1,748,916 research outputs found
Transformationspotential von NPM-ALK, p21SNFT und Tax in Reifen T Lymphozyten
No full textTo date it is not clear at which stage of differentiation mature T cell leukaemia/lymphoma is initiated. Previous studies in our group showed that mature T cells are relatively resistant to transformation. We wanted to further investigate the transformation potential of NPM-ALK, p21SNFT and the viral oncoprotein Tax on mature T cells. First, we analyzed the effects on T cell growth in vitro after transducing human T cell lines with gammaretroviral vectors encoding these genes. No growth or proliferation promoting effect of all three genes was observed. In the second part of the project, we transduced murine, mature T cells and/or haematopoietic stem cells (HPCs/HSCs) and transplanted these cells into Rag-1 deficient recipients. All mice transplanted with NPM-ALK transduced monoclonal mature T cells (OT-1) developed leukaemia/lymphoma. In contrast, only few NPM-ALK transduced polyclonal T cell and HPC/HSC transplanted mice developed leukaemia/lymphoma. From the p21SNFT group, only two mice transplanted with transduced OT-1 T cells developed leukaemia/lymphoma, which showed high eGFP and interestingly CD19 expression. No malignancies were observed in Tax transplanted animals so far. Furthermore, the recipients do not show any eGFP marking in the periphery. In conclusion, our results show that compared to polyclonal T cells, monoclonal T cells are transformable after gammaretroviral transfer of NPM-ALK and p21SNFT.Bislang ist nicht bekannt, in welchem Differenzierungsstadium reife T- Zell-Leukämien/Lymphome initiert werden. Frühere Studien in unserer Gruppe haben eine Resistenz reifer TZellen gegenüber der Transformation gezeigt. Nun sollte das transformierende Potential von NPM-ALK, p21SNFT und des viralen Onkoproteins Tax in reifen T- Zellen weiter untersucht werden. Zunächst wurden die Effekte der drei Proteine auf das Zellwachstum in vitro untersucht, indem humane T- Zelllinien mit gammaretroviralen Vektoren, die diese Gene kodierten, transduziert wurden. Für alle drei Gene konnte kein proliferationsfördernder Effekt beobachtet werden. Im zweiten Teil des Projekts wurden murine reife T- Zellen oder hämatopoetische Stammzellen ( HPCs/ HSCs) mit diesen Vektoren transduziert und in Rag-1 knockout Mäuse transplantiert. Alle Mäuse, die mit NPM-ALK transduzierten monoklonalen reifen T- Zellen (OT-1) transplantiert wurden, entwickelten Leukämien/ Lymphome. Im Gegensatz dazu entwickelten nur wenige der mit NPM-ALK transduzierten polyklonalen TZellen oder HPCs/ HSCs transplantierten Tiere Leukämien/ Lymphome. In der p21SNFT Gruppe zeigten nur zwei der Mäuse, die mit transduzierten OT-1 T- Zellen transplantiert wurden, Leukämien/ Lymphome. Diese exprimierten eGFP in hohem Maße und interessanterweise auch CD19. Für alle Tax transplantierten Tiere konnten bislang keine Leukämien/ Lymphome beobachtet werden. Das weiteren zeigten diese Tiere keine eGFP Expression im peripheren Blut. Zusammenfassend zeigen diese Resultate, dass monoklonale T- Zellen verglichen mit polyklonalen T- Zellen nach gammaretroviralem Transfer von NPM-ALK oder p21SNFT leichter transformierbar sind
Ultra-deep mutational analysis of NPM-ALK and possible implications on target therapy in anaplastic large cell lymphoma of childhood
Full text linkAnaplastic Large Cell Lymphoma (ALCL) represents a distinct subset of aggressive T-cell non-Hodgkin lymphoma (NHL) accounting for about 3% of adult NHL and 10 to 15% of childhood lymphomas. In the vast majority of the cases, ALCL is associated to chromosomal translocations, the most frequent being the t(2;5)(p23;q35), involving the Anaplastic Lymphoma Kinase (ALK) gene, which lead to aberrant NPM-ALK protein expression and kinase activity. It has been extensively demonstrated that aberrant
NPM-ALK expression contributes to the pathogenesis of ALK-positive ALCL, as it causes cell transformation through activation of several biological pathways related to cell proliferation, cell-cycle control and apoptosis. Although ALK-positive ALCL have a rather benign prognosis when treated with standard chemotherapy, the failure rate at two years is almost 30% for most of these regimens. Notably, most of relapses occur within the first year from the start of therapy, and long-term survival for relapsed disease is less than 50%. Aberrant ALK activity is one of the major oncogenic events not only in ALK-positive ALCL, but also in neuroblastoma, non-small cell lung cancer (NSCLC) and inflammatory myofibroblastic tumour (IMT) bearing ALK activating mutations/rearrangements, and the inhibition of ALK kinase activity was proven to substantially reduce cancer cell proliferation and invasiveness both in vitro and in vivo. Successful clinical experience with crizotinib further support the concept of ALK-specific inhibition as a valuable treatment strategy in ALK-positive ALCL, as well as in other
ALK-addicted tumours. However, similarly to other inhibitors selectively targeting oncogenic kinases, data on relapse to crizotinib due to newly acquired secondary mutations were reported. In this context, although a robust clinical response of ALCL patients to an ALK inhibitor is expected, some of those patients are also anticipated to develop resistance, making the knowledge of NPM-ALK kinase domain (KD) mutational status a valuable and mandatory information to the rational design of ALK-targeted therapies.
To detect somatic tumour mutations with potential utility for predicting treatment response in ALK-positive ALCL patients, we performed ultra-deep sequencing analysis on ALK exons 22-25, corresponding to the entire KD coding region, in 37 ALCL pediatric patients. Two low frequent point mutations were identified in two distinct cases, corresponding to the R1275Q and R1231Q amino acid changes. The R1275Q mutation has been already reported as one of the most frequent activating mutations in neuroblastoma, while the R1231Q amino acid substitution represents a novel ALK point mutation, which to our knowledge has never been reported neither in ALK receptor nor in other ALK-translocated kinases. The molecular implications of R1275Q and R1231Q point substitutions on NPM-ALK function and sensitivity to ALK-specific inhibition are still under our investigation. In addition to point mutation, oncokinase alternative spliced transcripts have been previously reported in patients with Bcr-Abl positive chronic myeloid leukemia and more recently ALK receptor isoforms were described in neuroblastoma. To our knowledge, however, NPM-ALK alternative splicing events have never been described. For the first time, we identified and characterized 9 NPM-ALK INDEL mutations, resulting from KD whole exons skipping or alternative canonical splicing sites recognition. To investigate the effect of INDEL mutations on the structure and activity of NPM-ALK, we performed molecular homology modelling and in vitro functional analysis. While all these mutants were shown to be kinase dead, we demonstrated that, when coespressed with wild-type NPM-ALK, these INDELs do interact with wild-type monomers and are likely to inhibit ALK kinase activity and increase sensitivity to treatment with crizotinib. This work demonstrates that NPM-ALK KD point mutations are extremely rare in newly diagnosed ALCL patients, but positive selection of mutated cells could not be excluded in case of an ALK-targeting therapy. Conversely, our results suggest that alternative splicing in NPM-ALK may represent a common event. A clear correlation between the presence of these variants and outcome could not be detected, possibly because of the restricted cohort of patients analyzed. However, we hypothesize that a significant impact of these mutations could be observed if an ALK-specific treatment is used. Patients bearing a consistent level of inactive NPM-ALK are therefore expected to respond differently to ALK kinase inhibitors; whether such a response will be increased or decreased, it remains to be elucidated
Pengaruh NPM, dan EPS terhadap Harga Saham pada perusahaan sektor industri barang konsumsi di ISSI (perusahaan terdaftar di Bursa Efek Indonesia)
No full textThe stock price is determined by the supply and demand for the stock it self in a capital market. Whe the higher the puchase of share, the stock price will tend to move up and vice versa. The purpose of this study is to analyze and determine the effect of Net Profit Margin (NPM) and Earning PER Share (EPS) on stock price in industrial sector companies consumer goods in the indonesian sharia stock index (ISSI). In this study using quantitative research with a descriptive approach method. The result of the study show that partially Net Profit Margin (NPM) has no effect on stock price and Earning Per Share (EPS) has no effect on stock price. Meanwhile the research result simultaneously show that Net Profit Margin (NPM) and Earning Per Share (EPS) have no significant effect on stock price
LC-MS/MS analysis of size exclusion chromatography after immunoaffinity purification of FH-NPM or FH-NPM-MLF1 interacting proteins.
No full textLC-MS/MS analysis of size exclusion chromatography after immunoaffinity purification of FH-NPM or FH-NPM-MLF1 interacting proteins.</p
Immunoaffinity purification and identification of FH-NPM and FH-NPM-MLF1 interacting proteins from K562 cells, by LC-MS/MS analysis.
No full textImmunoaffinity purification and identification of FH-NPM and FH-NPM-MLF1 interacting proteins from K562 cells, by LC-MS/MS analysis.</p
npm-miner dataset
No full textThis dataset contains the static analysis results of the 2000 top-downloaded packages included in npm-registry</p
Leeds-CDRC/NPM-Calculator: v1.0
No full text<p>First release of the NPM Calculator tool. This version is designed to assess user-entered single product information against the <a href="https://www.gov.uk/government/publications/the-nutrient-profiling-model">UK NPM (2004/5)</a> and scope for <a href="https://www.gov.uk/government/publications/restricting-promotions-of-products-high-in-fat-sugar-or-salt-by-location-and-by-volume-price/restricting-promotions-of-products-high-in-fat-sugar-or-salt-by-location-and-by-volume-price-implementation-guidance">HFSS legislation</a> around product placement.</p>
mipt-npm/plotly.kt: 0.3.1
No full text[0.3.1]
Added
Table widget implementation by @ArtificialPB
Mathjax header promoted to stable
Tabbed plots layout (experimental)
Trace value builders for functions and ranges (experimental)
Changed
Breaking API change! Trace text replaced by TraceValues
Moved to DataForge 0.3 API
Kotlin 1.4.30
JVM-IR
Plot Config moved to constructor
Replaced direct color accessor by a delegate
Fixed
https://github.com/mipt-npm/plotly.kt/issues/53
Add JQuery to Bootstrap header
Strengths And Weaknesses Of The New Public Management (NPM)- Cross-Sectional And Longitudinal Analysis
Full text linkThe paradigm of NPM, like its forerunners, has been trying to answer the same question for almost twenty years: how to implement policies, strategies, programs and projects, using the market-type mechanisms, so that the institutions of the state could achieve the desired results. The praises and criticism that have accompanied this paradigm along its evolution are fully justified. Indeed, the NPM has strengths and weaknesses as well, and one purpose of this paper is to identify them and to find answers to the following questions. Which components of the mechanism named NPM generate negative results? Why? What can be done? It is not easy to answer these questions, taking into consideration the multitude of factors influencing the public management, and especially the tremendous impacts of the accelerated process of globalization. The global problems of nowadays make any unilateral action of a government unconceivable, and this brings us to the concept of global public management (GPM). Nevertheless, the way forward will be the subject of another paper. The paper is structured in two main sections, as follows: The first section provides a conceptual framework, examining the multifaceted structure of the NPM and its mechanisms (the “state-of-the-art” of the “art of the state”). The second section suggests a theoretical framework on “measuring” the aggregate attribute of the NPM – the QoG – illustrated by practical cases, in a twofold perspective: longitudinal (variation in time) and cross-sectional (variation among countries).New Public Management, Global Public Management, Governance, New Institutional Economics, Bertelsmann Transformation Index, Corruption Perceptions Index, e-Government Index, Global Competitiveness Index, Human Development Index, Index of Freedom in the World, Transition Indicators, Worldwide Governance Indicators
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