BCL2-Family Dysregulation in B-Cell Malignancies: From Gene Expression Regulation to a Targeted Therapy Biomarker

BCL2-family proteins have a central role in the mitochondrial apoptosis machinery and their expression is known to be deregulated in many cancer types. Effort in the development of small molecules that selectively target anti-apoptotic members of this family i.e., Bcl-2, Bcl-xL, Mcl-1 recently opened novel therapeutic opportunities. Among these apoptosis-inducing agents, BH3-mimetics (i.e., venetoclax) led to promising preclinical and clinical activity in B cell malignancies. However, several mechanisms of intrinsic or acquired resistance have been described ex vivo therefore predictive markers of response as well as mechanism-based combinations have to be designed. In the present study, we analyzed the expression of the BCL2-family genes across 10 mature B cell malignancies through computational normalization of 21 publicly available Affimetrix datasets gathering 1,219 patient samples. To better understand the deregulation of anti- and pro-apoptotic members of the BCL2-family in hematological disorders, we first compared gene expression profiles of malignant B cells to their relative normal control (naïve B cell to plasma cells, n = 37). We further assessed BCL2-family expression according to tissue localization i.e., peripheral blood, bone marrow, and lymph node, molecular subgroups or disease status i.e., indolent to aggressive. Across all cancer types, we showed that anti-apoptotic genes are upregulated while pro-apoptotic genes are downregulated when compared to normal counterpart cells. Of interest, our analysis highlighted that, independently of the nature of malignant B cells, the pro-apoptotic BH3-only BCL2L11 and PMAIP1 are deeply repressed in tumor niches, suggesting a central role of the microenvironment in their regulation. In addition, we showed selective modulations across molecular subgroups and showed that the BCL2-family expression profile was related to tumor aggressiveness. Finally, by integrating recent data on venetoclax-monotherapy clinical activity with the expression of BCL2-family members involved in the venetoclax response, we determined that the ratio (BCL2+BCL2L11+BAX)/BCL2L1 was the strongest predictor of venetoclax response for mature B cell malignancies in vivo

Polychromatic guide star: feasibility study

International audienceAdaptive optics at astronomical telescopes aims at correcting in real time the phase corrugations of incoming wavefronts caused by the turbulent atmosphere, as early proposed by Babcock. Measuring the phase errors requires a bright source located within the isoplanatic patch of the program source. The probability that such a reference source exists is a function of the wavelength, of the required image quality (Strehl ratio), of the turbulence optical properties, and of the direction of the observation. It turns out that the sky coverage is disastrously low in particular in the visible wavelength range where, unfortunately, the gain in spatial resolution brought by adaptive optics is the largest. Foy and Labeyrie have proposed to overcome this difficulty by creating an artificial point source in the sky in the direction of the observation relying on the backscattered light due to a laser beam. This laser guide star (hereinafter referred to as LGS) can be bright enough to allow us to accurately measure the wavefront phase errors, except for two modes which are the piston (not relevant in this case) and the tilt. Pilkington has emphasized that the round trip time of the laser beam to the mesosphere, where the LGS is most often formed, is significantly shorter than the typical tilt coherence time; then the inverse-return-of-light principle causes deflections of the outgoing and the ingoing beams to cancel. The apparent direction of the LGS is independent of the tilt. Therefore the tilt cannot be measured only from the LGS. Until now, the way to overcome this difficulty has been to use a natural guide star to sense the tilt. Although the tilt is sensed through the entire telescope pupil, one cannot use a faint source because $APEX 90% of the variance of the phase error is in the tilt. Therefore, correcting the tilt requires a higher accuracy of the measurements than for higher orders of the wavefront. Hence current adaptive optics devices coupled with a LGS face low sky coverage. Several methods have been proposed to get a partial sky coverage for the tilt. The only one providing us with a full sky coverage is the polychromatic LGS (hereafter referred to as PLGS). We present here a progress report of the R&D; program Etoile Laser Polychromatique et Optique Adaptative (ELP-OA) carried out in France to develop the PLGS concept. After a short recall of the principles of the PLGS, we will review the goal of ELP-OA and the steps to get over to bring it into play. We finally shortly described the effort in Europe to develop the LGS

Polychromatic guide star: feasibility study

International audienceAdaptive optics at astronomical telescopes aims at correcting in real time the phase corrugations of incoming wavefronts caused by the turbulent atmosphere, as early proposed by Babcock. Measuring the phase errors requires a bright source located within the isoplanatic patch of the program source. The probability that such a reference source exists is a function of the wavelength, of the required image quality (Strehl ratio), of the turbulence optical properties, and of the direction of the observation. It turns out that the sky coverage is disastrously low in particular in the visible wavelength range where, unfortunately, the gain in spatial resolution brought by adaptive optics is the largest. Foy and Labeyrie have proposed to overcome this difficulty by creating an artificial point source in the sky in the direction of the observation relying on the backscattered light due to a laser beam. This laser guide star (hereinafter referred to as LGS) can be bright enough to allow us to accurately measure the wavefront phase errors, except for two modes which are the piston (not relevant in this case) and the tilt. Pilkington has emphasized that the round trip time of the laser beam to the mesosphere, where the LGS is most often formed, is significantly shorter than the typical tilt coherence time; then the inverse-return-of-light principle causes deflections of the outgoing and the ingoing beams to cancel. The apparent direction of the LGS is independent of the tilt. Therefore the tilt cannot be measured only from the LGS. Until now, the way to overcome this difficulty has been to use a natural guide star to sense the tilt. Although the tilt is sensed through the entire telescope pupil, one cannot use a faint source because $APEX 90% of the variance of the phase error is in the tilt. Therefore, correcting the tilt requires a higher accuracy of the measurements than for higher orders of the wavefront. Hence current adaptive optics devices coupled with a LGS face low sky coverage. Several methods have been proposed to get a partial sky coverage for the tilt. The only one providing us with a full sky coverage is the polychromatic LGS (hereafter referred to as PLGS). We present here a progress report of the R&D; program Etoile Laser Polychromatique et Optique Adaptative (ELP-OA) carried out in France to develop the PLGS concept. After a short recall of the principles of the PLGS, we will review the goal of ELP-OA and the steps to get over to bring it into play. We finally shortly described the effort in Europe to develop the LGS

Physiological effects of environmental chemicals on colour change in common cuttlefish: ex-vivo quantification on skin explants

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Physiological effects of environmental chemicals on colour change in common cuttlefish: ex-vivo quantification on skin explants

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Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

International audienceAbstract Background Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention. Results Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment. Conclusions Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53

Functionalized Oxides for Bifacial Solar Cells with Passivated Contacts: First Results of the OXYGEN Project

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