EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma

The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR

Maroon Archaeology Beyond the Americas: A View From Kenya

Archaeological research on Maroons—that is, runaway slaves—has been largely confined to the Americas. This essay advocates a more global approach. It specifically uses two runaway slave communities in 19th-century coastal Kenya to rethink prominent interpretive themes in the field, including “Africanisms,” Maroons’ connections to indigenous groups, and Maroon group cohesion and identity. This article’s analysis demonstrates that the comparisons enabled by a more globalized perspective benefit the field. Instead of eliding historical and cultural context, these comparisons support the development of more localized and historically specific understandings of individual runaway slave communities both in Kenya and throughout the New World

Influence of pump laser fluence on ultrafast structural changes in myoglobin

High-intensity femtosecond pulses from an X-ray free-electron laser enable pump probe experiments for investigating electronic and nuclear changes during light-induced reactions. On time scales ranging from femtoseconds to milliseconds and for a variety of biological systems, time-resolved serial femtosecond crystallography (TR-SFX) has provided detailed structural data for light-induced isomerization, breakage or formation of chemical bonds and electron transfer. However, all ultra-fast TR-SFX studies to date have employed such high pump laser energies that several photons were nominally absorbed per chromophore. As multiphoton absorption may force the protein response into nonphysiological pathways, it is of great concern whether this experimental approach allows valid inferences to be drawn vis-a-vis biologically relevant single-photon-induced reactions. Here we describe ultrafast pump-probe SFX experiments on photodissociation of carboxymyoglobin, showing that different pump laser fluences yield markedly different results. In particular, the dynamics of structural changes and observed indicators of the mechanistically important coherent oscillations of the Fe-CO bond distance (predicted by recent quantum wavepacket dynamics) are seen to depend strongly on pump laser energy. Our results confirm both the feasibility and necessity of performing TR-SFX pump probe experiments in the linear photoexcitation regime. We consider this to be a starting point for reassessing design and interpretation of ultrafast TR-SFX pump probe experiments such that biologically relevant insight emerges

Understanding uptake of continuous quality improvement in Indigenous primary health care: lessons from a multi-site case study of the Audit and Best Practice for Chronic Disease project

<p>Abstract</p> <p>Background</p> <p>Experimentation with continuous quality improvement (CQI) processes is well underway in Indigenous Australian primary health care. To date, little research into how health organizations take up, support, and embed these complex innovations is available on which services can draw to inform implementation. In this paper, we examine the practices and processes in the policy and organisational contexts, and aim to explore the ways in which they interact to support and/or hinder services' participation in a large scale Indigenous primary health care CQI program.</p> <p>Methods</p> <p>We took a theory-driven approach, drawing on literature on the theory and effectiveness of CQI systems and the Greenhalgh diffusion of innovation framework. Data included routinely collected regional and service profile data; uptake of tools and progress through the first CQI cycle, and data collected quarterly from hub coordinators on their perceptions of barriers and enablers. A total of 48 interviews were also conducted with key people involved in the development, dissemination, and implementation of the Audit and Best Practice for Chronic Disease (ABCD) project. We compiled the various data, conducted thematic analyses, and developed an in-depth narrative account of the processes of uptake and diffusion into services.</p> <p>Results</p> <p>Uptake of CQI was a complex and messy process that happened in fits and starts, was often characterised by conflicts and tensions, and was iterative, reactive, and transformational. Despite initial enthusiasm, the mixed successes during the first cycle were associated with the interaction of features of the environment, the service, the quality improvement process, and the stakeholders, which operated to produce a set of circumstances that either inhibited or enabled the process of change. Organisations had different levels of capacity to mobilize resources that could shift the balance toward supporting implementation. Different forms of leadership and organisational linkages were critical to success. The Greenhalgh framework provided a useful starting point for investigation, but we believe it is more a descriptive than explanatory model. As such, it has limitations in the extent to which it could assist us in understanding the interactions of the practices and processes that we observed at different levels of the system.</p> <p>Summary</p> <p>Taking up CQI involved engaging multiple stakeholders in new relationships that could support services to construct shared meaning and purpose, operationalise key concepts and tools, and develop and embed new practices into services systems and routines. Promoting quality improvement requires a system approach and organization-wide commitment. At the organization level, a formal high-level mandate, leadership at all levels, and resources to support implementation are needed. At the broader system level, governance arrangements that can fulfil a number of policy objectives related to articulating the linkages between CQI and other aspects of the regulatory, financing, and performance frameworks within the health system would help define a role and vision for quality improvement.</p

Cryo-Electron Tomography of Marburg Virus Particles and Their Morphogenesis within Infected Cells

Ultrastructural analysis of a filovirus assembling within infected eukaryotic cells reveals differences in structure and assembly mechanisms between related RNA viruses

The ineffectiveness of entrepreneurship policy:Is policy formulation to blame?

Entrepreneurship policy has been criticised for its lack of effectiveness. Some scholars, such as Scott Shane in this journal, have argued that it is ‘bad’ public policy. But this simply begs the question why the legislative process should generate bad policy? To answer this question this study examines the UK’s enterprise policy process in the 2009–2010 period. It suggests that a key factor for the ineffectiveness of policy is how it is formulated. This stage in the policy process is seldom visible to those outside of government departments and has been largely ignored by prior research. The application of institutional theory provides a detailed theoretical understanding of the actors and the process by which enterprise policy is formulated. We find that by opening up the ‘black box’ of enterprise policy formulation, the process is dominated by powerful actors who govern the process with their interests

Activation of cGMP-Dependent Protein Kinase Stimulates Cardiac ATP-Sensitive Potassium Channels via a ROS/Calmodulin/CaMKII Signaling Cascade

) channels, an ion channel critical for stress adaptation in the heart; however, the underlying mechanism remains largely unknown. The present study was designed to address this issue. channels was confirmed in intact ventricular cardiomyocytes, which was ROS- and CaMKII-dependent. Kinetically, PKG appeared to stimulate these channels by destabilizing the longest closed state while stabilizing the long open state and facilitating opening transitions. channels and contribute to cardiac protection against ischemia-reperfusion injury

Studies of new Higgs boson interactions through nonresonant HH production in the b¯bγγ fnal state in pp collisions at √s = 13 TeV with the ATLAS detector

A search for nonresonant Higgs boson pair production in the b ¯bγγ fnal state is performed using 140 fb−1 of proton-proton collisions at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. This analysis supersedes and expands upon the previous nonresonant ATLAS results in this fnal state based on the same data sample. The analysis strategy is optimised to probe anomalous values not only of the Higgs (H) boson self-coupling modifer κλ but also of the quartic HHV V (V = W, Z) coupling modifer κ2V . No signifcant excess above the expected background from Standard Model processes is observed. An observed upper limit µHH &lt; 4.0 is set at 95% confdence level on the Higgs boson pair production cross-section normalised to its Standard Model prediction. The 95% confdence intervals for the coupling modifers are −1.4 &lt; κλ &lt; 6.9 and −0.5 &lt; κ2V &lt; 2.7, assuming all other Higgs boson couplings except the one under study are fxed to the Standard Model predictions. The results are interpreted in the Standard Model efective feld theory and Higgs efective feld theory frameworks in terms of constraints on the couplings of anomalous Higgs boson (self-)interactions