The role of GSK3β for the pathogenesis of activated-B-cell type of diffuse large B cell lymphoma

Activated B cell like type of Diffuse Large B cell lymphoma (ABC-DLBCL) is one of the most aggressive types of Non-Hodgkin’s lymphoma and shows a bad prognosis even with treatment using the R-CHOP protocol. The hallmark of this type of DLBCL is the constitutive formation of a protein complex called the CBM complex, which is composed of CARMA1, BCL10 and MALT1. Moreover, the constitutive CBM complex formation has been shown to be responsible for the uncontrolled and stimulus independent activation of NF-κB signalling pathway. Glycogen synthase kinase 3β (GSK3β) is a protein kinase which was identified recently to be required for RelB degradation in T lymphocytes. Moreover, GSK3β was shown to be recruited to oncogenic CARMA1 in DLBCL cell lines. However, the role of GSK3β in CBM complex formation and the pathogenesis of ABC-DLBCL remains unravelled. The data presented in this thesis demonstrate that inhibition of GSK3β in Jurkat model system attenuated antigen receptor mediated MALT1 endoprotease activity evidenced by reduced cleavage of CYLD1 protein and RelB degradation. Moreover, GSK3β inhibition attenuated the antigen receptor induced canonical NF-κB activation as demonstrated by the reduction of stimulus induced IκBα degradation, the IKK complex activity, the NF-κB DNA binding activity and the expression of NF-κB target genes. This effect appears to be due to an attenuated CBM complex formation observed upon GSK3β inhibition. Moreover, GSK3β found to be a BCL10 kinase as it is capable of phosphorylating BCL10 at additional sites to the previously reported IKK2 mediated serine residues. The constitutive CBM complex dependent ABC-DLBCL cell lines showed also an attenuated proliferation upon the inhibition of GSK3β. However, the effect of GSK3β inhibition on GC-DLBCL cell proliferation was either attenuation or augmentation probably due to the activation of Wnt/β-catenin signalling pathway. In addition, MALT1 endoprotease activity and constitutive CBM complex formation in DLBCL cell lines were attenuated upon inhibition of GSK3β. Besides, the expression of NF-κB target gene BIRC3 was decreased in ABC- but not GC-DLBCL cells upon GSK3β inhibition. However, GSK3β plays a multi-faceted role in the pathogenesis of DLBCL not confined to NF-κB signalling pathway. The establishment of new immunohistochemistry protocols using antibodies specific for the GSK3β-mediated BCL10 phosphorylation sites might improve the ability of this technique to differentiate between ABC- and GC-DLBCL without the need of microarray analysis which is not available for daily diagnostic routine. Taken together, this study presented BCL10 phosphorylation as a novel regulatory mechanism by which GSK3β mediates the MALT1 endoprotease activity, CBM complex formation and the NF-κB signalling in activated T cells as well as the pathogenesis of DLBCL

GSK3β modulates NF-κB activation and RelB degradation through site-specific phosphorylation of BCL10

Abstract Glycogen synthase kinase 3β (GSK3β) is a ubiquitously expressed serine/threonine kinase involved in the regulation of various cellular functions, such as energy homoeostasis, cell growth and developmental processes. More recently, GSK3β has been identified as a part of a protein complex involved in the regulation of the CARMA1-BCL10-MALT1 complex (CBM complex) formation, which is a key signalling event upon antigen receptor engagement of B and T cells, required for the activation of the NF-κB and JNK pathways. However, conflicting reports have been published regarding the role of GSK3β for the activation of the NF-κB signalling pathways. Therefore, we aimed to determine the impact of GSK3β on the NF-κB signalling induced upon T cell activation. Blocking GSK3β by either pharmacologic inhibitors (SB216763 and SB415286) or by RNAi caused a reduced proteolysis of the MALT1 targets CYLD1, BCL10 and RelB as well as diminished IκBα degradation, NF-κB DNA binding and NF-κB activity. This negative effect on NF-κB appears to be due to a diminished CBM complex formation caused by a reduced BCL10 phosphorylation. Taken together, we provide here evidence for a novel regulatory mechanism by which GSK3β affects NF-κB signalling in activated T cells

When Security Risk Assessment Meets Advanced Metering Infrastructure: Identifying the Appropriate Method

Leading risk assessment standards such as the NIST SP 800-39 and ISO 27005 state that information security risk assessment (ISRA) is one of the crucial stages in the risk-management process. It pinpoints current weaknesses and potential risks, the likelihood of their materializing, and their potential impact on the functionality of critical information systems such as advanced metering infrastructure (AMI). If the current security controls are insufficient, risk assessment helps with applying countermeasures and choosing risk-mitigation strategies to decrease the risk to a controllable level. Although studies have been conducted on risk assessment for AMI and smart grids, the scientific foundations for selecting and using an appropriate method are lacking, negatively impacting the credibility of the results. The main contribution of this work is identifying an appropriate ISRA method for AMI by aligning the risk assessment criteria for AMI systems with the ISRA methodologies’ characteristics. Consequently, this work makes three main contributions. First, it presents a comprehensive comparison of multiple ISRA methods, including OCTAVE Allegro (OA), CORAS, COBRA, and FAIR, based on a variety of input requirements, tool features, and the type of risk assessment method. Second, it explores the necessary conditions for carrying out a risk assessment for an AMI system. Third, these AMI risk assessment prerequisites are aligned with the capabilities of multiple ISRA approaches to identify the best ISRA method for AMI systems. The OA method is found to be the best-suited risk assessment method for AMI, and this outcome paves the way to standardizing this method for AMI risk assessment

Two-phase multi-model automatic brain tumour diagnosis system from magnetic resonance images using convolutional neural networks

Abstract Brain tumour is a serious disease, and the number of people who are dying due to brain tumours is increasing. Manual tumour diagnosis from magnetic resonance images (MRIs) is a time consuming process and is insufficient for accurately detecting, localizing, and classifying the tumour type. This research proposes a novel two-phase multi-model automatic diagnosis system for brain tumour detection and localization. In the first phase, the system structure consists of preprocessing, feature extraction using a convolutional neural network (CNN), and feature classification using the error-correcting output codes support vector machine (ECOC-SVM) approach. The purpose of the first system phase is to detect brain tumour by classifying the MRIs into normal and abnormal images. The aim of the second system phase is to localize the tumour within the abnormal MRIs using a fully designed five-layer region-based convolutional neural network (R-CNN). The performance of the first phase was assessed using three CNN models, namely, AlexNet, Visual Geometry Group (VGG)-16, and VGG-19, and a maximum detection accuracy of 99.55% was achieved with AlexNet using 349 images extracted from the standard Reference Image Database to Evaluate Response (RIDER) Neuro MRI database. The brain tumour localization phase was evaluated using 804 3D MRIs from the Brain Tumor Segmentation (BraTS) 2013 database, and a DICE score of 0.87 was achieved. The empirical work proved the outstanding performance of the proposed deep learning-based system in tumour detection compared to other non-deep-learning approaches in the literature. The obtained results also demonstrate the superiority of the proposed system concerning both tumour detection and localization

The outcome of micro vascular reconstruction of the lower limb after resection of primary bone tumors

Background: Surgical and medical care for patients with bone and soft tissue tumors of the extremities continues to improve with advancement of chemotherapeutic strategies, surgical techniques, and understanding of pathogenesis. Aim and Objective: To Analysis of the results of lower limb preservation after neoplastic resection to reproduce an advisory algorithm for surgical decision making to achieve optimal functional results.Methods: This retrospective study was performed in the microsurgery unit Assiut university hospital between 2013 and 2019, involved (40) patients with primary malignant bone tumors and benign aggressive bone tumors who had wide local resection and reconstruction by vascularized fibula (osteoseptocutaneous flap). Results: The highest mean time of union rate was 5.75±2.06 for GCT. The least mean time of union rate was 3.86±1.21 forChondrosarcoma. the least Mean±SD of function was 2.83±0.75 in chondrosarcoma while the highest Mean±SD of emotional acceptance was 4±0.82 in Ewing sarcoma. The Mean±SD of pain were equal in both Ewing sarcoma and GCT. Conclusions: Benign aggressive tumors & primary malignant bone tumors now become not a rare tumor.  Free vascularized fibular graft is one of several methods of bone reconstruction after bone tumor resection. Using as a means of reconstruction.&nbsp