| 1. |
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| 2. |
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| 3. |
- Glasbey, JC, et al.
(author)
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- 2021
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swepub:Mat__t
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| 4. |
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| 5. |
- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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| 6. |
- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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| 7. |
- Balan, Andreia, et al.
(author)
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Effekten av fysisk aktivitet i matematikundervisningen
- 2019
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In: Forskning om undervisning och lärande. - 2000-9674 .- 2001-6131. ; 7:3, s. 6-27
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Journal article (peer-reviewed)abstract
- Syftet med denna studie är att få en bättre förståelse för hur fysisk aktivitet kan användas i skolan för att skapa mer gynnsamma förutsättningar för elevernas lärande i matematik. I studien har det undersökts om det finns en effekt av fysisk aktivitet på lång sikt på elevernas koncentration, arbetsminne och kunskaper i matematik av ett återkommande kort pass med fysisk aktivitet. Studien genomfördes med 175 elever i årskurs 7 på fyra olika skolor. Ett inledande pass på sju minuter med pulshöjande övningar introducerades i fem av tio grupper i början på matematiklektionen. Resultaten visar en förbättring av elevernas koncentration och arbetsminne i interventionsgruppen i förhållande till kontrollgruppen. Elever med olika kön och prestationsnivå påverkas på samma sätt av den fysiska aktiviteten. Det finns inte heller någon skillnad i hur elever som kommer från olika skolkontext påverkas av den fysiska aktiviteten.
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| 8. |
- Balan, Andreia, et al.
(author)
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Effekten av fysisk aktivitet i matematikundervisningen
- 2019
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In: Forskning om undervisning och lärande. - 2000-9674. ; 7:3, s. 6-27
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Journal article (peer-reviewed)abstract
- Syftet med denna studie är att få en bättre förståelse för hur fysisk aktivitet kan användas i skolan för att skapa mer gynnsamma förutsättningar för elevernas lärande i matematik. I studien har det undersökts om det finns en effekt av fysisk aktivitet på lång sikt på elevernas koncentration, arbetsminne och kunskaper i matematik av ett återkommande kort pass med fysisk aktivitet. Studien genomfördes med 175 elever i årskurs 7 på fyra olika skolor. Ett inledande pass på sju minuter med pulshöjande övningar introducerades i fem av tio grupper i början på matematiklektionen. Resultaten visar en förbättring av elevernas koncentration och arbetsminne i interventionsgruppen i förhållande till kontrollgruppen. Elever med olika kön och prestationsnivå påverkas på samma sätt av den fysiska aktiviteten. Det finns inte heller någon skillnad i hur elever som kommer från olika skolkontext påverkas av den fysiska aktiviteten.
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| 9. |
- Björkman, Anne, 1981, et al.
(author)
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Plant functional trait change across a warming tundra biome
- 2018
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 562:7725, s. 57-62
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Journal article (peer-reviewed)abstract
- The tundra is warming more rapidly than any other biome on Earth, and the potential ramifications are far-reaching because of global feedback effects between vegetation and climate. A better understanding of how environmental factors shape plant structure and function is crucial for predicting the consequences of environmental change for ecosystem functioning. Here we explore the biome-wide relationships between temperature, moisture and seven key plant functional traits both across space and over three decades of warming at 117 tundra locations. Spatial temperature–trait relationships were generally strong but soil moisture had a marked influence on the strength and direction of these relationships, highlighting the potentially important influence of changes in water availability on future trait shifts in tundra plant communities. Community height increased with warming across all sites over the past three decades, but other traits lagged far behind predicted rates of change. Our findings highlight the challenge of using space-for-time substitution to predict the functional consequences of future warming and suggest that functions that are tied closely to plant height will experience the most rapid change. They also reveal the strength with which environmental factors shape biotic communities at the coldest extremes of the planet and will help to improve projections of functional changes in tundra ecosystems with climate warming.
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| 10. |
- Botvinik-Nezer, Rotem, et al.
(author)
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Variability in the analysis of a single neuroimaging dataset by many teams
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
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Journal article (peer-reviewed)abstract
- Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.
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| 11. |
- Efsing, Pål, 1965-, et al.
(author)
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Ringhals Units 3 and 4 - Fluence determination in a historic and future perspective
- 2012
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In: Journal of ASTM International. - : ASTM International. - 1546-962X. ; 9:4, s. 104012-9
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Journal article (peer-reviewed)abstract
- The Ringhals site is situated on the Swedish southwest coastline. At the site, there are four operating nuclear power plants. Historically, the Swedish policy has been that the nuclear power plants were to be closed in 2010. The present position is to operate the units until their technical and economic lifetime has run out. The units shall be maintained and invested in to ensure a lifetime of at least 50 years, but the actions taken shall not limit the time to this date. When the initial surveillance capsules were evaluated, it was noted that the material properties of the weld material of unit 3 and 4 showed some deviations from the expected behaviour. Currently there is an extensive project running for re-evaluating the embrittlement situation from a long-term operating perspective. One part of the project is aimed at more accurately determining the fluence levels of the reactor pressure vessels (RPVs). The basis for the early evaluations of the dosimeters in the surveillance capsules and the corresponding fluence evaluation had an operating lifetime of 25 years as a target value. Therefore, the accuracy and refinement of the measurement and calculation were taken to be good enough to suit this life span. Looking back at the results from the dosimetry measurements there are a few discrepancies. Some of the dosimeters were disintegrated and some measurements had comparatively large uncertainties. When starting this project there were some re-evaluations done with the old fluence prediction model. For every new run and refinement there appeared new difficulties, and the decision was to start the evaluation from scratch.Then there are two questions remaining regarding the fluence: What is the current fluence level? What will the resulting fluence be after 60 years of operation, when we have up-rated output power of both reactors? This paper aims to describe the view of the fluence evaluation in the surveillance program of the RPV, both in a historical and prospective view.
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| 12. |
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| 13. |
- Green, Jenny, 1980-
(author)
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Elevers användande av formativ återkoppling i matematik
- 2014
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Licentiate thesis (other academic/artistic)abstract
- Students are often not satisfied with the feedback they receive, and do not always use it. Providing feedback on student learning has been shown to have a positive effect on learning, and is a key strategy in formative assessment. Students need to know (1) the goal, (2) their current level, and (3) the gap between these two, in order to advance towards the goal. In addition to receiving information about (1)-(3) above, students also need to actively engage with the feedback. In order to facilitate students’ use of the feedback given, a sample of upper-secondary mathematics students in this study received formative feedback (i.e. non-evaluative, supportive, timely and specific). The purpose of this research was to examine how students experienced this formative feedback, how they used it, and how experience, usage and goal orientation interacted.Data collection was done in the following steps. First, an intervention test with two calculation problems was given to the students. The answers were then handed in and processed based on theories of formative assessment and feedback. The students were given the formative feedback and, in order to capture their first impressions, they were asked how they perceived it. The next step was the regular teacher’s test – to give the students an opportunity to use the feedback. Finally, in-depth interviews were conducted in order to study students’ experiences of the formative feedback.An attempt was made to find factors explaining why the students use, or don’t use, their feedback. The students experienced the feedback in different ways, most notably finding the feedback useful, confusing or frightening. Some of these experiences indicate a view that assessment focuses on whether or not a mathematics question is answered correctly. Consequently, they view feedback as an extracurricular activity rather than as a learning situation. Some students seem to be able to overcome the contextual barriers and some do not even experience any barriers at all. The results suggest that it is essential to integrate feedback in the day-to-day instruction in order to increase the likelihood that all the students will derive benefit from it.
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| 14. |
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| 15. |
- Green, Jenny, et al.
(author)
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Formative mathematics assessment in upper secondary school
- 2014
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In: Proceedings of the 38<sup> th</sup> Conference of the International Group for the Psychology of Mathematics Education in Vancouver, Canada 2014. ; , s. 312-312
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Conference paper (other academic/artistic)
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| 16. |
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| 17. |
- Green, Jenny
(author)
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Primary students' experiences of formative feedback in mathematics
- 2023
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In: Education Inquiry. - : Informa UK Limited. - 2000-4508. ; 14:3, s. 285-305
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Journal article (peer-reviewed)abstract
- Feedback does not always engage students. To better understand why this happens, the present study analysed Grade 2 (7- to 8-year-old) students' experiences of formative feedback in mathematics to identify aspects with potential importance for student engagement. The researcher processed the students' experiences with the help of stimulated recall and semi-structured interviews. Most of the students appreciated feedback that focused on the process, instead of simply offering solution methods. However, due to a conflict between teachers and students regarding the social and socio-mathematical norms, some of the students did not understand the purpose while others wanted the teacher to state the solution method. This shows that it is important not only which norms are established, but also that this is done at an early stage. Thus, both teachers and students need to understand and accept the norms, and potentially establish new norms, if the current ones are counterproductive.
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| 18. |
- Hansson, Katarina, et al.
(author)
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Belastning av miljögifter på vatten : Kartläggning av källor till miljögifter
- 2009
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Reports (other academic/artistic)abstract
- Denna rapport sammanställer information om belastningen av organiska miljögifter och metaller på ytvatten. I projektet har 16 olika ämnen och ämnesgrupper valts ut som prioriterade. Dessa ämnen är upptagna i ramdirektivet för vatten och/eller i HELCOMs Baltic Sea Action Plan (BSAP) och är intressanta ur både ett nationellt och ett regionalt perspektiv.I syfte att ge förslag till en beräkningsmetodik har en inventering av datatillgången genomförts. I den sammanställningen presenteras vilka miljöövervakningsdata och övriga datakällor som kan ligga till grund för emissionsberäkningar. I samband med det identifierades dataluckor.Uppgifter om punktutsläpp av organiska miljögifter till vatten är knapphändiga i EMIR-databasen. Med undantag för vissa enstaka ämnen och anläggningar finns det i EMIR-databasen endast data gällande utsläppen av metaller. Punktkällor för utsläpp till vatten är industrier, gruvor, avloppsreningsverk, värmevärk samt icke rapporterande punktkällor, som t.ex. enskilda avlopp. De diffusa källorna av organiska ämnen och metaller är atmosfärisk deposition, läckage från jordbruks- och skogsmark, dagvatten, lakvatten från deponier samt re-emission från sediment.I rapporten föreslås en stegvis metodik för kvantifiering av utsläppen av organiska ämnen och metaller till vatten. Beräkning bör i första hand baseras på rena emissionsdata. Om dessa inte finns tillgängliga bör omräkning från miljöövervakningsdata tillämpas. Screeningdata och övriga regionala data och resultat från enskilda forskningsrapporter kan utnyttjas i brist på annan information, men innebär att trendanalyser av data inte kan genomföras. I de fall där rena emissionsdata och miljöövervakningsdata saknas, kan statistik om användning av varor och produkter innehållande de aktuella ämnena utnyttjas som ett mått på trender eller på den diffusa belastningen.I rapporten har vi kvantifierat belastningen av metaller och vissa organiska ämnen och ämnesgrupper från atmosfäriska depositionen och rapporterande punktkällor. Dessa resultat pekar på att för metallerna är bidraget från atmosfären större än utsläppen från kända punktkällor, men det är också viktigt att poängtera att de framtagna resultaten är delvis beräknade från mycket osäkert underlag. De diffusa utsläppen utgör även en viktig spridningskälla till förekomst av organiska ämnen i ytvattnet.För att i framtiden kunna genomföra bra emissionsberäkningar av miljögifter till vatten bör metodiken för de enskilda källorna utvecklas. Dessutom krävs det vidare arbete med metodikutvecklingen och bättre datatillgång.
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| 19. |
- Isaksson, Jenny, et al.
(author)
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Real-world evaluation of upfront docetaxel in metastatic castration-sensitive prostate cancer
- 2021
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In: World Journal of Clinical Oncology. - : Baishideng Publishing Group Inc. - 2218-4333. ; 12:11, s. 1009-1022
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Journal article (peer-reviewed)abstract
- BACKGROUNDThe majority of patients with newly diagnosed metastatic prostate cancer (PC) initially respond to androgen deprivation therapy (ADT) and are classified as metastatic castration-sensitive PC (mCSPC). Following months to years of ADT, the disease tends to become resistant to ADT. Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC. Following its implementation in routine care, this combined treatment strategy requires more detailed evaluation in a real-world setting.AIMTo assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC.METHODSA multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed. This region includes approximately 1.1 million citizens and the oncology departments of Linkoping, Jonkoping, and Kalmar. All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included. The primary endpoint was progression-free survival (PFS) at 12 mo, and the secondary endpoints were PFS at 24 mo, overall survival (OS), treatment intensity, adverse events, and unplanned hospitalizations. Exploratory analyses on potential prognostic parameters were performed.RESULTSNinety-four patients were eligible and formed the study cohort. PFS at 12 and 24 mo was 75% (95%CI: 66-84) and 58% (46-70), respectively. OS at 12 and 24 mo was 93% (87-99) and 86% (76-96). A total of 91% of patients (n = 86) were given docetaxel according to the standard protocol of 75 mg/m(2) every 3 wk (6 cycles), while 9% (n = 8) received a modified protocol of 50 mg/m(2) every 2 wk (9 cycles). The average overall dose intensity for those commencing standard treatment was 91%. Univariate Cox regression analyses show that baseline PSA > 180 vs < 180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors (HR 2.86, 95%CI: 1.39-5.87, P = 0.0041 and 3.36, 95%CI: 1.03-10.96, P = 0.045). Following multivariate analysis, statistical significance remained for PSA (2.51, 95%CI: 1.21-5.19, P = 0.013) but not for metastatic status (2.60, 95%CI: 0.78-8.65, P = 0.12). Febrile neutropenia was recorded in 21% (n = 20) of patients, and 26% (n = 24) had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course.CONCLUSIONResults from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.
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| 20. |
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| 21. |
- Kattge, Jens, et al.
(author)
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TRY plant trait database - enhanced coverage and open access
- 2020
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In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Journal article (peer-reviewed)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 22. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 23. |
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| 24. |
- Miyamoto, Reiko, et al.
(author)
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Student perceptions of growth-facilitating and growth-constraining factors of practice placements : A comparison between Japanese and United Kingdom occupational therapy students
- 2019
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In: Occupational Therapy International. - : Hindawi Publishing Corporation. - 0966-7903 .- 1557-0703.
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Journal article (peer-reviewed)abstract
- This study compared growth-facilitating and growth-constraining experiences of practice placements as perceived by occupational therapy students from Japan and the United Kingdom (UK). Fifteen students from Japan and 14 from the UK used a nominal group technique (NGT) to rank, individually and in groups, their subjective learning experiences during practice placements. Qualitative analysis and simple tabulation based on ranking of items obtained in the NGT were performed. Five item categories were identified from both Japanese and UK students: self-reflection, the role of supervisor, sense of responsibility, clinical knowledge and skills, and time management. Results showed that all students perceived opportunities for self-reflection and feedback from supervisors as growth facilitating and students’ passive attitudes towards requirements of practice placements as growth constraining. Countryspecific differences between students were observed in clinical knowledge and skills, sense of responsibility, and time management. Japanese students perceived that preparatory study led to successfully treating clients during placement, and they tended to commit to placement assignments at the expense of time outside. UK students valued working independently with a sense of responsibility but considered time-management problems within their placement hours as growth constraining. These differences can be explained by different social norms and expectations of students from Japan and the UK.
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| 25. |
- Nordigården, Amanda, et al.
(author)
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Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice
- 2011
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In: British Journal of Haematology. - : Blackwell Publishing. - 0007-1048 .- 1365-2141. ; 155:2, s. 198-208
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Journal article (peer-reviewed)abstract
- Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.
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| 26. |
- Rudisch, Julian, et al.
(author)
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Developmental characteristics of disparate bimanual movement skills in typically developing children
- 2018
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In: Journal of motor behavior. - : Taylor & Francis. - 0022-2895 .- 1940-1027. ; 50:1, s. 8-16
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Journal article (peer-reviewed)abstract
- Mastery of many tasks in daily life requires role differentiated bimanual hand use with high spatiotemporal cooperation and minimal interference. The authors investigated developmental changes in the performance of a disparate bimanual movement task requiring sequenced movements. Age groups were attributed to changes in CNS structures critical for bimanual control such as the corpus callosum (CC) and the prefrontal cortex; young children (5–6 years old), older children (7–9 years old), and adolescents (10–16 years old). Results show qualitative changes in spatiotemporal sequencing between the young and older children which typically marks a phase of distinct reduction of growth and myelination of the CC. Results show qualitative changes in spatiotemporal sequencing between the young and older children, which coincides with distinct changes in the growth rate and myelination of the CC. The results further support the hypothesis that CC maturation plays an important role in the development of bimanual skills.
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| 27. |
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| 28. |
- Sarwar, Martuza, et al.
(author)
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The role of PIP5K1 alpha/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1 alpha inhibitor
- 2019
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In: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 38:3, s. 375-389
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Journal article (peer-reviewed)abstract
- Despite recent improvement in adjuvant therapies, triple-negative, and ER+ subtypes of breast cancer (BC) with metastatic potentials remain the leading cause of BC-related deaths. We investigated the role of phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), a key upstream factor of PI3K/AKT, and the therapeutic effect of PIP5Kα inhibitor on subtypes of BC. The clinical importance of PIP5K1α and its association with survivals were analyzed using three BC cohorts from Nottingham (n = 913), KM plotter (n = 112) and TCGA (n = 817). Targeted overexpression or knockdown of PIP5K1α were introduced into BC cell lines. The effects of PIP5K1α and its inhibitor on growth and invasion of BC were confirmed by using in vitro assays including proliferation, migration, apoptosis and luciferase reporter assays and in vivo xenograft mouse models. All statistical tests were two-sided. PIP5K1α was associated with poor patient outcome in triple-negative BC (for PIP5K1α protein, p = 0.011 and for mRNA expression, p = 0.028, log-rank test). 29% of triple-negative BC had PIP5K1A gene amplification. Elevated level of PIP5K1α increased expression of pSer-473 AKT (p < 0.001) and invasiveness of triple-negative MDA-MB-231 cells (p < 0.001). Conversely, inhibition of PIP5K1α using its inhibitor ISA-2011B, or via knockdown suppressed growth and invasiveness of MDA-MB-231 xenografts (mean vehicle-treated controls = 2160 mm3, and mean ISA-2011B-treated = 600 mm3, p < 0.001). ISA-2011B-treatment reduced expression of pSer-473 AKT (p < 0.001) and its downstream effectors including cyclin D1, VEGF and its receptors, VEGFR1 and VEGFR2 (p < 0.001) in xenograft tumors. In ER+ cancer cells, PIP5K1α acted on pSer-473 AKT, and was in complexes with VEGFR2, serving as co-factor of ER-alpha to regulate activities of target genes including cyclin D1 and CDK1. Our study suggests that our developed PIP5K1α inhibitor has a great potential on refining targeted therapeutics for treatment of triple-negative and ER+ BC with abnormal PI3K/AKT pathways.
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| 29. |
- Wang, Tianyan, et al.
(author)
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PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer
- 2022
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In: Frontiers in Cell and Developmental Biology. - : Frontiers Media S.A.. - 2296-634X. ; 10
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Journal article (peer-reviewed)abstract
- PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.
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