263 research outputs found
Dissecting magnetar variability with Bayesian hierarchical models
Neutron stars are a prime laboratory for testing physical processes under
conditions of strong gravity, high density, and extreme magnetic fields. Among
the zoo of neutron star phenomena, magnetars stand out for their bursting
behaviour, ranging from extremely bright, rare giant flares to numerous, less
energetic recurrent bursts. The exact trigger and emission mechanisms for these
bursts are not known; favoured models involve either a crust fracture and
subsequent energy release into the magnetosphere, or explosive reconnection of
magnetic field lines. In the absence of a predictive model, understanding the
physical processes responsible for magnetar burst variability is difficult.
Here, we develop an empirical model that decomposes magnetar bursts into a
superposition of small spike-like features with a simple functional form, where
the number of model components is itself part of the inference problem. The
cascades of spikes that we model might be formed by avalanches of reconnection,
or crust rupture aftershocks. Using Markov Chain Monte Carlo (MCMC) sampling
augmented with reversible jumps between models with different numbers of
parameters, we characterise the posterior distributions of the model parameters
and the number of components per burst. We relate these model parameters to
physical quantities in the system, and show for the first time that the
variability within a burst does not conform to predictions from ideas of
self-organised criticality. We also examine how well the properties of the
spikes fit the predictions of simplified cascade models for the different
trigger mechanisms.Comment: accepted for publication in The Astrophysical Journal; code available
at https://bitbucket.org/dhuppenkothen/magnetron, data products at
http://figshare.com/articles/SGR_J1550_5418_magnetron_data/129242
MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models
Targeting the DNA damage response (DDR) in tumors with defective DNA repair
is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is
frequently deregulated in human cancers. In this study, we explored the effects of
MEK inhibition on the homologous recombination pathway and explored the potential
for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated
prodrug.
We studied effects of combining pimasertib, a selective allosteric inhibitor of
MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate
[ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug
evofosfamide in ovarian and pancreatic cancer cell lines. Apoptosis was assessed
by Caspase 3/7 assay and protein expression was detected by immunoblotting.
DNA damage response was monitored with γH2AX and RAD51 immunofluorescence
staining. In vivo antitumor activity of pimasertib with evofosfamide were assessed
in pancreatic cancer xenografts.
We found that BRCA2 protein expression was downregulated following pimasertib
treatment under hypoxic conditions. This translated into reduced homologous
recombination repair demonstrated by levels of RAD51 foci. MEK inhibition was
sufficient to induce formation of γH2AX foci, suggesting that inhibition of this pathway
would impair DNA repair. When combined with olaparib or evofosfamide, pimasertib
treatment enhanced DNA damage and increased apoptosis. The combination of
pimasertib with evofosfamide demonstrated increased anti-tumor activity in BRCA
wild-type Mia-PaCa-2 xenograft model, but not in the BRCA mutated BxPC3 model.
Our data suggest that targeted MEK inhibition leads to impaired homologous
recombination DNA damage repair and increased PARP inhibition sensitivity in BRCA-
2 proficient cancers
Optical emission spectroscopy of metal-halide lamps: Radially resolved atomic state distribution functions of Dy and Hg
Absolute line intensity measurements are performed on a metal-halide lamp. Several transitions of atomic and ionic Dy and atomic Hg are measured at different radial positions from which we obtain absolute atomic and ionic Dy intensity profiles. From these profiles we construct the radially resolved atomic state distribution function (ASDF) of the atomic and ionic Dy and the atomic Hg. From these ASDFs several quantities are determined as functions of radial position, such as the (excitation) temperature, the ion ratio Hg^+/Dy^+, the electron density, the ground state, and the totaldensity of Dy atoms and ions. Moreover, these ASDFs give us insight about the departure from equilibrium. The measurements show a hollow density profile for the atoms and the ionization of atoms in the center. In the outer parts of the lamp molecules dominate
Conjugated linoleic acid induces apoptosis through estrogen receptor alpha in human breast tissue
Dynamic Regulation of Tgf-B Signaling by Tif1γ: A Computational Approach
TIF1γ (Transcriptional Intermediary Factor 1 γ) has been implicated in
Smad-dependent signaling by Transforming Growth Factor beta (TGF-β).
Paradoxically, TIF1γ functions both as a transcriptional repressor or as an
alternative transcription factor that promotes TGF-β signaling. Using
ordinary differential-equation models, we have investigated the effect of
TIF1γ on the dynamics of TGF-β signaling. An integrative model that
includes the formation of transient TIF1γ-Smad2-Smad4 ternary complexes is
the only one that can account for TGF-β signaling compatible with the
different observations reported for TIF1γ. In addition, our model predicts
that varying TIF1γ/Smad4 ratios play a critical role in the modulation of
the transcriptional signal induced by TGF-β, especially for short
stimulation times that mediate higher threshold responses. Chromatin
immunoprecipitation analyses and quantification of the expression of TGF-β
target genes as a function TIF1γ/Smad4 ratios fully validate this
hypothesis. Our integrative model, which successfully unifies the seemingly
opposite roles of TIF1γ, also reveals how changing TIF1γ/Smad4 ratios
affect the cellular response to stimulation by TGF-β, accounting for a
highly graded determination of cell fate
Stimulation of MMP-11 (stromelysin-3) expression in mouse fibroblasts by cytokines, collagen and co-culture with human breast cancer cell lines
BACKGROUND: Matrix metalloproteinases (MMPs) are central to degradation of the extracellular matrix and basement membrane during both normal and carcinogenic tissue remodeling. MT1-MMP (MMP-14) and stromelysin-3 (MMP-11) are two members of the MMP family of proteolytic enzymes that have been specifically implicated in breast cancer progression. Expressed in stromal fibroblasts adjacent to epithelial tumour cells, the mechanism of MT1-MMP and MMP-11 induction remains unknown. METHODS: To investigate possible mechanisms of induction, we examined the effects of a number of plausible regulatory agents and treatments that may physiologically influence MMP expression during tumour progression. Thus NIH3T3 and primary mouse embryonic fibroblasts (MEFs) were: a) treated with the cytokines IL-1β, IL-2, IL-6, IL-8 and TGF-β for 3, 6, 12, 24, and 48 hours; b) grown on collagens I, IV and V; c) treated with fibronectin, con-A and matrigel; and d) co-cultured with a range of HBC (human breast cancer) cell lines of varied invasive and metastatic potential. RESULTS: Competitive quantitative RT-PCR indicated that MMP-11 expression was stimulated to a level greater than 100%, by 48 hour treatments of IL-1β, IL-2, TGF-β, fibronectin and collagen V. No other substantial changes in expression of MMP-11 or MT1-MMP in either tested fibroblast culture, under any treatment conditions, were observed. CONCLUSION: We have demonstrated significant MMP-11 stimulation in mouse fibroblasts using cytokines, matrix constituents and HBC cell lines, and also some inhibition of MT1-MMP. Our data suggest that the regulation of these genes in the complex stromal-epithelial interactions that occur in human breast carcinoma, is influenced by several mechanisms
NOX4-dependent ROS production by stromal mammary cells modulates epithelial MCF-7 cell migration
BACKGROUND: The influence of the stromal microenvironment on the progression of epithelial cancers has been demonstrated.
Unravelling the mechanisms by which stromal cells affect epithelial behaviour will contribute in understanding cellular malignancy.
It has been proposed that redox environment has a role in the acquisition of malignancy. In this work, we studied the influence
of epithelial cells on the stromal redox status and the consequence of this phenomenon on MCF-7 cell motility.
METHODS: We analysed in a co-culture system, the effect of RMF-EG mammary stromal cells on the migratory capacity of MCF-7 cell
line. To test whether the NOX-dependent stromal redox environment influences the epithelial migratory behaviour, we knocked
down the expression of NOX4 using siRNA strategy. The effect of TGF-b1 on NOX4 expression and activity was analysed by qPCR,
and intracellular ROS production was measured by a fluorescent method.
RESULTS: Migration of MCF-7 breast epithelial cells was stimulated when co-cultured with RMF-EG cells. This effect depends on
stromal NOX4 expression that, in turn, is enhanced by epithelial soluble factors. Pre-treatment of stromal cells with TGF-b1
enhanced this migratory stimulus by elevating NOX4 expression and intracellular ROS production. TGF-b1 seems to be a major
component of the epithelial soluble factors that stimulate NOX4 expression.
CONCLUSIONS: Our results have identified that an increased stromal oxidative status, mainly provided by an elevated NOX4
expression, is a permissive element in the acquisition of epithelial migratory properties. The capacity of stromal cells to modify their
intracellular ROS production, and accordingly, to increase epithelial motility, seems to depend on epithelial soluble factors among
which TGF-b1 have a decisive role.This work was supported by the grant (1080196 to JM) from the
Fondo Nacional de Ciencia y Tecnologı´a (FONDECYT) of Chile
Endosialin expression in relation to clinicopathological and biological variables in rectal cancers with a Swedish clinical trial of preoperative radiotherapy
<p>Abstract</p> <p>Background</p> <p>The importance of changes in tumour-associated stroma for tumour initiation and progression has been established. Endosialin is expressed in fibroblasts and pericytes of blood vessels in several types of tumours, and is involved in the progression of colorectal cancer. In order to see whether endosialin was related to radiotherapy (RT) response, and clinicopathological and biological variables, we investigated endosialin expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative RT.</p> <p>Methods</p> <p>Endosialin was immunohistochemically examined in normal mucosa, including distant (<it>n </it>= 72) and adjacent (<it>n </it>= 112) normal mucosa, and primary tumours (<it>n </it>= 135). Seventy-three of 135 patients received surgery alone and 62 received additional preoperative RT.</p> <p>Results</p> <p>Endosialin expression in the stroma increased from normal mucosa to tumour (<it>p </it>< 0.0001) both in RT and non-RT group. In the RT group, endosialin expression in the stroma was positively associated with expression of cyclooxygenase-2 (Cox-2) (<it>p </it>= 0.03), p73 (<it>p </it>= 0.01) and phosphates of regenerating liver (PRL) (<it>p </it>= 0.002). Endosialin expression in the tumour cells of both in the RT group (<it>p </it>= 0.01) and the non-RT group (<it>p </it>= 0.06) was observed more often in tumours with an infiltrative growth pattern than in tumours with an expansive growth pattern. In the RT group, endosialin expression in tumour cells was positively related to PRL expression (<it>p </it>= 0.02), whereas in the non-RT group, endosialin expression in tumour cells was positively related to p73 expression (<it>p </it>= 0.01).</p> <p>Conclusions</p> <p>Endosialin expression may be involved in the progression of rectal cancers, and was related to Cox-2, p73 and PRL expression. However, a direct relationship between endosialin expression and RT responses in patients was not found.</p
Human breast cancer stem cell markers CD44 and CD24: enriching for cells with functional properties in mice or in man?
Identification of breast cancer stem cells as the cells within breast tumors that have the ability to give rise to cells that make up the bulk of the tumor mass has shifted the focus of cancer research. However, there is still much debate concerning the unique nature of the markers that distinguish cancer stem cells in the breast. As such, understanding whether CD44+/CD24- breast cancer cells are merely more successful in overcoming an engraftment incompatibility that exists when injecting human cells into the mouse adipose tissue or are indeed bona fide cancer stem cells is of great importance
Sudden emergence of a Neisseria gonorrhoeae clade with reduced susceptibility to extended-spectrum cephalosporins, Norway
Neisseria gonorrhoeae multilocus sequence type (ST)-7827 emerged in a dramatic fashion in Norway in the period 2016–2018. Here, we aim to shed light on the provenance and expansion of this ST. ST-7827 was found to be polyphyletic, but the majority of members belonged to a monophyletic clade we termed PopPUNK cluster 7827 (PC-7827). In Norway, both PC-7827 and ST-7827 isolates were almost exclusively isolated from men. Phylogeographical analyses demonstrated an Asian origin of the genogroup, with multiple inferred exports to Europe and the USA. The genogroup was uniformly resistant to fluoroquinolones, and associated with reduced susceptibility to both azithromycin and the extended-spectrum cephalosporins (ESCs) cefixime and ceftriaxone. From a genetic background including the penA allele 13.001, associated with reduced ESC susceptibility, we identified repeated events of acquisition of porB alleles associated with further reduction in ceftriaxone susceptibility. Transmission of the strain was significantly reduced in Norway in 2019, but our results indicate the existence of a recently established global reservoir. The worrisome drug-resistance profile and rapid emergence of PC-7827 calls for close monitoring of the situation
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