1,394 research outputs found
Oral tolerance to cancer can be abrogated by T regulatory cell inhibition
Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut
Observation of the Nernst signal generated by fluctuating Cooper pairs
Long-range order is destroyed in a superconductor warmed above its critical
temperature (Tc). However, amplitude fluctuations of the superconducting order
parameter survive and lead to a number of well established phenomena such as
paraconductivity : an excess of charge conductivity due to the presence of
short-lived Cooper pairs in the normal state. According to an untested theory,
these pairs generate a transverse thermoelectric (Nernst) signal. In amorphous
superconducting films, the lifetime of Cooper pairs exceeds the elastic
lifetime of quasi-particles in a wide temperature range above Tc; consequently,
the Cooper pairs Nernst signal dominate the response of the normal electrons
well above Tc. In two dimensions, the magnitude of the expected signal depends
only on universal constants and the superconducting coherence length, so the
theory can be unambiguously tested. Here, we report on the observation of a
Nernst signal in such a superconductor traced deep into the normal state. Since
the amplitude of this signal is in excellent agreement with the theoretical
prediction, the result provides the first unambiguous case for a Nernst effect
produced by short-lived Cooper pairs
The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma
The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care
A Bragg glass phase in the vortex lattice of a type II superconductor
Although crystals are usually quite stable, they are sensitive to a
disordered environment: even an infinitesimal amount of impurities can lead to
the destruction of the crystalline order. The resulting state of matter has
been a longstanding puzzle. Until recently it was believed to be an amorphous
state in which the crystal would break into crystallites. But a different
theory predicts the existence of a novel phase of matter: the so-called Bragg
glass, which is a glass and yet nearly as ordered as a perfect crystal. The
lattice of vortices that can contain magnetic flux in type II superconductors
provide a good system to investigate these ideas. Here we show that neutron
diffraction data of the vortex lattice in type II superconductors provides
unambiguous evidence for a weak, power-law decay of the crystalline order
characteristic of a Bragg glass. The theory also predicts accurately the
electrical transport properties of superconductors; it naturally explains the
observed phase transition and the dramatic jumps in the critical current
associated with the melting of the Bragg glass. Moreover the model explains
experiments as diverse as X-ray scattering in disordered liquid crystals and
conductivity of electronic crystals.Comment: 9 pages, 4 figure
Nonlinear Sigma Model for Disordered Media: Replica Trick for Non-Perturbative Results and Interactions
In these lectures, given at the NATO ASI at Windsor (2001), applications of
the replicas nonlinear sigma model to disordered systems are reviewed. A
particular attention is given to two sets of issues. First, obtaining
non-perturbative results in the replica limit is discussed, using as examples
(i) an oscillatory behaviour of the two-level correlation function and (ii)
long-tail asymptotes of different mesoscopic distributions. Second, a new
variant of the sigma model for interacting electrons in disordered normal and
superconducting systems is presented, with demonstrating how to reduce it,
under certain controlled approximations, to known ``phase-only'' actions,
including that of the ``dirty bosons'' model.Comment: 25 pages, Proceedings of the NATO ASI "Field Theory of Strongly
Correlated Fermions and Bosons in Low - Dimensional Disordered Systems",
Windsor, August, 2001; to be published by Kluwe
A compendium and functional characterization of mammalian genes involved in adaptation to Arctic or Antarctic environments
Many mammals are well adapted to surviving in extremely cold environments. These species have likely accumulated genetic changes that help them efficiently cope with low temperatures. It is not known whether the same genes related to cold adaptation in one species would be under selection in another species. The aims of this study therefore were: to create a compendium of mammalian genes related to adaptations to a low temperature environment; to identify genes related to cold tolerance that have been subjected to independent positive selection in several species; to determine promising candidate genes/pathways/organs for further empirical research on cold adaptation in mammals
The N-terminal intrinsically disordered domain of mgm101p is localized to the mitochondrial nucleoid.
The mitochondrial genome maintenance gene, MGM101, is essential for yeasts that depend on mitochondrial DNA replication. Previously, in Saccharomyces cerevisiae, it has been found that the carboxy-terminal two-thirds of Mgm101p has a functional core. Furthermore, there is a high level of amino acid sequence conservation in this region from widely diverse species. By contrast, the amino-terminal region, that is also essential for function, does not have recognizable conservation. Using a bioinformatic approach we find that the functional core from yeast and a corresponding region of Mgm101p from the coral Acropora millepora have an ordered structure, while the N-terminal domains of sequences from yeast and coral are predicted to be disordered. To examine whether ordered and disordered domains of Mgm101p have specific or general functions we made chimeric proteins from yeast and coral by swapping the two regions. We find, by an in vivo assay in S.cerevisiae, that the ordered domain of A.millepora can functionally replace the yeast core region but the disordered domain of the coral protein cannot substitute for its yeast counterpart. Mgm101p is found in the mitochondrial nucleoid along with enzymes and proteins involved in mtDNA replication. By attaching green fluorescent protein to the N-terminal disordered domain of yeast Mgm101p we find that GFP is still directed to the mitochondrial nucleoid where full-length Mgm101p-GFP is targeted
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