Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 ...overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.
Deregulation of epigenetic mechanisms, including microRNA, contributes to leukemogenesis and drug resistance by interfering with cancer-specific molecular pathways. Here, we show that the balance ...between miR-194-5p and its newly discovered target BCL2-associated transcription factor 1 (BCLAF1) regulates differentiation and survival of normal hematopoietic progenitors. In acute myeloid leukemias this balance is perturbed, locking cells into an immature, potentially 'immortal' state. Enhanced expression of miR-194-5p by treatment with the histone deacetylase inhibitor SAHA or by exogenous miR-194-5p expression re-sensitizes cells to differentiation and apoptosis by inducing BCLAF1 to shuttle between nucleus and cytosol. miR-194-5p/BCLAF1 balance was found commonly deregulated in 60 primary acute myeloid leukemia patients and was largely restored by ex vivo SAHA treatment. Our findings link treatment responsiveness to re-instatement of miR-194-5p/BCLAF1 balance.
Objective: To analyze the effect of the juice obtained from two varieties of sweet orange (Citrus sinensis L. Osbeck), Moro (a blood orange) and Navelina (a blond orange), on fat accumulation in mice ...fed a standard or a high-fat diet (HFD). Methods: Obesity was induced in male C57/Bl6 mice by feeding a HFD. Moro and Navelina juices were provided instead of water. The effect of an anthocyanin-enriched extract from Moro oranges or purified cyanidin-3-glucoside (C3G) was also analyzed. Body weight and food intake were measured regularly over a 12-week period. The adipose pads were weighted and analyzed histologically; total RNA was also isolated for microarray analysis. Results: Dietary supplementation of Moro juice, but not Navelina juice significantly reduced body weight gain and fat accumulation regardless of the increased energy intake because of sugar content. Furthermore, mice drinking Moro juice were resistant to HFD-induced obesity with no alterations in food intake. Only the anthocyanin extract, but not the purified C3G, slightly affected fat accumulation. High-throughput gene expression analysis of fat tissues confirmed that Moro juice could entirely rescue the high fat-induced transcriptional reprogramming. Conclusion: Moro juice anti-obesity effect on fat accumulation cannot be explained only by its anthocyanin content. Our findings suggest that multiple components present in the Moro orange juice might act synergistically to inhibit fat accumulation.
Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. Although the molecular mechanisms of RAS GEF catalysis have been unveiled, ...how SOS1 acquires RAC GEF activity and what is the physio-pathological relevance of this activity is much less understood. Here we show that SOS1 is tyrosine phosphorylated on Y1196 by ABL. Phosphorylation of Y1196 controls SOS1 inter-molecular interaction, is required to promote the exchange of nucleotides on RAC in vitro and for platelet-derived growth factor (PDGF) activation of RAC- and RAC-dependent actin remodeling and cell migration. SOS1 is also phosphorylated on Y1196 by BCR-ABL in chronic myelogenous leukemic cells. Importantly, in these cells, SOS1 is required for BCR-ABL-mediated activation of RAC, cell proliferation and transformation in vitro and in a xenograft mouse model. Finally, genetic removal of Sos1 in the bone marrow-derived cells (BMDCs) from Sos1
mice and infected with BCR-ABL causes a significant delay in the onset of leukemogenesis once BMDCs are injected into recipient, lethally irradiated mice. Thus, SOS1 is required for full transformation and critically contribute to the leukemogenic potential of BCR-ABL.
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•Corrosion protection system for HV power cables in undersea application.•Analysis of the electrical parameters affecting the electric potential distribution in cable layers and ...surrounding medium.•Analytical criteria for active cathodic protection system design.•2D analytical approach supported by a detailed 3D finite element analysis (FEM).
This paper focuses on the performance analysis of the corrosion protection system of HV power cables for undersea applications. The aim of the work is to describe the relations between the main electrical parameters affecting the electric potential distribution in the cable layers and in the surrounding medium, when an active cathodic protection (CP) arrangement is used. In particular, the analysis focuses on the design of an active CP for reducing corrosion phenomena of the cable metallic shield. This study is based on a 2D analytical approach supported by a detailed 3D finite element analysis (FEM). It gives evidence to the relation between the electrical variables and the design criteria of the active cathodic protection system.
Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) ...activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure.
The EU DEMO Plant Electrical System (PES) main scopes are to supply all the plant electrical loads and to deliver to the Power Transmission Grid (PTG) the net electrical power generated. The studies ...on the PES during the Pre-Concept Design (PCD) Phase were mainly addressed to understand the possible issues, related to the special features both of the power generated, with respect to a power plant of the same size, and of the power to be supplied to the electrical loads. For this purpose, the approach was to start the design of the different PES components adopting technologies already utilized in fusion experiments and in Nuclear Power Plants (NPP) to verify their applicability and identify possible limits when scaled to the DEMO size and applied to the specific pulsed operating conditions. This work is not completed, however several issues have been already identified related to the pulsed operation of the turbine generator, the large amount of recirculation power, the very high peaks of active power required for the plasma formation and control, the huge reactive power demand, if thyristor converter technology was adopted to supply the superconducting coils, etc.. The paper gives an overview on the features and scope of the PES and its subsystems, on the main achievements during the Pre-Concept Design (PCD) Phase, on the challenges for the development of the conceptual design in the next framework program and on the plan to face them.
Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In ...tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in normal human fibroblasts the PML protein associates with few telomeres, preferentially when they are damaged. Proliferation-induced telomere attrition or their damage due to alteration of the shelterin complex enhances the telomeric localization of PML, which is increased in human T-lymphocytes derived from patients genetically deficient in telomerase. In normal fibroblasts, PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence. Expression of the leukemia protein PML/RARα in hematopoietic progenitors displaces PML from telomeres and induces telomere shortening in the bone marrow of pre-leukemic mice. Our work provides a novel view of the physiologic function of PML, which participates in telomeres surveillance in normal cells. Our data further imply that a diminished PML function may contribute to cell senescence, genomic instability, and tumorigenesis.
•Electromagnetic interaction of DEMO VV and TF represented with system of spring and damper coupled in series.•Transient electromagnetic analysis for the evaluation of stiffness and damping ...coefficients.•Transient structural simulation of VV with VDEs loads.•Accelerations and displacements peaks during VDEs evaluated in relevant location of VV.
In tokamaks during plasma vertical displacement events (VDEs) electrical currents occur in the vacuum vessel (VV) and in the in-vessel components (IVCs) that interact with the strong magnetic field generating large electromagnetic (EM) loads. The aim of the present work is the evaluation of the peak displacements and accelerations of the DEMO VV in case of VDEs. Four types of VDEs are investigated that are specified to generate the most severe net loads. The assessment considers also the electromagnetic-mechanical coupling between the VV and the toroidal field (TF) coils whose characteristic stiffness and damping coefficients were determined through a transient EM analysis. In a second step a transient dynamic analysis was performed using a structural finite element (FE) model of the VV to evaluate the displacement and acceleration peaks during the VDEs in relevant locations of the VV.
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