Results of Polish Adult Leukemia Study Group (PALG) project assessing TP53 mutations with next-generation sequencing technology in relapsed and refractory chronic lymphocytic leukemia patients — an 18-month update

Indtroduction and methods: In chronic lymphocytic leukemia (CLL), molecular and cytogenetic diagnostics are crucial for the determination of accurate prognosis and treatment choice. Among different genetic aberrations, del(17p13) or TP53 mutations constitute high-risk factors, and early identification of such defects is a high priority for CLL patients. While cytogenetic diagnostics is well-established and accessible for the majority of CLL patients in Poland, molecular diagnostics of TP53 mutations is performed only in a few ERIC-certified centers (eight as of September 2020), and only two of these employ next-generation sequencing (NGS) for routine analysis of TP53 status in CLL patients. Here we report the interim results of a project assessing TP53 mutations with NGS technology in relapsed or refractory CLL patients with confirmed negative del(17p13) status. 249 patients from 32 clinical centers were included in the study. Results: NGS analysis revealed TP53 mutations in 42/249 (17%) patients, half of whom (21/249, 8.5%) had subclonal mutations (VAF ≤10%). These results are in line with published data in relapsed/refractory CLL patients. Conclusions: The results of the project demonstrated the feasibility and accuracy of NGS testing in CLL patients despite several initial logistical and technical obstacles. Our study also proved that, with appropriate funding, CLL patients from any hematological center in Poland can have access to state-of-the-art molecular diagnostic

Polymorphisms within autophagy-related genes as susceptibility biomarkers for multiple myeloma: a meta-analysis of three large cohorts and functional characterization

Functional data used in this project have been meticulously catalogued and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/, accessed on 12 February 2020) using the MOLGENIS open-source platform for scientific data.Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte hemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP corre lated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+ IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4 ) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4 ). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.This work was supported by the European Union’s Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), Consejería de Transformación Económica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB).This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.This work was supported by the European Union’s Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), Consejería de Transformación Económica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB). This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).Peer reviewe

Technological issues and modelization of biomass driers

Zsfassung in dt. SpracheMan kann Pflanzen als Energiespeicher betrachten, da die Sonnenstrahlen von ihnen absorbieren, umgewandelt und in chemischer Form gespeichert werden. Die Umwandlungseffizienz der Pflanzen ist oft abhängig von der Klimazone. Damit Biomasse konkurrenzfähig zu Kohle, Gas oder Öl ist, müssen die Erträge pro Hektar gesteigert werden, indem zum Beispiel schnell wachsende Pflanze gezüchtet werden, oder eine Beeinflussung der Photosynthese durch Genmanipulation stattfindet. Ein Vergleich der landwirtschaftlichen Nutzung für den Anbau von Energiepflanzen und normaler Landwirtschaft zeigt, in Bezug auf die Wirtschaftlichkeit, ob ein Umstieg rentabel ist. Zu steigender Konkurrenzfähigkeit der Biomasse tragen neue Verfahren und höhere Effizienz der Umwandlungsanlagen bei. Eine Auflistung der Verfahren die es ermöglichen Biomasse in Wärme, Elektrizität oder flüssige Stoffe umzuwandeln, zeigt welche Biomasse für welchen Zweck am Geeignetesten ist. Der Vergleich der Biomasse mit anderen erneuerbaren Energiequellen wie Photovoltaik, Windenergie oder der Solarwärme zeigt ihre momentane maximale Effizienz, sowie die Kosten für solche Anlagen und Zukunftsperspektiven der einzelnen Bereiche. Die Charakterisierung der wichtigsten Parameter für die Holzqualität zeigt, was getan werden muss um eine optimale Prozessführung zu gewährleisten. Bei der Anlieferung verfügt das Holz nicht über die benötigten Eigenschaften für die Vergasung, insbesonders ist die Feuchtigkeit des Holzes ein Problemfaktor. Ein Vergleich zwischen den einzelnen Trocknungsanlagen zeigt, welche sich am Besten für die nachfolgende Holzvergasung eignen würde. Ein vereinfachtes mathematisches Model eines Drehrohrtrockners beschreibt, das Verhalten des Trocknungs-Mediums und der Biomasse, am Eingang und Ausgang der Anlage. Dadurch soll eine Hilfstellung, zur Entscheidungen in Bezug auf die richtige Wahl der Trockneranlage, gegeben werden. Durch Internetrecherchen wurde am internationalen Markt nach Produzenten gesucht, welche Informationen über möglichen Faktoren die einen Einfluss auf die Größe, Funktionalität und die Kosten eines Trockners haben, und diese dann zur Verfügung stellten.Sun energy that hits the earth's surface can be stored in different ways, namely by the evaporation of water, through air heating causing air movements or by plants converting sun energy into a chemical form by means of photosynthesis.There is a big gap between the maximum theoretical photosynthesis efficiency of plants and their actual efficiency achieved under normal conditions. In order to make biomass more competitive to fossil energy, its yield per hectare has to rise, for instance through breeding of fast growing plants or the genetic manipulation of photosynthesis. Biomass and therefore stored chemical energy can be dissipated into heat, electricity or liquid products through either a thermo-chemical, a physico-chemical or a bio-chemical process, whereby each of these processes makes use of the most suitable type of biomass. A comparison between biomass and other renewable energy suppliers such as photovoltaics, wind power plants or CSP power plants, provides an overview of the best possible mode of application. Furthermore, a focus is put on wood and the necessary pre-treatment for gasification. In order to ensure an ideal gasification process, some parameters of the quality of wood have to be controlled before its usage. Freshly harvested wood is not suitable for gasification and is therefore dried until a moisture content of 15 to 20 percent is reached. By comparing the advantages and disadvantages of different types of dryers, a selection is made facilitating the choice of the most suitable dryer for gasification. In order to describe the behaviour of the drying medium (superheated steam) and wood moisture at the inlet and outlet side of the rotary drum dryer, a simplified mathematical model was carried out. An examination of the international market regarding such apparatuses provides an overview of the most important producers. All the information obtained is used to find main parameters affecting size, performance and costs of a rotary drum dryer.11

BAYESIAN CONFIDENCE INTERVALS FOR THE NUMBER AND THE SIZE OF LOSSES IN THE OPTIMAL BONUS–MALUS SYSTEM

Most of the so far proposed Bonus–Malus Systems (BMSs) establish a premium only according to the number of accidents, without paying attention to the vehicle damage severity. [Frangos and Vrontos 2001] proposed the optimal BMS design based not only on the number of accidents of a policyholder, but also on the size of loss of each accident. In our work, we apply the approach presented by Frangos and Vrontos to construct the Bayesian confidence intervals for both the number of accidents and the amount of damage caused by these accidents. We also conduct some simulations in order to create tables of estimates for both the numbers and the sizes of losses and to compute the realizations of the corresponding Bayesian confidence intervals. We compare the results obtained by using our simulation studies with the appropriate results derived through an application of an asymmetric loss function and its certain modification.93-10

The cosmic ray detector for the NICA collider

Multi-Purpose Detector (MPD) is a main part of a new Ion Collider fAcility (NICA) located in Dubna, Russia. To increase MPD functionality, it was proposed to add an additional muon trigger system for off-beam calibration of the MPD sub-detectors and for rejection of cosmic ray background during experiments. The system could also be very useful for astrophysical observations of cosmic showers initiated by high energy primary particles. This article describes the main goals of MCORD detector and the early stage of MCORD design, based on plastic scintillators with silicon photomultiplier photodetectors (SiPM) for scintillation readout and electronic system based on MicroTCA standard

The cosmic ray detector for the NICA collider

Multi-Purpose Detector (MPD) is a main part of a new Ion Collider fAcility (NICA) located in Dubna, Russia. To increase MPD functionality, it was proposed to add an additional muon trigger system for off-beam calibration of the MPD sub-detectors and for rejection of cosmic ray background during experiments. The system could also be very useful for astrophysical observations of cosmic showers initiated by high energy primary particles. This article describes the main goals of MCORD detector and the early stage of MCORD design, based on plastic scintillators with silicon photomultiplier photodetectors (SiPM) for scintillation readout and electronic system based on MicroTCA standard

Does a multiple myeloma polygenic risk score predict overall survival of myeloma patients?

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) iden-tified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consor-tium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associa-tions were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P &lt; 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma

Identification of novel genetic loci for risk of multiple myeloma by functional annotation

Multiple myeloma (MM) is one of the most common hematological malignancies, accounting for 20% of all newly diagnosed hematological cancers [1]. The most recent data from Cancer Today show that in 2020 the number of new MM cases was 176,404 worldwideThis work was partially supported by: intramural funding of DKFZ; Horizon 2020 of the European Union, grant 856620; the Intramural Research Program of the National Cancer Institute, National Institutes of Health, grant number U01CA271014 and U01 CA249955. Open Access funding enabled and organized by Projekt DEAL.Peer reviewe