Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with down-regulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties to immortalized human Schwann cells, and down-regulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small molecule inhibition of Wnt signaling effectively reduced viability of MPNST cell lines, and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors.
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that occur spontaneously, or from benign plexiform neurofibromas, in the context of the genetic disorder Neurofibromatosis Type 1 (NF1). The current standard treatment includes surgical resection, high-dose chemotherapy, and/or radiation. To date, most targeted therapies have failed to demonstrate effectiveness against plexiform neurofibromas and MPNSTs. Recently, several studies suggested that the mTOR and MAPK pathways are involved in the formation and progression of MPNSTs. Everolimus (RAD001) inhibits the mTOR and is currently FDA approved for several types of solid tumors. PD-0325901 (PD-901) inhibits MEK, a component of the MAPK pathway, and is currently in clinical trials. Here, we show in vitro than MPNST cell lines are more sensitive to inhibition of cellular growth by Everolimus and PD-901 than immortalized human Schwann cells. In combination, these drugs synergistically inhibit cell growth and induce apoptosis. In two genetically engineered mouse models of MPNST formation, modeling both sporadic and NF1-associated MPNSTs, Everolimus, or PD-901 treatment alone each transiently reduced tumor burden and size, and extended lifespan. However, prolonged treatment of each single agent resulted in the development of resistance and reactivation of target pathways. Combination therapy using Everolimus and PD-901 had synergistic effects on reducing tumor burden and size, and increased lifespan. Combination therapy allowed persistent and prolonged reduction in signaling through both pathways. These data suggest that co-targeting mTOR and MEK may be effective in patients with sporadic or NF1-associated MPNSTs.
Doxorubicin is a commonly used chemotherapeutic employed to treat multiple human cancers, including numerous sarcomas and carcinomas. Furthermore, doxorubicin possesses strong fluorescent properties that make it an ideal reagent for modeling drug delivery by examining its distribution in cells and tissues. However, while doxorubicin fluorescence and lifetime have been imaged in live tissue, its behavior in archival samples that frequently result from drug and treatment studies in human and animal patients, and murine models of human cancer, has to date been largely unexplored. Here, we demonstrate imaging of doxorubicin intensity and lifetimes in archival formalin-fixed paraffin-embedded sections from mouse models of human cancer with multiphoton excitation and multiphoton fluorescence lifetime imaging microscopy (FLIM). Multiphoton excitation imaging reveals robust doxorubicin emission in tissue sections and captures spatial heterogeneity in cells and tissues. However, quantifying the amount of doxorubicin signal in distinct cell compartments, particularly the nucleus, often remains challenging due to strong signals in multiple compartments. The addition of FLIM analysis to display the spatial distribution of excited state lifetimes clearly distinguishes between signals in distinct compartments such as the cell nuclei versus cytoplasm and allows for quantification of doxorubicin signal in each compartment. Furthermore, we observed a shift in lifetime values in the nuclei of transformed cells versus nontransformed cells, suggesting a possible diagnostic role for doxorubicin lifetime imaging to distinguish normal versus transformed cells. Thus, data here demonstrate that multiphoton FLIM is a highly sensitive platform for imaging doxorubicin distribution in normal and diseased archival tissues.
<p>Supplementary Table and Figure Legends-PDF file 123K, Supplementary Table and Figure Legends</p>
<p>Supplementary Figure 2 - PDF file 109K, Overexpression of activated β-catenin and knockdown of AXIN1 or GSK3B results in increased Wnt signaling and an induction of oncogenic properties in immortalized human Schwann cells</p>
Global warming is an established issue in society and, with grid computing systems continuously growing in power consumption levels, conserving energy is of utmost importance. Geographically extensive systems in particular are beginning to be in high demand and are given tasks which are computationally intensive and include large data sets. Grids allow the sharing of data and resources in dynamic, multi-institutional virtual organizations [1], and examples of grids can be found in medicine, physics, and astronomy. When jobs sent to these systems are able to access crucial data with ease, unnecessary work done by the system is avoided, and energy can be saved.
in their widely-read account of Material powers (2010, 21), with The matter of mimesis we seek 'to extend thinking beyond the familiar division between what is and is not "material"' . Ongoing debates in anthropology and the sociology of knowledge over 'assemblages' , 'actants' and 'quasi-objects' (hybrids of the social and the natural) are currently reshaping scholarly models of materiality in ways that challenge claims about material determinism. The implications of these discussions for other disciplines are still unfolding. Our volume has approached materiality from the vantage point of the replicated object, a fruitful and provocative instance that allows us to construct the complex relations between social and political agency, meaning, making and use for a variety of different cultures and circumstances. At the same time, we as scholars feel a need to be reflexively attentive to our own position, given the major transformations in techniques, media and technologies of replication such as 3D printing, cloning, and digital humanities that are in the process of reshaping not only our labour as scholars, but even its object; not only our source materials, but even our understanding of what counts as a source; not only our daily lives, but even our sense of self. Such was historically the case with new media. Benjamin's The work of art in the age of mechanical reproduction (1936), for example, famously grapples with the way that theories of artistic creativity based on appeals to subjectivity, genius and autonomy were challenged by the mechanical reproduction of works of art. Benjamin saw the value of a work of art as both reduced by reproduction and rendered subject to political interventions which altered its original meaning. Today, we face similar challenges, albeit posed by very different media, which present viewers with increasing difficulties in differentiating between reality and its many representations, as the essays of both Conte and Kromholz in this volume vividly illustrate. It is not infidelity in the act of representation that concerns us (as it did early moderns); rather, it is the ever-growing accuracy that new technologies afford that is problematic, for it seems to obliterate even the possibility of authenticity, originality and especially uniqueness. In
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