The poor prognosis of pancreatic cancer is due to rapid locoregional invasion, the early development of metastases, and the limited efficacy of current therapies. To date, none of the identified ...oncogenes and suppressors involved in this disease have led to efficient treatments. Here, we describe that the scaffold protein ArgBP2 is repressed during oncogenic transformation of the pancreas. We could show, using a pancreatic cancer cell line model, that this repression of ArgBP2 participates in the progression of this disease. Interestingly, in vitro analyses revealed that the antitumoral potential of ArgBP2 is linked to the control of cell adhesion and migration rather than to the regulation of cell proliferation or sensitivity to apoptosis. Moreover, we could detail part of the molecular mechanism responsible by identifying new ArgBP2-interacting proteins, and show that this function is partly achieved by the control of a WAVE/PTP-PEST/c-Abl signaling complex. These findings point to a new mechanism of pancreatic cancer progression leading to invasion and metastasis and suggest that the ArgBP2 signaling pathway could represent a new target for cancer therapy.
Excessive alcohol consumption has long been known to be the primary cause of chronic pancreatitis (CP) but genetic risk factors have been increasingly identified over the past 25 years. The scale and ...scope of gene-alcohol interactions in CP nevertheless remain unclear.
All studies that had obtained genetic variant data concurrently on alcoholic CP (ACP) patients, non-ACP (NACP) patients and normal controls were collated. Employing normal controls as a common baseline, paired OR
and OR
(odds ratios associated with ACP and NACP, respectively) values were calculated and used to assess gene-alcohol interactions.
Thirteen variants involving
,
,
,
,
,
and
, and varying from very rare to common, were collated. Seven variants had an OR
> OR
, which was regarded as an immediate indicator of gene-alcohol interactions in CP. Variants with an OR
< OR
were also found to interact with alcohol consumption by virtue of their impact on age at first pancreatitis symptoms in ACP.
This study revealed evidence for extensive gene-alcohol interactions in CP. Our findings lend support to the hypothesis that alcohol affects the expression of genetically determined CP and highlight a predominant role of weak-effect variants in the development of ACP.
The deuterium excess of polar ice cores documents past changes in evaporation conditions and moisture origin. New data obtained from the European Project for Ice Coring in Antarctica Dome C East ...Antarctic ice core provide new insights on the sequence of events involved in Termination II, the the transition between the penultimate glacial and interglacial periods. This termination is marked by a north—south seesaw behavior, with first a slow methane concentration rise associated with a strong Antarctic temperature warming and a slow deuterium excess rise. This first step is followed by an abrupt north Atlantic warming, an abrupt resumption of the East Asian summer monsoon, a sharp methane rise, and a CO₂ overshoot, which coincide within dating uncertainties with the end of Antarctic optimum. Here, we show that this second phase is marked by a very sharp Dome C centennial deuterium excess rise, revealing abrupt reorganization of atmospheric circulation in the southern Indian Ocean sector.
The von Hippel-Lindau tumor suppressor protein (pVHL) has emerged as a key factor in cellular responses to oxygen availability, being required for the oxygen-dependent proteolysis of α subunits of ...hypoxia inducible factor-1 (HIF). Mutations in VHL cause a hereditary cancer syndrome associated with dysregulated angiogenesis, and up-regulation of hypoxia inducible genes. Here we investigate the mechanisms underlying these processes and show that extracts from VHL-deficient renal carcinoma cells have a defect in HIF-α ubiquitylation activity which is complemented by exogenous pVHL. This defect was specific for HIF-α among a range of substrates tested. Furthermore, HIF-α subunits were the only pVHL-associated proteasomal substrates identified by comparison of metabolically labeled anti-pVHL immunoprecipitates from proteosomally inhibited cells and normal cells. Analysis of pVHL/HIF-α interactions defined short sequences of conserved residues within the internal transactivation domains of HIF-α molecules sufficient for recognition by pVHL. In contrast, while full-length pVHL and the p19 variant interact with HIF-α, the association was abrogated by further N-terminal and C-terminal truncations. The interaction was also disrupted by tumor-associated mutations in the β-domain of pVHL and loss of interaction was associated with defective HIF-α ubiquitylation and regulation, defining a mechanism by which these mutations generate a constitutively hypoxic pattern of gene expression promoting angiogenesis. The findings indicate that pVHL regulates HIF-α proteolysis by acting as the recognition component of a ubiquitin ligase complex, and support a model in which its β domain interacts with short recognition sequences in HIF-α subunits.
Doppler mean gradient (MG) can underestimate aortic stenosis (AS) severity in patients with atrial fibrillation (AF) compared to patients in sinus rhythm (SR), potentially delaying intervention in ...AF. This study compared outcomes in patients with AF and SR following transcatheter aortic valve replacement (TAVR) and investigated delay in TAVR based on computed tomography aortic valve calcium score (AVCS).
Patients who underwent TAVR from 2013 to 2017 for native valve severe AS were identified from an institutional database. Baseline characteristics and overall survival were compared between those in SR and AF. There were 820 patients (mean age 81 years; 41.6% female) included. AF was present in 356 patients. Patients in AF were older (82.2 vs. 80.5, p = 0.003), had lower MG compared to SR patients (42.0 vs. 44.9, p = 0.002) with similar indexed aortic valve area (0.4 vs. 0.4, p = 0.17). Median AVCS was higher in AF (males: AF 2850.0 vs. SR 2561.0, p = 0.044; females: AF 1942.0 vs. SR 1610.5, p = 0.025). Projected AVCS assuming same age of diagnosis was similar between AF and SR. Median survival post-TAVR was worse in AF compared to SR (3.2 vs 5.4 years, log rank p < 0.001). AF, lower MG, higher RVSP, dialysis, diabetes, and significant TR were associated with higher mortality (p < 0.05 for all).
Older age and higher AVCS in patients with AF compared to SR suggests that AS was both underestimated and more advanced at TAVR referral.
Autism has been considered as a deficit in prediction of the upcoming event or of the sensory consequences of our own movements. To test this hypothesis, we recorded eye movements from ...high-functioning autistic adolescents and from age-matched controls during a blanking paradigm. In this paradigm, adolescents were instructed to follow a moving target with their eyes even during its transient disappearance. Given the absence of visual information during the blanking period, eye movements during this period are solely controlled on the basis of the prediction of the ongoing target motion. Typical markers of predictive eye movements such as the number and accuracy of predictive saccades and the predictive reacceleration before target reappearance were identical in the two populations. In addition, the synergy of predictive saccades and smooth pursuit observed during the blanking periods, which is a marker for the quality of internal models about target/eye motions, was comparable between these two populations. These results suggest that, in our large population of high-functioning autistic adolescent, both predictive abilities and internal models are left intact in Autism, at least for low-level sensorimotor transformations.
•We investigated predictive mechanisms during ocular tracking performance in ASD adolescents using a target motion blanking paradigm.•Anticipatory pursuit responses before target onset and target reappearance after a transient blanking are normal in ASD participants.•At target reappearance, saccades and pursuit are well coordinated in both groups.•Predictive mechanisms and internal models for oculomotor control are preserved in adolescents with Autism.
BRADSHAW: a system for automated molecular design Green, Darren V. S.; Pickett, Stephen; Luscombe, Chris ...
Journal of computer-aided molecular design,
07/2020, Volume:
34, Issue:
7
Journal Article
Peer reviewed
Open access
This paper introduces BRADSHAW (
B
iological
R
esponse
A
nalysis and
D
esign
S
ystem using an
H
eterogenous,
A
utomated
W
orkflow), a system for automated molecular design which integrates methods ...for chemical structure generation, experimental design, active learning and cheminformatics tools. The simple user interface is designed to facilitate access to large scale automated design whilst minimising software development required to introduce new algorithms, a critical requirement in what is a very fast moving field. The system embodies a philosophy of automation, best practice, experimental design and the use of both traditional cheminformatics and modern machine learning algorithms.
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