Responses to Tumour initiating factors and Regulation of Normal and Malignant Haematopoiesis

The haematopoietic stem cell (HSC) resides within a specific environment enabling it to retain its self-renewal capacity or quiescent state. It is proposed that the HSC niche is hypoxic, a milieu within which the HSC is protected from intrinsic and extrinsic stimuli. We have investigated the haematopoietic phenotype of an HSC in a mouse model where hypoxia-regulated Vegfa expression is abrogated. In Vegfaδ/δ mice, the HRE in the Vegfa promoter has been deleted at both alleles, thereby inhibiting HIF-binding and subsequent activation of Vegfa expression following hypoxia. We show that hypoxic regulation of Vegfa expression within the haematopoietic system affects haematopoietic differentiation and numbers of HSCs to a small extent. Interestingly, Vegfa expression was shown to be reduced in highly purified HSCs from bone marrow of Vegfaδ/δ mice but not in mature cells, suggesting that the niche of the HSC is hypoxic. Acute lymphoblastic leukaemia (ALL) is the most common malignancy among children. Contemporary treatment protocols result in cure rates of 80-85% but 15-20% of children still experience relapse. A group of patients do therefore not benefit from conventional therapy underlining the urgent need to identify additional biomarkers at diagnosis. We have investigated the expression of VEGF-A, its receptors VEGFR-1 and VEGFR-2 as well as PTEN and SHP1 in childhood ALL using immunohistochemistry. We observed that the expression of VEGFR-1, PTEN and SHP1 in mononuclear cells of children with ALL were significantly different to the expression of mononuclear cells in children with no malignant disease. VEGFR-1, PTEN and SHP1 may be potential prognostic factors for childhood ALL. Chromosomal translocations are reported in approximately 65% of all acute leukaemias. Reports have identified leukaemic translocations in human peripheral blood of healthy individuals supporting the hypothesis that leukaemic transformation is a multistep process. The t(10;11)(p13-14;q14-21) translocation is a reciprocal translocation and forms both an in-frame CALM·AF10 and AF10·CALM fusion. The long latency period prior to the onset of leukaemia in CALM·AF10 mice models suggests that the fusion protein alone does not cause leukaemic development. We hypothesise that AF10·CALM is required for the full leukaemic phenotype. In an in vitro model, we found that t(10;11)(p13-14;q14-21) reciprocal fusions have individual effects on cell biology and, when found in combination, have either a more pronounced or an inhibitory effect on leukaemogenesis. This highlights the importance of examining both fusion proteins in a two transcript reciprocal translocation as they on their own may have individual characteristics

Bortom vänster- och högerdikotomin: Politiska attityder och värderingar hos svenska väljare

Denna enkätstudie undersökte nyanserna bakom vänster-höger dikotomin. Detta gjordes genom en empirisk studie som tittade på såväl skillnaderna mellan de politiska blocken som inom dessa. Sex skalor som avsåg mäta attityder och värderingar kopplade till förändring respektive jämlikhet jämfördes med val av parti i det svenska riksdagsvalet 2010. Deltagarna var indelade i två grupper, med 314 deltagare i den ena och 286 i den andra. Studiens hypoteser var att skillnader avseende attityder och värderingar kopplade till jämlikhet och förändring skulle finnas såväl inom som mellan vänster- och högerblocket, främst rörande vänsterblockets inställning till social förändring. Den empiriska undersökningen gav stöd till hypoteserna. Resultatet visade att förändringsdimensionen, till skillnad från jämlikhetsdimensionen inte är kopplad till vänster-höger skalan i Sverige. Vi visade på att skillnader i attityder och värderingar fanns både mellan och inom blocken. Den tydligaste skillnaden rör förändringsdimensionen där Socialdemokraternas väljare är betydligt mindre för förändring än Miljöpartiet och Vänsterpartiets väljare. Överlag har Socialdemokraternas väljare mer gemensamt med Folkpartiets och Centerpartiets väljare än övriga vänsterväljare. Dessa fynds konsekvenser för den svenska blockpolitiken diskuteras.This survey study explored the nuance behind the left-right ideological dichotomy. This was done by empirically studying the differences both between and inside the political left and right. Six scales were used to measure the political attitudes and basic personal values connected to change and equality. These were compared with voting in the Swedish national elections in 2010. The participants were divided into two groups with 314 participants in one and 286 in the other. Differences in attitudes and values both between and inside the political left and right was hypothesized, differences mainly inside the political left regarding attitudes and values toward social change. The empirical study gave support for the hypothesis. The results showed that the change dimension were not associated to the left-right dimension in Sweden, the equality dimension, however, was. Differences regarding both attitudes and values were found both between and inside the political blocks. The main differences was found within the change dimension were the Social democrat voters where significantly less positive towards social change than were the Environment party voters and the Left party voters. The Social democrats had more attitudes and values in common with the voters of the Folk party and Center party than the Environment party and the Left party. The consequences of these results on the Swedish block policies are further discussed

Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche.

Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or upregulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfa(δ/δ), where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfa(δ/δ) mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-Vegfa axis

A Novel murine model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease.Work in the Huntly laboratory is funded by CRUK, The European Research Council (ERC), Leukaemia Lymphoma Research, the Kay Kendall Leukaemia Fund, Wellcome Trust, the Medical Research Council (UK), the Leukemia Lymphoma Society America and the Cambridge NIHR Biomedical Research centre. David Adams is funded by Cancer Research UK and Wellcome Trust. Steffen Koschmieder has received funding from Deutsche José Carreras Leukämie-Stiftung (DJCLS; grant 10/23).This is the final published version. It first appeared at http://dx.doi.org/10.1084/jem.2014166

Förklarandet av Neurala Nätverk menade för PIM-elimination

Passive Intermodulation is a type of distortion affecting the sensitive receiving signals in a cellular network, which is a growing problem in the telecommunication field. One way to mitigate this problem is through Passive Intermodulation Cancellation, where the predicted noise in a signal is modeled with polynomials. Recent experiments using neural networks instead of polynomials to model this noise have shown promising results. However, one drawback with neural networks is their lack of explainability. In this work, we identify a suitable method that provides explanations for this use case. We apply this technique to explain the neural networks used for Passive Intermodulation Cancellation and discuss the result with domain expertise. We show that the input space as well as the architecture could be altered, and propose an alternative architecture for the neural network used for Passive Intermodulation Cancellation. This alternative architecture leads to a significant reduction in trainable parameters, a finding which is valuable in a cellular network where resources are heavily constrained. When performing an explainability analysis of the alternative model, the explanations are also more in line with domain expertise.Passiv Intermodulation är en typ av störning som påverkar de känsliga mottagarsignalerna i ett mobilnät. Detta är ett växande problem inom telekommunikation. Ett tillvägagångssätt för att motverka detta problem är genom passiv intermodulations-annullering, där störningarna modelleras med hjälp av polynomiska funktioner. Nyligen har experiment där neurala nätverk används istället för polynomiska funktioner för att modellera dessa störningar påvisat intressanta resultat. Användandet av neurala nätverk är dock förenat med vissa nackdelar, varav en är svårigheten att tyda och tolka utfall av neurala nätverk. I detta projekt identifieras en passande metod för att erbjuda förklaringar av neurala nätverk tränade för passiv intermodulations-annullering. Vi applicerar denna metod på nämnda neurala nätverk och utvärderar resultatet tillsammans med domänexpertis. Vi visar att formatet på indatan till neurala nätverket kan manipuleras, samt föreslår en alternativ arkitektur för neurala nätverk tränade för passiv intermodulations-annullering. Denna alternativa arkitektur innebär en avsevärd reduktion av antalet träningsbara parametrar, vilket är ett värdefullt resultat i samband med mobilnät där det finns kraftiga begränsningar på hårdvaruresurser. När vi applicerar metoder för att förklara utfall av denna alternativa arkitektur finner vi även att förklaringarna bättre motsvarar förväntningarna från domänexpertis

Combining Flexibility and Efficiency in Automotive Assembly : Preparing for New Powertrain Vehicles

Global warming and peak oil are drawing attention to new types of energy technologies. Since transportation is one of the main contributors to carbon emissions and one of the biggest consumers of oil, new technologies to propel vehicles are being introduced. For the automotive industry, where the Internal Combustion Engine (ICE) has had complete dominance for some hundred years, the transition to new powertrains will be challenging for the entire operation. These new powertrain vehicles must not only be developed and tested, which is an enormous challenge in itself; they must also be manufactured with the same efficiency as ICE vehicles in order to reach a competitive price. There is great uncertainty regarding which powertrain solution will become the next paradigm, or even if there will be a new propulsion paradigm as dominant as the ICE. This, in combination with the fact that these new powertrain vehicles will initially be produced in relatively small volumes, probably calls for them to be produced in current manufacturing facilities mixed with ICE vehicles. This challenge is the foundation for this research. In order to manage the manufacturing challenges related to the introduction of new powertrain vehicles, both theoretical and empirical data have been analysed in this research. The empirical data is taken mainly from interviews, the author’s own observations and workshops with Volvo Cars and SAAB Automobile. In order to produce new powertrain vehicles in existing facilities, flexibility are identified as central components in this research. However, the flexibility needs to be achieved without affecting the efficiency of the manufacturing system. To achieve flexible automotive final assembly, four key flexibilities are identified in this research: Mix Flexibility New Product Flexibility Modification Flexibility Volume Flexibility To achieve these flexibilities, three key factors are identified and investigated in this research: Mixed Model AssemblyModularity Platform Strategy This research describes these key factors’ relationship with one another, as well as their relationship to the key flexibilities. This research describes how the key factors are used to achieve flexibility in current final assembly, and how they can be used in future automotive final assembly. This is presented as a relationship model to combine flexibility and efficiency in automotive final assembly. A first step towards a stringent automotive product architecture-platform-vehicle structure is presented, along with key factors that are important in a successful automotive platform strategy. Guidelines are also described for how new powertrain vehicles should be designed in order to achieve as efficient final assembly as possible

Combining Flexibility and Efficiency in Automotive Assembly : Preparing for New Powertrain Vehicles

Global warming and peak oil are drawing attention to new types of energy technologies. Since transportation is one of the main contributors to carbon emissions and one of the biggest consumers of oil, new technologies to propel vehicles are being introduced. For the automotive industry, where the Internal Combustion Engine (ICE) has had complete dominance for some hundred years, the transition to new powertrains will be challenging for the entire operation. These new powertrain vehicles must not only be developed and tested, which is an enormous challenge in itself; they must also be manufactured with the same efficiency as ICE vehicles in order to reach a competitive price. There is great uncertainty regarding which powertrain solution will become the next paradigm, or even if there will be a new propulsion paradigm as dominant as the ICE. This, in combination with the fact that these new powertrain vehicles will initially be produced in relatively small volumes, probably calls for them to be produced in current manufacturing facilities mixed with ICE vehicles. This challenge is the foundation for this research. In order to manage the manufacturing challenges related to the introduction of new powertrain vehicles, both theoretical and empirical data have been analysed in this research. The empirical data is taken mainly from interviews, the author’s own observations and workshops with Volvo Cars and SAAB Automobile. In order to produce new powertrain vehicles in existing facilities, flexibility are identified as central components in this research. However, the flexibility needs to be achieved without affecting the efficiency of the manufacturing system. To achieve flexible automotive final assembly, four key flexibilities are identified in this research: Mix Flexibility New Product Flexibility Modification Flexibility Volume Flexibility To achieve these flexibilities, three key factors are identified and investigated in this research: Mixed Model AssemblyModularity Platform Strategy This research describes these key factors’ relationship with one another, as well as their relationship to the key flexibilities. This research describes how the key factors are used to achieve flexibility in current final assembly, and how they can be used in future automotive final assembly. This is presented as a relationship model to combine flexibility and efficiency in automotive final assembly. A first step towards a stringent automotive product architecture-platform-vehicle structure is presented, along with key factors that are important in a successful automotive platform strategy. Guidelines are also described for how new powertrain vehicles should be designed in order to achieve as efficient final assembly as possible

Elva principer för specialoperationer? En studie av specialförbandens framgångar

Recent studies have shown an increased relevancy for special operations warfare. Special operations have been acclaimed as a cost beneficial means of achieving strategic ends. Although this is the case there is a significant lack in the realm of contemporary special operations theory. Operation Barrasin 2000 and Operation Neptune Spear in 2011 have both been renowned for being daring, well conducted but foremost successful. Nevertheless, thorough research of these operations signals their absence. This study contributes to the field by examining these two successful special operations through the lens of a theoretical framework, based on prominent special operations theorists, in order to determine what principles led to their prosperity. Although a majority of the theoretical principles could be recognised in both operations, not all of these were beneficial to the outcome. The results have shown that the principles of strategic and political comprehension, technology, practice, intelligence, personal commitment and speed mainly contributed to success. Conclusions also show that the principle of intelligence could be considered superior to the other principles. This conclusion is drawn due to the fact that accurate intelligence enabled several of the other principles, for example practice and strategic and political comprehension.

Elva principer för specialoperationer? En studie av specialförbandens framgångar

Recent studies have shown an increased relevancy for special operations warfare. Special operations have been acclaimed as a cost beneficial means of achieving strategic ends. Although this is the case there is a significant lack in the realm of contemporary special operations theory. Operation Barrasin 2000 and Operation Neptune Spear in 2011 have both been renowned for being daring, well conducted but foremost successful. Nevertheless, thorough research of these operations signals their absence. This study contributes to the field by examining these two successful special operations through the lens of a theoretical framework, based on prominent special operations theorists, in order to determine what principles led to their prosperity. Although a majority of the theoretical principles could be recognised in both operations, not all of these were beneficial to the outcome. The results have shown that the principles of strategic and political comprehension, technology, practice, intelligence, personal commitment and speed mainly contributed to success. Conclusions also show that the principle of intelligence could be considered superior to the other principles. This conclusion is drawn due to the fact that accurate intelligence enabled several of the other principles, for example practice and strategic and political comprehension.