Adjacent long non-coding RNA PVT1 and MYC co-operate in breast cancer with gain of 8q24

University of Minnesota Ph.D. dissertation. August 2013. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Anindya Bagchi. 1 computer file (PDF); viii, 107 pages, appendices A-B.Copy number gain of 8q24 is a common structural abnormality in human cancers. Although MYC is usually assumed to be responsible for 8q24 gain cancer, the role of the other genes in the 8q24 region remains mostly unknown. We derived chromosome engineered mice with an extra copy of Myc-Gsdmc region which is syntenic to the common region gained in human 8q24-associated cancer. These mice show aberrant differentiation and loss of proliferation arrest of mammary epithelial cells, excessive branching of mammary ducts, and increased sensitization to mammary tumors. In contrast, mice carrying a duplication of either Myc or Pvt1-Gsdmc were found to be insufficient for neoplasia. We show that the long non-coding RNA Pvt1 and adjacent Myc can co-operate in tumorigenesis. Furthermore, PVT1 can regulate MYC protein stability in human breast cancer cells. Our study reveals a novel mechanism of MYC regulation by a long non-coding RNA in cancer cells and could provide therapeutic targets

Patient-derived xenografts undergo murine-specific tumor evolution

Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of pre-existing minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Importantly, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have important implications for PDX-based modeling of human cancer

Bone Morphogenetic Protein Signaling: Implications in Urology

The bone morphogenetic proteins (BMPs), as members of the transforming growth factor-β (TGF-β) superfamily, not only control bone formation, but also regulate multiple key steps during embryonic development and differentiation. Furthermore, BMPs play critical roles in maintaining the homeostasis of the cardiovascular, pulmonary, reproductive, urogenital, and nervous systems in adult life. Like all members of the TGF-β superfamily, BMP signaling is mediated through a heteromeric complex of type I and type II transmembrane serine/threonine kinase receptors. The subsequent signal transduction cascade includes either the canonical Smad-dependent or non-canonical Smad-independent pathways. Reflecting the critical function of BMPs, BMP signaling is tightly regulated at multiple steps by various mechanisms including extracellular endogenous antagonists, neutralizing antibodies/extracellular soluble receptor domains, small molecule inhibitors, cytoplasmic inhibitory Smads, and transcriptional co-repressors. Recently, dorsomorphin, the first small molecule inhibitor of BMP signaling, was identified and suggested as a useful tool for dissecting the mechanisms of signaling pathways and for developing novel therapeutics for diverse human diseases that are related to the BMP signaling pathways. In this article, we discuss various mechanisms involved in regulating BMP signaling pathways and their implications for urology

Understanding of copolymers containing pyridine and selenophene simultaneously and their polarity conversion in transistors

By simultaneously considering the powerful electron-accepting capability of pyridine and the strong selenophene (Se)-Se interaction of selenophene, we present here the design and synthesis of both pyridine and selenophene-containing, pyridine-flanked diketopyrrolopyrrole and 4,7-di(selenophen-2-yl)-2,1,3-benzothiadiazole-based copolymers (P1 and P2) for use in organic field-effect transistors, where P1 has a shorter branched position of the side chains in relation to the backbone as compared to P2. The structure-property relationships associated with branching point engineering in the copolymers are established by applying a range of technical analyses. Overall, P1 interestingly exhibits both a higher hole and electron mobility of up to 1.2 cm(2) V-1 s(-1) and 0.21 cm(2) V-1 s(-1), respectively, which are over one order of magnitude higher than that of P2. This observation demonstrates the opposite view of the branching points away from the backbone for high-performing organic field-effect transistors. Besides, by doping sodium bicarbonate and molybdenum trioxide with electrodes, we succeeded in affecting the transition from ambipolarity of P1 to unipolar n- and p-type characteristics, respectively. These findings improve our understanding of both the role of branching point engineering in enhancing the carrier transport and the use of doping for switching the polarity of P1

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements