ABT-737 and/or folate reverse the PDGF-induced alterations in the mitochondrial apoptotic pathway in low-grade glioma patients

Elevated activation of the platelet-derived growth factor (PDGF) pathway, apoptosis evasion phenotype, and global DNA hypomethylation are hallmarks frequently observed in cancers, such as in low-grade glioma (LGG). However, the orchestration of these malignant functions is not fully elucidated in LGG. Our study reveals that the co-presence of these hallmarks in the same LGG is frequent and confers poor prognosis in patients with LGG. Our data also indicate that the apoptosis evasion phenotype of these cells harboring a hypomethylation-induced activation of the PDGF pathway is associated with a hypomethylation of the bcl-xl and bcl-w genes and the phosphorylation and/or downregulation of three major pro-apoptotic BH3-only proteins: PUMA, Bad, and Bim. Consistent with this, we demonstrate that the use of folate, a DNA-methylating agent, promotes the reprogramming of the sensitivity of glioma cells to ABT-737/etoposide-induced apoptosis and reduces the dose of ABT-737 required to promote etoposide-induced apoptosis. This work supports the idea that the inclusion of folate and/or ABT-737 could be a promising adjuvant in the design of anti-glioma therapeutic protocols in clinical studies

Using field-based entomological research to promote awareness about forest ecosystem conservation

Interactions between plants, insect herbivores and associated predators represent the majority of terrestrial biodiversity. Insects are vital food sources for many other organisms and provide important ecosystem functions and services including pollination, waste removal and biological control. We propose a complete and reproducible education programme to guide students to understand the importance of managing and conserving forest ecosystems in their region through the study of insect ecology and natural history. Our programme involved lectures, workshops and field surveys of insects with a group of 60 high school students in Eastern Africa (Ethiopia). It addresses the key stages of an entomological research project including: 1) general entomological knowledge and understanding the role of insects in terrestrial diversity and in ecosystem functioning and services; (2) the proposal of simple research questions including hypothesis development and evaluation using scientific literature, 3) fieldwork using different types of light traps; 4) sorting and identification of the insect orders using simple diagnostic keys and illustrated plates; 5) analysing and interpreting the results and 6) demonstrating findings to peers and a public audience. Identifying insects, exploring their natural history and understanding their functions in the field bring the students towards a better understanding and awareness of the importance of forest ecosystem conservation

Low-biofouling membranes prepared by liquid-induced phase separation of the PVDF/polystyrene-b-poly (ethylene glycol) methacrylate blend

In the present work, the focus is laid on the formation, and low-biofouling properties of polyvinylidene fluoride (PVDF) membranes modified using an amphiphilic copolymer additive: polystyrene-b-poly (ethylene glycol) methacrylate (PS-b-PEGMA). PVDF was blended with PS-b-PEGMA and membranes were prepared by liquid-induced phase separation. The additive played a significant role on membrane formation, slightly decreasing surface porosity, reducing the shrinkage during phase separation, and increasing both the size and porosity of macrovoids. Owing to its numerous hydrophilic moieties, the copolymer was believed to promote solvent and nonsolvent exchanges during phase inversion. In addition, it significantly enhanced surface hydrophilicity and matrix hydration capability. Indeed, water was easily trapped by the PEGylated chains spread onto the surface and within the matrix, and then stored in the larger macrovoids. It led to an important reduction of protein adsorption, including bovine serum albumin (65%) and lysozyme (89%). Bacterial attachment tests revealed that adhesion of Escherichia coli and Staphylococcus epidermidis was almost totally prevented (over 99% reduction of attachment), which demonstrates the excellent efficiency of PS-b-PEGMA copolymer to provide PVDF membranes with low-biofouling properties

Serum-Nutrient Starvation Induces Cell Death Mediated by Bax and Puma That Is Counteracted by p21 and Unmasked by Bcl-xL Inhibition

The cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) is a multifunctional protein known to promote cell cycle arrest and survival in response to p53-dependent and p53 independent stimuli. We herein investigated whether and how it might contribute to the survival of cancer cells that are in low-nutrient conditions during tumour growth, by culturing isogenic human colorectal cancer cell lines (HCT116) and breast cancer cell lines in a medium deprived in amino acids and serum. We show that such starvation enhances, independently from p53, the expression of p21 and that of the pro-apoptotic BH3-only protein Puma. Under these conditions, p21 prevents Puma and its downstream effector Bax from triggering the mitochondrial apoptotic pathway. This anti-apoptotic effect is exerted from the cytosol but it is unrelated to the ability of p21 to interfere with the effector caspase 3. The survival function of p21 is, however, overcome by RNA interference mediated Bcl-xL depletion, or by the pharmacological inhibitor ABT-737. Thus, an insufficient supply in nutrients may not have an overt effect on cancer cell viability due to p21 induction, but it primes these cells to die, and sensitizes them to the deleterious effects of Bcl-xL inhibitors regardless of their p53 status

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

La protéine à domaine BH3 PUMA (P53 Upregulated Modulator of Apoptosis) est un agoniste de Bax (implications dans la dépendance de cellules cancéreuses aux protéines anti-apoptotiques)

Les protéines à domaine BH3, un sous-groupe des protéines de la famille de Bcl-2, sont des régulateurs majeurs du processus apoptotique en connectant une voie de signalisation pro-apoptotique spécifique vers les autres membres. Cependant, le mécanisme précis par lequel ces protéines induisent l'apoptose demeure mal déterminé. Nous avons montré dans cette étude que PUMA, un médiateur essentiel de la fonction apoptotique de p53, peut interagir avec la protéine pro-apoptotique à multidomaine Bax et induire directement son activation. L'analyse des domaines de Bax impliqués dans cette interaction a montré un rôle essentiel des résidus situés dans la partie C-terminale de l'hélice 1. Un peptide correspondant à ce domaine minimal peut inhiber l'interaction entre le domaine BH3 de PUMA et Bax ainsi que sa capacité à stimuler l'activité apoptotique de Bax. De plus, nous avons montré que l'expression de PUMA par des cellules tumorales est responsable de leur dépendance à la protéine anti-apoptotique Bcl-xL. PUMA est également impliqué dans l'apoptose induite par le composé antagoniste des protéines anti-apoptotiques ABT-737, lequel peut stimuler l'interaction entre les protéines endogènes PUMA et Bax. Nous concluons donc que la capacité de PUMA à fonctionner comme un agoniste de Bax est responsable de la dépendance de cellules tumorales aux protéines anti-apoptotiques, laquelle peut être mise à profit dans un traitement anti-cancéreux basé sur l'inhibition de ces protéines.BH3-only proteins, a subgroup of the Bcl-2 family of proteins, are major regulators of apoptotic process as they connect a specific pro-apoptotic pathway to the other members. However, the precise mechanism by which they induce apoptosis is still poorly understood. We have shown in this study that PUMA, an essential mediator of p53 apoptotic function, can bind to the multidomain pro-apoptotic protein Bax and directly induce its activation. The analysis of the domains of Bax implicated in this interaction has shown an essential role of the residues situated in the C-terminal part of the helix 1. A peptide encompassing this minimal domain can inhibit the interaction between the BH3 domain of PUMA and Bax, and inhibit its ability to stimulate Bax apoptotic function. Moreover, we have shown that the expression of PUMA in cancer cells is responsible for their dependence on the anti-apoptotic proteins Bcl-xL. PUMA is also implicated in the apoptosis induced by the compound inhibitor of anti-apoptotic proteins ABT-737, which can stimulate the interaction between endogenous PUMA and Bax proteins. We thus conclude that the ability of PUMA to work as an agonist of Bax is responsible for the dependence of cancer cells to anti-apoptotic proteins, which can be used in an anticancer treatment based on the inhibition of these proteins.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

μSPIDER CAD TOOL: CASE STUDY OF NOC IP GENERATION FOR FPGA

International audienceThis paper introduces the μSpider CAD tool for NoC design under latency and bandwidth constraints and describes the different steps of the associated design flow. We show how the tool can be used to automatically generate a NOC IP compliant with Xilinx EDK tool. We present synthesis results and a real implementation of a video application based on a multi-processor architecture. Finally we conclude about research to be done at application/OS levels above current work to achieve a complete and efficient implementation of a multi-processor embedded system

Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression

International audienceResistance of solid cancer cells to chemotherapies and targeted therapies is not only due to the mutational status of cancer cells but also to the concurring of stromal cells of the tumor ecosystem, such as immune cells, vasculature and cancer-associated fibroblasts (CAFs). The reciprocal education of cancer cells and CAFs favors tumor growth, survival and invasion. Mitochondrial function control, including the regulation of mitochondrial metabolism, oxidative stress and apoptotic stress are crucial for these different tumor progression steps. In this review, we focus on how CAFs participate in cancer progression by modulating cancer cells metabolic functions and mitochondrial apoptosis. We emphasize that mitochondria from CAFs influence their activation status and pro-tumoral effects. We thus advocate that understanding mitochondria-mediated tumor-stroma interactions provides the possibility to consider cancer therapies that improve current treatments by targeting these interactions or mitochondria directly in tumor and/or stromal cells

Mitotic stress-induced secretome primes cancer cells to apoptosis and maximizes paclitaxel response in breast tumors when combined with BCL-xL-targeting BH3 mimetics

International audienceWe recently identified a previously unappreciated ability of antimitotics to propagate apoptotic priming across cancer cell populations. The underlying paracrine cytotoxic signal, fueled by undead cells activating the cGAS/STING pathway, is required for in vivo antitumor response and it can be further exploited by delayed, but not synchronous, BCL-xL inhibition