| 1. |
- Holm, Björn, et al.
(författare)
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An improved synthesis of a galactosylated hydroxylysine building block and its use in solid-phase glycopeptide synthesis
- 2000
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Ingår i: Tetrahedron. ; 56, s. 1579-86
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Tidskriftsartikel (refereegranskat)abstract
- Different protective groups for (5R)-5-hydroxy-L-lysine were investigated in silver silicate promoted glycosylations with aceto-bromogalactose as glycosyl donor. Best results were obtained with Fmoc-Hyl(Cbz)-OAll, which was glycosylated in 80% yield. Removal of the allyl group gave a beta-D-galactosylated building block which was used in solid-phase synthesis of a glycopeptide from type II collagen. Such glycopeptides are required for studies of rheumatoid arthritis in a mouse that is transgenic for HLA-DR4, i.e. the class ii MHC molecule associated with rheumatism in humans.
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| 2. |
- Krauss, Tobias, et al.
(författare)
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Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors
- 2018
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Ingår i: Endocrine-Related Cancer. - : BIOSCIENTIFICA LTD. - 1351-0088 .- 1479-6821. ; 25:9, s. 783-793
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were >= 2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off >= 2.8 cm, 44% and 91% for TVDT cut-off of <= 24 months). In 117 of 273 patients, PanNETs > 1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs < 2.8 cm vs >= 2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.
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| 3. |
- Wellner, Eric, et al.
(författare)
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Synthesis of a C-glycoside analogue of β-D-galactosyl hydroxynorvaline and its use in immunological studies
- 2000
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Ingår i: ChemBioChem. - : John Wiley & Sons. - 1439-4227 .- 1439-7633. ; 1:4, s. 272-280
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Tidskriftsartikel (refereegranskat)abstract
- A C-linked isostere of β-d-galactosylated hydroxynorvaline has been prepared in eight steps from per-O-benzylated galactopyranolactone. Addition of a homoallylic Grignard reagent to the lactone, reduction of the resulting hemiacetal with triethylsilane, and a Wittig reaction with Garner's aldehyde were key steps in this synthesis. The C-linked building block was then incorporated at position 264 into the fragment CII(256–270) from type II collagen by solid-phase synthesis using a combination of the tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) protective group strategies. Deprotection of the benzylated C-linked galactosyl moiety was achieved simultaneously with cleavage of the glycopeptide from the solid phase by using triethylsilyl trifluoromethanesulfonate in TFA. Helper T-cell hybridomas obtained in a mouse model for rheumatoid arthritis responded to the C-linked glycopeptide when presented by class II MHC molecules. However, 10- to 20-fold higher concentrations were required as compared to when O-linked β-d-galactosylated hydroxynorvaline or hydroxylysine (Hyl) were present at position 264 of CII(256–270). Thus, replacement of a single oxygen atom by a methylene group in the carbohydrate moiety of a glycopeptide antigen had a substantial influence on the T-cell response. This reveals that T cells are able to recognize the carbohydrate moiety of glycopeptide antigens with high specificity. Finally, the results suggest that structural modifications of β-d-Gal-Hyl264in CII(256–270) may give altered peptide ligands that can be used for induction of tolerance in autoimmune rheumatoid arthritis.
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