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Abstract Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing “immune classes” among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune “risk factors.” By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

Hemoglobinopathies including thalassemias are among the most frequent genetic disorders worldwide. Primarily, these entities result from germline variants in the globin gene clusters and their cis-acting regulatory elements, and thus the WHO classifies thalassemias as inherited diseases. Non-inherited disorders of globin chain synthesis mimicking the phenotype of thalassemias have also been described and are referred to as acquired thalassemias. These forms mainly affect the alpha-globin genes and are observed at much lower frequencies...

Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.

Abstract Background Considering the clinical and genetic characteristics, acute lymphoblastic leukemia (ALL) is a rather heterogeneous hematological neoplasm for which current standard diagnostics require various analyses encompassing morphology, immunophenotyping, cytogenetics, and molecular analysis of gene fusions and mutations. Hence, it would be desirable to rely on a technique and an analytical workflow that allows the simultaneous analysis and identification of all the genetic alterations in a single approach. Moreover, based on the results with standard methods, a significant amount of patients have no established abnormalities and hence, cannot further be stratified. Methods We performed WTS and WGS in 279 acute lymphoblastic leukemia (ALL) patients (B-cell: n = 211; T-cell: n = 68) to assess the accuracy of WTS, to detect relevant genetic markers, and to classify ALL patients. Results DNA and RNA-based genotyping was used to ensure correct WTS-WGS pairing. Gene expression analysis reliably assigned samples to the B Cell Precursor (BCP)-ALL or the T-ALL group. Subclassification of BCP-ALL samples was done progressively, assessing first the presence of chromosomal rearrangements by the means of fusion detection. Compared to the standard methods, 97% of the recurrent risk-stratifying fusions could be identified by WTS, assigning 76 samples to their respective entities. Additionally, read-through fusions (indicative of CDKN2A and RB1 gene deletions) were recurrently detected in the cohort along with 57 putative novel fusions, with yet untouched diagnostic potentials. Next, copy number variations were inferred from WTS data to identify relevant ploidy groups, classifying an additional of 31 samples. Lastly, gene expression profiling detected a BCR-ABL1-like signature in 27% of the remaining samples. Conclusion As a single assay, WTS allowed a precise genetic classification for the majority of BCP-ALL patients, and is superior to conventional methods in the cases which lack entity defining genetic abnormalities.

This review focuses on techniques for modifying the surface of carbon that is produced from sustainable resources, such as pyrolytic carbon. Many of these materials display high specific surface area and fine particle distribution. Functionalization of a surface is a commonly used approach in designing desired surface properties of the treated material while retaining its bulk properties. Usually, oxidation is a primary step in carbon functionalization. It can be performed as wet oxidation, which is a type of chemical surface modification. Wet oxidation is usually performed using nitric acid and hydrogen peroxide, as well as using hydrothermal and solvothermal oxidation. On the other side, dry oxidation is representative of physical surface modification. This method is based on corona discharge and plasma oxidation which are promising methods that are in line with green chemistry approaches. Whilst the oxidation of the carbon surface is a well-known method, other chemical modification techniques, including cycloadditions and various radical reactions on graphene layers, are presented as an alternative approach. Regarding secondary functionalization, coupling organosilanes to activated carbon is a common technique. Organosilanes bearing reactive groups present a bridge between inorganic species and polymer systems, e.g., epoxy and polyurethane resins, and facilitate the use of carbonaceous materials as reinforcing components for polymers and thermosetting resins. Along with the presented functionalization methods, this review also provides an overview of new applications of modified (i.e., functionalized) carbon materials, e.g., for the building industry, wastewater treatment, semiconducting materials and many more.

Summary: Background: Haploinsufficiency (HI) resulting from deletion of the long arm of chromosome 5 [del(5q)] and the accompanied loss of heterozygosity are likely key pathogenic factors in del(5q) myeloid neoplasia (MN) although the consequences of del(5q) have not been yet clarified. Methods: Here, we explored mutations, gene expression and clinical phenotypes of 388 del(5q) vs. 841 diploid cases with MN [82% myelodysplastic syndromes (MDS)]. Findings: Del(5q) resulted as founder (better prognosis) or secondary hit (preceded by TP53 mutations). Using Bayesian prediction analyses on 57 HI marker genes we established the minimal del(5q) gene signature that distinguishes del(5q) from diploid cases. Clusters of diploid cases mimicking the del(5q) signature support the overall importance of del(5q) genes in the pathogenesis of MDS in general. Sub-clusters within del(5q) patients pointed towards the inherent intrapatient heterogeneity of HI genes. Interpretation: The underlying clonal expansion drive results from a balance between the “HI-driver” genes (e.g., CSNK1A1, CTNNA1, TCERG1) and the proapoptotic “HI-anti-drivers” (e.g., RPS14, PURA, SIL1). The residual essential clonal expansion drive allows for selection of accelerator mutations such as TP53 (denominating poor) and CSNK1A1 mutations (with a better prognosis) which overcome pro-apoptotic genes (e.g., p21, BAD, BAX), resulting in a clonal expansion. In summary, we describe the complete picture of del(5q) MN identifying the crucial genes, gene clusters and clonal hierarchy dictating the clinical course of del(5q) patients. Funding: Torsten Haferlach Leukemia Diagnostics Foundation. US National Institute of Health (NIH) grants R35 HL135795, R01HL123904, R01 HL118281, R01 HL128425, R01 HL132071, and a grant from Edward P. Evans Foundation.

Measurable residual disease (MRD) quantified by multiparameter flow cytometry (MFC) is a strong and independent prognostic factor in acute myeloid leukemia (AML). However, several technical factors may affect the final read-out of the assay. Experts from the MRD Working Party of the European LeukemiaNet evaluated which aspects are crucial for accurate MFC-MRD measurement. Here, we report on the agreement, obtained via a combination of a cross-sectional questionnaire, live discussions, and a Delphi poll. The recommendations consist of several key issues from bone marrow sampling to final laboratory reporting to ensure quality and reproducibility of results. Furthermore, the experiences were tested by comparing two 8-color MRD panels in multiple laboratories. The results presented here underscore the feasibility and the utility of a harmonized theoretical and practical MFC-MRD assessment and are a next step toward further harmonization.

Globally, reducing CO2 emissions is an urgent priority. The hydrogen economy is a system that offers long-term solutions for a secure energy future and the CO2 crisis. From hydrogen production to consumption, storing systems are the foundation of a viable hydrogen economy. Each step has been the topic of intense research for decades; however, the development of a viable, safe, and efficient strategy for the storage of hydrogen remains the most challenging one. Storing hydrogen in polymer-based carriers can realize a more compact and much safer approach that does not require high pressure and cryogenic temperature, with the potential to reach the targets determined by the United States Department of Energy. This review highlights an outline of the major polymeric material groups that are capable of storing and releasing hydrogen reversibly. According to the hydrogen storage results, there is no optimal hydrogen storage system for all stationary and automotive applications so far. Additionally, a comparison is made between different polymeric carriers and relevant solid-state hydrogen carriers to better understand the amount of hydrogen that can be stored and released realistically.

There is a wide application field for anti-adhesive and hydrophobic coatings, stretching from self-cleaning surfaces over anti-graffiti and release coatings to demolding aids in the production of polymers. The typical materials for the latter are hard coatings, including TiN, CrN, diamond-like carbon, etc. Alternatively, organosilane coatings based on perfluorinated compounds or molecules with long alkyl side chains can be employed. Although these functional layers are generally required to be invisible, there is a demand for a straightforward approach, which enables the temporary control of successful and homogeneous application as well as abrasion and wear of the coatings during use. For this purpose, a visibility-on-demand property was introduced to an already established anti-adhesive organosilane coating by incorporation of 1,8-naphthalimide-N-propyltriethoxysilane (NIPTES) as a fluorescent marker molecule. While the naphthalimide unit provides blue fluorescence under UV irradiation, the ethoxy groups of NIPTES enable the covalent coupling to the coating as a result of the hydrolysis and condensation reactions. As a consequence, the fluorescent marker molecule NIPTES can simply be added to the coating solution as an additional organosilane component, without the need for changes in the approved deposition procedure. The generated fluorescent anti-adhesive coatings were characterized by contact angle measurements, atomic force microscopy (AFM), as well as by different spectroscopic techniques, including FTIR, UV-Vis, fluorescence and X-ray photoelectron spectroscopy (XPS). In addition, the on-demand control function provided by the introduced fluorescence properties was evaluated along an injection molding process.

Template-based electrodeposition is a versatile technique for the fabrication of freestanding nanowires. However, nanowires of refractory metals, like niobium, have remained inaccessible via this technique due to preferential hydrogen evolution in aqueous solutions. In this work, we have developed a synthetic strategy for template-based electrodeposition of niobium nanowires using an ionic liquid. Optimal growth conditions have been determined using cyclic voltammetry. Structural characterization using transmission electron microscopy, electron diffraction, and energy dispersive spectroscopy showed that the niobium nanowires were polycrystalline with an average grain size of 14 nm. The use of ionic liquid-based electrolytes for nanowire deposition could be expanded to other metals improving material quality due to their high stability, good conductivity, and wide electrochemical window. Keywords: Niobium, Nanowire, Ionic liquid, Template-based electrodeposition

The data presented in this article characterize the thermomechanical and microhardness properties of a novel melamine-formaldehyde resin (MF) intended for the use as a self-healing surface coating. The investigated MF resin is able to undergo reversible crosslinking via Diels Alder reactive groups. The microhardness data were obtained from nanoindentation measurements performed on solid resin film samples at different stages of the self-healing cycle. Thermomechanical analysis was performed under dynamic load conditions. The data provide supplemental material to the manuscript published by Urdl et al. 2020 (http://doi.org/10.1016/j.eurpolymj.2020.109601, [1]) on the self-healing performance of this resin, where a more thorough discussion on the preparation, the properties of this coating material and its application in impregnated paper-based decorative laminates can be found [1].

Straightforward and versatile surface modification, functionalization and coating have become a significant topic in material sciences. While physical modification suffers from severe drawbacks, such as insufficient stability, chemical induced grafting processes efficiently modify organic and inorganic materials and surfaces due to covalent linkage. These processes include the “grafting from” method, where polymer chains are directly grown from the surface in terms of a surface-initiated polymerization and the “grafting to” method where a preformed (macro)-molecule is introduced to a preliminary treated surface via a coupling reaction. Both methods require an initiating species that is immobilized at the surface and can be triggered either by heat or light, whereas light induced processes have recently received increasing interest. Therefore, a major challenge is the ongoing search for suitable anchor moieties that provide covalent linkage to the surface and include initiators for surface-initiated polymerization and coupling reactions, respectively. This review containing 205 references provides an overview on photoinitiators which are covalently coupled to different surfaces, and are utilized for subsequent photopolymerizations and photocoupling reactions. An emphasis is placed on the coupling strategies for different surfaces, including oxides, metals, and cellulosic materials, with a focus on surface coupled free radical photoinitiators (type I and type II). Furthermore, the concept of surface initiation mediated by photoiniferters (PIMP) is reviewed. Regarding controlled radical polymerization from surfaces, a large section of the paper reviews surface-tethered co-initiators, ATRP initiators, and RAFT agents. In combination with photoinitiators or photoredox catalysts, these compounds are employed for surface initiated photopolymerizations. Moreover, examples for coupled photoacids and photoacid generators are presented. Another large section of the article reviews photocoupling and photoclick techniques. Here, the focus is set on light sensitive groups, such as organic azides, tetrazoles and diazirines, which have proven useful in biochemistry, composite technology and many other fields.

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between ‘normal’, pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.

Despite substantial progress achieved in unraveling the genetics of AML in the past decade, its treatment outcome has not substantially improved. Therefore, it is important to better understand how genetic mutations translate to phenotypic features of AML cells to further improve response predictions and to find innovative therapeutic approaches. In this respect, aberrant splicing is a crucial contributor to the pathogenesis of hematological malignancies. Thus far, altered splicing is well characterized in relation to splicing factor mutations in AML. However, splicing profiles associated with mutations in other genes remain largely unexplored. In this study, we explored differential splicing profiles associated with two of the most common aberrations in AML: FLT3-ITD and NPM1 mutations. Using RNA-sequencing data of a total of 382 primary AML samples, we found that the co-occurrence of FLT3-ITD and mutated NPM1 is associated with differential splicing of FAB-type specific gene sets. Despite the FAB-type specificity of particular gene sets, the primary functions perturbed by differential splicing in all three FAB types include cell cycle control and DNA damage response. Interestingly, we observed functional divergence between alternatively spliced and differentially expressed genes in FLT3-ITD+/NPM1+ samples in all analyzed FAB types, with differential expression affecting genes involved in hematopoietic differentiation. Altogether, these observations indicate that concomitant FLT3-ITD and mutated NPM1 are associated with the maturation state-specific differential splicing of genes with potential oncogenic relevance.

The photo-reversible [4πs+4πs] cycloaddition reaction of pendant anthracene moieties represents a convenient strategy to impart wavelength dependent properties into hydrogenated carboxylated nitrile butadiene rubber (HXNBR) networks. The present article provides the 1H NMR data on the reaction kinetics of the side chain functionalization of HXNBR. 2-(Anthracene-9-yl)oxirane with reactive epoxy groups is covalently attached to the polymer side chain of HXNBR via ring opening reaction between the epoxy and the carboxylic groups. Along with the identification, 1H NMR data on the quantification of the attached functional groups are shown in dependence on reaction time and concentration of 2-(anthracene-9-yl)oxirane. Changes in the modification yield are reflected in the mechanical properties and DMA data of photo-responsive elastomers are illustrated in dependence on the number of attached anthracene groups. DMA curves over repeated cycles of UV induced crosslinking (λ>300 nm) and UV induced cleavage (λ=254 nm) are further depicted, demonstrating the photo-reversibility of the thermo-mechanical properties. Interpretation and discussion of the data are provided in “Design and application of photo-reversible elastomer networks by using the [4πs+4πs] cycloaddition reaction of pendant anthracene groups” (Manhart et al., 2016) [1].

The confluence of deep sequencing and powerful machine learning is providing an unprecedented peek at the darkest of the dark genomic matter, the non-coding genomic regions lacking any functional annotation. While deep sequencing uncovers rare tumor variants, the heterogeneity of the disease confounds the best of machine learning (ML) algorithms. Here we set out to answer if the dark-matter of the genome encompass signals that can distinguish the fine subtypes of disease that are otherwise genomically indistinguishable. We introduce a novel stochastic regularization, ReVeaL, that empowers ML to discriminate subtle cancer subtypes even from the same 'cell of origin'. Analogous to heritability, implicitly defined on whole genome, we use predictability (F1 score) definable on portions of the genome. In an effort to distinguish cancer subtypes using dark-matter DNA, we applied ReVeaL to a new WGS dataset from 727 patient samples with seven forms of hematological cancers and assessed the predictivity over several genomic regions including genic, non-dark, non-coding, non-genic, and dark. ReVeaL enabled improved discrimination of cancer subtypes for all segments of the genome. The non-genic, non-coding and dark-matter had the highest F1 scores, with dark-matter having the highest level of predictability. Based on ReVeaL's predictability of different genomic regions, dark-matter contains enough signal to significantly discriminate fine subtypes of disease. Hence, the agglomeration of rare variants, even in the hitherto unannotated and ill-understood regions of the genome, may play a substantial role in the disease etiology and deserve much more attention.

The data present in this article affords insides in the characterization of a newly described bi-functional furan-melamine monomer, which is used for the production of monodisperse, furan-functionalized melamine-formaldehyde particles, as described in https://doi.org/10.1016/j.eurpolymj.2019.04.006 Urdl et al., 2019. In the related research article Urdl et al., 2019 data interpretations can be found. The furan-functionalization of particles is necessary to perform reversible Diels-Alder reactions with maleimide (BMI) crosslinker to form thermoreversible network systems. To understand the reaction conditions of Diels-Alder (DA) reaction with a Fu-Mel monomer and a maleimide crosslinker, model DA reaction were performed and evaluated using dynamic FT-IR measurements. During retro Diels-Alder (rDA) reactions of the monomer system, it was found out that some side reaction occurred at elevated temperatures. The data of evaluating the side reaction is described in one part of this manuscript. Additional high resolution SEM images of Fu-Mel particles are shown and thermoreversible particle networks with BMI2 are shown. The data of different Fu-Mel particle networks with maleimide crosslinker are presented. Therefore, the used maleimide crosslinker with different spacer lengths were synthesized and the resulting networks were analyzed by ATR-FT-IR, SEM and DSC. Keywords: Melamine-formaldehyde, Furan-functionalized particle, Diels-alder reaction, Thermoset

Abstract. AML with RUNX1-RUNX1T1 fusion is a WHO entity with a favorable outcome following intensive chemotherapy. The absence of RUNX1-RUNX1T1 transcripts in remission defines complete molecular response and correlates with a superior survival. However, a significant proportion of patients still relapses and defining molecular risk factors that identify patients at diagnosis or at molecular remission that are at risk of relapse could help tailor treatment strategies for those high risk patients. Here, we analyze a cohort of 94 patients that reach a molecular remission (MR) following intensive treatment and identify 21 patients that relapse despite achieving MR. Using targeted sequencing of 63 genes implicated in hematologic malignancies we show that at diagnosis patients who relapse following MR have a higher burden of co-mutated genes than patients that do not relapse (median = 2 vs median = 0; P = 0.0156). This resulted in a relapse free survival rate of 65% vs 86% at 2 years, respectively (≥1 co-mutation vs no co-mutation, P = 0.02) with a trend for inferior overall survival (n.s.). Applying sensitive sequencing to reassess mutations at relapse in paired samples of 17/21 patients we demonstrate a net loss of co-mutations at relapse: median 2 (range 0–5) vs 1 (0–4) at diagnosis and relapse (P = 0.048). At relapse more patients had no detected co-mutation compared to diagnosis (47% vs 17%, P = 0.034). Co-mutations at diagnosis, therefore, might represent a general susceptibility of the AML clone to acquire mutations and the true nature of 2nd hit mutations that drive leukemia has to be defined for AML with RUNX1-RUNX1T1 fusion.

Photopolymerization has undergone significant development in recent years. It enables fast and easy processing of materials with customized properties and allows precise printing of complex surface geometries. Nevertheless, photopolymerization is mainly applied to cure thin films since the low curing depth limits the fast production of large volumes. Frontal photopolymerization (FPP) is suitable to overcome these limitations so that curing of centimeter-thick (meth)acrylic layers can be accomplished within minutes by light induction only. Prerequisites, however, are the low optical density of the resin and bleaching ability of the photoinitiator. To date, tailored FPP-resins are not commercially available. This study discusses the potential of long-chain polyether dimethacrylates, offering high-temperature resistance and low optical density, as crosslinkers in photobleaching resins and investigates the mechanical properties of photofrontally-cured copolymers. Characteristics ranging from ductile to hard and brittle are observed in tensile tests, demonstrating that deep curing and versatile material properties are achieved with FPP. Analyzed components display uniform polymerization over a depth of four centimeters in Fourier transform infrared spectroscopy and swelling tests.

Photopolymerization offers substantial advantages in terms of time, temperature, energy consumption, and spatial control of the initiation. The application however is strongly limited due to the constrained penetration of light into thick films. Strategies to overcome the problem of limited curing depth, as well as to improve the curing of shadow areas, involve dual curing, frontal polymerization, and upconversion of particles. Whereas excellent results have been accomplished applying photofrontal polymerization on a theoretical level, few studies report on practical applications achieving high curing depth within short time. This study aims to investigate the potential of photofrontal polymerization, performed only with photoinitiator and light, for the fast and easy production of several-centimeter-thick (meth)acrylic layers. Monomer/ initiator systems were evaluated with respect to their optical density as well as photobleaching behavior. Moreover, depth-dependent polymerization was studied in specimens of varying monomer ratio and photoinitiator concentration. When an ideal photoinitiator concentration was selected, curing up to 52 mm in depth was accomplished within minutes.

The only cytogenetic aberration defining a myelodysplastic syndrome subtype is the deletion of the long arm of chromosome 5, which, along with morphological features, leads to the diagnosis of myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5. These patients show a good prognosis and respond to treatment such as lenalidomide, but some cases progress to acute myeloid leukemia; however, the molecular mutation pattern is rarely characterized. Therefore, we investigated a large cohort of 123 myelodysplastic syndrome patients with isolated deletion of the long arm of chromosome 5, diagnosed following the World Health Organization classifications 2008 and 2016, by sequencing 27 genes. A great proportion of patients showed no or only one mutation. Only seven genes showed mutation frequencies >5% (SF3B1, DNMT3A, TP53, TET2, CSNK1A1, ASXL1, JAK2). However, the pattern of recurrently mutated genes was comparable to other myelodysplastic syndrome subtypes by comparison to a reference cohort, except that of TP53 which was significantly more often mutated in myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5. As expected, SF3B1 was frequently mutated and correlated with ring sider-oblasts, while JAK2 mutations correlated with elevated platelet counts. Surprisingly, SF3B1 mutations led to significantly worse prognosis within cases with isolated deletion of the long arm of chromosome 5, but showed a comparable outcome to other myelodysplastic syndrome subtypes with SF3B1 mutation. However, addressing genetic stability in follow-up cases might suggest different genetic mechanisms for progression to secondary acute myeloid leukemia compared to overall myelodysplastic syndrome patients.

Current recommendations for diagnosing myelodysplastic syndromes endorse flow cytometry as an informative tool. Most flow cytometry protocols focus on the analysis of progenitor cells and the evaluation of the maturing myelomonocytic lineage. However, one of the most frequently observed features of myelodysplastic syndromes is anemia, which may be associated with dyserythropoiesis. Therefore, analysis of changes in flow cytometry features of nucleated erythroid cells may complement current flow cytometry tools. The multicenter study within the IMDSFlow Working Group, reported herein, focused on defining flow cytometry parameters that enable discrimination of dyserythropoiesis associated with myelodysplastic syndromes from non-clonal cytopenias. Data from a learning cohort were compared between myelodysplasia and controls, and results were validated in a separate cohort. The learning cohort comprised 245 myelodysplasia cases, 290 pathological, and 142 normal controls; the validation cohort comprised 129 myelodysplasia cases, 153 pathological, and 49 normal controls. Multivariate logistic regression analysis performed in the learning cohort revealed that analysis of expression of CD36 and CD71 (expressed as coefficient of variation), in combination with CD71 fluorescence intensity and the percentage of CD117+ erythroid progenitors provided the best discrimination between myelodysplastic syndromes and non-clonal cytopenias (specificity 90%; 95% confidence interval: 84–94%). The high specificity of this marker set was confirmed in the validation cohort (92%; 95% confidence interval: 86–97%). This erythroid flow cytometry marker combination may improve the evaluation of cytopenic cases with suspected myelodysplasia, particularly when combined with flow cytometry assessment of the myelomonocytic lineage.

The aim of this study was the investigation of the use of modified talcum for supporting crosslinking and as novel nucleating agent for physical foaming of polyethylene. For the modification of the talcum, a thermal initiator was linked to the talcum surface. During the extrusion process, the initiator decomposes, and gas and radicals are formed. The gas generates the nucleation of cells and the radicals support the crosslinking process between the polymer chains. The modification of the talcum was performed in three steps: The first step was the grafting of alkoxysilanes onto the talcum surface. The second step was the chlorination of the thermal initiator for an easier linkage, and the last step was the linking between the initiator and the silanes grafted onto the talcum surface. For this study, two investigations were carried out. One investigation was the analysis of the crosslinking effect with the modified talcum. For this purpose, polyethylene plates were compression molded and the viscoelastic properties were measured with a parallel plate rheometer. The use of the modified talcum led to a higher crosslinking density. The second investigation was the physical foaming experiment in an extrusion process with nitrogen as blowing agent using both a pure and the modified talcum as nucleating agents. The foamed samples were characterized in terms of density, cell size and cell density, and compared with each other. The blend with the modified nucleating agent indicated a foam structure with a smaller mean cell size and a lower density compared to the use of the pristine nucleating agent.

The development of leukemia is a step-wise process that is associated with molecular diversification and clonal selection of neoplastic stem cells. Depending on the number and combinations of lesions, one or more sub-clones expand/s after a variable latency period. Initial stages may develop early in life or later in adulthood and include premalignant (indolent) stages and the malignant phase, defined by an acute leukemia. We recently proposed a cancer model in which the earliest somatic lesions are often age-related early mutations detectable in apparently healthy individuals and where additional oncogenic mutations will lead to the development of an overt neoplasm that is usually a preleukemic condition such as a myelodysplastic syndrome. These neoplasms may or may not transform to overt acute leukemia over time. Thus, depending on the type and number of somatic mutations, clonal hematopoiesis (CH) can be divided into CH with indeterminate potential (CHIP) and CH with oncogenic potential (CHOP). Whereas CHIP mutations per se usually create the molecular background of a neoplastic process, CHOP mutations are disease-related or even disease-specific lesions that trigger differentiation and/or proliferation of neoplastic cells. Over time, the acquisition of additional oncogenic events converts preleukemic neoplasms into secondary acute myeloid leukemia (sAML). In the present article, recent developments in the field are discussed with a focus on CHOP mutations that lead to distinct myeloid neoplasms, their role in disease evolution, and the impact of additional lesions that can drive a preleukemic neoplasm into sAML.

Printed circuit boards (PCBs) have a wide range of applications in electronics where they are used for electric signal transfer. For a multilayer build-up, thin copper foils are alternated with epoxy-based prepregs and laminated to each other. Adhesion between copper and epoxy composites is achieved by technologies based on mechanical interlocking or chemical bonding, however for future development, the understanding of failure mechanisms between these materials is of high importance. In literature, various interfacial failures are reported which lead to adhesion loss between copper and epoxy resins. This review aims to give an overview on common coupling technologies and possible failure mechanisms. The information reviewed can in turn lead to the development of new strategies, enhancing the adhesion strength of copper/epoxy joints and, therefore, establishing a basis for future PCB manufacturing.

Chronic myeloid leukemia cells acquire resistance to tyrosine kinase inhibitors through mutations in the ABL1 kinase domain. The T315I mutation mediates resistance to imatinib, dasatinib, nilotinib and bosutinib, whereas sensitivity to ponatinib remains. Mutation detection by conventional Sanger sequencing requires 10%–20% expansion of the mutated subclone. We studied the T315I mutation development by ultra-deep sequencing on the 454 XL+ platform (Roche) in comparison to Sanger sequencing. By ultra-deep sequencing, mutations were detected at loads of 1%–2%. We selected 40 patients who had failed first-line to third-line treatment (imatinib, dasatinib, nilotinib) and had high loads of the T315I mutation detected by Sanger sequencing. We confirmed T315I mutations by ultra-deep sequencing and investigated the mutation dynamics by backtracking earlier samples. In 20 of 40 patients, we identified the T315I three months (median) before Sanger sequencing detection limits were reached. To exclude sporadic low percentage mutation development without subsequent mutation outgrowth, we selected 42 patients without resistance mutations detected by Sanger sequencing but loss of major molecular response. Here, no mutation was detected by ultradeep sequencing. Additional non-T315I resistance mutations were found in 20 of 40 patients. Only 15% had two mutations per cell; the other cases showed multiple independently mutated clones and the T315I clone demonstrated a rapid outgrowth. In conclusion, T315I mutations could be detected earlier by ultra-deep sequencing compared to Sanger sequencing in a selected group of cases. Earlier mutation detection by ultra-deep sequencing might allow treatment to be changed before clonal increase of cells with the T315I mutation.

Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84–4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25–11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.

Five types of nanofillers, namely, silica, surface-silylated silica, alumina, surface-silylated alumina, and boron nitride, were tested in this study. Nanocomposites composed of an epoxy/amine resin and one of the five types of nanoparticles were tested as dielectrics with a focus on (i) the surface functionalization of the nanoparticles and (ii) the water absorption by the materials. The dispersability of the nanoparticles in the resin correlated with the composition (OH content) of their surfaces. The interfacial polarization of the thoroughly dried samples was found to increase at lowered frequencies and increased temperatures. The β relaxation, unlike the interfacial polarization, was not significantly increased at elevated temperatures (below the glass-transition temperature). Upon the absorption of water under ambient conditions, the interfacial polarization increased significantly, and the insulating properties decreased or even deteriorated. This effect was most pronounced in the nanocomposite containing silica, and occurred as well in the nanocomposites containing silylated silica or non-functionalized alumina. The alternating current (AC) breakdown strength of all specimens was in the range of 30 to 35 kV·mm−1. In direct current (DC) breakdown tests, the epoxy resin exhibited the lowest strength of 110 kV·mm−1; the nanocomposite containing surface-silylated alumina had a strength of 170 kV·mm−1. In summary, water absorption had the most relevant impact on the dielectric properties of nanocomposites containing nanoparticles, the surfaces of which interacted with the water molecules. Nanocomposites containing silylated alumina particles or boron nitride showed the best dielectric properties in this study.