1,555 research outputs found
Exchange-dependent relaxation in the rotating frame for slow and intermediate exchange - modeling off-resonant spin-lock and chemical exchange saturation transfer
Chemical exchange observed by NMR saturation transfer (CEST) and spin-lock
(SL) experiments provide an MRI contrast by indirect detection of exchanging
protons. The determination of the relative concentrations and exchange rates is
commonly achieved by numerical integration of the Bloch-McConnell equations. We
derive an analytical solution of the Bloch-McConnell equations that describes
the magnetization of coupled spin populations under radiofrequency
irradiation.As CEST and off-resonant SL are equivalent, their steady-state
magnetization and dynamics can be predicted by the same single eigenvalue: the
longitudinal relaxation rate in the rotating frame R1rho. For the case of
slowly exchanging systems, e.g. amide protons, the saturation of the small
proton pool is affected by transverse relaxation (R2b). It turns out, that R2b
is also significant for intermediate exchange, such as amine- or
hydroxyl-exchange or paramagnetic CEST agents, if pools are only partially
saturated. We propose a solution for R1rho that includes R2 of the exchanging
pool by extending existing approaches, and verify it by numerical simulations.
With the appropriate projection factors, we obtain an analytical solution for
CEST and SL for nonzero R2 of the exchanging pool, whilst considering the
dilution by direct water saturation across the entire Z-spectra. This allows
the optimization of irradiation parameters and the quantification of
pH-dependent exchange rates and metabolite concentrations. In addition, we
propose evaluation methods that correct for concomitant direct saturation
effects. It is shown that existing theoretical treatments for CEST are special
cases of this approach
Emerging role of egfr mutations in creating an immune suppressive tumour microenvironment
Several types of tumours overexpress the Epidermal Growth Factor Receptor (EGFR) in either wild type or mutated form. These tumours are often highly aggressive and difficult to treat. The underlying mechanisms for this phenomenon have remained largely unresolved, but recent publications suggest two independent mechanisms that may contribute. According to one line of research, tumours that overexpress the EGFR grow autonomously and become “addicted” to growth factor signalling. Inhibition of this signal using EGFR inhibitors can, therefore, induce cell death in tumour cells and lead to tumour shrinkage. The other line of research, as highlighted by recent findings, suggests that the overexpression, specifically of mutant forms of the EGFR, may create an immune-suppressive and lymphocyte depleted microenvironment within tumours. Such a lymphocyte depleted microenvironment may explain the resistance of EGFR overexpressing cancers to tumour therapies, particularly to check-point inhibitor treatments. In this article, we discuss the recent data which support an immune modulatory effect of EGFR signalling and compare these published studies with the most recent data from The Cancer Genome Atlas (TCGA), in this way, dissecting possible underlying mechanisms. We thereby focus our study on how EGFR overexpression may lead to the local activation of TGFβ, and hence to an immune suppressive environment. Consequently, we define a novel concept of how the mitogenic and immune modulatory effects of EGFR overexpression may contribute to tumour resistance to immunotherapy, and how EGFR specific inhibitors could be used best to enhance the efficacy of tumour therapy
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