Detection of NPM1 exon 12 mutations and FLT3 – internal tandem duplications by high resolution melting analysis in normal karyotype acute myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Molecular characterisation of normal karyotype acute myeloid leukemia (NK-AML) allows prognostic stratification and potentially can alter treatment choices and pathways. Approximately 45–60% of patients with NK-AML carry <it>NPM1 </it>gene mutations and are associated with a favourable clinical outcome when <it>FLT3</it>-internal tandem duplications (ITD) are absent. High resolution melting (HRM) is a novel screening method that enables rapid identification of mutation positive DNA samples.</p> <p>Results</p> <p>We developed HRM assays to detect <it>NPM1 </it>mutations and <it>FLT3</it>-ITD and tested diagnostic samples from 44 NK-AML patients. Eight were <it>NPM1 </it>mutation positive only, 4 were both <it>NPM1 </it>mutation and <it>FLT3</it>-ITD positive and 4 were <it>FLT3</it>-ITD positive only. A novel point mutation Y572C (c.1715A>G) in exon 14 of <it>FLT3 </it>was also detected. In the group with <it>de novo </it>NK-AML, 40% (12/29) were <it>NPM1 </it>mutation positive whereas <it>NPM1 </it>mutations were observed in 20% (3/15) of secondary NK-AML cases. Sequencing was performed and demonstrated 100% concordance with the HRM results.</p> <p>Conclusion</p> <p>HRM is a rapid and efficient method of screening NK-AML samples for both novel and known <it>NPM1 </it>and <it>FLT3 </it>mutations. <it>NPM1 </it>mutations can be observed in both primary and secondary NK-AML cases.</p

Agronomic and Economic Performance Characteristics of Conventional and Low-External-Input Cropping Systems in the Central Corn Belt

We conducted a 9-ha field experiment near Boone, IA, to test the hypothesis that yield, weed suppression, and profit characteristics of low-external-input (LEI) cropping systems can match or exceed those of conventional systems. Over a 4-yr period, we compared a conventionally managed 2-yr rotation system {corn (Zea mays L.)/soybean [Glycine max (L.) Merr.]} with two LEI systems: a 3-yr corn/soybean/small grain + red clover (Trifolium pratense L.) rotation, and a 4-yr corn/soybean/small grain + alfalfa (Medicago sativa L.)/alfalfa rotation. Synthetic N fertilizer use was 59 and 74% lower in the 3- and 4-yr systems, respectively, than in the 2-yr system; similarly, herbicide use was reduced 76 and 82% in the 3- and 4-yr systems. Corn and soybean yields were as high or higher in the LEI systems as in the conventional system, and weed biomass in corn and soybean was low (≤4.2 g m−2) in all systems. Experimentally supplemented giant foxtail (Setaria faberi Herrm.) seed densities in the surface 20 cm of soil declined in all systems; supplemented velvetleaf (Abutilon theophrasti Medik.) seed densities declined in the 2- and 4-yr systems and remained unchanged in the 3-yr system. Without subsidy payments, net returns were highest for the 4-yr system ($540 ha−1 yr−1), lowest for the 3-yr system ($475 ha−1 yr−1), and intermediate for the 2-yr system ($504 ha−1 yr−1). With subsidies, differences among systems in net returns were smaller, as subsidies favored the 2-yr system, but rank order of the systems was maintained

A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value

Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid β Pathogenicity

Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Aβ42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Aβ42 to form protofibrils and its effect on neuronal dysfunction and degeneration in a Drosophila model of Alzheimer disease. Our findings provide a quantitative description of the molecular basis for the pathogenicity of Aβ and link directly and systematically the intrinsic properties of biomolecules, predicted in silico and confirmed in vitro, to pathogenic events taking place in a living organism

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma:an open-label phase 2 trial

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.</p

Type 2 Diabetes Modifies the association of Cad Genomic Risk Variants With Subclinical atherosclerosis

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC

Vilhelm Lundstedt’s ‘Legal Machinery’ and the Demise of Juristic Practice

This article aims to contribute to the academic debate on the general crisis faced by law schools and the legal professions by discussing why juristic practice is a matter of experience rather than knowledge. Through a critical contextualisation of Vilhelm Lundstedt’s thought under processes of globalisation and transnationalism, it is argued that the demise of the jurist’s function is related to law’s scientification as brought about by the metaphysical construction of reality. The suggested roadmap will in turn reveal that the current voiding of juristic practice and its teaching is part of the crisis regarding what makes us human