Selinexor overcomes hypoxia-induced drug resistance in multiple myeloma

Increased levels of the nuclear export protein, exportin 1 (XPO1), were demonstrated in multiple myeloma (MM) patients. Targeting XPO1 with selinexor (the selective inhibitor of nuclear export; SINE compound KPT-330) demonstrates broad antitumor activity also in patient cells resistant to bortezomib; hence, it is a promising target in MM patients. Hypoxia is known to mediate tumor progression and drug resistance (including bortezomib resistance) in MM cells. In this study, we tested the effects of selinexor alone or in combination with bortezomib in normoxia and hypoxia on MM cell survival and apoptosis in vitro and in vivo. In vitro, selinexor alone decreased survival and increased apoptosis, resensitizing MM cells to bortezomib. In vivo, we examined the effects of selinexor alone on tumor initiation and tumor progression, as well as selinexor in combination with bortezomib, on tumor growth in a bortezomib-resistant MM xenograft mouse model. Selinexor, used as a single agent, delayed tumor initiation and tumor progression, prolonging mice survival. In bortezomib-resistant xenografts, selinexor overcame drug resistance, significantly decreasing tumor burden and extending mice survival when combined with bortezomib

Assessing electronic government readiness of public organisations: effect of internal factors (case of Egypt).

Governments have become more and more interested in embracing Information and Communication Technology (ICT), and have made a remarkable progress over the last few years. Electronic Government (e-government) - described as the strategic use of ICT to transform the public sector - is presently recognised as a driver and a key enabler of citizen-centric, cooperative, and seamless modern governance. E-government implementation implies not only a profound transformation in the way government interacts with the governed, but also a reinvention of its internal processes and how public organisations carry their business both internally as well as externally while interacting with the other segments of the community. Based on the literature, it is frequently claimed that the availability of an effective E-Government Readiness (EGR) assessment framework is a necessary condition for advancing e-government proper implementation. Most e-government appraisal models address the Electronic Service (e-service) dimension of e-government that focuses on the services provided by the government to the citizens on the Internet. This gives a very narrow perspective to e-government ignoring a key dimension: the Electronic Administration (e-administration), that highlights the importance of modernising the public sector, increasing government productivity, and transforming its internal processes. Furthermore, developed models assess E-Government Readiness (EGR) on a country as a whole without conducting an in-depth assessment on a public organisation scale. In addition, the majority of these models do not take into consideration the opinion of the civil servants involved in such e-government programs, a key stakeholder that affects their success. The objective of this thesis is to develop a framework that assesses EGR focusing on e-administration within public organisations through obtaining its employees‟ feedback. The suggested framework investigated the internal factors affecting EGR categorised into four dimensions: (i) strategy, (ii) people, (iii) technology, and (iv) processes. A number of measuring constructs are identified under each dimension. The framework components, relationships, and hypotheses were derived from the literature on Electronic Readiness (e-readiness), EGR, Information Systems (IS) and Electronic Commerce (e-commerce) success. In order to test the proposed framework, the thesis examined the relations and interactions of these components in an emerging e-government environment using four case studies of different characteristics to represent public organisations in Egypt. These organisations cover municipalities, investment, tax payment, and health sectors. Quantitative data collection method was through distributing a questionnaire to a sample of employees in each organisation. Data obtained from the questionnaire in each organisation was triangulated with data gathered from other sources of evidence: (i) interviews with top management, (ii) documentations, (iii) archival records, and (iv) observations. Findings of the empirical research were evaluated against the framework suggested in the beginning leading to a final framework that assesses EGR of public organisations. Findings revealed that framework's hypotheses were all confirmed. Concerning Egypt's EGR assessment, results proved that processes, technology, and people have a high effect on EGR, whereas strategy has a modest impact on it. This reflects that strategy is not given a high value in terms of e-government and that top management need to further promote e-government within public Egyptian organisations. Findings revealed also the modest impact of strategy on the two dimensions: technology and processes compared with its high effect on people. The research highlighted also the different measuring constructs that have the highest weights in each of the four dimensions. This helps in understanding e-government environment of public organisations in Egypt, showing the main components that affect EGR. The thesis though provides a rich insight into investigating e-administration within public organisations especially in a developing country such as Egypt, and presents a systematic approach to assess EGR of public organisations based on the four e-government building blocks: (i) strategy, (ii) people, (iii) technology, and (iv) processes. Therefore the thesis contributes to research areas in the literature related to assessments of information systems, e-commerce, e-readiness, and e-government readiness

CORRELATION BETWEEN CHRONIC KIDNEY DISEASES AND HEMATOLGICAL DATA IN SABRATHA HOSPITAL IN LIBYA

In chronic kidney failure, there is impairment in the excretion of toxic non-volatile solutes, with consequent increase in the plasma concentrations of all metabolites derived mainly from protein metabolism, characterized by increased urea and creatinine, the prevalence and severity of anemia are related to the kidney disease stage and the relative deficiency or reduction in erythropoietin production is the main cause. This study aimed at checking the correlation between anemia and chronic kidney diseases in patients who underwent hemodialysis in Sabratha Hospital in the West of Libya. This study was conducted on 60 patients (36 males and 24 females) with chronic renal failure from October 2015 to April 2016 and a group of 40 (20 males and 20 females) individuals as control. The results of the study concluded that there is a correlation between progression of chronic kidney diseases and reduction in hemoglobin, red blood cells count, hematocrit, and serum iron.Keywords: Chronic kidney diseases, Chronic kidney disease, Anemia, Renal failur

EHV-1 Pathogenesis: Current in vitro Models and Future Perspectives

Primary infection and pathogenesis of equine herpesvirus type 1 (EHV-1) require an intricate interaction of virus with the mucosal epithelium, mononuclear cells and the vascular endothelium. Studies on EHV-1 have been facilitated by the development of different in vitro models that recapitulate the in vivo tissue complexity. The available in vitro assays can be categorized into (i) models mimicking the epithelium-peripheral blood mononuclear cell (PBMC) interaction, which include ex vivo mucosal (nasal and vaginal) explants and equine respiratory epithelial cells (EREC) cultures; and (ii) PBMC-endothelium mimicking models, including flow chamber and contact assays. These in vitro models have proven their worth in attempts to recapitulate the in vivo architecture and complexity, produce data relevant to natural host infection, and reduce animal use due to in vivo experiments. Although horse models are still needed for certain experiments, e.g., EHV-1 myeloencephalopathy or vaccination studies, available in vitro models can be used to obtain highly valuable data on virus-host tissue interactions. Microfluidic based 3D culture system (e.g., horse-on-a-chip) could be a potential upgraded version of these in vitro models for future research

The non-coding RNA landscape of plasma cell dyscrasias

Despite substantial advancements have been done in the understanding of the pathogenesis of plasma cell (PC) disorders, these malignancies remain hard-to-treat. The discovery and subsequent characterization of non-coding transcripts, which include several members with diverse length and mode of action, has unraveled novel mechanisms of gene expression regulation often malfunctioning in cancer. Increasing evidence indicates that such non-coding molecules also feature in the pathobiology of PC dyscrasias, where they are endowed with strong therapeutic and/or prognostic potential. In this review, we aim to summarize the most relevant findings on the biological and clinical features of the non-coding RNA landscape of malignant PCs, with major focus on multiple myeloma. The most relevant classes of non-coding RNAs will be examined, along with the mechanisms accounting for their dysregulation and the recent strategies used for their targeting in PC dyscrasias. It is hoped these insights may lead to clinical applications of non-coding RNA molecules as biomarkers or therapeutic targets/agents in the near future

Toward Smart Moving Target Defense for Linux Container Resiliency

This paper presents ESCAPE, an informed moving target defense mechanism for cloud containers. ESCAPE models the interaction between attackers and their target containers as a "predator searching for a prey" search game. Live migration of Linux-containers (prey) is used to avoid attacks (predator) and failures. The entire process is guided by a novel host-based behavior-monitoring system that seamlessly monitors containers for indications of intrusions and attacks. To evaluate ESCAPE effectiveness, we simulated the attack avoidance process based on a mathematical model mimicking the prey-vs-predator search game. Simulation results show high container survival probabilities with minimal added overhead.Comment: Published version is available on IEEE Xplore at http://ieeexplore.ieee.org/document/779685

The Role of Equine Herpesvirus Type 4 Glycoprotein K in Virus Replication

Equine herpesvirus 4 (EHV-4) is an important equine pathogen that causes respiratory tract disease among horses worldwide. Glycoprotein K (gK) homologues have been identified in several alphaherpesviruses as a major player in virus entry, replication, and spread. In the present study, EHV-4 gK-deletion mutant has been generated by using bacterial artificial chromosome technology and Red mutagenesis to investigate the role of gK in EHV-4 replication. Our findings reported here show that gK is essential for virus replication <em>in vitro</em> and that the gK-negative strain was not able to be reconstituted in equine cells. It is noteworthy that these findings agree with the previously published study describing gK deletion in other alphaherpesviruses