ALBERT

Description: Subnational socio-economic datasets are required if we are to assess the impacts of global environmental changes and to improve adaptation responses. Institutional and community efforts should concentrate on standardization of data collection methodologies, free public access, and geo-referencing. Nature Climate Change 5 503 doi: 10.1038/nclimate2593

Description: Zusammenfassung Die Resilienz einer regionalen Ökonomie hängt maßgeblich davon ab, inwiefern relevantes spezifisches Humankapital zwischen deren Wirtschaftsaktivitäten wieder verwertet werden kann. Zu diesem Zweck wird das Instrumentarium Industry Space, das sich auf die Ähnlichkeiten in der Nutzung von Humankapital bzw. Skill-Relatedness zwischen Branchen stützt, zur Beschreibung der Wissensbasis zwischen den vorhandenen Wirtschaftszweigen einer Region sowie zur Analyse von dessen Wachstumsperspektiven und Resilienz vorgestellt. Beim Industry Space handelt es sich um ein Netzwerk von Branchen, die skill-related sind. Am Beispiel des Saarlandes wird mithilfe dieses Instrumentariums für den Zeitraum 2008 bis 2012 gezeigt, dass dessen Resilienz durch die Spezialisierung auf traditionelle Industriezweige, welche miteinander skill-related sind, gestärkt wird. Aber die im Zuge des Strukturwandels dieser Altindustrieregion entstandenen jungen technologieintensiven Branchen sind nicht mit dem älteren verarbeitenden Gewerbe verbunden, so dass hierdurch regionale Wachstumspotenziale unausgeschöpft bleiben.

Description: Background: The invention of Next Generation Sequencing (NGS) has spurred research into human diseases, especially in the field of malignancy. In acute myeloid leukemia (AML), a plethora of novel alterations have been identified, including mutations in epigenetic regulator genes (e.g. IDH1, IDH2, DNMT3A), genes coding for proteins of the cohesin complex (e.g. SMC1A, SMC3, STAG2) and spliceosome genes (e.g. SF3B1, U2AF1). Although the diagnostic and prognostic implications of many of these alterations are not yet clear, there is increasing evidence that several of them might have major implications for understanding the disease biology or for patient-treatment. Thus, there is increasing need to reliably detect these mutations in large patient groups in clinically relevant time-frames and at an affordable cost. Due to the large number of genes to be screened, amplicon-based NGS represents an attractive detection method. Although, several assays have been reported, integrating different numbers of genes, it is currently unclear whether they really allow reliable detection of alterations in a reproducible way. Here we report our results from a round robin comparison of the detection of known AML-variants using a highly multiplexed, single tube assay coamplifying a total of 568 amplicons covering 54 entire genes or hot spot gene regions involved in leukemia (TruSight Myeloid sequencing panel; Illumina), with respect to the sensitivity, reproducibility and quantitative accuracy. Material and Methods: Ten European laboratories routinely involved in molecular AML diagnostics participated in this study. All groups performed two sequencing runs, each containing 8 samples. These samples were centrally aliquoted and distributed, the analyses were done in a blinded fashion. Six out of the 8 samples on each run were derived from a set of 9 samples composed of DNA isolated from the blasts of 18 different newly diagnosed AML patients mixed at a 1:1 ratio, with 50 ng of DNA being used for the library preparation. Three of these 9 samples were analyzed in replicate in separate runs by each group. The remaining two samples were a commercial test DNA containing 10 known single nucleotide variants (SNV) or insertion/deletion (InDel) alterations with defined variant allele frequencies (VAF) between 4 and 25% and DNA derived from the OCI-AML3 AML cell line (mutant for DNMT3A and NPM1). Sequencing was performed on MiSeq NGS systems (Illumina) using 2x151 bp-runs. Sequencing data were analyzed by all laboratories using the VariantStudio software (Illumina), with the threshold for mutation calling set at 3%. Results: Analysis of data quality indicated that 85% of the samples met the predefined acceptance criteria (〉=95% amplicons with at least 500 reads/amplicon), the median coverage was 7379 reads/amplicon (range 0-47403 reads). Of the 9 mutations present in the positive control, 7 were called at least once in the two replicates by all labs, two mutations with a VAF of 5% were missed by 1 and 4 participants, respectively. Overall, the VAF calls for this sample showed a high level of accuracy across the participants (median coefficient of variation 5%, range 0-22.5%) as well as excellent intra- and inter-laboratory reproducibility (Fig.1). In total, the 9 primary leukemic samples contained 43 known variants in 19 genes, including all commonly mutated genes in AML, i.e. CEBPA, DNMT3A,RUNX1, NPM1, FLT3, WT1. For these samples, the sensitivity was 95.7%. Based on the entire data set (positive control and leukemic samples), the calculated sensitivity of the assay for known variants with an expected VAF〉=5% was 93.3%. The rate of non-calls was slightly higher for InDels (14/179; 7.8%) than for SNVs (25/407; 6.1%; P=.47). Two 57-bp long insertions in FLT3 exons 14/15 were not called, which is expected due to the specifications of the assay (max. detectable InDel length

Description: Background De novo acute myeloid leukemia (AML) is a malignant disorder of hematopoietic stem and progenitor cells usually characterized by a rapid clinical onset. Despite this clinical manifestation, recent evidence suggests that premalignant stem cells might be present in patients with AML, which can persist after chemotherapy in some patients and induce clonal hematopoiesis. Little is known about the prevalence of clonal persistence and about the molecular basis. In order to study the prevalence of this phenomenon and to better understand the underlying molecular mechanisms, we investigated AML patients in remission for clonal persistence of cells after chemotherapy. Patients and methods: All patients included in this analysis were treated within a prospective treatment protocol of the Study Alliance Leukemia (SAL). The primary study cohort consisted of 61 female patients with intermediate risk cytogenetics achieving hematologic complete remission (CR), whose DNA material was available at CR. Clonality analysis was based on X-chromosome inactivation testing using the HUMARA assay. DNA from diagnostic samples of patients presenting with evidence for X-chromosome skewing in CR was analyzed using amplicon based resequencing on a MiSeq next generation sequencing (NGS)-system for DNMT3A, ASXL1, ASXL2, TET1, TET2, EZH1, EZH2, IDH1 and IDH2. Results: Of the 61 patients included, 52 were heterozygous for the STR in the human androgen receptor gene. In CR, 22 of these 52 patients (42%) showed evidence for a skewed X-chromosome representation, indicating persistence of clonal hematopoiesis in remission. The NGS-based analysis of genes involved in epigenetic regulation revealed mutations in 13/22 (59%) of the patients. DNMT3A was most frequently mutated (11/13 patients), either alone or in combination with other alterations (TET2, EZH2). Interestingly, two patients showed somatic alterations in the TET1 gene. In remission, clonal persistence of these alterations was detected in all 13 patients with mutations at diagnosis at levels between 0.8 and 50% as documented using ultradeep-NGS. To get an idea on the prevalence of clonal persistence in other cytogenetic groups, we analyzed 22 low risk (i.e. CBF-leukemias) as well as 18 poor risk (-7, complex karyotype) patients using the HUMARA assay. Here we observed similar results, with 13/19 informative patients showing clonal persistence in low-risk group (68%) compared to 7/14 patients (50%) in the poor risk population. Since all these analyses were confined to female patients and potentially limited by the sensitivity of the HUMARA method, we went on to look for persistence of clonal molecular markers using more sensitive ultra-deep NGS. Because DNMT3A exon 23 was the common alteration in this initial analysis, we screened a cohort of 48 patients with mutations in NPM1 and comutations in DNMT3A. In this separate cohort, persistence of the DNMT3A mutations at CR or during follow-up (FU) was detected in 42 patients (87.5%) at levels between 0.5 and 50% (median 11.1%). No difference was seen between male and female patients, the median age was 51 years, persistence was seen even in young patients at 26 years of age. During FU, the DNMT3A VAF level rose further in all patients analyzed, arguing for a clonal advantage of the mutant cells. All patients with relapse and available material showed high levels of DNMT3A at time of relapse. However, correlation of DNMT3A mutant allele levels at CR1 with the incidence of relapse showed no significant impact of the VAF for the development of relapse. Conclusions: Our data indicate that clonal persistence of premalignant cells carrying clonal alterations in epigenetic regulator genes is a common phenomenon in patients in continuous CR. DNMT3A is the most common lesion persisting, the majority of patients with this mutations retain it at CR and during FU. These data indicate that de novo AML develops from preleukemic stem and progenitor cells in many patients. Preliminary data indicate that this persistence per se is not associated with inferior outcome. Disclosures Schuster: AgenDix GmbH: Employment. Thiede:AgenDix GmbH: Equity Ownership, Research Funding; Illumina: Research Support, Research Support Other.

Description: Background: Relapse of disease remains the major cause of treatment failure in patients with acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS), even after allogeneic hematopoietic stem cell transplantation (HSCT). Treatment of relapsed AML or MDS is difficult, especially after HSCT, and long-term prognosis of patients suffering from relapse is dismal. One approach to overcome this problem is to use sensitive molecular diagnostic strategies to detect recurring disease already at the level of minimal residual disease (MRD), thus avoiding the development of overt hematologic relapse by treatment of patients at the stage of molecular relapse. We have recently implemented preemptive treatment with the demethylating drug 5-Azacitidine (AZA) in patients with molecular evidence of recurrent disease in a prospective Phase II study (RELAZA). In this study, 80% of the patients showed responses, with reduction of MRD and prolonged leukemia free survival, 20% of patients even showed molecular clearance of their leukemia and long-term disease free survival. More recently, results from several groups studying demethylating agents in MDS or AML suggested that patients with mutations in genes involved in epigenetic DNA-modification, such as TET2, DNMT3A or IDH1 or IDH2 might be more responsive to treatment with these drugs. Since we observed varying clinical response in the patients treated preemptively with AZA for molecular evidence of recurrent disease, we correlated the clinical response in these patients with the presence of mutations in epigenetic regulator genes in order to identify potential predictors of response. Patients and Methods: A cohort of 44 patients (23 f/21 m), median age 55.6 years (range 21-75 years), in hematological remission with AML (N=40) or MDS (N=4) were given AZA to treat molecular relapse defined by mutant NPM1 (N=23) or CD34+ chimerism (N=21). Patients were monitored post allogeneic HSCT (N=26) or standard chemotherapy (N=18). The cohort received a median of 5 cycles of AZA (ranging from 1-18 cycles). DNA taken at first diagnosis was analyzed using amplicon based resequencing on a MiSeq next generation sequencing system for the following genes, either analyzing the complete coding region (EZH1, EZH2, DNMT3A, TET1 and TET2) or hot-spot regions (ASXL1, ASXL2, IDH1, IDH2). First diagnosis samples were unavailable for 4 patients. In these, DNA from sorted CD34+ cells taken at the time of molecular relapse was used as a substitute. Results: Amplicon sequencing revealed mutations in one or more genes in 25/44 patients (56.8%). With 15 mutations (34%), DNMT3A was the most frequently mutated gene, the majority of the alterations (9; 60%) were located in exon 23. Mutations in TET2 were found in 8 patients, IDH1 was mutated twice, ASXL2, EZH2 and TET1 were mutated once each. In 20 of the 44 patients (45.5%), no mutations in the investigated genes were found. A comparison of primary response to AZA-treatment (defined as stabilization or decrease of the MRD-marker) between patients with and without mutations revealed no significant difference (79.2 vs 66.6%; P=.48). Likewise, the rate of hematologic relapse was comparable in both cohorts (54% vs. 56%). However, a more detailed look at the patients with mutations revealed differences. The highest initial response rate was observed in patients with DNMT3A mutations (87%), whereas patients with isolated TET2 mutations were less likely to respond (50%). Also, the rate of hematologic relapse was highest in patients with TET2-mutations (75%) compared to patients with DNMT3A-mutations alone (41.6%). In support of a role of TET2-mutations in mediating resistance, an analysis of matched diagnosis and relapse samples in three patients indicated persistence of TET2-loss of function mutations in one patient as well as an acquisition of a second mutant TET2- allele or a switch to a loss-of function-mutation in two patients, indicating that a clonal evolution favoring a subclone with an inactivating TET2-allele under treatment with AZA occurred. Conclusions: Our data confirm that mutations in epigenetic regulator genes are common in patients with AML. Although based on small numbers, these preliminary data do not support that mutations in these genes are associated per se with an improved response to treatment with AZA, but might indicate a differential effect of certain alterations, i.e. DNMT3A-mutations or mutations of TET2. Disclosures Middeke: Genzyme: Speakers Bureau. Thiede:AgenDix GmbH: Equity Ownership, Research Funding; Illumina: Research Support, Research Support Other.

Description: Only scarce information is available on doctorate recipients’ career outcomes ( BuWiN, 2013 ). With the current information base, graduate students cannot make an informed decision on whether to start a doctorate or not ( Benderly, 2018 ; Blank et al., 2017 ). However, administrative labor market data, which could provide the necessary information, are incomplete in this respect. In this paper, we describe the record linkage of two data sets to close this information gap: data on doctorate recipients collected in the catalog of the German National Library (DNB), and the German labor market biographies (IEB) from the German Institute of Employment Research. We use a machine learning-based methodology, which (a) improves the record linkage of data sets without unique identifiers, and (b) evaluates the quality of the record linkage. The machine learning algorithms are trained on a synthetic training and evaluation data set. In an exemplary analysis, we compare the evolution of the employment status of female and male doctorate recipients in Germany.

Description: In dieser Arbeit wurde fur einen Zeitraum von 49 Jahren das Auftreten von Starkniederschlagsereignissen untersucht. Einerseits wurde für diesen Zeitraum eine Analyse der Haufigkeiten der Großwetterlagen durchgeführt und andererseits wurden einzelne Starkniederschlagsereignisse anhand von Fallbeispielen untersucht. Desweiteren wurde an ausgewählten Starkniederschlagsereignissen ein Vergleich von beobachteten Niederschlagswerten mit vorhergesagten Niederschlägen des Lokal Modells des DWD durchgeführt um eventuelle orografische Verstärkungsfaktoren zu bestimmen. Dafür wurden Verteilungskarten des Niederschlags, der Niederschlagsquotienten u.a. für beide Datensätze angefertigt. Es ließ sich feststellen, dass zum Großteil die räumliche Verteilung der Niederschläge von dem Lokal Modell recht gut vorhergesagt wurde. Allerdings gibt es bei der Stärke der Niederschläge größere Defizite. Als letzte Betrachtung wurde mit den gemessenen Niederschlägen eine Höhenregression durchgeführt. Mit Hilfe dessen konnte die Höhenabhangigkeit des Niederschlags auf die Topografie des Lokal Modells übertragen werden. Es wurde deutlich, dass allein eine Beachtung der Höhenabhängigkeit nicht ausreicht um eine orografische Verstärkung durch die Mittelgebirge zu beschreiben. Es müssen zusätzlich die Abhängigkeiten von dem Luv-Lee-Effekt und der herrschenden Wetterlage sowie die Jahreszeit mit berücksichtigt werden.