BreakThrough Digest Medical News |
- Drugs found to both prevent and treat Alzheimer’s disease in mice
- Poliovirus vaccine trial shows early promise for recurrent glioblastoma
- Mayo Clinic: How gold nanoparticles can help fight ovarian cancer
- Resistance to last-line antibiotic makes bacteria resistant to immune system
- Study suggests new source of kidneys for transplant
- The compound in the Mediterranean diet that makes cancer cells ‘mortal’
- Immune protein could stop diabetes in its tracks
| Drugs found to both prevent and treat Alzheimer’s disease in mice Posted: 20 May 2013 09:00 PM PDT Researchers at USC have found that a class of pharmaceuticals can both prevent and treat Alzheimer’s Disease in mice. 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 |
| Poliovirus vaccine trial shows early promise for recurrent glioblastoma Posted: 20 May 2013 09:00 PM PDT An attack on glioblastoma brain tumor cells that uses a modified poliovirus is showing encouraging results in an early study to establish the proper dose level, researchers at Duke Cancer Institute report.
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 |
| Mayo Clinic: How gold nanoparticles can help fight ovarian cancer Posted: 20 May 2013 09:00 PM PDT Positively charged gold nanoparticles are usually toxic to cells, but cancer cells somehow manage to avoid nanoparticle toxicity. Mayo Clinic researchers found out why, and determined how to make the nanoparticles effective against ovarian cancer cells. The discovery is detailed in the current online issue of the Journal of Biological Chemistry.
“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 |
| Resistance to last-line antibiotic makes bacteria resistant to immune system Posted: 20 May 2013 09:00 PM PDT Bacteria resistant to the antibiotic colistin are also commonly resistant to antimicrobial substances made by the human body, according to a study in mBio®, the online open-access journal of the American Society for Microbiology. Cross-resistance to colistin and host antimicrobials LL-37 and lysozyme, which help defend the body against bacterial attack, could mean that patients with life-threatening multi-drug resistant infections are also saddled with a crippled immune response. Colistin is a last-line drug for treating several kinds of drug-resistant infections, but colistin resistance and the drug’s newfound impacts on bacterial resistance to immune attack underscore the need for newer, better antibiotics.
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 |
| Study suggests new source of kidneys for transplant Posted: 19 May 2013 09:00 PM PDT Nearly 20 percent of kidneys that are recovered from deceased donors in the U.S. are refused for transplant due to factors ranging from scarring in small blood vessels of the kidney’s filtering units to the organ going too long without blood or oxygen. But, what if instead of being discarded, these organs could be “recycled” to help solve the critical shortage of donor organs?
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 |
| The compound in the Mediterranean diet that makes cancer cells ‘mortal’ Posted: 19 May 2013 09:00 PM PDT New research suggests that a compound abundant in the Mediterranean diet takes away cancer cells’ “superpower” to escape death. 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 |
| Immune protein could stop diabetes in its tracks Posted: 18 May 2013 09:00 PM PDT .Melbourne researchers have identified an immune protein that has the potential to stop or reverse the development of type 1 diabetes in its early stages, before insulin-producing cells have been destroyed.
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 |
| You are subscribed to email updates from BreakThrough Digest Medical News To stop receiving these emails, you may unsubscribe now. | Email delivery powered by Google |
| Google Inc., 20 West Kinzie, Chicago IL USA 60610 | |
