Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43

Glioblastoma Multiforme (GBM) is an aggressive adult primary brain tumor with poor prognosis. GBM patients develop resistance to the frontline chemotherapy, temozolomide (TMZ). As the connexins (Cx) have been shown to have a complex role in GBM, we investigated the role of Cx43 in TMZ resistance. Cx43 was increased in the TMZ-resistant low passage and cell lines. This correlated with the data in The Cancer Genome Atlas. Cx43 knockdown, reporter gene assays, chromatin immunoprecipitation assay, real-time PCR and western blots verified a role for Cx43 in TMZ resistance. This occurred by TMZ-resistant GBM cells being able to activate epidermal growth factor receptor (EGFR). In turn, EGFR activated the JNK-ERK1/2-AP-1 axis to induce Cx43. The increased Cx43 was functional as indicated by gap junctional intercellular communication among the resistant GBM cells. Cell therapy could be a potential method to deliver drugs, such as anti-EGF to tumor cells. Similar strategies could be used to reverse the expression of Cx43 to sensitize GBM cells to TMZ. The studies showed the potential for targeting EGF in immune therapy. These agents can be used in conjunction with stem cell therapy to treat GBM

Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis

SummaryHerein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible “metastatic conditioning” in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments

Evolution of occupational asthma: Does cessation of exposure really improve prognosis?

SummaryAimTo assess the evolution of occupational asthma (OA) depending on whether the patient avoids or continues with exposure to the offending agent.MethodsStudy in patients diagnosed with OA using a specific inhalation challenge. Patients underwent the following examinations on the same day: clinical interview, physical examination, forced spirometry, methacholine test and determination of total IgE. Clinical improvement, deterioration or no change were defined according to the changes seen on the GINA severity scale at the time of diagnosis.ResultsOf the 73 patients finally included, 55 had totally ended exposure and 18 continued to be exposed at work. Clinical improvement was observed in 47% of those who had terminated exposure and in 22% of those who remained exposed; clinical deterioration was observed in 14% and 17% respectively (p = 0.805). Logistical regression analysis, including the type of agent and the persistence or avoidance of exposure among the variables, did not show any predictive factors of clinical evolution. Similarly, the changes in FEV1 and in bronchial hyperresponsiveness were not associated with the avoidance or continuation of exposure to the causative agent.ConclusionsAvoiding exposure to the causative agent in patients with OA does not seem to improve prognosis in this disease. Despite these findings, there is insufficient evidence to recommend a change in current management guidelines

Ianus: an Adpative FPGA Computer

Dedicated machines designed for specific computational algorithms can outperform conventional computers by several orders of magnitude. In this note we describe {\it Ianus}, a new generation FPGA based machine and its basic features: hardware integration and wide reprogrammability. Our goal is to build a machine that can fully exploit the performance potential of new generation FPGA devices. We also plan a software platform which simplifies its programming, in order to extend its intended range of application to a wide class of interesting and computationally demanding problems. The decision to develop a dedicated processor is a complex one, involving careful assessment of its performance lead, during its expected lifetime, over traditional computers, taking into account their performance increase, as predicted by Moore's law. We discuss this point in detail

Nature of the spin-glass phase at experimental length scales

We present a massive equilibrium simulation of the three-dimensional Ising spin glass at low temperatures. The Janus special-purpose computer has allowed us to equilibrate, using parallel tempering, L=32 lattices down to T=0.64 Tc. We demonstrate the relevance of equilibrium finite-size simulations to understand experimental non-equilibrium spin glasses in the thermodynamical limit by establishing a time-length dictionary. We conclude that non-equilibrium experiments performed on a time scale of one hour can be matched with equilibrium results on L=110 lattices. A detailed investigation of the probability distribution functions of the spin and link overlap, as well as of their correlation functions, shows that Replica Symmetry Breaking is the appropriate theoretical framework for the physically relevant length scales. Besides, we improve over existing methodologies to ensure equilibration in parallel tempering simulations.Comment: 48 pages, 19 postscript figures, 9 tables. Version accepted for publication in the Journal of Statistical Mechanic

The three dimensional Ising spin glass in an external magnetic field: the role of the silent majority

We perform equilibrium parallel-tempering simulations of the 3D Ising Edwards-Anderson spin glass in a field. A traditional analysis shows no signs of a phase transition. Yet, we encounter dramatic fluctuations in the behaviour of the model: Averages over all the data only describe the behaviour of a small fraction of it. Therefore we develop a new approach to study the equilibrium behaviour of the system, by classifying the measurements as a function of a conditioning variate. We propose a finite-size scaling analysis based on the probability distribution function of the conditioning variate, which may accelerate the convergence to the thermodynamic limit. In this way, we find a non-trivial spectrum of behaviours, where a part of the measurements behaves as the average, while the majority of them shows signs of scale invariance. As a result, we can estimate the temperature interval where the phase transition in a field ought to lie, if it exists. Although this would-be critical regime is unreachable with present resources, the numerical challenge is finally well posed.Comment: 42 pages, 19 figures. Minor changes and added figure (results unchanged

Thermodynamic glass transition in a spin glass without time-reversal symmetry

Spin glasses are a longstanding model for the sluggish dynamics that appears at the glass transition. However, spin glasses differ from structural glasses for a crucial feature: they enjoy a time reversal symmetry. This symmetry can be broken by applying an external magnetic field, but embarrassingly little is known about the critical behaviour of a spin glass in a field. In this context, the space dimension is crucial. Simulations are easier to interpret in a large number of dimensions, but one must work below the upper critical dimension (i.e., in d<6) in order for results to have relevance for experiments. Here we show conclusive evidence for the presence of a phase transition in a four-dimensional spin glass in a field. Two ingredients were crucial for this achievement: massive numerical simulations were carried out on the Janus special-purpose computer, and a new and powerful finite-size scaling method.Comment: 10 pages, 6 figure

Why is there no queer international theory?

Over the last decade, Queer Studies have become Global Queer Studies, generating significant insights into key international political processes. Yet, the transformation from Queer to Global Queer has left the discipline of International Relations largely unaffected, which begs the question: if Queer Studies has gone global, why has the discipline of International Relations not gone somewhat queer? Or, to put it in Martin Wight’s provocative terms, why is there no Queer International Theory? This article claims that the presumed non-existence of Queer International Theory is an effect of how the discipline of International Relations combines homologization, figuration, and gentrification to code various types of theory as failures in order to manage the conduct of international theorizing in all its forms. This means there are generalizable lessons to be drawn from how the discipline categorizes Queer International Theory out of existence to bring a specific understanding of International Relations into existence