| 1. |
- Berntson, Martin, 1972, et al.
(författare)
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Skolverket bör backa om religionskunskap
- 2019
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Ingår i: Svenska Dagbladet. - : Schibsted Forlag. - 1101-2412. ; :2019-11-01
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 2. |
- Cosner, Casey C., et al.
(författare)
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Evolution of Concise and Flexible Synthetic Strategies for Trichostatic Acid and the Potent Histone Deacetylase Inhibitor Trichostatin A
- 2013
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Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :1, s. 162-172
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Tidskriftsartikel (refereegranskat)abstract
- (R)-(+)-Trichostatic acid and (R)-(+)-trichostatin A (TSA) are natural products that have attracted considerable attention in the field of epigenetic therapies. TSA in particular is a naturally occurring hydroxamic acid having potent activity as a histone deacetylase inhibitor (HDACi) and having significant potential for treatment of a myriad of genetically based diseases. Development of TSA and other trichostatic acid derivatives into useful small-molecule therapies has been hindered by the low natural abundance and high cost associated with these compounds. We report herein our collective efforts towards the development of concise and scalable routes for the synthesis of trichostatic acid and TSA in both racemic and enantioenriched forms. Three independent synthetic pathways were developed with varying degrees of efficiency and convergency. In the first synthesis, the key step was a vinylogous Horner-Wadsworth-Emmons condensation. A Marshall propargylation reaction was used as the key step in the second synthesis, and Pd-catalyzed a-alkenylation of a ketone zinc enolate by using various functionalized alkenyl or dienyl halides was developed for the third synthesis. The second pathway proved to be readily amenable to an enantioselective modification, and both the second and third pathways were straightforwardly adapted for the facile preparation of new analogues of trichostatic acid and TSA.
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| 3. |
- Holmquist Mengelbier, Linda, et al.
(författare)
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Effect of hypoxia on the tumor phenotype: the neuroblastoma and breast cancer models
- 2006
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Ingår i: Advances in experimental medicine and biology. - 0065-2598. ; 587, s. 179-193
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Konferensbidrag (refereegranskat)abstract
- The tumor oxygenation status associates with aggressive behavior. Oxygen shortage, hypoxia, is a major driving force behind tumor vascularization, and hypoxia enhances mutational rate, metastatic spread, and resistance to radiation and chemotherapy. We recently discovered that hypoxia promotes dedifferentiation of neuroblastoma and breast carcinoma cells and development of stem cell-like features. In both these tumor forms there is a correlation between low differentiation stage and poor outcome, and we conclude that the dedifferentiating effect of lowered oxygen adds to the aggressive phenotype induced by hypoxia. With neuroblastoma and breast carcinoma as human tumor model systems, we have addressed questions related to hypoxia-induced molecular mechanisms governing malignant behavior of tumor cells, with emphasis on differentiation and growth control. By global gene expression analyses we are currently screening for gene products exclusively expressed or modified in hypoxic cells with the aim to use them as targets for treatment.
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| 4. |
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| 5. |
- Löfstedt, Tobias, et al.
(författare)
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HIF-1alpha induces MXI1 by alternate promoter usage in human neuroblastoma cells.
- 2009
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 315:11, s. 1924-1936
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Tidskriftsartikel (refereegranskat)abstract
- Adaptation to low oxygen conditions is essential for maintaining homeostasis and viability in oxygen-consuming multi-cellular tissues, including solid tumors. Central in these processes are the hypoxia-inducible transcription factors, HIF-1 and HIF-2, controlling genes involved in e.g. glucose metabolism and neovascularization. Tumor hypoxia and HIF expression have also been associated with a dedifferentiated phenotype and increased aggressiveness. In this report we show that the MAX interactor-1 (MXI1) gene is directly regulated by HIF proteins in neuroblastoma and breast cancer cells. HIF-binding and transactivation were detected within MXI1 gene regulatory sequences in the vicinity of the MXI1-0 promoter, leading to rapid induction of the alternate MXI1-0 isoform followed by a long-term induction of both the MXI1-0 and MXI1 isoforms. Importantly, knock-down of MXI1 had limited effect on MYC/MYCN activity under hypoxia, an observation that might be related to the different functional attributes of the two MXI1 isoforms.
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| 6. |
- Löfstedt, Tobias, et al.
(författare)
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Hypoxia inducible factor-2alpha in cancer.
- 2007
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Ingår i: Cell Cycle. - 1551-4005. ; 6:8, s. 919-926
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Tidskriftsartikel (refereegranskat)abstract
- Poorly oxygenated ( hypoxic) tumors are frequently more aggressive compared to corresponding tumors that are better oxygenated. Adaptation to hypoxia is primarily mediated by two closely related hypoxia inducible transcription factor complexes, HIF-1 and HIF-2, which become stabilized and activated at low oxygen levels. Whether HIF-1 and HIF-2 have different roles in tumorigenesis is an open question and an issue we discuss. With focus on HIF-2, we summarize reported phenotypical changes of HIF genetic models and HIF expression patterns during normal development, in adult non - malignant tissues and in tumors. We further address the much - discussed subject of target gene preferences between HIF-1 and HIF-2, given that both transcription factors bind to the same DNA motif. Finally, we also discuss the observations that the oxygen - sensitive HIF-2 alpha subunit is accumulated and active under non - hypoxic conditions as exemplified by HIF-2 alpha expressing tumor macrophages and neuroblastoma cells located in seemingly well - vascularized tumor regions and how this phenomenon is related to tumor aggressiveness.
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| 7. |
- Löfstedt, Tobias, et al.
(författare)
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Induction of ID2 expression by hypoxia-inducible factor-1 - A role in dedifferentiation of hypoxic neuroblastoma cells
- 2004
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 279:38, s. 39223-39231
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Tidskriftsartikel (refereegranskat)abstract
- ID ( inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2. Because of its involvement in normal neural crest development and its ability to inhibit proneuronal bHLH proteins, the hypoxic induction of ID2 was of particular interest. Here we report fast induction kinetics of ID2 expression in hypoxic neuroblastoma cells. The up-regulation of ID2 was abolished by addition of actinomycin D, implicating a hypoxia-driven transcriptional mechanism. Analyzing the ID2 promoter revealed several potential binding sites for hypoxia-inducible factors. Subsequent electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated two functional HIF-1 binding sites within ID2 gene regulatory sequences located at -725 and -1893 relative to the transcriptional initiation point. In transfection assays, DNA constructs of the ID2 promoter, including the functional HIF-1 binding sites, induced luciferase reporter activity in a HIF-1-specific manner. These observations demonstrate that ID2 is actively engaged by hypoxia and represents a novel HIF-1 target. Hypoxia-induced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors.
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| 8. |
- Löfstedt, Tobias
(författare)
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Transcriptional Regulation by Hypoxia-Inducible Factors in Tumor Cells
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a major cause of human morbidity and mortality, and the risk of developing cancer is about one in three life times. Neuroblastoma is the most common extra-cranial solid tumor among children and arises from early sympathetic nervous system (SNS) cells arrested in their development. Generally, a low tumor cell differentiation correlates to poor prognosis. Solid tumors, like neuroblastoma, frequently contain regions of oxygen deficiency ? hypoxia ? caused by a high rate of cellular proliferation and abnormal intratumoral blood supply. In this hypoxic microenvironment cancer cells undergo genetic and molecular changes, allowing continued survival and proliferation. Tumor hypoxia is also associated with increased aggressiveness, resistance to therapy and poor outcome. Cancer cells become less differentiated in response to hypoxia, which we previously demonstrated in neuroblastoma as well as breast cancer cells, indicating an evolvement of a more aggressive phenotype. In the present studies we find evidence of potential mechanisms behind the hypoxia-mediated de-differentiation of neuroblastoma cells. Hypoxia (1% O2) induced the expression of the negative transcription factor ID2 (Paper I), involved in blocking the function of tissue-specific basic helix-loop-helix (bHLH) proteins, such as the SNS-specifying transcription factors HASH-1 and dHAND. Hypoxic up-regulation of ID2 was dependent on direct in vivo DNA-binding and activity of hypoxia-inducible factors (HIF), the master transcriptional regulators of oxygen homeostasis. Induction of ID2 expression occurs as an early HIF-mediated hypoxic event, potentially leading to a more immature state. HIF-1alpha and HIF-2alpha, however differently, are both essential for normal development and are highly implicated in tumor progression. In Paper II we show that HIF-1alpha and HIF-2alpha share several target genes, but mediate regulation of these under different temporal and oxygen-dependent conditions. Interestingly, HIF-2alpha, but not HIF-1alpha, was present in neuroblastoma tumor cells near blood vessels, and thus in apparently better oxygenized tumor regions. In vitro, HIF-1alpha protein was transiently stabilized at hypoxia and primarily governed acute hypoxic responses, whereas HIF-2alpha became more important at prolonged hypoxia. In addition, high HIF-2alpha activity, including induction of classic hypoxic targets such as VEGF, was detected in cultured neuroblastoma cells already at 5% O2, a physiologically relevant oxygen level, similar to the findings in vivo. In a large clinical neuroblastoma material, significant correlations between high HIF-2alpha levels and high VEGF content, advanced tumor stage and poor outcome were found. These observations clearly suggest an oncogenic role of HIF-2alpha, and implicate HIF-2alpha as an independent prognostic marker in neuroblastoma. The MXI1 (MAX-interactor 1) gene, a reported MYC antagonist, has been detected by us and others as a commonly hypoxia-induced gene. In Paper III we further demonstrate that HIF proteins, via direct binding to hypoxia-response elements (HRE), up-regulate MXI1 mRNA and protein in both hypoxic neuroblastoma and breast cancer cells. Interestingly, reducing MXI1 levels had no overall effects on MYC/MYCN activity in hypoxic neuroblastoma cells. Instead, MXI1 appeared to be important in augmenting the hypoxic response, potentially by enhancing specific HIF-1 target gene induction. HIF proteins are primarily stabilized and activated in response to lowered oxygen concentrations. However, growth factor-induced signaling can promote HIF-1alpha protein synthesis as well as transactivation, even under normoxic conditions. In Paper IV we characterize a novel such a pathway, where stem cell factor (SCF)-evoked c-Kit-signaling leads to increased HIF-1alpha protein, HRE-activation and induction of several HIF-1alpha targets, such as VEGF and GLUT1, already at normoxia. In addition we find a reciprocal positive feedback loop between c-Kit and HIF-1alpha, where induced HIF-1alpha mediates reinforcement of c-Kit expression. Overall, this thesis shows the impact of HIF proteins on tumor cell behavior, principally as central hypoxic transcriptional regulators governing the expression of genes with potential importance in several biological processes, such as growth and differentiation, determining cancer cell aggressiveness as well as adaptation to low oxygen conditions.
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| 9. |
- Pedersen, Malin, et al.
(författare)
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Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.
- 2008
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 98:103, s. 98-103
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Tidskriftsartikel (refereegranskat)abstract
- Signaling by the receptor for stem cell factor (SCF), c-Kit, is of major importance for hematopoiesis, melanogenesis and reproduction, and the biological responses are commonly proliferation and cell survival. Thus, constitutive activation due to c-Kit mutations is involved in the pathogenesis of several forms of cancer, e.g. leukemias, gastrointestinal stromal tumors and testicular tumors. Tumor survival requires oxygen supply through induced neovascularization, a process largely mediated by the vascular endothelial growth factor (VEGF), a prominent target of the transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-2. Using Affymetrix microarrays we have identified genes that are upregulated following SCF stimulation. Interestingly, many of the genes induced were found to be related to a hypoxic response. These findings were corroborated by our observation that SCF stimulation of the hematopoietic cell lines M-07e induces HIF-1alpha and HIF-2alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, an effect that could be reversed by siRNA against HIF-1alpha. We also show that SCF-induced accumulation of HIF-1alpha is dependent on both the PI-3-kinase and Ras/MEK/Erk pathways. Our data suggest a novel mechanism of SCF/c-Kit signaling in angiogenesis and tumor progression.
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| 10. |
- Svensson, Katrin, et al.
(författare)
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Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells.
- 2011
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 108:32, s. 13147-13152
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Tidskriftsartikel (refereegranskat)abstract
- Highly malignant tumors, such as glioblastomas, are characterized by hypoxia, endothelial cell (EC) hyperplasia, and hypercoagulation. However, how these phenomena of the tumor microenvironment may be linked at the molecular level during tumor development remains ill-defined. Here, we provide evidence that hypoxia up-regulates protease-activated receptor 2 (PAR-2), i.e., a G-protein-coupled receptor of coagulation-dependent signaling, in ECs. Hypoxic induction of PAR-2 was found to elicit an angiogenic EC phenotype and to specifically up-regulate heparin-binding EGF-like growth factor (HB-EGF). Inhibition of HB-EGF by antibody neutralization or heparin treatment efficiently counteracted PAR-2-mediated activation of hypoxic ECs. We show that PAR-2-dependent HB-EGF induction was associated with increased phosphorylation of ERK1/2, and inhibition of ERK1/2 phosphorylation attenuated PAR-2-dependent HB-EGF induction as well as EC activation. Tissue factor (TF), i.e., the major initiator of coagulation-dependent PAR signaling, was substantially induced by hypoxia in several types of cancer cells, including glioblastoma; however, TF was undetectable in ECs even at prolonged hypoxia, which precludes cell-autonomous PAR-2 activation through TF. Interestingly, hypoxic cancer cells were shown to release substantial amounts of TF that was mainly associated with secreted microvesicles with exosome-like characteristics. Vesicles derived from glioblastoma cells were found to trigger TF/VIIa-dependent activation of hypoxic ECs in a paracrine manner. We provide evidence of a hypoxia-induced signaling axis that links coagulation activation in cancer cells to PAR-2-mediated activation of ECs. The identified pathway may constitute an interesting target for the development of additional strategies to treat aggressive brain tumors.
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| 11. |
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| 12. |
- Veitonmäki, Niina, et al.
(författare)
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A human icam-1 antibody isolated by a function-first approach has potent macrophage-dependent antimyeloma activity in vivo.
- 2013
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 23:4, s. 502-515
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Tidskriftsartikel (refereegranskat)abstract
- We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.
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| 13. |
- Ålöw, Tobias, et al.
(författare)
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Recensioner
- 2016
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Ingår i: Svensk Exegetisk Årsbok. - Uppsala : Svenska exegetiska sällskapet. - 1100-2298. ; 81, s. 217-284
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Recension (övrigt vetenskapligt/konstnärligt)abstract
- Book reviews:Herbert W. Basser with Marsha B. CohenThe Gospel of Matthew and Judaic Traditions: A Relevance-based Commentary(Tobias Ålöw)Alicia J. Batten och John S. Kloppenborg (red.)James, 1 & 2 Peter, and Early Jesus Traditions(Leonhard Franke)Bible Works 10 (Bo Krister Ljungberg)Derek R. BrownThe God of This Age: Satan in the Churches and Letters of the Apostle Paul(Torsten Löfstedt)William P. Brown (ed.)The Oxford Handbook of the Psalms (David Willgren)Constantine R. CampbellAdvances in the Study of Greek: New Insights for Reading the New Testament (Jan H. Nylund)Nancy L. deClaissé-Walford (ed.) The Shape and Shaping of the Book of Psalms: The Current State of Scholarship(David Willgren)Nancy L. deClaissé-Walford, Rolf A. Jacobson and Beth Laneel Tanner The Book of Psalms(David Willgren)Thomas B. Dozeman, Konrad Schmid och Baruch J. Schwartz (red.) The Pentateuch: International Perspectives on Current Research(Stig Norin)Ole Jakob FiltvedtThe Identity of God’s People and the Paradox of Hebrews(Mikael Tellbe)David Hellholm, Tor Vegge, Øyvind Norderval and Christer Hellholm (eds.)Ablution, Initiation, and Baptism: Late Antiquity, Early Judaism, and Early Christianity(James A. Kelhoffer)Wesley Hill Paul and the Trinity: Persons, Relations, and the Pauline Letters(Mikael Tellbe)Douglas S. HuffmanVerbal Aspect Theory and the Prohibitions in the Greek New Testament(Jan H. Nylund)Thomas KazenScripture, Interpretation, or Authority? Motives and Arguments in Jesus’ Halakic Conflicts(Cecilia Wassén)Judith M. LieuMarcion and the Making of a Heretic: God and Scripture in the Second Century(James A. Kelhoffer)L. Michael Morales (ed.)Cult and Cosmos: Tilting Toward a Temple-Centered Theology(Stefan Green)Mark D. Nanos och Magnus Zetterholm (red.)Paul within Judaism: Restoring the First-Century Context to the Apostle(Martin Landgren)Carol A. Newsom och Brennan W. BreedDaniel: A Commentary(LarsOlov Eriksson)Maren Niehoff (red.)Homer and the Bible in the Eyes of Ancient Interpreters(Blazenka Scheuer)Kurt L. NollCanaan and Israel in Antiquity: A Textbook on History and Religion(Richard Pleijel)Ken Parry (ed.) The Wiley Blackwell Companion to Patristics(Carl Johan Berglund)Ralf Rothenbusch“... abgesondert zur Tora Gottes hin”: Ethnisch-religiöse Identitäten im Esra/Nehemiabuch(Lena-Sofia Tiemeyer)Michael L. SatlowHow the Bible Became Holy(Martin Wessbrandt)Birke Siggelkow-BernerDie jüdischen Feste im Bellum Judaicum des Flavius Josephus(Birger Olsson)Lena-Sofia Tiemeyer och Hans M. Barstad (red.)Continuity and Discontinuity: Chronological and Thematic Development in Isaiah 40–66(Stefan Green)W. Dennis Tucker Jr.Constructing and Deconstructing Power in Psalms 107–150(David Willgren)Helmut Utzschneider och Wolfgang OswaldExodus 1–15(LarsOlov Eriksson)Urban C. Von WahldeThe Gospel and Letters of John, vol. 1:Introduction, Analysis, and Reference The Gospel and Letters of John, vol. 2: Commentary on the Gospel of JohnThe Gospel and Letters of John, vol. 3: Commentary on the Three Johannine Letters(Birger Olsson)Benjamin L. WhiteRemembering Paul: Ancient and Modern Contests over the Image of the Apostle(Martin Wessbrandt)
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