'New paradigm' in the way drugs can be manufactured: New method to build important heparin drug

ScienceDaily (Oct. 27, 2011) — Robert Linhardt is working to forever change the way some of the most widely used drugs in the world are manufactured. In a new studying appearing in the journal Science, he and his partner in the research, Jian Liu, have announced an important step toward making this a reality.

Linhardt, the Ann and John H. Broadbent Jr. '59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer Polytechnic Institute, and Jian Liu, a professor in the Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill, have discovered an entirely new process to manufacture ultra-low molecular weight heparin.

The research shows that the drug is identical in performance and safety to the current and successful anticoagulant fondaparinux, but is purer, faster, and less expensive to produce.

"This research represents an entirely new paradigm in drug manufacturing," Linhardt said. "With this discovery, we have successfully demonstrated that replacing the current model of drug production with a chemoenzymatic approach can greatly reduce the cost of drug development and manufacturing, while also increasing drug performance and safety, and reduce the possibility of outside drug contamination. It is our hope that this is the first step in the adoption of this method for the manufacture of many other drugs."

The new process uses chemicals and enzymes to reduce the number of steps in production of fondaparinux from approximately 50 steps down to just 10 to 12. In addition, it increases the yield from that process 500-fold compared to the current fondaparinux process, and could decrease the cost of manufacture by a similar amount, according to Linhardt.

Fondaparinux, which is sold as a name-brand drug and was also recently approved by the FDA as a generic drug, is a synthetic anticoagulant used to treat deep vein thrombosis, with over $500 million in annual sales. It is part of a much larger family of anticoagulant drugs known as heparins. But, unlike most heparin products, it is chemically synthesized from non-animal materials. All other heparin-based drugs currently on the market use materials from the intestines of pigs and lungs of cattle as source materials. Such animal materials are more likely to become contaminated, according to Linhardt.

"When we rely on animals, we open ourselves up for spreading viruses and prion diseases like mad cow disease through the use of these heparins," Linhardt said. "And because most of the raw material is imported, we often can't be sure of exactly what we are getting."

But, fondaparinux is extremely costly to produce, according to Linhardt. "The process to produce the drug involves many steps to purify the material and creates tons and tons of hazardous waste to dispose of," Linhardt said.

The new process developed by Linhardt and Liu greatly reduces the number of steps involved in the production of the drug. This reduces the amount of waste produced and the overall cost of producing the drug.

"Cost should no longer be a major factor in the use or production of this drug," Linhardt said.

The process uses sugars and enzymes that are identical to those found in the human body to build the drug piece by piece. The backbone of the material is first built sugar by sugar and then decorated with sulfate groups through the use of enzymes to control its structure and function in the body.

Linhardt and Liu have already begun testing the drug in animal models with successful results and think the drug could be quickly transferred to the market.

"Because the new drug is biologically identical in its performance to the already approved fondaparinux, the approval process for this new drug should work very similar to the approval process used for fondaparinux," Linhardt said. He also thinks that this combined chemical and enzymatic synthesis can be quickly brought to patients in need and adapted for the production of many other improved carbohydrate-containing drugs.

"During this study, we were able to quickly build multiple doses in a simple laboratory setting and feel that this is something than can be quickly and easy commercialized to reduce the cost of this drug and help to shift how pharmaceutical companies approach the synthesis of carbohydrate-containing drugs."

The finding is part of a much larger body of work occurring in the Linhardt lab to completely replace all types of heparin-based or other glycoprotein-based drugs with safer, low-cost, synthetic versions that do not rely on foreign, potentially contaminated animal sources.

The research is funded by the National Institutes of Health.

Linhardt and Liu were joined in the research by Yongmei Xu, Haoming Xu, Renpeng Liu, and Juliana Jing of the University of North Carolina, Chapel Hill; Sayaka Masuko of Rensselaer Polytechnic Institute; and Majde Takieddin and Shaker Mousa of the Albany College of Pharmacy and Health Sciences.

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Journal Reference:

Yongmei Xu, Sayaka Masuko, Majde Takieddin, Haoming Xu, Renpeng Liu, Juliana Jing, Shaker A. Mousa, Robert J. Linhardt, Jian Liu. Chemoenzymatic Synthesis of Homogeneous Ultralow Molecular Weight Heparins. Science, 2011; 334 (6055): 498-501 DOI: 10.1126/science.1207478

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Use of over-the-counter thyroid support pills is risky, researcher finds

ScienceDaily (Oct. 27, 2011) — People who use over-the-counter "thyroid support'' supplements may be putting their health at risk, according to a study being presented at the annual meeting of the American Thyroid Association. The supplements contain varying amounts of two different kinds of thyroid hormones apparently derived in large part from chopped up animal thyroid glands, says the study's senior investigator, Victor Bernet, M.D., an endocrinologist at Mayo Clinic in Florida.

The hormones are known as T3, or triiodothyronine, and T4, or thyroxine. They are regulated by the U.S. Food and Drug Administration and intended for use only in prescription medication because they can cause significant health issues, such as an increase in heart rate, heart irregularities and palpitations, nervousness, and diarrhea, Dr. Bernet says.

"These hormones have effects throughout the body, which is why they are controlled," he says.

Not only did nine of the 10 supplements studied have animal hormone, the amount of hormones in the products varied significantly, sometimes exceeding doses used for individual patients and comparable to levels found in prescription thyroid medication, Dr. Bernet says.

The supplements likely do not give most people the results they are seeking, such as weight loss or less fatigue, he says.

"The amount of thyroid hormone a normal person would have to take to lose weight would be dangerously high and there is no evidence that use of thyroid hormone effectively treats fatigue when used in people without actual hypothyroidism," he says.

Because physicians have seen a number of abnormal thyroid tests from patients using over-the-counter supplements, Dr. Bernet became interested in this issue when he heard reports of such cases as chairman of the American Thyroid Association's public health committee. He worked with researchers including endocrinologists at Walter Reed Army Medical Center, where he practiced at the time.

The researchers bought 10 commercially available thyroid supplements from stores or websites and used high-pressure liquid chromatography to separate and identify the chemical components of T3 and T4. Nine of the 10 contained T3 and five of them would deliver as much, or more, than 50 percent of the total amount of T3 produced by the body daily.

Four of the 10 supplements contained T4, and some of those contained a dose that could be twice as much as what an adult needs each day. Only one supplement had no detectable T3 or T4.

The results show there is a need for more effective monitoring of the contents of over-the-counter thyroid support products and more patient education about the products' potential health risks, Dr. Bernet says.

The study was funded by the Department of Clinical Investigation at Walter Reed Army Medical Center, which, in August 2011, became the Walter Reed National Military Medical Center.

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Building better HIV antibodies: Biologists create neutralizing antibody that shows increased potency

ScienceDaily (Oct. 27, 2011) — Using highly potent antibodies isolated from HIV-positive people, researchers have recently begun to identify ways to broadly neutralize the many possible subtypes of HIV. Now, a team led by biologists at the California Institute of Technology (Caltech) has built upon one of these naturally occurring antibodies to create a stronger version they believe is a better candidate for clinical applications.

Current advances in isolating antibodies from HIV-infected individuals have allowed for the discovery of a large number of new, broadly neutralizing anti-HIV antibodies directed against the host receptor (CD4) binding site -- a functional site on the surface of the virus that allows for cell entry and infection. Using a technique known as structure-based rational design, the team modified one already-known and particularly potent antibody -- NIH45-46 -- so that it can target the binding site in a different and more powerful way. A study outlining their process was published in the Oct. 27 issue of Science Express.

"NIH45-46 was already one of the most broad and potent of the known anti-HIV antibodies," says Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and senior author on the study. "Our new antibody is now arguably the best of the currently available, broadly neutralizing anti-HIV antibodies."

By conducting structural studies, the researchers were able to identify how NIH45-46 interacted with gp120 -- a protein on the surface of the virus that's required for the successful entry of HIV into cells -- to neutralize the virus. Using this information, they were able to create a new antibody (dubbed NIH45-46G54W) that is better able to grab onto and interfere with gp120. This improves the antibody's breadth -- or extent to which it effectively targets many subtypes of HIV -- and potency by an order of magnitude, according to Ron Diskin, a postdoctoral scholar in Bjorkman's lab at Caltech and the paper's lead author.

"Not only did we design an improved version of NIH45-46, our structural data are calling into question previous assumptions about how to make a vaccine in order to elicit such antibodies," says Diskin. "We hope that these observations will help to guide and improve future immunogen design."

By improving the efficacy of antibodies that can neutralize HIV, the researchers point to the possibility of clinical testing for NIH45-46G54W and other antibodies as therapeutic agents. It's also plausible that understanding effective neutralization by powerful antibodies may be useful in vaccine development.

"The results uncover the structural underpinnings of anti-HIV antibody breadth and potency, offer a new view of neutralization by CD4-binding site anti-HIV antibodies, and establish principles that may enable the creation of a new group of HIV therapeutics," says Bjorkman, who is also a Howard Hughes Medical Institute investigator.

Other Caltech authors on the study, "Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design," include Paola M. Marcovecchio, Anthony P. West, Jr., Han Gao, and Priyanthi N.P. Gnanapragasm. Johannes Scheid, Florian Klein, Alexander Abadir, and Michel Nussenweig from Rockefeller University, and Michael Seaman from Beth Israel Deaconess Medical Center in Boston also contributed to the paper. The research was funded by the Bill & Melinda Gates Foundation, the National Institutes of Health, the Gordon and Betty Moore Foundation, and the German Research Foundation.

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The above story is reprinted from materials provided by California Institute of Technology. The original article was written by Katie Neith.

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Ron Diskin, Johannes F. Scheid, Paola M. Marcovecchio, Anthony P. West, Jr., Florian Klein, Han Gao, Priyanthi N. P. Gnanapragasam, Alexander Abadir, Michael S. Seaman, Michel C. Nussenzweig, Pamela J. Bjorkman. Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design. Science, Published online Oct. 27, 2011 DOI: 10.1126/science.1213782

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Three key questions for the IT industry

ScienceDaily (Oct. 27, 2011) — Today's multicore processors are not being utilized in a sufficiently intelligent way. They get too hot and run slowly because they are used inefficiently. At the same time, transistors are becoming so small that they will ultimately become unreliable. Major European research organizations are now attempting to create a revolution in computer architecture.

Are you disappointed with the performance of your new computer or phone? Then perhaps rightly so. Their clock frequency has not risen significantly since 2000. Overheating problems and limited battery capacity are forcing manufacturers to limit power usage substantially, typically to 100 W per chip.

"You can't sell a mobile device with bulky sophisticated cooling. So we can't increase the clock frequency, a problem that multicore processors were designed to avoid," says Per Stenström, Professor of Computer Engineering at Chalmers University of Technology and project coordinator for a new center called Eurecca.

"So far, multicore systems have merely yielded marginal performance improvements. It will be increasingly difficult to keep all the processors busy without exceeding the power limit."

Today modern microprocessors typically have six cores. The problem is that no one can as yet optimally program even two-core (two parallel processors on the same chip) computers. The same problem has also baffled giants such as Intel and Microsoft. Basically what is needed is moving from sequential to parallel programming -- i.e. the art of getting several processors to operate together as efficient, well trained sports teams instead of inefficiently coordinated superstars. This second technological challenge goes by the name of concurrency.

"The industry is not yet mature for this step, and we lag behind in terms of education and research," says Per Stenström.

That's why three leading universities in computer architecture are now founding the European Research Center on Computer Architecture (EuReCCA). The planned center so far comprises fifty research scientists, but computer technology institutions from all parts of Europe are joining at a rapid rate, all coordinated by Chalmers. The aim is to make pioneering progress in the development of systems involving multicore processors and paradigms for their productive programming, which should ultimately result in new generations of products and innovative company start-ups.

Eurecca should above all boost the competitive power of the European computer industry, which is a world leader in computers for embedded applications such as cars and mobile phones. A modern car contains no less than about fifty processors. British ARM processors are found in mobile phones from manufacturers such as Nokia, SonyEricsson and Apple. European research projects normally run for three years, but Eurecca will be set up as a longer term Eurolab structure.

"We want to have a permanent structure in order to sustain a long-term focus on bringing innovations out to industry. This has not worked in a satisfactory way in Europe so far. To build up functional systems of knowledge transfer is not something that can be done in three years," says Per Stenström.

The Eurolab structure is also needed to build up streamlined education in computer technology at master and doctoral level throughout Europe. The aim is to get together to nurture a new generation of computer architects ready to lead system innovations based on the parallel philosophy in high demand.

The third technical challenge is miniaturization. Transistor dimensions are halved every 18 months. Soon, transistors will be only a few tens of atoms in size. Along the way they become increasingly unreliable, which will present an enormous challenge for computer system designers in the future. No one currently knows how to tackle this.

"We quite simply have to create a revolution in computer architecture," says Per Stenström, who expects national and European funding for Eurecca, as well as investments from industry.

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Joking, pretending with toddlers gives them head start in life skills

ScienceDaily (Oct. 27, 2011) — Parents who joke and pretend with their toddlers are giving their children a head start in terms of life skills. Most parents are naturals at playing the fool with their kids, says a new research project funded by the Economic and Social Research Council (ESRC). However parents who feel they may need a little help in doing this can learn to develop these life skills with their tots.

"Parents, carers and early years educators shouldn't underestimate the importance of interacting with young children through jokes and pretending," researcher Dr Elena Hoicka points out. "Spending time doing this fun stuff with kids helps them learn how to do it themselves and gives them a set of skills which are important in childhood and beyond."

The latest research findings on joking and pretending with children will be highlighted at a half-day event organised as part of the ESRC's Festival of Social Science 2011. One key aim of the event will be to boost parents' confidence in joking and pretending with their toddlers through a range of hands-on activities.

Dr Hoicka's study has examined how the two very similar concepts of joking and pretending develop in children aged between 15 and 24 months. Explaining the difference between joking and pretending, Dr Hoicka says: "Both involve intentionally doing or saying the wrong thing. However, joking is about doing something wrong just for the sake of it. In contrast, pretending is about doing something wrong which is imagined to be right. For example, parents might use a sponge like a duck while pretending but use a cat as a duck when joking."

The study examined whether parents offer different cues such as tone or pitch of voice in order to help their toddlers understand and differentiate between joking and pretending. Findings reveal that parents rely on a range of language styles, sound and non-verbal cues. For example, when pretending, parents often talk slowly and loudly and repeat their actions. Conversely, parents tend to cue their children to jokes by showing their disbelief through language, and using a more excited tone of voice.

"We found that most parents employ these different cues quite naturally to help their toddlers understand and differentiate these concepts," Dr Hoicka points out. "While not all parents feel confident in their natural abilities, the research does show that making the effort to interact in this way with toddlers is important. Knowing how to joke is great for making friends, dealing with stress, thinking creatively and learning to 'think outside the box'. Pretending helps children learn about the world, interact with others, be creative and solve problems."

Parents can learn more about the different cues used in joking and pretending during an event to be held later this week. "We will be offering a range of activities to help parents experiment with joking and pretending," says Dr Hoicka. "We will also give some short talks on the early development of joking and pretending in toddlers as well as some initial findings from our research project."

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Gender differences: Viewing TV coverage of terrorism has more negative effect on women, study finds

ScienceDaily (Oct. 27, 2011) — Exposure to television coverage of terrorism causes women to lose psychological resources much more than men, which leads to negative feelings and moodiness. This has been shown in a new study, conducted at the University of Haifa and soon to be published in Anxiety, Stress & Coping, that examined the differences between men and women in a controlled experiment environment.

An earlier study conducted by Prof. Moshe Zeidner of the Department of Counseling and Human Development at the University of Haifa and Prof. Hasida Ben-Zur of the University of Haifa's School of Social Work, has shown that viewing television coverage of terrorism causes viewers to lose psychological resources, such the sense of significance or success, and causes a feeling of being threatened. The current study set out to examine whether there are differences between men and women in the levels of psychological resource loss.

According to the authors of the new study, earlier research dealing with gender differences in the effects of traumatic events examined data based on questionnaires relating to past experiences. The present study is now taking a new step as it is examining these differences in a controlled experiment environment in which all of the participants are exposed to the same events and report on their feelings immediately following the events.

In order to create such a controlled environment, men and women were shown news video clips reporting on terrorist attacks that took place over the past few years and which resulted in serious casualties. In parallel, two other groups of men and women were shown news coverage of "regular," everyday news events.

The results of this study show that the women who viewed terrorism coverage testified to higher levels of feeling threatened and lower levels of psychological resources compared to the men who viewed the same news reports. These gender differences were not found amongst the control groups. The study has also found that the feeling of being threatened and loss of resources has an effect on the senses and lead to a higher level of negativity, such as hostility and moodiness.

"It is possible that the differences between men and women are founded in gender socialization, 'teaching' women to respond to terrorism with more anxiety than men," said Prof. Moshe Zeidner.

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Hasida Ben-Zur, Moshe Zeidner. Gender differences in loss of psychological resources following experimentally-induced vicarious stress. Anxiety, Stress & Coping, 2011; DOI: 10.1080/10615806.2011.619526

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Speedy 3-D X-rays in the operating room

ScienceDaily (Oct. 27, 2011) — Having an operation always places strain on patients, and this is especially true of complicated operations. Surgeons use 3D X-rays to check the results before the patient has left the operating room. This does help to avoid possible complications, but it also means interrupting the surgery. Fraunhofer researchers are now developing a 3D X-ray system that can be integrated seamlessly into operating procedure -- with no more forced interruptions.

To find out how this system works, visit the Medica 2011 trade fair in Düsseldorf from November 16 to 19.

Mrs. S. is more than a little anxious: she is due to be given a spinal implant in three days' time. The elderly lady is worried about complications -- and not without reason, since complicated operational procedures such as those on the spine, the head or the ankle are a challenge even for highly experienced surgeons. In order to reduce the risk of complications in more difficult operations and to avoid the need for follow-up surgery, doctors carry out progress checks with the help of three-dimensional X-ray images while the operation is in progress. These 3D images allow them to check on the position of implants and fracture fragments, so as to determine the relative positions of pieces of bone or to position implants with millimeter accuracy. The trouble is, currently available 3D X-ray systems such as C-arms interfere with the surgeon's work. The X-ray source and detector have to move in circles around the patient, which takes up a lot of space; if the C-arm were installed on the operating table permanently, it would impede access to patients. So the device must be wheeled over to the operating table to capture the images and then moved out of the way again. This is a nuisance -- and it takes up time, as it entails an interruption to the surgery.

Researchers at the Fraunhofer Institute for Production Systems and Design Technology IPK are currently working on a solution to this problem. Together with the Charité -- Universitätsmedizin Berlin university hospital and Ziehm Imaging GmbH, they are developing ORBIT, a 3D X-ray scanner that can be integrated into operations and does not cause any delays.

"Unlike existing three-dimensional imaging procedures, ORBIT doesn't have to surround the patient to capture images. Instead, it's an open system in which the X-ray source follows a circular path above the operating table. This makes capturing images much quicker, because it does away with time-consuming preparations," says Professor Dr.-Ing. Erwin Keeve of the Berliner Zentrum für Mechatronische Medizintechnik, a center founded by the IPK and Charité. "It takes about 15 minutes to bring a C-arm into position, record individual projected images of the patient and then convert them into 3D image data. Since X-ray scanning takes less time with ORBIT, it speeds up the overall surgical procedure. Plus it's an easier system to use, which means doctors will be more inclined to make this diagnostic tool a routine part of their work," Keeve explains. The device has another big advantage: While implants and screws can cause interference in C-arm scans, ORBIT images feature far fewer artifacts caused by these metal objects because its X-ray source and its detector do not move in the same plane. Keeve is happy to report that "our initial experiments have been a success."

Modular system

ORBIT is made up of three modules: There is a maneuverable X-ray source fitted to an articulated bracket. This swivel arm can be attached to the ceiling or mounted on a wheeled stand for mobile applications, but either way the X-ray scans are always carried out from above. There is a digital flat panel detector recessed into the operating table. Finally, there is a monitor -- either mobile or wall-mounted -- to display the X-ray images. The researchers have already filed a patent application for this system.

Construction of an initial prototype is currently underway and comprehensive testing will begin in 2012. The system is set to be ready for market in three to five years' time. Those who wish to find out more about ORBIT will have their first chance at Medica 2011 in Düsseldorf.

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