227 research outputs found
Inverse magnetocaloric effect in ferromagnetic Ni-Mn-Sn alloys
The magnetocaloric effect (MCE) in paramagnetic materials has been widely
used for attaining very low temperatures by applying a magnetic field
isothermally and removing it adiabatically. The effect can be exploited also
for room temperature refrigeration by using recently discovered giant MCE
materials. In this letter, we report on an inverse situation in Ni-Mn-Sn
alloys, whereby applying a magnetic field adiabatically, rather than removing
it, causes the sample to cool. This has been known to occur in some
intermetallic compounds, for which a moderate entropy increase can be induced
when a field is applied, thus giving rise to an inverse magnetocaloric effect.
However, the entropy change found for some ferromagnetic Ni-Mn-Sn alloys is
just as large as that reported for giant MCE materials, but with opposite sign.
The giant inverse MCE has its origin in a martensitic phase transformation that
modifies the magnetic exchange interactions due to the change in the lattice
parameters.Comment: 12 pages, 4 figures, to appear in Nature Materials (online published,
15 May 2005
Potency analysis of cellular therapies: the emerging role of molecular assays
Potency testing is an important part of the evaluation of cellular therapy products. Potency assays are quantitative measures of a product-specific biological activity that is linked to a relevant biological property and, ideally, a product's in vivo mechanism of action. Both in vivo and in vitro assays can be used for potency testing. Since there is often a limited period of time between the completion of production and the release from the laboratory for administration to the patient, in vitro assays such are flow cytometry, ELISA, and cytotoxicity are typically used. Better potency assays are needed to assess the complex and multiple functions of cellular therapy products, some of which are not well understood. Gene expression profiling using microarray technology has been widely and effectively used to assess changes of cells in response to stimuli and to classify cancers. Preliminary studies have shown that the expression of noncoding microRNA which play an important role in cellular development, differentiation, metabolism and signal transduction can distinguish different types of stem cells and leukocytes. Both gene and microRNA expression profiling have the potential to be important tools for testing the potency of cellular therapies. Potency testing, the complexities associated with potency testing of cellular therapies, and the potential role of gene and microRNA expression microarrays in potency testing of cellular therapies is discussed
Cancer stem cell markers in breast cancer: pathological, clinical and prognostic significance
INTRODUCTION: The cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. Hence, CSCs are potentially of profound clinical importance. We set out to establish the clinical relevance of breast CSC markers by profiling a large cohort of breast tumours in tissue microarrays (TMAs) using immunohistochemistry (IHC). METHODS: We included 4, 125 patients enrolled in the SEARCH population-based study with tumours represented in TMAs and classified into molecular subtype according to a validated IHC-based five-marker scheme. IHC was used to detect CD44/CD24, ALDH1A1, aldehyde dehydrogenase family 1 member A3 (ALDH1A3) and integrin alpha-6 (ITGA6). A 'Total CSC' score representing expression of all four CSC markers was also investigated. Association with breast cancer specific survival (BCSS) at 10 years was assessed using a Cox proportional-hazards model. This study was complied with REMARK criteria. RESULTS: In ER negative cases, multivariate analysis showed that ITGA6 was an independent prognostic factor with a time-dependent effect restricted to the first two years of follow-up (hazard ratio (HR) for 0 to 2 years follow-up, 2.4; 95% confidence interval (95% CI), 1.2 to 4.8; P = 0.009). The composite 'Total CSC' score carried independent prognostic significance in ER negative cases for the first four years of follow-up (HR for 0 to 4 years follow-up, 1.3; 95% CI, 1.1 to 1.6; P = 0.006). CONCLUSIONS: Breast CSC markers do not identify identical subpopulations in primary tumours. Both ITGA6 and a composite Total CSC score show independent prognostic significance in ER negative disease. The use of multiple markers to identify tumours enriched for CSCs has the greatest prognostic value. In the absence of more specific markers, we propose that the effective translation of the CSC hypothesis into patient benefit will necessitate the use of a panel of markers to robustly identify tumours enriched for CSCs
Cell-scale degradation of peritumoural extracellular matrix fibre network and its role within tissue-scale cancer invasion
Local cancer invasion of tissue is a complex, multiscale process which plays
an essential role in tumour progression. Occurring over many different temporal
and spatial scales, the first stage of invasion is the secretion of matrix
degrading enzymes (MDEs) by the cancer cells that consequently degrade the
surrounding extracellular matrix (ECM). This process is vital for creating
space in which the cancer cells can progress and it is driven by the activities
of specific matrix metalloproteinases (MMPs). In this paper, we consider the
key role of two MMPs by developing further the novel two-part multiscale model
introduced in [33] to better relate at micro-scale the two micro-scale
activities that were considered there, namely, the micro-dynamics concerning
the continuous rearrangement of the naturally oriented ECM fibres within the
bulk of the tumour and MDEs proteolytic micro-dynamics that take place in an
appropriate cell-scale neighbourhood of the tumour boundary. Focussing
primarily on the activities of the membrane-tethered MT1-MMP and the soluble
MMP-2 with the fibrous ECM phase, in this work we investigate the MT1-MMP/MMP-2
cascade and its overall effect on tumour progression. To that end, we will
propose a new multiscale modelling framework by considering the degradation of
the ECM fibres not only to take place at macro-scale in the bulk of the tumour
but also explicitly in the micro-scale neighbourhood of the tumour interface as
a consequence of the interactions with molecular fluxes of MDEs that exercise
their spatial dynamics at the invasive edge of the tumour
Stiffness Gradients Mimicking In Vivo Tissue Variation Regulate Mesenchymal Stem Cell Fate
Mesenchymal stem cell (MSC) differentiation is regulated in part by tissue stiffness, yet MSCs can often encounter stiffness gradients within tissues caused by pathological, e.g., myocardial infarction ∼8.7±1.5 kPa/mm, or normal tissue variation, e.g., myocardium ∼0.6±0.9 kPa/mm; since migration predominantly occurs through physiological rather than pathological gradients, it is not clear whether MSC differentiate or migrate first. MSCs cultured up to 21 days on a hydrogel containing a physiological gradient of 1.0±0.1 kPa/mm undergo directed migration, or durotaxis, up stiffness gradients rather than remain stationary. Temporal assessment of morphology and differentiation markers indicates that MSCs migrate to stiffer matrix and then differentiate into a more contractile myogenic phenotype. In those cells migrating from soft to stiff regions however, phenotype is not completely determined by the stiff hydrogel as some cells retain expression of a neural marker. These data may indicate that stiffness variation, not just stiffness alone, can be an important regulator of MSC behavior
The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system
Transforming growth factor-beta (TGF-beta) has opposing roles in breast cancer progression by acting as a tumor suppressor in the initial phase, but stimulating invasion and metastasis at later stages. In contrast to the mechanisms by which TGF-beta induces growth arrest, the pathways that mediate tumor invasion are not well understood. Here, we describe a TGF-beta-dependent invasion assay system consisting of spheroids of MCF10A1 normal breast epithelial cells (M1) and RAS-transformed (pre-)malignant derivatives (M2 and M4) embedded in collagen gels. Both basal and TGF-beta-induced invasion of these cell lines was found to correlate with their tumorigenic potential; M4 showing the most aggressive behavior and M1 showing the least. Basal invasion was strongly inhibited by the TGF-beta receptor kinase inhibitor SB-431542, indicating the involvement of autocrine TGF-beta or TGF-beta-like activity. TGF-beta-induced invasion in premalignant M2 and highly malignant M4 cells was also inhibited upon specific knockdown of Smad3 or Smad4. Interestingly, both a broad spectrum matrix metalloproteinase (MMP) inhibitor and a selective MMP2 and MMP9 inhibitor mitigated TGF-beta-induced invasion of M4 cells, while leaving basal invasion intact. In line with this, TGF-beta was found to strongly induce MMP2 and MMP9 expression in a Smad3- and Smad4-dependent manner. This collagen-embedded spheroid system therefore offers a valuable screening model for TGF-beta/Smad- and MMP2- and MMP9-dependent breast cancer invasion.Urolog
Self-assisted Amoeboid Navigation in Complex Environments
Background: Living cells of many types need to move in response to external
stimuli in order to accomplish their functional tasks; these tasks range from
wound healing to immune response to fertilization. While the directional motion
is typically dictated by an external signal, the actual motility is also
restricted by physical constraints, such as the presence of other cells and the
extracellular matrix. The ability to successfully navigate in the presence of
obstacles is not only essential for organisms, but might prove relevant in the
study of autonomous robotic motion.
Methodology/principal findings: We study a computational model of amoeboid
chemotactic navigation under differing conditions, from motion in an
obstacle-free environment to navigation between obstacles and finally to moving
in a maze. We use the maze as a simple stand-in for a motion task with severe
constraints, as might be expected in dense extracellular matrix. Whereas agents
using simple chemotaxis can successfully navigate around small obstacles, the
presence of large barriers can often lead to agent trapping. We further show
that employing a simple memory mechanism, namely secretion of a repulsive
chemical by the agent, helps the agent escape from such trapping.
Conclusions/significance: Our main conclusion is that cells employing simple
chemotactic strategies will often be unable to navigate through maze-like
geometries, but a simple chemical marker mechanism (which we refer to as
"self-assistance") significantly improves success rates. This realization
provides important insights into mechanisms that might be employed by real
cells migrating in complex environments as well as clues for the design of
robotic navigation strategies. The results can be extended to more complicated
multi-cellular systems and can be used in the study of mammalian cell migration
and cancer metastasis
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