379 research outputs found
Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine
Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly solid tumours. This is due to a generally late-stage diagnosis of a primarily treatment-refractory disease. Several large-scale sequencing and mass spectrometry approaches have identified key drivers of this disease and in doing so highlighted the vast heterogeneity of lower frequency mutations that make clinical trials of targeted agents in unselected patients increasingly futile. There is a clear need for improved biomarkers to guide effective targeted therapies, with biomarker-driven clinical trials for personalised medicine becoming increasingly common in several cancers. Interestingly, many of the aberrant signalling pathways in PDAC rely on downstream signal transduction through the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, which has led to the development of several approaches to target these key regulators, primarily as combination therapies. The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker-driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway
Protecting habitats in low-intensity tropical farmland using carbon-based payments for ecosystem services
Tropical land-use change for agricultural expansion is the primary driver of global biodiversity decline. Efforts to stem this decline often focus on protecting pristine habitats or returning farmland to forest, yet such approaches fail to protect vulnerable taxa reliant on habitats within low-intensity farmland. We assess the economic viability of carbon-based payments for ecosystem services (PES) to protect farmland trees and fallowing in Ghana, which provide vital wintering sites for imperiled Afro-palearctic migrant birds and enhance landscape-level carbon storage. We estimate the carbon breakeven prices (BEPs) associated with alternative agricultural management scenarios that protect existing farmland trees. BEPs associated with tree protection on existing farmland were very low, ranging from US6.45 t−1 CO2. Extending and reintroducing fallow periods also carried competitive BEPs, US15.45 t−1 CO2, when combined with the protection of 50 trees per hectare. Accounting for leakage and economic uncertainty increased BEPs considerably, but scenarios protecting farmland trees and extending fallow periods remained below EU Emissions Trading Scheme prices. Protecting low-intensity farmland habitats and associated biodiversity is cost-effective under carbon-based PES. Implementation should be combined with efforts to close yield gaps, providing greater local food security and resilience
Three-dimensional organotypic matrices from alternative collagen sources as pre-clinical models for cell biology.
Organotypic co-cultures bridge the gap between standard two-dimensional culture and mouse models. Such assays increase the fidelity of pre-clinical studies, to better inform lead compound development and address the increasing attrition rates of lead compounds within the pharmaceutical industry, which are often a result of screening in less faithful two-dimensional models. Using large-scale acid-extraction techniques, we demonstrate a step-by-step process to isolate collagen I from commercially available animal byproducts. Using the well-established rat tail tendon collagen as a benchmark, we apply our novel kangaroo tail tendon collagen as an alternative collagen source for our screening-ready three-dimensional organotypic co-culture platform. Both collagen sources showed equal applicability for invasive, proliferative or survival assessment of well-established cancer models and clinically relevant patient-derived cancer cell lines. Additional readouts were also demonstrated when comparing these alternative collagen sources for stromal contributions to stiffness, organization and ultrastructure via atomic force microscopy, second harmonic generation imaging and scanning electron microscopy, among other vital biological readouts, where only minor differences were found between the preparations. Organotypic co-cultures represent an easy, affordable and scalable model to investigate drug responses within a physiologically relevant 3D platform
Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease- and drug-dependent dynamic regulation of cell-cell junctions in live tissue
E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and
quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining
E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during
disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53
or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments
Atmospheric Heating and Wind Acceleration: Results for Cool Evolved Stars based on Proposed Processes
A chromosphere is a universal attribute of stars of spectral type later than
~F5. Evolved (K and M) giants and supergiants (including the zeta Aurigae
binaries) show extended and highly turbulent chromospheres, which develop into
slow massive winds. The associated continuous mass loss has a significant
impact on stellar evolution, and thence on the chemical evolution of galaxies.
Yet despite the fundamental importance of those winds in astrophysics, the
question of their origin(s) remains unsolved. What sources heat a chromosphere?
What is the role of the chromosphere in the formation of stellar winds? This
chapter provides a review of the observational requirements and theoretical
approaches for modeling chromospheric heating and the acceleration of winds in
single cool, evolved stars and in eclipsing binary stars, including physical
models that have recently been proposed. It describes the successes that have
been achieved so far by invoking acoustic and MHD waves to provide a physical
description of plasma heating and wind acceleration, and discusses the
challenges that still remain.Comment: 46 pages, 9 figures, 1 table; modified and unedited manuscript;
accepted version to appear in: Giants of Eclipse, eds. E. Griffin and T. Ake
(Berlin: Springer
Physics of Solar Prominences: I - Spectral Diagnostics and Non-LTE Modelling
This review paper outlines background information and covers recent advances
made via the analysis of spectra and images of prominence plasma and the
increased sophistication of non-LTE (ie when there is a departure from Local
Thermodynamic Equilibrium) radiative transfer models. We first describe the
spectral inversion techniques that have been used to infer the plasma
parameters important for the general properties of the prominence plasma in
both its cool core and the hotter prominence-corona transition region. We also
review studies devoted to the observation of bulk motions of the prominence
plasma and to the determination of prominence mass. However, a simple inversion
of spectroscopic data usually fails when the lines become optically thick at
certain wavelengths. Therefore, complex non-LTE models become necessary. We
thus present the basics of non-LTE radiative transfer theory and the associated
multi-level radiative transfer problems. The main results of one- and
two-dimensional models of the prominences and their fine-structures are
presented. We then discuss the energy balance in various prominence models.
Finally, we outline the outstanding observational and theoretical questions,
and the directions for future progress in our understanding of solar
prominences.Comment: 96 pages, 37 figures, Space Science Reviews. Some figures may have a
better resolution in the published version. New version reflects minor
changes brought after proof editin
Multiwavelength studies of MHD waves in the solar chromosphere: An overview of recent results
The chromosphere is a thin layer of the solar atmosphere that bridges the
relatively cool photosphere and the intensely heated transition region and
corona. Compressible and incompressible waves propagating through the
chromosphere can supply significant amounts of energy to the interface region
and corona. In recent years an abundance of high-resolution observations from
state-of-the-art facilities have provided new and exciting ways of
disentangling the characteristics of oscillatory phenomena propagating through
the dynamic chromosphere. Coupled with rapid advancements in
magnetohydrodynamic wave theory, we are now in an ideal position to thoroughly
investigate the role waves play in supplying energy to sustain chromospheric
and coronal heating. Here, we review the recent progress made in
characterising, categorising and interpreting oscillations manifesting in the
solar chromosphere, with an impetus placed on their intrinsic energetics.Comment: 48 pages, 25 figures, accepted into Space Science Review
Looking forward through the past: identification of 50 priority research questions in palaeoecology
1. Priority question exercises are becoming an increasingly common tool to frame future agendas in conservation and ecological science. They are an effective way to identify research foci that advance the field and that also have high policy and conservation relevance. 2. To date, there has been no coherent synthesis of key questions and priority research areas for palaeoecology, which combines biological, geochemical and molecular techniques in order to reconstruct past ecological and environmental systems on time-scales from decades to millions of years. 3. We adapted a well-established methodology to identify 50 priority research questions in palaeoecology. Using a set of criteria designed to identify realistic and achievable research goals, we selected questions from a pool submitted by the international palaeoecology research community and relevant policy practitioners. 4. The integration of online participation, both before and during the workshop, increased international engagement in question selection. 5. The questions selected are structured around six themes: human–environment interactions in the Anthropocene; biodiversity, conservation and novel ecosystems; biodiversity over long time-scales; ecosystem processes and biogeochemical cycling; comparing, combining and synthesizing information from multiple records; and new developments in palaeoecology. 6. Future opportunities in palaeoecology are related to improved incorporation of uncertainty into reconstructions, an enhanced understanding of ecological and evolutionary dynamics and processes and the continued application of long-term data for better-informed landscape management
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