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Natural Product Can Boost Animal Immune Health

Cow's head (Agricultural Research Service, USDA)

(Agricultural Research Service, USDA)

31 October 2014. Tests by Avivagen Inc. show an ability of beta-carotene to spontaneously oxidize that offers a natural alternative to antibiotics added to livestock feed to reduce illness and gain weight. The researchers from Avivagen, an animal health products company in Ottawa, Canada and National Research Council of Canada published their findings in today’s issue of the online journal PLoS One.

Antibiotics fed to livestock for other than therapeutic reasons are considered a factor in increasing resistance to antibiotics in humans, thus posing a threat to public health. A 2013 report on antibiotic resistance from Centers for Disease Control and Prevention says, “The use of antibiotics for promoting growth is not necessary, and the practice should be phased out.” Food and Drug Administration later that year wrote voluntary guidelines for industry on antibiotic use in food-producing animals.

Avivagen makes natural health products for pets and food animals, including those based on an oxidized form of beta-carotene, a food source of vitamin A and antioxidants. The oxidized beta-carotene, called OxC-Beta, was found by Avivagen and other researchers to have potentially beneficial properties for animals, including higher quantities of oxygen — some 8 molecules of oxygen per molecule of beta-carotene, from processes not related to vitamin A. These properties suggest OxC-Beta could be biologically active and help generate an immune response to pathogens or inflammation.

The paper investigates the biochemical properties of oxidized cartenoids, the name given to substances like beta-carotene, and tests their effects in the lab on indicators of animals’ immune functions. One property not yet been fully understood is the ability of oxidized cartenoids to form oxygen copolymer compounds. The researchers treated human blood and tissue cells with OxC-Beta, then subjected the copolymer compounds created by oxidized beta-carotene to fluorescence activated cell sorting or FACS analysis to measure immune system potential. The results show increased immune receptor levels on the treated cells, compared to the untreated cells.

The team also fed lab mice with OxC-Beta and tested their intestinal tissues for expression of genes related to the immune system. The findings show higher expression of CD14 and TLR4 genes, associated with activation or regulation of the innate immune system, providing an immediate response to invading pathogens.  The results also show increased activity of immune system cytokine and phagocyte cells, when pretreated with OxC-Beta, compared to untreated cells.

The researchers believe the development of oxygen copolymers by oxidized beta-carotene also applies to other cartenoids, which suggests this potential boost for the immune system can be replicated in other cartenoid-rich fruits and vegetables.

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Ebola-Marburg Vaccine Development, Testing Contract Awarded

Ebola health care workers

Ebola health care workers in Guinea (European Commission-ECHO/USIAD)

31 October 2014. A biodefense unit of the U.S. Department of Defense awarded a contract to vaccine maker Profectus BioSciences Inc. for development and testing of a vaccine protecting against the two major Ebola strains and related Marburg viruses. The $9.5 million contract with the Baltimore company came from DoD’s Medical Countermeasure Systems-Joint Vaccine Acquisition Program, through Battelle Memorial Institute.

The work involves further development and preclinical testing of a single vaccine protecting against the Zaire and Sudan strains of Ebola, as well as the related hemorrhagic Marburg virus. Preclinical testing is expected to lead to an investigational new drug application with the U.S. Food and Drug Administration to conduct human clinical trials of the vaccine. FDA is authorized to grant emergency approval for clinical trials in situations where conditions call for a rapid decision.

Profectus BioSciences’ vaccine technology is licensed from research at the lab of Yale University virologist John Rose that genetically engineers viruses to reduce their effect, while providing a delivery mechanism safe for humans. Used alone the technology, says Profectus, leads to rapid expansion of immune-system B cells, and with an engineered DNA booster, also stimulates T cell production. The company first applied this technology to a vaccine for HIV that in preclinical and early clinical studies is shown to be safe and induce an immune response in both HIV-positive and negative individuals.

About 5 years ago, Profectus began work on applying this technology to Ebola and Marburg viruses, with Thomas Geisbert at the University of Texas Galveston National Laboratories and Heinz Feldmann at NIH’s Rocky Mountain Laboratories in Montana. The collaboration, says the company, led to studies with lab rodents and monkeys showing single doses of the vaccines protecting against the Ebola Zaire strain and Marburg viruses, up to 1,000 times the lethal exposure.

Including the new contract, Profectus received $37.4 million for development of Ebola vaccines since March 2014 from DoD, NIH, and other agencies. The most recent contract, of $8.6 million, was awarded on 22 October from the Biomedical Advanced Research and Development Authority in Department of Health and Human Services to advance Profectus’s vaccine for the Ebola Zaire strain into clinical trials.

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Drug/Device Therapy Trial Shows Fast Migraine Relief

Migraine pain

(R. Nial Bradshaw, Flickr)

30 October 2014. A late-stage clinical trial shows a medical device designed to deliver migraine drugs deep into nasal cavities achieved headache relief in as little as 30 minutes among patients, and sustained that relief for as long as 48 hours compared to a placebo. The biopharmaceutical company Avanir Pharmaceuticals Inc. in Aliso Viejo, California licensed the drug delivery technology last year from OptiNose, which led the trial. The findings appear today online in the journal Headache.

Migraine is a neurological syndrome causing severe headaches along with nausea, vomiting, and extreme sensitivity to light and sound. In some cases, migraines are preceded by warning episodes called aura including flashes of light, blind spots, or tingling in arms and legs. Migraine Foundation says the syndrome is one of the top 20 disabling disorders and estimates some 36 million people suffer migraines in the U.S., including 14 million who experience migraines nearly every day or more often.

The Avanir/OptiNose solution delivers sumatriptan, a widely used migraine drug, in powder form. Sumatriptan, approved by FDA in 1992, stimulates serotonin receptors in the brain. Serotonin is a neurotransmitter chemical generated in the brain, regulating signals between neurons that helps maintain mood balance. Decreased levels of serotonin are associated with depression.

The Avanir/OptiNose device, code-named AVP-825, aims to bypass a problem with sumatriptan in pill form, namely its absorption in the stomach which delays and impedes reaching the areas of the brain where the drug is needed. The device carries a measured dose of the medication in dry powder form, with a piece that fits in the patient’s nostril and a separate piece that goes in the mouth. The patient exhales into the device, which sends the dose of sumatriptan into the nose and into the nasal passages, deeper than can be delivered with a nasal spray, according to OptiNose, for transfer into the blood stream near the brain.

The clinical trial tested AVP-825 to deliver a lower dose (22 milligrams) of sumatriptan against a placebo, in this case a lactose powder also delivered with a similar device, among 230 migraine patients in the U.S. The patients were randomly divided between those receiving sumatriptan or the placebo. The primary objective of the trial was to measure the extent of relief from headache pain within 2 hours, in cases of a single moderate or severe migraine attack.

The results show a more patients using AVP-825 (42%) achieved headache relief as soon as 30 minutes after the treatment, compared to those receiving the placebo (27%). After 2 hours, about two-thirds (68%) of the patients using AVP-825 were headache-free, compared to 45 percent with the placebo. Total migraine symptom relief — headache, nausea, sound and light sensitivity — were experienced by 19 percent of the patients with AVP-825, compared to 9 percent of the placebo patients.

In addition, the pain relief was sustained at 24 and 48 hours following the treatments in greater proportions among AVP-825 patients than with placebo patients. No serious adverse reactions were reported in the trial. One patient taking AVP-825 reported mild skin tingling, called paresthesia.

Avanir says it submitted a new drug application for AVP-825 with FDA, which set 26 November 2014 as its target date for completing the review.

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Synthetic Blood Thinner Antidote Developed

Blood bag (NIH)

(National Institutes of Health)

30 October 2014. Medical and biochemical researchers at University of British Columbia in Vancouver, Canada designed a polymer antidote for heparin that in lab animals neutralizes anti-coagulant activity and appears to be well tolerated. The team led by chemistry and pathology professor Jayachandran Kizhakkedathu published its findings yesterday in the journal Science Translational Medicine (paid subscription required).

Heparin is an anti-coagulant drug given to patients with medical conditions that lead to blood clots or to prevent formation of clots during surgery and with catheters. The drug works by diminishing the blood’s ability to clot, but if overdosed or complications develop, can lead to excessive bleeding. In these cases, an antidote is needed to reverse the anti-coagulant action of heparin.

Antidotes to heparin themselves, however, can lead to complications such as low blood pressure and in some cases a serious reaction similar to life-threatening anaphylactic shock, with toxicity varying from patient to patient. Also, while heparin is a common established drug — it is now available as a generic — its various forms have somewhat different chemistries, making it difficult to come up with a single antidote for all types in its class.

Kizhakkedathu and colleagues sought to develop a single antidote for heparin, what they call a universal heparin reversal agent, which would also be safe and simple in design to keep it inexpensive to produce. The team designed a new type of positively-charged polymer molecule that neutralizes the negatively-charged complex of heparin and proteins that breaks up clots and prevent further clotting. In addition, the polymer is coated in a protective layer of polyethylene glycol, a common additive to drugs, which in this case prevents it from interacting with other charged molecules in blood.

The researchers tested the polymer antidote in lab blood samples to find the most effective formulation, then tested that formulation with lab rats and mice. Tests with animals showed their universal reversal agent works as well or better in neutralizing the anti-coagulant activity of various heparin compounds. The team also tested dose tolerance of the antidote, and found at all levels tested, the mice survive with no differences in body weight or signs of toxicity after 29 days, compared to a control group. Likewise, analysis of tissue samples from livers, kidneys, and spleens in the test mice shows no damage after 29 days.

Kizhakkedathu and UBC co-authors Rajesh Shenoi, Cedric Carter, and Donald Brooks are the inventors of the technology protected under a U.S. patent and assigned to the university. The researchers say they plan to further develop the polymer antidote for clinical trials in 3 to 5 years.

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Taking a break

Least terns

(A. Kotok)

26 October 2014. Science & Enterprise is taking a break from blogging for a few days. We’ll return on Thursday, 30 October.

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Costs to Support Stroke Survivors Stay High for 10 Years

Dominique Cadilhac

Dominique Cadilhac (Monash University)

24 October 2014. Researchers at Monash University in Australia calculated long-term costs to stroke patients, finding the financial burden on patients and their care givers remains significant for 10 years following the stroke episode. The team led by Monash medical school professor Dominique Cadilhac reported its findings in yesterday’s issue of the journal Stroke (paid subscription required).

Cadilhac, with colleagues at Monash and affiliated institutions in Australia, sought a longer-term estimation of financial burdens faced by stroke patients to reflect longer survival periods with the condition. According to the New York Times, more than 3 in 4 of patients survive a first stroke during the first year, and more than half survive beyond 5 years. Previous studies offered financial estimates as long as 5 years, indicating costs were highest in the first year after the episode, while declining in subsequent years.

The researchers were particularly interested in uncovering differences between costs incurred by people experiencing ischemic strokes, where arteries to the brain narrow and become blocked, and hemorrhagic stroke, where blood vessels in the brain become weak and rupture. About 85 percent of strokes are ischemic strokes.

The team sampled 286 patients as part of the ongoing North East Melbourne Stroke Incidence Study, or Nemesis, with 243 patients having an ischemic stroke and 43 experiencing a hemorrhagic stroke. Data from interviews with patients were combined with population statistics from 2010 and applied to cost-of-illness models. The models were adjusted to account for a larger sampling area than previous Nemesis collections and new rates for 10-year survival and recurrence of strokes.

Cadilhac and colleagues found costs incurred by patients average $US 4,764 per year over 10 years for ischemic strokes, compared to $5,365 per year for hemorrhagic strokes. While the costs incurred by people with ischemic strokes after 10 years are comparable to the costs experienced in years 3 to 5 following the episode, costs for people with hemorrhagic strokes after 10 years are 24 percent higher than in years 3 to 5. The higher long-term costs for hemorrhagic stroke patients are attributed to the greater need for assisted-living facilities.

The researchers also found medication costs for all stroke patients rise over the 10 year survival period, accounting for 13 percent of expenses after 5 years, compared to 20 percent of the total after 10 years.

“We now have a much better picture of the long term costs of stroke,” says Cadilhac in a university statement. “Our research confirms there is no decline in costs beyond 5 years for survivors of stroke, in fact medical and other costs including those incurred by care givers continue for many years.”

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Paper-Based Synthetic Bio Sensors, Circuits Developed

Paper strip with color-indicated proteins

Paper strip with color-indicated proteins (Wyss Institute, Harvard University)

24 October 2014. Biomedical engineers at Harvard University designed systems with simple sensors applied on paper to detect complex cellular reactions that can speed use of point-of-care diagnostics in the field. Findings from the team at Harvard’s Wyss Institute for Biologically Inspired Engineering, with colleagues from Boston University and Howard Hughes Medical Institute in Chevy Chase, Maryland, appear in two articles published yesterday in the journal Cell (paid subscription required).

Both papers, from the labs of Wyss Institute faculty Peng Yin and James Collins, seek to make it possible for advances in synthetic biology to reach researchers and clinicians outside the controlled environments of laboratories. “Synthetic biology,” says Collins in a university statement, “has been confined to the laboratory, operating within living cells or in liquid–solution test tubes.”

Using paper as a test environment, say the researchers, takes more than transferring lab processes to a new medium, but the development of what Collins calls a “sterile, abiotic operating system upon which we can rationally design synthetic, biological mechanisms to carry out specific functions.” Keith Pardee, staff scientist and first author of the first Cell paper, devised a process with proteins that illuminate and change colors to provide detection of biochemical changes.

“We’ve harnessed the genetic machinery of cells and embedded them in the fiber matrix of paper, which can then be freeze dried for storage and transport,” notes Pardee. Freeze-drying makes it possible to store the paper strips at room temperature for up to a year. Technicians in the field then only need to add water to activate the paper strips.

The researchers devised several types of paper strips in the study containing detectors for small-molecule and RNA mechanisms. Among the proof-of-concept tests devised were sensors for glucose and antibiotic–resistant bacteria, as well as a detector to determine different strains of the Ebola virus. Pardee says the paper-based system makes it possible to return results in 90 minutes or less for some tests now taking 2 to 3 days. The Ebola strain detector, for example, returns results in about an hour.

The paper-based sensors in the first study applied a development described in the second Cell study, programmable circuits designed from scratch to regulate the expression of genes. “We looked at our progress to rationally design dynamic DNA nanodevices in test tubes,” says senior author Yin, and applied that same fundamental principle to solve problems in synthetic biology.” The bio-circuits, called toehold switches, are designed to detect RNA signatures, then produce a specific protein.

Postdoctoral fellow Alex Green, first author of the second paper, applied his previous work in materials science and software engineering to devise the programmable bio-circuit technology. Lab tests of the circuits show they regulate all-synthetic gene expression some 40 times better than controllers adapted from natural elements. The reliability of the bio-circuits makes it possible to link them together into more complex devices performing multiple functions, such as detecting a bacteria or virus and releasing a specific drug in response.

The following video tells more about and demonstrates the technologies described in the two studies.

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Biotech, McGill Univ Partner on Soil Enhancement Microbes

Soybean field (ARS/USDA)

Soybean field (Agricultural Research Service/USDA)

23 October 2014. Inocucor Technologies Inc. and McGill University are collaborating on development of new types of microbes that improve soil for greater yields of large-scale crops such as corn and soybeans. Financial details of the research and licensing agreement between the company and university, both in Montreal, Quebec, Canada, were not disclosed.

Inocucor Technologies produces soil enhancement products based on microbial consortia, communities of engineered microbes, similar to bacteria or yeast, designed to produce desired outcomes in their environments. The company’s technology, invented by its founders Maggie Bywater-Ekegärd and Ananda Fitzsimmons, produces microbes with a fermentation process that boost the soil’s ability to stimulate the crop’s seed, plant, and root system. The engineered microbes send and receive biochemical signals with plant cells to achieve these results.

Bywater-Ekegärd and Fitzsimmons continue as vice presidents of Inocucor.

In the deal with McGill University, Inocucor engages the lab of plant biologist Donald Smith who earlier carried out sponsored field trials of the company’s current Garden Solution soil enhancement product. Smith’s research interests include studies of rhizobacteria that increase the growth and yield of many crops.

Garden Solution is designed to accelerate maturation and increase yields of vegetable and fruit crops. The collaboration with McGill aims to produce a new type of microbial product more applicable to large-scale agricultural crops including wheat, corn, canola, and soybeans. Trials conducted by Smith at McGill include tests of the company’s current formulation with soybeans and corn.

“Inocucor’s microbial innovations have huge implications for agriculture,” says Smith in an Inocucor statement. “The McGill team will study these active microbials with the intention of creating products for conventional farmers that give them a sustainable way to enhance yields and improve long-term health of soils.”

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IBM, Health Tech, Univ Designing Critical Care Mobile System



23 October 2014. IBM, University of Michigan, and mobile health technology company AirStrip are developing a system to provide real time monitoring and analytics for patients with chronic or critical disorders. The system is being designed to collect data directly from patients and provide early warning initially for hemodynamic decompensation, a type of heart failure and potentially lethal complication for critically ill and injured people. Financial and intellectual property aspects of the collaboration were not disclosed.

Hemodynamic decompensation results in a sudden worsening of heart functions. The ensuing reduction in heart output is marked by hypertension, malfunctions in heart muscles, and restriction of blood supply to tissues. Attempts by the heart to compensate for these deteriorating conditions only increases the damage, leading to a downward spiral for the patient.

Data in this early warning system for hemodynamic decompensation will come from sensors worn by patients, while in the hospital and at home, linked to their electronic health records. University of Michigan’s Center for Integrative Research in Critical Care in Ann Arbor will design algorithms to process these data and identify predictive risk factors that can alert clinicians of impending deterioration in the patient’s condition.

IBM will adapt its InfoSphere Streams analytics platform to integrate the real-time patient monitoring data with health records information and the algorithms from Michigan. IBM says InfoSphere Streams is designed to combine structured and unstructured data, like those often found in health IT records.

AirStrip, in San Antonio, Texas, develops mobile systems for clinicians that combine real time patient monitoring with data from electronic health records. AirStrip will adapt its AirStrip One platform designed for reporting patient data for clinicians on smartphones and tablets, which will receive the stream of integrated real-time data and analytics, for display and interaction on clinicians’ Apple, Android and Windows devices.

Early intervention in these cases is expected to improve care of critically ill patients and help reduce admission to intensive care units. The partners in the project say if this first application is a success, the system could be expanded to to detect deterioration in other chronic conditions, such as diabetes, chronic obstructive pulmonary disease (COPD), and congestive heart failure. The system can also be part of a more comprehensive model of continuous hospital-to-home patient monitoring.

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Hat tip: MedCity News

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Clinical Trial Proposals Sought for ALS Treatments

3-D brain wiring illustration

3-D brain wiring illustration (NIH)

22 October 2014. A group of U.S. organizations promoting research on therapies for amyotrophic lateral sclerosis or ALS are seeking proposals from academic-industry research teams for intermediate stage clinical trials to test treatment candidates for the disease. The organizations — ALS Association, ALS Accelerated Therapeutics or ALS ACT, and Northeast ALS Consortium — plan to award up to $1.5 million in research support, with letters of intent due by 9 January 2015.

Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is a progressive disorder that attacks nerve cells or neurons controlling voluntary muscle movements. In ALS, motor neurons in the brain stop sending signals to motor neurons in the spinal cord, and thus stop sending signals to muscles. Muscles begin to weaken and atrophy, eventually losing control over voluntary muscle movement. The result is disability and paralysis, including respiratory functions, leading to death. ALS affects 1 in about 30,000 people in the U.S., with 5,000 new cases each year.

At present there is no cure for ALS and only one approved drug — Riluzole, marketed as Rilutek by Sanofi — that slows the progress of the disease. The organizations say the research funded in this initiative can fill an urgent need for more treatments, particularly those beyond preclinical and early safety studies on humans.

Proposals should outline intermediate-stage studies of interventions that include markers to measure the therapy’s affect on the body, as well as a plan to collect samples for studies involving biomarkers. Intermediate-stage trials, sometimes called phase 2 trials, are studies involving larger numbers of patients than the small samples used in earlier safety studies, and test the effectiveness of the drug, as well as watch for safety or side-effects issues.

The organizations encourage teams comprised of academic and industry researchers, including those from pharmaceutical and biotechnology companies, to submit proposals. Letters of intent are due by 9 January 2015, with invitations to send in full proposals issued on 23 January. Full proposals are due by 2 March 2015, with evaluations conducted by a review panel from ALS ACT.

The winning proposal will be announced in May 2015. The successful bidder, say the organizations, will retain control of the study as well as intellectual property of the therapy being tested.

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