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Archive - Mar 2014

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March 12th

Stem Cells Embedded in Sutures May Improve Healing in Achilles Tendon Injuries

Researchers have found that sutures embedded with stem cells led to quicker and stronger healing of Achilles tendon tears than traditional sutures, according to a new study published in the March 2014 issue of Foot & Ankle International (published by SAGE). Achilles tendon injuries are common for professional, collegiate, and recreational athletes. These injuries are often treated surgically to reattach or repair the tendon if it has been torn. Patients have to keep their legs immobilized for a while after surgery before beginning their rehabilitation. Athletes may return to their activities sooner, but risk rerupturing the tendon if it has not healed completely. Drs. Lew Schon, Samuel Adams, and Elizabeth Allen and researchers Margaret Thorpe, Brent Parks, and Gary Aghazarian from MedStar Union Memorial Hospital in Baltimore, Maryland, conducted the study. They compared traditional surgery, surgery with stem cells injected in the injury area, and surgery with special sutures embedded with stem cells in rats. The results showed that the group receiving the stem cell sutures healed better. "The exciting news from this early work is that the stem cells stayed in the tendon, promoting healing right away, during a time when patients are not able to begin aggressive rehabilitation. When people can't fully use their leg, the risk is that atrophy sets in and adhesions can develop which can impact how strong and functional the muscle and tendon are after it is reattached," said Dr. Schon. "Not only did the stem cells encourage better healing at the cellular level, the tendon strength itself was also stronger four weeks following surgery than in the other groups in our study," he added.

Scientists ID Extracellular Matrix Proteins That Aid Metastasis

About 90 percent of cancer deaths are caused by tumors that have spread from their original locations. This process, known as metastasis, requires cancer cells to break loose from their neighbors and from the supportive scaffold that gives tissues their structure. MIT cancer biologists have now discovered that certain proteins in this structure, known as the extracellular matrix, help cancer cells make their escape. The researchers identified dozens of proteins that surround highly metastatic tumors, but not less aggressive tumors, and found that four of those proteins are critical to metastasis. The findings could lead to new tests that predict which tumors are most likely to metastasize, and may also help to identify new therapeutic targets for metastatic tumors, which are extremely difficult to treat. “The problem is, all the current drugs are targeted to primary tumors. Once a metastasis appears, in many cases, there’s nothing you can do about it,” says Dr. Richard Hynes, leader of the research team and a member of MIT’s Koch Institute for Integrative Cancer Research. “In principle, one could imagine interfering with some of these extracellular proteins and blocking metastasis in a patient. We’re a long way from that, but it’s not inconceivable.” Koch Institute postdoc Dr. Alexandra Naba is the lead author of the study, which appears in the March 11 online edition of the journal eLife. Other authors are Dr. Steven Carr, director of the Proteomics Platform at the Broad Institute; Dr. Karl Clauser, a research scientist at the Broad Institute; and Dr. John Lamar, a research scientist at the Koch Institute. The extracellular matrix is made mostly of collagens, proteins that provide structural support for living tissues.

Protein Key to Cell Motility Has Implications for Halting Cancer Metastasis

"Cell movement is the basic recipe of life, and all cells have the capacity to move," says Roberto Dominguez, Ph.D., professor of Physiology at the Perelman School of Medicine, University of Pennsylvania. Motility – albeit on a cellular spatial scale -- is necessary for wound healing, clotting, fetal development, nerve connections, and the immune response, among other functions. On the other hand, cell movement can be deleterious when cancer cells break away from tumors and migrate to set up shop in other tissues during cancer metastasis. The Dominguez team, with postdoctoral fellow David Kast, Ph.D., and colleagues, reported online ahead of print on Marh 2, 2014 in Nature Structural & Molecular Biology how a key cell-movement protein called IRSp53 is regulated in a resting and active state, and what this means for cancer-cell metastasis. "We characterized how IRSp53 connects to the cell-motility machinery," says Dr. Kast. "It does this by starting the formation of cell filopodia - extensions that form when a cell needs to move." "Cells move like an inchworm," explains Dr. Dominguez. "Filopodia are at the leading edge of moving cells." The trailing end of the cell follows the move forward through contraction of actin and myosin in the cytoskeleton, much like muscle contraction. A cell pushes out the leading edge of its membrane, and sticks it down on whatever it is moving across, namely other cells, and then moves the cell body along, unsticking the back end. This sets the cell up for its next move. IRSp53 contains a region called a BAR domain that binds to and shapes cell membranes. Other parts of the protein connect it to the cytoskeleton (internal bits that give a cell structure and shape). Together, through the binding of cell membranes and other proteins IRSp53 regulates cell movement.

Turing’s Far-Reaching Theory of Morphogenesis Validated 60 Years After His Death

British mathematician Alan Turing’s (image) accomplishments in computer science are well known—he’s the man who cracked the German Enigma code, expediting the Allies’ victory in World War II. He also had a tremendous impact on biology and chemistry. In his only paper in biology, Turing proposed a theory of morphogenesis, or how identical copies of a single cell differentiate, for example, into an organism with arms and legs, a head and tail. Now, 60 years after Turing’s death, researchers from the University of Pittsburgh (Pitt) and Brandeis University have provided the first experimental evidence that validates Turing’s theory in cell-like structures. The team published its findings online in PNAS on March 10. Turing, in 1952, was the first to offer an explanation of morphogenesis through chemistry. He theorized that identical biological cells differentiate and change shape through a process called intercellular reaction-diffusion. In this model, chemicals react with each other and diffuse across space—say between cells in an embryo. These chemical reactions are managed by the interaction of inhibitory and excitatory agents. When this interaction plays out across an embryo, it creates patterns of chemically different cells. Turing predicted six different patterns could arise from this model. At Brandeis, Dr. Seth Fraden, professor of physics, and Dr. Irv Epstein, professor of chemistry, created rings of synthetic, cell-like structures with activating and inhibiting chemical reactions to test Turing’s model. Pitt’s Dr. G. Bard Ermentrout, University Professor of Computational Biology and professor of mathematics in the Kenneth P. Dietrich School of Arts and Sciences, undertook mathematical analysis of the experiments. The researchers observed all six patterns plus a seventh unpredicted by Turing.

March 12th

Bladder Cancer Patient with Rare mTOR Mutations Shows Exceptional Drug Response

A patient with advanced bladder cancer experienced a complete response for 14 months to the drug combination everolimus and pazopanib in a phase I trial, and genomic profiling of his tumor revealed two alterations that may have caused this exceptional response, according to a study published onine on March 13, 2014 in Cancer Discovery, a journal of the American Association for Cancer Research (AACR). This information can help identify cancer patients who may respond to everolimus. Exceptional responders are cancer patients who had a complete response or partial response for at least six months to treatment in a clinical trial in which less than 10 percent of patients responded, according to the National Cancer Institute. "Studying exceptional responses can help us understand the specific reasons why some tumors are highly sensitive to certain anticancer agents," said Nikhil Wagle, M.D., an instructor in medicine at Dana-Farber Cancer Institute, and an associate member at the Broad Institute in Cambridge, Massachusetts. "We can use that information to identify patients whose tumors have genetic alterations similar to those found in exceptional responders, and treat them with those same agents. "We conducted a phase I clinical trial of two anticancer agents—the mTOR inhibitor everolimus, and pazopanib, another drug used to treat kidney cancer—and one of our patients developed near complete remission of his bladder cancer which lasted for 14 months," said Dr. Wagle.

Gut Microbiota Networks May Influence Autoimmune Processes in Type 1 Diabetes

The interactions of the gut microbiota in children with typical diabetes autoantibodies differ from those in healthy children. The fact that these differences already exist before antibodies are detectable in the blood adds to the growing evidence that microbial DNA, the so-called microbiome, may be involved in the development of autoimmune processes. Scientists from the Helmholtz Zentrum München have published their findings online on March 7, 2014 in the specialist journal Diabetes. As part of the BABYDIET study, the scientists compared the composition and interaction of the gut microbiota in children who went on to develop diabetes-specific autoantibodies in their blood with data from children who were autoantibody-negative. The BABYDIET study examines the nutritional factors that may influence the risk of diabetes. In the course of the study, the team headed by PD Dr. Peter Achenbach and Professor Anette-Gabriele Ziegler from the Institute of Diabetes Research, as well as Dr. David Endesfelder and Dr. Wolfgang zu Castell from the Scientific Computing Research Unit at the Helmholtz Zentrum München, ascertained that the diversity and number of bacteria present in the gut were similar in both collectives. However, bacterial interaction networks in the gut varied significantly in the two groups - even in the first years of life, months or years before one group developed the typical diabetes autoantibodies. Colonies of bacteria form what is known as the microbiome, and the genetic information contained within it influences the host organism. For some time, the microbiome has been associated with different diseases; the gut microbiome, in particular, is thought to play a role in the pathogenesis of metabolic diseases such as diabetes.

Precursor of European Rhinos Found in Vietnam

A team of scientists from the University of Tübingen in Germany and the Senckenberg Center for Human Evolution and Palaeoenvironment Tübingen was able to recover fossils of two previously unknown mammal species that lived about 37 million years ago. The newly described mammals show a surprisingly close relationship to prehistoric species known from fossil sites in Europe. The work was published in Zitteliana. The location of the finds was the open lignite-mining pit in Na Duong in Vietnam. Here, the team of scientists was also able to make a series of further discoveries, including three species of fossilized crocodiles and several new turtles. Southeast Asia is considered a particularly species-rich region, even in prehistoric times – a so-called hotspot of biodiversity. For several decades now, scientists have postulated close relationships that existed in the late Eocene (ca. 38-34 million years ago) between the faunas of that region and Europe. The recent findings by the research team under leadership of Professor Dr. Madelaine Böhme serve as proof that some European species originated in Southeast Asia. One of the newly described mammals is a rhinoceros, Epiaceratherium naduongense. The anatomy of the fossil teeth allows identifying this rhinoceros as a potential forest dweller. The other species is the so-called “Coal Beast”, Bakalovia orientalis. This pig-like ungulate, closely related to hippos, led a semi-aquatic lifestyle, i.e., it preferred the water close to bank areas. At that time, Na Duong was a forested swampland surrounding Lake Rhin Chua. The mammals’ remains bear signs of crocodile attacks. Indeed, the excavation site at Na Duong contains the fossilized remains of crocodiles up to 6 meters in length. In the Late Eocene, the European mainland presented a very different aspect than it does today.

Molecules Tailored to Defeat Malaria Parasite

The malaria parasite is particularly pernicious because it is built to develop resistance to treatments. The lack of new therapeutic approaches also contributes to the persistence of this global scourge. A study led by Dr. Didier Picard, professor at the Faculty of Sciences of the University of Geneva (UNIGE), Switzerland, describes a new class of molecules targeting the two problems at the same time. Using ultra sophisticated computerized modelling tools, the researchers were successful in identifying a type of candidate molecules toxic for the pathogen, but not for the infected human red blood cells. The study, led in collaboration with researchers from the Geneva-Lausanne School of Pharmacy (EPGL) and the University of Basel, has been published online on March 3, 2014 in the Journal of Medicinal Chemistry. The most severe form of malaria is caused by infection with Plasmodium falciparum. The eradication of this parasite is even more difficult as it becomes resistant to treatments. The group led by Dr. Picard is closely interested in the protein heat shock protein 90 (HSP90), which plays a central role for several factors involved in the life cycle, survival, and resistance of the pathogen. Expressed in organisms as diverse as bacteria and mammalian cells, HSP90 acts as a "chaperone," by helping other proteins during both normal and stressful periods. In the Plasmodium, HSP90 protects parasitic proteins during high fevers triggered by its presence. The chaperone also participates in the maturation of the pathogen in human red blood cells. "Our goal was to determine if there was a difference between the human form and the parasitic form of HSP90 that we could exploit for therapeutic purposes," explains Tai Wang, a Ph.D. student at the Department of Cell Biology of UNIGE.

Scientists Confirm Link Between Missing X-Chromosome DNA and Birth Defects

In 2010, scientists in Italy reported that a woman and her daughter showed a puzzling array of disabilities, including epilepsy and cleft palate. The mother had previously lost a 15-day-old son to respiratory failure, and the research team noted that the mother and daughter were missing a large chunk of DNA on their X chromosome. But the researchers were unable to definitively show that the problems were tied to that genetic deletion. Now a team from the University of Pennsylvania (Penn) and The Children’s Hospital of Philadelphia (CHOP) has confirmed that those patients’ ailments resulted from the genetic anomaly. Creating mice that lacked the same region of DNA, the Penn and CHOP researchers showed that these animals suffered the same problems that afflicted the mother, daughter and son — cleft palate, epilepsy and respiratory difficulties, a condition called human Xq22.1 deletion syndrome. And, by clarifying the syndrome’s genetic basis, the researchers have laid the foundation for identifying the underlying molecular mechanism of these troubles and potentially treating them at their biological root. “This study has demonstrated that deleting this region in mice causes them to respond like humans with the same deletion,” said Dr. P. Jeremy Wang, senior author on the study and professor in the Penn School of Veterinary Medicine’s Department of Animal Biology. “Now that we have a mouse model, we can dissect and try to genetically pinpoint which genes are responsible.” Dr. Wang co-led the study with his postdoctoral researcher Dr. Jian Zhou. Additional coauthors included Penn Vet’s Dr. N. Adrian Leu and CHOP’s Drs. Ethan Goldberg, Lei Zhou and Douglas Coulter. The study appears online on February 25, 2014 in the journal Human Molecular Genetics.

March 11th

Finding Hiding Place of Human Cytomegalovirus Could Lead to New Treatments

Discovering where a common virus hides in the body has been a long-term quest for scientists. Up to 80 percent of adults harbor the human cytomegalovirus (HCMV), which can cause severe illness and death in people with weakened immune systems. Now, researchers at Wake Forest Baptist Medical Center's Institute for Regenerative Medicine report that stem cells that encircle blood vessels can be a hiding place, suggesting a potential treatment target. In the American Journal of Transplantation (published online on March 4, 2011, ahead of print), senior scientist Graca Almeida-Porada, M.D., Ph.D., professor of regenerative medicine at Wake Forest Baptist, and colleagues report that perivascular stem cells, which are found in bone marrow and surround blood vessels in the body's organs, are a reservoir of HCMV. The virus, which is a member of the herpes family, is unnoticed in healthy people. Half to 80 percent of all adults in the U.S. are infected with HCMV, according to the Centers for Disease Control and Prevention. In people with weakened immune systems, including those with HIV, undergoing chemotherapy, or who are organ or bone marrow transplant recipients, the virus can become re-activated. Once re-activated, HCMV can cause a host of problems – from pneumonia to inflammation of the liver and brain – that are associated with organ rejection and death. "There are anti-viral medications designed to prevent HCMV from re-activating, but HVMC infection remains one of the major complications after both organ and bone marrow transplants," said Dr. Almeida-Porada.