| 1. |
- Bergh, Anders, et al.
(författare)
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Cobalt-mediated solid phase synthesis of 3-O-alkynylbenzyl galactosides and their evaluation as galectin inhibitors
- 2006
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 62:35, s. 8309-8317
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Tidskriftsartikel (refereegranskat)abstract
- Methyl beta-D-galactoside was converted to the corresponding 3,4-O-stannylene acetal, which was selectively benzylated with 3-iodobenzyl bromide and coupled to a polymer-bound propargylic ether via a Sonogashira reaction. The polymer-bound carbohydrate substrate was cleaved from the resin with different carbon nucleophiles in a cobalt-mediated Nicholas reaction. The product 3-O-alkynylbenzyl galactosides were screened towards galectin-1, -3, -7, -8N and -9N in a competitive fluorescence polarisation assay. Particularly potent inhibitors were identified against galectin-7 with affinity enhancements up to one order of magnitude due to the 3-O-alkynylbenzyl moiety. (c) 2006 Elsevier Ltd. All rights reserved.
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| 2. |
- Gudey, Shyam Kumar, et al.
(författare)
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TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1
- 2014
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Ingår i: Science Signaling. - : American Association for the Advancement of Science. - 1945-0877 .- 1937-9145. ; 7:307
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor-beta (TGF beta) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGF beta type I receptor (T beta RI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-alpha-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of T beta RI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a gamma-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGF beta increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the T beta RI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved T beta RI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, T beta RI-ICD bound to the promoter and increased the transcription of the gene encoding T beta RI. The TRAF6- and PS1-induced intramembrane proteolysis of T beta RI promoted TGF beta-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the gamma-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl)-propionamide}, generation of T beta RI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that gamma-secretase inhibitors may be useful for treating aggressive prostate cancer.
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| 3. |
- Hamidi, Anahita, et al.
(författare)
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TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α
- 2017
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Ingår i: Science Signaling. - : American Association for the Advancement of Science. - 1945-0877 .- 1937-9145. ; 10:486
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- TGF-β signaling stimulates various intracellular pathways that can promote migration in tumor cells. These pathways are generally thought to be either dependent or independent of transcription factors called SMADs. One of the SMAD-independent pathways (PI3K-AKT) is mediated by a direct interaction between PI3K and the TGF-β type I receptor. However, Hamidi et al. found that the TGF-β–induced activation of PI3K depends on another ubiquitin ligase–mediated mechanism and a SMAD protein but is independent of the kinase function of TβRI. The binding of TGF-β to its receptor triggered the recruitment of PI3K and the ubiquitin ligase TRAF6, which polyubiquitylated the regulatory PI3K subunit p85α, thus enabling phosphorylation of the catalytic PI3K subunit p110, but only in the presence of SMAD7. The abundance of ubiquitylated p85α correlated with migration in cultured cells and prostate tumor grade in patient samples. TRAF6 mediates activation of the other “SMAD-independent” (JNK) pathway. These data suggest that, although distinct, the TGF-β signaling pathways are not as insulated from each other as was once thought.
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| 4. |
- Bergh, Anders, et al.
(författare)
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Carbohydrate functionalization using cationic iron carbonyl complexes
- 2008
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Ingår i: Carbohydrate Research. - : Elsevier BV. - 1873-426X .- 0008-6215. ; 343:10-11, s. 1808-1813
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Tidskriftsartikel (refereegranskat)abstract
- Cationic iron carbonyl cyclohexadiene complexes were employed in the derivatization of the 3-OH position of unprotected and protected methyl beta-D-galactopyranosides using two different approaches, giving access to galactopyranosides with an aromatic or cyclohexadienoic functionality in this position. (c) 2008 Elsevier Ltd. All rights reserved.
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| 5. |
- Roberge, Jean-Michel, et al.
(författare)
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Socio-ecological implications of modifying rotation lengths in forestry
- 2016
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 45, s. 109-123
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Tidskriftsartikel (refereegranskat)abstract
- The rotation length is a key component of even-aged forest management systems. Using Fennoscandian forestry as a case, we review the socioecological implications of modifying rotation lengths relative to current practice by evaluating effects on a range of ecosystem services and on biodiversity conservation. The effects of shortening rotations on provisioning services are expected to be mostly negative to neutral (e.g. production of wood, bilberries, reindeer forage), while those of extending rotations would be more varied. Shortening rotations may help limit damage by some of today's major damaging agents (e.g. root rot, cambium-feeding insects), but may also increase other damage types (e.g. regeneration pests) and impede climate mitigation. Supporting (water, soil nutrients) and cultural (aesthetics, cultural heritage) ecosystem services would generally be affected negatively by shortened rotations and positively by extended rotations, as would most biodiversity indicators. Several effect modifiers, such as changes to thinning regimes, could alter these patterns.
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| 6. |
- Aittomaki, K, et al.
(författare)
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Genetics and assisted reproduction technology
- 2005
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Ingår i: Acta Obstet Gynecol Scand. - : Wiley. ; 84:5, s. 463-473
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Tidskriftsartikel (refereegranskat)abstract
- In the past 20 years, a significant improvement has been shown in the treatment for infertility in both women and men through the development of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Only donated sperm could be previously used for treatment; now oocytes can also be donated. Furthermore, the combination of IVF and ICSI with advanced genetic methods has made preimplantation genetic diagnosis possible for many genetic conditions. These methods enable genetic testing of the early human embryo by using only a single cell, one blastomere biopsied from the embryo, as the sample from which the diagnosis of many chromosome rearrangements and other inherited diseases can be made. It has also been established that a considerable proportion of infertility is caused by genetic defects, which have several implications for infertility treatment. The purpose of this review is to give a concise introduction on how genetics is involved in assisted reproduction technology to specialists who may not be working in this particular field of gynecology, but who would need some knowledge of this for proper care of their patients.
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| 7. |
- Kiflemariam, Sara, et al.
(författare)
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In situ sequencing identifies TMPRSS2-ERG fusion transcripts, somatic point mutations and gene expression levels in prostate cancers
- 2014
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 234:2, s. 253-261
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Tidskriftsartikel (refereegranskat)abstract
- Translocations contribute to the genesis and progression of epithelial tumours and in particular to prostate cancer development. To better understand the contribution of fusion transcripts and visualize the clonal composition of multifocal tumours, we have developed a technology for multiplex in situ detection and identification of expressed fusion transcripts. When compared to immunohistochemistry, TMPRSS2-ERG fusion-negative and fusion-positive prostate tumours were correctly classified. The most prevalent TMPRSS2-ERG fusion variants were visualized, identified, and quantitated in human prostate cancer tissues, and the ratio of the variant fusion transcripts could for the first time be directly determined by in situ sequencing. Further, we demonstrate concurrent in situ detection of gene expression, point mutations, and gene fusions of the prostate cancer relevant targets AMACR, AR, TP53, and TMPRSS2-ERG. This unified approach to in situ analyses of somatic mutations can empower studies of intra-tumoural heterogeneity and future tissue-based diagnostics of mutations and translocations.
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| 8. |
- Stenson, Lena, et al.
(författare)
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Localization of hormone-sensitive lipase to rat Sertoli cells and its expression in developing and degenerating testes
- 1994
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Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 355:2, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- Using in situ hybridization, hormone-sensitive lipase was found to be expressed in a stage-dependent manner in Sertoli cells of rat testis. No expression was found in Leydig cells but expression in spermatids could not be excluded. These results suggest a role for hormone-sensitive lipase in the metabolism of lipid droplets in Sertoli cells, in contrast to its previously proposed function in steroid biosynthesis. The expression of testicular hormone-sensitive lipase mRNA and protein, both larger in size compared to other tissues, coincided with the onset of spermatogenesis and was dependent on scrotal localization of the testis, suggesting a temperature-dependent, pretranslational regulation of expression.
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| 9. |
- Bergh, Anders, 1971
(författare)
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Derivatising Carbohydrates for Biological Applications
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Carbohydrates have a wide variety of functions in Nature. The somewhat old view of carbohydrates only functioning as building blocks or energy sources, has been overturned by the newer insight that carbohydrates are deeply involved in recognition processes, such as receptors for bacteria, viruses, antibodies and proteins. A good example of the latter is the beta-D-galactose recognising family, the galectins. The biological rules of this family, with its fourteen members, are not yet fully elucidated but there is ample evidence that they affect cancer and tumor progression, regulation of the cell cycle and are involved in the immunosystem, e.g. recognition and killing of bacteria. It has also been proven that galectins are associated with myocardial infarction, parasite infection and allergic inflammation. To study these types of interactions and mechanisms we need tools. Two such tools are synthetic glycoconjugates and derivatised carbohydrates. In this thesis we have developed a mild and effective methodology for neoglycoconjugate synthesis, utilising hydrophobic didecyl squaric ester. The generality of this methodology was proven in synthesis of various neoglycoconjugates as well as a trimeric globotetraose derivative. The sequence of formation and subsequent reaction of a cobalt hexacarbonyl complexed propargylic cation, is known as the Nicholas reaction. This reaction has been studied and used as a methodology for synthesising novel galectin inhibititors in solid phase. The method was proven to be both straightforward and flexible and the solid phase approach simplified the purification procedure significantly. The synthesised inhibitors were tested against galectin-1, -2, -3, -7, -8N and -9N. Their affinitiy ranged from poor to good. By using a cationic dienyl iron carbonyl complex in conjunction with either acetylated methyl beta-D-galactopyranoside or a preformed stannylene acetal, alkylations were proven to be effective. In the case of the acetylated methyl beta-D-galactopyranoside, the resulting diene could be aromatised. Work is in progress to aromatise the selectively unprotected methyl-beta-D-galactopyranoside.
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| 10. |
- Bergh, Anders, et al.
(författare)
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Didecyl squarate — A practical amino-reactive cross-linking reagent for neoglycoconjugate synthesis
- 2001
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Ingår i: Glycoconjugate Journal. - 1573-4986. ; 18:8, s. 615-621
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Tidskriftsartikel (refereegranskat)abstract
- The present paper describes the synthesis and use of the hydrophobic squaric decyl ester glycosides in neoglycoconjugate chemistry. The 2-aminoethyl glycosides of agr-D-mannopyranose, lactose, globotriose, globotetraose, GM3, and sialyl Lewisx, as well as the 2-(2-aminoethylthio)ethyl glycoside of agr-D-mannopyranose, beta-D-glucopyranose, and galabiose were reacted with squaric acid didecyl ester to afford the hydrophobic squaric decyl ester glycosides. These glycosides were efficient reagents for the conjugation to amino-functional microtiter plates, BSA and aminated Sepharose EAH 4B. The decyl ester moiety of the squaric decyl ester glycosides constitutes a traceless hydrophobic tag, which has the major advantage, as compared to the corresponding ethyl esters, that it enables easy purification of the glycosides with silica chromatography and that unreacted excesses glycosides from conjugation reaction mixtures can easily be recovered by means of C18 solid phase extraction.
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