver tumour fluoresces green.
“This technique has the advantage of being simple and robust,” said Professor Paul French, from the Department of Physics at Imperial, who led the development of OPT. “Unlike the other 3-D optical imaging techniques, it doesn’t rely on focused light, so it is relatively gentle on the organism being imaged. This makes it particularly good for imaging live animals across long timescales.”
The ability to perform studies over time allows researchers to assess disease progression in the same organism over spans of weeks to months. It is also able to yield high-resolution 3-D images at a fraction of the time and cost of other imaging techniques. In one study the team repeatedly imaged zebrafish expressing red fluorescent blood vessels over a period of five months.
Such longitudinal studies will enable research into potential long-term side effects of drug treatments including adverse reactions and the development of drug resistance.
“It’s well known that individuals can respond differently to the same drug treatment, therefore techniques such as ours could provide valuable information regarding disease progression and drug efficacy,” added Professor French.
The team are currently combining OPT with other techniques, such as fluorescence lifetime imaging, to map cell signalling processes. This could be used to monitor cell death, making it potentially useful to test chemotherapy drugs and identifying whether the drug is having unwanted side effects.
University College London
New imaging platform tracks cancer progressionTreatment option for Alzheimer’s disease possible
Dr Brough said: “There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer’s disease worse.
“Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells.”
He added: “Until now, no drug has been available to target this pathway, so we are very excited by this result.
“However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don’t always faithfully replicate the human disease.
“Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs.
“We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans.”
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, said: “Testing drugs already in use for other conditions is a priority for Alzheimer’s Society - it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch.
“These promising lab results identify a class of existing drugs that have potential to treat Alzheimer’s disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer’s disease at this stage – studies in people are needed first.”
Fenamate NSAIDs inhibit the NLRP3 inflammasome and 2 protect against Alzheimer’s disease in rodent models, published in the journal Nature Communications. DOI: 10.1038/NCOMMS12504
Please note, this study is experimental and doctors do not prescribe Mefenamic Acid as a treatment for Alzheimer’s Disease. For queries about treatment and care, please contact Alzheimer’s Society on 0330 333 0804. or email [email protected]
Treatment option for Alzheimer’s disease possibleThe Medical Minute: The dangerous allure of performance-enhancing drugs
Imagine you dedicate your whole life to becoming the best in your chosen sport. You put in the work, make big sacrifices and finally make the Olympic team. You have a shot at a medal — and all the money, fame and influence that comes with it.
Then, someone offers you a magic pill with two guarantees — that you won’t get caught and that you’ll win everything. There’s just one catch: you’ll be dead within five years from the pill’s side effects.
Would you take it?
A popular 1995 survey of Olympic hopefuls found that more than 50 percent of those given that proposal said they’d do it, lending insight into why many of the world’s best athletes are tempted by performance-enhancing drugs, even when the risks are high.
“I think that really speaks to the mentality,” said Dr. Matthew Silvis, director of primary care sports medicine at Penn State Health Milton S. Hershey Medical Center. “They are not really thinking about life down the road because they are so wrapped up in the moment. This is their opportunity.”
The list of substances that can mean the difference between winning and not winning is long, and includes everything from testosterone and anabolic steroids to red-cell boosters, depending on the effect you want. The drugs act on the body to enhance athletic performance by increasing muscle mass or boosting the amount of blood and oxygen carried to muscles.
While football players are more likely to use steroids or testosterone to beef up, cyclists may be tempted by EPO, or erythropoietin, a drug designed to help patients in kidney failure, which some athletes use to increase their endurance.
“Doping is really something that is present in all sports,” Silvis said. “It depends on how much the governing body of that sport is looking for it.”
He said scientists behind performance-enhancing drugs work hard to create products that are more difficult to detect, with the latest frontier being alteration of a person’s genetics to be a better athlete.
“From an ethical perspective, sports should be about who is the most naturally gifted and who works the hardest, but sometimes it’s about who has the best scientist in their corner to give them the edge,” Silvis said.
Once the games are over, the leftover effects of doping can derail even the healthiest athlete’s system.
Those who take EPO can find their body creating so many red blood cells that they develop clots and pulmonary embolisms.
Weight lifters who use testosterone have experienced shrinking testicles and deep, scarring, cystic acne on their chest and back, as well as swelling of the arms and legs, fluid retention, stretch marks and psychiatric problems such as depression, anxiety and insomnia. Women who use testosterone can become permanently infertile.
Because many of the drugs are administered by injections, there is also the risk of being infected with a dirty needle.
Dr. Cayce Onks, a family and sports medicine specialist at the Medical Center, said doping controversies have been part of the Olympics since its earliest days.
This year’s headlines about the Russian Olympic team are just the latest in the saga, although with 270 Russian athletes now cleared to compete, he said it’s probably the biggest scandal to date.
These days, the incentives to take a chance on performance-enhancing drugs are huge.
“Anyone who gets a gold medal has the benefit of TV contracts, announcer gigs, commercials and all the money that comes with it. It’s not just the prestige and satisfaction of competing at that level and winning,” Onks said. “Tenths of seconds can mean the difference between a medal and no medal, so whatever they can do to get that extra tenth, they want to try.”
The Medical Minute is a weekly health news feature produced by Penn State Health Milton S. Hershey Medical Center. Articles feature the expertise of faculty physicians and staff, and are designed to offer timely, relevant health information of interest to a broad audience.
Contacts:
Scott Gilbert
Work Phone:
717-531-1887
1 in 5 are discharged from hospital with unstable vital signs, and experience higher readmission and death rates Aug 09, 2016
DALLAS – Twenty percent of people hospitalized are released before all vital signs are stable, a pattern that is associated with an increased risk of death and hospital readmission, a new study by UT Southwestern Medical Center researchers shows.
As hospital stays have shortened dramatically over the past 30 years, there is increasing concern that patients are being discharged before all vital signs have stabilized, putting them at risk of adverse events after discharge. However, no studies to date have examined the extent to which patients are discharged with unstable vital signs, and whether this practice is actually associated with higher post-discharge mortality and readmission rates, the researchers said.
“We found that nearly 1 in 5 hospitalized adults is discharged with one or more vital sign instabilities such as an elevated heart rate or low blood pressure,” said lead author, Dr. Oanh Nguyen, Assistant Professor of Internal Medicine and Clinical Sciences. “This finding is an important patient safety issue because patients who had vital sign abnormalities on the day of discharge had higher rates of hospital readmission and death within 30 days even after adjusting for many other risk factors.”
The researchers assessed electronic medical records (EMR) of 32,835 unique individuals from six Dallas-Fort Worth area hospitals, and noted abnormalities in temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation within 24 hours of discharge. Nearly 20 percent had one or more abnormalities, with elevated heart rate being the most common vital sign instability (affecting about 10 percent). About 13 percent were readmitted or died, and individuals with three or more instabilities had a nearly four-fold increase in the odds of death.
“Our findings, that ‘vital signs are still vital’ have important implications for the development of national discharge guidelines to improve patient safety for the 35 million individuals being discharged from hospitals in the U.S. annually,” said co-lead author, Dr. Anil Makam, Assistant Professor of Internal Medicine and Clinical Sciences.
“At a time when people are developing complicated, black box computerized algorithms to identify patients at high risk of readmission, our study highlights that the stability of vital signs, something doctors review with their own eyes every day, is a simple, clinically objective means of assessing readiness and safety for discharge. There’s a good reason we call them vital signs,” said senior author Dr. Ethan A. Halm, Chief of the William T. and Gay F. Solomon Division of General Internal Medicine, Chief of the Division of Outcomes and Health Services Research in the Department of Clinical Sciences at UT Southwestern, and Director of UT Southwestern’s Center for Patient-Centered Outcomes Research. “It is important for clinicians to look at all of the vital signs in the 24 hours prior to discharge and not just the last set or the best ones in judging a patient’s readiness for discharge.”
Researchers concluded that:
- Discharge guidelines should include objective vital sign criteria for judging stability on discharge to improve disposition planning and post-discharge patient safety.
- At a minimum, patients with one instability on discharge should be discharged with caution.
- Close outpatient follow-up and appropriate patient education about warning signs and symptoms that merit urgent medical attention may be warranted.
- Individuals with two or more instabilities should likely remain in the hospital for continued treatment and observation in the absence of extenuating circumstances.
- Though post-acute care facilities are frequent sites of post-discharge care for those discharged with vital sign instabilities, patients sent to these facilities had still higher rates of readmission and death, suggesting that an alternate site of discharge may have been more appropriate for a significant subset of these individuals.
Other researchers included Dr. Song Zhang, Associate Professor of Clinical Sciences; and researchers from Parkland Health & Hospital System, the Parkland Center for Clinical Innovation (PCCI), and Texas Health Resources.
The study, which appears in the Journal of General Internal Medicine, was supported by grant funding from the Agency for Healthcare Research and Quality, the UT Southwestern Center for Patient-Centered Outcomes Research, the National Institutes of Health, the Commonwealth Foundation, and the UT Southwestern KL2 Scholars Program.
The UT Southwestern Center for Patient-Centered Outcomes Research, led by Dr. Halm, Professor of Internal Medicine and Clinical Sciences, who holds the Walter Family Distinguished Chair in Internal Medicine in Honor of Albert D. Roberts, M.D., is supported by a $5 million grant from the federal Agency for Healthcare Research and Quality and seeks to assess the benefits and harms of different preventive, diagnostic, therapeutic, and health delivery system interventions to inform decision-making, highlighting comparisons and outcomes that matter to people.
The Center works in conjunction with UT Southwestern’s Center for Translational Medicine, part of a $28.6 million grant from the NIH to promote rapid translation of basic laboratory findings into patient care. The Center is a member of a national Clinical and Translational Science Award Consortium that includes more than 60 medical research institutions.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.
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Media Contact: Cathy Frisinger
214-648-3404
Email
Only 15 percent of preventable spina bifida and anencephaly being prevented worldwide, study finds
Woodruff Health Sciences Center
Approximately only 15 percent of global cases of spina bifida and anencephaly that are preventable through folic acid fortification are actually being prevented according to a study led by epidemiologists and nutrition scientists from the Departments of Epidemiology and Global Health at Emory’s Rollins School of Public Health and the Food Fortification Initiative.
Published in the July edition of Birth Defects Research Part A Clinical and Molecular Teratology, the study emphasizes the preventable morbidity and mortality caused by the lack of cost-effective, easily implementable, and proven strategy of government-required folic acid fortification of food (also termed mandatory fortification). The researchers measured the current status of folic acid-preventable spina bifida and anencephaly (FAP SBA) worldwide. This was particularly significant as it was the 25th anniversary of the Medical Research Council study that proved unequivocally that folic acid prevents a majority of spina bifida and anencephaly.
According to study results, in the year 2015, there were about 35,500 fewer births with spina bifida and anencephaly, a commendable prevention achieved in 58 countries through mandatory folic acid fortification of wheat and maize flour. However, this also points to the urgency of preventing about 233,000 other FAP SBA cases that are still occurring in the remaining countries without effective folic acid interventions, say the authors. Most of Europe, Africa, and Asia is not implementing mandatory fortification with folic acid. Researchers believe that the implementation of mandatory fortification with folic acid offers governments a rapid way to prevent FAP SBA-associated disability and mortality, and to help countries achieve their health-related Sustainable Development Goalsrelated to reduction in infant and under-five mortality.
"No baby in the world should develop preventable birth defects such as FAP SBA and congenital rubella syndrome, because we have a known preventable strategy to aid against these conditions," says Dr. Godfrey P. Oakley Jr., MD, a pediatrician and the director of the Center for Spina Bifida Prevention at Emory’s Rollins School of Public Health. "Ignoring a preventable strategy for preventing serious birth defects can be compared to having a vaccine for Zika virus and not using it."
Contact
Melva Robertson
404-727-5692
[email protected]
Surgical removal of the thymus benefits myasthenia gravis patients without a chest tumor, according to NEJM paper
First-ever randomized study of thymectomy was led by faculty member at Jacobs School of Medicine and Biomedical Sciences at UB
BUFFALO, N.Y. –- A new study in the New England Journal of Medicine addresses a question doctors have sought to clarify for decades: whether a surgery conducted since the 1940s benefits the patients it targets.
The study to be published August 11 (available online on August 10 at 5 p.m.) found that surgical removal of the thymus gland from patients with myasthenia gravis, a rare autoimmune disease that affects neuromuscular function, provides significant benefit in patients who do not have a chest tumor.
Myasthenia gravis (MG) results from an immune-mediated disruption of communication between nerve and muscle – the neuromuscular junction. Symptoms may include droopy eyelids; blurred or double vision; difficulty speaking, swallowing and breathing; and muscle weakness. Some patients develop thymoma, a benign tumor of the thymus gland. The disease affects as many as 60,000 Americans and its incidence has been increasing, in part as a result of improved diagnostic techniques and an aging population.
The new study provides a definitive answer that neurologists have sought for decades, according to Gil I. Wolfe, MD, Irvin and Rosemary Smith Chair of the Department of Neurology in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, clinical chair of the worldwide study and first author.
Solid confirmation
“These findings solidly confirm the early use of thymectomy in managing myasthenia gravis,” he said. “These findings tell patients they can be even more assured that thymectomy is a positive step to take in the management of their condition.”
Since the 1940s, thymectomy has been used in MG patients, both in patients with a chest tumor called thymoma and those without. Wolfe said it is widely accepted that patients with a thymoma need to have it surgically removed. But the data have not been as clear in MG patients who do not present with a tumor.
“Until this study, the only evidence was from non-randomized studies that contained significant bias issues,” said Wolfe, an expert on neuromuscular disorders with a special focus on MG, who was awarded the 2015 Doctor of the Year award from the Myasthenia Gravis Foundation of America. Wolfe sees patients through UBMD Neurology at Buffalo General Medical Center.
Around 2000, when he was at the University of Texas Southwestern, Wolfe worked with colleagues in the field, John Newsom-Davis, MD; Henry Kaminski, MD; Fred Jaretzki, MD and Gary D. Cutter, PhD, to develop a study that would provide the data that neurologists needed to correctly assess the value of thymectomy.
The global study is the longest and one of the largest randomized studies in the history of MG. It ran from 2006 until 2012 with 126 patients with MG who participated in centers located on almost every continent. It judged the effectiveness of thymectomy by comparing disease status of patients and how much of the corticosteroid prednisone they needed after the surgery compared to patients who did not have surgery.
Less prednisone
The study found that thymectomy patients needed approximately one-third less prednisone to control their disease than did those who did not have the surgery. Their need for steroid-sparing immunosuppresants, such as azathioprine, was reduced by nearly two-thirds.
Wolfe said: “We were quite satisfied to see that thymectomy conferred benefits on disease status measures by the Quantitative Myasthenia Gravis (QMG) score, reduced the need for corticosteroids and other immunosuppressants, reduced hospitalization needs, and also, according to most measures, reduced the side effect burden.”
Only a few decades ago, approximately a third of all patients with MG died from it, but new diagnostic techniques and treatments have dramatically improved both the quality of life and longevity of patients. Today, the lifespan for myasthenia gravis patients matches that of the general population.
mercredi 10 août 2016
Research suggests new tool for cancer treatment based on cell type
WEST LAFAYETTE, Ind. – A new tumor model has been shown to predict how certain types of cancer cells react differently to a commonly used chemotherapy drug, a potential tool for "precision medicine," in which drug treatment is tailored to individual patients and certain cancer types.
Drug resistance and various subtypes of tumors represent critical bottlenecks for effective chemotherapy.
"This means rapid and accurate screening of effective drugs and drug combinations can be extremely useful to realize precision medicine for cancer therapy," said Bumsoo Han, a Purdue University professor of mechanical and biomedical engineering
Recent research findings demonstrate that a new tumor-modeling platform called a tumor-microenvironment-on-chip (T-MOC) can be used to visualize and quantify how different types of cancer cells react differently to the chemotherapy drug doxorubicin. The drug sometimes failed during testing to kill cancer cells yet stopped their growth.
"So, there are differences in the response to the drug based on cancer type," Han said. "Our platform makes it possible to assess the efficacy of chemotherapeutic drugs according to cell-type; for example, which cells actually died from this drug, which cells didn't die but stopped actively growing, or even which cells survived the drug."
Based on experimental data, the researchers developed a theoretical model to quantify and ultimately predict the effectiveness of drugs depending on the type of cancer cell being treated.
The findings were detailed in a paper published in the July issue of Molecular Pharmaceutics. The paper was authored by graduate student Kyeonggon Shin, undergraduate Brett S. Klosterhoff and Han.
Researchers performed experiments using the T-MOC platform that could help usher in precision medicine, in which drug treatment is tailored to specific patients and certain cell types.
"We are providing a new tool, a new platform to test drugs and drug delivery systems for precision medicine," Han said.
The device is about 4.5 centimeters (1.8 inches) square and contains "microfluidic" channels where cancer cells were cultured within a three-dimensional "extracellular matrix," a scaffold-like material found between cells in living tissue. The experiments also incorporated "interstitial fluid," which is found inside tumors and is thought to be a barrier to drug delivery.
Three types of human breast cancer cell lines were cultured on the T-MOC platform, and their drug response and resistance to doxorubicin were characterized by time-lapse fluorescence microscopy.
"Particularly in breast cancer, there are different subgroups of cancers," Han said. "Depending on the subgroup, the drug response is different. So, to study the efficacy of a drug and its nanoparticle formulation, we examined how the drug and nanoparticles were transported through the interstitial space and uptaken by different types of cancer cells."
Two of the three types of breast cancer cells tested were triple negative breast cancer, one of the most-difficult-to-treat forms of the disease.
"Even within triple negative there are additional subtypes, so this is not one single disease," Han said. "The targeting drugs only work with certain types of cells."
The findings also showed some cell types take up drugs more rapidly than others.
"You can see that, depending on the cell type, the response to the same drug is different and the drug uptake is different," he said.
Future research will involve comparing and validating research results with data from laboratory animal tests and incorporating a more complex mixture of tumor stromal components in the T-MOC experiments. Ultimately, in precision medicine, a patient's tumor cells might be studied using a T-MOC system to determine the proper drug and dosage to use before beginning treatment, Han said.
Research to fabricate the microfluidic device was performed at the Birck Nanotechnology Center in Purdue's Discovery Park. The work also is associated with the Purdue University Center for Cancer Research.
The research was partially funded by the National Institutes of Health; a Collaboration in Translational Research Award from the Indiana Clinical and Translational Sciences Institute; the Walther Cancer Foundation; and the Digital Human Project.
Writer: Emil Venere, 765-494-4709, [email protected]
Source: Bumsoo Han, 765-494-5626, [email protected]
ABSTRACT
Characterization of Cell-Type-Specific Drug Transport and Resistance of Breast Cancers Using Tumor-Microenvironment-on-Chip
Kyeonggon Shin,† Brett S. Klosterhoff,† and Bumsoo Han*
†School of Mechanical Engineering, Purdue University, West Lafayette, Indiana 47907, United States §Weldon School of Biomedical Engineering, Birck Nanotechnology Center, and Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States * Corresponding author, e-mail [email protected]
Heterogeneous response and resistance of cancer cells to chemotherapeutic drugs pose a significant challenge for successful cancer treatments. In this study, an integrated experimental and theoretical analysis of cellular drug transport was developed. The experimental platform, called tumor-microenvironment-on-chip (T-MOC), is a microfluidic platform where cancer cells were cultured within a three-dimensional extracellular matrix perfused with interstitial fluid. Three types of human breast cancer cell lines (MCF-7, MDA-MB-231, and SUM-159PT) were cultured on this T-MOC platform, and their drug response and resistance to doxorubicin were characterized by time-lapse quantitative fluorescence microscopy. To study the effects of nanoparticle-mediated drug delivery, the transport and action of doxorubicin encapsulated nanoparticles were also examined. Based on the experimental data obtained, a theoretical model was developed to quantify and ultimately predict the cellular transport processes of drugs cell-type specifically. The results demonstrate that the cellular drug transport can be celltype-specifically quantified by rate constants representing the uptake and efflux of doxorubicin across the cellular membrane.
Infant gut microbiota linked to milk allergy resolution
Cow’s milk allergy is the most common food allergy in young children, affecting 2-3%. A child may have to live with the limitations imposed by milk allergy for several years, as recent studies have shown that milk allergy often continues into later childhood and adulthood. Parents of milk allergic children often ask allergists to gauge whether their child’s milk allergy will resolve. The etiology and course of food allergy may involve deviation from immune tolerance that is driven by diet, commensal microbiota, and interactions between them. Previous work in this area has relied upon culture methods, which allow for examination of species specifically targeted and cultured, but exclude the large majority of bacterial organisms that cannot be cultured. These excluded organisms may play key roles in the natural history of milk allergy.
In a recent article published in The Journal of Allergy and Clinical Immunology (JACI) Bunyavanich and colleagues addressed the hypothesis that gut microbiota play a role in the natural history of milk allergy. Bunyavanich and colleagues used high-throughput sequencing to comprehensively characterize the infant gut microbiota of 226 children age 3-16 months with cow’s milk allergy. Their use of high-throughput sequencing allowed them to systematically profile bacterial taxa in the infant gut environment, including the vast majority that cannot be cultured. The research team followed these children up to age 8 years, finding that 56.6% of them outgrew their milk allergy. They used computational biology approaches to examine for links between early-life gut microbiota diversity, composition, and milk allergy resolution.
Dr. Bunyavanich and her colleagues found enrichment of specific bacterial taxa-- Clostridia and Firmicutes-- in the infant gut microbiome of 3-6 month old subjects whose milk allergy resolved by age 8 years. The microbiota of these young infants whose milk allergy resolved were associated with decreased fatty acid metabolism. The team’s results are the first to address the relationship between gut microbiota and food allergy resolution. Their findings suggest directions for prospective examination of the identified microbiota for potential therapeutic consideration. Early infancy may be an important window during which gut microbiota shape food allergy outcomes.
The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
American Academy of Allergy, Asthma & Immunology
Infant gut microbiota linked to milk allergy resolutionNew model sheds light on secondary bacterial pneumonia
Research could pave way to prevent secondary infections in people with influenza A virus
BUFFALO, N.Y. – For years, researchers have known that the bacteria Staphylococcus aureus (S. aureus) can trigger severe, sometimes deadly, secondary bacterial pneumonia in some people who are subsequently infected with influenza A virus, but scientists have not known exactly how this happens.
Now, University at Buffalo scientists have developed a new model for studying this phenomenon, which could lead to new ways to prevent secondary bacterial infections. The findings were published this week in mBio, an online open-access journal of the American Society for Microbiology.
“This study has established a physiologically relevant model, so we can now more carefully evaluate the actual events involved after colonization with S. aureus and identify the primary factors that can lead to secondary bacterial pneumonia,” said Anthony Campagnari, PhD, senior author and professor in the Department of Microbiology and Immunology and the Department of Medicine in the Jacobs School of Medicine and Biomedical Sciences at UB.
S. aureus is one of the most common causes of secondary bacterial pneumonia in cases of seasonal influenza. Scientists have been studying this phenomenon by introducing S. aureus directly into the lungs of mice. However, this does not mimic the natural pathogenesis of infection.
In the new model, Ryan Reddinger, a doctoral candidate in the UB Department of Microbiology and Immunology who is working in Campagnari’s lab, developed a technique where S. aureus stably colonizes the nares (nostrils) of mice and these animals are subsequently infected with influenza A virus to see what would happen.
“Ryan’s work demonstrated that influenza A virus infection leads to the dissemination of S. aureus from the nasal cavity into the lungs, resulting in the development of secondary bacterial pneumonia in these mice,” said Campagnari. “The model is very relevant to the current physiologic state in humans where individuals are colonized by S. aureus in the nares and subsequently acquire a viral infection.
“The fascinating thing about this model is when we colonize mice with S. aureus it remains in the nares for up to seven days, without obvious signs of disease and does not appear to move to the lungs on its own,” Campagnari noted. “The bacteria only disseminates to the lungs in response to the subsequent viral infection.”
When someone has a viral infection, certain physiologic changes occur in the nasopharynx that are related to damage of host cells and host responses, including increased body temperature and release of glucose, norepinephrine and the cellular energy carrier, adenosine triphosphate or ATP. With their model, the UB researchers discovered that a combination of these factors, in the absence of influenza A virus, will cause S. aureus to leave the nasopharynx and travel to the lungs.
“We don’t know why the viral infection induces the bacteria to disseminate to the lung, but now we can evaluate potential mechanisms more closely because of this model,” said Campagnari. “In addition, this model could be adapted to study other virus-bacterial interactions.”
Founded in 1846, the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo is beginning a new chapter in its history with the largest medical education building under construction in the nation. The eight-story, 628,000-square-foot facility is scheduled to open in 2017. The new location puts superior medical education, clinical care and pioneering research in close proximity, anchoring Buffalo’s evolving comprehensive academic health center in a vibrant downtown setting. These new facilities will better enable the school to advance health and wellness across the life span for the people of New York and the world through research, clinical care and the education of tomorrow’s leaders in health care and biomedical sciences. The school’s faculty and residents provide care for the community’s diverse populations through strong clinical partnerships and the school’s practice plan, UBMD Physicians’ Group.
Peanut allergy prevention strategy does not impact growth or nutrition
The primary results of the LEAP trial, published in 2015 showed that consumption of peanut from infancy led to an 81 percent relative reduction in subsequent development of the allergy compared to avoiding peanut altogether. Although an effective strategy for the prevention of peanut allergy in high-risk infants, regular peanut consumption from infancy and throughout early childhood could have unexpected consequences for growth and nutrition.
In a recent paper published in The Journal of Allergy and Clinical Immunology (JACI) Feeney and colleagues report secondary results from the LEAP Study.
The original LEAP trial randomly assigned 640 infants aged 4 to 11 months to regularly consume at least 6g peanut protein per week or to avoid peanut until 5 years of age. In this publication, the researchers report on the feasibility of regular consumption of peanut products from infancy and whether this dietary intervention would have any adverse effects on infant and child growth and nutrition. Adherence to peanut consumption or avoidance advice was assessed by dietary questionnaires; nutritional intake assessed from three day prospective food diaries and growth evaluated from anthropometric measurements (weight, height, body mass index, waist circumference and skinfold thickness) recorded at regular clinic visits.
The study found that peanut consumers easily achieved the recommended weekly peanut intake, consuming 7.5 grams weekly on average. Importantly, the introduction of peanut in breast-feeding infants did not affect the duration of breast-feeding. They did not observe any differences for measures of infant and child growth between the peanut consumers and avoiders at any point during the study, even when comparing the subgroup of children with the highest peanut intakes with those who avoided peanut. There were no differences in energy (calorie) and protein intakes, although consumers had higher fat intakes and avoiders had higher carbohydrate intakes; these differences were greatest for the subgroup of children with the highest peanut intakes. Sodium (salt) intakes were above recommended intakes in both groups, there were no differences between intakes for consumers compared to avoiders. There were also no differences for intakes of micronutrients such as calcium, iron, zinc and vitamin D. The children in the consumption group made some different food choices to the avoiders. Peanut products appeared to be eaten instead of foods such as crisps and savoury snacks, high fibre bread, fruit juice & smoothies and spreads.
Introduction of peanut proved feasible in infants at high risk of peanut allergy and did not affect the duration of breast-feeding nor impact negatively on growth or nutrition. Energy balance was achieved in both groups through variations in intakes from fat and carbohydrate while protein homeostasis was maintained.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
American Academy of Allergy, Asthma & Immunology
Peanut allergy prevention strategy does not impact growth or nutritionA breakthrough in combating malaria with odour-baited trap for mosquitoes
The use of a newly-developed mosquito trap incorporating human odour has resulted in a 70% decline in the population of the most significant malaria mosquito on the Kenyan island of Rusinga. After the introduction of the odour-baited traps on the island the proportion of people with malaria was 30% lower among those living in houses with a trap compared to people living in houses who were yet to receive a trap. The study was published today in The Lancet, a leading scientific journal. Prof. Willem Takken led the three-year study with Wageningen University scientists and researchers from the Kenyan International Centre of Insect Physiology and Ecology (ICIPE) and the Swiss Tropical and Public Health Institute (Swiss TPH).
Zika and dengue fever
The odour-baited trap may also offer a solution to diseases like dengue fever and the Zika virus. Aedes aegypti (the yellow fever mosquito), is a vector for these viruses. This mosquito is attracted to the same humanised scent that attracts malaria mosquitoes. Zika and dengue fever could therefore be combated with the odour-baited traps.
Better living conditions
The success of the new approach is the combination of the odour-baited trap with mosquito nets, anti-malaria drugs, and a solid social strategy. The odour-baited traps need electricity to operate, but there is no central electricity supply on Rusinga, an island in Lake Victoria. Solar panels were installed on the roofs of homes. These not only provided electricity for the mosquito traps but also provided the homes with power for light and to charge a mobile phone. The use of solar energy to control malaria gave rise to the project name: SolarMal. Great efforts were also made in relation to education about malaria and actively engaging the inhabitants of Rusinga in the project. Thanks to this combined approach, all 25,000 inhabitants of Rusinga participated in the study. When the odour-baited traps are used, the use of insecticides to combat the mosquito population can be minimised, thus avoiding any harmful side effects of such products. The Wageningen anti-malaria approach therefore has positive effects in reducing the spread of malaria as well as positive effects on the living conditions of the population.
Malaria: a major cause of death and an economic problem
Every minute, a child dies of malaria. This disease costs Africa twelve billion dollars a year in health-care costs and lost productivity, particularly in the agricultural sector. Fighting malaria without using insecticides is vital to world food production. “The effect of the disease on agricultural production is hugely underestimated,” says Willem Takken. “As children with malaria need access to hospital care, their parents cannot work on the land and as a result food production rates decline. If those parents themselves also suffer from malaria infections four or five times a year, they are also not able to work for around six weeks. In such cases, extra labour needs to be brought in or the crop will be lost. An African household loses 10% of its annual incomes through malaria. It is for good reason that reducing the prevalence of malaria was included in the ten millennium development goals formulated by the UN.”
The World Health Organization (WHO) is aiming to eradicate malaria by 2030. To this end, investments are being made in the development of vaccines against the parasite and in combating the vectors of the parasite: the mosquitoes. The odour-baited trap - named ‘the Suna trap’ - represents an effective and safe solution in the fight against the mosquito.
Publication
The effect of mass mosquito trapping on malaria transmission and disease burden (SolarMal): a stepped-wedge cluster-randomised trial. Tobias Homan, Alexandra Hiscox, Collins K Mweresa, Daniel Masiga, Wolfgang R Mukabana, Prisca Oria, Nicolas Maire, Aurelio Di Pasquale, Mariabeth Silkey, Jane Alaii, Teun Bousema, Cees Leeuwis, Thomas A Smith, Willem Takken. The Lancet on line publicatie, 9 augustus 2016.
Distraction Techniques Can Soothe Shot Anxiety During This Year’s Flu Season
A typical visit to the pediatrician when it is time for a child to get a shot can include tears, tantrums and might not seem worth the trouble. But with the FluMist not being offered by many physicians this year due to ineffectiveness, doctors at Nationwide Children’s Hospital recommend your child still get the flu shot. To calm shot-related anxiety, parents can ask their pediatrician about distraction techniques to help comfort their child when receiving a shot.
“The Centers for Disease Control and the American Academy of Pediatrics have issued recommendations against the FluMist this year,” said Dennis Cunningham, MD, medical director for epidemiology and infection control at Nationwide Children's Hospital. “However, everyone 6 months and older should still get a flu vaccine injection unless they have medical reasons to avoid them. Vaccinations are the most effective way to protect against influenza, a very serious disease that affects the lungs and respiratory tract.”
Evidence-based medicine has proven that developmentally appropriate support measures do help to reduce fear and procedure-related stress for children
“Adults should keep in mind that they often set the stage for how the child will cope,” said Donna Trentel, MSA, CCLS, director of family and volunteer services at Nationwide Children’s. “Kids of all ages naturally tune into the signals given by adults pay attention to your stress level, word choices, and cues you are sending your child.”
Infants, for example, respond well to swaddling, pacifiers and breastfeeding for pain control. Younger children (2-6 years old) respond well to distractions like videos, music, singing and special positioning, opportunities for choice and control such as to watch or not watch, picking which arm is used, and having a role like holding the bandage. Older children (6 years and older) respond well to relaxation such as deep breathing, praise, and guided imagery, like imagining and talking about a favorite place.
“It’s not uncommon for a child to feel anxious or scared when it’s time to get a shot,” said Melissa Winterhalter, MD, physician with the Section of Ambulatory Pediatrics at Nationwide Children’s Hospital. “If a child is really upset, or crying, or anxious, we’ll stop and really look for those distraction techniques to relax the child, to ease the pain so that it’s a quick and easy process for both the child and the family.”
One method Dr. Winterhalter’s team has begun using for her patients is a friendly animal-shaped cold pack that also vibrates when placed on the injection site. The various sensations scramble the pain response that the body feels, so a child will feel the cold or the vibrations and not necessarily the pain from the injection. Tools such as this, along with other distractions, can help soothe a child and make the experience easier.
“Parents are the key to success,” said Dr. Winterhalter. “If there is something that works well for your child, let your pediatrician know so they can implement that technique. Parents can also help by talking to their child openly and honestly about any procedure beforehand, so they understand what is happening and what to expect.”
Click here to learn more about distraction techniques for children.
Nationwide Children's Hospital
Distraction Techniques Can Soothe Shot Anxiety During This Year’s Flu SeasonBetter off without it: Broken gene may help protect against ulcerative colitis
By Veronica Meade-Kelly, Broad Communications
We often think of the body as a machine, with every part—right down to each single gene—working with optimal efficiency to keep us healthy and disease-free. Take a single bolt out of that machine and something could go wrong—a part ceases to move at the proper speed perhaps, or worse, an entire system fails.
But what if you removed that hypothetical bolt and the “machine” actually worked better? What if missing that one part, for instance, helped the body burn fuel more efficiently, or prevented a glitch that would otherwise cause the machine to fall into disrepair? Were that the case, then perhaps studying that part and its function within the larger machine might reveal more about how the machine works—or might even suggest ways to fix things if the machine broke down.
Scientists have found that something akin to that in human genetics, where research has uncovered a handful of so-called “loss-of-function” (LoF) mutations that appear to help protect individuals from certain diseases. These mutations are slight variations in an individual’s genetic code that essentially “break” a gene, causing the gene to produce an incomplete (or “truncated”) protein that doesn’t function in the body the way it normally would.
In 2006, scientists found that such LoF mutations in the gene PCSK9, which produces a protein involved in cholesterol regulation, were associated with lower LDL cholesterol and a lower risk of heart attack. Subsequently, an LoF mutation in the gene CARD9 was found to confer protection against ulcerative colitis (UC) and Crohn’s disease, two debilitating inflammatory bowel diseases (IBDs). Such findings are promising because they point to a specific part of the genome that may be involved in inhibiting disease, suggesting potential therapeutic targets.
“The hypothesis is that if you inhibit that gene, you will mimic the effect of the mutation, which is to protect the individual from disease. This makes these loss-of-function mutations an attractive lead for drug developers,” explains Manuel Rivas, a computational scientist in the Broad Institute’s Medical and Population Genetics (MPG) Program.
Rivas and others are now conducting searches for other LoF mutations and, this week in Nature Communications, Rivas was first author of a paper that announced the discovery of such a protective mutation specific to UC, a chronic disease of the large intestine that affects roughly 700,000 people in the U.S. alone.
To track down the mutation, Rivas and colleagues, including senior author Mark Daly, who is co-director of Broad’s MPG Program, sequenced genes in regions of the genome that had been previously linked to IBD. Samples that they sequenced came from over 3,000 individuals—some with UC or Crohn’s disease, and others who were healthy controls. The team looked at the sequencing data for evidence of mutations that resulted in “broken” genes that did not produce functional proteins. The search produced a short list of LoF mutations that they then studied more closely, comparing the prevalence of these mutations in IBD sufferers versus healthy individuals.
“The assumption is that if you see many more copies of the LoF mutation in healthy controls compared to individuals who suffer from the disease, then that suggests a protective effect,” Rivas says.
The process led them to a single mutation in RNF186, a gene that’s biological function is just starting to be deciphered. Individuals with UC were unlikely to carry this mutation, while it was much more common in the healthy controls. Since those with the “broken” gene tended not to get UC, the findings suggest that the gene and the protein it produces might somehow play a role in the development of the disease. That makes RNF186 and its protein a promising focus for follow-up studies to determine whether they, or related biological pathways, might make effective targets for therapeutics.
“The nice thing about these protective alleles that disrupt or knockout the function of a gene is they get us closer to understanding the biological role of the gene—what it does in health and disease,” says Daly, who is also founding chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School. “That’s why there is great enthusiasm for this approach of looking for mutations that break genes; these insights can directly inform the development of new therapies that will have genetic evidence suggesting their safety and efficacy.”
One of the keys to finding such mutations, the researchers say, is access to large collections of genetic samples. Since these LoF mutations may be rare, they may only appear—and so may only be detectable—in large studies. For this study, the researchers benefited from the availability of large sample collections and the willingness of scientists at several institutions and in many countries to share data. Access to the deCODE database turned out to be particularly helpful. deCODE houses and analyzes vast amounts of data from genetic samples taken from Iceland. Since the Icelandic population is relatively isolated, specific rare mutations may be passed on and retained among the people who live on the island, and can therefore appear with greater frequency than in other populations. For instance, the mutation found in RNF186 was four times more common in the population represented in the deCODE data than in other data sets.
“We are incredibly grateful to our colleagues around the globe who were willing to openly share their data. It was that spirit of collaboration that enabled this discovery to be confirmed so rapidly,” Daly says.
Now that the mutation has been identified, the next steps are to explore the function of the RNF186 protein more in depth and to determine what role it may play in UC. The goal is to elucidate the biology underlying the disease enough that drug developers can explore potential treatments that may mimic the effects of the mutation. That path has worked thus far for PCSK9, where the LoF mutation was shown to help protect against heart attack. That discovery has inspired treatments currently in clinical trials.
The researchers are also looking to follow up this study with others seeking LoF mutations.
“For me as a statistical geneticist, I’m interested in taking this approach to a broader set of traits and diseases and integrating many other data types. Focusing on these ‘broken’ genes has proven to be a valuable approach; it helps us efficiently home in on relevant biology,” Rivas says.
Paper cited:
Rivas, MA et al. A protein truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nature Communications. Online August 9, 2016.
Broad Institute
Better off without it: Broken gene may help protect against ulcerative colitisCancer investigations should consider evolution as a cause: Deakin research
The reasons people and animals develop cancer in some organs but not in others may have more to do with evolution than any lifestyle or genetic factors, new research led by Deakin University in partnership with the National Centre for Scientific Research of France.
The research, published in the latest edition of Trends in Cancer, argues that evolution has protected essential but unpaired organs from tumour development, such as the heart. However, larger and often paired organs, such as the liver, are more likely to develop cancers, as they might be less essential to survival.
Researcher Dr Beata Ujvari, from Deakin’s Centre for Integrative Ecology, within the School of Life and Environmental Sciences, said the difference in cancer prevalence between organs had previously been accredited to intrinsic factors such as stem cell numbers and high mutation rates in certain organs, or to extrinsic factors such as cigarette smoking and pollution.
“We propose that also considering organs as distinct but connected ecosystems whose different vulnerabilities to malignant transformation may be partially explained by how essential each organ is for survival,” Dr Ujvari said.
“For example, the relative rarity of heart and brain cancers can potentially be attributed to the low cellular turnover in these organs, and therefore to the low opportunities for cancer causing mutations.
“We think that turnover rates may also be low in these organs because they are crucial to survival. While the cell turnover rate is approximately 4-15% per year in the heart, and 2.7% in the brain, the intestinal epithelium completely self-renews approximately every five days.”
The scientists predict that after the effects of stem cell numbers, rates of cell division, and exposure to toxins and infection are taken into consideration, the ecology of different organs will account for considerable differences in vulnerability to cancer.
They are currently working on a formal test to prove or disprove their hypothesis.
“This kind of evolutionary ecological analysis of variations in different organs may prove of great value in cancer prevention and treatment,” Dr Ujvari said.
The research, Evolutionary Ecology of Organs: A Missing Link in Cancer Development?, is part of a recently-awarded International Associated Laboratory project (Laboratory Without Walls), given by the National Centre for Scientific Research (CNRS) to build collaboration between Deakin University and the CNRS of France.
The project, which is the first of its kind awarded between France and Australia, will allow Dr Ujvari to explore the links between evolution and cancer, with her French colleague Professor Frédéric Thomas, her co-author on the newly published research.
Both scientists use evolutionary and ecological knowledge to understand how cancer is developing and evolving, and also to investigate the impact of cancer in wildlife and in ecosystems.
“By combining approaches on different biological models, we can expand our understanding to various ecological and evolutionary scales,” Dr Ujvari said.
“Oncology as a scientific field has, until now, developed in relative isolation from ecological and evolutionary sciences. This is unfortunate because links between these disciplines have the mutual potential to reveal new perspectives and lines of research.
“For instance, while cancer is traditionally considered as a distinct pathology from a medical point of view, interdisciplinary approaches reveal that it is instead an unavoidable dynamic phenomenon governed by evolutionary principles and ecological relationships.
“This project aims to fill an important gap in ecology and evolution, exploring a research direction never explored before.”
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Paleo side effects probed
Despite growing in popularity, the Paleo diet causes more negative side effects than traditional diets according to research from Edith Cowan University published today.
The Australian-first study involved 39 healthy women, with half eating a Paleo diet while the rest were assigned the Australian Guide to Healthy Eating (AGHE) diet over a four-week period.
More than one in five women who ate the Paleo diet reported instances of diarrhoea, compared with none of the AGHE group.
The Paleo group also reported higher rates of tiredness, and trouble sleeping.
The research follows another ECU study released earlier this year that found the Paleo diet to be more effective for weight loss than the AGHE.
Negative side effects
Associate Professor Amanda Devine said that while more research was needed to determine the exact causes, the side effects may be a result of the Paleo diet cutting out dairy foods and grains.
“We know that whole grains are a great source of dietary fibre, and a lack of fibre can impact the microbes in your gut, which could in turn cause problems like diarrhoea,” she said.
“Similarly, dairy products contain the amino acid tryptophan which increases sleep-inducing compounds serotonin and melatonin which helps regulate sleeping patterns. So removing dairy from your diet could adversely affect your sleep.”
More than half of the Paleo group also reported that the diet increased their average cost of groceries, compared to only six per cent of the AGHE group.
Long term implications
Lead researcher Angela Genoni said work was now underway on a new research project examining the long-term impact of following the Paleo diet, particularly on gut health.
“Removing entire food groups like dairy and grains from your diet is likely to impact overall health,” she said.
“This is why we are recruiting for a larger study involving participants that will look at the long-term effects of adhering to a Paleo diet.”
Long-term Paleo followers are encouraged to email Angela Genoni if they are interested in participating in this research.
Compliance, palatability and feasibility of Paleolithic and AGHE diets in healthy women: a 4wk dietary intervention was published in Nutrients.
Edith Cowan University
Paleo side effects probedlundi 8 août 2016
Age-Related Infertility May Be Caused By Scarred Ovaries
Women’s inability to produce healthy eggs as they grow older may be caused by ovarian aging
CHICAGO --- Women’s decreased ability to produce healthy eggs as they become older may be due to excessive scarring and inflammation in their ovaries, reports a new Northwestern Medicine study in mice.
This is the first study to show the ovarian environment ages and that aging affects the quality of eggs it produces. These findings could result in new treatments that preserve fertility by delaying ovarian aging.
Most reproductive research focuses on women’s eggs and trying to understand why their number and quality deteriorate as a woman enters her forties. Deteriorating eggs contribute to infertility, miscarriages and birth defects.
But in this study scientists examined the reproductive age-related changes that occur in the environment in which the eggs develop, known as the ovarian stroma. The environment in which cells grow and develop can greatly influence their quality and function, but surprisingly little is known about how the ovarian stroma changes with age.
“Under the microscope, eggs from reproductively young and old animals may look identical, but the environment in which they are growing is completely different,” said lead study author Francesca Duncan, executive director of the Center for Reproductive Science at Northwestern University Feinberg School of Medicine. “Ovaries from reproductively old mice are fibrotic and inflamed. There is no way this environment won’t impact the eggs growing in it, and it very likely contributes to their decrease in quality.”
The study was published August 5 in the journal Reproduction. Duncan led the study when she was at the University of Kansas Medical Center.
In this study, researchers analyzed ovarian tissue from populations of reproductively “young” (equivalent to women in their early twenties) and “old” mice (equivalent to women ages 38-45). They consistently identified fibrosis in the reproductively “old” mice. This age period is associated with a decline in reproductive function and egg quality in both humans and mice. In some reproductively “old” mice, up to 35 percent of the ovarian tissue was fibrotic.
Researchers also found a type of immune cell (multinucleated macrophage giant cells) in the ovaries of reproductively “old” mice only. When found in other tissues, these cells are associated with chronic inflammation. They also found ovaries from mice of advanced reproductive age expressed genes and produced proteins that are highly inflammatory.
“Our work establishes fibrosis and inflammation as hallmarks of the aging ovary and lays the foundation for considering the use of anti-fibrotic or anti-inflammatory treatments to delay or counteract the impact of reproductive aging,” said Duncan, also an associate research professor in obstetrics and gynecology at Feinberg.
“People tend to overlook that the egg is growing in a complex environment, and no one has taken a deep look at what is happening to that environment with age,” Duncan added. “It’s an underappreciated area.”
The findings have broader implications for women’s health because ovarian fibrosis is a key feature of polycystic ovary syndrome, a common endocrine system disorder among women of reproductive age, and is also a consequence of chemotherapy and radiation, Duncan said.
Duncan’s research team is currently investigating how to therapeutically target the ovarian environment to improve reproductive function.
This work was supported by the Center for Reproductive Health After Disease (P50 HD076188), the National Centers for Translational Research in Reproduction and Infertility, the Centers of Biomedical Research Excellence (P20 GM104936), the National Center for Research Resources (P20 RR021940), the National Institute of General Medical Sciences (P20 GM103549) and the National Institute of Environmental Health Sciences ‘Training Program in Environmental Toxicology’ (T32 ES007079) of the National Institutes of Health.
Northwestern University
Age-Related Infertility May Be Caused By Scarred OvariesAir pollution linked to lung cancer survival time
USC researchers found that survival of patients in areas with high regional pollution was about three years shorter than for those in areas with lower levels of pollution
xposure to air pollution has many impacts across the life span and has now been linked to survival of patients after being diagnosed with lung cancer, the most commonly diagnosed cancer over the past several decades.
“We thought that if ambient air pollution is a carcinogen that can drive lung cancer development, then exposure to air pollution in patients already diagnosed with lung cancer could promote the progression of their disease through the same biological pathways,” said Sandrah Eckel, assistant professor of preventive medicine at the Keck School of Medicine of USC and lead author of the research. Eckel and colleagues at the Keck School decided to more closely explore the question of whether lung cancer survival times might be affected by air pollution.
Their research, published this month in Thorax, shows that the length of time that lung cancer patients live after diagnosis varies depending on their exposures to regional pollution. Researchers found that the median survival for people diagnosed with early stage lung cancers who lived in areas with high levels of regional pollution was approximately three years shorter than for people who lived in areas with lower levels of pollution.
“We focused on California, since there are a wide range of air pollution levels here and one of the largest and longest running air quality monitoring networks and cancer registry system in the U.S.,” Eckel said.
Eckel and her team of researchers looked at lung cancer data from over 350,000 patients in the California Cancer Registry who were diagnosed with lung cancer between 1988-2009. From the extensive and detailed dataset, the team assigned air pollution exposure levels based on the average exposure at the patient’s residence at diagnosis.
Unique study
“This study is unique in that it looks at another modifiable risk factor, besides smoking, that can impact lung cancer survival after diagnosis. The California Cancer Registry data provided a large, population-based sample of all lung cancer cases diagnosed in California over the last 20 years, minimizing the biases often encountered in other types of study designs,” Eckel said.
In general, the stage of cancer at diagnosis is a major determinant of survival, with patients diagnosed with earlier stage cancer living longer. As expected, the impacts of air pollution on survival were most evident in patients diagnosed at an early stage, when their cancer was localized to only their lungs. The median survival in patients with localized cancer at diagnosis living in areas with higher levels of fine particulate matter (2.5 micrometers in diameter) was only 2.4 years as compared to 5.7 years in patients living in areas with lower levels of fine particulate matter.
Patients whose cancer had spread to other parts of their bodies had shorter survival times overall and showed little difference in survival time whether they had high or low exposures to air pollution. These patterns of association persisted even after adjusting for numerous socio-demographic characteristics and type of cancer treatment.
More research needed
The study’s findings are intriguing, but additional research is needed to determine the causality of the association between air pollution and lung cancer survival rates.
Even so, the findings suggest that newly diagnosed lung cancer patients might want to consider taking precautions to reduce their own exposures to air pollution. As lung cancer screening in emphasized, more patients will likely be diagnosed at early stages — and they could potentially benefit the most from reduced air pollution exposures.
What can lung cancer patients with a locally diagnosed cancer do to take action that may effectively extend their survival times? Frank Gilliland, senior investigator on the study, said, “In the short-term, common-sense precautions to reduce personal exposure to air pollution exposures include avoidance of places and times with high air pollution levels and using indoor home filtration systems. In the long-term, air quality standards should be evaluated to consider whether they are adequately protecting human health.”
The article, “Air pollution affects lung cancer survival time” by Sandrah P Eckel, Myles Cockburn, Yu-Hsiang Shu, Huiyu Deng, Frederick W Lurmann, Lihua Liu and Frank D Gilliland. (http://ift.tt/2aCI0bX) appears in Thorax, Published Online First (Aug. 4, 2016)
This work was supported by the Southern California Environmental Health Sciences Center (grant 5P30ES007048) funded by the National Institute of Environmental Health Sciences; the Hastings Foundation; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement U58DP003862-01 awarded to the California Department of Public Health.
University of Southern California
Air pollution linked to lung cancer survival timeDiabetics should put paleo on pause, expert warns
“There have been only two trials worldwide of people with type 2 diabetes on what looks to be a paleo diet,” said Associate Professor Andrikopoulos, a researcher at the University of Melbourne Department of Medicine, based at the Austin Hospital.
“Both studies had fewer than 20 participants, one had no control diet, and at 12 weeks or less, neither study lasted long enough for us to draw solid conclusions about the impact on weight or glycemic control.”
Associate Professor Andrikopoulos, who is also President of the Australian Diabetes Society, recommended people with type 2 diabetes seek advice from their GPs, registered dietitians and diabetes organisations.
“Most paleo diets insist on avoiding refined sugar and processed food, which is consistent with dietary guidelines worldwide,” he said.
“But when you start cutting out whole grains and dairy, which are absent from many forms of the paleo diet, you may forgo important sources of fibre and calcium.
“And high-fat, zero-carb diets promoted by some celebrities make this worse, as they can lead to rapid weight gain, as well as increase your risk of heart disease.”
Associate Professor Andrikopoulos says people with diabetes benefited most from regular exercise and the Mediterranean diet — olive oil, fats from fish, legumes and low in refined sugar.
“While it’s tempting to emulate celebrities who look great and can spend a lot of time at the gym, if you’re already overweight or you live a sedentary life, it may be quite risky to adopt a high-fat diet… and if you have diabetes, it’s downright dangerous.
“The internet is full of testimonials from people saying a particular diet worked for them because they cut calories and lost weight, but people with diabetes in particular need to approach those claims with caution and seek advice from their health care professional.”
Diabetics should put paleo on pause, expert warnsTSRI Scientists Pinpoint Ebola’s Weak Spots
New Study Illuminates Structure of Mystery Protein
LA JOLLA, CA – Scientists at The Scripps Research Institute (TSRI) now have a high-resolution view of exactly how the experimental therapy ZMapp targets Ebola virus.
The new study is also the first to show how an antibody in the ZMapp “drug cocktail” targets a second Ebola virus protein, called sGP, whose vulnerable spots had previously been unknown.
“This sGP protein is tremendously important,” said TSRI Professor Erica Ollmann Saphire, who co-led the study with TSRI Associate Professor Andrew Ward. “This is the roadmap we need to target the right molecules in infection.”
“Determining the proper balance in targeting these two Ebola proteins will be key to building improved therapeutics,” added Ward.
The study was published August 8, 2016 in the journal Nature Microbiology.
Zooming in on ZMapp
Scientists need detailed images of Ebola virus’s molecular structure. Like enemy reconnaissance, structures can show where Ebola is vulnerable and how medical treatments can neutralize it.
TSRI scientists are harnessing an imaging technique called cryo-electron microscopy (in which a sample is pelted with electrons) to create high-resolution, 3-D images of Ebola virus and the antibodies that fight it.
“We’re at the cutting edge of our ability to resolve high-resolution protein complexes,” said TSRI Research Associate C. Daniel Murin, co-first author of the new study with TSRI Research Associate Jesper Pallesen.
In the new study, the researchers used cryo-electron microscopy to see exactly how Ebola virus interacts with the three antibodies in the ZMapp experimental therapy produced by Mapp Biopharmaceutical, also a study collaborator.
The researchers had imaged these interactions at a low resolution in a 2014 study, but the new study revealed substantially more details, including the exact angles the antibodies use to approach the molecule on the surface of the virus, termed its surface glycoprotein (GP), and the individual amino acid contact points at which the antibodies bind GP. This information provides new clues to researchers trying to make the antibodies even more effective.
“The three components of ZMapp, now resolved at high-resolution, can be further engineered in a structure-based manner for improved potency,” said Ward.
Solving an Elusive Structure
Next, the researchers took a closer look at one of the three antibodies that make up ZMapp, called 13C6. This antibody is unique because it can also target the soluble Ebola protein sGP.
sGP’s role in infection is a mystery. Ebola virus makes the protein profusely, indicating that it is important, but then sGP appears just to float in a person’s blood serum. One theory is that sGP may be essential in the natural host “reservoir.”
“Eighty to ninety percent of what Ebola virus makes in infection is this shed molecule,” said Saphire. “It’s like a smoke screen, and we need to know where it is similar to our target GP and where it is different.”
To add to the mystery, Ebola makes GP and sGP using the same gene. A small difference in the way the gene is read changes how the molecules are shaped and changes their roles.
One obstacle to understanding sGP is that it is too small to be seen with cryo-electron microscopes. To solve this problem, the researchers added “bulk” by pairing sGP with antibodies, including 13C6. This allowed them to kill two birds with one stone—they could see sGP’s structure while also studying how antibodies interact with it.
The new image shows the binding sites, or “epitopes,” the antibody targets. “We can see hot spots on this virus that we can hit,” said Pallesen.
This study is the latest research from the Viral Hemorrhagic Fever Consortium, an international partnership of research institutes led by Saphire. The researchers said collaboration with the consortium was key to this study, allowing scientists to share samples and data, including viral genetic sequences isolated from patients in the most recent Ebola outbreak.
In addition to Saphire, Ward, Murin and Pallesen, authors of the study, “Structures of Ebola virus GP and sGP in complex with therapeutic antibodies,” were Natalia de Val, Christopher A. Cottrell, Kathryn M. Hastie, Hannah Turner and Marnie Fusco of TSRI; Kristian G. Andersen of TSRI and the Scripps Translational Science Institute; Andrew I. Flyak and James E. Crowe of Vanderbilt University and Larry Zeitlin of Mapp Biopharmaceutical.
This study was supported by the National Institutes of Health (NIH, grant R01 AI067927), the NIH’s National Institute of Allergy and Infectious Diseases (grant U19AI109762 and U19AI109711) and the National Science Foundation.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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Unraveling Zika
A cattle disease spread by bodily fluids may offer clues for stemming the epidemic
By Genevieve Rajewski
As Rio de Janeiro welcomes athletes to the 2016 Olympic and Paralympic Games, concerns about the Zika virus continue to grow. The virus has spread to 68 countries and been linked to serious birth defects and brain damage in newborns and to a potentially fatal neurological condition in adults. Brazil reported its first outbreak of Zika in 2015. There is no vaccine.
Fearing that an influx of tens of thousands of competitors and visitors from around the world could fuel rampant transmission of the virus, some members of the scientific community had urged that the Olympics be postponed or moved out of Brazil. A number of athletes, including some of the world’s top golfers, have withdrawn from the games, citing Zika.
Zika is transmitted through the bite of infected mosquitoes, and the virus can also be passed from a pregnant mother to her fetus, according to the Centers for Disease Control (CDC). The national public health agency has warned that people who have sex with infected men are also at risk for contracting the virus.
On Aug. 1, the CDC issued an unprecedented alert to pregnant women and their partners, urging them not to go into a small community north of downtown Miami, where 15 people have contracted the Zika virus after being bitten by mosquitoes there. The National Institutes of Health announced in July that it plans to fund a study of the U.S. Olympic team to gain a better understanding of how long the virus lingers in the body.
However, until there’s data from studies of humans, animal diseases that are similar to Zika may offer some immediate clues for stopping the outbreak, says Sumiko Mekaru, V03, an epidemiologist formerly with HealthMap, a Boston Children’s Hospital research group that specializes in infectious disease surveillance, and now a vice president at the research group’s spinoff company, Epidemico.
“When there is a dearth of information like there is with Zika, you start asking, what have we seen before that might inform our knowledge of this threat?” she says. “Zika may be more closely related to dengue and yellow fever—infections also spread by mosquitoes—but we haven’t seen microcephaly [the abnormally small head found in human newborns with Zika] with those diseases,” says Mekaru, who contributed to an article examining the striking similarities between Zika and the cow disease known as bovine viral diarrhea virus (BVD).
Her HealthMap colleague, veterinarian Lauren Marsh, wrote the article for the research group’s Disease Daily website after she noticed the clinical similarities between Zika and BVD, which she’d seen when she cared for food animals. She discovered that BVD, like Zika, is a member of the Flaviviridae family of viruses, although each is from a different branch of the family. Zika belongs to the branch that typically is spread by insects, whereas BVD belongs to the Flaviviridae subgroup of viruses known to be transferred via bodily fluids, including semen, and from infected mothers to their fetuses.
BVD can cause a variety of problems in calves—from miscarriage and embryo death to birth defects—depending on when the infection occurred during pregnancy, says Christopher Mantell, a graduate student in conservation medicine at Cummings School who also contributed to Marsh’s article, along with Maimuna Majumder, E13, MPH13, now a doctoral student at MIT. In developing calves, BVD targets the eyes and central nervous system and often causes brain and skull deformities, including microcephaly, the birth defect that first brought the Brazilian cases of Zika to international attention.
Despite the intriguing parallels between BVD and Zika, viruses in the BVD branch of the Flaviviridae family tree are quite distinct from those belonging to the mosquito- and tick-transmitted branch, according to Sam Telford, a professor of infectious disease and global health at Cummings School. Still, he wonders whether Zika is transmitted more commonly like BVD, through bodily fluids.
“I am still amazed that it was only two months ago that Zika-infected mosquitoes were finally found in Brazil—long after the epidemic started,” says Telford, an expert on infections spread by mosquitos and ticks. He says that this may be the result of the lack of funding to study the role of mosquitoes in the global proliferation of Zika, but that it may also be because the insects are not the main cause of the infection. The real risk for transmission could be sexual, he theorizes.
“As a public health professional, I am hoping that prevention of sexually transmitted diseases is reinforced for all Olympic athletes in Brazil,” says Telford. “If reducing the risk for Zika is a byproduct of those efforts, all the better.”
Genevieve Rajewski can be reached at [email protected].
Unraveling Zika
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