Genomic characterization of ETV6/RUNX1-positive acute lymphoblastic leukemia

The t(12;21) translocation generates the ETV6/RUNX1 fusion gene, present in 25% of childhood acute lymphoblastic leukemia. This fusion gene is important for leukemia development but is not sufficient for leukemia to arise. Hence, the additional genetic changes present in leukemic ETV6/RUNX1-positive cells give important clues regarding the history of the leukemia. The aim of this thesis has been to characterize thoroughly the genetic changes present in ETV6/RUNX1-positive ALL. In Article I, seventeen ETV6/RUNX1-positive ALLs were characterized using array CGH. This revealed that gain of Xq material, present in six cases, was the most common copy number aberration (CNA). A large number of genes was present in the commonly gained region but the high and specific expression of SPANXB identified this gene as a likely target of the gain. In Article II, 24 ALLs were analyzed using 500K single nucleotide polymorphism arrays. The data from these ALLs were combined with previously published external SNP array data from 140 ETV6/RUNX1-positive ALLs. A high number of recurrent CNAs could be identified in this dataset. The recurrent CNAs were further analyzed using hierarchical clustering, connected pair analysis, and oncogenetic tree models. These analyzes revealed that the majority of cases had acquired a unique set of recurrent CNAs, indicating that the process of acquiring CNAs is unique for each ALL. In Article III, exome sequencing was used to sequence all protein coding genes in two ETV6/RUNX1-positive ALLs. Seven somatic single nucleotide mutations were present in each ALL, six of these were in genes previously implicated in cancer

Styrmedelspotential på vägen mot ett hållbart transportsystem

In this study suggested political instruments for a future sustainable transportation system are analyzed. This is done by a survey study with answers from municipality workers in ten different municipalities in the Scania region, southern Sweden. The questions covers the respondents transportation habits and their opinions on 19 different political instruments and how these instruments, if put in place in the future, could potentially change their day to day transportation habits. The Swedish transport administration and a state report on fossil free transportation have suggested these political instruments to be used or investigated for future use to reach the goal of having a fossil fuel independent vehicle fleet in 2030. All instruments are of the types economic or administrative and regard costs of using cars and public transport or other aspects that could make cars a less attractive choice of transportation and public transport a more attractive choice. The results show that the highest potential to steer the respondents towards more sustainable transportation habits are lower price on public transport and higher price on fossil fuels (through higher taxes on carbon dioxide and/or energy). Even more noticeable is the large differences in potential between different instruments. Hopefully this can put things in perspective and raise the question once again of what is an efficient political instrument for climate mitigation. The study also shows the difference in potential for some instruments on respondents living in urban or rural areas. For example respondents in urban areas are more positive to using carpools and respondents in rural areas are more positive to working from home

Whole-exome sequencing of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), the most common malignant disorder in childhood, is typically associated with numerical chromosomal aberrations, fusion genes or small focal deletions, thought to represent important pathogenetic events in the development of the leukemia. Mutations, such as single nucleotide changes, have also been reported in childhood ALL, but these have only been studied by sequencing a small number of candidate genes. Herein, we report the first unbiased sequencing of the whole exome of two cases of pediatric ALL carrying the ETV6/RUNX1 (TEL/AML1) fusion gene (the most common genetic subtype) and corresponding normal samples. A total of 14 somatic mutations were identified, including four and seven protein-altering nucleotide substitutions in each ALL. Twelve mutations (86%) occurred in genes previously described to be mutated in other types of cancer, but none was found to be recurrent in an extended series of 29 ETV6/RUNX1-positive ALLs. The number of single nucleotide mutations was similar to the number of copy number alterations as detected by single nucleotide polymorphism arrays. Although the true pathogenetic significance of the mutations must await future functional evaluations, this study provides a first estimate of the mutational burden at the genetic level of t(12;21)-positive childhood ALL.Leukemia advance online publication, 18 November 2011; doi:10.1038/leu.2011.333

The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia.

High hyperdiploid (51-67 chromosomes) acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies, comprising 30% of all pediatric B cell-precursor ALL. Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomies being seen in over 75% of cases, but the pathogenesis remains poorly understood. We performed whole-genome sequencing (WGS) (n = 16) and/or whole-exome sequencing (WES) (n = 39) of diagnostic and remission samples from 51 cases of high hyperdiploid ALL to further define the genomic landscape of this malignancy. The majority of cases showed involvement of the RTK-RAS pathway and of histone modifiers. No recurrent fusion gene-forming rearrangement was found, and an analysis of mutations on trisomic chromosomes indicated that the chromosomal gains were early events, strengthening the notion that the high hyperdiploid pattern is the main driver event in this common pediatric malignancy

Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.

Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects

Integrative analysis of gene expression and copy number alterations using canonical correlation analysis

Supplementary Figure 1. Representation of the samples from the tuning set by their coordinates in the first two pairs of features (extracted from the tuning set) using regularized dual CCA, with regularization parameters tx = 0.9, ty = 0.3 (left panel), and PCA+CCA (right panel). We show the representations with respect to both the copy number features and the gene expression features in a superimposed way, where each sample is represented by two markers. The filled markers represent the coordinates in the features extracted from the copy number variables, and the open markers represent coordinates in the features extracted from the gene expression variables. Samples with different leukemia subtypes are shown with different colors. The first feature pair distinguishes the HD50 group from the rest, while the second feature pair represents the characteristics of the samples from the E2A/PBX1 subtype. The high canonical correlation obtained for the tuning samples with regularized dual CCA is apparent in the left panel, where the two points for each sample coincide. Nevertheless, the extracted features have a high generalization ability, as can be seen in the left panel of Figure 5, showing the representation of the validation samples. 1 Supplementary Figure 2. Representation of the samples from the tuning set by their coordinates in the first two pairs of features (extracted from the tuning set) using regularized dual CCA, with regularization parameters tx = 0, ty = 0 (left panel), and tx = 1, ty = 1 (right panel). We show the representations with respect to both the copy number features and the gene expression features in a superimposed way, where each sample is represented by tw

Feasibility to use whole-genome sequencing as a sole diagnostic method to detect genomic aberrations in pediatric B-cell acute lymphoblastic leukemia

IntroductionThe suitability of whole-genome sequencing (WGS) as the sole method to detect clinically relevant genomic aberrations in B-cell acute lymphoblastic leukemia (ALL) was investigated with the aim of replacing current diagnostic methods.MethodsFor this purpose, we assessed the analytical performance of 150 bp paired-end WGS (90x leukemia/30x germline). A set of 88 retrospective B-cell ALL samples were selected to represent established ALL subgroups as well as ALL lacking stratifying markers by standard-of-care (SoC), so-called B-other ALL.ResultsBoth the analysis of paired leukemia/germline (L/N)(n=64) as well as leukemia-only (L-only)(n=88) detected all types of aberrations mandatory in the current ALLTogether trial protocol, i.e., aneuploidies, structural variants, and focal copy-number aberrations. Moreover, comparison to SoC revealed 100% concordance and that all patients had been assigned to the correct genetic subgroup using both approaches. Notably, WGS could allocate 35 out of 39 B-other ALL samples to one of the emerging genetic subgroups considered in the most recent classifications of ALL. We further investigated the impact of high (90x; n=58) vs low (30x; n=30) coverage on the diagnostic yield and observed an equally perfect concordance with SoC; low coverage detected all relevant lesions.DiscussionThe filtration of the WGS findings with a short list of genes recurrently rearranged in ALL was instrumental to extract the clinically relevant information efficiently. Nonetheless, the detection of DUX4 rearrangements required an additional customized analysis, due to multiple copies of this gene embedded in the highly repetitive D4Z4 region. We conclude that the diagnostic performance of WGS as the standalone method was remarkable and allowed detection of all clinically relevant genomic events in the diagnostic setting of B-cell ALL

Teater spelar roll i matematikundervisningen: En kvalitativ studie om hur sju lärares attityder till sin matematikundervisning påverkas genom en teaterföreställning

Syfte Studiens syfte var att påverka sju lärares attityder till sin matematikundervisning. Syftet förtydligades genom fem frågeställningar, dessa var: · Hur beskriver lärarna sin matematikundervisning? · Vad innebär matematik för lärarna? · Varifrån hämtar lärarna sin inspiration till sin matematikundervisning? · Är lärarna tillfredställda med sin matematikundervisning? · På vilket sätt påverkar en teaterföreställning lärarnas matematikundervisning? Metod Då vi själva skapade en situation för att påverka lärarnas attityder till sin matematikundervisning är studien att betrakta som aktionsforskning. Denna situation bestod av en matematikteater tillsammans med en uppföljande klassdiskussion. På vilket sätt lärarnas attityder påverkades undersöktes därefter med hjälp av en kvalitativ metod i form av frågeformulär och intervjuer. Totalt spelades teaterföreställningen i sex klasser på fem olika skolor och sju lärare besvarade frågeformulären och intervjuades. De lärare som deltog i studien arbetar alla på skolor inom Göteborgs kommun med elever från förskoleklass till och med skolår två. Resultat Vi kan se att lärarna påverkats i sina attityder till sin matematikundervisning. Det som teaterföreställningen och den efterföljande klassdiskussionen främst synliggjorde för lärarna var att många av eleverna hade en begränsad uppfattning om vad matematik är. Trots att få av lärarna var tillfredställda med sitt sätt att undervisa i ämnet matematik så kommer de antagligen inte att göra några större förändringar med anledning av vårt besök. Däremot kommer flera av lärarna att plocka in flera praktiska moment i matematikundervisningen och framförallt påvisa för eleverna att dessa praktiska moment är matematik och därmed försöka vidga elevernas uppfattning om ämnet. Den enda läraren som tidigare undervisat utan matematikbok funderar på att i vissa sammanhang börja använda sig av en sådan. Hon menar att man inte ska förkasta den form som boken har utan snarare hur man förhåller sig till den. Ingen av lärarna nämner att de redan tidigare fått inspiration till sin matematik- undervisning från någon teaterföreställning. Vi anser utifrån den här studien att det är fullt möjligt att inspirera lärare genom en teaterföreställning

Flygbildsbaserad skyddszonsinventering vid Segeå

Creating a 6-20 meter wide grass zone in between a watercourse and farm land is a fairly simple method to reduce nutrient losses and thereby also to reduce eutrophication in lakes, watercourses and oceans. This zone is called a riparian buffer zone. Farmers in Sweden have had the opportunity to apply for environmental grants from the Swedish Department of Agriculture for such buffer zones since 1996. The grant exists to compensate the reduction of profit that comes with decreasing farmland area. This is one of many measures developed in the pursuit of the Swedish environmental goal of having no eutrophication. The same goal is pursued on a regional level by the seven municipalities included in the Segeå watershed in southwestern Scania. They want to know if the actual riparian buffer zone area coincides with the buffer zone area which the Department of Agriculture is granting money for, how the use of this grant has developed from 2007 to 2010 and if it is possible to create more buffer zones in the watershed. Mapping the current and future potential buffer zones has been made by aerial photo interpretation. Statistical data from the Department of Agriculture for 2007 and 2010 has been summarized and compared. The result indicates riparian buffer zones existing on twice the amount of land compared to what grants are given for. Potentially new buffer zones can be created on approximately 18 percent of the total watercourse stretch.Att anlägga en vallbesådd zon på 6-20 meter mellan vattendrag och åkermark, en så kallad skyddszon, är ett tämligen enkelt sätt att minska näringsläckaget från jordbruket och därmed minska övergödningen i sjöar, vattendrag och hav. För sådan typ av skyddszon har lantbrukare sedan 1996 kunnat få miljöersättning från Jordbruksverket för att kompensera förlusten i skörden på grund av minskad åkerareal. Detta är en av flera viktiga åtgärder som kommit till i strävan att uppnå det svenska miljömålet Ingen övergödning. Samma mål strävar man också efter inom Segeåprojektet i sydvästra Skåne, ett samarbete mellan sju kommuner (Segeås vattendragsförbund) vars yt- och markvatten rinner ut i Segeå. Segeås vattendragsförbund vill veta om den verkliga skyddszonsarean överensstämmer med den area som Jordbruksverket betalar ut miljöersättning för, hur möjligheterna ser ut för att anlägga mer skyddszoner och hur utvecklingen av miljöersättningsberättigad mark sett ut från 2007 till 2010. För att kunna kartlägga andelen befintliga och potentiella skyddszoner i området har en inventering utförts med hjälp av flygbilder och statistik från Jordbruksverket har sammanställts och jämförts för att se utvecklingen från 2007 till 2010. Denna studie visar att skyddszonsarean längs Segeå är ungefär dubbelt så stor som den skyddszonsarea som Jordbruksverkets miljöersättning omfattar. Utöver detta finns det potential att anlägga nya skyddszoner på en total sträckning av cirka 18 procent av vattendragets längd

Hybrid leadership : managers experiences of leading employees both at the office and remotely

Under våren 2020 beslutade Folkhälsomyndigheten (u å) om rekommendationen att alla arbetstagare som hade möjlighet att arbeta hemifrån skulle göra det. Uppsatsen bygger på en kvalitativ studie där syftet var att ta reda på mer om chefers upplevelser av hybridledarskap. Studien gjordes i två organisationer, den ena hade ett hybridledarskap innan Covid-19 pandemin och den andra fick det som en följd av pandemin. Studien syftade också till att få kännedom om upplevelsen kring hybridledarskap skiljde sig åt mellan de olika organisationernas chefer. Vidare ville vi undersöka om chefer upplevde att delar av ledarskapet underlättas eller försvåras vid ett hybridledarskap. I Sverige har begreppet hybridledarskap förknippas med ledarskap som uppkommit på grund av Covid-19 pandemin. Det kopplas till förutsättningen att chefer leder medarbetare som inte alltid är på samma fysiska plats som chefen. Hybridledarskap fanns innan pandemin, men inte begreppet i sig med samma innebörd som idag. Studiens teoretiska referensram utgår ifrån olika teorier och begrepp tillhörande ledarskap. Teorier som tittats närmare på har en utgångspunkt i tillit, och de är LMX, Teori X och Teori Y samt tillit som ledningsfilosofi. Vi ville undersöka hur chefers ledarskap förhöll sig i relation till dessa teorier och begrepp. En upptäckt var att alla chefer anser sig leda utifrån ett tillitsperspektiv. Vi ville också titta på om chefernas upplevelser av hybridledarskap skiljde sig åt mellan organisationerna samt om det fanns några lärdom att dra utifrån det för de båda organisationerna. Vi har sett både skillnader, likheter samt upptäckt lärdomar att föra vidare