This advance in nanomedicine combines the extraordinarily small size of nanoparticles, existing cancer drugs, and small interfering RNA (siRNA) that shut down the ability of cancer cells to resist attack.

The combination of these forces resulted in the virtual disappearance of lung tumors in experimental animals.

Lung cancer is the leading cancer killer in both men and women. Despite advances in surgery, chemotherapy still plays a major role in its treatment. However, that treatment is constrained by the toxic effects of some drugs needed to combat it and the difficulty of actually getting those drugs into the lungs.

The findings were made by Oleh Taratula at Oregon State University and Tamara Minko and O. Garbuzenko at Rutgers University and the Cancer Institute of New Jersey. They were just published in the Journal of Controlled Release.

“Lung cancer damage is usually not localized, which makes chemotherapy an important part of treatment,” said Taratula, an assistant professor in the OSU College of Pharmacy and co-author on this study. “However, the drugs used are toxic and can cause organ damage and severe side effects if given conventionally through intravenous administration.

“A drug delivery system that can be inhaled is a much more efficient approach, targeting just the cancer cells as much as possible,” he said. “Other chemotherapeutic approaches only tend to suppress tumors, but this system appears to eliminate it.”

A patent is being applied for on the technology, and more testing will be necessary before it is ready for human clinical trials, the researchers said.

The foundation of the new system is a “nanostructured lipid nanocarrier,” tiny particles much smaller than a speck of dust that are easily inhaled and also readily attach to cancer cells. This carrier system delivers the anticancer drug. However, it also brings siRNA that makes the cancer cell more vulnerable.

Cancer cells often have two forms of resistance to drugs ? “pump” resistance that tends to pump the drug out of cells, and “nonpump” resistance that helps keep the cell from dying. The siRNA used in this system helps to eliminate both those forms of resistance, and leaves the cancer cell vulnerable to the drug being used to kill it.

By being inhaled, this system also avoids degradation of the chemotherapeutic agents that occurs when they are injected, researchers said. They arrive in more intact form, ready to do their job on lung cancer cells, while minimizing any side effects.

In more conventional chemotherapy for lung cancer, the drugs tend to accumulate in the liver, kidney and spleen, with much less of the drugs ever making it to the lungs. In this study, the amount of the drug delivered to the lungs rose to 83 percent with the inhalation approach, versus 23 percent with injection.

This work was supported by the National Cancer Institute, National Science Foundation, and the Department of Defense.

Contact: Oleh Taratula
oleh.taratula@oregonstate.edu
541-737-3424
Oregon State University

The formula, developed in the Department of Microbiology, is applied directly on the skin. The principle ingredient is a circular, 70 amino acid protein known as AS-48, produced by Enterococcus bacteria and with no proven haemolytic or toxic activity.

As University of Granada Professor and project lead researcher Mercedes Maqueda-Abreu explains, “the human skin is the first physical barrier protecting our bodies from the exterior, but it also has to be considered as a biological barrier housing beneficial microorganisms, the microbiota of the skin, populated by bacteria and different fungus species that stop pathogens from developing.” Altering the natural equilibrium of these microorganisms leads to infections that are sometimes difficult to treat?like acne (acne vulgaris), “a very common skin infection, principally in puberty, that causes aesthetic and health problems and damages self-esteem,” or other very common skin infections produced by Staphylococcus aureus or Streptococcus pyogenes.

Ineffective treatments

The Propionibacterium acnes bacteria is responsible for this infection when it develops, out of control, in areas abundant in sebaceous secretions. Current treatments are not always effective because resistance develops or undesirable side effects occur. Skin infections caused by S. aureus and S. pyogenes are increasingly demonstrating antibiotic multiresistance. They lead to serious pathologies but, to some extent, are susceptible to topical antibacterial treatment too.

The new formula developed at the University of Granada?and patented through the Office for the Transfer of Research Results (Otri)”draws on natural substances with antibacterial activity, so they can be used as cosmetic and/or pharmaceutical ingredients in the treatment and prophylaxis of these infections,” affirms Prof. Maqueda-Abreu.

The AS-48 protein, on which the patented formula is based, has a broad spectrum of action against Gram-positive bacteria. These include important pathogens such as different species of staphylococcus, streptococcus, clostridia, micobacteriaceae and listeria, among others. Potentially, it could have many applications in human and animal clinical care and as a biopreservative in foods.

“In vitro, topical use of AS-48 alone, or together with agents that enhance its activity, has proved highly efficient in controlling the microorganisms responsible for the skin infections we’re talking about”, says Prof. Maqueda-Abreu.

The formula patented at the University of Granada, which does not lose activity when stored at different temperatures or on account of interactions between the active molecules and cosmetic compounds has, moreover, a further added advantage: as AS-48 targets the bacteria cell membrane, pathogen resistance is highly unlikely to develop.

Corresponding author:

Mercedes Maqueda Abreu
Department of Microbiology, University of Granada

mmaqueda@ugr.es
34-958-242-857
University of Granada

The drugs, known as “TSPO ligands,” are currently used for certain types of neuroimaging.

“We looked at the effects of TSPO ligand in young adult mice when pathology was at an early stage, and in aged mice when pathology was quite severe,” said lead researcher Christian Pike of the USC Davis School of Gerontology. “TSPO ligand reduced measures of pathology and improved behavior at both ages.”

The team’s findings were published online by the Journal of Neuroscience on May 15. Pike’s coauthors include USC postdoctoral scientists Anna M. Barron, Anusha Jayaraman and Joo-Won Lee; as well as Donatella Caruso and Roberto C. Melcangi of the University of Milan and Luis M. Garcia-Segura of the Instituto Cajal in Spain.

The most surprising finding for Pike and his team was the effect of TSPO ligand in the aged mice. Four treatments?once per week over four weeks?in older mice resulted in a significant decrease of Alzheimer’s-related symptoms and improvements in memory ? meaning that TSPO ligands may actually reverse some elements of Alzheimer’s disease.

“Our data suggests the possibility of drugs that can prevent and treat Alzheimer’s,” Pike said. “It’s just mouse data, but extremely encouraging mouse data. There is a strong possibility that TSPO ligands similar to the ones used in our study could be evaluated for therapeutic efficacy in Alzheimer’s patients within the next few years.”

Next, the team will next focus on understanding how TSPO ligands reduce Alzheimer’s disease pathology. Building on the established knowledge that TSPO ligands can reduce inflammation?shielding nerve cells from injury and increasing the production of neuroactive hormones in the brain?the team will study which of these actions is the most significant in fighting Alzheimer’s disease so they can develop newer TSPO ligands accordingly.

The research was funded by the National Institutes of Health (grant number AG05142), the American-Australian Association, the Japan Society for the Promotion of Science and the Fondazione San Paolo.

Contact: Robert Perkins
perkinsr@usc.edu
213-740-9226
University of Southern California

The treatment, developed at Duke and tested in an ongoing phase 1 study, capitalizes on the discovery that cancer cells have an abundance of receptors that work like magnets drawing the poliovirus, which then infects and kills the cells.

The investigational therapy, known as PVSRIPO, uses an engineered form of the virus that is lethal to cancer cells, while harmless to normal cells. Infused directly into the patient’s tumor, the virus-based therapy also triggers the body’s immune fighters to launch an attack against the infected tumor cells.

Preliminary data, presented at the upcoming 2013 Annual Meeting of the American Society of Clinical Oncology in Chicago (ASCO abstract #2094), previews the results of seven patients enrolled in the study whose tumors reoccurred despite traditional treatments for glioblastoma multiforme, the most common and aggressive brain tumor.

Of the patients enrolled in the study, three have responded well to the drug. One patient remains disease-free 12 months after treatment, another 11 months post-treatment and the third is disease-free after five months. With traditional treatment, about half of glioblastoma patients see recurrent tumor growth within eight weeks.

Two patients in the study did not fair as well; one had recurrent tumor growth after two months, and another’s condition declined after four months. The remaining two patients have been treated in the last three and two months, respectively, and currently remain disease free.

“These early results are intriguing,” said Annick Desjardins, M.D., FRCPC, principal investigator and associate professor of medicine at Duke University School of Medicine. “Current therapies for glioblastoma are limited because they cannot cross the blood-brain barrier and often do not specifically attack the tumor. This treatment appears to overcome those problems. We are eager to see additional results as we move forward with our study.”

In addition to Desjardins, study authors include J. H. Sampson, K.B. Peters, T. Ranjan, G. Vlahovic, S. Threatt, J.E. Herndon II, A. Friedman, H.S. Friedman, D.D. Bigner and M. Gromeier.

Contact: Sarah Avery
sarah.avery@duke.edu
919-660-1306
Duke University Medical Center

“This study identifies a novel mechanism that protects ovarian cancer cells by preventing the cell death or apoptosis which should occur when they encounter positively charged nanoparticles,” say the senior authors of this study, Priyabrata Mukherjee, Ph.D., a Mayo Clinic molecular biologist, and Y.S. Prakash, M.D., Ph.D., a Mayo Clinic anesthesiologist and physiologist.

Why Cancer Cells Survived

Gold nanoparticles can have many medical uses, from imaging and aiding diagnoses to delivering therapies. In this case, using a special preparation to put positive ionic charges on the surface, the nanoparticle is intended to act as a targeted destructor of tumor cells while leaving healthy cells alone. The nanoparticles are supposed to kill cells by causing cellular calcium ion levels to increase. But researchers discovered that a regulatory protein in the mitochondria essentially buffers the rising calcium by transporting it into the mitochondria, thus subverting cell death. Cancer cells have an abundance of this transporter and may thus be protected from nanoparticle toxicity.

The research team discovered that if they inhibit calcium uptake into the mitochondria, sufficient cellular stress builds up, making the gold nanoparticles more effective in destroying cancer cells.

The researchers say that understanding how mitochondrial transport mechanisms work will help in the design of targeted therapies against cancer. They called for nanoparticle developers to integrate this new mechanistic knowledge into their processes for designing nanoparticle properties to be used in therapy.

The study was a team effort between researchers at Mayo Clinic including Mayo authors Rochelle Arvizo, Ph.D., Sounik Saha, Ph.D., Michael Thompson, and Resham Bhattacharya, Ph.D.; and the University of Massachusetts at Amherst including Daniel Moyano and Vincent Rotello, Ph.D.

About Mayo Clinic

Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit http://www.mayoclinic.org/about and http://www.mayoclinic.org/news.

Journalists can become a member of the Mayo Clinic News Network for the latest health, science and research news and access to video, audio, text and graphic elements that can be downloaded or embedded.

Contact: Bob Nellis
newsbureau@mayo.edu
507-284-5005
Mayo Clinic

Corresponding author David Weiss of Emory University says the results show that colistin therapy can fail patients in two ways. “The way that the bacteria become resistant [to colistin] allows them to also become resistant to the antimicrobials made by our immune system. That is definitely not what doctors want to do when they’re treating patients with this last line antibiotic,” says Weiss.

Although it was developed fifty years ago, colistin remains in use today not so much because it’s particularly safe or effective, but because the choices for treating multi-drug resistant Acinetobacter baumannii and other resistant infections are few and dwindling. Colistin is used when all or almost all other drugs have failed, often representing a patient’s last hope for survival.

Weiss says he and his colleagues noted that colistin works by disrupting the inner and outer membranes that hold Gram-negative bacterial cells together, much the same way two antimicrobials of the human immune system, LL-37 and lysozyme, do. LL-37 is a protein found at sites of inflammation, whereas lysozyme is found in numerous different immune cells and within secretions like tears, breast milk, and mucus, and both are important defenses against invading bacteria. Weiss and his collaborators from Emory, the CDC, Walter Reed Army Institute of Research, and Grady Memorial Hospital in Atlanta set out to find whether resistance to colistin could engender resistance to attack by LL-37 or lysozyme.

Looking at A. baumannii isolates from patients around the country, they noted that all the colistin-resistant strains harbored mutations in pmrB, a regulatory gene that leads to the modification of polysaccharides on the outside of the cell in response to antibiotic exposure. Tests showed a tight correlation between the ability of individual isolates to resist high concentrations of colistin and the ability to resist attacks by LL-37 or lysozyme.

This was very convincing, write the authors, that mutations in the pmrB gene were responsible for cross-resistance to LL-37 and lysozyme, but to get closer to a causative link between treatment and cross-resistance, they studied two pairs of A. baumannii isolates taken from two different patients before and after they were treated for three or six weeks with colistin. The results helped confirm the cross-resistance link: neither strain taken before treatment was resistant to colistin, LL-37, or lysozyme, but the strains taken after treatment showed significant resistance to colistin and lysozyme. (One post-colistin isolate was no more or less resistant to LL-37 than its paired pre-colistin isolate.) Like the resistant strains tested earlier, both post-colistin isolates harbored crucial mutations in the pmrB gene that apparently bestow the ability to resist treatment.

The authors point out that the apparent link between resistance to colistin and cross-resistance to antimicrobial agents of the immune system could well extend to other pathogens that are treated with colistin, including Pseudomonas aeruginosa and Klebsiella pneumoniae. Weiss says he plans to follow up with studies to determine whether this bears out.

For Weiss, the problems with colistin are symptomatic of a much larger trio of problems: increasing levels of drug resistance, cuts in federal funding for antibiotic research, and lack of incentives for pharmaceutical companies to invest in antibiotic R&D. “We don’t have enough antibiotics, and it’s really important for the research community and the public to support increases in funding for research to develop new antibiotics,” says Weiss.

“We got complacent for a while and the bugs are becoming resistant. This is something we can reverse – or make a lot better – if we have the resources.”

mBio® is an open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields. It can be found online at http://mbio.asm.org.

The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM’s mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Contact: Jim Sliwa
jsliwa@asmusa.org
202-942-9297
American Society for Microbiology

Researchers at Wake Forest Baptist Medical Center and colleagues, reporting in the journal Biomaterials, found that human kidneys discarded for transplant can potentially serve as a natural “scaffolding material” for manufacturing replacement organs in the lab using regenerative medicine techniques.

According to the authors, more than 2,600 donor kidneys are discarded each year in the U.S. “With about 100,000 people in the U.S. awaiting kidney transplants, it is devastating when an organ is donated but cannot be used,” said Giuseppe Orlando, M.D., Ph.D., lead author, a Wake Forest Baptist transplant surgeon and regenerative medicine researcher. “These discarded organs may represent an ideal platform for investigations aimed at manufacturing kidneys for transplant.”

The research involved pumping a mild detergent through kidneys that were refused for transplant. The goal of the process, called decellularization, is to remove all cells ? leaving only the organ structure or “skeleton,” known in regenerative medicine terms as a scaffold. Ultimately, the patient’s own cells could be placed in this scaffold, creating a customized organ that the patient theoretically would not reject.

In fact, an analysis of the decellularized organs revealed that antigens likely to cause an immune response were removed in the cleaning process. “This finding has significant implications,” said Orlando. “It indicates that transplantation of such customized kidneys could be performed without the need for anti-rejection therapy. In addition, these kidneys maintain their innate three-dimensional architecture, their basic biochemistry, as well as their vessel network system. When we tested their ability to be transplanted (in pigs), these kidneys were able to maintain blood pressure, suggesting a functional and resilient vasculature.”

While the project is in its infancy, the idea represents a potential solution to the extreme shortage of donor kidneys. According to the authors, the probability in the U.S. of receiving a kidney transplant within five years of being added to the waiting list is less than 35 percent, and people age 60 or older who are placed on the waiting list only have a 50 percent chance of ever receiving a kidney.

The science of regenerative medicine has already had success in engineering skin, cartilage, bladders, urine tubes, trachea and blood vessels in the lab that were successfully implanted in patients. Most of these structures were able to receive oxygen and nutrients from nearby tissues until they developed their own blood vessel supply. However, more complex organs such as the kidney, liver, heart and pancreas are larger with dense cellular networks and must have their own oxygen supply to survive. The need for a blood supply is why scientists are exploring the possibility of using donor organs and “seeding” them with a patient’s own cells.

As the research continues, the scientists will need to assess whether discarded organs with certain defects can be used to benefit patients. For example, some kidneys are rejected because of fibrosis (scarring) in the tiny vessels throughout the organ. Can these organs be recycled? Orlando said that time will tell but that early clinical data suggests that fibrotic lesions are reversible and that the human body has the ability to remodel kidney fibrosis and restore normal anatomy.

The research was supported in part by a grant from the state of North Carolina.

Co-researchers were Christopher Booth, B.S., Zhan Wang, Ph.D., Christina L. Ross, Ph.D., Emma Moran, B.S., Marcus Salvatory, M.D., Yousef Al-Shraideh, M.D., Umar Farooq, M.D., Alan C. Farney, M.D., Ph.D., Jeffrey Rogers, M.D., Samy Iskandar, M.D., Ph.D., Frank Marini, Ph.D., Robert J. Stratta, M.D., and Shay Soker, Ph.D., Wake Forest Baptist; Giorgia Totonelli, M.D., Ph.D., Panagiotis Maghsoudlou, M.S., Mark Turmaine, Ph.D., Alan Burns, Ph.D., Paolo De Coppi, M.D., Ph.D., University College London; and Ginger Delario, Ph.D., Carolina Donor Services.

Media contacts: Karen Richardson, krchrdsn@wakehealth.edu, 336-716-4453; Media Relations Office, 336-716-4587.

Wake Forest Baptist Medical Center (http://www.wakehealth.edu) is a fully integrated academic medical center located in Winston-Salem, North Carolina. The institution comprises the medical education and research components of Wake Forest School of Medicine, the integrated clinical structure and consumer brand Wake Forest Baptist Health, which includes North Carolina Baptist Hospital and Brenner Children’s Hospital, the creation and commercialization of research discoveries into products that benefit patients and improve health and wellness, through Wake Forest Innovations, Wake Forest Innovation Quarter, a leading center of technological discovery, development and commercialization, as well as a network of affiliated community-based hospitals, physician practices, outpatient services and other medical facilities. Wake Forest School of Medicine is ranked among the nation’s best medical schools and is a leading national research center in fields such as regenerative medicine, cancer, neuroscience, aging, addiction and public health sciences. Wake Forest Baptist’s clinical programs have consistently ranked as among the best in the country by U.S .News & World Report for the past 20 years.

Contact: Karen Richardson
krchrdsn@wakehealth.edu
336-716-4453
Wake Forest Baptist Medical Center

By altering a very specific step in gene regulation, this compound essentially re-educates cancer cells into normal cells that die as scheduled.

One way that cancer cells thrive is by inhibiting a process that would cause them to die on a regular cycle that is subject to strict programming. This study in cells, led by Ohio State University researchers, found that a compound in certain plant-based foods, called apigenin, could stop breast cancer cells from inhibiting their own death.

Much of what is known about the health benefits of nutrients is based on epidemiological studies that show strong positive relationships between eating specific foods and better health outcomes, especially reduced heart disease. But how the actual molecules within these healthful foods work in the body is still a mystery in many cases, and particularly with foods linked to lower risk for cancer.

Parsley, celery and chamomile tea are the most common sources of apigenin, but it is found in many fruits and vegetables.

The researchers also showed in this work that apigenin binds with an estimated 160 proteins in the human body, suggesting that other nutrients linked to health benefits ? called “nutraceuticals” ? might have similar far-reaching effects. In contrast, most pharmaceutical drugs target a single molecule.

“We know we need to eat healthfully, but in most cases we don’t know the actual mechanistic reasons for why we need to do that,” said Andrea Doseff, associate professor of internal medicine and molecular genetics at Ohio State and a co-lead author of the study. “We see here that the beneficial effect on health is attributed to this dietary nutrient affecting many proteins. In its relationship with a set of specific proteins, apigenin re-establishes the normal profile in cancer cells. We think this can have great value clinically as a potential cancer-prevention strategy.”

Doseff oversaw this work with co-lead author Erich Grotewold, professor of molecular genetics and director of Ohio State’s Center for Applied Plant Sciences (CAPS). The two collaborate on studying the genomics of apigenin and other flavonoids, a family of plant compounds that are believed to prevent disease.

The research appears this week in the online early edition of the journal Proceedings of the National Academy of Sciences.

Though finding that apigenin can influence cancer cell behavior was an important outcome of the work, Grotewold and Doseff point to their new biomedical research technique as a transformative contribution to nutraceutical research.

They likened the technique to “fishing” for the human proteins in cells that interact with small molecules available in the diet.

“You can imagine all the potentially affected proteins as tiny fishes in a big bowl. We introduce this molecule to the bowl and effectively lure only the truly affected proteins based on structural characteristics that form an attraction,” Doseff said. “We know this is a real partnership because we can see that the proteins and apigenin bind to each other.”

Through additional experimentation, the team established that apigenin had relationships with proteins that have three specific functions. Among the most important was a protein called hnRNPA2.

This protein influences the activity of messenger RNA, or mRNA, which contains the instructions needed to produce a specific protein. The production of mRNA results from the splicing, or modification, of RNA that occurs as part of gene activation. The nature of the splice ultimately influences which protein instructions the mRNA contains.

Doseff noted that abnormal splicing is the culprit in an estimated 80 percent of all cancers. In cancer cells, two types of splicing occur when only one would take place in a normal cell ? a trick on the cancer cells’ part to keep them alive and reproducing.

In this study, the researchers observed that apigenin’s connection to the hnRNPA2 protein restored this single-splice characteristic to breast cancer cells, suggesting that when splicing is normal, cells die in a programmed way, or become more sensitive to chemotherapeutic drugs.

“So by applying this nutrient, we can activate that killing machinery. The nutrient eliminated the splicing form that inhibited cell death,” said Doseff, also an investigator in Ohio State’s Davis Heart and Lung Research Institute. “Thus, this suggests that when we eat healthfully, we are actually promoting more normal splice forms inside the cells in our bodies.”

The beneficial effects of nutraceuticals are not limited to cancer, as the investigators previously showed that apigenin has anti-inflammatory activities.

The scientists noted that with its multiple cellular targets, apigenin potentially offers a variety of additional benefits that may even occur over time. “The nutrient is targeting many players, and by doing that, you get an overall synergy of the effect,” Grotewold explained.

Doseff is leading a study in mice, testing whether food modified to contain proper doses of this nutrient can change splicing forms in the animals’ cells and produce an anti-cancer effect.

Additional co-authors are first author Daniel Arango, a Ph.D. student in the Molecular, Cellular and Developmental Biology graduate program; and Kengo Morohashi, Alper Yilmaz, Arti Parihar and undergraduate Bledi Brahimaj of the Department of Molecular Genetics, all at Ohio State; and Kouji Kuramochi of Kyoto Prefectural University in Japan. Doseff, Arango and Parihar are affiliated with Ohio State’s Division of Pulmonary, Allergy, Critical Care and Sleep Medicine.

Contact: Pam Frost Gorder
Gorder.1@osu.edu
614-292-9475
Ohio State University

The discovery has wider repercussions, as the protein is responsible for protecting the body against excessive immune responses, and could be used to treat, or even prevent, other immune disorders such as multiple sclerosis and rheumatoid arthritis.

Professor Len Harrison, Dr Esther Bandala-Sanchez and Dr Yuxia Zhang led the research team from the Walter and Eliza Hall Institute that identified the immune protein CD52 as responsible for suppressing the immune response, and its potential for protecting against autoimmune diseases. The research was published today in the journal Nature Immunology.

So-called autoimmune diseases develop when the immune system goes awry and attacks the body’s own tissues. Professor Harrison said CD52 held great promise as a therapeutic agent for preventing and treating autoimmune diseases such as type 1 diabetes.

“Immune suppression by CD52 is a previously undiscovered mechanism that the body uses to regulate itself, and protect itself against excessive or damaging immune responses,” Professor Harrison said. “We are excited about the prospect of developing this discovery to clinical trials as soon as possible, to see if CD52 can be used to prevent and treat type 1 diabetes and other autoimmune diseases. This has already elicited interest from pharmaceutical companies.”

Type 1 diabetes is an autoimmune disease that develops when immune cells attack and destroy insulin-producing beta cells in the pancreas. Approximately 120,000 Australians have type 1 diabetes and incidence has doubled in the last 20 years. “Type 1 diabetes is a life-long disease,” Professor Harrison said. “It typically develops in children and teenagers, and it really makes life incredibly difficult for them and their families. It also causes significant long-term complications involving the eyes, kidneys and blood vessel damage, and at great cost to the community.”

Professor Harrison said that T cells that have or release high levels of CD52 are necessary to maintain normal balance in the immune system. “In a preclinical model of type 1 diabetes, we showed that removal of CD52-producing immune cells led to rapid development of diabetes. We think that cells that release CD52 are essential to prevent the development of autoiummune disease, and that CD52 has great potential as a therapeutic agent,” he said.

CD52 appears to play a dominant role in controlling or suppressing immune activity in the early stages of the immune response, Professor Harrison said. “We identified a specialised population of immune cells (T cells) that carry high levels of CD52, which they release to dampen the activity of other T cells and prevent uncontrolled immune responses,” Professor Harrison said. “The cells act as an early ‘braking’ mechanism.”

Professor Harrison said his goal is to prevent and ultimately cure type 1 diabetes. “In animal models we can prevent and cure type 1 diabetes,” Professor Harrison said. “I am hopeful that these results will be translatable into humans, hopefully in the not-too-distant future.”

The research was supported by the National Health and Medical Research Council of Australia and the Victorian Government.

Contact: Liz Williams
williams@wehi.edu.au
61-405-279-095
Walter and Eliza Hall Institute

The prevailing theory on the development of OA focuses on joint cartilage, suggesting that unstable mechanical pressure on the joints leads to more and more harm to the cartilage?and pain to the patient?until the only treatment option left is total knee or hip replacement. The new theory, reported May 19 in Nature Medicine, suggests that initial harm to the cartilage causes the bone underneath it to behave improperly by building surplus bone. The extra bone stretches the cartilage above and speeds its decline.

“If there is something wrong with the leg of your chair and you try to fix it by replacing the cushion, you haven’t solved the problem,” says Xu Cao, Ph.D., director of the Center for Musculoskeletal Research in the Department of Orthopaedic Surgery at the Johns Hopkins University School of Medicine. “We think that the problem in OA is not just the cartilage ‘cushion,’ but the bone underneath,” he adds.

Joints are formed at the intersection of two bones. To prevent the grinding and wearing down of the ends of the bones, they are capped with a thin layer of cartilage, which not only provides a smooth surface for joint rotation but also absorbs some of the weight and mechanical strain placed on the joint. The degeneration of this protective layer causes extreme pain leading to limited mobility.

Cao says degeneration is most frequently initiated by instability in the load-bearing joints of the knee and hip caused by injury or strain, so athletes, overweight people and people whose muscles are weakened by aging are at highest risk of developing OA. The prevalence of the disease is rapidly increasing; it currently affects 27 million Americans and may double by 2030. The only treatment available is pain management, or surgical replacement of the arthritic joint with a prosthetic one.

Cao says that the lack of effective drugs or a complete understanding of the underlying process that causes OA to progress led his group to search for a different underlying cause. “We began to think of cartilage and the bone underneath it, called subchondral bone, as functioning as a single unit,” says Cao. “That helped us to see the ways in which the bone was responding to changes in the cartilage and exacerbating the problem.”

Using mice with ACL (anterior cruciate ligament) tears, which are known to lead to OA of the knee, the researchers found that, as soon as one week after the injury, pockets of subchondral bone had been “chewed” away by cells called osteoclasts. This process activated high levels in the bone of a protein called TGF-beta1, which, in turn, recruited stem cells to the site so that they could create new bone to fill the holes. Cao calls these pockets of new bone formation “osteoid islets.”

But the bone building and the bone destruction processes were not coordinated in the mice, and the bone building prevailed, placing further strain on the cartilage cap. It is this extraneous bone formation that Cao and his colleagues believe to be at the heart of OA, as confirmed in a computer simulation of the human knee.

With this new hypothesis in hand, complete with a protein suspect, the team tried several methods to block the activity of TGF-beta1. When a TGF-beta1 inhibitor drug was given intravenously, the subchondral bone improved significantly, but the cartilage cap deteriorated further. However, when a different inhibitor of TGF-beta1, an antibody against it, was injected directly into the subchondral bone, the positive effects were seen in the bone without the negative effects on the cartilage. The same result was also seen when TGF-beta1 was genetically disrupted in the bone precursor cells alone.

“Our results are potentially really good news for patients with OA,” says Cao. “We are already working to develop a clinical trial to test the efficacy of locally applied TGF-beta1 antibodies in human patients at early stages of OA.” If successful, their nonsurgical treatment could make OA ? and the pain and debilitation it causes ? halt in its tracks, he says.

Other authors of the report include Gehua Zhen, Xiaofeng Jia, Janet Crane, Simon Mears, Frederic Askin, Frank Frassica, Weizhong Chang, John Carrino, Andrew Cosgarea, Dmitri Artemov, Lee Riley, Paul Sponseller and Mei Wan of the Johns Hopkins University School of Medicine; Chunyi Wen, Jie Yao and William Weijia Lu of the University of Hong Kong; and Yu Li, Qianming Chen, Zhihe Zhao and Xuedong Zhou of Sichuan University.

This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK057501, DK08098).

Contact: Catherine Kolf
ckolf@jhmi.edu
443-440-1929
Johns Hopkins Medicine

The article reinterprets data from the ‘Global Burden of Disease: 2010′ study which shows that all of the top ten causes of premature death and disability, and top ten behavioural risk factors driving rates of ill-health around the world, affect men more than they affect women (see tables in Notes to Editors).

In every region of the world men die at a younger age than women and the smallest decline in global mortality rates over the past 40 years has been experienced by young men aged 25-39 years.

The commentary, written by Dr Sarah Hawkes of the UCL Institute for Global Health and Dr Kent Buse of UNAIDS, reviews the responses of major global health institutions and finds that efforts and resources are focused more often on the health needs of women. The authors argue that global health institutions should start tackling the social norms and commercial interests that push men to take risks with their health.

“Gender norms drive risk-taking,” says Dr Sarah Hawkes. “Drinking alcohol and smoking, in particular, are subject to social pressures which have resulted in men globally running three times the risk of ill-health from these behaviours compared to women. These norms and customs are clearly perpetuated by all of us, and exploited by commercial interests.”

Dr Hawkes, an expert in sexual health, continues: “The global health community has made real strides in acknowledging and addressing unsafe sex, we must now do the same for ‘unsafe gender’.

“We recognise that women are disadvantaged in many societies and consider the advancement of women central to sustainable development, but this does not imply that the international community has no responsibility to promote and protect men’s health too.”

Co-author Dr Kent Buse, Chief, Political Affairs and Strategy at UNAIDS, says: “It is more or less universally acknowledged that gender plays a significant role in the risks associated with unsafe/unprotected sex ? in this case placing women at greater risk. So why is it so difficult to accept that gender also plays a role in the risk of other major burdens of illness and premature death globally ? particularly those that effect men disproportionately?

“The global health community is taking a short-sighted view,” continues Dr Buse. “The drivers of ill-health in men are the same drivers of the emerging burden of illness in women. It is time that policy-makers face up to gender in global health and tackle the interests that stand between us and good health for everyone.”

The views were echoed by Professor Chris Murray of the University of Washington, author of the original study on which this analysis is based: “We as a society should not have lower aspirations for health for males than females. Everyone deserves a chance at a long life in full health, regardless of where they live, their gender, or their economic situation.”

Professor Davidson Gwatkin from the Johns Hopkins Bloomberg School of Public Health stated: “This is by far the most interesting and thought-provoking piece on gender inequalities I have read in a long time. The international health community stands to benefit greatly from such iconoclastic thinking and from the extensive discussion it deserves to generate.”

Notes to Editors:

Hawkes S., Buse K., Gender and global health: evidence, policy and inconvenient truths. The Lancet 2013; 381:1783-87 The paper will be available from: http://www.thelancet.com/themed/women-deliver-2013

Media contacts:

For a copy of the paper, or to speak to one of the authors, contact David Weston in the UCL Press Office, T: +44 (0) 203 108 3844, d.weston@ucl.ac.uk

Additional data:

Table 1: Top ten contributors to disability adjusted life years, all ages, globally, 2010

This table compares the years of life lost due to ill-health, disability or death, between men and women. For example, for every year that a woman’s life is cut short by death or disability related to heart disease, a man will lose 1.58 years of potential healthy life due to the same condition.

Cause Ratio of male:female burden

All causes 1.22

Top 10 Causes

Ischemic heart disease 1.58

Lower respiratory infections 1.26

Cerebrovascular disease 1.21

Diarrhoeal diseases 1.05

HIV/AIDS 1.19

Low back pain 1.14

Malaria 1.19

Preterm birth complications 1.33

Chronic obstructive pulmonary disease 1.31

Road injury 2.96

Totals of top 10 causes 1.34

Table 2 – top 10 risk factors for ill health globally, all ages, 2010

This table shows the ratio (males to females) of people affected by specific risks to health (such as smoking, drinking alcohol etc.)

Risk Factor Ratio of male:female risk

High blood pressure 1.35

Tobacco smoking 3.38

Alcohol use 2.98

Household air pollution 1.25

Low fruit 1.70

High body mass index 1.07

High plasma fasting glucose 1.23

Childhood underweight 1.14

Ambient Particulate matter pollution 1.59

Physical inactivity 1.15

About UCL (University College London):

Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender and the first to provide systematic teaching of law, architecture and medicine.

We are among the world’s top universities, as reflected by our performance in a range of international rankings and tables. According to the Thomson Scientific Citation Index, UCL is the second most highly cited European university and the 15th most highly cited in the world.

UCL has nearly 25,000 students from 150 countries and more than 9,000 employees, of whom one third are from outside the UK. The university is based in Bloomsbury in the heart of London, but also has two international campuses ? UCL Australia and UCL Qatar. Our annual income is more than £800 million.

Contact: David Weston
d.weston@ucl.ac.uk
44-020-310-83844
University College London

In young people, blood vessels appear to be able to compensate for the effects of obesity. But after middle age, this adaptability is lost, and arteries become progressively stiffer as body fat rises ? potentially increasing the risk of dying from cardiovascular disease.

The researchers suggest that the harmful effects of body fat may be related to the total number of years that a person is overweight in adulthood. Further research is needed to find out when the effects of obesity lead to irreversible damage to the heart and arteries, they said.

Obesity is known to be a major risk factor for heart disease, but the reasons for this are not fully understood.

Researchers at the Medical Research Council (MRC) Clinical Sciences Centre at Imperial College London scanned 200 volunteers to measure the speed of blood flow in the aorta, the biggest artery in the body. Blood travels more quickly in stiff vessels than in healthy elastic vessels, so this allowed them to work out how stiff the walls of the aorta were using an MRI scanner.

In young adults, those with more body fat had less stiff arteries. However, after the age of 50 increasing body fat was associated with stiffer arteries in both men and women.

Body fat percentage, which can be estimated by passing a small electric current through the body, was more closely linked with artery stiffness than body mass index, which is based just on weight and height. Men are on average about 21 per cent fat and women 31 per cent fat.

The research was funded by the MRC, the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, and the British Heart Foundation, and published in the journal Hypertension.

Dr Declan O’Regan, who led the study, said: “The effects of having more fat seem to be different depending on your age. It looks like young people may be able to adapt to excess body fat, but by middle age the cumulative exposure to years of obesity may start to cause permanent damage to the arteries. One implication is that the potential beneficial effects of weight loss may depend on your age and how long you have been overweight. This is something we plan to study further.

“We don’t know for sure how body fat makes arteries stiffer, but we do know that certain metabolic products in the blood may progressively damage the elastic fibres in our blood vessels. Understanding these processes might help us to prevent the harmful effects of obesity.”

For further information please contact:

Contact: Sam Wong
sam.wong@imperial.ac.uk
44-207-594-2198
Imperial College London

“J147 is an exciting new compound because it really has strong potential to be an Alzheimer’s disease therapeutic by slowing disease progression and reversing memory deficits following short-term treatment,” says lead study author Marguerite Prior, a research associate in Salk’s Cellular Neurobiology Laboratory.

Despite years of research, there are no disease-modifying drugs for Alzheimer’s. Current FDA-approved medications, including Aricept, Razadyne and Exelon, offer only fleeting short-term benefits for Alzheimer’s patients, but they do nothing to slow the steady, irreversible decline of brain function that erases a person’s memory and ability to think clearly.

According to the Alzheimer’s Association, more than 5 million Americans are living with Alzheimer’s disease, the sixth leading cause of death in the country and the only one among the top 10 that cannot be prevented, cured or even slowed.

J147 was developed at Salk in the laboratory of David Schubert, a professor in the Cellular Neurobiology Laboratory. He and his colleagues bucked the trend within the pharmaceutical industry, which has focused on the biological pathways involved in the formation of amyloid plaques, the dense deposits of protein that characterize the disease. Instead, the Salk team used living neurons grown in laboratory dishes to test whether their new synthetic compounds, which are based upon natural products derived from plants, were effective at protecting brain cells against several pathologies associated with brain aging. From the test results of each chemical iteration of the lead compound, they were able to alter their chemical structures to make them much more potent. Although J147 appears to be safe in mice, the next step will require clinical trials to determine whether the compound will prove safe and effective in humans.

“Alzheimer’s disease research has traditionally focused on a single target, the amyloid pathway,” says Schubert, “but unfortunately drugs that have been developed through this pathway have not been successful in clinical trials. Our approach is based on the pathologies associated with old age-the greatest risk factor for Alzheimer’s and other neurodegenerative diseases-rather than only the specificities of the disease.”

To test the efficacy of J147 in a much more rigorous preclinical Alzheimer’s model, the Salk team treated mice using a therapeutic strategy that they say more accurately reflects the human symptomatic stage of Alzheimer’s. Administered in the food of 20-month-old genetically engineered mice, at a stage when Alzheimer’s pathology is advanced, J147 rescued severe memory loss, reduced soluble levels of amyloid, and increased neurotrophic factors essential for memory, after only three months of treatment.

In a different experiment, the scientists tested J147 directly against Aricept, the most widely prescribed Alzheimer’s drug, and found that it performed as well or better in several memory tests.

“In addition to yielding an exceptionally promising therapeutic, both the strategy of using mice with existing disease and the drug discovery process based upon aging are what make the study interesting and exciting,” says Schubert, “because it more closely resembles what happens in humans, who have advanced pathology when diagnosis occurs and treatment begins.” Most studies test drugs before pathology is present, which is preventive rather than therapeutic and may be the reason drugs don’t transfer from animal studies to humans.

Prior and her colleagues say that several cellular processes known to be associated with Alzheimer’s pathology are affected by J147, including an increase in a protein called brain-derived neurotrophic factor (BDNF), which protects neurons from toxic insults, helps new neurons grow and connect with other brain cells, and is involved in memory formation. Postmortem studies show lower than normal levels of BDNF in the brains of people with Alzheimer’s.

Because of its broad ability to protect nerve cells, the researchers believe that J147 may also be effective for treating other neurological disorders, such as Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS), as well as stroke, although their study did not directly explore the drug’s efficacy as a therapy for those diseases.

The Salk researchers say that J147, with its memory enhancing and neuroprotective properties, along with its safety and availability as an oral medication, would make an “ideal candidate” for Alzheimer’s disease clinical trials. They are currently seeking funding for such a trial.

Other researchers on the study were Richard Dargusch, Jennifer L. Ehren and Chandra Chiruta, of the Salk Institute.

The work was supported by the Alzheimer’s Drug Discovery Foundation, the Bundy Foundation, the Fritz Burns Foundation, the George E. Hewitt Foundation, the Alzheimer’s Association, and the National Institutes of Health.

About the Salk Institute for Biological Studies:

The Salk Institute for Biological Studies is one of the world’s preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer’s, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.

Contact: Andy Hoang
AHoang@salk.edu
619-861-5811
Salk Institute

Now a team of Tel Aviv University researchers, including Dr. Shimon Rochkind of TAU’s Sackler Faculty of Medicine and Tel Aviv Sourasky Medical Center and Prof. Zvi Nevo of TAU’s Department of Human Molecular Genetics and Biochemistry have invented a method for repairing damaged peripheral nerves. Through a biodegradable implant in combination with a newly-developed Guiding Regeneration Gel (GRG) that increases nerve growth and healing, the functionality of a torn or damaged nerve could ultimately be restored.

This innovative project is now gaining international recognition. Its initial successes were reported recently at several renowned scientific congresses, including the World Federation of Neurological Societies and the European Neurological Society. And the therapy, already tested in animal models, is only a few years away from clinical use, says Dr. Rochkind.

Like healing in the womb

A nerve is like an electrical cable. When severed or otherwise damaged, power can no longer be transferred and the cable loses its functionality. Similarly, a damaged nerve loses the ability to transfer signals for movement and feeling through the nervous system.

But Dr. Rochkind and Prof. Nevo found a way to breach the gap. In their method, two severed ends of a damaged nerve are reconnected by implanting a soft, biodegradable tube, which serves as a bridge to help the nerve ends connect. The innovative gel which lines the inside of the tube nurtures nerve fibers’ growth, encouraging the nerve to reconnect the severed ends through the tube, even in cases with massive nerve damage, Dr. Rochkind says.

The key lies in the composition of the gel, the researchers say, which has three main components: anti-oxidants, which exhibit high anti-inflammatory activities; synthetic laminin peptides, which act as a railway or track for the nerve fibers to grow along; and hyaluronic acid, commonly found in the human fetus, which serves as a buffer against drying, a major danger for most implants. These components allow the nerve to heal the way a fetus does in the womb ? quickly and smoothly.

Keeping cells safe for transplant

The implant has already been tested in animal models, and the gel by itself can be used as a stand-alone product, acting as an aid to cell therapy. GRG is not only able to preserve cells, it can support their survival while being used for therapy and transplantation, says Dr. Rochkind. When grown in the gel, cells show excellent development, as well as intensive fiber growth. This could have implications for the treatment of diseases such as Parkinson’s, for which researchers are actively exploring cell therapy as a potential solution.

American Friends of Tel Aviv University supports Israel’s leading, most comprehensive and most sought-after center of higher learning. Independently ranked 94th among the world’s top universities for the impact of its research, TAU’s innovations and discoveries are cited more often by the global scientific community than all but 10 other universities.

Internationally recognized for the scope and groundbreaking nature of its research and scholarship, Tel Aviv University consistently produces work with profound implications for the future.

Contact: George Hunka
ghunka@aftau.org
212-742-9070
American Friends of Tel Aviv University

From microscopes to MRI scanners, imaging technology is growing ever more vital in the world’s hospitals, whether for the diagnosis of illness or for research into new cures. Imaging technology requires dyes or contrast agents of some sort. Current contrast agents and dyes are expensive, difficult to work with and far from ideal. Now, Danish chemists have discovered a new dye and proved its worth against any of the dyes currently available.

Thomas Just Sørensen and Bo Wegge Laursen are chemists at the University of Copenhagen, Denmark. In a series of publications in well-regarded scientific publications, they have shown that the aza-oxa-trangulenium dyes have the potential to outperform all fluorescent dyes currently used in imaging.

“Our dyes are ten times better, far cheaper and easier to use. The latter I believe, will lead to expanded opportunities and broadened use, by physicians and researchers in developing countries, for example.” Says Thomas Just Sørensen.

Visual noise blocks correct diagnosis

It might seem odd, but one of the central challenges when taking pictures of cells and organs, is to avoid noise. The agents that make it possible to see microscopic biological structures are luminescent, but then, so is tissue. Consequently, the contrast agent’s light risks being overpowered by “light noise”. Just as the dial and hands of a watch might glow-in-the-dark, tissue becomes luminescent when exposed to light. Tissue and other organic structures luminesce, or lights up, for 10 nanoseconds after exposure to light. The light-life of an ordinary dye is the same ? 10 nanoseconds. But triangulenium dyes produce light for an entire 100 nanoseconds.

The long life of the triangulenium dyes means that an image can be produced without background noise. Furthermore, the extra 90 nanoseconds opens the possibility of filming living images of the processes occurring within cells, for example when a drug attacks an illness.

Neither expensive, nor difficult or technically demanding

Medical image analysis departments currently devote an incredible amount of time to staining samples, because all samples must be treated with two agents. The use of triangulenium dyes necessitates only one dye. And in contrast with typical dyes, no specialized equipment is needed to see the dyes in tissue samples. A lens from a pair of polarized sunglasses and an ordinary microscope are all that are required.

Open Source dye despite obvious competitiveness

When one compares the advantages of triangulenium dyes against the three million Danish kroner per gram price tag of traditional dyes,(500.000$US)(320.000£) you would expect that the new dye would immediately out-compete its predecessors. However, up to now Sørensen and Laursen have had to give their dye away. “I know that our dye is better, but biologists and physicians don’t. Therefore, we are giving the dye away to anyone that wants to perform a comparison test. Someone who needs to assess the health of sick people wouldn’t dare to rely on an untested substance. Only when several researchers have shown triangulenium dyes to perform just as effectively as its predecessors can we hope for our substance to become more widely adopted,” concludes Thomas Just Sørensen.

Contact: Jes Andersen
jean@science.ku.dk
45-30-50-65-82
University of Copenhagen

The study, led by the University of Melbourne and published in the Journal of Clinical Psychopharmacology, revealed Kava could be an alternative treatment to pharmaceutical products for the hundreds of thousands of Australians who suffer from Generalised Anxiety Disorders (GAD).

Lead researcher, Dr Jerome Sarris from the Department of Psychiatry at the University of Melbourne, said GAD is a complex condition that significantly affected people’s day-today lives. Existing medications have a modest clinical effect and new effective options were needed for patients with anxiety.

“Based on previous work we have recognised that plant based medicines may be a viable treatment for patients with chronic anxiety. In this study we’ve been able to show that Kava offers a potential natural alternative for the treatment of chronic clinical anxiety. Unlike some other options it has less risk of dependency and less potential for side effects,” he said.

The study also found that people’s genetic differences (polymorphisms) of certain neurobiological mechanisms called GABA transporters, may modify their response to Kava.

“If this finding is replicated, it may pave the way for simple genetic tests to determine which people may be likely to have a beneficial anxiety-reducing effect from taking Kava,” Dr Sarris said.

During the eight-week study, 75 patients with clinically diagnosed Generalised Anxiety Disorder were given Kava or placebo, and anxiety levels were regularly assessed.

Results showed a significant reduction in anxiety for the Kava group compared to the placebo group at the end of the study.

In participants diagnosed with moderate to severe GAD, Kava had an even greater effect in reducing anxiety. Following the completion of the controlled phase, 26 per cent of the Kava group were classified as in remission from their symptoms compared to six per cent of the placebo group.

Participants in the Kava group were given tablets twice per day consisting of water-soluble extracted Kava (peeled rootstock) for a total dose of 120mg of kavalactones for the first three-week controlled phase. In cases of non-response this was increased to a double-dose twice per day for the second three-week controlled phase. Participants in the placebo group took matching dummy tablets in the same manner.

Kava was also well tolerated. Results showed no significant differences across the two groups for liver function which had previously been a concern for Kava’s medicinal use. In addition there were no considerable adverse reactions that could be attributed to Kava and no difference in withdrawal or addiction between the groups.

An additional novel finding of the study, recently published in Phytotherapy Research was that Kava increased women’s sex drive compared to those in the placebo group, believed to be due to the reduction of anxiety, rather than any aphrodisiac effect.

Future studies confirming the genetic relationship to therapeutic response, and any libido-improving effects from Kava is now required.

Dr Sarris said these significant findings are of importance to sufferers of anxiety and to the South Pacific region which relies on Kava as a major export.

The study was funded by the NHMRC and Integria Healthcare who manufacture MediHerb and Thompson’s Kava products.

Contact: Rebecca Scott
rebeccas@unimelb.edu.au
61-383-440-181
University of Melbourne

The study, published in the May 9 edition of the New England Journal of Medicine, isolated the molecular mutation that causes chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) in some patients. That mutation, occurring in a gene called colony stimulating factor 3 receptor (CSF3R), initiates a chain reaction involving other gene families known as SRC, JAK, and TNK2, which subsequently drives these diseases.

This discovery is promising for patients as it will aid in diagnosing these cancers, which are currently difficult for physicians to distinguish from other leukemias. More importantly, the study results suggest that these patients could be helped by existing FDA-approved drugs designed to inhibit the chain reactions impacting JAK and SRC/TNK2, though clinical trials are needed.

“Our ability to rapidly pinpoint a new cancer-driving mutation demonstrates the power of integrating improved genome sequencing technology. It will accelerate our ability to tailor treatments to individuals and each research victory gives us more insight into the nature of this complex disease,” said Jeffrey W. Tyner, Ph.D., an assistant professor with the OHSU Knight Cancer Institute and Cell & Developmental Biology Department, whose lab led the research. “What distinguished this research was our method for matching voluminous amounts of gene sequencing data with drug sensitivity data to quickly deduce which mutations were relevant in causing disease and this allows us to make a difference for patients who don’t currently have good therapeutic options.”

Tyner and the other researchers who conducted this study used a combination of tests not yet commonly deployed together for research on primary specimens collected from cancer patients. They performed gene sequencing on specimens from 27 patients, creating a profile of the possible genetic causes of these diseases. This enabled them to highlight the important mutations that were common among CNL and aCML patients. As they gathered information on potentially relevant mutations, they simultaneously tested how fresh samples of patients’ cancer cells responded to different drugs. This enabled the scientists to link drug efficacy to CSF3R gene mutations.

The two-pronged study approach provided researchers with the ability to quickly home in on and verify a root cause of these rare forms of leukemia. Of the 27 patients in the study, 16, or about 59 percent, had the CSF3R mutation.

“This approach allows us to rapidly discover mutations that are fundamental to cancer growth and identify drugs that might be used to combat them,” said Julia Maxson, Ph.D., of the OHSU Knight Cancer Institute, who was first author on the study. “Our findings are not only promising for the treatment of patients with CNL and aCML but also validate our approach to identify new drug targets in cancer.”

In fact, during the study period, a CNL patient was treated with the FDA-approved drug ruxolitinib, which inhibits the cancer cell growth initiated by the CSF3R mutation. This treatment resulted in a dramatic improvement in the patient’s condition.

CNL and aCML impact several hundred patients in the United States each year. Patients afflicted with these conditions typically live only two to three years. These forms of cancer have also been difficult to diagnose because there wasn’t enough known about their genetic drivers. Knowing that they are defined by mutations in CSF3R provides physicians with a means to confirm a diagnosis. Tests for this mutation are already available; the OHSU Knight Diagnostic Laboratories’ GeneTrails panel for leukemias has the capability to check for this mutation.

In an editorial that accompanies the study in the New England Journal of Medicine, Jerald Radich, M.D., of the Fred Hutchinson Cancer Research Center in Seattle, wrote that the approach is “an example of what genetically informed treatment may look like in the near future.” Radich continued: “This is how we will beat cancer, one gene, one disease at a time.”

This study was funded by the Leukemia & Lymphoma Society, The V Foundation, William Lawrence & Blanche Hughes Foundation, Gabrielle’s Angel Foundation and the Howard Hughes Medical Institute. Researchers who contributed are also supported by grants (including 5UL1RR024140, 1-K99-CA151670-01A1, 4 R00CA151457-03 and 5P30CA069533-13) offered through the National Institutes of Health, including the National Cancer Institute.

In in addition to Tyner and Maxson, contributors from OHSU: Angela G. Fleischman, M.D., Ph.D.; Anupriya Agarwal, Ph.D.; Christopher A. Eide, B.A.; Daniel Bottomly, M.S.; Beth Wilmot, Ph.D.; Shannon K. McWeeney, Ph.D.; Cristina E. Tognon, Ph.D.;; Bill H. Chang, M.D., Ph.D.; Marc M. Loriaux, M.D., Ph.D. and Brian J. Druker, M.D.

Other contributes are Jason Gotlib, M.D., of Stanford Cancer Institute, Stanford University School of Medicine; Daniel A. Pollyea, M.D., of the University of Colorado School of Medicine; J. Blake Pond, M.S., and Robert H. Collins, M.D., of the University of Texas Southwestern Medical Center; Basem Goueli, M.D., Ph.D., of St. Luke’s Regional Cancer Center; Stephen T. Oh, M.D., Ph.D., of Washington University; and Michael W. Deininger, M.D., Ph.D., University of Utah.

Contact: Elisa Williams
willieli@ohsu.edu
503-494-8231
Oregon Health & Science University

“We know that one function of our immune system is to detect and destroy pre-malignant cells before they can become cancer,” said lead author Lance D. Miller, Ph.D., associate professor of cancer biology at Wake Forest Baptist. “However, sometimes the immune system becomes unresponsive to the presence of these cells and a tumor develops.”

This unresponsiveness can be temporary, and the immune system can remain alerted to the fact that there’s a problem. Immune cells can stand post along the borders of the tumor and even infiltrate the tumor core, where they may gain a better position for eventual attack. “We now have technologies that allow us to quantify aspects of this interaction and from that information we can make predictions about cancer outcomes, Miller said.”

The study published online ahead of print last month in the journal Genome Biology.

This approach is known as gene expression profiling, and by studying the expression profiles of 2,000 human breast tumors, Miller and his team identified several immune gene signatures that reflect the abundance and anti-tumor properties of different types of tumor-infiltrating immune cells. They found that in certain aggressive types of breast cancer, such as basal-like or triple negative disease, these immune signatures were highly predictive of cancer recurrence years after initial treatment.

“Strikingly, the patients who seemed to benefit the most were those with highly proliferative and clinically aggressive disease,” Miller said. “In these cases, high expression levels of the immune genes predicted for recurrence-free survival, while low immune gene expression predicted for a high likelihood of cancer recurrence.”

An important next step, Miller said, will be translating this into a diagnostic test that may help doctors make more informed treatment decisions.

“Knowing a tumor’s immunogenic disposition could help oncologists know whether to prescribe more or less aggressive treatment regimens, or perhaps, to know which drugs, specifically, will be most effective,” he said.

For doctors like Bayard Powell, M.D., chief of hematology and oncology at Wake Forest Baptist’s Comprehensive Cancer Center, new drugs designed to enhance anti-tumor immune responses are beginning to play a major role in the treatment of certain forms of cancer.

“At Wake Forest Baptist we are now fighting cancer with state-of-the-art therapies including immunotherapeutics,” Powell said. “How a tumor’s immunogenic disposition influences the effectiveness of immunotherapeutic drugs is an important question that could lead to valuable new strategies in personalized medicine.”

Co-authors include: Jeff W. Chou, Ph.D., Mark C. Willingham, M.D., Jimmy Ruiz, M.D., James P. Vaughn, Ph.D., Purnima Dubey, Ph.D., and Timothy L. Lash, Ph.D., all of Wake Forest Baptist; Srikanth Nagalla, M.D., M.S., Jefferson University Hospitals; Stephen J. Hamilton-Dutoit, M.D., Aarhus University Hospital, Institute of Pathology, Denmark; Jonas Bergh, M.D., Ph.D., Karolinska Institute, Sweden; Christos Sotiriou, M.D., Ph.D., Jules Bordet Institute, Belgium, and Michael A. Black, Ph.D., University of Otago, New Zealand.

Contact: Bonnie Davis
bdavis@wakehealth.edu
336-716-4977
Wake Forest Baptist Medical Center

“We think this one type of cell may be useful in treating several types of neurodevelopmental and neurodegenerative disorders in a targeted way,” said Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF and co-lead author on the paper.

The researchers generated and transplanted a type of human nerve-cell progenitor called the medial ganglionic eminence (MGE) cell, in experiments described in the May 2 edition of Cell Stem Cell. Development of these human MGE cells within the mouse brain mimics what occurs in human development, they said.

Kriegstein sees MGE cells as a potential treatment to better control nerve circuits that become overactive in certain neurological disorders. Unlike other neural stem cells that can form many cell types ? and that may potentially be less controllable as a consequence ? most MGE cells are restricted to producing a type of cell called an interneuron. Interneurons integrate into the brain and provide controlled inhibition to balance the activity of nerve circuits.

To generate MGE cells in the lab, the researchers reliably directed the differentiation of human pluripotent stem cells ? either human embryonic stem cells or induced pluripotent stem cells derived from human skin. These two kinds of stem cells have virtually unlimited potential to become any human cell type. When transplanted into a strain of mice that does not reject human tissue, the human MGE-like cells survived within the rodent forebrain, integrated into the brain by forming connections with rodent nerve cells, and matured into specialized subtypes of interneurons.

These findings may serve as a model to study human diseases in which mature interneurons malfunction, according to Kriegstein. The researchers’ methods may also be used to generate vast numbers of human MGE cells in quantities sufficient to launch potential future clinical trials, he said.

Kriegstein was a co-leader of the research, along with Arturo Alvarez-Buylla, PhD, UCSF professor of neurological surgery; John Rubenstein, MD, PhD, UCSF professor of psychiatry; and UCSF postdoctoral scholars Cory Nicholas, PhD, and Jiadong Chen, PhD.

Nicholas utilized key growth factors and other molecules to direct the derivation and maturation of the human MGE-like interneurons. He timed the delivery of these factors to shape their developmental path and confirmed their progression along this path. Chen used electrical measurements to carefully study the physiological and firing properties of the interneurons, as well as the formation of synapses between neurons.

Previously, UCSF researchers led by Allan Basbaum, PhD, chair of anatomy at UCSF, have used mouse MGE cell transplantation into the mouse spinal cord to reduce neuropathic pain, a surprising application outside the brain. Kriegstein, Nicholas and colleagues now are exploring the use of human MGE cells in mouse models of neuropathic pain and spasticity, Parkinson’s disease and epilepsy.

“The hope is that we can deliver these cells to various places within the nervous system that have been overactive and that they will functionally integrate and provide regulated inhibition,” Nicholas said.

The researchers also plan to develop MGE cells from induced pluripotent stem cells derived from skin cells of individuals with autism, epilepsy, schizophrenia and Alzheimer’s disease, in order to investigate how the development and function of interneurons might become abnormal ? creating a lab-dish model of disease.

One mystery and challenge to both the clinical and pre-clinical study of human MGE cells is that they develop at a slower, human pace, reflecting an “intrinsic clock”. In fast-developing mice, the human MGE-like cells still took seven to nine months to form interneuron subtypes that normally are present near birth.

“If we could accelerate the clock in human cells, then that would be very encouraging for various applications,” Kriegstein said.

Other UCSF co-authors of the Cell Stem Cell study include Yunshuo Caroline Tang, a MD/PhD student; research specialists Nadine Chalmers and Christine Arnold; and UCSF postdoctoral fellows Daniel Vogt, PhD, and Ying-Jiun Chen, PhD.

Additional co-authors are Stanford University neurosurgery resident Derek Southwell, MD, PhD; Monash University professors of immunology and stem cell research Edouard Stanley, PhD, and Andrew Elefanty, PhD; and Yoshiki Sasai, PhD, from the RIKEN Center for Developmental Biology.

The research was funded by the California Institute of Regenerative Medicine, the National Institutes of Health, and the Osher Foundation. Arnold Kriegstein, Arturo Alvarez-Buylla, John Rubenstein, and Cory Nicholas are co-founders and shareholders of Neurona Therapeutics. An application for a patent, “In Vitro Production of Medial Ganglionic Eminence Precursor Cells,” has been filed.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Contact: Jeffrey Norris
jeff.norris@ucsf.edu
415-502-6397
University of California – San Francisco

Neurologists have long believed RLS is related to a dysfunction in the way the brain uses the neurotransmitter dopamine, a chemical used by brain cells to communicate and produce smooth, purposeful muscle activity and movement. Disruption of these neurochemical signals, characteristic of Parkinson’s disease, frequently results in involuntary movements. Drugs that increase dopamine levels are mainstay treatments for RLS, but studies have shown they don’t significantly improve sleep. An estimated 5 percent of the U.S. population has RLS.

The small new study, headed by Richard P. Allen, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine, used MRI to image the brain and found glutamate ? a neurotransmitter involved in arousal ? in abnormally high levels in people with RLS. The more glutamate the researchers found in the brains of those with RLS, the worse their sleep.

The findings are published in the May issue of the journal Neurology.

“We may have solved the mystery of why getting rid of patients’ urge to move their legs doesn’t improve their sleep,” Allen says. “We may have been looking at the wrong thing all along, or we may find that both dopamine and glutamate pathways play a role in RLS.”

For the study, Allen and his colleagues examined MRI images and recorded glutamate activity in the thalamus, the part of the brain involved with the regulation of consciousness, sleep and alertness. They looked at images of 28 people with RLS and 20 people without. The RLS patients included in the study had symptoms six to seven nights a week persisting for at least six months, with an average of 20 involuntary movements a night or more.

The researchers then conducted two-day sleep studies in the same individuals to measure how much rest each person was getting. In those with RLS, they found that the higher the glutamate level in the thalamus, the less sleep the subject got. They found no such association in the control group without RLS.

Previous studies have shown that even though RLS patients average less than 5.5 hours of sleep per night, they rarely report problems with excessive daytime sleepiness. Allen says the lack of daytime sleepiness is likely related to the role of glutamate, too much of which can put the brain in a state of hyperarousal ? day or night.

If confirmed, the study’s results may change the way RLS is treated, Allen says, potentially erasing the sleepless nights that are the worst side effect of the condition. Dopamine-related drugs currently used in RLS do work, but many patients eventually lose the drug benefit and require ever higher doses. When the doses get too high, the medication actually can make the symptoms much worse than before treatment. Scientists don’t fully understand why drugs that increase the amount of dopamine in the brain would work to calm the uncontrollable leg movement of RLS.

Allen says there are already drugs on the market, such as the anticonvulsive gabapentin enacarbil, that can reduce glutamate levels in the brain, but they have not been given as a first-line treatment for RLS patients.

RLS wreaks havoc on sleep because lying down and trying to relax activates the symptoms. Most people with RLS have difficulty falling asleep and staying asleep. Only getting up and moving around typically relieves the discomfort. The sensations range in severity from uncomfortable to irritating to painful.

“It’s exciting to see something totally new in the field ? something that really makes sense for the biology of arousal and sleep,” Allen says.

As more is understood about this neurobiology, the findings may not only apply to RLS, he says, but also to some forms of insomnia.

The study was funded in part by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (R01 NS075184 and NS044862), the National Institute on Aging (P10-AG21190) and the National Center for Research Resources (M01RR02719).

Allen has received honoraria serving on advisory boards from impax, Pfizer and UCB and honoraria for scientific lectures, consultancy and research support from UCB, GSK, Pfizer and Pharmacosmos.

Other Johns Hopkins researchers involved in the study include Peter B. Barker, D.Phil.; Alena Horska, Ph.D.; and Christopher J. Earley, M.D., Ph.D.

Contact: Stephanie Desmon
sdesmon1@jhmi.edu
410-955-8665
Johns Hopkins Medicine

Allergies are very common in industrialized countries. It has been suggested that exposure to harmless bacteria during infancy may be protective against the development of allergy. However, it has been difficult to pinpoint which bacteria a baby should be exposed to, and at what time and by which route this exposure should ideally occur.

Swedish researchers at the Sahlgrenska Academy, University of Gothenburg, now report that a simple habit may give significant protection against allergy development, namely, the parental sucking on the baby’s pacifier.

In a group of 184 children, who were followed from birth, the researchers registered how many infants used a pacifier in the first 6 months of life and how the parents cleaned the pacifier. Most parents rinsed the pacifier in tap water before giving it to the baby, e.g., after it had fallen on the floor. However, some parents also boiled the pacifier to clean it. Yet other parents had the habit of putting the baby’s pacifier into their mouth and cleaning it by sucking, before returning it to the baby.

It was found that children whose parents habitually sucked the pacifier were three times less likely to suffer from eczema at 1.5 years of age, as compared with the children of parents who did not do this. When controlled for other factors that could affect the risk of developing allergy, such as allergy in the parents and delivery by Caesarean section, the beneficial effect of parental sucking on the pacifier remained.

Pacifier use per se had no effect on allergy development in the child. Boiling the pacifier also did not affect allergy development in a statistically proven fashion.

No more upper respiratory infections were seen in the children whose parents sucked on their dummies, as compared with the other children, as evidenced by diaries kept by the parents in which they noted significant events, such as infections.

Saliva is a very rich source of bacteria and viruses, and the researchers believe that oral commensal microbes are transferred from parent to infant when they suck on the same pacifier. When the composition of the bacterial flora in the mouth was compared between infants whose parents sucked on their pacifiers and those whose parent did not, it was found to differ, supporting this hypothesis.

According to “the hygiene hypothesis”, the development of allergy can be attributed in part to a paucity of microbial stimulation during early infancy.

“Early establishment of a complex oral microflora might promote healthy maturation of the immune system, thereby counteracting allergy development”, says professor Agnes Wold who led the study.

The study, which is published in the scientific journal Pediatrics, was performed by a team that consisted of paediatricians specialized in allergic diseases, as well as microbiologists and immunologists. The research team has previously conducted large-scale studies on the gut microbiota in relation to allergy development and showed in 2009 that a complex gut microbiota very early in life reduces the risk of allergy development.

The research involves the drug Dz13, a targeted molecular therapy, which was developed at the University of New South Wales (UNSW) and has now been found to be safe in a clinical trial of patients with the common skin cancer, basal-cell carcinoma.

“This is the first report of a drug of this type to be used in humans,” says UNSW Medicine’s Professor Levon Khachigian, who has been developing the DNAzyme technology for 10 years.

“It’s a smart drug, which targets a bad protein that controls tumour growth and spread,” says Professor Khachigian, the Director of the UNSW Centre for Vascular Research. The collaborative trial was conducted by researchers from UNSW, the University of Sydney and Royal Prince Alfred Hospital.

The findings have been published today in the prestigious journal The Lancet.

“Even though we were only testing for safety, there were unexpected positive effects,” says Professor Khachigian.

“The drug knocked down levels of this bad protein and the tumours shrunk in the majority of patients.”

The researchers hope subsequent trials will prove that larger doses of the drug over a longer time period will be more effective.

“Targeted molecular therapy like this might also offer novel, effective, and less invasive therapeutic options for basal-cell carcinoma,” says Professor Gary Halliday, from the University of Sydney, who is one of the co-authors of the study.

If the next stages of the clinical trials in basal-cell carcinoma are successful, the researchers hope that within three years, the drug could be used as a treatment for these cancers, reducing scarring and the costs and inconvenience associated with surgery.

Basal-cell carcinoma is the most common cancer among fair-skinned people worldwide with Australia having the highest incidence.

“This may be a ‘one-size fits all’ therapy, because it targets a master regulator gene called c-Jun which appears to be involved in a range of diseases,” says Professor Khachigian, who predicts that melanoma and eye diseases including macular degeneration and diabetic retinopathy are the likely future targets for research.

A phase one trial in skin melanoma is expected to begin in a month.

“We tested the antibody in various ways, including on tumour cells from myeloma patients that have been transplanted into mice. The tests showed that the antibody is able to destroy myeloma cells”, explains Markus Hansson, a researcher at Lund University in Sweden.

Using a ‘biological library’ of thousands of antibodies from the company BioInvent in Lund, the team singled out antibody BI-505, shown to have a powerful effect on the tumour cells in both cell studies and animal experiments. It has also been tested in an initial safety study on seriously ill patients, and a study of its treatment effects has just started.

“This study will include patients who have just been diagnosed and therefore still feel fairly well. We want to test the antibody treatment before the patients are treated with any other drugs”, says Markus Hansson.

Today there are a number of drugs to treat multiple myeloma, but no cure. None of the drugs are able to eradicate the disease, meaning cancer cells increase in number after a period of remission. Survival has been extended with new treatments, but less than half of all patients live longer than five years from diagnosis.

Myeloma occurs when a specific type of cell in the bone marrow is converted into tumour cells. Blood formation is disrupted and patients suffer from a lack of blood resulting in fatigue. The bones can be weakened with a risk of fractures and compacted vertebrae, and patients sometimes suffer kidney failure as a result of the disease.

Antibodies are a part of the immune system, fighting off foreign bodies. Antibody-based drugs are now used to treat certain inflammatory diseases and types of cancer.

The treatment study in Lund will involve 15 patients and is expected to be completed this year. If the results are good, Markus Hansson and his colleagues hope to be able to continue testing BI-505 in larger-scale studies. They will be studying the best way of using the new antibody: alone or in combination with other drugs; at the start of the disease or at a later stage.

Contact: Markus Hansson
markus.hansson@med.lu.se
46-705-931-110
Lund University

“Lots of nutrients are key for children to have healthy bones. One of these appears to be magnesium,” said lead author Steven A. Abrams MD, FAAP, professor of pediatrics at Baylor College of Medicine in Houston. “Calcium is important, but, except for those children and adolescents with very low intakes, may not be more important than magnesium.”

While it is known that magnesium is important for bone health in adults, few studies have looked at whether magnesium intake and absorption are related to bone mineral content in young children. This study aimed to fill that gap.

Researchers recruited 63 healthy children ages 4 to 8 years old who were not taking any multivitamins or minerals to participate in the study. Children were hospitalized overnight twice so their calcium and magnesium levels could be measured.

Participants filled out food diaries prior to hospitalization. All foods and beverages served during their hospital stay contained the same amount of calcium and magnesium they consumed in a typical day based on the diaries. Foods and beverages were weighed before and after each meal to determine how much calcium and magnesium the subjects actually consumed. In addition, parents were given scales to weigh their child’s food for three days at home after the first inpatient stay and for three days at home prior to the second inpatient stay so that dietary intake of calcium and magnesium could be calculated accurately.

While hospitalized, children’s levels of calcium and magnesium were measured using a technique that involved giving them non-radioactive forms of magnesium and calcium, called stable isotopes, intravenously and orally. Urine was collected for 72 hours. By measuring the stable isotopes in the urine, the researchers could determine how much calcium and magnesium were absorbed into the body. Bone mineral content and density were measured using total body dual-energy X-ray absorptiometry.

Results showed that the amounts of magnesium consumed and absorbed were key predictors of how much bone children had. Dietary calcium intake, however, was not significantly associated with total bone mineral content or density.

“We believe it is important for children to have a balanced, healthy diet with good sources of minerals, including both calcium and magnesium,” Dr. Abrams concluded.

To view the abstract, “Magnesium but Not Calcium Intake Is Significantly Associated with Bone Mineral Status in 4 to 8 Year Old Children,” go to http://www.abstracts2view.com/pas/view.php?nu=PAS13L1_2715.3.

The Pediatric Academic Societies (PAS) are four individual pediatric organizations that co-sponsor the PAS Annual Meeting ? the American Pediatric Society, the Society for Pediatric Research, the Academic Pediatric Association, and the American Academy of Pediatrics. Members of these organizations are pediatricians and other health care providers who are practicing in the research, academic and clinical arenas. The four sponsoring organizations are leaders in the advancement of pediatric research and child advocacy within pediatrics, and all share a common mission of fostering the health and well-being of children worldwide. For more information, visit http://www.pas-meeting.org.

Contact: Debbie Jacobson
djacobson@aap.org
847-434-7084
American Academy of Pediatrics

“To date, it is beyond any doubt that the sudden loss of the inherited skin and localized hair color can affect those individuals in many fundamental ways,” said Karin U. Schallreuter, M.D., study author from the Institute for Pigmentary Disorders in association with E.M. Arndt University of Greifswald, Germany and the Centre for Skin Sciences, School of Life Sciences at the University of Bradford, United Kingdom. “The improvement of quality of life after total and even partial successful repigmentation has been documented.”

To achieve this breakthrough, Schallreuter and colleagues analyzed an international group of 2,411 patients with vitiligo. Of that group, 57 or 2.4 percent were diagnosed with strictly segmental vitiligo (SSV), and 76 or 3.2 percent were diagnosed with mixed vitiligo, which is SSV plus non-segmental vitiligo (NSV). They found that for the first time, patients who have SSV within a certain nerval distribution involving skin and eyelashes show the same oxidative stress as observed in the much more frequent general NSV, which is associated with decreased antioxidant capacities including catalase, thioredoxin reductase, and the repair mechanisms methionine sulfoxide reductases. These findings are based on basic science and clinical observations, which led to successful patient outcomes regarding repigmentation of skin and eyelashes.

“For generations, numerous remedies have been concocted to hide gray hair,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal, “but now, for the first time, an actual treatment that gets to the root of the problem has been developed. While this is exciting news, what’s even more exciting is that this also works for vitiligo. This condition, while technically cosmetic, can have serious socio-emotional effects of people. Developing an effective treatment for this condition has the potential to radically improve many people’s lives.”

FASEB is composed of 26 societies with more than 100,000 members, making it the largest coalition of biomedical research associations in the United States. Our mission is to advance health and welfare by promoting progress and education in biological and biomedical sciences through service to its member societies and through collaborative advocacy.

Details: Karin U. Schallreuter, Mohammed A. E. L. Salem, Sarah Holtz, and A. Panske. Basic evidence for epidermal H2O2/ONOO?-mediated oxidation/nitration in segmental vitiligo is supported by repigmentation of skin and eyelashes after reduction of epidermal H2O2 with topical NB-UVB-activated pseudocatalase PC-KUS. FASEB J doi:10.1096/fj.12-226779 ; http://www.fasebj.org/content/early/2013/04/29/fj.12-226779.abstract

Contact: Cody Mooneyhan
cmooneyhan@faseb.org
301-634-7104
Federation of American Societies for Experimental Biology

As of today, there have been 127 confirmed cases of H7N9 in mainland China with 27 deaths. A lack of information about the virus and its mode of transmission has led to public concerns that H7N9 could be a pandemic waiting to happen.

To quantify the risk of this happening scientists from the Hong Kong Baptist University and Chinese University of Hong Kong have generated a map of H7N9 risk in eastern China. The map is based on the northwards migratory patterns of birds (from the 4th February to the end of April) using environmental and meteorological data over the same 12 weeks – from Zhejiang, Shanghai, and Jiangsu, to Liaoning, Jilin, and Heilongjiang.

The distribution of potentially infected poultry was also included in the model. The majority of early cases of H7N9 were found in Shanghai, but Shanghai is not a big poultry exporter so the model shows limited transmission via this route. In contrast, Jiangsu distributes poultry to Shanghai, Zhejiang, and beyond.

Prof Jiming Liu who led the study explained, “By basing our model on wild bird migration and distribution of potentially infected poultry we are able to produce a time line of the estimated risk of human infection with H7N9. The preliminary results of our study made a prediction of bird flu risk which could explain the pattern of the most recent cases. By extending the model we will be able to predict future infection risks across central and western China, which will aid in surveillance and control of H7N9 infections. Since the effect of poultry-to-poultry infection is not really understood it may become necessary to regulate the activity of poultry markets.”

Prof Xiao-Nong Zhou from the Chinese Center for Disease Control and Prevention who was also involved in this study commented, “We are continuing to work on research into the sources of infection of H7N9 and the mode of transmission. However so far there is no evidence of the sustained human-to-human transmission required for a pandemic to occur.”

Media Contact

Dr Hilary Glover
Scientific Press Officer, BioMed Central
Mob: +44 (0) 778 698 1967

Notes

1. Inferring the potential risks of H7N9 infection by spatiotemporally characterizing bird migration and poultry distribution in eastern China
Benyun Shi, Shang Xia, Guo-Jing Yang, Xiao-Nong Zhou and Jiming Liu
Infectious Diseases of Poverty 2013, 2:8 doi:10.1186/2049-9957-2-8

http://www.idpjournal.com/content/pdf/2049-9957-2-8.pdf

Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central’s open access policy.

2. Infectious Diseases of Poverty is an open access, peer-reviewed journal publishing topic areas and methods that address essential public health questions relating to infectious diseases of poverty. These include various aspects of the biology of pathogens and vectors, diagnosis and detection, treatment and case management, epidemiology and modeling, zoonotic hosts and animal reservoirs, control strategies and implementation, new technologies and application. Transdisciplinary or multisectoral effects on health systems, ecohealth, environmental management, and innovative technology are also considered.

3. BioMed Central is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector. @BioMedCentral

Contact: Hilary Glover
hilary.glover@biomedcentral.com
44-020-319-22370
BioMed Central

Take one step out the front door, and an individual brain cell fires. Pass by your rose bush on the way to the car, another specific neuron fires. And so it goes. Ultimately, the brain constructs its own pinpoint geographical chart that is far more precise than anything you’d find on Google Maps.

But just how neurons make these maps of space has fascinated scientists for decades. It is known that several types of stimuli influence the creation of neuronal maps, including visual cues in the physical environment ? that rose bush, for instance ? the body’s innate knowledge of how fast it is moving, and other inputs, like smell. Yet the mechanisms by which groups of neurons combine these various stimuli to make precise maps are unknown.

To solve this puzzle, UCLA neurophysicists built a virtual-reality environment that allowed them to manipulate these cues while measuring the activity of map-making neurons in rats. Surprisingly, they found that when certain cues were removed, the neurons that typically fire each time a rat passes a fixed point or landmark in the real world instead began to compute the rat’s relative position, firing, for example, each time the rodent walked five paces forward, then five paces back, regardless of landmarks. And many other mapping cells shut down altogether, suggesting that different sensory cues strongly influence these neurons.

Finally, the researchers found that in this virtual world, the rhythmic firing of neurons that normally speeds up or slows down depending on the rate at which an animal moves, was profoundly altered. The rats’ brains maintained a single, steady rhythmic pattern.

The findings, reported in the May 2 online edition of the journal Science, provide further clues to how the brain learns and makes memories.

The mystery of how cells determine place

“Place cells” are individual neurons located in the brain’s hippocampus that create maps by registering specific places in the outside environment. These cells are crucial for learning and memory. They are also known to play a role in such conditions as post-traumatic stress disorder and Alzheimer’s disease when damaged.

For some 40 years, the thinking had been that the maps made by place cells were based primarily on visual landmarks in the environment, known as distal cues ? a tall tree, a building ? as well on motion, or gait, cues. But, as UCLA neurophysicist and senior study author Mayank Mehta points out, other cues are present in the real world: the smell of the local pizzeria, the sound of a nearby subway tunnel, the tactile feel of one’s feet on a surface. These other cues, which Mehta likes to refer to as “stuff,” were believed to have only a small influence on place cells.

Could it be that these different sensory modalities led place cells to create individual maps, wondered Mehta, a professor with joint appointments in the departments of neurology, physics and astronomy. And if so, do these individual maps cooperate with each other, or do they compete? No one really knew for sure.

Virtual reality reveals new clues

To investigate, Mehta and his colleagues needed to separate the distal and gait cues from all the other “stuff.” They did this by crafting a virtual-reality maze for rats in which odors, sounds and all stimuli, except distal and gait cues, were removed. As video of a physical environment was projected around them, the rats, held by a harness, were placed on a ball that rotated as they moved. When they ran, the video would move along with them, giving the animals the illusion that they were navigating their way through an actual physical environment.

As a comparison, the researchers had the rats ? six altogether ? run a real-world maze that was visually identical to the virtual-reality version but that included the additional “stuff” cues. Using micro-electrodes 10 times thinner than a human hair, the team measured the activity of some 3,000 space-mapping neurons in the rats’ brains as they completed both mazes.

What they found intrigued them. The elimination of the “stuff” cues in the virtual-reality maze had a huge effect: Fully half of the neurons being recorded became inactive, despite the fact that the distal and gate cues were similar in the virtual and real worlds. The results, Mehta said, show that these other sensory cues, once thought to play only a minor role in activating the brain, actually have a major influence on place cells.

And while in the real world, place cells responded to fixed, absolute positions, spiking at those same positions each time rats passed them, regardless of the direction they were moving ? a finding consistent with previous experiments ? this was not the case in the virtual-reality maze.

“In the virtual world,” Mehta said, “we found that the neurons almost never did that. Instead, the neurons spiked at the same relative distance in the two directions as the rat moved back and forth. In other words, going back to the front door-to-car analogy, in a virtual world, the cell that fires five steps away from the door when leaving your home would not fire five steps away from the door upon your return. Instead, it would fire five steps away from the car when leaving the car. Thus, these cells are keeping track of the relative distance traveled rather than absolute position. This gives us evidence for the individual place cell’s ability to represent relative distances.”

Mehta thinks this is because neuronal maps are generated by three different categories of stimuli ? distal cues, gait and “stuff” ? and that all are competing for control of neural activity. This competition is what ultimately generates the “full” map of space.

“All the external stuff is fixed at the same absolute position and hence generates a representation of absolute space,” he said. “But when all the stuff is removed, the profound contribution of gait is revealed, which enables neurons to compute relative distances traveled.”

The researchers also made a new discovery about the brain’s theta rhythm. It is known that place cells use the rhythmic firing of neurons to keep track of “brain time,” the brain’s internal clock. Normally, Mehta said, the theta rhythm becomes faster as subjects run faster, and slower as running speed decreases. This speed-dependent change in brain rhythm was thought to be crucial for generating the ‘brain time’ for place cells. But the team found that in the virtual world, the theta rhythm was uninfluenced by running speed.

“That was a surprising and fascinating discovery, because the ‘brain time’ of place cells was as precise in the virtual world as in the real world, even though the speed-dependence of the theta rhythm was abolished,” Mehta said. “This gives us a new insight about how the brain keeps track of space-time.”

The researchers found that the firing of place cells was very precise, down to one-hundredth of a second, “so fast that we humans cannot perceive it but neurons can,” Mehta said. “We have found that this very precise spiking of neurons with respect to ‘brain-time’ is crucial for learning and making new memories.”

Mehta said the results, taken together, provide insight into how distinct sensory cues both cooperate and compete to influence the intricate network of neuronal activity. Understanding how these cells function is key to understanding how the brain makes and retains memories, which are vulnerable to such disorders as Alzheimer’s and PTSD.

“Ultimately, understanding how these intricate neuronal networks function is a key to developing therapies to prevent such disorders,” he said.

In May, Mehta joined 100 other scientists in Washington, D.C., to help shape President Obama’s BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies), with the goal of trying to tease out how this most complicated of organs works.

Other authors of the study included Pascal Ravassard, Ashley Kees and Bernard Willers, all lead authors, and David Ho, Daniel A. Aharoni, Jesse Cushman and Zahra M. Aghajan of UCLA. Funding was provided by the W.M. Keck foundation, a National Science Foundation career award grant and a National Institutes of Health grant (5R01MH092925-02).

The UCLA Department of Neurology, with over 100 faculty members, encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks in the top two among its peers nationwide in National Institutes of Health funding.

For more news, visit the UCLA Newsroom and follow us on Twitter.

Contact: Mark Wheeler
mwheeler@mednet.ucla.edu
310-794-2265
University of California – Los Angeles

The study, led by Janet L. Stanford, Ph.D., co-director of the Prostate Cancer Research Program and a member of the Hutchinson Center’s Public Health Sciences Division, followed about 1,000 Seattle-area prostate cancer patients. Approximately 30 percent of the study participants reported using statin drugs to control their cholesterol. After a mean follow-up of almost eight years, the researchers found that the risk of death from prostate cancer among statin users was 1 percent as compared to 5 percent for nonusers.

“If the results of our study are validated in other patient cohorts with extended follow-up for cause-specific death, an intervention trial of statin drugs in prostate cancer patients may be justified,” Stanford said.

“While statin drugs are relatively well tolerated with a low frequency of serious side effects, they cannot be recommended for the prevention of prostate cancer-related death until a preventive effect on mortality from prostate cancer has been demonstrated in a large, randomized, placebo-controlled clinical trial,” said first author Milan S. Geybels, M.Sc., formerly a researcher in Stanford’s group who is now based at Maastricht University in The Netherlands.

The study is unique in that most prior research of the impact of statin use on prostate cancer outcomes has focused on biochemical recurrence ? a rising PSA level ? and not prostate cancer-specific mortality. “Very few studies of statin use in relation to death from prostate cancer have been conducted, possibly because such analyses require much longer follow-up for the assessment of this prostate cancer outcome,” Geybels said.

The potential biological explanation behind the association between statin use and decreased mortality from prostate cancer may be related to cholesterol- and non-cholesterol-mediated mechanisms.

An example of the former: When cholesterol is incorporated into cell membranes, these “cholesterol-rich domains” play a key role in controlling pathways associated with survival of prostate cancer cells.

An example of the latter: Statin drugs inhibit an essential precursor to cholesterol production called mevalonate. Lower levels of mevalonate may reduce the risk of fatal prostate cancer.

“Prostate cancer is an interesting disease for which secondary prevention, or preventing poor long-term patient outcomes, should be considered because it is the most common cancer among men in developed countries and the second leading cause of cancer-related deaths,” Geybels said. “While many prostate cancer patients have indolent, slow-growing tumors, others have aggressive tumors that may recur or progress to a life-threatening disease despite initial therapy with radiation or surgery. Therefore, any compound that could stop or slow the progression of prostate cancer would be beneficial,” he said.

The National Cancer Institute, a grant from the Dutch Cancer Society and additional support from Fred Hutchinson Cancer Research Center and the Prostate Cancer Foundation funded the research.

At Fred Hutchinson Cancer Research Center, home to three Nobel laureates, interdisciplinary teams of world-renowned scientists seek new and innovative ways to prevent, diagnose and treat cancer, HIV/AIDS and other life-threatening diseases. Fred Hutch’s pioneering work in bone marrow transplantation led to the development of immunotherapy, which harnesses the power of the immune system to treat cancer with minimal side effects. An independent, nonprofit research institute based in Seattle, Fred Hutch houses the nation’s first and largest cancer prevention research program, as well as the clinical coordinating center of the Women’s Health Initiative and the international headquarters of the HIV Vaccine Trials Network. Private contributions are essential for enabling Fred Hutch scientists to explore novel research opportunities that lead to important medical breakthroughs. For more information visit http://www.fredhutch.org or follow Fred Hutch on Facebook, Twitter or YouTube.

Contact: Kristen Woodward
kwoodwar@fhcrc.org
206-667-5095
Fred Hutchinson Cancer Research Center

Steven C. Zimmerman, the Roger Adams Professor of Chemistry at the U. of I., led the group in developing and demonstrating the compound. The National Institutes of Health supported the work published in the journal ACS Chemical Biology.

Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults, affecting one in 8,000 people in North America. It causes progressive weakness as the muscles deteriorate over time. There is no treatment available for the disease; though a few measures can help ease some symptoms, nothing can halt their inevitable progression.

“This is a disease that currently doesn’t have any treatment, so we have a huge interest in finding therapeutic agents,” said graduate student Amin Haghighat Jahromi, the first author of the paper.

Myotonic dystrophy type 1, called DM1 for short, is caused by a mutation to one gene. In a healthy person, one small segment of the gene ? a DNA sequence of CTG ? is repeated a few times. In someone with DM1, the sequence is repeated more than 50 times, even up to thousands of repeats. The sequence is transcribed into RNA over and over, like a skipping record stuck in a loop. The repetitive RNA binds to the protein MBNL1, which is essential for regulating protein balance in cells. The RNA traps the MBNL1 protein in aggregates within the cell’s nucleus.

“The RNA is functioning in an abnormal way, and unfortunately, it’s toxic,” Zimmerman said. “MNBL regulates a process called alternative splicing that controls how much of different proteins are made. Affected cells make the proteins, just not at the right levels, so all the levels are imbalanced. There are more than 100 proteins that are affected.”

The Illinois group developed a small molecule that could infiltrate the nucleus and bind to the RNA, forcing it to let go of MBNL1 so the protein can do its job. The molecule is small and water-soluble so it can cross the membrane into the cell, which has been a challenge for researchers attempting to use methods with larger molecules. It specifically targets only the repeating RNA sequence so as not to interfere with other cellular functions.

The researchers administered the molecule to live cells that have the disease features of DM1. Using advanced microscopy methods, they were able to watch the cells over time to see how they responded to the molecule. In only a few hours, they saw the clusters within the nucleus break up and were able to measure that the MBNL1 protein had increased its regulatory activity.

“This is the first study that gives direct evidence for the function of the compound,” Jahromi said. “We track how the cell is changing upon treatment with the compound and see the effect directly.”

Next, the researchers plan to begin collaborating with other groups to test their molecule in fruit flies and mice. Although the molecule will need many rounds of testing for toxicity, efficacy, metabolism and possible side effects before human trials can begin, finding a molecule that works in living cells is an important first step toward making a drug that could treat myotonic dystrophy.

“We’re close to developing drug candidates that can be tested in animals. And if it works in animals, then we move hopefully into clinical trials with humans,” Zimmerman said. “It’s heartbreaking, at one level, to say we’re years away from something that’s going to be in the clinic. On the other hand, we now have targets. We now know how to go after this disease. It gives patients and their families a bit of hope.”

Editor’s note:

To reach Steven C. Zimmerman, call 217-333-6655; email sczimmer@illinois.edu.

A proof version of the paper, “A Novel CUGexp·MBNL1 Inhibitor With Therapeutic Potential for Myotonic Dystrophy Type 1,” is available online.

Contact: Liz Ahlberg
eahlberg@illinois.edu
217-244-1073
University of Illinois at Urbana-Champaign

They identified blood-based biological markers that are associated with the build up of a toxic protein in the brain which occurs years before symptoms appear and irreversible brain damage has occurred.

“Early detection is critical if we are to make any real difference in the battle against Alzheimer’s, giving those at risk a much better chance of receiving treatment earlier, before it’s too late to do much about it,” said Dr Samantha Burnham from CSIRO’s Preventative Health Flagship.

Alzheimer’s is the leading cause of dementia. One quarter of a million Australians currently suffer from dementia and given our ageing population, this is predicted to increase to one million people by 2050.

Sophisticated mathematical models were used to analyse data from 273 participants in the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL).

This identified nine markers that correlate with brain positron emission tomography (PET) imaging measurements of a toxic protein, amyloid beta, which deposits in the brain as plaques early in disease development.

“The progressive build up of the toxic protein, amyloid beta, is one of the earliest changes in the brain associated with the development of Alzheimer’s disease,” said Dr Noel Faux, from the Florey Institute for Neuroscience and Mental Health.

“A recent study from the AIBL team showed that amyloid beta levels become abnormal about 17 years before dementia symptoms appear. This gives us a much longer time to intervene to try to slow disease progression if we are able to detect cases early.”

Dr Burnham adds “We hope our continued research will lead to the development of a low cost, minimally invasive population based screening test for Alzheimer’s.”

“A blood test would be the ideal first stage to help identify many more people at risk before a diagnosis is confirmed with cognitive tests and PET imaging or cerebral spinal fluid (CSF) testing.”

The results have been published in the journal Molecular Psychiatry.

Contact: Andreas Kahl
Andreas.Kahl@csiro.au
61-883-038-888
CSIRO Australia

“The synthetic compounds we used in our study may show promise in helping the body fight HIV-1 infection,’” said Yuri Persidsky, M.D., Ph.D., a researcher involved in the work from the Department of Pathology and Laboratory Medicine at Temple University School of Medicine in Philadelphia, PA. “As compounds like these are improved further and made widely available, we will continue to explore their potential to fight other viral diseases that are notoriously difficult to treat.”

To make this discovery, scientists used a cell culture model to infect human macrophages with HIV-1 and added synthetic compounds similar to the active ingredient in marijuana to activate the CB2 receptor. At different times during the infection, samples from the culture were taken to see if the replication of the HIV virus was decreased. The researchers observed diminished HIV growth and a possible protective effect from some HIV-1 complications.

“HIV/AIDS has posed one of the most significant health challenges in modern medicine,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. “Recent high profile vaccine failures mean that all options need to be on the table to prevent or treat this devastating infection. Research on the role of cannabinoid type 2 receptors and viral infection may one day allow targeting these receptors to be part of combination therapies that use exploit multiple weaknesses of the virus simultaneously.”

The Journal of Leukocyte Biology publishes peer-reviewed manuscripts on original investigations focusing on the cellular and molecular biology of leukocytes and on the origins, the developmental biology, biochemistry and functions of granulocytes, lymphocytes, mononuclear phagocytes and other cells involved in host defense and inflammation. The Journal of Leukocyte Biology is published by the Society for Leukocyte Biology.

Details: Servio H. Ramirez, Nancy L. Reichenbach, Shongshan Fan, Slava Rom, Steven F. Merkel, Xu Wang, Wen-zhe Ho, and Yuri Persidsky. Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists. J. Leukoc. Biol. May 2013 93:801-810; doi:10.1189/jlb.1012523 ; http://www.jleukbio.org/content/93/5/801.abstract

Contact: Cody Mooneyhan
cmooneyhan@faseb.org
301-634-7104
Federation of American Societies for Experimental Biology

Arteries form in utero and during development, but can also form in adults when organs become deprived of oxygen ? for example, after a heart attack. The organs release a molecular signal called VEGF. Working with mice, the Yale-UCL team discovered that in order for VEGF-driven artery formation to occur, VEGF must bind with two molecules known as VEGFR2 and NRP1, and all three must work as a team.

The researchers examined mice that were lacking a particular part of the NRP1 molecule that transports VEGF and VEGFR2 to a signaling center inside blood vessel walls. They observed that the internal organs of these mice contained poorly constructed arterial branches. Further, the mice where unable to efficiently repair blood vessel blockage through the formation of new arteries.

“We have identified an important new mechanism that regulates VEGFR2 transport in vascular cells,” said corresponding author Michael Simons, professor of medicine and cell biology, and director of the cardiovascular research center at Yale School of Medicine. “This opens new therapeutic opportunities for developing drugs that would either stimulate or inhibit blood vessel formation ? important goals in cardiovascular and anti-cancer therapies, respectively.” Simons also has an appointment as honorary professor of medicine at UCL.

The Yale-UCL collaboration began more than three years ago, as an intensive global effort to improve the human condition through biomedical research and translational medicine. The Yale-UCL alliance has provided many opportunities to date for high-level scientific research, and clinical and educational collaboration.

Co-senior author is Christiana Ruhrberg, professor of neuronal and vascular development at the Institute of Ophalmology at University College London. Ruhrberg also has an appointment as adjunct professor of medicine at Yale School of Medicine.

Other authors are A. Lanahan, X. Zhang, Z.W. Zhuang, F. Rivera-Molina, C. Prahst, J. Zhang, Y. Wang, D. Toomre of Yale; A. Fantin of University College London, and K.R. Speichinger and G.E. Davis of the University of Missouri.

The study was supported by grants from the National Institutes of Health (HL62289) and a Wellcome Trust Junior Investigator award.

Contact: Helen Dodson
helen.dodson@yale.edu
203-436-3984
Yale University

In a study conducted at Texas Biomed’s Southwest National Primate Research Center, researchers found that the immune modulator GS-9620, which targets a receptor on immune cells, reduced both the virus levels and the number of infected liver cells in chimpanzees chronically infected with hepatitis B virus (HBV). Chimpanzees are the only species other than humans that can be infected by HBV. Therefore, the results from this study were critical in moving the drug forward to human clinical trials which are now in progress.

The new report, co-authored by scientists from Texas Biomed and Gilead Sciences, appears in the May issue of Gastroenterology. Gilead researchers had previously demonstrated that the same therapy could induce a cure of hepatitis infection in woodchucks that were chronically infected with a virus similar to human HBV.

“This is an important proof-of-concept study demonstrating that the therapy stimulates the immune system to suppress the virus and eliminate infected liver cells,” said co-author Robert E. Lanford, Ph.D., of Texas Biomed. “One of the key observations was that the therapy continued to suppress virus levels for months after therapy was stopped.

The current therapy for HBV infection targets the virus and works very well at suppressing viral replication and delaying progression of liver disease, but it is a lifelong therapy that does not provide a cure.

“This GS-9620 therapy represents the first conceptually new treatment for HBV in more than a decade, and combining it with the existing antiviral therapy could be transformative in dealing with this disease,” stated Lanford.

The Gilead drug binds a receptor called Toll-Like Receptor 7 that is present in immune cells. The receptor normally recognizes invading viruses and triggers the immune system to suppress viral replication by the innate immune response and kill infected cells by the adaptive immune response, thus orchestrating both arms of the immune system.

HBV damages the liver, leading to cirrhosis and liver cancer. Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer death. According to the United States Centers for Disease Control and Prevention (CDC), up to 1.4 million Americans are chronically infected with HBV.

The World Health Organization estimates that two billion people have been infected with the hepatitis B virus, resulting in more than 240 million people with chronic infections and 620,000 deaths every year.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, Calif., Gilead has operations in North America, Europe and Asia Pacific. For more information on Gilead Sciences, please visit the company’s website at http://www.gilead.com.

About Texas Biomed

Texas Biomed, formerly the Southwest Foundation for Biomedical Research, is one of the world’s leading independent biomedical research institutions dedicated to advancing health worldwide through innovative biomedical research. Located on a 200-acre campus on the northwest side of San Antonio, Texas, the Institute partners with hundreds of researchers and institutions around the world, targeting advances in the fight against AIDS, hepatitis, malaria, parasitic infections and a host of other infectious diseases, as well as cardiovascular disease, diabetes, obesity, cancer, psychiatric disorders, and problems of pregnancy. For more information on Texas Biomed, go to http://www.TxBiomed.org, or call Joe Carey, Texas Biomed’s Vice President for Public Affairs, at 210-258-9437.

The study analysed the efficacy of probiotics in preventing the development of HE in 160 cirrhotic patients over a period of approximately nine months and found significant improvements in reducing patients’ arterial ammonia levels after three months of treatment with probiotics.

Ammonia, produced by gut bacteria, is thought to be one of the main mediators of cerebral dysfunction in HE. Probiotics work by enriching the gut flora with a non-urease producing microorganisms, which decrease ammonia production. Probiotics are live microorganisms (mostly bacteria) that produce a health benefit on the host when administered in adequate amounts.

Twice as many patients taking a placebo developed overt HE (the study’s primary endpoint) compared to patients taking probiotics in the form of a capsule.

EASL’s Treasurer, Prof. Mauro Bernardi welcomed the findings and said they would provide a positive impact for cirrhotic patients at risk of developing HE for whom the prognosis is typically very poor.

Prof. Bernardi said: “Hepatic encephalopathy is an insidious disease that’s caused by an accumulation of toxins in the blood that are normally removed by the liver. Treatment normally involves the use of antibiotics or laxatives to suppress the production of toxic substances in the intestine but there is still a great deal of room for improvement so it will be exciting to see the results of further studies to determine if clinicians have a new form of treatment on the cards.”

Hepatic encephalopathy is a spectrum of neuropsychiatric abnormalities including personality changes, intellectual impairment and reduced levels of consciousness in patients with liver failure, after exclusion of other known brain disease.

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress? 2013.

Notes to Editors

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL’s main focus on education and research is delivered through numerous events and initiatives, including:

• The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
• Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
• Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
• Journal of Hepatology published monthly
• Participation in a number of policy initiatives at European levelM.

About The International Liver CongressTM 2013

The International Liver Congress? 2013, the 48th annual meeting of the European Association for the study of the Liver, is being held at the RAI Convention Centre in Amsterdam from April 24 ? 28, 2013.

The congress annually attracts in excess of 9,000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

References:

1 M.K Lunia, AN OPEN LABEL RANDOMISED CONTROLLED TRIAL OF PROBIOTICS FOR PRIMARY PROPHYLAXIS OF HEPATIC ENCEPHALOPATHY IN PATIENTS WITH CIRRHOSIS. Presented at the International Liver CongressTM 2013

2 A. Agrawal, Secondary Prophylaxis of Hepatic Encephalopathy in Cirrhosis, An Open-Label, Randomized Controlled Trial of Lactulose, Probiotics, and No Therapy. Available http://www.medscape.com/viewarticle/767674_3 [Accessed 9/4/13]

3 World Health Organization and Food and Agriculture Organizationof the United Nations. Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Ava http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf [Accessed 9/4/13]

Contact: Dimple Natali
easlpressoffice@cohnwolfe.com
44-790-013-8904
European Association for the Study of the Liver

HBV cccDNA is organized into mini-chromosomes within the nucleus of infected cells by histone and non-histone proteins. Despite the availability of efficient therapies against HBV, long-term persistence of cccDNA necessitates life-long treatments to suppress the virus. The following three experimental studies demonstrate effective HBV-cccDNA targeting/depletion using novel therapeutic approaches which offer the potential of a cure.

Liver regeneration induces strong reduction of viral replication and cccDNA levels, but not complete cccDNA eradication; without antiviral treatment, de novo HBV infection can be re-established.

Key findings of research in HBV-infected human hepatocytes using the uPA/SCID chimeric mouse system show that liver regeneration induces strong reduction of viral replication and cccDNA levels, with rapid formation of cccDNA-free hepatocytes. However, because complete cccDNA eradication is not achieved, in the absence of antiviral treatment, de novo HBV infection could be re-established in quiescent (non-dividing) human hepatocytes. This suggests that induction of hepatocyte turn-over together with antiviral drugs inducing viral suppression, such as nucleoside analogues and IFN, or blocking cell entry, may accelerate the clearance of the viral minichromosome.

Targeting epigenetic control of nuclear cccDNA minichromosome to suppress HBV transcription and replication may form basis for other therapeutic approaches to curing chronic HBV infection.

In the infected liver cell the rate of replication of HBV is regulated by the acetylation or methylation of histone proteins which surround the cccDNA minichromosome ? so called epigenetic regulation. In a separate innovative study, the suppression of HBV transcription and replication by small molecules that target the epigenetic control of nuclear cccDNA minichromosome was investigated. The different classes of small molecules studied included: Class I, II and III histone deacetylase inhibitors (HDACi); p300 and PCAF histone acetyltransferases (HAT) inhibitors; hSirt1 activators; JMJD3 histone demethylase inhibitors.

The combined inhibition of p300 and PCAF HATs resulted in an evident reduction of HBV replication which mirrored the decrease of pgRNA transcription. The hSirt1/2 activator MC2791 and the JMJD3 inhibitor MC3119, albeit with different efficiency, inhibited both HBV replication and cccDNA transcription. Results represent a proof of concept that activation of hSirt1 and Ezh2 (through the inhibition of its functional antagonist JMJD3) by small molecules can induce an active epigenetic suppression of HBV cccDNA minichromosome similar to that observed with IFN?, and lead to persistent cccDNA silencing.

Lymphtoxin beta receptor (LTbR) agonisation represents basis for novel alternative therapeutic approach to curing chronic HBV infection.

The final study demonstrated that stimulating the lymphtoxin beta receptor (LTbR) provides an effective, long lasting and non-cytopathic mechanism for achieving effective HBV-cccDNA depletion in infected hepatocytes. Cell culture models including HBV-infected HepaRG cells and primary human hepatocytes were used to test the effect of antibodies stimulating human LTbR (BS1 or CBE11). Results show that a strong and dose-dependent anti-HBV effect was achieved by activation of the LTbR. All HBV replication markers were decreased with this treatment, including cccDNA in cells where HBV infection was already established.

Hepatitis B is the most prevalent cause of chronic viral hepatitis and a major global health problem. Prof. Fabien Zoulim, EASL Educational Councillor commented on the exciting new data: “In chronic hepatitis B infection, the viral genome forms a stable minichromosome – the covalently closed circular DNA (cccDNA) – which can persist throughout the lifespan of the hepatocyte.”

“Current treatments focus on suppression of HBV and discovery of compounds directly targeting cccDNA has been one of the major challenges to curing HBV infection; but these preliminary data show novel therapeutic approaches can be applied to successfully target cccDNA with the long-term aspiration of finding a cure” added Prof. Fabien Zoulim.

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress? 2013.

Notes to Editors

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL’s main focus on education and research is delivered through numerous events and initiatives, including:

• The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
• Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
• Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
• Journal of Hepatology published monthly
• Participation in a number of policy initiatives at European level

About The International Liver CongressTM 2013

The International Liver Congress? 2013, the 48th annual meeting of the European Association for the study of the Liver, is being held at the RAI Convention Centre in Amsterdam from April 24 ? 28, 2013. The congress annually attracts in excess of 9000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

References:

1 Allweiss L et al, PROLIFERATION OF HEPATITIS B VIRUS INFECTED HUMAN HEPATOCYTES INDUCES SUPPRESSION OF VIRAL REPLICATION AND RAPID CCCDNA DECREASE IN HUMANIZED MICE. Presented at the International Liver Congress? 2013

2 Palumbo GA et al, SUPPRESSION OF HEPATITIS B VIRUS (HBV) TRANSCRIPTION AND REPLICATION BY SMALL

3 MOLECULES THAT TARGET THE EPIGENETIC CONTROL OF NUCLEAR CCCDNA MINICHROMOSOME. Presented at the International Liver Congress? 2013 4 Lucifora J et al, LYMPHOTOXIN BETA RECEPTOR ACTIVATION LEADS TO DEGRADATION OF HBV CCCDNA FROM INFECTED HEPATOCYTES. Presented at the International Liver Congress? 2013

Contact: Dimple Natali
easlpressoffice@cohnwolfe.com
44-079-001-38904
European Association for the Study of the Liver

The groundbreaking study by Brittany Pequegnat and Guelph chemistry professor Mario Monteiro appears this month in the journal Vaccine.

They developed a carbohydrate-based vaccine against the gut bug, Clostridium bolteae.

C. bolteae is known to play a role in gastrointestinal disorders, and it often shows up in higher numbers in the GI tracts of autistic children than in those of healthy kids.

More than 90 per cent of children with autism spectrum disorders suffer from chronic, severe gastrointestinal symptoms. Of those, about 75 per cent suffer from diarrhea, according to current literature.

“Little is known about the factors that predispose autistic children to C. bolteae,” said Monteiro. Although most infections are handled by some antibiotics, he said, a vaccine would improve current treatment.

“This is the first vaccine designed to control constipation and diarrhea caused by C. bolteae and perhaps control autism-related symptoms associated with this microbe,” he said.

Autism cases have increased almost sixfold over the past 20 years, and scientists don’t know why. Although many experts point to environmental factors, others have focused on the human gut.

Some researchers believe toxins and/or metabolites produced by gut bacteria, including C. bolteae, may be associated with symptoms and severity of autism, especially regressive autism.

Pequegnat, a master’s student, and Monteiro used bacteria grown by Mike Toth, a Guelph PhD student in the lab of microbiology professor Emma Allen-Vercoe.

The new anti- C. bolteae vaccine targets the specific complex polysaccharides, or carbohydrates, on the surface of the bug.

The vaccine effectively raised C. bolteae-specific antibodies in rabbits. Doctors could also use the vaccine induced antibodies to quickly detect the bug in a clinical setting, said Monteiro.

The vaccine might take more than 10 years to work through pre-clinical and human trials, and it may take even longer before a drug is ready for market, Monteiro said.

“But this is a significant first step in the design of a multivalent vaccine against several autism-related gut bacteria,” he said.

Monteiro has studied sugar-based vaccines for two other gastric pathogens: Campylobacter jejuni, which causes travellers’ diarrhea, and Clostridium difficile, which causes antibiotic-associated diarrhea.

The research was supported by the Natural Sciences and Engineering Research Council.

Contact: Prof. Mario Monteiro
monteiro@uoguelph.ca
519-824-4120 x53447
University of Guelph

The drug, called sofosbuvir, offers more effective treatment for most patients studied in a Phase 3 clinical trial who had no other treatment options, report researchers in The New England Journal of Medicine. After three months of combined therapy with sofosbuvir and the antiviral drug ribavirin, the patient response rate for those with genotype 2 was 93 percent, and 61 percent in patients with genotype 3.

This new study is one of several testing new hepatitis C drugs that were published April 23 in an online edition of NEJM. The journal publication coincides with the International Liver Congress 2013 in Amsterdam, the Netherlands, where the results also will be presented.

“The new sofosbuvir therapy offers a much-needed alternative to standard therapy with interferon, which can cause significant side effects for hepatitis C patients,” says the study’s lead investigator, Dr. Ira Jacobson, chief of the Division of Gastroenterology and Hepatology and Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medical College.

“We have dreamed for years of being able to eliminate interferon from our hepatitis C regimens and this study is one of several that are finally bringing us very close to realizing that goal,” says Dr. Jacobson, who is also a gastroenterologist at the Center for Advanced Digestive Care at New York-Presbyterian Hospital/Weill Cornell Medical Center and medical director of the Center for the Study of Hepatitis C, a collaboration between Weill Cornell, NewYork-Presbyterian/Weill Cornell and The Rockefeller University.

The 207 patients enrolled in the clinical trial, known as POSITRON, either did not respond to interferon, could not tolerate it or were unwilling to use it, despite the fact that there were no other treatment options available to them.

“This new treatment represents a paradigm shift in the way that hepatitis C is going to be treated,” says Dr. Jacobson. “We are achieving the same or higher cure rates in many patients with sofosbuvir, compared to interferon, and we are doing it in half the time with a drug that has a remarkable safety profile.”

Dr. Jacobson estimates that up to half of patients with hepatitis C infection either can’t use interferon or don’t want to use it. “Sofosbuvir is an extremely promising treatment for this population. It is widely hoped that combinations of potent antiviral drugs will eventually replace the use of interferon, in general, for most hepatitis C patients.”

The drug sofosbuvir works by interfering with the ability of the hepatitis C virus to replicate. The drug also confers a high barrier to developing the complication of drug resistance. The U.S. Food and Drug Administration (FDA) has not yet approved sofosbuvir. However, results of the four clinical trials published in the NEJM were used to support the regulatory filing submitted to the FDA by the drug’s developer, Gilead Sciences, Inc.

No Treatment Options for Many Patients

Approximately 170 million people are infected with hepatitis C worldwide and 350,000 people die each year from the disease. According to federal statistics, there are an estimated four million people in the U.S. infected with hepatitis C. As there are often no symptoms, most people with hepatitis C are unaware that they are infected.

When left untreated, hepatitis C virus can cause progressive liver disease such as cirrhosis, liver cancer and liver failure. The virus is spread by contact with infected blood, such as through blood transfusions, injection drug use or sexual contact.

There are seven major genotypes of hepatitis C, but most cases are 1, 2 or 3. Genotype 1 is the most common subtype in the U.S. Genotypes 2 and 3 are more common in Europe than in the U.S. and genotype 3 is very prevalent on the Indian subcontinent.

In the study, three-fourths of participants (207) were randomized to treatment with sofosbuvir and ribavirin while one-fourth (71) of participants were randomized to a placebo treatment. All of the patients either did not respond to interferon, or did not want to use it. “This mirrors what happens frequently in the clinic,” says Dr. Jacobson. “Between 15 and 30 percent of patients with hepatitis C genotype 2 or 3 infections do not have a response to interferon therapy and do not have alternate treatment options.”

Patients were enrolled internationally at 63 sites in the United States, Canada, Australia and New Zealand.

Study results show the response rate for all treated patients with sofosbuvir was 78 percent compared to 0 percent in participants treated with placebo agents. Patients with genotype 2 had a higher cure rate (93 percent) than those with genotype 3 (61 percent), and patients without cirrhosis had a higher response rate (81 percent) compared with participants diagnosed with cirrhosis (61 percent).

The results of another clinical trial, led by Dr. David R. Nelson of the University of Florida at Gainesville, were incorporated into this NEJM manuscript publication. This clinical trial study, called FUSION, was designed to test sofosbuvir and ribavirin in hepatitis C patients with genotype 2 or 3 who had failed interferon therapy.

In FUSION, the drug regimen was tested for both 12 and 16 weeks in patients with genotype 2 or 3. The findings showed that extended use of sofosbuvir resulted in a higher cure rate in both genotypes, but that the difference seen in genotype 3 was highly significant. For genotype 2, 12 versus 16 weeks of treatment resulted in response rates of 86 percent compared to 94 percent; and for genotype 3, the response rates were 30 percent versus 62 percent, respectively.

“Given the absence to date of alternative therapies for patients with genotype 2 or 3 who have failed interferon therapy or for whom it is not an option, treatment with the new sofosbuvir regimen offers a vast improvement,” Dr. Jacobson says. “But the optimal duration of treatment for genotype 3 patients, in order to maximize their chance of cure, remains undefined. It could be longer than 16 weeks.” Dr. Jacobson adds that future clinical studies will continue to define the optimal length of treatment duration for patients with genotype 3, and that other antiviral drugs in combination with sofosbuvir might shorten the duration of treatment needed to maximize the rates of response.

Both the POSITRON and FUSION studies were funded by Gilead Sciences. Another paper in the same edition of the NEJM reports two additional studies of sofosbuvir-containing therapy, one evaluating a 12 week regimen of peginterferon, ribavirin and sofosbuvir in patients with genotypes 1, 4, 5 and 6 who have never been treated before; the other reporting results of a trial comparing 24 weeks of peginterferon and ribavin with 12 weeks of sofosbuvir and ribavirin in treatment naïve patients with genotypes 2 and 3.

Dr. Jacobson is a consultant, lecturer and a funded research investigator for Gilead Sciences.

As medical director of the collaborative Center for the Study of Hepatitis C at Weill Cornell, NewYork-Presbyterian/Weill Cornell and Rockefeller, Dr. Jacobson’s research has long been funded by Maurice R. Greenberg, The Starr Foundation and the Greenberg Medical Research Institute. The Center, founded in 2000, is the only comprehensive, multidisciplinary center dedicated to the study of hepatitis C and hepatic disease in the New York tri-state area.

The study co-authors include Dr. Stuart C. Gordon from Henry Ford Health Systems, Detroit, Mich,; Dr. Kris V. Kowdley from Virginia Mason Medical Center, Seattle, Wash.; Dr. Eric M. Yoshida from University of British Columbia, Vancouver, Canada; Dr. Jordan Feld from the University of Toronto, Canada; Dr. Maribel Rodriguez-Torres of Fundacion de Investigacion, San Juan, Puerto Rico; Dr. Mark S. Sulkowski from Johns Hopkins University School of Medicine, Baltimore, Md.; Dr. Mitchell L. Shiffman from the Liver Institute of Virginia, Bon Secours Hampton Roads Health System, Newport News, Va.; Dr. Eric Lawitz from University of Texas Health Science Center, San Antonio, Texas; Dr. M. Tarek Al-Assi from Texas Digestive Disease Consultants, Arlington, Texas; Dr. Gregory Everson from University of Colorado Denver, Aurora, Colo.; Dr. Michael Bennett from Medical Associates Research Group, San Diego, Calif.; Dr. Eugene Schiff from the University of Miami, Miami, Fla.; Dr. Keyur Patel of Duke University, Durham, N.C.; Dr. Stephen Pianko of Monash Medical Centre and Monash University, Melbourne, Australia; and Dr. G. Mani Subramanian, Dr. Di An, Dr. Ming Lin, Dr. John McNally, Dr. Diana Brainard, Dr. William T. Symonds and Dr. John G. McHutchison from Gilead Sciences, in Foster City, Calif.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University’s medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson’s disease, and most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.

Contact: Lauren Woods
law2014@med.cornell.edu
646-317-7401
Weill Cornell Medical College

Interferon-? can trigger autoimmune reactions in patients, i.e., pathological reactions of the immune system. Interferon-? has been seen to date as an active substance that boosts the immune system and fights tumor cells directly. It is used, for example, in the therapy of malignant melanomas, certain forms of leukemia and cutaneous T-cell lymphomas. “The immune system is usually able to effectively destroy cancer cells. At the same time, however, there are also so-called tumor-associated tolerance processes that protect the tumor cells from being destroyed by the immune system. Autoimmune reactions, which are known side effects of therapies with IFN-?, may indicate that this anti-tumor treatment blocks tolerance mechanisms and thus improves the immune system’s natural ability for tumor rejection,” explained Professor Dr. Kerstin Steinbrink, senior physician at the Department of Dermatology of the Mainz University Medical Center, which is supervising the research project “Analysis of the Effect of Type I Interferons on Immunological Tolerance Processes” funded by the German Cancer Aid. The purpose of this project is to analyze the effects of IFN-? and other type I interferons on various immune cells that exhibit tolerogenic potential in vitro and also in melanoma patients.

The knowledge gained through this project should contribute to the development of improved therapy strategies for overcoming tolerance mechanisms associated with tumors. An additional objective is to enhance the efficacy of therapy with type I interferons. Steinbrink’s research team is looking to reduce potential side effects as much as possible.

“This research project is taking a patient-oriented approach. The research team led by Professor Dr. Kerstin Steinbrink will profit from its expertise in the area of immunological tolerance that it has gained over several years,” said Professor Dr. Ulrich Förstermann, Chief Scientific Officer of the Mainz University Medical Center.

Contact: Dr. Reneé Dillinger-Reiter
pr@unimedizin-mainz.de
49-613-117-7424
Johannes Gutenberg Universitaet Mainz

“If it works as well in humans, this could confer a substantial benefit on patients afflicted with this deadly disease,” says Anthony van den Pol, a researcher on the study. The research was published online ahead of print in the Journal of Virology.

Most normal cells resist virus infection by activating antiviral processes that protect nearby cells. “The working hypothesis was that since many cancer cells show a deficient ability to withstand virus infection, maybe a fast-acting virus such as VSV would be able to infect and kill cancer cells before the virus was eliminated by the immune system,” says van den Pol. And indeed, the virus was able to selectively infect multiple deadly human melanomas that had been implanted in a mouse model, yet showed little infectivity towards normal mouse cells, he says.

Many different mechanisms are involved in innate immunity, the type of immunity that combats viral infection. van den Pol plans to investigate which specific mechanisms are malfunctioning in cancer cells, knowledge that would be hugely beneficial both in understanding how cancer affects immunity, and in enhancing a virus’ ability to target cancer cells, he says.

Melanoma is the most deadly skin cancer. Most melanomas are incurable once they have metastasized into the body. The incidence of melanoma has tripled over the last three decades, and it accounts for approximately 75 percent of skin cancer-related deaths.

A copy of the manuscript can be found online at http://bit.ly/asmtip0413b. Formal publication is scheduled for the June 2013 issue of the Journal of Virology.

(G. Wollmann, J.N. Davis, M.W. Bosenberg, and A.N. van den Pol, 2013. Vesicular stomatitis virus variants selectively infect and kill human melanomas but not normal melanocytes. J. Virol. Published ahead of print 3 April 2013 , doi:10.1128/JVI.03311-12)

Journal of Virology is a publication of the American Society for Microbiology (ASM). The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. Its mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Contact: Jim Sliwa
jsliwa@asmusa.org
202-942-9297
American Society for Microbiology

Two types of adipose (fat) tissue ? brown and white — are found in mammals. Unlike the more predominant white adipose tissue (WAT) which stores fat, BAT burns fat to produce heat when the body is exposed to cold and also plays a role in energy metabolism. Human studies have shown that greater quantities of BAT are associated with lower body weight. BAT has been a major focus of study among scientists and pharmaceutical companies based on its potential as a treatment to combat obesity, a major risk factor for type 2 diabetes.

Studies in mice have identified two types of BAT: constitutive or “classical” BAT which is present at birth and persists throughout life and recruitable or “beige” BAT which can be produced from within white fat in response to metabolic conditions. These two types of BAT may also be present in humans.

Previous studies have identified the human neck as a primary location for BAT deposits. To determine the precise locations of these deposits, Joslin scientists obtained fat samples from five neck regions of patients undergoing neck surgery. Analysis of the samples showed that BAT was most abundant in deep regions of the neck, near the carotid sheath and longus colli muscles. These samples expressed the BAT marker gene, uncoupling protein 1 (UCP1), which is involved in heat generation. “BAT is most abundant in the deep locations of the neck, close to the sympathetic chain and the carotid arteries, where it likely helps to warm blood and raise body temperature. Now that we know where brown fat is, we can easily collect more cells for further study,” says Aaron M. Cypess, M.D., Ph.D., senior author and Assistant Investigator in the Section of Integrative Physiology and Metabolism and Assistant Professor at Harvard Medical School.

In analyzing genetic expression in superficial and deep human neck fat tissue, the fat from deep locations was found to most closely resemble cells from constitutive mouse BAT, the kind already known to consume large quantities of glucose and fat.

The Joslin scientists compared the oxygen consumption rate (OCR), which demonstrates the capacity to burn calories, of human BAT cells to mouse constitutive BAT cells and human WAT. This is the first study to directly measure brown fat cells’ OCR at baseline. The OCR of the human BAT cells from the deep location next to the longus colli was nearly 50 percent of the mouse BAT cells; in contrast, the OCR of human WAT was only one-hundredth of the OCR found in the most active human BAT from the longus colli depot. “We show that at baseline, brown fat cells have a great capacity to burn fat,” says Dr. Cypess.

The scientists were able to grow new functional brown fat cells (adipocytes) by differentiating precursor cells (preadipocytes) derived from both superficial and deep human neck fat tissue. When stimulated, the cells expressed the same genes as naturally occurring brown fat cells. This is the first report of the production of brown fat cells (adipogenesis) that can respond to pharmacological stimulation.

The Joslin scientists are following up on this study to learn more about the functions of BAT, including how it affects energy balance and uses glucose. Having the ability to produce brown fat cells outside the body will make it possible to develop drugs and other potential treatments that increase BAT activity to combat obesity. “Our research has significant practical applications. If we stimulate the growth of brown fat in people, it may burn their white fat and help them lose weight, which lessens insulin resistance and improves diabetes,” says Dr. Cypess.

This study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Harvard University and its affiliated academic health care centers, the Harvard Stem Cell Institute, and Eli Lilly Foundation.

About Joslin Diabetes Center

Joslin Diabetes Center, located in Boston, Massachusetts, is the world’s largest diabetes research and clinical care organization. Joslin is dedicated to ensuring that people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure. Joslin is an independent, nonprofit institution affiliated with Harvard Medical School.

Our mission is to prevent, treat and cure diabetes. Our vision is a world free of diabetes and its complications. For more information, visit http://www.joslin.org.

About Joslin Research

Joslin Research comprises the most comprehensive and productive effort in diabetes research under one roof anywhere in the world. With 30?plus faculty?level investigators and an annual research budget of $36 million, Joslin researchers focus on unraveling the biological, biochemical and genetic processes that underlie the development of type 1 and type 2 diabetes and related complications.

Joslin research is highly innovative and imaginative, employing the newest tools in genetics, genomics and proteomics to identify abnormalities that may play a role in the development of diabetes and its complications. Joslin Clinic patients, and others with diabetes, have the option of participating in clinical trials at Joslin to help translate basic research into treatment innovations.

Joslin has one of the largest diabetes training programs in the world, educating 150 M.D. and Ph.D. researchers each year, many of whom go on to head diabetes initiatives at leading institutions all over the globe. For more information, visit http://www.joslinresearch.org.

Contact: Jeffrey Bright
jeffrey.bright@joslin.harvard.edu
Joslin Diabetes Center

Vitamin D is crucial for good bone health and muscle strength; adequate amounts help the body maintain bone density reducing the risk of fracture, osteomalacia, osteoarthritis and osteoporosis. The nutrient also plays an integral role in modulating the immune system to help fight infections like the flu and reduces the risk of many common diseases including cancer, cardiovascular disease, depression and diabetes.

The study to be presented consisted of 30 healthy adults who were randomized to take capsules containing 2000 International Units (IU) of vitamin D2, 2000 IU of vitamin D3 or 2000 IU of mushroom powder containing vitamin D2 once a day for 12 weeks during the winter. Baseline serum 25?hydroxyvitamin D [25(OH)D], a measure to determine a person’s vitamin D status, were not significantly different among the groups. The serum 25(OH)D levels among the three groups gradually increased and plateaued at seven weeks and were maintained for the following five weeks. After 12 weeks of the vitamin D supplements, serum 25(OH)D levels were not statistically significantly different than those who ingested 2000 IU of vitamin D2 in mushroom powder.

“These results provide evidence that ingesting mushrooms which have been exposed to ultraviolet light and contain vitamin D2, are a good source of vitamin D that can improve the vitamin D status of healthy adults. Furthermore we found ingesting mushrooms containing vitamin D2 was as effective in raising and maintaining a healthy adult’s vitamin D status as ingesting a supplement that contained either vitamin D2 or vitamin D3,” said Michael F. Holick, PhD, MD, the principal investigator of the abstract. The study is available on line concurrently in the journal Dermato-Endocrinology. “These results confirm other studies that have demonstrated that ingesting vitamin D2 either from fortified orange juice, a supplement or a pharmaceutical formulation were all capable of increasing total circulating 25(OH) D concentrations for at least 3 months, and up to 6 years,” added Holick, the senior author of the study.

According to Holick and his coauthors ingesting mushrooms containing vitamin D2 can be an effective strategy to enhance a persons’ vitamin D status. “The observation that some mushrooms when exposed to UVB light also produce vitamin D3 and vitamin D4 can also provide the consumer with at least two additional vitamin Ds,” he added.

In a second poster presentation, the researchers were able to determine how mushrooms make vitamin D2 and found that the process is similar to what occurs in human skin after sun exposure. They were also able to show that mushrooms not only produce vitamin D2, but can produce vitamin D3 and vitamin D4.

“Although it has been previously reported that mushrooms have the ability to produce both vitamin D2 and vitamin D4, through our own research we were able to detect several types of vitamin Ds and provitamin Ds in mushroom samples including vitamin D3 which is also made in human skin,” added Holick.

According to the researchers these abstracts as well as the on line published study demonstrate that mushrooms are another good natural food source for vitamin D that can easily be found in ones’ local grocery store.

Funding for this research was provided in part by the Mushroom Council.

Contact: Gina DiGravio

gina.digravio@bmc.org
617-638-8480
Boston University Medical Center

The study, led by investigator E. Mitchell Seymour, Ph.D., of the University of Michigan Health System, studied the effects of a high fat, American-style diet both with added grapes and without grapes (the control diet) on the heart, liver, kidneys, and fat tissue in obesity-prone rats. The grapes ? a blend of red, green and black varieties ? were provided as a freeze-dried grape powder and integrated into the animals’ diets for 90 days.

Specifically, the results showed that three months of a grape-enriched diet significantly reduced inflammatory markers throughout the body, but most significantly in the liver and in abdominal fat tissue. Consuming grapes also reduced liver, kidney and abdominal fat weight, compared with those consuming the control diet. Additionally, grape intake increased markers of antioxidant defense, particularly in the liver and kidneys.

Metabolic syndrome is a cluster of conditions that occur together ? increased blood pressure, a high blood sugar level, excess body fat around the waist or low HDL (the good cholesterol) and increased blood triglycerides ? significantly increasing the risk for heart disease, stroke and Type 2 diabetes. Intake of fruits and vegetables is thought to reduce these risks, and grapes have shown benefits in multiple studies. Metabolic syndrome is a major public health concern, and is on the rise in the U.S.

“Our study suggests that a grape-enriched diet may play a critical role in protecting against metabolic syndrome and the toll it takes on the body and its organs,” said Seymour. “Both inflammation and oxidative stress play a role in cardiovascular disease progression and organ dysfunction in Type 2 diabetes. Grape intake impacted both of these components in several tissues which is a very promising finding.”

This work extends and reinforces the findings of Seymour’s previously published research which demonstrated that a grape-enriched diet reduced risk factors for heart disease and diabetes in obesity-prone rats.

Experimental Biology is a multidisciplinary, scientific meeting focused on research and life sciences, covering general fields of study such as anatomy, biochemistry, nutrition, pathology and pharmacology. The meeting is comprised of nearly 14,000 scientists and exhibitors.

Contact: Justin Harris
juaha@umich.edu
734-764-2220
University of Michigan Health System

Improved Bowel Health

Recently published in the Journal of Nutrition, Timm et al. reported that 36 healthy adults consuming 20 grams of added fibre, either STA-LITE® Polydextrose or PROMITOR® Soluble Corn Fibre* per day, in addition to their usual lower fibre diet, which was approximately 13-14 g/day compared to the recommended 25 g/day for women and 38 g/day for men (3), experienced improved laxation with minimal gastrointestinal tolerance issues4. These results indicate that both types of fibre tested in this study are well tolerated and can be successfully added to the diet to help meet dietary recommendations.

“Since people aren’t meeting their fibre goals with the foods they currently eat, adding fibres to foods is a realistic and simple way to address this global public health concern,” said Joanne Slavin, PhD, RD of the University of Minnesota, an expert in fibre research and lead investigator of this study.

Maintained Satiety after a Meal

Another study which was presented this week at the American Society for Nutrition Experimental Biology conference in Boston, using a double blind, randomized cross-over design found that an emerging fibre, soluble fibre dextrin (SFD) from Tate & Lyle, may help promote satiety, or the feeling of fullness, from 3 to 8.5 hours after consumption (5). Tate & Lyle’s soluble fibre dextrin is a resistant dextrin that can be isolated from tapioca or corn.

Researchers from Iowa State University provided 41 healthy adults with lunch including a test beverage containing 10 or 20 g of fibre from tapioca SFD versus a maltodextrin control beverage followed by a snack two and a half hours later. The study participants reported feeling fuller, less feeling of hunger and less desire to eat compared to the control beverage from 3 to 8.5 hours after consumption of the beverage that contained 20 g of fibre as SFD, while the SFD had no impact on appetite or overall food intake during the first 2.5 hours post consumption. These results indicate that the SFD may be slowly digested leading to delayed effects on appetite. “This newly developed soluble fibre dextrin can increase fibre intake, helping consumers meet fibre recommendations, while simultaneously controlling their appetite which may lead to reduced energy intake,” stated James Hollis, PhD, a lead researcher on the study.

Increased Calcium Absorption

A third study (6), also presented at the American Society for Nutrition Experimental Biology conference in Boston, assessed the effect of PROMITOR® Soluble Corn Fibre* (SCF) on fecal microbiota (bacterial environment of the gut) in relation to calcium absorption in 24 racially diverse, male and female adolescents?a population in need of adequate calcium intake for bone growth and development. Researchers from Purdue University found that when the adolescents consumed 12 g/day of SCF versus a control, they experienced a 12% increase in calcium absorption. This increase in calcium absorption was correlated with significant increases in specific strains of beneficial bacteria, namely Bacteroides, Alistipes, Butyricicoccus, Oscillibacter, and Dialister in the gut suggesting that SCF may increase calcium absorption through changes in gut microbiota (6).

“Emerging research on soluble corn fibre indicates that added fibres provide health benefits such as increased calcium absorption via their effect on beneficial bacteria” said Connie Weaver, PhD, a lead researcher on this study. This is the first study to show that increases in these specific bacteria were significantly correlated with the observed increase in calcium absorption.

Meeting Fibre Intake Recommendations

Most fibre recommendations for adults call for intakes ranging from 25-38 g/day depending on country specific worldwide guidelines (3). While individuals should increase their consumption of dietary fibre from sources such as fruits, vegetables, nuts, legumes and whole grains, fibres added to foods, like PROMITOR® Soluble Corn Fibre*, STA-LITE® Polydextrose, and soluble fibre dextrin, can help close the gap between recommended and actual intakes of fibre while providing additional health benefits such as increased calcium absorption, improved gut health, and increased satiety.

“The results from these new studies add to the growing body of research that supports the addition of fibres to foods that consumers are already eating, which easily allows for increased fibre intakes and provides added health benefits,” said Priscilla Samuel, PhD, Director of Global Nutrition for Tate & Lyle. “Tate & Lyle is committed to investment in innovation and research to ensure that our ingredients, which can be incorporated into great tasting foods, can also help consumers meet their nutrition, health and wellness needs every day.”

*PROMITOR® Soluble Gluco Fibre in Europe

About Tate & Lyle:

Tate & Lyle is a global provider of ingredients and solutions to the food, beverage and other industries, operating from over 30 production facilities around the world.

Tate & Lyle operates through two global business units, Speciality Food Ingredients and Bulk Ingredients, supported by Innovation and Commercial Development. The Group’s strategy is to become the leading global provider of Speciality Food Ingredients through a disciplined focus on growth, and by driving the Bulk Ingredients business for sustained cash generation to fuel this growth.

Speciality Food Ingredients include starch-based speciality ingredients (corn-based speciality starches, sweeteners and fibres), no calorie sweeteners (including SPLENDA® Sucralose) and Food Systems which provides blended ingredient solutions. Bulk Ingredients include corn-based bulk sweeteners, industrial starches and fermentation products (primarily acidulants). The co-products from both divisions are primarily sold as animal feed.

Tate & Lyle is listed on the London Stock Exchange under the symbol TATE.L. American Depositary Receipts trade under TATYY. In the year to 31 March 2012, Tate & Lyle sales totalled £3.1 billion. http://www.tateandlyle.com. SPLENDA® is a trademark of McNeil Nutritionals, LLC.

References:

1. U.S. Department of Agriculture and U.S. Department of Health and Human Services. Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans, 2010. http://www.cnpp.usda.gov/dgas2010-dgacreport.htm
2. Spiller GA (ed.) CRC Handbook of Dietary Fiber in Human Nutrition, 3rd Edition. CRC Press LLC, Boca Raton, Fla. 2001.
3. Gray J. Dietary Fibre. Definition, Analysis, Physiology and Health. ILSI Europe Dietary Fibre Concise Monograph Series. 2006. http://www.ilsi.org.ar/index.php?com=descarga&que=publicaciones&id=80
4. Timm DA, Thomas W, Boileau TW, Williamson-Hughes PS, Slavin JL. Polydextrose and Soluble Corn Fiber Increase Five-Day Fecal Wet Weight in Healthy Men and Women. J Nutr. 143:473-478;2013.
5. Hutchinson C, Hsu WH, Hollis JH. Effect of soluble fiber dextrin on postprandial appetite and subsequent food intake in healthy adults. Presented at Experimental Biology. Boston, MA. April 20-24, 2013.
6. Whisner CM, Nakatsu CH, Martin BR, McCabe LD, McCabe GP, Weaver CM. Soluble corn fiber modulates calcium absorption by altering colonic microbiota.. Poster at Experimental Biology. Boston, MA. April 20-24, 2013.

Contact: Allison Parker
aparker@foodminds.com
312-258-9500
FoodMinds LLC

To evaluate the protective effects of berries on brain function, specifically the ability of the brain to clear toxic accumulation, researchers from the Human Nutrition Research Center on Aging at Tufts University and University of Maryland Baltimore County recently fed rats a berry diet for 2 months and then looked at their brains after irradiation, a model for accelerated aging. All of the rats were fed berries 2 months prior to radiation and then divided into two groups- one was evaluated after 36 hours of radiation and the other after 30 days.

“After 30 days on the same berry diet, the rats experienced significant protection against radiation compared to control,” said investigator Shibu Poulose, PhD. “We saw significant benefits to diets with both of the berries, and speculate it is due to the phytonutrients present.”

The researchers looked at neurochemical changes in the brain, in particular what is known as autophagy, which can regulate the synthesis, degradation and recycling of cellular components. It is also the way in which the brain clears toxic accumulations. “Most diseases of the brain such as Alzheimer’s and Parkinson’s have shown an increased amount of toxic protein. Berries seem to promote autophagy, the brain’s natural housekeeping mechanism, thereby reducing the toxic accumulation,” said Poulose.

The researchers are currently conducting a human study in older people ages 60-75. “We have a lot of animal work that suggests these compounds will protect the aged brain and reverse some of behavioral deficits. We are hoping it will translate to human studies as well,” said Dr. Barbara Shukitt-Hale, the lead investigator conducting the human study.

This study was funded by the USDA and a grant from NASA.

About Experimental Biology 2013

Experimental Biology’s mission is to share the newest scientific concepts and research findings shaping future and current clinical advances ? and to give scientists and clinicians an unparalleled opportunity to hear from colleagues working on similar biomedical problems using different disciplines. With six sponsoring societies and another 20 U.S. and international guest societies, the annual meeting brings together scientists from throughout the United States and the world, representing dozens of scientific areas, from laboratory to translational to clinical research. The meeting also offers a wide spectrum of professional development sessions.

About the American Society for Nutrition

The American Society for Nutrition (ASN) is the preeminent professional organization for nutrition research scientists and clinicians around the world. ASN is dedicated to bringing together the top nutrition researchers, medical practitioners, policy makers and industry leaders to advance our knowledge and application of nutrition. Founded in 1928, ASN publishes The American Journal of Clinical Nutrition (AJCN), The Journal of Nutrition (JN), and Advances in Nutrition and provides a wide range of education and professional development opportunities to advance nutrition research, practice, and education. Visit ASN online at http://www.nutrition.org.

Contact: Suzanne Price
sprice@nutrition.org
617-954-3976
Federation of American Societies for Experimental Biology

In two presentations today (Saturday) and tomorrow (Sunday) researchers will tell the 2nd Forum of the European Society for Radiotherapy and Oncology (ESTRO) that image-guided brachytherapy is able to deliver very high doses, which prevent the tumour from growing in over 90% of patients, with few serious side-effects.

One of the problems with radiotherapy for cervical cancer is that the vagina receives a high dose of radiotherapy, which can cause symptoms such as vaginal dryness, vaginal narrowing and shortening, with a loss of flexibility (stenosis), vaginal inflammation (mucositis), bleeding, or a hole in the wall of the vagina (vaginal fistula) ? one of the most serious but rare complications. The bowel and bladder can also be affected by radiotherapy for cervical cancer.

Image-guided brachytherapy involves delivering radiotherapy to the tumour by placing a radioactive source in an applicator, positioned internally in the tumour region. Imaging, either by repeated computer tomography (CT) scans or preferably magnetic resonance imaging (MRI), is used at the time of brachytherapy in order to delineate both the tumour and organs at risk in relation the applicator. This enables radiation oncologists to measure and evaluate the tumour response to the treatment, and adjust the dose accordingly, while sparing surrounding organs. [1]

However, until now, there have been few studies investigating the relationship between the dose of radiotherapy and the effects it has on the vagina during brachytherapy for cervical cancer, according to Ms Kathrin Kirchheiner (MSc), who will be reporting on the international, multi-centre prospective clinical trial EMBRACE (European and international study on MRI-guided brachytherapy in locally advanced cervical cancer) at the meeting today (Saturday).

“To date, the EMBRACE study has followed 523 patients in 19 centres for an average of 14 months to establish a benchmark for clinical outcome with regard to control of the tumour’s growth, patient survival, adverse effects of treatment and quality of life,” said Ms Kirchheiner, who is a PhD student in the Department of Radiotherapy at the Medical University Vienna (Austria). [1]

Patients with cervical cancer that had started to spread from the original site to nearby tissues and lymph nodes (locally advanced cancer) underwent external beam radiotherapy, chemotherapy and MRI-guided brachytherapy. The vagina and the effects of the treatment on it (morbidity) were assessed at the start of treatment, every three months afterwards for the first year, once every six months in the second and third year, and annually thereafter. MRI was used to assess the amount of dose being delivered to the upper part of the vaginal wall.

“Our results show that severe vaginal side-effects are rare,” said Ms Kirchheiner. “The majority of patients are likely to experience mild to moderate (grade 1 or 2) vaginal morbidity in the first two years after the end of treatment. The most frequently reported symptom is vaginal shortening and narrowing in the upper vagina. We performed a dose response analysis to measure the relationship between the amount of dose delivered to the upper vaginal wall and the probability of vaginal morbidity and found that with increasing dose to this region, the probability for moderate vaginal morbidity increases significantly.”

This is the first time that the occurrence of mild and moderate side-effects on the vagina have been systematically recorded and related to the amount of radiation dose in this way. “This is important for patients because studies on their quality of life have shown that mild and moderate vaginal symptoms and associated sexual dysfunction can cause long-term distress in cervical cancer survivors, but until now a clear dose response relationship had not been established.

“Brachytherapy is an essential part of the curative treatment of locally advanced cervical cancer, because of the high dose that can be delivered to the tumour while sparing organs at risk of damage from the treatment. With the possibility of dose adaptation and optimisation in image guided adaptive brachytherapy, a highly individualised and tailored treatment has become possible, comparable to the targeted, personalised therapies in medical oncology,” concluded Ms Kirchheiner.

The second study is retro-EMBRACE, which collected data on 592 patients in 12 institutions in Europe and Asia. Associate Professor Kari Tanderup, of the Department of Oncology at Aarhus University Hospital, Denmark, will be reporting results from this retrospective study tomorrow (Sunday).

“When using radiotherapy to treat cervical cancer there is a certain distribution of absorbed dose within the body and it is essential to know the dose level needed for local control of the tumour. However, there has been a wide range of brachytherapy schedules throughout the world with application of different dose levels for cervical cancer, and there has been limited evidence for a clearly defined dose response relationship,” she will say.

“One of the reasons is that most cervical cancer brachytherapy experience has been based on planning on radiographs and not 3D imaging. With radiographs it is difficult to assess the dose to the tumour precisely, whereas with MRI or CT guided brachytherapy is it now possible to assess the dose to the tumour with much higher precision. With the retroEMBRACE study it has been possible for the first time to assess a dose response relationship in a large number of patients in a multicentre setting. We looked at different dose levels and found a significant increase in local control with higher doses.”

Cervical cancer patients were treated with external beam radiotherapy, chemotherapy and image-guided adaptive brachytherapy (IGABT) based on MRI or CT scans. The amount of residual tumour (known as “high risk clinical tumour volume” or HR CTV) was assessed after the external beam radiotherapy in order to plan IGABT, and to target the residual tumour. “By taking the residual tumour into account we are able to tailor the brachytherapy dose to the individual patient and to the individual tumour response. We call this ‘adaptive radiotherapy’ because we adapt our treatment to changes which occur during radiochemotherapy,” explains Prof Tanderup.

“Our study shows very clearly that the higher the dose the better the tumour’s response to the brachytherapy for the entire patient population. It is possible to obtain local control in over 90 percent of patients with application of very high doses of over 90Gy. Brachytherapy is a very appropriate technique to obtain highly focused boost doses, and retroEMBRACE shows that it is actually possible to deliver doses greater than 90Gy for a significant fraction of the patients. It would not be possible to achieve doses greater than 90Gy with external beam radiotherapy without significantly increasing dose to critical organs, and therefore brachytherapy is a crucial component of radiotherapy in cervix cancer. Furthermore, the study also enables us to analyse results in patients with different risks of their tumours recurring or continuing to grow.”

She will conclude: “The retroEMBRACE study is important for the community because it establishes evidence for a dose response relationship in locally advanced cervical cancer; it shows that local control in over 90 percent of patients can be obtained with the use of MRI-guided brachytherapy; retroEMBRACE makes it possible for institutions to change their dose prescription in order to optimise the balance between local control and adverse side-effects; and it demonstrates that the adaptive target concept which has been developed for MRI-guided brachytherapy is robust in a multicentre setting.”

President of ESTRO, Professor Vincenzo Valentini, a radiation oncologist at the Policlinico Universitario A. Gemelli, Rome, Italy, commented: “This is a tangible example of how large series of data, collected by collaborative networks, and high quality treatment that takes advantage of the latest advances in imaging, can help radiation oncologists to adapt treatments to individual patients so as to give them the best chance of a cure with fewer side-effects.”

[1] Brachytherapy, where the radiation source is placed inside the body, differs from external beam radiotherapy, where the radiation is delivered from outside the body using linear accelerators.

[2] EMBRACE recruited patients from centres in Europe, North America and India. Retro-EMBRACE looked at data from patients from Austria, Denmark, France, The Netherlands, UK, Slovenia, Thailand and Ireland.

[3] EMBRACE was sponsored by the Medical University of Vienna, and funded by Nucletron (an Elekta company) and Varian Medical Systems. Retro-EMBRACE was supported by funding from Nucletron (an Elekta company) and Varian Medical Systems.

Contact: Emma Mason
wordmason@mac.com
European Society for Radiotherapy and Oncology (ESTRO)

That’s the question biologists at UC San Diego sought to answer after they demonstrated last May that algae can be engineered to produce a vaccine that blocks malaria transmission. In a follow up study, published online today in the scientific journal Applied and Environmental Microbiology, they got their answer: Not yet, although the same method may work as a vaccine against a wide variety of viral and bacterial infections.

In their most recent study, which the authors made freely available on the Applied and Environmental Microbiology website at http://aem.asm.org/, the researchers fused a protein that elicits an antibody response in mice against the organism that causes malaria, Plasmodium falciparum, which afflicts 225 million people worldwide, with a protein produced by the bacterium responsible for cholera, Vibrio cholera, that binds to intestinal epithelial cells. They then genetically engineered algae to produce this two-protein combination, or “fusion protein,” freeze dried the algae and later fed the resulting green powder to mice. The researchers hypothesized that together these proteins might be an effective oral vaccine candidate when delivered using algae.

The result? The mice developed Immunoglobulin A (IgA) antibodies to both the malarial parasite protein and to a toxin produced by the cholera bacteria. Because IgA antibodies are produced in the gut and mucosal linings, they don’t protect against the malarial parasites, which are injected directly into the bloodstream by mosquitoes. But their study suggests that similar fusion proteins might protect against infectious diseases that affect mucosal linings using their edible freeze-dried algae.

“Many bacterial and viral infections are caused by eating tainted food or water,” says Stephen Mayfield, a professor of biology at UC San Diego who headed the study. “So what this study shows is that you can get a really good immune response from a recombinant protein in algae that you feed to a mammal. In this case, it happens to be a mouse, but presumably it would also work in a human. That’s really encouraging for the potential for algae-based vaccines in the future.”

The scientists say bacterial infections caused by Salmonella, E. coli and other food and water-borne pathogens could be prevented in the future with inexpensive vaccines developed from algae that could be eaten rather than injected. “It might even be used to protect against cholera itself,” said James Gregory, a postdoctoral researcher in Mayfield’s lab and the first author of the paper. In his experiments with mice, he said, Immunoglobulin G (IgG) antibodies?which are found in blood and tissues?were produced against the cholera toxin, “but not the malaria antigen and we don’t quite understand why.”

Part of the difficulty in creating a vaccine against malaria is that it requires a system that can produce structurally complex proteins that resemble those made by the parasite, thus eliciting antibodies that disrupt malaria transmission. Most vaccines created by engineered bacteria are relatively simple proteins that stimulate the body’s immune system to produce antibodies against bacterial invaders.

Three years ago, a UC San Diego team of biologists headed by Mayfield, who is also the director of the San Diego Center for Algae Biotechnology, a research consortium seeking to develop transportation fuels from algae, published a landmark study demonstrating that many complex human therapeutic proteins, such as monoclonal antibodies and growth hormones, could be produced by the common algae Chlamydomonas. That got Gregory wondering if complex malarial transmission blocking vaccine candidates could also be produced by Chlamydomonas. Two billion people live in malaria endemic regions, making the delivery of a malarial vaccine a costly and logistically difficult proposition, especially when that vaccine is expensive to produce. So the UC San Diego biologists set out to determine if this alga, an organism that can produce complex proteins very cheaply, could produce malaria proteins that would inhibit infections from malaria.

“It’s too costly to vaccinate two billion people using current technologies,” explained Mayfield. “Realistically, the only way a malaria vaccine will ever be used in the developing world is if it can be produced at a fraction of the cost of current vaccines. Algae have this potential because you can grow algae any place on the planet in ponds or even in bathtubs.”

Collaborating with Joseph Vinetz, a professor of medicine at UC San Diego and a leading expert in tropical diseases who has been working on developing vaccines against malaria, the researchers showed in their earlier study, published in the open access journal PLoS ONE last May that the proteins produced by the algae, when injected into laboratory mice, made antibodies that blocked malaria transmission from mosquitoes.

The next step was to see if they could immunize mice against malaria by simply feeding the genetically engineered algae. “We think getting oral vaccines in which you don’t have to purify the protein is the only way in which you can make medicines dramatically cheaper and make them available to the developing world,” says Mayfield. “The Holy Grail is to develop an orally delivered vaccine, and we predict that we may be able to do it in algae, and for about a penny a dose. Our algae-produced malarial vaccine works against malarial parasites in mice, but it needs to be injected into the bloodstream.”

Although an edible malarial vaccine is not yet a reality, he adds, “this study shows that you can make a pretty fancy protein using algae, deliver it to the gut and get IgA antibodies that recognize that protein. Now we know we have a system that can deliver a complex protein to the right place and develop an immune response to provide protection.”

Mayfield is also co-director of the Center for Food & Fuel for the 21st Century, a new research unit that has brought together researchers from across the campus to develop renewable ways of improving the nation’s food, fuel, pharmaceutical and other bio-based industries and is this week hosting a major symposium on the subject at the Institute of the Americas at UC San Diego.

Two other researchers in Mayfield’s laboratory, Aaron Topol and David Doerner, participated in the research study, which was supported by grants from the San Diego Foundation, the California Energy Commission (500-10-039) and the National Science Foundation (CBET-1160184).

Contact: Kim McDonald
kmcdonald@ucsd.edu
858-534-7572
University of California – San Diego

The new coronavirus, called nCoV, was first identified in Saudi Arabia in September 2012. As of April 16, 2013, the World Health Organization has reported 17 cases with 11 deaths, primarily in the Middle East. Although the case count is small, the new coronavirus has transmitted from human-to-human in situations where people?mainly family members?have had close contact with those infected.

Because of the high fatality rate, scientists at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) saw an urgent need to identify therapeutic options. In laboratory tests using cells from two species of monkey, the researchers found that either ribavirin or interferon-alpha 2b, drugs currently approved for hepatitis C therapy, inhibited nCoV from replicating when used individually. However, the required drug concentrations exceeded what is recommended for people. By combining the two antivirals, the scientists established an effective treatment dose at a drug level that is achievable in people. The NIAID researchers plan to confirm these results in a recently developed monkey model of nCoV infection. (http://www.niaid.nih.gov/news/newsreleases/2013/Pages/NovelCoronavirus.aspx)

ARTICLES:
Falzarano et al. Inhibition of novel human coronavirus-EMC replication by a combination of interferon-alpha2b and ribavirin. Scientific Reports DOI: 10.1038/srep01686 (2013).

Munster et al. Novel Human Coronavirus Causes Pneumonia in a Macaque Model Resembling Human Disease. New England Journal of Medicine DOI: 10.1056/NEJMc1215691 (2013).

Vincent Munster, Ph.D., chief of the virus ecology unit in NIAID’s Laboratory of Virology, is leading the NIAID team investigating the new coronavirus.

To schedule interviews, please contact Ken Pekoc, (301) 402-1663, kpekoc@niaid.nih.gov.

NIAID conducts and supports research?at NIH, throughout the United States, and worldwide?to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.

NIH…Turning Discovery Into Health

Contact: Ken Pekoc
kpekoc@niaid.nih.go
301-402-1663
NIH/National Institute of Allergy and Infectious Diseases

A new minimally invasive tumor ablation technique is providing hope for liver cancer patients who can’t undergo surgery or thermal ablation, a study shows.

The study of 22 patients at the Universitatsklinikum Regensberg in Regensberg, Germany, found that irreversible electroporation (IRE) successfully destroyed tumor tissue in 70% of these patients. These patients were not responsive to conventional therapy or their tumor was in a location that was not suitable for standard treatment, said Dr. Philipp Wiggermann, lead author of the study. “If one considers that IRE was really the only option for these patients, the results are very promising,” he said.

There were two major complications in the study, but neither of them was life-threatening, said Dr. Wiggermann. One patient suffered partial thrombosis of the left portal vein. “It is not clear that the IRE procedure caused the partial thrombosis, but since it appeared after the ablation treatment, it was considered as a therapy-associated side effect,” he said. There was accidental injury to another patient’s gallbladder during the ablation treatment. “Accidental injury to surrounding organs is a risk of all percutaneous ablation techniques. Treatment of liver tumors is especially difficult due to the respiratory movement of the diaphragm leading to continuous shifting of the organ position,” said Dr. Wiggermann.

IRE disrupts the cell membrane and results in cell death. It is currently undergoing clinical investigation for treatment of malignant liver and lung lesions, Dr. Wiggermann said.

Dr. Wiggermann’s study will be presented April 18 at the ARRS Annual Meeting in Washington, DC.

Contact: Samantha Schmidt
sschmidt@arrs.org
703-858-4316
American Roentgen Ray Society

In a new report, published online today in Clinical Infectious Diseases, IDSA identified only seven new drugs in development for the treatment of infections caused by multidrug-resistant gram-negative bacilli (GNB) bacteria. GNB, which include the “nightmare bacteria” to which the Centers for Disease Control and Prevention (CDC) alerted the public in its March 2013 Vital Signs report, represent the most pressing medical need. Importantly, there is no guarantee that any of the drugs currently in development to treat GNB will make it across the finish line to FDA approval and none of them will work against the most resistant bugs we’re worried about today.

“In the past, the 10 x ’20 goal would have been considered modest, but today the barriers to approval of nine additional antibiotics by 2020 seem insurmountable,” said Henry Chambers, MD, chair of IDSA’s Antimicrobial Resistance Committee (ARC). “Some progress has been made in the development of new antibiotics, but it’s not nearly enough, and we absolutely must accelerate our efforts.”

“We’re losing ground because we are not developing new drugs in pace with superbugs’ ability to develop resistance to them. We’re on the precipice of returning to the dark days before antibiotics enabled safer surgery, chemotherapy and the care of premature infants. We’re all at risk,” said Helen W. Boucher, MD, lead author of the policy paper and a member of IDSA’s Board of Directors and ARC.

Entitled “10 x ’20 Progress: Development of New Drugs Active against Gram-negative Bacilli: An Update from the Infectious Diseases Society of America,” the paper outlines actions that must be taken to address the synergistic crises of an anemic antibiotic pipeline coupled with an explosion in multi-drug resistant pathogens. A multi-pronged approach is needed, including new economic incentives to encourage antibiotic research and development (R&D); clarification of FDA’s requirements for antibiotic approval; increased research funding; improved infection prevention; and new public health efforts including better data collection and surveillance of drug resistance and use of antibiotics. We also need to encourage “antibiotic stewardship,” which includes measures that health care facilities, providers and even patients can take to preserve the life-saving power of antibiotics by limiting their inappropriate use.

IDSA leaders have been exploring with other stakeholders specific solutions to address the pipeline problem including the creation of a Limited Population Antibacterial Drug (LPAD) approval pathway to speed drugs to approval as well as new R&D tax credits and reimbursement models. Congressional Republican leaders in the U.S. House of Representatives announced last month their intent to make fixing the antibiotic R&D pipeline a priority for the 113th Congress.

Ironically, at this urgent time of greatest need, the number of pharmaceutical companies investing in antibiotic R&D has plummeted. Pharmaceutical companies typically put R&D resources into the development of chronic disease drugs ? including those to treat high cholesterol, diabetes, and cancer ? which provide significant financial rewards, partly because they are intended to be taken for long periods of time. Antibiotics, which are intended to be taken for short courses, just can’t compete. The results are playing out in real time, with the smaller pharmaceutical company Polymedix ? which has one of the seven drugs in development noted in the 10 x ’20 paper ? filing for bankruptcy protection in early April 2013. Moreover, the policy update reports that only four large multinational companies remain in antibiotic R&D. One of these, AstraZeneca, which has two of the seven drugs in development, plans to reduce its future investments in antibiotics, its CEO, Pascal Soriot, recently announced. The current pipeline of antibiotics is fragile indeed, and the dwindling roster of antibiotic developers has dire consequences for public health, patient care and national security.

New antibiotics are critically necessary to save the lives of people such as Josh Nahum, a healthy 27-year-old man who died from an overwhelming Enterobacter aerogenes infection as he was recovering in the hospital after a skydiving accident. Although his doctors tried desperately to save Josh, they ran out of antibiotics to treat this virulent bug. Read more about Josh’s story and the experiences of others whose lives have been devastated by antibiotic resistance: http://www.idsociety.org/Joshs_Story.aspx.

IDSA first warned of the looming antibiotic apocalypse with its 2004 report, “Bad Bugs, No Drugs.” Nearly 50 other medical societies and organizations, including the American Medical Association, have endorsed the 10 x ’20 initiative so far.

“IDSA is committed to ensuring proper use of currently-available antibiotics to make certain we can continue to count on them. But that is not enough. Simply put, the antibiotic pipeline is on life support and novel solutions are required to resuscitate it ? now,” said IDSA President David A. Relman, MD. “In the past year, the heads of CDC and the World Health Organization, along with the United Kingdom’s chief medical officer, have all sounded the alarm about rising rates of antibiotic resistance. The lack of new antibiotics to treat these potentially life-threatening infections signals the end of modern medicine as we know it.”

To see the policy update, which appears in the May 15 issue of Clinical Infectious Diseases (CID), contact Jerica Pitts (jpitts@pcipr.com) at 312-558-1770. See also a fact sheet on antimicrobial resistance here: http://www.idsociety.org/AntibioticResistanceFactSheet-April2013.pdf.

EDITOR’S NOTE: Although the paper published in CID recognizes two drugs approved by the FDA since 2009, the 10 x ’20 Initiative was launched in April 2010 following the approval of one of these drugs.

The Infectious Diseases Society of America (IDSA) is an organization of physicians, scientists, and other health care professionals dedicated to promoting health through excellence in infectious diseases research, education, patient care, prevention, and public health. The Society, which has more than 10,000 members, was founded in 1963 and is based in Arlington, Va. For more information, see http://www.idsociety.org.

Contact: Jerica Pitts
jpitts@pcipr.com
312-558-1770
Infectious Diseases Society of America

Previous research has established that caffeine interferes with processes in cancer cells that control DNA repair, a finding that has generated interest in using the stimulant as a chemotherapy treatment. But given the toxic nature of caffeine at high doses, researchers from the U of A instead opted to use it to identify genes and pathways responsible for DNA repair.

“The problem in using caffeine directly is that the levels you would need to completely inhibit the pathway involved in this DNA repair process would kill you,” said Shelagh Campbell, co-principal investigator. “We’ve come at it from a different angle to find ways to take advantage of this caffeine sensitivity.”

The research team found that fruit flies with a mutant gene called melanoma antigen gene, or MAGE, appeared normal when fed a regular diet but died when fed food supplemented with caffeine. On closer inspection, they found the mutant flies’ cells were super-sensitive to caffeine, with the drug triggering “cell suicide” called apoptosis.

Through this work, researchers identified three genes responsible for a multi-protein complex, called SMC5/SMC6/MAGE, which regulates DNA repair and the control of cell division. Neither process works properly in cancer cells.

This finding is significant because it means that scientists one day could be able to take advantage of cancer-cell sensitivity to caffeine by developing targeted treatments for cancers with specific genetic changes.

The study was led by Rachel Wevrick and Shelagh Campbell, who published their results in the March issue of the peer-reviewed journal PLOS One.

Contact: Bryan Alary
bryan.alary@ualberta.ca
780-492-0436
University of Alberta