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Patent Awarded for Replacement Pancreas Cell Processes

U.S. Patent and Trademark Office

U.S. Patent and Trademark Office (A. Kotok)

6 November 2014. ViaCyte Inc., a biotechnology company in San Diego, received a patent for its processes in making early stage pancreatic cells to replace defective cells in patients with type 1 diabetes. Patent number 8,859,286 was awarded in mid-October by U.S. Patent and Trademark Office to inventor Alan Agulnick, a researcher at ViaCyte, and assigned to the company.

Type 1 diabetes is a chronic condition where the pancreas makes no or very little insulin, a hormone that enables glucose or sugar to produce energy. The disorder can be inherited or aggravated by environmental factors, but the body’s immune system begins destroying islet cells in the pancreas, called beta cells, that produce insulin.

About 5 percent of the 29 million Americans with diabetes have type 1 diabetes. People with type 1 diabetes must replace the insulin missing from their pancreas, or face life-threatening consequences from the build-up of glucose in the bloodstream. Patients with the disorder must constantly monitor their blood glucose levels, and inject insulin with a syringe or wear an insulin replacement pump.

ViaCyte’s lead product is a system called VC-01 that produces and delivers insulin with an artificial pancreas. In the system, insulin is made with replacement beta cells, derived from cultured human stem cells. The replacement beta cells, in an early precursor state similar to their natural counterparts, are contained in a device implanted under the skin of the patient, where they develop into mature beta cells and produce insulin. The system, says ViaCyte, also enables the development of blood vessels to provide oxygen for the growth of mature beta cells and distribution of insulin to the body.

The patent covers the company’s processes for deriving precursor beta cells from human stem cells. The processes describe the cultures and agents employed to differentiate stem cells into precursor beta cells, as well as alternative methods covering the use of both human embryonic stem cells and adult induced pluripotent stem cells.

ViaCyte is testing the safety and efficacy of its VC-01 system in a clinical trial enrolling up to 6 patients with type 1 diabetes. The company says it implanted the first VC-01 device as part of this study in late October.

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Bone Drugs Found as Possible Breast Cancer Therapy

Mike Rogers

Mike Rogers (Garvan Institute)

6 November 2014. Medical researchers at the Garvan Institute in Sydney, Australia found common drugs to treat bone loss could treat breast and other other tumors outside the skeleton. The team led by Garvan research fellow Mike Rogers, with colleagues in Scotland and the U.S., published its findings online in the journal Cancer Discovery (paid subscription required).

Rogers and colleagues investigated a phenomenon reported in clinical trials where some women with breast cancer were given bisphosphonates, established widely-prescribed drugs to treat bone loss due to osteoporosis, and found less spread of their cancers and longer survival times. Bisphosphonates have a high affinity for calcium crystals in bone, where they bind with and deposit into the weakened bone structure. These drugs are also used to treat weakening of bone tissue in multiple myeloma and late-stage cancers that spread to bones.

The Garvan team looked into the way bisphosphonates work for clues to their effects on cancers unrelated to bones. They identified a possible link in tiny calcium deposits associated with breast tumors that sometimes appear in mammograms, and conducted tests with bisphosphonates for a connection between the drugs and breast tumors.

In tests on lab mice with mammary tumors and treated with bisphosphonates, researchers found aberrant immune system cells called macrophages that would normally attack healthy tissue instead attacked the tumor cells with calcium deposits. Bisphosphonates, the team discovered, bind to the minute specks of calcium in much the same way they bind to the calcium in bone. The macrophages then attack tumor cells with bisphosphonates attached instead of healthy tissue.

“We do not yet fully understand how the macrophages revert from being ‘bad cops’ to being ‘good cops’,” says Rogers in a Garvan Institute statement, “although it is clear that this immune cell interacts with tumors, and probably changes its function in the presence of bisphosphonates.”

The researchers were able to witness and record this process occurring in real time, using a form of laser scanning microscope. The team treated the bisphosphonates with a fluorescent stain and watched as the macrophages surround and devour the tumor cells. “I clearly remember the moment we first saw macrophages behaving like little Pacmen and gobbling up the drug,” says co-author Tri Phan. “It was astounding.” (See video below)

The team then repeated the test with human tumor tissue from a breast cancer patient in an affiliated hospital, and found the same actions occurring of macrophages attacking bisphosphonate-bound cells as they witnessed in mice. The researchers next plan to analyze the changes happening in macrophages to better understand the process that changes their actions from attacking healthy tissue to attacking cancer cells.

The following brief (12-second) video shows a macrophage, in green, absorbing a red-stained complex of calcium and bisphosphonates in a breast tumor.

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Big Data Project Seeks to Autocomplete Software Code

Binary code illustration

(Digitalgov.gov)

5 November 2014. A new project led by computer scientists at Rice University in Houston aims to apply big data analytics and data mining for software developers to generate code the same way as search engines anticipate or correct the entry of search terms. The 4 year, $11 million initiative is funded by Defense Advanced Research Projects Agency, or Darpa, and includes researchers from University of Texas-Austin, University of Wisconsin-Madison, and software code-quality company GrammaTech in Ithaca, New York.

Darpa is supporting this research as part of its Mining and Understanding Software Enclaves, or Muse, program that the agency hopes will change the way software is written. For Muse, Darpa seeks to engage a wide range of capabilities including programming languages, program analysis, theorem proving and verification, testing, compilers, software engineering, machine learning, databases, statistics, and systems from many domains.  The program’s Web site notes it “intends to emphasize creating and leveraging open source technology.”

A central feature of Muse is a public compendium of open source software representing hundreds of billions of lines of code. A specification mining engine would accompany this body of software that harnesses big data analytics to populate and maintain inferences about software properties, behavior, and vulnerabilities. From this base, Darpa expects Muse to generate new ways of automatically generating and repairing complex code.

The system created by the Rice project, known as Pliny — named after the Roman philosopher credited with writing the first encyclopedia — will be designed to read the first lines of code, then recommend the rest of the code. In addition, Pliny would test the code for bugs and security vulnerabilities. “You can think of this as autocomplete for code, but in a far more sophisticated way,” says Rice’s Vivek Sarkar in a university statement. Sarkar is chair of Rice’s computer science department and principal investigator on the project.

The Rice team expects to employ Bayesian statistics, which apply mathematical principles to calculate conditional probabilities. In Bayesian models, probabilities are constantly refined with the introduction of new evidence, creating new conditions and outcomes. Co-investigator on the project Chris Jermain, a fellow Rice computer scientist says, “Much like today’s spell-correction algorithms, it will deliver the most probable solution first, but programmers will be able to cycle through possible solutions if the first answer is incorrect.”

Sarkar tells more about the Pliny project in the following video.

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High-Speed Artery Imaging Technology in Development

Cross-sectional view of artery

Cross-sectional view of an artery made with laser/ultrasound imaging process. Fatty plaque deposits are highlighted in green. (Ji-Xin Cheng, Purdue University)

5 November 2014. A process to capture high-speed three-dimensional images of plaque deposits in arteries and analyze their chemical makeup for diagnosing heart conditions is being developed by Purdue University in West Lafayette, Indiana. The team from the lab of Purdue biomedical engineer and chemist Ji-Xin Cheng, with colleagues from Indiana University School of Medicine, University of California campuses in Davis and Irvine, and sensor technology company Spectral Energies in Ohio, reported yesterday on recent advances in the journal Scientific Reports.

Purdue filed a patent application for the technology. Cheng and first author Pu Wang, a postdoctoral researcher in Cheng’s lab, founded the company Vibronix Inc. to take the technology to market.

The build-up of plaque in the arteries is a major cause of heart attacks and strokes, when plaque either breaks off or forms clots that block the arteries to the heart or brain. Plaque is made up of cholesterol and other fatty substances, as well as calcium, cellular waste and fibrin, the material that helps blood clot. Not all plaque is the same, however, and being able to identify the nature of plaque in the arteries can determine if the plaque may break off and trigger a heart attack.

Evaluating plaque in arteries requires knowing not only the amount of build-up, but also its composition, which up to now is hampered by the lack of high-speed imaging. Current technologies can take low-resolution images of the arterial wall, or test samples of plaque in lab cultures, such as in an autopsy, but none can yet accurately and reliably identify risky plaque deposits in live patients.

The technique developed by Cheng and colleagues combines laser and ultrasound processes. The laser process emits 2,000 pulses per second, a rate the researchers say is a 100-fold increase over current technologies. Each pulse of the laser, generated in the near infrared spectrum, is capable of capturing an image. In addition, the process does not require dyes to highlight targets for the images.

The laser also heats the tissue, causing it to expand and produce non-damaging pressure waves that can be detected by ultrasound and converted by a transducer into electrical signals for measurement. Signals returned by the ultrasound act as indicators of the carbon and hydrogen bonds in molecules making up fatty plaque deposits on the arterial wall, and their risk of breaking loose.

In the paper, the team tested the technique on a pig’s artery with atherosclerosis, or hardening of the arteries from plaque deposits. The combination of laser and ultrasound processes returns 3-D images of plaque build-up in the artery, highlighting the higher (10-fold) densities of carbon-hydrogen bonds in the fatty substances contained in the plaque, which indicate vulnerability of deposits to break apart and cause a heart attack.

The researchers plan to extend the tests to live animals and eventually clinical trials. Cheng says the system can be made small enough to fit on an endoscope, a device to produce images inside an artery, inserted and guided by a catheter. Vibronix, the company commercializing the technology, aims to produce such a device.

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Patent Issued for Engineered Peptides Forming Hydrogels

Susan Sung

Susan Sung (PepGel LLC)

4 November 2014. Bioengineers at Kansas State University received a patent for their invention of a peptide, a protein-like compound, that turns into water-based gels for a number of medical applications. U.S. Patent and Trademark Office awarded patent number 8,835,395 to Xiuzhi (Susan) Sun, professor of grain science and bioengineering at Kansas State, as well as 2012 doctoral recipient Hongzhou Huang, on 16 September.

The inventors founded PepGel LLC, a company in Manhattan, Kansas (also home of Kansas State) that licensed the research from the university. PepGel aims to commercialize the technology, producing hydrogels for building matrices used in tissue engineering and regenerative medicine. Sun is the company’s board chair and chief technologist, while Huang directs PepGel’s research and development work.

Peptides are chains of 2 or more amino acids linked together in short chains, but smaller than more complex proteins. Sun and Huang designed a peptide with 19 amino acids and the ability to self-assemble into three-dimensional nanofiber networks. This self-assembly property can be enhanced to form hydrogels, by changing the pH level (base to acid) of the peptide or adding an ion, such as calcium to the compound.

Hydrogels are networks of material that contain primarily water, but maintain enough substance to form into 3-D gelatinous structures. The body naturally forms some materials, such as vitreous humor in the eyes and cartilage, containing protein hydrogels.

“This hydrogel system has large variations and flexibility in controlling the gel stiffness, viscoelastic behavior, and surface properties,” says Sun in a university statement. The peptides developed by Sun and Huang also contain both water-seeking and water-resistant segments that give their hydrogels the ability to transform into a liquid state, then back into a gel.

In addition, the size of the nanofibers and pores in the hydrogel are similar to extracellular matrices found in nature that give structural support to surrounding cells. This similarity to natural matrices offers opportunities to apply Sun and Huang’s hydrogels to repair or regeneration of human tissue.

Because of their wide range of properties, the hydrogels covered by the patent can be used for a range of biomedical applications in addition to tissue repair. Sun is collaborating in research on applying hydrogels to cancer drug delivery, stem cell cultures, wound healing, drug encapsulation, and vaccine adjuvants.

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Child-Safe Coating Devised for Button Batteries

Button batteries

(Gerhard H. Wrodnigg, Wikimedia Commons)

4 November 2014. Engineers and medical researchers at Massachusetts Institute of Technology and hospitals affiliated with Harvard Medical School developed a coating for small batteries that tests show could prevent poisoning when swallowed accidentally by young children. The team from the labs of Robert Langer at MIT and Jeffrey Karp at Brigham and Women’s Hospital in Boston published its findings yesterday in Proceedings of the National Academy of Sciences (paid subscription required).

Button batteries power small electronic devices like watches and toys, and are made from compacted metals and metal oxides divided by a separator infused with electrolytes. Regulations and standards requiring locked battery compartments reduced somewhat the number of accidental ingestions of button batteries in 2013 to 3,366. But a swallowed button battery can cause choking, tissue wounds in the esophagus, and chemical burns from electricity generated by the battery.

The researchers aimed for a solution that makes button batteries safer for children if accidentally swallowed, yet still work normally when installed in electronic devices. Their investigations led to an inexpensive material used today in electronics known as quantum tunneling composites that can switch from insulator to conductor when force is applied.

Quantum tunneling composites are rubber-like polymers filled with metal fibers that in their normal state are too far apart to conduct a current. But when compacted, the fibers come into contact, conducting the electrons in a phenomenon called quantum tunneling. This response to pressure makes quantum tunneling composites useful for keyboards and touch screens.

Inside electronic devices, button batteries are compacted and thus in a somewhat pressured state. The team hypothesized a coating of quantum tunneling composites on button batteries would respond to this normal pressure inside a device and enable the batteries to produce a current. Yet inside a child’s esophagus or gastrointestinal tract the battery would not be under pressure and thus would not produce a current that burns.

The researchers calculated the amount of force generated by peristalsis, the muscle contractions moving food through the digestion process, and found the pressure produced by peristalsis, even under extreme conditions, was not enough to produce a current on a coated button battery. They then tested a coated button battery in the esophagus of a pig, and found no evidence of damage to the animal. In addition, their tests show coated button batteries operate normally inside electronic devices.

“We think this is a relatively simple solution,” says Karp in an MIT statement, “that should be easy to scale, won’t add significant cost, and can address one of the biggest problems associated with ingestion of these batteries.” The researchers are working on methods that manufacturers can adopt to produce coated batteries and are seeking industry partners.

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Trial Shows Weight Loss Drug Can Help Stop Smoking

Hand holding cigarette (NIMH)

(National Institute of Mental Health)

3 November 2014. First results from an intermediate-stage clinical trial shows lorcaserin HCl, a drug approved to help people lose weight, also helps regular smokers stop smoking. The findings were reported today by Eisai Inc. and Arena Pharmaceuticals Inc., who offer lorcaserin HCl under the brand name Belviq. The companies say more results will be reported at a future scientific meeting.

Lorcaserin HCl, or lorcaserin hydrochloride, is a chemical that binds to and activates serotonin 2C receptors in the brain. Serotonin is a neurotransmitter, a chemical regulating signals between neurons or nerve cells, in this case a key reward pathway affecting mood, pleasure, and memory, influencing an individual’s responses to food, sex, and social interaction.

Arena developed lorcaserin HCl as a drug to help obese and overweight patients lose weight, in conjunction with changes in diet and exercise. Lorcaserin HCl is a 10 milligram tablet that targets a hunger receptor in the brain, so individuals taking the drug feel satisfied while eating less, although the drug’s precise mechanism to achieve this result is not yet known. After approval by FDA as a weight-control drug in 2012, Arena enlisted Eisai for its distribution and marketing beginning in June 2013.

The clinical trial, conducted by Arena, enrolled 603 adult participants at 31 sites in the U.S., who smoked 10 or more cigarettes a day. The study randomly assigned participants to receive either lorcaserin HCl twice a day, once a day, or a placebo for 12 weeks. The primary end-point or objective of the study was complete abstinence from smoking for the last 4 weeks, 9 through 12.

Results show 15 percent participants taking lorcaserin HCl twice a day are able to achieve complete abstinence for the last 4 weeks, compared to 9 percent for participants taking the drug once a day, and 6 percent for those receiving the placebo. The difference in quit rate between twice a day and placebo participants is large enough to be statistically reliable.

The study also has a number of secondary measures related to smoking and eating behavior. The companies reported only differences in weight, which show participants taking the drug twice a day losing 0.98 kilograms (2.2 lbs), compared to the placebo participants who losing 0.01 kilograms (0.02 lbs).  Adverse effects reported by participants include headache, nausea, constipation, dizziness, and dry mouth, which the companies say are similar to previous trials of lorcaserin HCl.

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Gates Foundation Funds Malaria Vaccine Development

Mosquito (Germán Meyer)

(Germán Meyer/Flickr)

3 November 2014. The Bill and Melinda Gates Foundation is awarding $156 million for a new type of malaria vaccine that prevents infection and transmission of the disease. Bill Gates, co-chair of the foundation, announced the grant to the Path Malaria Vaccine Initiative yesterday during keynote remarks at the American Society of Tropical Medicine and Hygiene’s annual meeting in New Orleans.

Malaria is caused by infections from the Plasmodium parasite transmitted by mosquitoes. In humans, the parasite multiplies in the liver, then infects red blood cells. Symptoms, including headache, fever, and vomiting, occur 10 to 15 days following transmission from a mosquito bite. World Health Organization says the disease occurs in nearly 100 countries, with some 207 million cases in 2012, causing 607,000 deaths.

Public health authorities generally focus on containing malaria, by protecting against or controlling mosquitoes, called vector control, with bed nets and spraying of mosquito breeding areas. The Gates Foundation says it wants to support a more aggressive effort leading to eradication of malaria, starting with more effective vaccines, which is the goal of the Path Malaria Vaccine Initiative.

A problem preventing effective control of malaria is the development of a natural immunity to the disease by people living in regions affected by malaria. While they may not show symptoms following infections, these immune individuals still host parasites and transmit them to mosquitoes, which in turn infect other people.

Ashley Birkett, director of Path, says in a statement from the organization, “Vaccines are likely to provide the best opportunity to complement drugs and vector-control measures in reducing transmission to zero, and they are the single most important intervention for preventing reintroduction.” The initiative says it aims to develop vaccines that both protect people against malaria infection from mosquitoes, as well as prevent mosquitoes from becoming infected with the parasite after feeding on a person with malaria, thus preventing further transmission.

Path plans to advance a vaccine candidate through early field trials, providing evidence for product development by 2017. The vaccine is expected to target the point in the Plasmodium life cycle, when the parasite is transitioning between human and mosquito hosts, which is also the point when the parasite is fewest in number. The vaccine, therefore, would induce immunity at the point where the parasite is most susceptible to attack, and for which it has no natural defenses.

The Path initiative says it will use a hybrid lab/clinical study it calls challenge trials, where healthy human volunteers test vaccines against a placebo under controlled lab conditions, taking advantage of malaria’s high cure rate if caught early. In challenge trials, the volunteers will be exposed to malaria parasites to assess the efficacy and safety of the vaccines, while being closely monitored by medical staff. If signs of infection occur, the volunteers can be treated quickly. Monoclonal antibodies — engineered, highly targeted molecules — will also be developed to validate target antigens in the challenge trials.

The $156 million to Path Malaria Vaccine Initiative is part of a $500 million commitment announced by Gates at the New Orleans meeting. Gates told the audience his foundation is increasing its malaria program budget by 30 percent to more than $200 million per year.

News of the malaria grant at the American Society of Tropical Medicine and Hygiene (ASTMH) meeting was largely overshadowed by the state of Louisiana’s travel and quarantine restrictions on meeting attendees from regions where Ebola is occurring. In a 30 October statement the organization said it does not agree with the state’s policy. “ASTMH firmly believes,” says the statement, “the single best way to safeguard Americans and the world is to end the epidemic in West Africa with the help of our best-trained, brave men and women.”

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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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