The phosphoinositide-3 kinase/Akt (PI3K/Akt) pathway has a central role in cancer cell metabolism and proliferation. More importantly, it is one of the cardinal pro-survival pathways mediating ...resistance to apoptosis. The role of Akt in response to an energetic stress is presently unclear. Here, we show that Sestrin2 (Sesn2), also known as Hi95, a p53 target gene that protects cells against oxidative and genotoxic stresses, participates in the protective role of Akt in response to an energetic stress induced by 2-deoxyglucose (2-DG). Sesn2 is upregulated in response to an energetic stress such as 2-DG and metformin, and mediates the inhibition of mammalian target of rapamycin (mTOR), the major cellular regulator of energy metabolism. The increase of Sesn2 is independent of p53 but requires the anti-apoptotic pathway, PI3K/Akt. Inhibition of Akt, as well as loss of Sesn2, sensitizes cells to 2-DG-induced apoptosis. In addition, the rescue of Sesn2 partially reverses the pro-apoptotic effects of 2-DG. In conclusion, we identify Sesn2 as a new energetic stress sensor, which appears to be protective against energetic stress-induced apoptosis that integrates the pro-survival function of Akt and the negative regulation of mTOR.
Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of ...FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.
Urbanization process is a major factor of change in the Mediterranean region where pre-urban cities and new urban settlements have raised over the past decades. Several cities rapidly became regional ...centres or international nodes according to economic and political pressures. Urbanization (and informal settlement) causes land cover changes which can lead to deeper social, economic and environmental changes. The main objective of this paper is to provide time-series information to define and locate the evolution trends of the Tunis Metropolitan Area. In a first step, satellite imagery has been used (1986–1996 SPOT XS) to extract the land cover, identify the urbanization processes and estimate the changes. One of the main aspects is to locate informal settlement areas that grow significantly along the roadway networks in the Tunisian capital. Results show a global progression of the built-up areas of 13% in 10 years. In a second step, the urban growth evolution has been approached by using a potential model that provides general trends of feasible urban expansion, taking into account protection laws of natural and agricultural land. This type of model has not been tested on developing cities and as such it corresponds to a new planning contribution for planners who have no concept of spatially how their urban areas have changed over time and where the growth is occurring. In this case, it has been calibrated over the period of 1986–1996, and then applied to predict the location of the built-up growth over the next 10 years (1996–2006). These results can provide local authorities and other stakeholders with information towards decision support documents for future planning and monitoring plans. Moreover, they can be updated systematically through the integration of remote sensing data.
The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore ...representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.
This paper presents MultiSenGE that is a new large scale multimodal and multitemporal benchmark dataset covering one of the biggest administrative region located in the Eastern part of France. ...MultiSenGE contains 8,157 patches of 256 × 256 pixels for the Sentinel-2 L2A , Sentinel-1 GRD images in VV-VH polarization and a Regional large scale Land Use/Land Cover (LULC) topographic reference database. With MultiSenGE, we contribute to the recents developments towards shared data use and machine learning methods in the field of environmental science. The purpose of this dataset is to propose relevant and easy-access dataset to explore deep learning methods. We use MultiSenGE to evaluate the performance for urban areas using well-known deep learning techniques. These results serve as a baseline for future research on remote sensing applications using the multi-temporal and multimodal aspects of MultiSenGE. With all patches georeferenced at a 10 meters spatial resolution covering the whole Grand-Est Region, MultiSenGE provides an opportunity for environmental benchmark dataset will help to advance data-driven techniques for land use/land cover remote sensing applications.
► Classification of very high resolution images driven by domain knowledge. ► Knowledge is represented as a hierarchy of concepts to find in the images. ► A matching process between the regions and ...the concepts of the knowledge base is used.
The increasing availability of High Spatial Resolution (HSR) satellite images is an opportunity to characterize and identify urban objects. Thus, the augmentation of the precision led to a need of new image analysis methods using region-based (or object-based) approaches. In this field, an important challenge is the use of domain knowledge for automatic urban objects identification, and a major issue is the formalization and exploitation of this knowledge. In this paper, we present the building steps of a knowledge-base of urban objects allowing to perform the interpretation of HSR images in order to help urban planners to automatically map the territory. The knowledge-base is used to assign segmented regions (i.e. extracted from the images) into semantic objects (i.e. concepts of the knowledge-base). A matching process between the regions and the concepts of the knowledge-base is proposed, allowing to bridge the semantic gap between the images content and the interpretation. The method is validated on Quickbird images of the urban areas of Strasbourg and Marseille (France). The results highlight the capacity of the method to automatically identify urban objects using the domain knowledge.
Abstract
Temporary Surface Water (TSW) is defined as waterbody experiencing frequent drying phases (small ponds, puddles, and wetlands) or correspond to surfaces frequently affected by flooding, thus ...causing hazards to human, settlements, and infrastructures. The Zorn is one of main river in Grand-Est, France which overwhelmed by strong precipitations from the Storm Eleanor (Cyclone Burglind). It caused inundation in Zorn surrounding areas. On 23 January 2018, data reported that floods occurred in Zorn watershed near to the municipalities of Brumath, Hoerdt and Hochfelden. Zorn River lies in the Moselle and Bas-Rhin departments with 580 km of linear streams. Historically, floods are frequently occurred in the Zorn watershed area. The municipalities of Eschbourg, Brumath and Dossenheim-sur-Zinsel are the most affected floods areas. Synthetic Aperture Radar (SAR) is an effective way to detect surface water over large areas. Sentinel-1 is a new available SAR, and its spatial resolution and short temporal baselines have the potential for surface water rapid mapping. Thus, the objective is to perform rapid mapping to produce flood map around the catchment of the Zorn River (next to Brumath).
Metformin is the most widely used antidiabetic drug because of its proven efficacy and limited secondary effects. Interestingly, recent studies have reported that metformin can block the growth of ...different tumor types. Here, we show that metformin exerts antiproliferative effects on melanoma cells, whereas normal human melanocytes are resistant to these metformin-induced effects. To better understand the basis of this antiproliferative effect of metformin in melanoma, we characterized the sequence of events underlying metformin action. We showed that 24 h metformin treatment induced a cell cycle arrest in G0/G1 phases, while after 72 h, melanoma cells underwent autophagy as demonstrated by electron microscopy, immunochemistry, and by quantification of the autolysosome-associated LC3 and Beclin1 proteins. In addition, 96 h post metformin treatment we observed robust apoptosis of melanoma cells. Interestingly, inhibition of autophagy by knocking down LC3 or ATG5 decreased the extent of apoptosis, and suppressed the antiproliferative effect of metformin on melanoma cells, suggesting that apoptosis is a consequence of autophagy. The relevance of these observations were confirmed in vivo, as we showed that metformin treatment impaired the melanoma tumor growth in mice, and induced autophagy and apoptosis markers. Taken together, our data suggest that metformin has an important impact on melanoma growth, and may therefore be beneficial in patients with melanoma.
Aberrant expression of Secreted Protein Acidic and Rich in Cysteine (SPARC)/osteonectin has been associated with an invasive tumor cell phenotype and poor outcome in human melanomas. Although it is ...known that SPARC controls melanoma tumorigenesis, the precise role of SPARC in melanoma cell survival is still unclear. Here, we show that SPARC has a cell-autonomous survival activity, which requires Akt-dependent regulation of p53. Suppression of SPARC by RNA interference in several human melanoma cells and xenografted A375 tumors triggers apoptotic cell death through the mitochondrial intrinsic pathway and activation of caspase-3. Cell death induced by depletion of SPARC is dependent on p53 and induction of Bax, and results in the generation of ROS. Stabilization of p53 in SPARC-depleted cells is associated with a decrease in Akt-mediated activating phosphorylation of MDM2. Inhibition of Akt signaling pathway is important for the observed changes as overexpression of constitutively active Akt protects cells against apoptosis induced by SPARC depletion. Conversely, increased expression of SPARC stimulates Akt and MDM2 phosphorylation, thus facilitating p53 degradation. Finally, we show that overexpression of SPARC renders cells more resistant to the p53-mediated cytotoxic effects of the DNA-damaging drug actinomycin-D. Our study indicates that SPARC functions through activation of Akt and MDM2 to limit p53 levels and that acquired expression of SPARC during melanoma development would confer survival advantages through suppression of p53-dependent apoptotic pathways.
Spleen tyrosine kinase (SYK) was recently identified as a new target in acute myeloid leukemia (AML); however, its mechanistic role in this disease is poorly understood. Based on the known ...interaction between SYK and mammalian target of rapamycin (mTOR) signaling in lymphoma, we hypothesized that SYK may regulate mTOR signaling in AML. Both small-molecule inhibition of SYK and SYK-directed shRNA suppressed mTOR and its downstream signaling effectors, as well as its upstream activator, AKT. Moreover, the inhibition of multiple nodes of the phosphatidylinositol 3'-kinase (PI3K) signaling pathway enhanced the effects of SYK suppression on AML cell viability and differentiation. Evaluation of the collateral mitogen-activated protein kinase (MAPK) pathway revealed a heterogeneous response to SYK inhibition in AML with downregulation of MEK and extracellular signal-regulated kinase (ERK) phosphorylation in some AML cell lines but a paradoxical increase in MEK/ERK phosphorylation in RAS-mutated AML. These studies reveal SYK as a regulator of mTOR and MAPK signaling in AML and demonstrate that inhibition of PI3K pathway activity enhances the effects of SYK inhibition on AML cell viability and differentiation.
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