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VanSchaeybroeck S.,Queens University of Belfast | Kalimutho M.,Queens University of Belfast | Dunne P.,Queens University of Belfast | Carson R.,Queens University of Belfast | And 13 more authors.
Cell Reports | Year: 2014

There are currently no approved targeted therapies for advanced KRAS mutant (KRASMT) colorectal cancer (CRC). Using a unique systems biology approach, we identified JAK1/2-dependent activation of STAT3 as the key mediator of resistance toMEK inhibitors in KRASMT CRC invitro and invivo.Further analyses identified acute increases in c-MET activity following treatment with MEK inhibitors in KRASMT CRC models, which was demonstrated to promote JAK1/2-STAT3-mediated resistance. Furthermore, activation of c-MET following MEK inhibition was found tobe due to inhibition of the ERK-dependent metalloprotease ADAM17, which normally inhibits c-MET signaling by promoting shedding of its endogenous antagonist, soluble "decoy" MET. Most importantly, pharmacological blockade of this resistance pathway with either c-MET or JAK1/2 inhibitors synergisticallyincreased MEK-inhibitor-induced apoptosis and growth inhibition invitro and invivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients. © 2014 The Authors. Source


Xenopoulos P.,Sloan Kettering Institute | Kang M.,Sloan Kettering Institute | Kang M.,Cornell University | Puliafito A.,Candiolo Cancer Institute FPO | And 2 more authors.
Cell Reports | Year: 2015

The pluripotent epiblast (EPI) is the founder tissue of almost all somatic cells. EPI and primitive endoderm (PrE) progenitors arise from the inner cell mass (ICM) of the blastocyst-stage embryo. The EPI lineage isdistinctly identified by its expression of pluripotency-associated factors. Many of these factors have been reported to exhibit dynamic fluctuations of expression in embryonic stem cell cultures. Whether these fluctuations correlating with ICM fate choice occur invivo remains an open question. Using single-cell resolution quantitative imaging of a Nanog transcriptional reporter, we noted an irreversible commitment to EPI/PrE lineages invivo. A period of apoptosis occurred concomitantly with ICM cell-fate choice, followed by a burst of EPI-specific cell proliferation. Transitions were occasionally observed from PrE-to-EPI, but not vice versa, suggesting that they might be regulated and not stochastic. We propose that the rapid timescale of early mammalian embryonic development prevents fluctuations in cell fate. © 2015 The Authors. Source


Fiori A.,Candiolo Cancer Institute FPO | Mignone A.,5T S.r.l. | Rospo G.,Candiolo Cancer Institute FPO
Information Sciences | Year: 2016

Automatic Vehicle Monitoring (AVM) systems are exploited by public transport companies to manage and control their fleet of vehicles. However, these systems are usually based on the background knowledge of the transport network which can change during the time and in some cases can be missing or erroneous. GPS data and other information captured by the vehicles during their work can be exploited to update the network knowledge. This paper presents a novel approach, namely DeCoClu (Density Consensus Clustering), that aims at mining the topology of a public transport network by means of a consensus clustering density-based approach. In particular, the method exploits static information from time series of positioning signals (i.e., GPS data) to infer geographical locations of stops by means of a consensus clustering strategy based on a new distance function. Moreover, the logical pathway of a route (i.e., stops sequence) is defined by an Hamiltonian cycle. Experiments performed on real-data collections provided by a public transport company demonstrate the effectiveness of the proposed approach. © 2015 Elsevier Inc. All rights reserved. Source


Siravegna G.,University of Turin | Siravegna G.,Candiolo Cancer Institute FPO | Bardelli A.,University of Turin | Bardelli A.,Candiolo Cancer Institute FPO | Bardelli A.,FIRC Institute of Molecular Oncology IFOM
Clinical Cancer Research | Year: 2014

A blood-based molecular test might direct recommendations for systemic therapies in patients with earlystage breast cancer undergoing surgery with curative intent. A new study suggests that droplet digital PCR (ddPCR) can be used to detect cancer-specific DNA alterations in plasma with sensitivity suitable for monitoring minimal residual disease. © 2014 American Association for Cancer Research. Source


Seano G.,University of Turin | Seano G.,Candiolo Cancer Institute FPO | Seano G.,Harvard University | Chiaverina G.,University of Turin | And 22 more authors.
Nature Cell Biology | Year: 2014

The mechanism by which angiogenic endothelial cells break the physical barrier of the vascular basement membrane and consequently sprout to form new vessels in mature tissues is unclear. Here, we show that the angiogenic endothelium is characterized by the presence of functional podosome rosettes. These extracellular-matrix-degrading and adhesive structures are precursors of de novo branching points and represent a key feature in the formation of new blood vessels. VEGF-A stimulation induces the formation of endothelial podosome rosettes by upregulating integrin α6 β1. In contrast, the binding of α6β1 integrin to the laminin of the vascular basement membrane impairs the formation of podosome rosettes by restricting α6β1 integrin to focal adhesions and hampering its translocation to podosomes. Using an ex vivo sprouting angiogenesis assay, transgenic and knockout mouse models and human tumour sample analysis, we provide evidence that endothelial podosome rosettes control blood vessel branching and are critical regulators of pathological angiogenesis. © 2014 Macmillan Publishers Limited. All rights reserved. Source

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