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Translational Medicine This strategy revealed that the combined detection of protein products of the HNF4α, TGFβ, and integrin networks could represent an early noninvasive marker to predict pancreatic adenocarcinoma progression. "After establishing this system in the animal model, we want, together with other investigators, to analyze how well some of these candidate markers can predict invasiveness in humans," Dr. Zaret says. This system also helps circumvent one of the major challenges hindering the study of cancer progression in humans, the heterogeneity of the lesions that are present upon diagnosis in patients. "But because we can use human cells that progress from early to invasive stages, we are in a position to longitudinally assess dynamic changes, and gain new insights into disease progression," he adds. maintain the same allelic replication pattern as they divide," Dr. Cedar says. Even though these cells also exhibit asynchronous replication, one of their distinguishing features is that the early- and latereplicating alleles alternate during successive generations. "This makes adult hematopoietic cells pluripotent in terms of their allelic choice," he explains. This phenomenon refects a new dimen- sion of stem cell plasticity. "Maternal or paternal alleles can be expressed until a certain point during stem cell development, until they make a decision, and after that this pattern becomes fxed and it cannot change any longer," Dr. Cedar continues. As these and many other advances illustrate, cellular reprogramming transcends interdisciplinary boundaries and is set to answer biological questions from areas that, historically, were not thought to be associated with stem cell biology or with development. Along with regenerative medicine, felds such as immunology, oncology, and chromatin biology also stand to beneft from advances in cellular reprogramming. While translating research fndings to clinical benefts still has to surpass signifcant hurdles, the prospect to reshape the therapeutic arena is witnessing a transformative era. Mirus 4G 54% Allelic Exclusion "Allelic exclusion has historically been a poorly understood topic," says Howard Cedar, M.D., Ph.D., professor of biochemistry and genetics at the Hebrew University of Jerusalem. Described in cells of the immune, olfactory, and other systems, allelic exclusion refers to the process of expressing only one allele of a gene, while the other one remains silent. The human immune system is able to generate an estimated 10 billion different types of antibodies, a recombinatorial diversity that is mostly controlled at the level of DNA rearrangements. "But every antibodyproducing cell ends up synthesizing only one type of antibody, even though the existence of two alleles makes it theoretically possible to produce a different type of antibody from each allele, so there is a paradox here," says Dr. Cedar. Allelic exclusion at the immunoglobulin locus, intensely debated over time, was initially thought to occur through a feedback process, in which rearrangements at one allele could signal to switch the other allele off. "It turns out that a different mechanism is in place," Dr. Cedar says. He and his colleagues have revealed, for the frst time, the possibility to identify the allele that will undergo rearrangements and become functional based on particular chromatin signatures that involve specifc histone acetylation and methylation patterns. "We can already identify the allele that is marked to be used for recombination, in a cell that does not even know yet that it will produce antibodies," he explains. Dr. Cedar and colleagues further observed that in the region encoding the immunoglobulin genes, one allele always replicates early during the cell cycle, while the other one replicates late, a phenomenon termed asynchronous replication. "It is always the early-replicating allele that will undergo rearrangement," Dr. Cedar says. In pre-B and B cells this phenomenon is clonal, meaning that the same replication pattern will be maintained for all the progeny of a cell and after subsequent cell divisions, as well. Not all cells exhibit this pattern, though. "Adult hematopoietic stem cells do not Transfection Manual Technology has advanced since the year 2000, have your transfections? NEW! Trans IT-X2™ Dynamic Delivery System Fast forward to 2013 and achieve superior transfections with an advanced non-liposomal, polymeric system that effciently delivers both DNA and RNA out of the endosome and into the cytoplasm, overcoming a critical barrier to nucleic acid delivery. The TransIT-X2™ Dynamic Delivery System gives researchers: X2 Efficiency–exceptional broad spectrum transfection X2 Versatility–cutting edge delivery of plasmid DNA and siRNA Functional Co-delivery of Plasmid DNA and siRNA. TransIT-X2™ Dynamic Delivery System was used to simultaneously transfect Cy™5-labeled plasmid DNA (blue) encoding nuclear YFP (yellow) and Cy™3-labeled siRNA (red) into HeLa cells. Actin cytoskeleton is stained green. X2 Technology–novel non-liposomal delivery Visit www.TheTransfectionExperts.com for full experimental details. www.TheTransfectionExperts.com ADVANCE YOUR TRANSFECTIONS. Request a FREE SAMPLE of TransIT-X2™ Dynamic Delivery System. Visit www.TheTransfectionExperts.com, call 888.530.0801 (U.S. only) or +1.608.441.2852 (outside the U.S.) Providing gene delivery expertise since 1995 ©2013 All rights reserved Mirus Bio LLC. TransIT-X2 is a trademark of Mirus Bio LLC. Genetic Engineering & Biotechnology News | GENengnews.com | September 1, 2013 | 47