| 1. |
- Delwar, Zahid M., et al.
(författare)
-
Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells
- 2012
-
Ingår i: Investigational New Drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 30:4, s. 1302-1310
-
Tidskriftsartikel (refereegranskat)abstract
- Gliomas are the most common primary brain tumor, and their treatment is still a challenge. Here, we evaluated the antiproliferative effect of a novel combination of two potent oxidative stress enhancers: menadione (M) and sodium orthovanadate (SO). We observed both short-term and prolonged growth inhibitory effects of M or SO alone as well as in combination (M:SO) on DBTRG.05MG human glioma cells. A stronger antiproliferative effect was observed in the short-term proliferation assay with the M:SO combination compared to either investigated agent alone. In the long-term proliferation assay, a 10-day exposure to M:SO at concentrations of 10 mu M:17.5 mu M or 17.5 mu M:10 mu M was enough to kill 100% of the cells; no cell regrowth was observed after re-incubation in drug-free media. When used in combination, the single concentration of M and SO could be decreased by 2.5- to 5-fold of those used for each experimental drug alone and still obtain a similar antiproliferative effect. The underlying molecular mechanism was investigated by co-incubating M:SO with dithiothreitol (DTT) and genistein. Both substances partially neutralized the effects of the M:SO combination, showing additive effects. This observation suggests a role of oxidative stress and tyrosine kinase stimulation in the M:SO cytotoxic effect. Our results indicate that M:SO combination is an attractive alternative for glioma treatment that encourages further study. The neutralizing effects of genistein and DTT reveal a possibility for their use in the minimization of potential M:SO systemic toxicity.
|
|
| 2. |
- Vita, Marina F., et al.
(författare)
-
Pankiller effect of prolonged exposure to menadione on glioma cells: potentiation by vitamin C
- 2011
-
Ingår i: Investigational New Drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 29:6, s. 1314-1320
-
Tidskriftsartikel (refereegranskat)abstract
- Menadione (Vitamin K3) has anti-tumoral effects against a wide range of cancer cells. Its potential toxicity to normal cells and narrow therapeutic range limit its use as single agent but in combination with radiation or other anti-neoplastic agents can be of therapeutic use. In this paper, we first evaluated the early (within 3 h) effect of menadione on ongoing DNA replication. In normal rat cerebral cortex mini-units menadione showed an age dependent anti-proliferative effect. In tissue mini-units prepared from newborn rats, menadione inhibited ongoing DNA replication with an IC (50) of approximately 10 mu M but 50 mu M had no effect on mini-units from prepared adult rat tissue. The effect of short (72 h) and prolonged exposure (1-2 weeks) to menadione alone in the DBTRG.05MG human glioma cells line and in combination with vitamin C was studied. After short period of exposure data show that menadione alone or in combination with vitamin C provided similar concentration-response curves (and IC50 values). Prolonged exposure to these drugs was evaluated by their ability to kill 100% of glioma cells and prevent regrowth when cells are re-incubated in drug-free media. In this long-term assay, menadione:vitamin C at a ratio 1:100 showed higher anti-proliferative activity when compared to each drug alone and allowed to reduce each drug concentration between 2.5 to 5-fold. Similar anti-proliferative effect was demonstrated in 8 patient derived glioblastoma cell cultures. Our data should be able to encourage further advanced studies on animal models to evaluate the potential use of this combination therapy for glioma treatment.
|
|
| 3. |
- Darabi, Anna, et al.
(författare)
-
HLA-I Antigen Presentation and Tapasin Influence Immune Responses Against Malignant Brain Tumors - Considerations for Successful Immunotherapy.
- 2014
-
Ingår i: Anti-Cancer Agents in Medicinal Chemistry. - 1875-5992. ; 14:8, s. 1094-1100
-
Tidskriftsartikel (refereegranskat)abstract
- Human leukocyte antigen class I (HLA-I) presents antigenic peptides to cytotoxic CD8+ T cells (CTLs). This is a pivotal step in the generation of CTL responses. Both the quantity and quality of peptide-HLA-I (pHLA-I) complexes are crucial for CTL responses, but the level of HLA-I expression per se is also directly involved in dictating NK-cell responses. Antigen processing machinery (APM) proteins are involved in the maturation of HLA-I and in the selection of which peptides are - or are not - presented. Thus, these proteins are key players in shaping the immune response to cells in health and disease. In this review, we recap the most important features of APM components and their synergistic work to assure proper pHLA-I cell surface expression. We pay special attention to the HLA-I dedicated multifunctional protein, tapasin, and in relation to the different tapasin-dependency of HLA-I allomorphs we also discuss allomorph specific traits in maturation, structure and linkage to malignant diseases and brain tumors in particular. We next discuss the possibilities of restoring or manipulating the immune responses against brain tumors. In this context we discuss IFNγ therapy, cytostatics and irradiation. Finally, we integrate current views and knowledge to set the direction for future emphasis in the area of immunotherapy against brain tumors.
|
|
| 4. |
- Davidsson, Josef, et al.
(författare)
-
Relapsed childhood high hyperdiploid acute lymphoblastic leukemia : presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations.
- 2010
-
Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 24:5, s. 924-31
-
Tidskriftsartikel (refereegranskat)abstract
- Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% of patients still relapse. It is important to identify these patients already at diagnosis to ensure proper risk stratification. We have investigated 11 paired diagnostic and relapse samples with single nucleotide polymorphism array and mutation analyses of FLT3, KRAS, NRAS and PTPN11 in order to identify changes associated with relapse and to ascertain the genetic evolution patterns. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (P<0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. On the basis of the genetic relationship between the paired samples, three groups were delineated: (1) identical genetic changes at diagnosis and relapse (2 of 11 cases), (2) clonal evolution with all changes at diagnosis being present at relapse (2 of 11) and (3) clonal evolution with some changes conserved, lost or gained (7 of 11), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern.
|
|
| 5. |
|
|
| 6. |
- Eltschkner, Sandra, et al.
(författare)
-
The structure of songbird MHC class I reveals antigen binding that is flexible at the N-terminus and static at the C-terminus
- 2023
-
Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Long-distance migratory animals such as birds and bats have evolved to withstand selection imposed by pathogens across the globe, and pathogen richness is known to be particularly high in tropical regions. Immune genes, so-called Major Histocompatibility Complex (MHC) genes, are highly duplicated in songbirds compared to other vertebrates, and this high MHC diversity has been hypothesised to result in a unique adaptive immunity. To understand the rationale behind the evolution of the high MHC genetic diversity in songbirds, we determined the structural properties of an MHC class I protein, Acar3, from a long-distance migratory songbird, the great reed warbler Acrocephalus arundinaceus (in short: Acar). The structure of Acar3 was studied in complex with pathogen-derived antigens and shows an overall antigen presentation similar to human MHC class I. However, the peptides bound to Acar3 display an unusual conformation: Whereas the N-terminal ends of the peptides display enhanced flexibility, the conformation of their C-terminal halves is rather static. This uncommon peptide-binding mode in Acar3 is facilitated by a central Arg residue within the peptide-binding groove that fixes the backbone of the peptide at its central position, and potentially permits successful interactions between MHC class I and innate immune receptors. Our study highlights the importance of investigating the immune system of wild animals, such as birds and bats, to uncover unique immune mechanisms which may neither exist in humans nor in model organisms.
|
|
| 7. |
- Follin, Elna, et al.
(författare)
-
In silico peptide-binding predictions of passerine MHC class I reveal similarities across distantly related species, suggesting convergence on the level of protein function.
- 2013
-
Ingår i: Immunogenetics. - : Springer Science and Business Media LLC. - 1432-1211 .- 0093-7711. ; 65:4, s. 299-311
-
Tidskriftsartikel (refereegranskat)abstract
- The major histocompatibility complex (MHC) genes are the most polymorphic genes found in the vertebrate genome, and they encode proteins that play an essential role in the adaptive immune response. Many songbirds (passerines) have been shown to have a large number of transcribed MHC class I genes compared to most mammals. To elucidate the reason for this large number of genes, we compared 14 MHC class I alleles (α1-α3 domains), from great reed warbler, house sparrow and tree sparrow, via phylogenetic analysis, homology modelling and in silico peptide-binding predictions to investigate their functional and genetic relationships. We found more pronounced clustering of the MHC class I allomorphs (allele specific proteins) in regards to their function (peptide-binding specificities) compared to their genetic relationships (amino acid sequences), indicating that the high number of alleles is of functional significance. The MHC class I allomorphs from house sparrow and tree sparrow, species that diverged 10 million years ago (MYA), had overlapping peptide-binding specificities, and these similarities across species were also confirmed in phylogenetic analyses based on amino acid sequences. Notably, there were also overlapping peptide-binding specificities in the allomorphs from house sparrow and great reed warbler, although these species diverged 30 MYA. This overlap was not found in a tree based on amino acid sequences. Our interpretation is that convergent evolution on the level of the protein function, possibly driven by selection from shared pathogens, has resulted in allomorphs with similar peptide-binding repertoires, although trans-species evolution in combination with gene conversion cannot be ruled out.
|
|
| 8. |
- Geironson Ulfsson, Linda, et al.
(författare)
-
Stability of peptide-HLA-I complexes and tapasin folding facilitation - tools to define immunogenic peptides
- 2012
-
Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 586:9, s. 1336-1343
-
Tidskriftsartikel (refereegranskat)abstract
- Only a small fraction of the peptides generated inside the cell end up being presented by HLA-I on the cell surface. High stability of peptide-HLA-I complexes and a low HLA-I tapasin-facilitation have been proposed to predict immunogenicity. We here set out to investigate if these parameters correlated and defined immunogenic peptides. Both peptide-HLA-B*08:01 and peptide-HLA-A*02:01 complexes showed small differences in tapasin-facilitation and larger differences in stability. This suggests that the stability of immunogenic peptide-HLA-I complexes vary above an HLA-I allomorph dependent lower limit (e. g. > 2 h for HLA-A*02:01), immunogenicity predicted by tapasin-facilitation may be defined by an equally allomorph unique upper value (e. g. tapasin-facilitation <1.5 for HLA-A*02:01), and variation above the stability-threshold does not directly reflect a variation in tapasin-facilitation. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
|
|
| 9. |
- Geironson Ulfsson, Linda, et al.
(författare)
-
Tapasin facilitation of MHC-I separates closely related allomorphs, is strongly influenced by peptide length and depends on stability
- 2013
-
Ingår i: ; , s. 83-83
-
Konferensbidrag (refereegranskat)abstract
- Only a small fraction of the peptides inside a cell are eventually presented by HLA-I on the cell surface. The presented peptides have HLA-I allomorph-specific motifs and length restrictions. Tapasin influences HLA-I antigen presentation both qualitatively and quantitatively to different degrees depending on both peptide sequence and HLA-I allomorph. The tapasin-dependence in cellular context has been shown to correspond to the facilitation of peptide- HLA-I complex formation by the first 87 amino acids of tapasin (Tpn1- 87) (i.e., tapasin-facilitation = Bmax Tpn1-87/Bmax Ctrl) in a biochemical assay. Both peptide length and tapasin-facilitation are important for HLA-I antigen presentation and we here set out to study if these two parameters relate to each other. We used a luminescent oxygen channeling assay and seven different peptide libraries (X7- X13) to study 16 HLA-A and -B allomorphs and the results show a broad spectrum of tapasin-facilitation of HLA-I allomorphs and that HLA-A allomorphs were generally less restricted than -B allomorphs83to peptides of the classical lengths of 8-10 amino acids. Since both stability and tapasin-facilitation have been suggested as discriminators of immunogenic peptides we used a scintillation proximity based assay to study the stability of peptide-HLA-I complexes formed with peptides of different lengths. The results demonstrate an inverse correlation between tapasin-facilitation and stability valid for different peptide mixes of specific lengths but also on the level of HLA-I allomorphs, suggesting that molecules of poor stability are either not in a conformation that allows tapasin to interact or have a conformation where association has no effect.
|
|
| 10. |
- Geironson Ulfsson, Linda, et al.
(författare)
-
Tapasin Facilitation of Natural HLA-A and -B Allomorphs Is Strongly Influenced by Peptide Length, Depends on Stability, and Separates Closely Related Allomorphs.
- 2013
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 191:7, s. 3939-3947
-
Tidskriftsartikel (refereegranskat)abstract
- Despite an abundance of peptides inside a cell, only a small fraction is ultimately presented by HLA-I on the cell surface. The presented peptides have HLA-I allomorph-specific motifs and are restricted in length. So far, detailed length studies have been limited to few allomorphs. Peptide-HLA-I (pHLA-I) complexes of different allomorphs are qualitatively and quantitatively influenced by tapasin to different degrees, but again, its effect has only been investigated for a small number of HLA-I allomorphs. Although both peptide length and tapasin dependence are known to be important for HLA-I peptide presentation, the relationship between them has never been studied. In this study, we used random peptide libraries from 7- to 13-mers and studied binding in the presence and absence of a recombinant truncated form of tapasin. The data show that HLA-I allomorphs are differentially affected by tapasin, different lengths of peptides generated different amounts of pHLA-I complexes, and HLA-A allomorphs are generally less restricted than HLA-B allomorphs to peptides of the classical length of 8-10 aa. We also demonstrate that tapasin facilitation varies for different peptide lengths, and that the correlation between high degree of tapasin facilitation and low stability is valid for different random peptide mixes of specific lengths. In conclusion, these data show that tapasin has specificity for the combination of peptide length and HLA-I allomorph, and suggest that tapasin promotes formation of pHLA-I complexes with high on and off rates, an important intermediary step in the HLA-I maturation process.
|
|
