| 1. |
- Andersson, Ann-Catrin, 1968-
(författare)
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Studies on Human Endogenous Retroviruses (HERVs) with Special Focus on ERV3
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human endogenous retroviruses (HERVs) represent approximately 7% of the human genome. This investigation was focused on one particular HERV, ERV3, with the main purpose of characterising its gene expression patterns and genomic distribution of ERV3-like sequences. Furthermore, this careful expression study should provide insights into the biological role of HERVs. The impact of HERVs in health and disease is not yet clarified. ERV3 is expressed as three envelope (env) transcripts, of which two also contain a cellular gene, H-plk (human proviral linked Krüppel). ERV3 env expression was mainly investigated at the RNA level. The gene expression of two other HERVs, HERV-K and HERV-E was analysed and compared with ERV3 activity.Real-time PCRs were developed and in combination with in situ hybridisation, it was found that ERV3 is expressed in a tissue- and cell-specific way. High levels of ERV3 mRNA (up to six times over Histone3.3) were demonstrated in placenta, sebaceous glands, foetal and adult adrenal glands, brown adipose tissue, corpus luteum, pituitary gland, thymus and testis. In monocytic cells including both normal monocytes and malignant U-937 cells, elevated mRNA levels were observed after retinoic acid (RA)-induced differentiation. ERV3-encoded Env protein was detected in selected cases, one following RA-treatment. In addition, several new ERV3-like sequences were discovered in the human genome. ERV3 was found to have conserved open reading frames in contrast to other ERV3-like sequences in the human genome. This suggests that ERV3 may be involved in important cellular processes such as differentiation, cell fusion, immunomodulation and protection against infectious retroviruses. The developed techniques and obtained results will allow further studies of HERV expression to better correlate HERV activity to both normal development and disease.
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| 2. |
- Antonio, L D, et al.
(författare)
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The non-random location of human oncogenes and tumour suppressor genes
- 2005
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Ingår i: Caryologia. - 0008-7114. ; 58:1, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- We have analysed 994 sites for oncogenes and tumour suppressor genes located within human chromosome bands. The data presented disclose that: 1) These cancer genes build ridges as well as hot spots, which are not related to the position of other types of genes present in these chromosomes. 2) The frequency of cancer genes is not directly related to chromosome length, to the number of DNA bases per chromosome or to the number of structural genes present in each chromosome. 3) Suppressor genes tend to occupy the same location as oncogenes. 4) Several cancer genes occur in as many as 15 different sites spread over 10 different chromosomes. 5) The main feature of the distribution of both oncogenes and suppressors, is that they tend to be located near telomeres. Moreover, their numbers decrease from the telomere to the centromere building a distinct gradient. The difference is statistically significant. The present evidence, taken together, indicates that the telomeric territory might be a preferential location of cancer related genes and thereby also of stem cell genes.
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| 3. |
- Badn, Wiaam, et al.
(författare)
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Low-dose combretastatin A4 phosphate enhances the immune response of tumor hosts to experimental colon carcinoma
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:15, s. 4714-4719
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Although there is a need to enhance the therapeutic efficiency in cancer by combining immunotherapeutic procedures with other therapy, combination with chemotherapy is complicated due to immunosuppressive effects of most chemotherapeutic drugs. The purpose of this investigation was to study whether combining tumor cell immunization with the vascular targeting drug combretastatin A4 phosphate (CA4P) would enhance tumor retardation and/or affect the antitumor immune response. Experimental Design: Rats with intrahepatic colon carcinoma were immunized weekly with IL-18/IFN gamma-transfected tumor cells, starting day 9, and were treated with a low-dose CA4P (2 mg/kg, 5 days a week starting day 7). The effect of CA4P was studied on tumor growth and on immune reactivity in vitro. Results: Rats with preexisting tumor, immunized and treated with low-dose CA4P, had a significantly retarded tumor growth compared with rats receiving CA4P or immunization alone. Splenocytes from rats treated with this combination had a significantly enhanced antitumor immune response compared with splenocytes from control rats. Exposure of nonadherent splenocytes to CA4P in vitro did not enhance their proliferation. However, 3-hour pretreatment of adherent splenocytes with 0.3 mu g/mL CA4P significantly enhanced proliferation and IFN gamma production of admixed nonadherent splenocytes, partly due to nitric oxide reduction. Combining the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester with CA4P and immunization further retarded tumor growth. Conclusion: Concomitant treatment of rats with progressively growing tumor with immunization and low-dose CA4P significantly enhances the therapeutic effect as compared with either treatment alone and results in an enhanced antitumor immune reactivity.
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| 4. |
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| 5. |
- Carlsson, Anders, et al.
(författare)
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Plasma proteome profiling reveals biomarker patterns associated with prognosis and therapy selection in glioblastoma multiforme patients
- 2010
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Ingår i: Proteomics Clinical Applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 4:6-7, s. 591-602
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Glioblastoma multiforme (GBM) is a frequent and aggressive type of primary brain tumor with a heterogeneous origin. GBM is highly therapy resistant and carries a dismal prognosis for the patient. The purpose of this discovery study was to define candidate plasma biomarker signatures for improved classification and novel means for selecting patients for refined individualized therapy. Experimental design: Here, we have for the first time investigated the applicability of large-scale recombinant antibody-based microarrays, targeting mainly immunoregulatory analytes, for sensitive and selective plasma protein profiling of GBM patients undergoing immunotherapy with autologous IFN-gamma transfected glioma cells Results: This proof-of-concept study showed that candidate plasma protein signatures associated with GBM were outlined that could be used for GBM classification, monitoring the effects of the immunotherapy as well as for stratifying patients according to the beneficial effect of the adopted immunotherapy Further, central key cytokines that could be utilized for optimization and/or refinement of the immunotherapeutic regime were indicated. Conclusions and clinical relevance: Candidate plasma proteins signatures associated with GBM was outlined, that could be used for GBM classification and for pre-operatively stratifying patients according to the beneficial effect of the adopted immunotherapy.
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| 6. |
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| 7. |
- Fan, Xiaolong, et al.
(författare)
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Glioma stem cells: Evidence and limitation.
- 2007
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 17:3, s. 214-218
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Forskningsöversikt (refereegranskat)abstract
- Gliomas, in particular the high-grade anaplastic glioma and glioblastoma multiforme (GBM), are manifested by morphological, genetic and phenotypic heterogeneity. Most of the studies hitherto have been performed on bulk glioma cells, with limited understanding on the origin and the relative contribution of particular glioma cell populations to glioma growth and progression. Recent studies have demonstrated the existence of a small fraction of glioma cells endowed with features of primitive neural progenitor cells and tumor-initiating function. Such cells have been defined as glioma stem cells. However, questions remain as to whether the currently identified glioma stem cells are the cell-of-origin for glioma initiation and progression, or the results of such processes. In this review, we discuss the current evidence and limitation in identifying glioma stem cells and the potential origin of glioma stem cells in the context of post-natal neural cell regeneration and their transformation mechanisms. The implication of these findings for glioma diagnosis and treatment will also be reviewed.
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| 8. |
- Gullberg, Urban, et al.
(författare)
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The cytotoxic eosinophil cationic protein (ECP) has ribonuclease activity
- 1986
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Ingår i: Biochemical and Biophysical Research Communications. ; 139:3, s. 1239-1242
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Tidskriftsartikel (refereegranskat)abstract
- The eosinophil cationic protein (ECP) is a specific cytotoxic constituent of granules. In this work we demonstrated that ECP has a ribonuclease activity. Purified ECP was resolved by ion exchange chromatography into subfractions, which all showed ribonuclease activity. Another eosinophil granule protein, EPX, identical with eosinophil-derived neurotoxin (EDN) had a 125-fold higher RNase activity than ECP. ECP may exert its cytotoxic effects on parasites and cells because of its extreme basicity alone or it may be internalized and act by degrading mRNA.
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| 9. |
- Johansson, Anna C, et al.
(författare)
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Enhanced expression of iNOS intratumorally and at the immunization site after immunization with IFNgamma-secreting rat glioma cells
- 2002
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Ingår i: Journal of Neuroimmunology. - 1872-8421. ; 123:1-2, s. 135-143
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Tidskriftsartikel (refereegranskat)abstract
- Nitric oxide (NO) can modulate both tumor growth and antitumor immune responses. In order to elucidate the mechanism of curative therapeutic immunization with IFNgamma-producing glioma cells, we examined the expression of inducible nitric oxide synthase (iNOS) in tissue sections from immunized animals. There was a significantly enhanced iNOS expression both intratumorally and at the immunization site. Although the mechanisms behind this dual expression of iNOS most probably are different, our results suggest a role for NO in both the induction and execution of the antitumor response.
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| 10. |
- Järås, Marcus, et al.
(författare)
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Human short-term repopulating cells have enhanced telomerase reverse transcriptase expression.
- 2006
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 108:3, s. 1084-1091
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Tidskriftsartikel (refereegranskat)abstract
- Telomerase activity has been suggested to be critically involved in hematopoietic stem cell (HSC) self-renewal. However, it has been unclear whether human HSCs have telomerase activity and how telomerase activity is regulated within the HSC and progenitor pool. Here, we isolated living cord-blood (CB) CD34+ cells with up-regulated human telomerase reverse transcriptase (hTERT) expression by using an hTERT-reporting adenoviral vector encoding destabilized green fluorescent protein (dGFP) driven by the hTERT promoter, and functionally characterized them in comparison with control vector–transduced CD34+ cells expressing GFP. Following a 2-day serum-free transduction protocol, cells were sorted into a dGFP+ and a GFP+ fraction. Cell-cycle analysis revealed that the dGFP+ cells had a greater proportion of cells in S/G2/M phase compared with the GFP+ cells, (56% ± 1.8% vs 35% ± 4.3%; P < .001) and fewer cells in G0 phase (8.1% ± 3.0% vs 20% ± 4.7%; P < .01) However, the colony-forming and short-term nonobese diabetic/severe combined immunodeficient (NOD/SCID) B2m–/– mice bone marrow–repopulating capacities were similar between the dGFP+ and the GFP+ cells. Interestingly, the dGFP+ cells had a 6-fold lower repopulating capacity in NOD/SCID mice compared with the GFP+ cells and lacked secondary NOD/SCID B2m–/– mice bone marrow–repopulating capacity. Thus, up-regulation of hTERT expression within the CB HSC pool is accompanied by decreased self-renewal capacity.
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| 11. |
- Karlsson, Christine, et al.
(författare)
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Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.
- 2007
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 33:4, s. 440-454
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM.
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| 12. |
- Kjellman, Christian, et al.
(författare)
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Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma
- 2000
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Ingår i: International Journal of Cancer. - 0020-7136. ; 89:3, s. 251-258
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Tidskriftsartikel (refereegranskat)abstract
- Human gliomas express TGF-beta but, so far the expression of downstream mediators has been investigated in only a few cell lines. We have examined tissue specimens of 23 gliomas: 3 astrocytomas grade II (AST), 8 anaplastic astrocytomas grade III (AAST), and 12 glioblastoma multiforme grade IV (GBM). We analyzed the mRNA expression of TGF-beta1, TGF-beta2, TGF-beta3, the TGF-beta receptors type I (TbetaR-I) and type II (TbetaR-II), Smad2, Smad3, and Smad4. mRNA expression of IL-10 and CD95 (FAS/APO-1) were also studied. We detected increased mRNA levels of the 3 TGF-beta isoforms, correlating with the degree of malignancy. TGF-beta3 mRNA was increased, particularly in AST and AAST, while TGF-beta1 and TGF-beta2 mRNAs were strongly expressed in GBM. TGF-beta normally up-regulates the TGF-beta receptors, and TbetaR-I and TbetaR-II showed stronger expression in all gliomas when compared to normal tissues. However, the mRNA expression of Smad2, Smad3, and Smad4 was decreased in GBM. IL-10 mRNA expression was detected in glioma tissues but not in glioma cell lines. No marked increase in the expression of soluble CD95 splicing variants was found in the gliomas compared with normal tissue. However, total CD95 mRNA was elevated among GBM tissues.
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| 13. |
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| 14. |
- Krona, Annika, 1973, et al.
(författare)
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Oncostatin M signaling in human glioma cell lines.
- 2005
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Ingår i: Oncology reports. - 1021-335X .- 1791-2431. ; 13:5, s. 807-11
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Tidskriftsartikel (refereegranskat)abstract
- We have recently found that oncostatin M (OSM) is overexpressed in most human brain tumors. The effects of OSM are unclear with conflicting reports of growth stimulatory or inhibitory effects in various cell types. The aim of this study was to investigate the effects of OSM in 5 glioma cell lines and 7 short-term cultures of human gliomas and in normal cultured human astrocytes. None of the cell lines and short-term cultured tumor cells expressed OSM in vitro. OSM signals through a gp130 containing receptor complex over the JAK/STAT pathway. Immunofluorescence and RT-PCR analysis showed that the tumor cells express gp130 and the other receptor components, LIFRbeta and OSMRbeta. OSM treatment induced phosphorylation of STAT3 and STAT1 indicating presence of a functional JAK/STAT pathway. No OSM effect on proliferation was observed. OSM gave no protective effects against tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced cytotoxicity.
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| 15. |
- Liu, Hua, et al.
(författare)
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Low dose Zebularine treatment enhances immunogenicity of tumor cells
- 2007
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 257:1, s. 107-115
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Tidskriftsartikel (refereegranskat)abstract
- Strategy: We have investigated how alterations in gene expression induced by the demethylating drug Zebularine affect the immune response tumor cells elicit. The rational has been to treat syngeneic rat colon cancer cells with Zebularine at different concentrations and then use these cells to study gene expression of different genes involved in cancer immunogenicity. Gene expressions were monitored by semi-quantitative PCR and real-time PCR. Results: Intriguingly there was a large increase in the production of indoleamine 2,3-dioxygenase (IDO) after treatment with 100 mu M Zebularine as compared with untreated tumor cells, whereas treatment with 20 mu M Zebularine caused a significant decrease of the IDO production. After immunization with syngeneic tumor cells, spleen cells were isolated and restimulated in vitro with irradiated tumor cells. Immune reactivity was measured by proliferation, and production of interferon gamma and interleukinl0. The immunogenicity of tumor cells treated in vitro with a low dose of Zebularine increased, whereas it decreased after high dose exposure. The inhibition of immunogenicity by 100 mu M Zebularine was shown to be counteracted by the IDO inhibitor I methyl-tryptophan (1MT), confirming that this effect of Zebularine is mainly caused by IDO induction. Differences using Zebularine-treated or non-treated cells for in vitro restimulation were marginal. Conclusion: Low dose treatment with Zebularine (20 mu M) decreases the production of the immunosuppressive IDO from rat colon cancer cells and enhances their immunogenicity, whereas high dose Zebularine treatment (100 mu M) enhances the IDO production from the cancer cells and suppresses their immunogenicity. This immunosuppression should be considered when cancer is treated with Zebularine or drugs acting in a similar way. (C) 2007 Published by Elsevier Ireland Ltd.
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| 16. |
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| 17. |
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| 18. |
- Nittby, Henrietta, et al.
(författare)
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Exposure to radiation from global system for mobile communications at 1,800 MHz significantly changes gene expression in rat hippocampus and cortex
- 2008
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Ingår i: The Environmentalist. - : Springer Science and Business Media LLC. - 0251-1088 .- 1573-2991. ; 28:4, s. 458-465
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Tidskriftsartikel (refereegranskat)abstract
- We have earlier shown that radio frequency electromagnetic fields can cause significant leakage of albumin through the blood-brain barrier of exposed rats as compared to non-exposed rats, and also significant neuronal damage in rat brains several weeks after a 2 h exposure to a mobile phone, at 915 MHz with a global system for mobile communications (GSM) frequency modulation, at whole-body specific absorption rate values (SAR) of 200, 20, 2, and 0.2 mW/kg. We have now studied whether 6 h of exposure to the radiation from a GSM mobile test phone at 1,800 MHz (at a whole-body SAR-value of 13 mW/kg, corresponding to a brain SAR-value of 30 mW/kg) has an effect upon the gene expression pattern in rat brain cortex and hippocampus-areas where we have observed albumin leakage from capillaries into neurons and neuronal damage. Microarray analysis of 31,099 rat genes, including splicing variants, was performed in cortex and hippocampus of 8 Fischer 344 rats, 4 animals exposed to global system for mobile communications electromagnetic fields for 6 h in an anechoic chamber, one rat at a time, and 4 controls kept as long in the same anechoic chamber without exposure, also in this case one rat at a time. Gene ontology analysis (using the gene ontology categories biological processes, molecular functions, and cell components) of the differentially expressed genes of the exposed animals versus the control group revealed the following highly significant altered gene categories in both cortex and hippocampus: extracellular region, signal transducer activity, intrinsic to membrane, and integral to membrane. The fact that most of these categories are connected with membrane functions may have a relation to our earlier observation of albumin transport through brain capillaries.
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| 19. |
- Nittby, Henrietta, et al.
(författare)
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Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Coping with the immune rejection of allotransplants or autologous cells in patients with an active sensitization towards their autoantigens and autoimmunity presently necessitates life-long immune suppressive therapy acting on the immune system as a whole, which makes the patients vulnerable to infections and increases their risk of developing cancer. New technologies to induce antigen selective long-lasting immunosuppression or immune tolerance are therefore much needed.
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| 20. |
- Persson, Annette, et al.
(författare)
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Cell type- and region- dependent coxsackie adenovirus receptor expression in the central nervous system.
- 2006
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 1573-7373 .- 0167-594X. ; 78:1, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Model systems have shown that adenoviral vector mediated transient gene expression can potentially be applied for the treatment of brain tumours, neurodegenerative diseases and brain injuries. Most studies utilized adenovirus serotype 5 (Ad5) based vectors, which as adhesion molecules require the coxsackie adenovirus receptor (CAR) as a critical determinant for cellular infection. In this report, we have systematically characterized CAR expression in the adult human central nervous system (CNS) by using immunohistochemistry. A total of 85 specimens from various CNS regions were investigated for CAR expression in a cell type-dependent context. The most marked staining positivity was found in the choroid plexus and the pituitary gland. The neocortex had scattered positive neurons, while the white matter was mainly negative. We need to consider the possible adverse effects and the possible damage caused by adenoviral gene therapy if the virus-vector also binds to normal brain cells.
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| 21. |
- Persson, Annette, et al.
(författare)
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Neuroblastomas and medulloblastomas exhibit more Coxsackie adenovirus receptor expression than gliomas and other brain tumors.
- 2007
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Ingår i: Neuropathology. - : Wiley. - 0919-6544 .- 1440-1789. ; 27:3, s. 233-236
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Tidskriftsartikel (refereegranskat)abstract
- Adenoviral vector-mediated treatment is a potential therapy for tumors of the central nervous system. To obtain a significant therapeutic effect by adenoviral vectors, a sufficient infection is required, the power of which depends predominantly on the level of Coxsackie adenovirus receptors. We stained surgical biopsies of central nervous system tumors and neuroblastomas for Coxsackie adenovirus receptors. For gliomas, the level of the receptor was low and markedly variable among individual tumors. By contrast, neuroblastomas and medulloblastomas exhibited a higher degree of Coxsackie adenovirus receptor expression than gliomas and other brain tumors. We conclude that neuroblastomas and medulloblastomas could be suitable for adenovirus-mediated gene therapy. Adverse effects of the treatment, however, must be considered because neurons and reactive astrocytes also express a significant amount of the receptor.
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| 22. |
- Persson, Bertil R, et al.
(författare)
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“Abscopal” Effect of Radiation Therapy Combined with Immune-Therapy Using IFN-γ Gene Transfected Syngeneic Tumor Cells, in Rats with Bilateral Implanted N29 Tumors
- 2011
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Ingår i: ISRN Immunology. - : Hindawi Limited. - 2090-5645 .- 2090-5653. ; 2011
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Tidskriftsartikel (refereegranskat)abstract
- The tumor growth rate response was studied on N29 rat glioma tumor cells subcutaneously implanted on both hind legs of Fischer-344 rats. At around 30 days after inoculation, RT was given with 60Co gamma radiation with 4 daily fractions of 5 Gy only to the right-lateral tumors. At days 26, 42, and 54 after inoculation, immunization was performed with irradiated syngeneic IFNγ-gene transfected cells. Tumor growth rate (TGR % per day) of the right-lateral irradiated tumor was significantly decreased (P<0.01) after RT alone and with the combination of RT and immunization. But immunization alone gave no significant decrease of the TGR but significantly increased time of survival. The TGR of the unirradiated left-lateral tumors was significantly decreased (P<0.02) only in the group of rats treated with RT alone. It is apparent that tumor cells killed by the radiation mediate suppression of tumor cells outside the target area. This effect is called the abscopal effect.
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| 23. |
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| 24. |
- Persson, Bertil R, et al.
(författare)
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Immunization with syngeneic interferon-gamma (IFN-g) secreting tumour cells enhance the Therapeutic effect and Abscopal effect from combined treatment of subcutaneously implanted contra-lateral N29 tumours on Fischer rats with Pulsed electric fields (PEF) and 60Co-gamma radiation.
- 2014
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Ingår i: Acta Scientiarum Lundensia. - 1651-5013. ; 2014:002, s. 1-30
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study is to study the Abscopal regression of subcutaneously implanted N29 rat glioma after immunization with syngeneic IFNg secreting cells and treatment of contra-lateral tumours with pulsed electric fields (PEF) and/or radiation therapy (RT). The study was performed on rats of the Fischer-344 strain with rat glioma N29 tumours implanted subcutaneously on the flank or on both the right treated hind leg and the left untreated hind leg. Once weekly for three weeks, the animals were given intra-peritoneal injections of irradiated, modified N29 tumour cells, secreting interferon-gamma (IFN-g). PEF was given with 16 exponentially decaying pulses at a maximum electric fields strength of 1400 V/cm and t1/e= 1 ms. RT was given with 60Co gamma radiation at daily fractions of 5 Gy, to a total absorbed dose of 20 Gy. The animals were arranged into controls and groups of various treatments: PEF, RT, PEF+RT and immunization (IFNg). Fitting the data obtained from consecutive measurements of tumour volume (TV) of each individual tumour to an exponential model TV = TV0*exp[TGR*t] estimated the tumours growth rate (TGR %per day) after the day of treatment (t = 0). TGR of the right-lateral treated tumour was significantly decreased for independent treatments with PEF and RT and with the combined treatment PEF+RT. With immunization (IFNg) alone and in combination with PEF there was, however, no significant decrease of the TGR of the right-lateral tumours. But in the combination of immunization with RT or PEF+RT there was a highly significant decrease of the TGR values. The Abscopal effect was evaluated by comparing the growth rate of the untreated contra lateral tumours with the treated tumours. TGR of the left-lateral untreated tumour in the groups with independent treatment of right-lateral tumours with PEF, was not significantly reduced. But the TGR values are significantly reduced in the group of rats treated with RT and the combination PEF + RT. With IFNg alone and in combinations with PEF or RT there was no significant decrease of the TGR in the left lateral tumours. But in the combination of IFNg with PEF+RT there was a highly significant decrease of the TGR values in the left lateral tumours. The specific therapeutic effect (STE = 1 - TGRExposed/ TGRCtrl ) after treatments with PEF was 0.30±0.01 and after RT 0.46±0.04 and after the combination PEF+RT 0.36+/- 0.08. After immunization with IFNg secreting tumour cells the STE 0.09+/- 0.07 is not significantly different from zero. Also for the combination of immunization and PEF the STE value of 0.07+/- 0.07 is not significantly different from zero. In the combination of immunization with RT the STE value was 0.32+/- 0.01 that is significantly different from zero and only slightly lower than for RT alone. The STE of the combination of immunization with (PEF+RT) resulted in an unexpectedly high STE value of 0.70+/- 0.08 that is highly significantly different from zero (p < 0.0001). The specific Abscopal effect (SAE = 1 - TGRUn-Exposed/ TGRCtrl ) of the contra lateral unexposed tumours in rats treated with PEF or RT are both significantly different from zero. For RT the average SAE value is 0.33+/- 0.04 and for PEF it is 0.11+/- 0.05. The SAE value for the combined treatment with PEF + RT is 0.26+/- 0.02 that is about the same as for RT alone. For immunization with IFNg secreting tumour cells only and IFNg +PEF the SAE values were not significantly different from zero. But IFNg combined with RT result in a SAE value of 0.18±0.12 and the combination of IFNg with PEF+RT results in an improved abscopal effect with the SAE value of 0.33+/- 0.06. After combined treatment with PEF + RT the average of the therapeutic enhancement ratio (TER = STEExperimental / STEIndependent) is 0.47 +/- 0.12 and the abscopal enhancement ratio (AER = SAEExperimental / SAEIndependent) is 0.61 +/- 0.1 respectively. With all three treatment modalities combined IFNg + PEF + RT and all combinations of independent treatments with PEF, RT or IFNg are considered, the average of the TER is 1.20+/- 0.15 and AER is 1.22+/- 0.20. This might indicate that there is a synergism on the tumours on both sides by combining PEF, RT and immunization with IFNg secreting cells. These results were first presented Nov 21-24, 2002, as Poster at Society of Neuro-Oncology (SNO) Annual Meeting, San Diego, USA (Persson et al 2002).
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| 25. |
- Persson, Bertil R, et al.
(författare)
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Radiation immunomodulatory gene tumor therapy of rats with intracerebral glioma tumors.
- 2010
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Ingår i: Radiation Research. - 0033-7587. ; 173:4, s. 433-440
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Tidskriftsartikel (refereegranskat)abstract
- Single-fraction radiation therapy with 5 or 15 Gy (60)Co gamma radiation was combined with intraperitoneal injections of syngeneic interferon gamma (IFN-gamma)-transfected cells in rats with intracerebral N29 or N32 glioma tumors at days 7, 21 and 35 after inoculation. For intracerebral N29 tumors, single-fraction radiation therapy with 5 or 15 Gy had no significant effect on the survival time. Immunization with IFN-gamma-transfected N29 cells significantly increased the survival time by 61%. Single-fraction radiation therapy with 5 Gy combined with immunization increased the survival time significantly by 87% and complete remissions by 75% while with 15 Gy the survival time increased 45% with 38% complete remissions. For intracerebral N32 tumors, single-fraction radiation therapy with 15 Gy increased the survival time significantly by 20%. Immunization by itself had no significant effect with IFN-gamma-transfected N32 cells, but combined with 15 Gy single-fraction radiation therapy it increased survival time significantly by 40%, although there were no complete remissions. Based on these findings, we suggest a new therapeutic regimen for malignant glioma using single-fraction radiation therapy with a target absorbed dose of the order of 5-10 Gy combined with clinically verified immunotherapy.
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| 26. |
- Persson, Bertil R, et al.
(författare)
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Survival of rats with N29 brain tumours after irradiation with 5 or 15 Gy and immunization with IFN-gamma secreting tumour cells
- 2008
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Ingår i: BioMedical Engineering and Informatics : New Development and the Future - Proceedings of the 1st International Conference on BioMedical Engineering and Informatics, BMEI 2008 - New Development and the Future - Proceedings of the 1st International Conference on BioMedical Engineering and Informatics, BMEI 2008. - 9780769531182 ; 2, s. 243-247
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Konferensbidrag (refereegranskat)abstract
- Intra cerebral tumours were inoculated into the brain of Fischer-344 syngeneic rats. After one week they were treated with either 5 or 15 Gy of Co-60-gamma radiation. The first immunization was given 1 hour before the radiation treatment and then two more times with 14-day intervals. Immunization was performed with 3 x 10(6) radiation sterilized IFN-gamma secreting tumour cells (N29) injected intraperitoneally. Neither radiation therapy with 5 or 15 Gy nor immunization with N29 cells alone had any significant effect on the length of survival of N29 tumour bearing rats. But radiation therapy with 5 Gy combined with immunization with IFN-gamma secreting syngeneic N29 cells resulted in 63 % complete remissions and significantly (p < 0.05) increased survival for the tumour bearing rats. Corresponding combination with 15 Gy RT resulted in 50% complete remissions. There is a possibility of a synergistic effect by optimal combination of radiation therapy and immunization.
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| 27. |
- Persson, Bertil R, et al.
(författare)
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Treatment of tumour cell with 5-aza-2-deoxycytidine (DAC) for immune tumour therapy of Glioma in Fischer-344 rats
- 2012
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Ingår i: Acta Scientiarum Lundensia. - 1651-5013. ; 2012:007, s. 1-21
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Fisher 344 rats with implanted N29 glioma tumours were treated with Pulsed Electric Fields (PEF) in combination with immunization using either IFN-gamma-gene-transfected syngeneic tumour cells or IFN-gamma transfected N29 cells treated with 10 micro-M 5-aza-2-deoxycytidine (DAC). Tumours (N29) were inoculated subcutaneously on both thighs of female F- 344 syngeneic rats. The left tumour was treated once with 16 exponential pulses with an electric field strength of 1400 V/cm, and 1.0 ms duration (time constant). No anticancer drugs were given at any time. The following day and then once weekly for three weeks, the animals were given intra-peritoneal injections of irradiated, modified N29 tumour cells. The results were evaluated by daily measuring the size of tumour on both sides of the animals. Treatment with solely PEF in 32 animals resulted in a specific growth rate decrease of 20±6 % on the PEF exposed tumour. The effect at the non targeted tumour was negligible (0±4 %). Treatment with IFN-gamma secreting tumour cells resulted in a significant decrease of tumour growth rate on the right tumour of 20± 2 % (p< 0.05) and no significant effect (3±0.3% ) was observed on the left tumour. Immunization with DAC treated IFN-gamma secreting cells in 12 animals showed no significant decreased growth rate, on neither the left nor the right tumours. By combining PEF+IFN-gamma no significant decrease in growth rate was achieved. But in the combination of PEF and IFN-gamma secreting cells grown in DAC medium the tumour growth rate decreased by about 50 % at the PEF treated tumour and there was a decrease of about 20% in tumour growth at the non-PEF treated tumour rate which is about the same as for PEF treatment alone. Immune therapy of rats with intracranial N32 tumours by immunization with IFN-gamma secreting syngeneic cells treated with DAC resulted in a slight (3%) but not significant increase in survival time. With a single RT fraction of 15 Gy there was, however, a significant increase of 32% in the length of survival time of the rats with N32 tumours (p<0.02). Radiation therapy with a single fraction of 15 Gy combined with immunization with IFN-gamma secreting syngeneic cells treated with DAC resulted in significant (p<0.01) 34% increased length of survival time for the N32 tumours although there were no complete remissions.
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| 28. |
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| 29. |
- Persson, Oscar, et al.
(författare)
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Distribution, cellular localization, and therapeutic potential of the tumor-associated antigen Ku70/80 in glioblastoma multiforme.
- 2010
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 1573-7373 .- 0167-594X. ; 97, s. 207-215
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies specifically targeting tumor-associated antigens have proved to be important tools in the treatment of human cancer. A desirable target antigen should be unique to tumor cells, abundantly expressed, and readily available for antibody binding. The Ku70/80 DNA-repair protein is expressed in the nucleus of most cells; it is, however, also present on the cell surface of tumor cell lines, and antibodies binding Ku70/80 at the cell surface were recently shown to internalize into tumor cells. To evaluate the potential of Ku70/80-antigen as a therapeutic target for immunotoxins in glioblastoma multiforme, we investigated binding and localization of Ku70/80-specific antibodies in tissue samples from glioblastomas and normal human brains, and in glioma cell cultures. Furthermore, the internalization and drug-delivery capacity were evaluated by use of immunotoxicity studies. We demonstrate that Ku70/80 is localized on the cell plasma membrane of glioma cell lines, and is specifically present in human glioblastoma tissue. Antibodies bound to the Ku70/80 antigen on the cell surface of glioma cells were found to internalize via endocytosis, and shown to efficiently deliver toxins into glioblastoma cells. The data further imply that different antibodies directed against Ku70/80 possess different abilities to target the antigen, in relation to its presentation on the cell surface or intracellular localization. We conclude that Ku70/80 antigen is uniquely presented on the plasma membrane in glioblastomas, and that antibodies specific against the antigen have the capacity to selectively bind, internalize, and deliver toxins into tumor cells. These results imply that Ku70/80 is a potential target for immunotherapy of glioblastoma multiforme.
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| 30. |
- Persson, Oscar, et al.
(författare)
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Microarray analysis of gliomas reveals chromosomal position-associated gene expression patterns and identifies potential immunotherapy targets.
- 2007
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 1573-7373 .- 0167-594X. ; 85:J1, s. 11-24
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas are among the most aggressive malignant tumors and the most refractory to therapy, in part due to the propensity for malignant cells to disseminate diffusely throughout the brain. Here, we have used 27 K cDNA microarrays to investigate global gene expression changes between normal brain and high-grade glioma (glioblastoma multiforme) to try and better understand gliomagenesis and to identify new therapeutic targets. We have also included smaller groups of grade II and grade III tumors of mixed astrocytic and oligodendroglial origin as comparison. We found that the expression of hundreds of genes was significantly correlated to each group, and employed a naive Bayesian classifier with leave-one-out cross-validation to accurately classify the samples. We developed a novel algorithm to analyze the gene expression data from the perspective of chromosomal position, and identified distinct regions of the genome that displayed coordinated expression patterns that correlated significantly to tumor grade. The regions identified corresponded to previously known genetic copy number changes in glioma (e.g. 10q23, 10q25, 7q, 7p) as well as regions not previously associated significantly with glioma (e.g. 1p13, 6p22). Furthermore, to enrich for more suitable targets for therapy, we took a bioinformatics approach and annotated our signatures with two published datasets that identified membrane/secreted genes from cytosolic genes. The resulting focused list of 31 genes included interesting novel potential targets as well as several proteins already being investigated for immunotherapy (e.g. CD44 and tenascin-C). Software for the chromosome analysis was developed and is freely available at http://base.thep.lu.se.
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| 31. |
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| 32. |
- Rebetz, Johan, et al.
(författare)
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Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:12
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Tidskriftsartikel (refereegranskat)abstract
- The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.
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| 33. |
- Rebetz, Johan, et al.
(författare)
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Glial Progenitor-Like Phenotype in Low-Grade Glioma and Enhanced CD133-Expression and Neuronal Lineage Differentiation Potential in High-Grade Glioma
- 2008
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6, s. 1107-1107
-
Tidskriftsartikel (refereegranskat)abstract
- Background: While neurosphere-as well as xenograft tumor-initiating cells have been identified in gliomas, the resemblance between glioma cells and neural stem/progenitor cells as well as the prognostic value of stem/progenitor cell marker expression in glioma are poorly clarified. Methodology/Principal Findings: Viable glioma cells were characterized for surface marker expression along the glial genesis hierarchy. Six low-grade and 17 high-grade glioma specimens were flow-cytometrically analyzed for markers characteristics of stem cells (CD133); glial progenitors (PDGFR alpha, A2B5, O4, and CD44); and late oligodendrocyte progenitors (O1). In parallel, the expression of glial fibrillary acidic protein (GFAP), synaptophysin and neuron-specific enolase (NSE) was immunohistochemically analyzed in fixed tissue specimens. Irrespective of the grade and morphological diagnosis of gliomas, glioma cells concomitantly expressed PDGFRa, A2B5, O4, CD44 and GFAP. In contrast, O1 was weakly expressed in all low-grade and the majority of high-grade glioma specimens analyzed. Co-expression of neuronal markers was observed in all high-grade, but not low-grade, glioma specimens analyzed. The rare CD133 expressing cells in low-grade glioma specimens typically co-expressed vessel endothelial marker CD31. In contrast, distinct CD133 expression profiles in up to 90% of CD45-negative glioma cells were observed in 12 of the 17 high-grade glioma specimens and the majority of these CD133 expressing cells were CD31 negative. The CD133 expression correlates inversely with length of patient survival. Surprisingly, cytogenetic analysis showed that gliomas contained normal and abnormal cell karyotypes with hitherto indistinguishable phenotype. Conclusions/Significance: This study constitutes an important step towards clarification of lineage commitment and differentiation blockage of glioma cells. Our data suggest that glioma cells may resemble expansion of glial lineage progenitor cells with compromised differentiation capacity downstream of A2B5 and O4 expression. The concurrent expression of neuronal markers demonstrates that high-grade glioma cells are endowed with multi-lineage differentiation potential in vivo. Importantly, enhanced CD133 expression marks a poor prognosis in gliomas.
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Salford, Leif, et al.
(författare)
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Search for effective therapy against glioblastoma multiforme - Clinical immunisation with autologous glioma cells transduced with the human interferon-gamma gene
- 2002
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Ingår i: Developments in Neuroscience. Proceedings of the 2nd International Mt Bandai Symposium for Neuroscience 2001. - 0531-5131. ; 1247, s. 211-220
-
Konferensbidrag (refereegranskat)abstract
- Based upon earlier experimental work by our group, we have started a human immuno-gene therapy study. The goal is to study the effects of immunisation with autologous tumour cells expressing gene sequences for human interferon-gamma For more than two decades we have sought for efficient treatment against malignant gliomas. Our most successful treatment in the animal models is immuno-gene therapy where murine genes for the cytokines IFN-gamma, IL-7 and B7-1 were chosen for their ability to stimulate different stages of the pathway for cytotoxic T lymphocyte (CTL) activation. Rats of the syngeneic inbred strain Fischer 344 had rat glioma cells of the N32 line inoculated in the right caudate nucleus, and 1 or 3 days later N32 cells transfected with either IFN-gamma, IL-7 or B7-1 genes were injected subcutaneously (and in some studies intraperitoneally). This treatment was repeated three to four times with 7- to 14-day interval and resulted in significantly improved survival compared with treatment with wild-type rat glioma cells (e.g. not transfected with the cytokine genes). The continued work concentrated on treatment with IFN-gamma secreting tumour cells of both the N32 line and also a newly developed ENU-induced rat glioma cell line called N29. This work proved the effectiveness of the technique. Cure was achieved in 72% of the animals treated with the IFN-gamma cells. Tumour-infiltrating leukocytes from N32-IFN-gamma-immunised animals showed a significantly stronger infiltration by CD8+ T-cells, significantly more NK cells, and an increased number of CD25-expressing T-cells. These results confirmed the possible usefulness of IFN-gamma-transfected tumour cells in the immune-therapy of rat brain tumours. The animal experiments have motivated us to start a human immuno-gene therapy study including 20 patients with glioblastoma multiforme (GBM), where >80% of the tumour can be surgically removed. The goal is to ascertain whether immunisation with autologous tumour cells expressing gene sequences for human interferon-gamma is safe for the patients, gives rise to an immunological response, and adds any beneficial effect to conventional therapy (tumour growth, prolonged survival). Hitherto, nine patients have been included in the study, two of which have received 6 and 10 immunisations, respectively. Two patients have died from their disease before cells have been ready for immunisation; in two cases no malignant cells have appeared in the cell cultures and three patients are ready to start their immunisation shortly. The immunisation takes place in the dermis of the upper arm. Seven days after each immunisation, a skin biopsy is taken from the centre of one of the injection sites. The composition of the cellular infiltration in the skin is studied by markers for T lymphocytes (CD3); helper cells, subset of T cells (CD4); killer cells, subset of T cells (CD8); natural killer cells (CD16) and B lymphocytes, B cells (CD20). Also the expression of cytokines for functional T cell subsets are studied: IL-2, IL-4, IL-10, IL-12, IL-18, TNF-alpha and IF-gamma and TGF-beta(1,2 and 3-) Peripheral blood is sampled both before and after operation and also after each immunisation event. Co-culture of this blood with tumour cells from the patient allows for a selection of T-cells that can recognise tumour-specific antigens. The results from the first human treatments are presented. (C) 2002 Published by Elsevier Science B.V.
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| 38. |
- Salford, Leif, et al.
(författare)
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The mammalian brain in the electromagnetic fields designed by man with special reference to blood-brain barrier function, neuronal damage and possible physical mechanisms
- 2008
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Ingår i: PROGRESS OF THEORETICAL PHYSICS SUPPLEMENT. - 0375-9687. ; :173, s. 283-309
-
Konferensbidrag (refereegranskat)abstract
- Life oil earth was formed during billions of years, exposed to, and shaped by the original physical forces such as gravitation, cosmic irradiation, atmospheric electric fields and the terrestrial magnetism. The Schumann resonances at 7.4 Hz are all example of oscillations possibly important for life.(1)) The existing organisms are created to function in harmony with these forces. However, in the late 19th century mankind introduced the use of electricity, in the early 20th century long-wave radio and in the 1940-ies short-wave radio. High frequency RF was introduced in the 50-ies as FM and television and during the very last decades, microwaves of the modern communication society spread around the world. Today, however, one third of the world's population is owner of the microwave-producing mobile phones and an even larger number is exposed to the cordless RF emitting systems. To what; extent are all living organisms affected by these, almost everywhere present radio frequency fields? And what will be the effects of many years of continuing exposure? Since 1989 Our group has studied the effects upon the mammalian blood-brain barrier (BBB) in rats by non-thermal radio frequency electromagnetic fields (RF-EMF). These have been shown to cause significantly increased leak-age of the rats' own blood albumin through the BBB of exposed rats, at energy levels of 1W/kg and below, as compared to non-exposed animals in a total series of about two thousand animals.(2)-6)) One remarkable observation is the fact that the lowest energy levels, with whole-body average power densities below 10mW/kg, give rise to the most pronounced albumin leakage. If mobile communication, even at extremely low energy levels, causes the users' own albumin to leak out through the BBB, also other unwanted and toxic molecules in the blood, may leak into the brain tissue and concentrate in and damage the neurons and glial cells of the brain. In later studies we have shown that a 2-h exposure to GSM 915 MHz, at non-thermal SAB-values of 0.2, 2 and 200 mW/kg, gives rise to significant neuronal damage, seen not only 50 days after the exposure 7) but also after 28 days but not after 14 days. Albumin extravasations and uptake into neurons was enhanced after 14 clays, but not after 28.(8)) in our continued research, also the non-thermal effects oil tissue structure and memory function of long-term exposure for 13 months are studied.(9)) We have also performed microarray analysis of brains from rats exposed to short term GSM both at 1,800 MHz and at 900MHz and have found significant effects upon gene expression of membrane associated genes as compared to control animals.(10),11)) Most of our findings support that living organisms are affected by the non-thermal radio frequency fields. Some other Studies agree while others find no effects. The mechanisms by which the EMFs may alter BBB permeability are not Well Understood. At low field strengths, the effects on body temperature are negligible and thus heating effects are not involved. A change in the physicochemical characteristics of membranes has been suggested as a cause.(12)) We have performed experiments to verify a quantum mechanical model for interaction with protein-bound ions. Our results show that controlled frequency and amplitude of ELF EM fields upon spinach plasma vesicles can steer transport over the membrane.(13)) This may be a first proof of a resonance phenomenon where appropriate levels of frequency and amplitude in the right combination have the potency to communicate with the biology of membranes and transport systems. Our study has prompted Lis to elaborate on magnetic resonance models; the Ion Cyclotron Resonance (ICR) model and the Ion Parametric Resonance (IPR) Model in an attempt to explain the occurrence of resonance frequencies. This is extensively described here under the heading: Mechanisms behind the effects of electromagnetical fields upon biology. We also bring forward the concept of solitons being active in membranes and DNA/RNA-transcription as a, possible mean to understand and prove the biological effects of EMF. The Nishinomiya-Yukawa International and Interdisciplinary Symposium 2007 raised the question: What is Life? An obvious and simple answer could be: It is DNA! The DNA strand can be looked upon as an antenna resonating in the microwave band 6GHz with its harmonics and subharmonics.(14)-18)) If this holds true, the dramatic situation might exist, that all living organisms have a receptor for the newly constructed and world-wide man-made microvaves, leading to a direct effect upon the function of DNA - in concordance with our experimental findings! Our generation invented the microwave emitters. We now have in imperative obligation to further investigate the links between EMF and biology in order to prevent possible detrimental effects of the microwaves.
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| 39. |
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| 40. |
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| 41. |
- Skog, Johan, et al.
(författare)
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Efficient internalization into low-passage glioma cell lines using adenoviruses other than type 5: an approach for improvement of gene delivery to brain tumours
- 2004
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Ingår i: Journal of General Virology. - : Microbiology Society. - 1465-2099 .- 0022-1317. ; 84:9, s. 2627-2638
-
Tidskriftsartikel (refereegranskat)abstract
- There is a need for improvement of the commonly used adenovirus vectors based on serotype 5. This study was performed on three adenovirus serotypes with a CAR-binding motif (Ad4p, Ad5p and Ad17p) and three non-CAR-binding serotypes (Ad11p, Ad16p and Ad21p). The capacity of these alternative adenovirus vector candidates to deliver DNA into low-passage glioma cell lines from seven different donors was evaluated. The non-CAR-binding serotype Ad16p was the most efficient serotype with regard to import of its DNA, as well as initiation of hexon protein expression. Ad16p established hexon expression in 60–80 % of the cell population in gliomas from all donors tested. The other non-CAR-binding serotypes, Ad11p and Ad21p, showed hexon expression in 25–60 and 40–80 % of cells, respectively. The corresponding figure for the best CAR-binding serotype, Ad5p, was only 25–65 %, indicating greater variability between cells from different donors than serotype Ad16p had. The other CAR-binding serotypes, Ad4p and Ad17p, were refractory to some of the gliomas, giving a maximum of only 45 and 40 % hexon expression, respectively, in the most permissive cells. Interestingly, the transduction capacity of the CAR-binding serotypes was not correlated to the level of CAR expression on the cells.
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| 42. |
- Vikman, Sofia, 1977-
(författare)
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Towards Immunotherapy of Midgut Carcinoid Tumors
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Classical midgut carcinoids belong to neuroendocrine tumors of the gastroenteropancreatic tract (GEP-NETs) and are associated with serotonin overproduction. The term midgut is derived from the tumors’ embryological site of origin: enterochromaffin cells in the lower jejunum, ileum, caecum and the ascending colon. Despite their rather benign nature, these tumors can metastasize to mesentery and liver, putting patients at risk for the so-called carcinoid syndrome. This syndrome is characterized by flushes, diarrhoea and valvular heart disease due to the excessive serotonin secretion by tumor cells. Treatment of metastatic disease is currently ineffective and T cell immunotherapy has been suggested as a novel approach. We propose a number of midgut carcinoid-associated proteins as potential antigens for immunotherapy. Chromogranin A (CGA), tryptophan hydroxylase 1 (TPH-1), vesicular monoamine transporter 1 (VMAT-1), caudal type homeobox transcription factor 2 (CDX-2), islet autoantigen 2 (IA-2) and survivin represent interesting candidates based on their fairly restricted neuroendocrine tissue expression. In pursuit of potential antigens we identified a novel splicing variant of VMAT-1, lacking the second last exon. The variant, denoted VMAT1Δ15, encodes a differently translated C-terminal compared to the native form, is localized in the endoplasmic reticulum (ER) instead of large dense core vesicles and is unable to accumulate serotonin. We identify several immunogenic HLA-A*0201-binding peptide epitopes derived from our proposed antigens by analyzing CD8+ T cell responses in blood from midgut carcinoid patients. We demonstrate immune recognition of midgut carcinoid tumors in patients and in vitro generation of activated CD8+ T cells recognizing these peptide epitopes in blood from healthy controls. Patients also exhibit increased frequencies of circulating regulatory T cells (Tregs) with suppressive quality and patient lymphocytes display a decreased proliferative capacity compared to healthy controls. Midgut carcinoid tumors are frequently infiltrated by T cells, however always in the presence of Foxp3-expressing Tregs. Midgut carcinoid-associated antigens recognized by CD8+ T cells are of great interest for cellular therapies such as modified DC vaccines or adoptive T cell transfer. However, the systemic and local suppression of Th1 immunity must be considered and likely corrected in order to obtain clinically effective immunotherapies.
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| 43. |
- Wang, Yong, et al.
(författare)
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Coxsackievirus and adenovirus receptor expression in non-malignant lung tissues and clinical lung cancers
- 2006
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Ingår i: Journal of Molecular Histology. - : Springer Science and Business Media LLC. - 1567-2379 .- 1567-2387. ; 37:3-4, s. 153-160
-
Tidskriftsartikel (refereegranskat)abstract
- Adenoviral vector mediated gene delivery has been applied in clinical trials and mechanistic studies to explore new treatment approaches for lung cancers. The expression of coxsackievirus adenovirus receptor (CAR), the primary receptor for the most commonly used adenovirus serotype 5 (Ad5)-based vectors, predominantly determines the permissiveness of lung cancer cells. CAR expression is also suggested to modulate tumor cell proliferation capacity. Here, we studied CAR expression in archival lung cancer specimens by using well-characterized CAR 72 antibodies. High levels of CAR expression were observed in most of the 32 cases of squamous cell carcinoma lung cancers and in all the five cases of small cell lung cancers investigated. In contrast, high levels of CAR expression were detected only in 6 of 22 adenocarcinoma lung cancers. The relative levels of CAR expression did not correlate with the pathologic grade in lung cancers, and was thus inconsistent with a role of modulating cancer cell proliferation. Of note, CAR expression was not detected in non-malignant alveolar cells. Our data suggest a preferred utility of Ad5 vector mediated gene delivery to squamous cell carcinoma lung cancers, small cell lung cancers, but not to the majority of adenocarcinoma lung cancers.
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| 44. |
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| 45. |
- Xue, Zhongtian, et al.
(författare)
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An epigenetic mechanism for high, synergistic expression of indoleamine 2,3-dioxygenase 1 (IDO1) by combined treatment with zebularine and IFN-γ: Potential therapeutic use in autoimmune diseases.
- 2012
-
Ingår i: Molecular Immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 51:2, s. 101-111
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Tidskriftsartikel (refereegranskat)abstract
- IDO1 can be induced by interferon gamma (IFN-γ) in multiple cell types. We have earlier described that the DNA methyltransferase inhibitor zebularine also induces IDO1 in several rat cell clones. We now describe a synergistic induction of IDO1 expression by IFN-γ and zebularine. To elucidate the mechanism of the IDO1 induction we have studied the methylation status in the promoter region of the IDO1 gene from both human monocytic THP-1 cells and H1D2 rat colon cancer cells. Interestingly, the IDO1 promoter is hypermethylated and IFN-γ is shown to induce a significant demethylation. The synergism in effect of zebularine and IFN-γ on IDO1 expression is paralleled by a similar synergistic effect on expression of two other IFN-γ-responsive genes, the transcription factors STAT1 and IRF1 with binding sites in the IDO1 promoter region. The demonstrated synergistic activation of IDO1 expression has implications in relation to therapeutic induction of immunosuppression in autoimmunity and chronic inflammation.
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| 46. |
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| 47. |
- Zhao, Xia, et al.
(författare)
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Influence of mast cells on the expression of adhesion molecules on circulating and migrating leukocytes in acute pancreatitis-associated lung injury
- 2005
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Ingår i: Lung. - : Springer Science and Business Media LLC. - 1432-1750 .- 0341-2040. ; 183:4, s. 253-264
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatitis-associated lung injury is an early-occurring and severe complication, still associated with substantial mortality. A number of inflammatory cells and their products are involved in the initiation and progress of the condition. In the present study, acute pancreatitis (AP) was induced by the intraductal infusion of 5% sodium taurodeoxycholate in the rat. Pulmonary endothelial barrier dysfunction was measured by plasma exudation of radiolabeled albumin. Expression of PECAM-1, ICAM-1, and L-selectin on neutrophils (CD11b(+)) and monocytes/macrophages (CD11b/c(+)), obtained from circulation and lung tissue, was measured I and 6 hours after AP induction (n = 10 rats/time point/group). Plasma levels of histamine and serotonin were determined. The role of mast cells was evaluated by pretreatment with the mast cell stabilizer cromolyn. Intraperitoneal administration of cromolyn downregulated pancreatitis-induced systemic increase of histamine at I hour (513 82 vs. 309 50, p < 0.05). Cromolyn prevented a decreased expression of PECAM-I on circulatory neutrophils and monocytes/macrophages and against an increased expression of ICAM-1 and PECAM-1 on pulmonary neutrophils and monocytes/ macrophages 6 hours after AP induction (about 40% vs. 10%, p < 0.01). The mast cell stabilizer also prevented pancreatitis-induced pulmonary endothelial barrier dysfunction at 6 hours. Thus, our data indicate that mast cells may play a critical role in the activation of leukocytes during the initiation of pancreatitis-associated lung injury by altering phenotypes of adhesion molecules.
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