Zhang D.,University of Kansas Medical Center |
O'Neil M.F.,University of Kansas Medical Center |
Cunningham M.T.,University of Kansas Medical Center |
Fan F.,University of Kansas Medical Center |
And 2 more authors.
Leukemia and Lymphoma | Year: 2010
The variable natural history of mucosa-associated lymphoid tissue (MALT) lymphoma poses a challenge in predicting clinical outcome. Since Wnt signaling, as indicated by nuclear localization of β-catenin, is believed to be key in stem cell activation and stem cell self-renewal, we explored the possibility that it might have a predictive value in marginal zone lymphoma. We chose to analyze pβ-catenin-S552 because its nuclear localization by immunohistochemistry appears to coincide with Wnt signaling-initiated tumorigenesis in intestinal and hematopoietic tissues. Wnt signaling and activation was studied in 22 tissue samples of extranodal marginal zone lymphoma, atypical lymphoid hyperplasia, reactive lymphoid hyperplasia, and normal lymphoid tissue to determine whether Wnt signaling could help distinguish MALT lymphoma from benign lesions. Compared to normal or reactive lymphoid tissue, we found increased nuclear expression of localized pβ-catenin-S552 in atypical lymphoid hyperplasia and extranodal marginal zone lymphoma. We show that the anti-pβ-catenin-S552 antibody may be useful in diagnosing and monitoring the progression of or response to therapy of MALT lymphoma. © 2010 Informa Healthcare USA, Inc. Source
Lu R.,Rush University |
Wu S.,Rush University |
Zhang Y.-G.,Rush University |
Xia Y.,University of Rochester |
And 9 more authors.
Oncogenesis | Year: 2014
Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA-strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of β-catenin signaling in cancer. © 2014 Macmillan Publishers Limited. Source
Oelz D.B.,Courant Institute of Mathematical Sciences |
Rubinstein B.Y.,Stowers Institute |
Mogilner A.,Courant Institute of Mathematical Sciences |
Mogilner A.,New York University
Biophysical Journal | Year: 2015
We investigate computationally the self-organization and contraction of an initially random actomyosin ring. In the framework of a detailed physical model for a ring of cross-linked actin filaments and myosin-II clusters, we derive the force balance equations and solve them numerically. We find that to contract, actin filaments have to treadmill and to be sufficiently cross linked, and myosin has to be processive. The simulations reveal how contraction scales with mechanochemical parameters. For example, they show that the ring made of longer filaments generates greater force but contracts slower. The model predicts that the ring contracts with a constant rate proportional to the initial ring radius if either myosin is released from the ring during contraction and actin filaments shorten, or if myosin is retained in the ring, while the actin filament number decreases. We demonstrate that a balance of actin nucleation and compression-dependent disassembly can also sustain contraction. Finally, the model demonstrates that with time pattern formation takes place in the ring, worsening the contractile process. The more random the actin dynamics are, the higher the contractility will be. © 2015 Biophysical Society. Source
For the first time, researchers at the Stowers Institute have mapped where recombination occurs across the whole genome of the fruit fly Drosophila melanogaster after a single round of meiosis. Their results indicate that separate mechanisms position the two main kinds of recombination events, crossovers and non-crossovers. The findings, which are reported online ahead of print in the journal Genetics, give important insights into the understanding of chromosomes and the mechanisms of inheritance. "It is amazing to me that more than 100 years after the discovery of genetic recombination in flies, we are only starting to understand just how these events are distributed," says R. Scott Hawley, Ph.D., an investigator at the Stowers Institute and senior author of the study. This genetic recombination takes place during a specialized form of cell division called meiosis. During meiosis, the cell copies all its chromosomes, pairs them up, and shuffles sections of genetic material between the arms of the paired or homologous chromosomes. This shuffling can occur one of two ways. In crossover events, large tracts of DNA are exchanged, like two people swapping playing cards. In non-crossover events, smaller pieces of DNA are copied from one arm and pasted onto another, like the crown from the King of Hearts in one player's hand suddenly appearing atop another player's King of Spades. Once the deck is sufficiently shuffled, the cell divides, and then divides again to create four cells, each carrying only one copy of the organism's genome. Recombination ensures that each gamete ends up with a unique copy of every chromosome, but when the process goes awry, it can result in chromosomal abnormalities. For example, improperly placed crossovers or the complete lack of crossovers on chromosome 21 are a major cause of trisomy 21 or Down Syndrome in humans. With one exception, all previous genetic studies of recombination in Drosophila have focused either on a single chromosome arm or on groups of flies pooled together. In this study, the Stowers researchers wanted to determine how both crossovers and non-crossovers are distributed across all five major chromosomal arms of fruit flies. Crossovers are relatively easy to identify because they involve entire chromosomal arms or parts of arms encompassing thousands of base pairs, the A's, C's, T's, and G's that make up DNA. But non-crossovers are tougher to spot, because they only involve a few hundred of those letters. Therefore, Danny Miller, an MD-PhD student at the University of Kansas Medical Center who is conducting his doctoral research in the Hawley lab, had to rely on whole genome sequencing and new computer algorithms to pinpoint the locations of both kinds of events. Miller, lead author of the study, says the project gave him the opportunity to delve into the genetic principles that underlie human health and disease. "I would like to keep doing research as a physician-scientist when I graduate," says Miller, who plans to pursue a specialty in pediatric oncology or pediatric medical genetics. "I want to have a good foundational understanding of genetics. Some people may gloss over these basic questions, instead of looking at the data and trying to answer them." In this study alone, Miller generated a vast amount of data. First, he mated two genetically distinct varieties of fruit flies, known to differ at roughly 500,000 different spots in their genetic code. Miller then sequenced the entire genomes of the resulting 196 progeny and wrote a custom computer program that could scan the 160 million bases of each fruit fly genome for evidence of recombination. The approach identified a total of 541 crossovers and 291 non-crossovers. Unlike crossovers, which are generally distributed over the distal two-thirds of the chromosome arms, the non-crossovers were spread uniformly among the five major chromosome arms. Non-crossovers formed in places where crossovers rarely do, such as near the knotty centromere that ties the arms of chromosomes together. And they popped up close together, in contrast to crossovers that respond to a phenomenon known as interference when they try to form near other crossovers. The researchers discovered that the number of crossovers varied widely not just according to their position along the chromosome arm, but also from chromosome to chromosome. For example, they identified five double crossovers on one arm of chromosome 2—fewer than expected. "The finding gives credence to a certain kind of lore that has circulated in the field—the idea that each of the chromosomal arms was behaving a little differently—but nobody really knew for sure because nobody had looked at each of the arms in the same experiment," says Hawley. "What we found was that each chromosome has its own rules for making sure it gets its crossovers exactly where it wants them." In addition to crossovers and non-crossovers, the researchers also noticed evidence of duplications and deletions caused by the presence of transposons, a special class of genetic elements that can jump from one area in the genome to another. These transposable elements are a serious problem for the meiotic machinery because they can skew the pairing of homologous chromosomes, triggering duplications or deletions of genetic material that affect the viability of an organism. The study identified transposable elements in 1-2 percent of the genome, in line with previous reports.
Martens L.,VIB |
Martens L.,Ghent University |
Chambers M.,Vanderbilt University |
Sturm M.,University of Tubingen |
And 16 more authors.
Molecular and Cellular Proteomics | Year: 2011
Mass spectrometry is a fundamental tool for discovery and analysis in the life sciences. With the rapid advances in mass spectrometry technology and methods, it has become imperative to provide a standard output format for mass spectrometry data that will facilitate data sharing and analysis. Initially, the efforts to develop a standard format for mass spectrometry data resulted in multiple formats, each designed with a different underlying philosophy. To resolve the issues associated with having multiple formats, vendors, researchers, and software developers convened under the banner of the HUPO PSI to develop a single standard. The new data format incorporated many of the desirable technical attributes from the previous data formats, while adding a number of improvements, including features such as a controlled vocabulary with validation tools to ensure consistent usage of the format, improved support for selected reaction monitoring data, and immediately available implementations to facilitate rapid adoption by the community. The resulting standard data format, mzML, is a well tested open-source format for mass spectrometer output files that can be readily utilized by the community and easily adapted for incremental advances in mass spectrometry technology. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Source