c-ABL AND ARG DRIVE CANCER CHEMORESISTANCE VIA ACTIVATION OF MULTIPLE SIGNALING PATHWAYS

Despite 35 years of clinical trials, there has been little improvement in one-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma due to resistance to all known agents. Regardless of advances in detection and prevention, diagnosis of metastatic disease remains a death sentence. Resistance mechanisms, including aberrant kinase signaling and drug transport pumps, indicate a need for identification of other therapeutic targets that impinge upon multiple signaling pathways. The Abl family of non-receptor tyrosine kinases (c-Abl, Arg) has been indicted as a causative force in leukemia for more than three decades; however, their role in solid tumors has only recently been described. We first demonstrated that activated Abl family kinases promote breast cancer development and progression, and recently identified them to be novel therapeutic targets in metastatic melanoma cells by demonstrating that they promote proliferation, survival, invasion, and metastasis. We now present evidence that inhibitors of Abl family kinases abrogate resistance to a number of commonly used chemotherapeutics (i.e., 5-fluorouracil, cisplatin, paclitaxel, camptothecin) in a panel of breast cancer cells. We proceed to show that inhibitors of Abl family kinases, likewise, sensitize both breast cancer and melanoma cells to doxorubicin by blocking cell proliferation and dramatically inducing apoptosis. These findings were extended to advanced multi-drug resistant melanoma cells, in which we show for the first time that c- Abl promotes expression of the drug transporter, ABCB1, during acquired resistance, and drugs that inhibit c-Abl/Arg prevent ABCB1 expression and function. Moreover, c-Abl/Arg also promote acquired chemoresistance independent of ABCB1 by modulating multiple survival pathways. We demonstrate that c-Abl/Arg promote chemoresistance by upregulating STAT3, preventing doxorubicin-mediated conversion of NF-κB into a transcriptional repressor, activating an HSP27/p38/Akt survival pathway, and modulating ERK signaling. Therefore, c-Abl/Arg promote chemoresistance in highly resistant melanoma cells by impinging on drug transporter and cell survival pathways. Taken together, these data indicate that c-Abl/Arg inhibitors are likely to reverse acquired resistance in metastatic melanomas harboring activated c-Abl/Arg, and thus, may be effective in a combination regimen

Econometric Estimation of Groundwater Depth Change for the High Plains Aquifer

This article presents a new method for estimating changes in depth to groundwater at a yearly, county level and incorporates these estimates as the dependent variable of econometric models for the High Plains aquifer. The High Plains (Ogallala) aquifer underlies eight states in the central United States and is the primary source of irrigation water for this large food producing region. The stock of groundwater is a finite, non-renewable resource with minimal recharge in most areas. Many fields of study, including hydrology and agricultural economics, are interested in depth to groundwater changes because they serve as a proxy for estimating groundwater stock changes. Economic data exist at the yearly, county level, but there are currently no yearly estimates for depth to groundwater changes making it difficult to reliably utilize economic optimization and production models that depend on groundwater data. Including the new estimates generated in this study as the dependent variable with climate, recharge, and irrigation as independent variables in panel econometric models (Pooled OLS, Random Effects, and Fixed Effects) with counties as the individuals produced statistically significant results. Further, models were found which consistently performed best when comparing coefficients and predicted values with outside estimates from hydrology studies. Advisor: Lilyan E. Fulginit

Simplicity of algebras associated to \'etale groupoids

We prove that the C*-algebra of a second-countable, \'etale, amenable groupoid is simple if and only if the groupoid is topologically principal and minimal. We also show that if G has totally disconnected unit space, then the associated complex *-algebra introduced by Steinberg is simple if and only if the interior of the isotropy subgroupoid of G is equal to the unit space and G is minimal.Comment: The introduction has been updated and minor changes have been made throughout. To appear in Semigroup Foru

Going outside the system: Gödel and the “I-it” structure of experience

It has often been argued that Gödel’s first incompleteness theorem has major implications for our understanding of the human mind. Gödel himself hoped that the results of his theorem, combined with Turning’s work on computers and phenomenological analysis, would establish that the human mind contains an element totally different from a finite combinatorial mechanism. Decades of attempts to establish this by reasoning about Gödel’s theorem and Turing’s work are now widely taken to be unsuccessful. The present article, in accord with Gödel’s suggestion, adds extended phenomenological analysis to the discussion. It also focuses on the “going outside the system” step central to Gödel’s method of proof, rather than on the implications of the theorem itself. Analysis of the “I-it” intentional structure, held by phenomenology to underlie all ordinary experience, yields a simple model that (i) resolves long-standing conceptual problems associated with the “I-it”, the most basic structure of phenomenology, (ii) clarifies the “going outside” step crucial to Gödel’s method of proof, (iii) avoids conceptual problems associated with this step, (iv) identifies the step as an instance of a natural pre-mathematical operation of ordinary thought, and (v) suggests that the step itself is intrinsically non-algorithmic. Logical analysis of role of this step in Gödel’s proof then shows, independently of phenomenological considerations, that anything (human or not) that can prove Gödel’s theorem soundly by his method cannot be entirely algorithmic. Further implications for the nature of the mind are then suggested

A Bayesian approach to high fidelity interferometric calibration II: demonstration with simulated data

In a companion paper, we presented BayesCal, a mathematical formalism for mitigating sky-model incompleteness in interferometric calibration. In this paper, we demonstrate the use of BayesCal to calibrate the degenerate gain parameters of full-Stokes simulated observations with a HERA-like hexagonal close-packed redundant array, for three assumed levels of completeness of the a priori known component of the calibration sky model. We compare the BayesCal calibration solutions to those recovered by calibrating the degenerate gain parameters with only the a priori known component of the calibration sky model both with and without imposing physically motivated priors on the gain amplitude solutions and for two choices of baseline length range over which to calibrate. We find that BayesCal provides calibration solutions with up to four orders of magnitude lower power in spurious gain amplitude fluctuations than the calibration solutions derived for the same data set with the alternate approaches, and between $\sim10^7$ and $\sim10^{10}$ times smaller than in the mean degenerate gain amplitude on the full range of spectral scales accessible in the data. Additionally, we find that in the scenarios modelled only BayesCal has sufficiently high fidelity calibration solutions for unbiased recovery of the 21 cm power spectrum on large spectral scales ($k_\parallel \lesssim 0.15~h\mathrm{Mpc}^{-1}$). In all other cases, in the completeness regimes studied, those scales are contaminated

Virus detection and identification using random multiplex (RT)-PCR with 3'-locked random primers

<p>Abstract</p> <p>Background</p> <p>PCR-based detection and identification of viruses assumes a known, relatively stable genome. Unfortunately, high mutation rates may lead to extensive changes in viral nucleic acid sequences making dedicated PCR primer use problematic. Furthermore, in bioterrorism, viral consensus sequences can be genetically modified as a countermeasure to RT-PCR and DNA chip detection. Accordingly, there is a great need for the development of rapid and universal virus detection and identification technologies.</p> <p>Results</p> <p>We report herein that viral genomic DNA or RNA can be separated from host nucleic acids in plasma by filtration and nuclease digestion, and randomly amplified in a single PCR using a mixture of primers designed to be resistant to primer-dimer amplification (5'-VVVVVVVVAA-3', V = A, G or C; 3⁸or 6561 primers). We have termed this novel PCR method Random Multiplex (RT)-PCR since hundreds of overlapping PCR amplifications occur simultaneously. Using this method, we have successfullydetected and partially sequenced 3 separate viruses in human plasma without using virus-specific reagents (<it>i.e., </it>Adenovirus Type 17, Coxsackievirus A7, and Respiratory Syncytial Virus B). The method is sensitive to ~1000 genome equivalents/ml and may represent the fastest means of detection of unknown viruses.</p> <p>Conclusion</p> <p>These studies suggest that the further development of random multiplex (RT)-PCR may lead to a diagnostic assay that can universally detect viruses in donated blood products as well as in patients suffering with idiopathic disease states of possible viral etiology.</p

The Routledge Handbook of Global Development

This Handbook provides a comprehensive analysis of some of the world’s most pressing global development challenges – including how they may be better understood and addressed through innovative practices and approaches to learning and teaching. Featuring 61 contributions from leading and emerging academics and practitioners, this multidisciplinary volume is organized into five thematic parts exploring: changes in global development financing, ideologies, norms and partnerships; interrelationships between development, natural environments and inequality; shifts in critical development challenges, and; new possibilities for positive change. Collectively, the handbook demonstrates that global development challenges are becoming increasingly complex and multi-faceted and are to be found in the Global ‘North’ as much as the ‘South’. It draws attention to structural inequality and disadvantage alongside possibilities for positive change. The Handbook will serve as a valuable resource for students and scholars across multiple disciplines including Development Studies, Anthropology, Geography, Global Studies, Indigenous and Postcolonial Studies, Political Science, and Urban Studies