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- Stenman, U H, et al.
(författare)
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Summary report of the TD-3 workshop: characterization of 83 antibodies against prostate-specific antigen
- 1999
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Ingår i: Tumor Biology. - : Springer Science and Business Media LLC. - 1423-0380 .- 1010-4283. ; 20:Suppl. 1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Twelve research groups participated in the ISOBM TD-3 Workshop in which the reactivity and specificity of 83 antibodies against prostate-specific antigen (PSA) were investigated. Using a variety of techniques including cross-inhibition assays, Western blotting, BIAcore, immunoradiometric assays and immunohistochemistry, the antibodies were categorized into six major groups which formed the basis for mapping onto two- and three-dimensional (2-D and 3-D) models of PSA. The overall findings of the TD-3 Workshop are summarized in this report. In agreement with all participating groups, three main antigenic domains were identified: free PSA-specific epitopes located in or close to amino acids 86-91; discontinuous epitopes specific for PSA without human kallikrein (hK2) cross-reactivity located at or close to amino acids 158-163; and continuous or linear epitopes shared between PSA and hK2 located close to amino acids 3-11. In addition, several minor and partly overlapping domains were also identified. Clearly, the characterization of antibodies from this workshop and the location of their epitopes on the 3-D model of PSA illustrate the importance of selecting appropriate antibody pairs for use in immunoassays. It is hoped that these findings and the epitope nomenclature described in this TD-3 Workshop are used as a standard for future evaluation of anti-PSA antibodies.
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- BALZARINI, J, et al.
(författare)
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OXATHIIN CARBOXANILIDE DERIVATIVES - A CLASS OF NONNUCLEOSIDE HIV-1-SPECIFIC REVERSE-TRANSCRIPTASE INHIBITORS (NNRTIS) THAT ARE ACTIVE AGAINST MUTANT HIV-1 STRAINS RESISTANT TO OTHER NNRTIS
- 1995
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Ingår i: ANTIVIRAL CHEMISTRY & CHEMOTHERAPY. - : SAGE Publications. - 0956-3202 .- 2040-2066. ; 6:3, s. 169-178
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The HIV-1-specific oxathiin carboxanilide derivative 1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)carbonyl]amino]benzoate (NSC 615985) (designated UC84) has potent activity against HIV-1(IIIB) (50% effective concentration: 0.015 μg ml−1). UC84 was found to select for a 138-Lys mutant virus strain in HIV-1-infected CEM cell cultures. When the 138-Lys mutation was introduced solely in the p51 subunit of the p51/p66 reverse transcriptase (RT) heterodimer by site-directed mutagenesis, the enzyme proved 10-fold more resistant to UC84 than when the amino acid mutation was introduced solely in the p66 subunit of the p51/p66 RT heterodimer. These data provided clear evidence for a structural and functional role of the p51 subunit in the sensitivity/resistance of the enzyme to UC84. UC84 also proved to be virtually inactive against mutant HIV-1 strains containing the 100-lle, 106-Ala, 138-Lys or 181-Cys mutation in their RT. However, minor structural changes in the molecule, such as replacement of the oxygen of the amide moiety by sulfur, or the isopropyl ester moiety by cyclopentyl or a secondary butyl, or the methyl group of the oxathiin part by ethyl, made the compound markedly more inhibitory to one or several HIV-1 mutant strains. For example, compound 131 (1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)thioxomethyl]amino]benzoate was only 2-fold more active than the parent compound UC84 against wild-type HIV-1, but 30- to 100-fold more inhibitory to HIV-1 mutant strains that contained the 100-11e, 106-A1a, 138-Lys or 181-Cys in their RT. These findings should be taken into account when selecting suitable drug candidates for the treatment of HIV-1 infections, particularly those that have developed resistance to other non-nucleoside RT inhibitors (NNRTIs).
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- Björk-Eriksson, Thomas, 1960, et al.
(författare)
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The in vitro radiosensitivity of human head and neck cancers
- 1998
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Ingår i: Br J Cancer. - 0007-0920. ; 77:12, s. 2371-5
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Tidskriftsartikel (refereegranskat)abstract
- A study was made of the intrinsic radiosensitivity of 140 biopsy and surgical specimens of malignant head and neck tumours of different histologies. Using a soft-agar clonogenic assay, the material was assessed for the ability to grow in culture (colony-forming efficiency; CFE) and inherent tumour radiosensitivity (surviving fraction at 2 Gy, SF2). The success rate for obtaining growth was 74% (104/140) with a mean CFE of 0.093% (median 0.031) and a range of 0.002-1.3%. SF2 was obtained for 88 of 140 specimens, representing a success rate of 63% with a mean SF2 of 0.48 (median 0.43) and a range of 0.10-1.00. There were no significant differences in radiosensitivity between different sites of the head and neck region. There were no significant relationships between SF2 and disease stage, nodal status, tumour grade, patient age, primary tumour growth pattern and CFE. The results were compared with those for other tumour types previously analysed with the same assay. The distribution of the SF2 values for the head and neck tumours was similar to that for 145 cervix carcinomas and there was no significant difference in mean radiosensitivity between the two tumour types. Also, there was no significant difference in radiosensitivity between head and neck tumours and either breast or colorectal cancers. However, a group of eight lymphomas was significantly more radiosensitive. These results confirm the feasibility of carrying out radiosensitivity measurements using a soft-agar clonogenic assay on head and neck tumours. In addition, the work has shown that radiosensitivity is independent of many clinical parameters and that the mean value is similar to that reported for cervix carcinomas.
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- Björk-Eriksson, Thomas, 1960, et al.
(författare)
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The lack of correlation between proliferation (Ki-67, PCNA, LI, Tpot), p53 expression and radiosensitivity for head and neck cancers
- 1999
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Ingår i: Br J Cancer. - 0007-0920. ; 80:9, s. 1400-4
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Tidskriftsartikel (refereegranskat)abstract
- A study was made of the relationship between measurements of radiosensitivity versus proliferation and p53 status in head and neck cancers. Inherent tumour radiosensitivity was assessed as surviving fraction at 2 Gy (SF2) using a clonogenic soft agar assay (n = 77). The results were compared to data on proliferation obtained by both flow cytometry (labelling index (LI), the potential doubling time (Tpot) n = 55) and immunohistochemistry (Ki-67 and PCNA; n = 68), together with immunohistochemical p53 expression (n = 68). There were no overall significant differences in the median values of the various parameters analysed for the different sites within the head and neck region, disease stages, grades of tumour differentiation or nodal states. A subgroup analysis showed that oropharyngeal (n = 22) versus oral cavity (n = 35) tumours were more radiosensitive (P = 0.056) and had a higher Ki-67 index (P = 0.001). Node-positive tumours had higher LI (P = 0.021) and a trend towards lower Tpot (P = 0.067) values than node-negative ones. No correlations were seen between SF2 and any of the parameters studied. The long-standing dogma of an increased radiosensitivity of rapidly proliferating cells in contrast to slowly proliferating cells was not confirmed. The study shows that parallel measurements of different biological markers can be obtained for a large number of patients with head and neck cancers. The independence of the various parameters studied suggests that there may be potential for their combined use as prognostic factors for the outcome of radiotherapy.
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- Karlsson, Niclas G., 1966, et al.
(författare)
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Molecular characterization of the large heavily glycosylated domain glycopeptide from the rat small intestinal Muc2 mucin.
- 1996
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Ingår i: Glycoconjugate journal. - 0282-0080. ; 13:5, s. 823-31
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Tidskriftsartikel (refereegranskat)abstract
- The largest high-glycosylated domain, glycopeptide A, of the "insoluble' mucin complex of the rat small intestine has earlier been purified and characterized (Carlstedt et al., 1993, J Biol Chem 268: 18771-81). A rabbit antiserum raised against deglycosylated glycopeptide A was used to clone part of a mucin showing homology to the human MUC2 mucin (Hansson et al., 1994, Biochem Biophys Res Commun 198. 181-90). This serum specifically stained goblet cells (paranuclear) in the mouse small intestine. The size of the coding sequence of glycopeptide A was estimated by using reversed transcriptase PCR of mRNA from an inbred rat strain (GOT-W) using primers in the unique central and C-terminal parts of the proposed rat Muc2 sequences. The PCR and Southern blot of the PCR products showed a fragment of about 5.5 kb corresponding to about 1700 amino acids when the known Cys-rich sequences used for the primers were subtracted. This is slightly larger than the size estimated earlier by biochemical studies. The mRNA encoding the rat Muc2 was slightly smaller than the mRNA encoding the human MUC2 in a colorectal cell line. Although the size of glycopeptide A estimated from biochemical results and by PCR is not identical, the results obtained here further support that the "insoluble' mucin of the rat small intestine is encoded by the Muc2 gene. Most of the oligosaccharides in glycopeptide A were either neutral (40%) or sialylated (40%). The remaining ones were sulfated with the sulfate group attached to C-6 of N-acetylglucosamine linked to C-6 of the N-acetylgalactosaminitol as revealed by tandem mass spectrometry of the perdeuteroacetylated oligosaccharides. Eighteen oligosaccharides were found of which fourteen were characterized and found to be mostly novel. Our findings thus expand the current knowledge of the core peptide of the rat intestinal goblet cell mucin and provide a relatively complete picture of the glycosylation of a defined mucin domain.
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- Tullberg, Mats, 1965, et al.
(författare)
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CSF neurofilament and glial fibrillary acidic protein in normal pressure hydrocephalus.
- 1998
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 50:4, s. 1122-7
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Tidskriftsartikel (refereegranskat)abstract
- We examined CSF levels of markers of neuronal degeneration and astrogliosis-the light subunit of the neurofilament triplet protein (NFL) and the glial fibrillary acidic protein (GFAP)-in 65 patients with normal pressure hydrocephalus (NPH). NFL was increased sixfold (864 +/- 1,538 [mean +/- SD] versus 156 +/- 81 ng/L; p < or = 0.001) and GFAP twofold (1,116 +/- 1,085 versus 637 +/- 295 ng/L; p < or = 0.01) in NPH patients compared with neurologically healthy age-matched controls. No correlation was found between any particular symptom or sign and GFAP levels in CSF. The levels of NFL, on the other hand, were higher in patients with severe symptoms compared with those with moderate or no symptoms. Furthermore, there was a correlation between a high level of NFL and gait disturbance, incontinence, psychometric incapability, and social dysfunction. A high preoperative NFL level was associated with favorable outcome after shunt surgery. This indicates that NFL is a marker of ongoing and possibly still-reversible axonal damage in NPH.
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| 23. |
- Andersson, C B M, et al.
(författare)
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Bulk and surface electronic structure of InAs(110)
- 1998
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Ingår i: Surface Science. - 0039-6028 .- 1879-2758. ; 398:3, s. 395-
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Tidskriftsartikel (refereegranskat)abstract
- The InAs(110) cleavage surface has been investigated by angle-resolved photoelectron spectroscopy. A separation between the In 4d(5/2) bulk component and the valence band maximum of 16.8 eV is found to be consistent with normal emission spectra. Experimental energy band dispersions, E-i(k), for the four bulk valence bands are established along the Sigma-line of the bulk Brillouin zone. A bulk band structure calculation utilizing the augmented plane-wave method is made. The experimental and calculated E-i(k) dispersions are found to be in good agreement with each other. E-i(k(parallel to)) dispersions for two surface-related structures are established along the lines <(Gamma)over bar>-(M) over bar and (Y) over bar-(M) over bar of the surface Brillouin zone. (C) 1998 Elsevier Science B.V.
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- Balzarini, J, et al.
(författare)
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Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives
- 1996
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 93:14, s. 7295-7299
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Tidskriftsartikel (refereegranskat)abstract
- So324 is a 2',3'-dideoxy-2',3'-didehydrothymidine-5'-monophosphate (d4T-MP) prodrug containing at the phosphate moiety a phenyl group and the methylester of alanine linked to the phosphate through a phosphoramidate linkage. So324 has anti-HIV activity in human CEM, MT4, and monocyte/macrophage cells that is superior to that of d4T. In contrast to d4T, So324 is also able to inhibit HIV replication in thymidine kinase-deficient CEM cells. After uptake of So324 by intact human lymphocytes, d4T-MP is released and subsequently converted intracellularly to d4T-TP. In addition, accumulation of substantial amounts of a novel d4T derivative has been found. This d4T metabolite has been characterized as alaninyl d4T-MP. The latter metabolite accumulates at approximately 13- to 200-fold higher levels than d4T-TP depending the experimental conditions. Alaninyl d4T-MP should be considered as an intra- and/or extracellular depot form of d4T and/or d4T-MP. These findings may explain the superior anti-retroviral activity of So324 over d4T in cell culture.
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- BALZARINI, J, et al.
(författare)
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Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e., TSAO derivatives)
- 1995
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 92:12, s. 5470-5474
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Tidskriftsartikel (refereegranskat)abstract
- Five structurally related thiophene and furane analogues of the oxathiin carboxanilide derivative NSC 615985 (UC84) (designated UC10, UC68, UC81, UC42, and UC16) were identified as potent inhibitors of HIV-1 replication in cell culture and HIV-1 reverse transcriptase activity. These compounds were markedly active against a series of mutant HIV-1 strains, containing the Leu-100-->Ile, Val-106-->Ala, Glu-138-->Lys, or Tyr-181-->Cys mutations in their reverse transcriptase. However, the thiocarboxanilide derivatives selected for mutations at amino acid positions 100 (Leu-->Ile), 101 (Lys-->Ile/Glu), 103 (Lys-->Thr/Asp) and 141 (Gly-->Glu) in the HIV-1 reverse transcriptase. The compounds completely suppressed HIV-1 replication and prevented the emergence of resistant virus strains when used at 1.3-6.6 microM--that is, 10- to 25-fold lower than the concentration required for nevirapine and bis(heteroaryl)piperazine (BHAP) U90152 to do so. If UC42 was combined with the [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"- oxathiole-2",2"-dioxide)]-beta-D-pentofuranosyl (TSAO) derivative of N3-methylthymine (TSAO-m3T), virus breakthrough could be prevented for a much longer time, and at much lower concentrations, than if the compounds were used individually. Virus breakthrough could be suppressed for even longer, and at lower drug concentrations, if BHAP was added to the combination of UC42 with TSAO-m3T, which points to the feasibility of two- or three-drug combinations in preventing virus breakthrough and resistance development.
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| 32. |
- Berglund, B E, et al.
(författare)
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Sweden
- 1996
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Annan publikation (övrigt vetenskapligt/konstnärligt)
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- Johansson, A, et al.
(författare)
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Different subcellular localization of cytochrome b and the dormant NADPH-oxidase in neutrophils and macrophages: effect on the production of reactive oxygen species during phagocytosis.
- 1995
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Ingår i: Cellular immunology. - : Elsevier BV. - 0008-8749. ; 161:1, s. 61-71
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Tidskriftsartikel (refereegranskat)abstract
- When neutrophils and macrophages phagocytose a prey, e.g., complement (C3b)-opsonized yeast particles, the oxygen radical generating NADPH-oxidase is activated. In neutrophils, most of the production of oxygen metabolites occurred in an intracellular compartment, possibly in the phagolysosome. In contrast, no intracellular production could be detected in human macrophages. In these cells, the subcellular localization of the superoxide-generating NADPH-oxidase and associated cytochrome b was assessed in intact cells with indirect immunofluorescence and confocal laser scanning microscopy, and with subcellular fractionation, using centrifugation on Percoll density gradients. A dual localization of the cytochrome b as well as the dormant NADPH-oxidase activity in neutrophils was in agreement with earlier immunocytochemical, biochemical, and subcellular fractionation studies. Furthermore, most of the activity was recovered from the specific granules, whereas only a small fraction was retained in the plasma membrane. In contrast, the cytochrome b/NADPH-oxidase activity in macrophages localized primarily in the plasma membrane fraction. We suggest that the macrophages are incapable of producing reactive oxygen species intraphagosomally, due to an absence of a granule-localized pool of the membrane components of the NADPH-oxidase.
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- McGovern, P G, et al.
(författare)
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Comparison of medical care and one- and 12-month mortality of hospitalized patients with acute myocardial infarction in Minneapolis-St. Paul, Minnesota, United States of America and Göteborg, Sweden.
- 1997
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Ingår i: The American journal of cardiology. - : Excerpta Medica, Inc.. - 0002-9149 .- 1879-1913. ; 80:5, s. 557-62
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Tidskriftsartikel (refereegranskat)abstract
- We compared medical care and mortality through 1-year of hospitalized acute myocardial infarction (AMI) patients in 2 large metropolitan areas in the United States and Sweden. All hospitalized AMI discharges (International Classification of Diseases, 9th revision [ICD9] codes 410) occurring among 30 to 74-year-old residents of the Minneapolis-St. Paul metropolitan area in 1990 and Göteborg, Sweden, in 1990 to 1991 were identified and their medical records examined. There were dramatic differences in medical care during the index hospitalization of AMI patients between Minneapolis-St. Paul and Göteborg. Use of thrombolytic therapy, coronary angioplasty, bypass surgery, calcium antagonists and lidocaine was more common in Minneapolis-St. Paul; beta blockers were more frequently used in Göteborg, and aspirin use was similar. Despite these large differences, neither 28-day nor 1-year mortality of hospitalized AMI patients differed significantly. The marked differences found in the early treatment of AMI between Minneapolis-St. Paul and Göteborg, combined with the negligible differences observed in short- and long-term mortality, raise questions about the most effective and efficient allocation of medical resources.
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