•AML-MRC patients express dynamic ranges of MYC oncoprotein.•High MYC expression is associated with inferior survival in the AML-MRC patients.•High MYC level is associated with higher rates of TP53 ...and DNMT3A mutations.
MYC is an oncoprotein that coordinates the expression of genes involved in metabolism, cell differentiation and survival in various types of malignancies. However, the underlying oncogenic mechanisms and the clinical significance of MYC expression in the acute myeloid leukemia with myelodysplasia related changes (AML-MRC) remain to be answered. A total of 135 patients were retrospectively identified using Total Cancer Care (TCC) Moffitt Cancer Center (MCC) databases. Diagnosis of AML-MRC was based on the 2016 WHO classification utilizing bone marrow (BM) evaluation. MYC protein expression level was assessed by immunohistochemistry (IHC) staining using paraffin-embedded BM trephine biopsy samples obtained at the time of diagnosis or relapse. Concurrent somatic mutations were assessed using targeted next generation sequencing that include 54 genes. A total of 38% (n = 51) and 62% (n = 84) patients had high and low MYC expression, respectively. The most common somatic mutation in our cohort was TP53 followed by DNMT3A, and ASXL1. The median OS was significantly longer in low MYC patients (median OS 42.3 vs. 17.05 months, p = 0.0109). Multivariate analysis including MYC expression level, transplantation status, gender and age demonstrated high MYC expression (HR 1.77, 95% CI 1.004–3.104, p = 0.045) to be an independent poor prognostic factor. Further studies are needed to identify the underlying mechanism of MYC driven oncogenesis in AML-MRC. Additionally, the prognostic impact of MYC on the AML survival in a larger cohort that include diverse somatic mutations and chromosomal abnormalities requires further investigation.
For decades, the standard induction for patients with acute myeloid leukemia (AML) has been the combination of cytarabine with anthracycline (7 + 3 regimen). In August 2017 the US FDA approved ...CPX-351 (vyxeos), a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML (t-AML). This is the first approved treatment specifically for patients with this subgroup of AML. The approval was based on findings from a multicenter, randomized, open-label, phase III study of CPX-351 Versus 7 + 3 in patients 60-75 years old with newly diagnosed AML-MRC or t-AML. In this study CPX-351 had a higher median OS than 7 + 3 (9.56 vs 5.95 months, HR 0.69; 95% CI: 0.52 to 0.90, p = 0.005). In this profile, we review preclinical and clinical data, and discuss limitations and future directions with CPX-351 use in AML.
Chronic myelomonocytic leukemia (CMML) is a rare and heterogeneous hematological malignancy. It has been shown that the molecular abnormalities such as ASXL1, TET2, SETBP1, and SRSF2 mutations are ...common in Caucasian population.
We retrospectively analyzed 178 Chinese CMML patients. The targeted next generation sequencing (NGS) was used to evaluate 114 gene variations, and the prognostic factors for OS were determined by COX regression analysis.
The CMML patients showed a unique mutational spectrum, including TET2 (36.5%), NRAS (31.5%), ASXL1 (28.7%), SRSF2 (24.7%), and RUNX1 (21.9%). Of the 102 patients with clonal analysis, the ancestral events preferentially occurred in TET2 (18.5%), splicing factors (16.5%), RAS (14.0%), and ASXL1 (7.8%), and the subclonal genes were mainly ASXL1, TET2, and RAS. In addition, the secondary acute myeloid leukemia (sAML) transformed from CMML often had mutations in DNMT3A, ETV6, FLT3, and NPM1, while the primary AML (pAML) demonstrated more mutations in CEBPA, DNMT3A, FLT3, IDH1/2, NPM1, and WT1. It was of note that a series of clones were emerged during the progression from CMML to AML, including DNMT3A, FLT3, and NPM1. By univariate analysis, ASXL1 mutation, intermediate- and high-risk cytogenetic abnormality, CMML-specific prognostic scoring system (CPSS) stratifications (intermediate-2 and high group), and treatment options (best supportive care) predicted for worse OS. Multivariate analysis revealed a similar outcome.
The common mutations in Chinese CMML patients included epigenetic modifiers (TET2 and ASXL1), signaling transduction pathway components (NRAS), and splicing factor (SRSF2). The CMML patients with DNMT3A, ETV6, FLT3, and NPM1 mutations tended to progress to sAML. ASXL1 mutation and therapeutic modalities were independent prognostic factors for CMML.
Mutations in genes encoding chromatin regulators are early events contributing to developing asymptomatic clonal hematopoiesis of indeterminate potential and its frequent progression to myeloid ...diseases with increasing severity. We focus on the subset of myeloid diseases encompassing myelodysplastic syndromes and their transformation to secondary acute myeloid leukemia. We introduce the major concepts of chromatin regulation that provide the basis of epigenetic regulation. In greater detail, we discuss those chromatin regulators that are frequently mutated in myelodysplastic syndromes. We discuss their role in the epigenetic regulation of normal hematopoiesis and the consequence of their mutation. Finally, we provide an update on the drugs interfering with chromatin regulation approved or in development for myelodysplastic syndromes and acute myeloid leukemia.
Fog environment adoption rate is increasing day by day in the industry. Unauthorized accessing of data occurs due to the preservation of Identity and information of the users either at the endpoints ...or at the middleware. This paper proposes a methodology to protect and preserve the Identity during data transmission of the users. It uses fog computing for storage against security issues in the cloud and database environment. Cloud and database architectures failed to protect the data and Identity of users but the Fog computing based Identity management as a service (IDaaS) system can handle it with Security Assertion Mark-up Language (SAML) protocol and Pentatope based Elliptic Curve Crypto cipher. A detailed comparative study of the proposed and existing techniques is investigated by considering multi-authentication dialogue, security services, service providers, Identity, and access management.
In this paper, we present a novel OpenStack module called regsite for enabling easy access for researchers to OpenStack research clouds. Many researchers have an account in an Academic AAI ...federation, such as national research and education federations or the eduGAIN SAML meta-federation. The software solution presented here makes it possible to use these institutional accounts together with so-called virtual organization managers for authenticating and authorizing in OpenStack instances in a clean and secure way. An analysis of earlier generations of OpenStack-related developments trying to tackle the same problem is given. Many aspects of this software integration can be generalized to serve as a template for federative research cloud access.
The eIDAS regulation aims to provide an interoperable European framework to enable EU citizens to authenticate and communicate with services of other Member States by using their national electronic ...identity. While a number of high-level requirements (e.g., related to privacy and security) are established to make interoperability among Member States possible, the eIDAS regulation does not explicitly specify the technologies that can be adopted during the development phase to meet the requirements as mentioned earlier. To the best of our knowledge, there is no work available in the literature investigating the technological trends within the notified eIDAS electronic identity schemes used by Member States. To fill this gap, this paper analyzes how the different technological trends of notified schemes satisfy the requirements of the eIDAS regulation. To do this, we define a set of research questions that allow us to investigate the correlations between different design dimensions such as security, privacy, and usability. Based on these findings, we provide a set of lessons learned that would be valuable to the security community, as they can provide useful insights on how to more efficiently protect interoperable national digital identities. Furthermore, we provide a brief overview regarding the new eIDAS regulation (eIDAS 2.0) that aims to provide a more privacy-preserving electronic identity solution by moving from a centralized approach to a decentralized one.
Browser-based Single Sign-On (SSO) protocols relieve the user from the burden of dealing with multiple credentials thereby improving the user experience and the security. In this paper we show that ...extreme care is required for specifying and implementing the prototypical browser-based SSO use case. We show that the main emerging SSO protocols, namely SAML SSO and OpenID, suffer from an authentication flaw that allows a malicious service provider to hijack a client authentication attempt or force the latter to access a resource without its consent or intention. This may have serious consequences, as evidenced by a Cross-Site Scripting attack that we have identified in the SAML-based SSO for Google Apps and in the SSO available in Novell Access Manager v.3.1. For instance, the attack allowed a malicious web server to impersonate a user on any Google application. We also describe solutions that can be used to mitigate and even solve the problem.
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