| 1. |
- Elo, Laura L., et al.
(författare)
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Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming
- 2010
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Ingår i: Immunity. - : Cell Press. - 1074-7613 .- 1097-4180. ; 32:6, s. 852-862
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Tidskriftsartikel (refereegranskat)abstract
- Dissecting the molecular mechanisms by which T helper (Th) cells differentiate to effector Th2 cells is important for understanding the pathogenesis of immune-mediated diseases, such as asthma and allergy. Because the STAT6 transcription factor is an upstream mediator required for interleukin-4 (IL-4)-induced Th2 cell differentiation, its targets include genes important for this process. Using primary human CD4(+) T cells, and by blocking STAT6 with RNAi, we identified a number of direct and indirect targets of STAT6 with ChIP sequencing. The integration of these data sets with detailed kinetics of IL-4-driven transcriptional changes showed that STAT6 was predominantly needed for the activation of transcription leading to the Th2 cell phenotype. This integrated genome-wide data on IL-4- and STAT6-mediated transcription provide a unique resource for studies on Th cell differentiation and, in particular, for designing interventions of human Th2 cell responses.
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| 2. |
- Eskola, Olli, et al.
(författare)
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Tracer Level Electrophilic Synthesis and Pharmacokinetics of the Hypoxia Tracer [F-18]EF5
- 2012
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Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 14:2, s. 205-212
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Tidskriftsartikel (refereegranskat)abstract
- 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide labeled with [F-18]-fluorine ([F-18]EF5), a promising tracer for tumor hypoxia, has previously been synthesized in low yields and low specific radioactivity. In pharmacokinetic evaluations, in the presence of non-radioactive EF5, a uniform and low background uptake and high in vivo stability of [F-18]EF5 have been demonstrated. Our purpose was to increase the specific radioactivity of [F-18]EF5 to enable to study the pharmacokinetics at trace level. [F-18]EF5 was synthesized using high specific radioactivity electrophilic [F-18]F-2 as labelling reagent. Biodistribution of [F-18]EF5 was determined in a prostate tumor mouse model, and formation of radiolabelled metabolites was studied in mouse, rat and human plasma. On average, 595 +/- 153 MBq of [F-18]EF5 was produced. Specific radioactivity was 6.6 +/- 1.9 GBq/mu mol and the radiochemical purity exceeded 99.0%. [F-18]EF5 was distributed uniformly in tissues, with highest uptake in liver, kidney, and intestine. Several radiolabelled metabolites were detected in mouse plasma and tissues, whereas low amounts of metabolites were detected in human and rat plasma. [F-18]EF5 was synthesized by electrophilic labelling with high quality and high yields. Pharmacokinetics of [F-18]EF5 was determined at trace level in several species. Our results suggest that the trace-level approach does not affect the biodistribution of [F-18]EF5. Extensive metabolism was seen in mouse.
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| 3. |
- Jiang, Ronghuan, et al.
(författare)
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Which One Is the “Best”: a Cross-national Comparative Study of Students’ Strategy Evaluation in Equation Solving
- 2023
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Ingår i: International Journal of Science and Mathematics Education. - : Springer Science and Business Media LLC. - 1573-1774 .- 1571-0068. ; 21:4, s. 1127-1151
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Tidskriftsartikel (refereegranskat)abstract
- This cross-national study examined students’ evaluation of strategies for solving linear equations, as well as the extent to which their evaluation criteria were related to their use of strategies and/or aligned with experts’ views about which strategy is the best. A total of 792 middle school and high school students from Sweden, Finland, and Spain participated in the study. Students were asked to solve twelve equations, provide multiple solving strategies for each equation, and select the best strategy among those they produced for each equation. Our results indicate that students’ evaluation of strategies was not strongly related to their initial preferences for using strategies. Instead, many students’ criteria were aligned with the flexibility goals, in that a strategy that takes advantages of task context was more highly valued than a standard algorithm. However, cross-national differences in strategy evaluation indicated that Swedish and Finnish students were more aligned with flexibility goals in terms of their strategy evaluation criteria, while Spanish students tended to consider standard algorithms better than other strategies. We also found that high school students showed more flexibility concerns than middle school students. Different emphases in educational practice and prior knowledge might explain these cross-national differences as well as the findings of developmental changes in students’ evaluation criteria.
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| 4. |
- Martikainen, Miika, et al.
(författare)
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Oncolytic alphavirus SFV-VA7 efficiently eradicates subcutaneous and orthotopic human prostate tumours in mice
- 2017
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Ingår i: British Journal of Cancer. - : NATURE PUBLISHING GROUP. - 0007-0920 .- 1532-1827. ; 117:1, s. 51-55
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite recent therapeutic and diagnostic advances, prostate cancer remains the second leading cause of cancer-related deaths among men in the Western world. Oncolytic viruses that replicate selectively in tumour cells represent a novel treatment candidate for these malignancies.Methods: We analysed infectivity of avirulent Semliki Firest virus SFV-VA7 in human prostate cancer cell lines VCaP, LNCaP and 22Rv1 and in nonmalignant prostate epithelial cell line RWPE-1. Therapeutic potency of SFV-VA7 was evaluated in subcutaneous and orthotopic mouse LNCaP xenograft models.Results: SFV-VA7 infected and killed the tested human prostate cancer cell lines irrespective of their hormone response status, while the nonmalignant prostate epithelial cell line RWPE-1 proved highly virus resistant. Notably, a single peritoneal dose of SFV-VA7 was sufficient to eradicate all subcutaneous and orthotopic LNCaP tumours.Conclusions: Our results indicate that SFV-VA7 is a novel, promising therapeutic virus against prostate cancer warranting further testing in early clinical trials.
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| 5. |
- Star, Jon, et al.
(författare)
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Exploring students’ procedural flexibility in three countries
- 2022
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Ingår i: International Journal of STEM Education. - : Springer Science and Business Media LLC. - 2196-7822. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- Background In this cross-national study, Spanish, Finnish, and Swedish middle and high school students’ procedural flexibility was examined, with the specific intent of determining whether and how students’ equation-solving accuracy and flexibility varied by country, age, and/or academic track. The 791 student participants were asked to solve twelve linear equations, provide multiple strategies for each equation, and select the best strategy from among their own strategies. Results Our results indicate that knowledge and use of the standard algorithm for solving linear equations is quite widespread across students in all three countries, but that there exists substantial within-country variation as well as between-country variation in students’ reliance on standard vs. situationally appropriate strategies. In addition, we found correlations between equation-solving accuracy and students’ flexibility in all three countries but to different degrees. Conclusions Although it is increasingly recognized as an important construct of interest, there are many aspects of mathematical flexibility that are not well-understood. Particularly lacking in the literature on flexibility are studies that explore similarities and differences in students’ repertoire of strategies for solving algebra problems across countries with different educational systems and curricula. This study yielded important insights about flexibility and can push the field to explore the extent that within- and between-country differences in flexibility can be linked to differences in countries’ educational systems, teaching practices, and/or cultural norms around mathematics teaching and learning.
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| 6. |
- Säfholm, Annette, et al.
(författare)
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The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility.
- 2008
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 14:20, s. 6556-6563
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: An inherent problem in breast cancer treatment is that current therapeutic approaches fail to specifically target the dissemination of breast cancer cells from the primary tumor. Clinical findings show that the loss of Wnt-5a protein expression in the primary breast tumor predicts a faster tumor spread, and in vitro analyses reveal that it does so by inhibiting tumor cell migration. Therefore, we hypothesized that the reconstitution of Wnt-5a signaling could be a novel therapeutic strategy to inhibit breast cancer metastasis. EXPERIMENTAL DESIGN: We used in vitro techniques to show that 4T1 mouse breast cancer cells responded to the reconstitution of Wnt-5a signaling using our novel Wnt-5a mimicking hexapeptide, Foxy-5, in the same way as human breast cancer cells. Therefore, we could subsequently study its effect in vivo on the metastatic spread of cancer following the inoculation of 4T1 cells into mice. RESULTS: In vitro analyses revealed that both recombinant Wnt-5a and the Wnt-5a-derived Foxy-5 peptide impaired migration and invasion without affecting apoptosis or proliferation of 4T1 breast cancer cells. The in vivo experiments show that i.p. injections of Foxy-5 inhibited metastasis of inoculated 4T1 breast cancer cells from the mammary fat pad to the lungs and liver by 70% to 90%. CONCLUSIONS: These data provide proof of principle that the reconstitution of Wnt-5a signaling in breast cancer cells is a novel approach to impair breast tumor metastasis by targeting cell motility. In combination with existing therapies, this approach represents a potential novel therapeutic strategy for the treatment of breast cancer patients.
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| 7. |
- Tarkkonen, Kati M., et al.
(författare)
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Differential Roles of Fibroblast Growth Factor Receptors (FGFR) 1, 2 and 3 in the Regulation of S115 Breast Cancer Cell Growth
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- Fibroblast growth factors (FGFs) regulate the growth and progression of breast cancer. FGF signaling is transduced through FGF receptors 1-4, which have oncogenic or anti-oncogenic roles depending on the ligand and the cellular context. Our aim was to clarify the roles of FGFR1-3 in breast cancer cell growth in vitro and in vivo. Pools of S115 mouse breast cancer cells expressing shRNA against FGFR1, 2 and 3 were created by lentiviral gene transfer, resulting in cells with downregulated expression of FGFR1, FGFR2 or FGFR3 (shR1, shR2 and shR3 cells, respectively) and shLacZ controls. FGFR1-silenced shR1 cells formed small, poorly vascularized tumors in nude mice. Silencing of FGFR2 in shR2 cells was associated with strong upregulation of FGFR1 expression and the formation of large, highly vascularized tumors compared to the control tumors. Silencing FGFR3 did not affect cell survival or tumor growth. Overexpressing FGFR2 in control cells did not affect FGFR1 expression, suggesting that high FGFR1 expression in shR2 cells and tumors was associated with FGFR2 silencing by indirect mechanisms. The expression of FGFR1 was, however, increased by the addition of FGF-8 to starved shLacZ or MCF-7 cells and decreased by the FGFR inhibitor PD173074 in shR2 cells with an elevated FGFR1 level. In conclusion, our results demonstrate that FGFR1 is crucial for S115 breast cancer cell proliferation and tumor growth and angiogenesis, whereas FGFR2 and FGFR3 are less critical for the growth of these cells. The results also suggest that the expression of FGFR1 itself is regulated by FGF-8 and FGF signaling, which may be of importance in breast tumors expressing FGFs at a high level.
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| 8. |
- Tuomela, Johanna, et al.
(författare)
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Fast growth associated with aberrant vasculature and hypoxia in fibroblast growth factor 8b (FGF8b) over-expressing PC-3 prostate tumour xenografts
- 2010
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. Methods: Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([F-18] FDG) and hypoxia ([F-18] EF5), and intratumoral polarographic measurements of pO(2). Results: Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO(2) measurements, [F-18] EF5 and [F-18] FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. Conclusion: FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts.
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| 9. |
- Tuomela, Johanna M., et al.
(författare)
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Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice
- 2008
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Metastatic prostate cancer is associated with a high morbidity and mortality but the spreading mechanisms are still poorly understood. The aminobisphosphonate alendronate, used to reduce bone loss, has also been shown to inhibit the invasion and migration of prostate cancer cells in vitro. We used a modified orthotopic PC-3 nude mouse tumor model of human prostate cancer to study whether alendronate affects prostate tumor growth and metastasis. Methods: PC-3 cells ( 5 x 105) were implanted in the prostates of nude mice and the mice were treated with alendronate ( 0.5 mg/kg/day in PBS, s.c.) or vehicle for 4 weeks. After sacrifice, the sizes of tumor-bearing prostates were measured and the tumors and prostate-draining regional iliac and sacral lymph nodes were excised for studies on markers of proliferation, apoptosis, angiogenesis and lymphangiogenesis, using histomorphometry and immunohistochemistry. Results: Tumor occurrence in the prostate was 73% in the alendronate-treated group and 81% in the control group. Mean tumor size ( 218 mm(3), range: 96-485 mm(3), n = 11) in the alendronate-treated mice was 41% of that in the control mice ( 513 mm(3), range: 209 - 1350 mm(3), n = 13) ( p < 0.05). In the iliac and sacral lymph nodes of alendronate-treated mice, the proportion of metastatic area was only about 10% of that in control mice ( p < 0.001). Immunohistochemical staining of tumor sections showed that alendronate treatment caused a marked decrease in the number of CD34-positive endothelial cells in tumors ( p < 0.001) and an increase in that of ISEL positive apoptotic cells in tumors as well as in lymph node metastases ( p < 0.05) compared with those in the vehicle-treated mice. The density of m-LYVE-I-stained lymphatic capillaries was not changed. Conclusion: Our results demonstrate that alendronate treatment opposes growth of orthotopic PC-3 tumors and decreases tumor metastasis to prostate-draining lymph nodes. This effect could be at least partly explained by decreased angiogenesis and increased apoptosis. The results suggest that bisphosphonates have anti-tumoral and anti-invasive effects on primary prostate cancer.
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| 10. |
- Tuomela, Johanna, et al.
(författare)
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Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors
- 2009
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood. Methods: We studied the roles of VEGF-C and VEGFR3 in prostate cancer metastasis by blocking VEGFR3 using intravenous adenovirus-delivered VEGFR3-Ig fusion protein (VEGFR3-Ig) and by ectopic expression of VEGF-C in PC-3 prostate tumors in nude mice. Results: VEGFR3- Ig decreased the density of lymphatic capillaries in orthotopic PC-3 tumors (p < 0.05) and inhibited metastasis to iliac and sacral lymph nodes. In addition, tumor volumes were smaller in the VEGFR3-Ig-treated group compared with the control group (p < 0.05). Transfection of PC-3 cells with the VEGF-C gene led to a high level of 29/31 kD VEGF-C expression in PC-3 cells. The size of orthotopic and subcutaneous PC-3/VEGF-C tumors was significantly greater than that of PC-3/mock tumors (both p < 0.001). Interestingly, while most orthotopic PC-3 and PC-3/mock tumors grown for 4 weeks metastasized to prostate-draining lymph nodes, orthotopic PC3/VEGF-C tumors primarily metastasized to the lungs. PC-3/VEGF-C tumors showed highly angiogenic morphology with an increased density of blood capillaries compared with PC-3/mock tumors (p < 0.001). Conclusion: The data suggest that even though VEGF-C/VEGFR3 pathway is primarily required for lymphangiogenesis and lymphatic metastasis, an increased level of VEGF-C can also stimulate angiogenesis, which is associated with growth of orthotopic prostate tumors and a switch from a primary pattern of lymph node metastasis to an increased proportion of metastases at distant sites.
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