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Archive - Mar 12, 2014

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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.