BreakThrough Digest Medical News |
- Scientists unveil secrets of important natural antibiotic
- Study reveals new clues to Epstein-Barr virus
- Mushroom-supplemented soybean extract shows therapeutic promise for advanced prostate cancer
- New bioengineered ears look and act like the real thing
| Scientists unveil secrets of important natural antibiotic Posted: 20 Feb 2013 09:00 PM PST An international team of scientists has discovered how an important natural antibiotic called dermcidin, produced by our skin when we sweat, is a highly efficient tool to fight tuberculosis germs and other dangerous bugs.
Their results could contribute to the development of new antibiotics that control multi-resistant bacteria. Scientists have uncovered the atomic structure of the compound, enabling them to pinpoint for the first time what makes dermcidin such an efficient weapon in the battle against dangerous bugs. Although about 1700 types of these natural antibiotics are known to exist, scientists did not until now have a detailed understanding of how they work. The study, carried out by researchers from the University of Edinburgh and from Goettingen, Tuebingen and Strasbourg, is published in Proceedings of the National Academy of Sciences. Sweat spreads highly efficient antibiotics on to our skin, which protect us from dangerous bugs. If our skin becomes injured by a small cut, a scratch, or the sting of a mosquito, antibiotic agents secreted in sweat glands, such as dermcidin, rapidly and efficiently kill invaders. These natural substances, known as antimicrobial peptides (AMPs), are more effective in the long term than traditional antibiotics, because germs are not capable of quickly developing resistance against them. The antimicrobials can attack the bugs’ Achilles’ heel ? their cell wall, which cannot be modified quickly to resist attack. Because of this, AMPs have great potential to form a new generation of antibiotics. Scientists have known for some time that dermcidin is activated in salty, slightly acidic sweat. The molecule then forms tiny channels perforating the cell membrane of bugs, which are stabilised by charged particles of zinc present in sweat. As a consequence, water and charged particles flow uncontrollably across the membrane, eventually killing the harmful microbes. Through a combination of techniques, scientists were able to determine the atomic structure of the molecular channel. They found that it is unusually long, permeable and adaptable, and so represents a new class of membrane protein. The team also discovered that dermcidin can adapt to extremely variable types of membrane. Scientists say this could explain why active dermcidin is such an efficient broad-spectrum antibiotic, able to fend off bacteria and fungi at the same time. The compound is active against many well-known pathogens such as tuberculosis, Mycobacterium tuberculosis, or Staphylococcus aureus. Multi-resistant strains of Staphylococcus aureus, in particular, have become an increasing threat for hospital patients. They are insensitive towards conventional antibiotics and so are difficult to treat. Staphylococcus aureus infections can lead to life-threatening diseases such as sepsis and pneumonia. The international team of scientists hopes that their results can contribute to the development of a new class of antibiotics that is able to attack such dangerous germs. Dr Ulrich Zachariae of the University of Edinburgh’s School of Physics, who took part in the study, said: “Antibiotics are not only available on prescription. Our own bodies produce efficient substances to fend off bacteria, fungi and viruses. Now that we know in detail how these natural antibiotics work, we can use this to help develop infection-fighting drugs that are more effective than conventional antibiotics.” Contact: Catriona Kelly ### |
| Study reveals new clues to Epstein-Barr virus Posted: 20 Feb 2013 09:00 PM PST Epstein-Barr virus (EBV) affects more than 90 percent of the population worldwide and was the first human virus found to be associated with cancer. Now, researchers from Beth Israel Deaconess Medical Center (BIDMC) have broadened the understanding of this widespread infection with their discovery of a second B-cell attachment receptor for EBV.
The new findings, which currently appear on-line in Cell Reports, reinforce current directions being taken in the development of a vaccine to guard against EBV, and raise important new questions regarding the virus’s possible relationship to malaria and to autoimmune diseases. “Our discovery that CD35 is an attachment receptor for EBV helps explain several previously unsolved observations,” explains the study’s senior author Joyce Fingeroth, MD, a member of the Division of Infectious Diseases at BIDMC and Associate Professor of Medicine at Harvard Medical School. First discovered in the early 1960s, EBV is one of eight viruses in the human herpesvirus family. The virus affects nine out of 10 people at some point in their lifetimes. Infections in early childhood often cause no disease symptoms, but people infected during adolescence or young adulthood may develop infectious mononucleosis. EBV is also associated with several types of cancer, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and nasopharyngeal carcinoma, and has been linked to certain autoimmune disorders. “EBV was the first human virus that was discovered to be a tumor virus,” explains Fingeroth. “In fact, individuals who have had infectious mononucleosis have a four times increased risk of developing Hodgkin’s disease.” After the initial infection, the EBV virus remains in a person’s body for life. To gain entry, viruses must first attach to their host cells. For herpesviruses, receptors on the viral envelope become connected to complementary receptors on the cell membrane. In the case of EBV, the virus gains access to the immune system by attaching to primary B cells. Nearly 30 years ago, Fingeroth and her colleagues discovered that this attachment occurs via the CD21 protein, which until now was the only known B cell attachment receptor for EBV. The recent finding that B cells from a patient lacking CD21 can be infected and immortalized by EBV had indicated that an alternative attachment receptor must exist. The identification of this second receptor — CD35 — by Fingeroth’s team, led by first author Javier Ogembo, PhD, of BIDMC and the University of Massachusetts Medical School, not only underscores an important finding regarding primary infection but also underscores the importance of EBVgp350/220, (the virus protein that has been found to bind to both attachment receptors) for the development of a vaccine against EBV. “The EBV glycoprotein gp350/220 is the most abundant surface glycoprotein on the virus,” notes Fingeroth, adding that these results further suggest the virus fusion apparatus is the same for both receptors. “An EBV vaccine might be able to prevent infection or, alternatively, greatly reduce a person’s risk of developing infectious mononucleosis and EBV-associated cancers, without necessarily preventing the EBV infection itself.” Interestingly, she adds, whereas a human has now been identified to be lacking the CD21 receptor, no persons are known to lack CD35. “CD35 is a latecomer in evolution and in its current form, exists only in humans,” says Fingeroth. “We know that it is often targeted in autoimmune diseases and was recently identified as a malaria receptor. Our new discovery may, therefore, reveal new avenues for the exploration of unexplained links between EBV, autoimmune diseases, malaria and cancer.” ### In addition to Fingeroth and Ogembo, study coauthors include BIDMC investigators Lakshmi Kannan, Ionita Ghiran, Anne Nicholson-Weller and George Tsokos; and University of Massachusetts Medical School investigator Robert Finberg. This study was supported by a grant from the National Institutes of Health (R01A10635710) as well as support from the American Heart Association, the St. Baldrick’s Foundation, and the Cancer Research Institute. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and currently ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org. Contact: Bonnie Prescott |
| Mushroom-supplemented soybean extract shows therapeutic promise for advanced prostate cancer Posted: 19 Feb 2013 09:00 PM PST A natural, nontoxic product called genistein-combined polysaccharide, or GCP, which is commercially available in health stores, could help lengthen the life expectancy of certain prostate cancer patients, UC Davis researchers have found.
Paramita GhoshMen with prostate cancer that has spread to other parts of the body, known as metastatic cancer, and who have had their testosterone lowered with drug therapy are most likely to benefit. The study, recently published in Endocrine-Related Cancer, was conducted in prostate cancer cells and in mice. Lowering of testosterone, also known as androgen-deprivation therapy, has long been the standard of care for patients with metastatic prostate cancer, but life expectancies vary widely for those who undergo this treatment. Testosterone is an androgen, the generic term for any compound that stimulates or controls development and maintenance of male characteristics by binding to androgen receptors. The current findings hold promise for GCP therapy as a way to extend life expectancy of patients with low response to androgen-deprivation therapy. Paramita Ghosh, an associate professor in the UC Davis School of Medicine, led the pre-clinical study with a team that included UC Davis Comprehensive Cancer Center Director Ralph de Vere White, a UC Davis distinguished professor of urology. Ruth Vinall in the UC Davis Department of Urology and Clifford Tepper in the UC Davis Department of Biochemistry and Molecular Medicine directed the studies in mice; Ghosh’s laboratory conducted the cell studies. The research focused on GCP, a proprietary extract cultured from soybeans and shiitake mushrooms and marketed by Amino-Up of Sapporo, Japan. Researchers found that the combination of the compounds genistein and daidzein, both present in GCP, helps block a key mechanism used by prostate cancer cells to survive in the face of testosterone deprivation. The research team had earlier shown that when a patient’s androgen level goes down, cancerous prostate cells kick out a protein known as filamin A, which is otherwise attached to the androgen receptor in the cell’s nucleus. The androgen receptor regulates growth of prostate cancer cells. Once filamin A leaves the cancerous cell’s nucleus, that cell no longer requires androgens to survive. Thus, loss of filamin A allows these cells to survive androgen deprivation, at and the cancer essentially becomes incurable. The paper, titled “Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization,” shows for the first time that GCP keeps filamin A in the nucleus. As long as this protein remains attached to the androgen receptor, the cancerous cells need androgens to survive and grow. They die off when starved of androgens, thus prolonging the effects of androgen deprivation, which ultimately prolongs the patient’s life. The team’s hypothesis is that metastatic prostate cancer patients with the weakest response to androgen-deprivation therapy could be given GCP concurrently with androgen deprivation therapy to retain Filamin A in the nucleus, thereby allowing cancer cells to die off. De Vere White is now pursuing funding to begin GCP human clinical trials. Because GCP is a natural product rather than a drug, and requires fewer government approvals, it’s expected that these trials will proceed rapidly once funded. “We should know within the first eight months or so of human clinical trials if GCP works to reduce PSA levels,” says de Vere White, referring to prostate-specific antigen levels, a tumor marker to detect cancer. “We want to see up to 75 percent of metastatic prostate cancer patients lower their PSA levels, and GCP holds promise of accomplishing this goal. If that happens, it would probably be a greater therapy than any drug today.” ### The research was supported by a Biomedical Laboratory Research and Development service Merit Award (I01BX000400) from the Department of Veterans Affairs and by R01CA133209 from the National Cancer Institute. Other authors were Benjamin A. Mooso, Sheetal Singh, Salma Siddiqui, and Maria Mudryj of the VA Northern California Health Care System; Ruth L. Vinall, Rosalinda M. Savoy, Jean P. Cheung, and Yu Wang of the UC Davis Department of Urology; Clifford G. Tepper, Anthony Martinez, and Hsing-Jien Kung of the UC Davis Department of Biochemistry and Molecular Medicine; and Roble G. Bedolla of the University of Texas Health Science Center at San Antonio. UC Davis Comprehensive Cancer Center is the only National Cancer Institute-designated center serving the Central Valley and inland Northern California, a region of more than 6 million people. Its specialists provide compassionate, comprehensive care for more than 9,000 adults and children every year, and access to more than 150 clinical trials at any given time. Its innovative research program engages more than 280 scientists at UC Davis, Lawrence Livermore National Laboratory and Jackson Laboratory (JAX West), whose scientific partnerships advance discovery of new tools to diagnose and treat cancer. Through the Cancer Care Network, UC Davis collaborates with a number of hospitals and clinical centers throughout the Central Valley and Northern California regions to offer the latest cancer care. Its community-based outreach and education programs address disparities in cancer outcomes across diverse populations. For more information, visit http://cancer.ucdavis.edu. Contact: Dorsey Griffith |
| New bioengineered ears look and act like the real thing Posted: 19 Feb 2013 09:00 PM PST Physicians at Weill Cornell Medical College and biomedical engineers at Cornell University have succeeded in building a facsimile of a living human ear that looks and acts like a natural ear. Researchers believe their bioengineering method will finally succeed in the long quest by scientists and physicians to provide normal looking “new” ears to thousands of children born with a congenital ear deformity.
In their PLOS ONE study, the researchers demonstrate how 3D printing and new injectable gels made of living cells can be used to fashion ears that are identical to a human ear. Over a three-month period — the length of the study — these flexible ears steadily grew cartilage to replace the collagen that was used to help mold them. “I believe this will be the novel solution reconstructive surgeons have long wished for to help children born with absence or severe deformity of the ear,” says the study’s co-lead author, Dr. Jason Spector, director of the Laboratory for Bioregenerative Medicine and Surgery (LBMS) and associate professor of surgery of plastic surgery in the Department of Surgery at Weill Cornell Medical College and an adjunct associate professor in the Department of Biomedical Engineering at Cornell University. “A bioengineered ear replacement like this would also help individuals who have lost part or all of their external ear in an accident or from cancer.” Currently, replacement ears are constructed using materials that have a Styrofoam-like consistency or, sometimes, surgeons will build ears from rib that is harvested from a young patient. “This surgical option is very challenging and painful for children, and the ears rarely look totally natural or perform well,” says Dr. Spector, who is also a plastic and reconstructive surgeon at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. “All other attempts to ‘grow’ ears in the lab — including one 1997 study widely publicized by photos of ears implanted on the backs of mice — have failed in the long term.” This Cornell bioengineered ear is the best to date in appearing and acting like a natural ear, the researchers report. Also, the process of making the ears is fast — it takes a week at most. “This is such a win-win for both medicine and basic science, demonstrating what we can achieve when we work together,” says the study’s other lead author, Dr. Lawrence J. Bonassar, associate professor and associate chair of the Department of Biomedical Engineering at Cornell University. Scanning, Printing and Molding a Human Ear in a Week The deformity that both Dr. Spector and Dr. Bonassar seek to remedy is microtia, a congenital deformity in which the external ear is not fully developed. Although the causes for this disorder are not entirely understood, research has found that microtia can occur in children whose mothers took an acne medication during pregnancy. Typically, only a single ear is affected. The incidence of microtia varies from almost one to more than four per 10,000 births each year. Many children born with microtia have an intact inner ear, but experience hearing loss due to the missing external ear structure, which acts to capture and conduct sound. Dr. Spector and Dr. Bonassar have been collaborating on bioengineered human replacement parts since 2007, and Dr. Bonassar has also been working with other Weill Cornell physicians. For example, he and Weill Cornell’s neurological surgeon Dr. Roger Härtl are currently testing bioengineered disc replacements using some of the same techniques demonstrated in this current study. The researchers specifically work to develop replacements for human structures that are primarily made of cartilage — joints, trachea, spine, nose — because cartilage does not need to be vascularized with a blood supply in order to survive. To make the ears, Dr. Bonassar and his colleagues first took a combination laser scan and panoramic photo of an ear from twin girls, which provided a digitized 3D image of their ears on a computer screen. That took 30 seconds, and did not involve any ionizing radiation. The researchers then converted that image into a digitized “solid” ear and used a 3D printer to assemble a mold of the ear. The mold is like a box with a hole in the middle that is in the shape of the mirror image of the ear, say researchers. They injected animal-derived collagen into that ear mold, and then added nearly 250 million cartilage cells. The collagen served as a scaffold upon which cartilage could grow. Collagen is the main structural protein in the body of every mammal. Animal-based collagen is frequently used for cosmetic and plastic surgery. This high-density collagen gel, which Cornell researchers developed, resembles the consistency of flexible Jell-O when the mold is removed. “The process is fast,” Dr. Bonassar says. “It takes half a day to design the mold, a day or so to print it, 30 minutes to inject the gel and we can remove the ear 15 minutes later. We trim the ear and then let it culture for several days in a nourishing cell culture medium before it is implanted.” During the three-month observation period, the cartilage in the ears grew to replace the collagen scaffold. “Eventually the bioengineered ear contains only auricular cartilage, just like a real ear,” says Dr. Spector. Previous bioengineered ears have not been able to maintain their shape or dimensions over time, and the cells within them did not survive. The researchers are now looking at ways to expand populations of human ear cartilage cells in the laboratory so that these cells can be used in the mold. Dr. Spector says the best time to implant a bioengineered ear on a child would be when they are about 5- or 6-years-old, because at that age, ears are 80 percent of their adult size. “We don’t know yet if the bioengineered ears would continue to grow to their full size, but I suspect they will,” says Dr. Spector. “Surgery to attach the new ear would be straightforward — the malformed ear would be removed and the bioengineered ear would be inserted under a flap of skin at the site.” Dr. Spector says that if all future safety and efficacy tests work out, it might be possible to try the first human implant of a Cornell bioengineered ear in as little as three years. “The innovation in this study is two-fold,” says Dr. Bonassar. “The use of imaging technology to rapid and accurately make the shape of the ear implant is new, as is the high-density collagen gel for the mold.” “These bioengineered ears are highly promising because they precisely mirror the native architecture of the human ear,” Dr. Spector says. “They should restore hearing and a normal appearance to children and others in need. This advance represents a very exciting collaboration between physicians and basic scientists. It is a demonstration of what we hope to do together to improve the lives of these patients with ear deformity, missing ears and beyond.” ### Other co-authors of the study are Dr. Alyssa J. Reiffel, Dr. Karina A. Hernandez, and Justin L. Perez from the Laboratory for Bioregenerative Medicine and Surgery at Weill Cornell Medical College; and Concepcion Kafka, Samantha Popa, Sherry Zhou, Satadru Pramanik, Dr. Bryan N. Brown and Won Seuk Ryu, from the Department of Biomedical Engineering at Cornell University. 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. Office of External Affairs Contact: Contact: Lauren Woods
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