| 1. |
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| 2. |
- 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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| 3. |
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| 4. |
- Chen, S, et al.
(författare)
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Functional association of cytokine-induced SH2 protein and protein kinase C in activated T cells
- 2003
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377. ; 15:3, s. 403-409
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Tidskriftsartikel (refereegranskat)abstract
- TCR signaling is mediated by intracellular signaling molecules and nuclear transcription factors, which are tightly regulated by interaction with regulatory proteins such as Grb2 and SLAP. We reported recently that TCR stimulation induces the expression of cytokine-induced SH2 protein (CIS). The expression of CIS promotes TCR-mediated activation. We have now found specific interactions between CIS and activated protein kinase C (PKC) alpha, beta and theta in TCR-stimulated T cells. CIS was shown by in vitro kinase assay to associate with activated PKC. In CIS-expressing T cells isolated from CIS-transgenic mice, the amount of activated PKC associated with CIS was found to increase following TCR stimulation. By immunohistochemical analysis, CIS was also found to co-localize with PKCtheta at the plasma membrane of activated T cells. In addition to the interaction and intracellular co-localization of the CIS and PKC, an increase in the activation of AP-1 and NF-kappaB was noted in CIS-expressing T cells, after stimulation by either anti-CD3/CD28 or phorbol myristate acetate + ionomycin. These results suggest that CIS regulates PKC activation, and that this may be important for the activation of both the AP-1 and NF-kappaB pathways in TCR signaling.
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| 5. |
- Dai, Min, et al.
(författare)
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Tumor Regression and Cure Depends on Sustained Th1 Responses
- 2018
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Ingår i: Journal of Immunotherapy. - 1524-9557. ; 41:8, s. 369-378
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Tidskriftsartikel (refereegranskat)abstract
- While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly doses of various combinations of mAbs. Combinations of mAbs to CTLA4/PD1/CD137 (the 3 mAb combination) and to CTLA4/PD1/CD137/CD19 (the 4 mAb combination) were most efficacious to induce complete regression of both the injected tumor and an untreated tumor in the same mouse. Tumor cure was consistently associated with shifting a Th2 to a Th1 response in tumor-draining lymph nodes and spleen and it involved epitope specific and long-lived memory T cells as well as M1 macrophages. This shift and accompanying tumor rejection was harder to achieve as the treated tumors increased in size. Relapse of tumors which had initially regressed following treatment with immunomodulatory mAbs was associated with return of a Th2 microenvironment in tumors, tumor-draining lymph nodes and spleens rather than the emergence of immune-resistant tumor cells. While mAbs to CTLA4 plus PD-1 were therapeutically ineffective, combining the 2 of them with intraperitoneal cisplatin, 10 mg/kg, induced long-term complete tumor regression in most mice with small TC1 tumors and the therapeutic efficacy against larger tumors improved by administrating cisplatin together with the 3 or 4 mAb combination.
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| 6. |
- Dock, H., et al.
(författare)
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Maintenance of the E.coli dcm Methylation of the CMV Promoter, in Contrast to Hypomethylation of the Recognition Sequence of Transcription Factor NFkB in Transfected GBM Cells
- 2016
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Ingår i: Cloning & Transgenesis. - : OMICS Publishing Group. - 2168-9849. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- The human cytomegalovirus (CMV) immediate early promoter has been extensively used to drive target gene expression in transgenic mammalian cells. DNA methylation of the CMV promoter has been shown to be the reason for a reduced promoter activity and silencing of the target gene. We have established an in vitro model system, in which human brain cancer cells (glioblastoma multiforme, GBM) were transfected with pAdTrack-CMV-GFP plasmid, isolated from a dcm positive (dcm+) E. coli strain. We found that in two CCTGG sequences located at position from -304 to -300 nt and from -497 to -493 nt of the CMV promoter region, the internal C was methylated in all analyzed clones, i.e., the E. coli dcm methylation pattern is maintained in the CMV promoter region after its integration into the human genome. In contrast, we found that the recognition sites for the transcription factor NFkB and certain other transcription factors in the enhancer region of the CMV promoter (from -107 to -270 nt) were hypomethylated. This might explain why the CMV promoter maintained an active mode, driving the GFP expression despite the demonstrated methylation of the CMV promoter. We noticed that the CCTGG sequence is also contained in the binding sequence motif of transcription factor NFkB. Hence we have comprehensively studied transcription factors through a database searching, and the responsive elements that contain dcm methylation sequences CCW(A/T)GG. A list of transcription factors and the corresponding regulated genes are presented.
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| 7. |
- Feridani, Amir, et al.
(författare)
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Combined flow cytometry and confocal laser scanning microscopy for evaluation of BR96 antibody cancer cell targeting and internalization.
- 2007
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Ingår i: Cytometry Part A. - : Wiley. - 1552-4930 .- 1552-4922. ; 71A:6, s. 361-370
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Tidskriftsartikel (refereegranskat)abstract
- Background: Monoclonal antibodies (mAb) are important tools in the management of tumor disease, and the discovery of antibodies with both specific cancer cell targeting and capacity to enter the cells by internalization are critical to improve the therapeutic efficacy. Method: Antibody cancer cell targeting and internalization properties of fluoroscein-conjugated mAb made against Lewis Y (BR96) were evaluated quantitatively and qualitatively by means of flow cytometry (FCM) and confocal laser scanning microscopy (CLSM), respectively, on cells from a rat tumor cell line (BN7005-H1D2). Results: The study demonstrated a specific binding of BR96 to LewisY (LeY) located in the cell membrane and as BR96/LeY immunocomplexes (BR96/LeY) internalized into the cytoplasm. BR96/LeY was internalized into about 15% of the cells, usually distributed throughout the cytoplasm, but also located close to the nuclei. Cytotoxic effects by BR96 were indicated, and CLSM visualized subpopulations containing cells with bound or internalized BR96/LeY that possessed morphologically pyknotic nuclei and disrupted DNA. Conclusion: The spatial-temporal pattern by BR96 cell targeting and internalization processes of BR96/LeY into the cancer cells expressing LeY was demonstrated by FCM and CLSM. Used together, the FCM and CLSM techniques provide a valuable tool for preclinical analyses of antibody targeting and their capacities as carriers of cytotoxic conjugates for the use in cancer therapy.
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| 8. |
- Garkavij, Michael, et al.
(författare)
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Enhanced radioimmunotargeting of 125I-labeled L6-biotin monoclonal antibody (MAb) by combining preload of cold L6 MAb and subsequent immunoadsorption in rats
- 1995
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Ingår i: Cancer Research. - 1538-7445. ; 55:23 Suppl, s. 5874-5880
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Tidskriftsartikel (refereegranskat)abstract
- The present study investigates whether tumor:normal tissue uptake ratios of radiolabeled monoclonal antibodies can be further improved by a combination of extracorporeal immunoadsorption (ECIA) and preload with unlabeled idiotypic monoclonal antibody. Athymic rats, heterotransplanted with human lung carcinoma under the kidney capsule (SR tumor) and i.m. (IM tumor), were divided into four study groups: controls, ECIA, preload, and combined preload+ECIA. The preload+ECIA procedure reduced the whole-body and plasma activity by 48 and 89%, respectively. After such combined procedure, the uptake of 125I-labeled L6-biotin in SR tumors was unchanged, while the uptake in normal tissues was considerably reduced. Tumor (T):bone marrow ratio was then increased by 17.5 times (after ECIA) and by 4.5 times (24 h after ECIA). Similar enhancements were achieved for T:liver and T:kidney ratios. For the IM tumors, the ratios were not as high as for SR tumors. The effects on T:normal ratios of preload+ECIA in combination were synergistic. The combined procedure resulted both in an increased uptake and prolonged persistence of 125I-labeled L6-biotin in the SR tumors and also in a reduction of corresponding uptake values in organs critical for radiation.
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| 9. |
- Garkavij, Martin, et al.
(författare)
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Extracorporeal whole-blood immunoadsorption enhances radioimmunotargeting of iodine-125-labeled BR96-biotin monoclonal antibody
- 1997
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Ingår i: Journal of Nuclear Medicine. - 0161-5505. ; 38:6, s. 895-901
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Tidskriftsartikel (refereegranskat)abstract
- This study investigates the efficacy of tumor radioimmunotargeting with 125I-labeled BR96-biotin monoclonal antibody using a new method, whole-blood immunoadsorption (WBIA), based on direct adsorption of unbound monoclonal antibody (MAb) from blood without preceding separation of plasma. METHODS: Highly tumor-reactive, internalizing, chimeric BR96 MAb of isotype IgG1 binds to a tumor-associated Lewis-type (Le(Y)) cell surface antigen. Forty-six Brown Norwegian male rats were inoculated intramuscularly and beneath the liver or kidney capsule with syngeneic rat colon carcinoma BN7005, expressing Lewis-type antigen, and investigated. The rats were injected intravenously with 3.5-4.5 MBq 125I-labeled BR96-biotin. Twenty of the rats underwent WBIA starting 5 or 12 hr after injection. About six blood volumes were passed through an avidin-gel adsorption column during 2 hr. RESULTS: By using WBIA, whole-body radioactivity was reduced by 50%, and plasma activity by 85%. Both directly after completion of WBIA and 33 hr later, the activity uptake in tumors manifested only a nonsignificant decrease as compared with corresponding controls (p > 0.05) and had approximately similar time-activity curves. Uptake ratios for tumor (T):bone marrow, T:liver, T:kidney and T:lung were enhanced 2.3- to 3.5-fold in all three tumor models, as compared with controls. The ratio of liver tumor to bone marrow was improved from 10:1 to 30:1. CONCLUSION: This new method of WBIA yields significantly improved radioimmunotargeting of highly tumor-reactive, internalizing MAb BR96.
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| 10. |
- Garkavij, Michael, et al.
(författare)
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Improving radioimmonotargeting of tumors. Variation in the amount of L6 MAb administered, combined with an immunoadsorption system (ECIA)
- 1993
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 32:7-8, s. 853-859
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Tidskriftsartikel (refereegranskat)abstract
- Extracorporeal immunoadsorption (ECIA) is a new method for the selective removal of circulating radiolabeled monoclonal antibodies (MAb) from plasma to increase the uptake in tumor versus normal tissues (T/N-ratio). To ascertain whether the amount of MAb affects T/N ratios immediately and 24 h after ECIA, we used a rat model with two tumor sites--one intramuscular (im) and one below the subrenal capsule (SR). Extracorporeal immunoadsorption was done with an avidin-agarose column after injection of 125I-labeled biotinylated L6 MAb. The animals received 10, 50 or 250 micrograms of L6 only (controls), or followed by ECIA. The efficacy of the procedure in removing plasma activity was 80-95%. For both tumor sites, the highest T/N-ratios were obtained with 10 micrograms L6. All T/N-ratios significantly improved for SR tumors by a factor ranging from 3.2 (lung) to 12.6 (bone marrow). The T/N-ratios were still elevated 24 h after ECIA. Injection of larger amounts of MAb, probably causing a higher degree of tumor saturation, will not necessarily improve the T/N ratio after ECIA.
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| 11. |
- Huang, Yi Shu, et al.
(författare)
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Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis
- 2021
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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. - 1091-6490. ; 118:19
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Tidskriftsartikel (refereegranskat)abstract
- Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation inhibitors have previously been shown to promote regulatory T cell responses and, in the present study, we evaluated their potential to ameliorate chronic and acute animal models of rheumatoid arthritis. Of the drugs tested, decitabine was the most effective, producing a sustained therapeutic effect that was dependent on indoleamine 2,3-dioxygenase (IDO) and was associated with expansion of induced regulatory T cells, particularly at the site of disease activity. Treatment with decitabine also caused apoptosis of Th1 and Th17 cells in active arthritis in a highly selective manner. The molecular basis for this selectivity was shown to be ENT1, a nucleoside transporter, which facilitates intracellular entry of the drug and is up-regulated on effector T cells during active arthritis. It was further shown that short-term treatment with decitabine resulted in the generation of a population of regulatory T cells that were able to suppress arthritis upon adoptive transfer. In summary, a therapeutic approach using an approved drug is described that treats active inflammatory disease effectively and generates robust regulatory T cells with the IDO-dependent capacity to maintain remission.
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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. |
- Li, Suling, et al.
(författare)
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Cytokine-induced Src homology 2 protein (CIS) promotes T cell receptor-mediated proliferation and prolongs survival of activated T cells.
- 2000
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 191:6, s. 985-994
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Tidskriftsartikel (refereegranskat)abstract
- Members of the suppressor of cytokine signaling (SOCS) family were discovered as negative regulators of cytokine signaling by inhibition of the Janus kinase–signal transducer and activator of transcription (Jak-STAT) pathway. Among them, cytokine-induced Src homology 2 (SH2) protein (CIS) was found to inhibit the interleukin 3– and erythropietin-mediated STAT5 signaling pathway. However, involvement of SOCS proteins in other signaling pathways is still unknown. This study shows that the expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation. In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo. Forced expression of CIS also prolongs survival of CD4 T cells after TCR activation. Molecular events immediately downstream from the TCR are not changed in CIS-expressing CD4 T cells, but activation of mitogen-activated protein (MAP) kinase pathways by TCR stimulation is significantly enhanced. Together with the increased MAP kinase activation, a direct interaction of CIS and protein kinase Cθ was also demonstrated. These results suggest that CIS is one of the important regulators of TCR-mediated T cell activation. The functions of CIS, enhancing TCR signaling and inhibiting cytokine signaling, may be important in the regulation of immune response and homeostasis.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Mårtensson, Linda, et al.
(författare)
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A nonsurgical technique for blood access in extracorporeal affinity adsorption of antibodies in rats.
- 2007
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Ingår i: Artificial Organs. - : Wiley. - 0160-564X .- 1525-1594. ; 31:4, s. 312-316
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Tidskriftsartikel (refereegranskat)abstract
- Monoclonal antibodies for targeting cytotoxic conjugates to tumor cells are currently being evaluated together with extracorporeal affinity adsorption. The aim of the adsorption was to reduce undesired side effects in normal organs and to increase the tumor-to-normal tissue ratios. This technique is also applicable to several other therapeutic areas such as immune-mediated disorders, that is, autoimmunity, allergy, and transplantation rejection. We describe an improved technique for extracorporeal affinity adsorption of radiolabeled biotinylated antibodies in rats. Blood access is established through the tail artery and tail vein, without surgical insertion of permanent catheters. This technique is simple, does not require surgery, and causes only minimal stress to the animals. In addition, experiments can be carried out on several animals simultaneously. This new technique is of considerable benefit for studying extracorporeal affinity adsorption in rats, as experiments can be carried out with negligible anatomical and physiological interventions, compared to previously used techniques.
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| 20. |
- Mårtensson, Linda, et al.
(författare)
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Determining maximal tolerable dose of the monoclonal antibody BR96 labeled with 90Y or 177Lu in rats: establishment of a syngeneic tumor model to evaluate means to improve radioimmunotherapy.
- 2005
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 11:19 Pt 2, s. 7104-7108
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate therapeutic strategies, it is essential to use biological models reflecting important aspects of the clinical situation. The aim of the present study was to compare the maximal tolerable dose of the monoclonal antibody BR96 labeled with Y-90 or Lu-177 in immunocompetent rats. Maximal tolerable dose was defined as the highest activity that allows 100% of the animals to survive without clinical signs, such as infections, bleeding, or diarrhea, and with < 20% loss in body weight. Experimental Design: Increasing activity levels of BR96 labeled with Y-90 or Lu-177 were administered to groups of rats. Blood parameters, body weight, and general performance were monitored for 8 weeks. Results: Two days postinjection, all groups had decreased leukocyte counts down to 5% to 15% of initial values. Initiation of recovery (at 14-21 days) showed a dose-response relationship. All groups, except the group given the highest activity of Y-90 had complete resolution in their leukopenia. The decrease in platelets was delayed to days 7 to 14 postinjection with a dose dependent response regarding both severity of the nadir (10-40% of initial value) and the start of recovery. Animals in the groups given the highest activities of both Y-90 and Lu-177 exhibited skin infections on day 21. Conclusions: The results showed good reproducibility and dose-dependent toxicity for both radionuclides, indicating that the maximal tolerable dose for Lu-177 - BR96 (1,000 MBq/kg) is 1.7 times that for Y-90 - BR96 (600 MBq/kg) in rats. This model makes it feasible to evaluate strategies to escalate therapeutic doses to tumors without increasing normal tissue toxicity.
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| 21. |
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| 22. |
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| 23. |
- Mårtensson, Linda, et al.
(författare)
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Reduced myelotoxicity with sustained tumor concentration of radioimmunoconjugates in rats after extracorporeal depletion.
- 2007
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Ingår i: Journal of Nuclear Medicine. - 0161-5505. ; 48:2, s. 269-276
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the possibility of decreasing the myelotoxicity associated with radioimmunotherapy (RIT) by extracorporeal depletion of radioimmunoconjugates (RIC) from the circulation. The optimal combination of radionuclide and the time interval between injection of the RIC and the subsequent extracorporeal depletion procedure was assessed in immunocompetent rats, with respect to both myelotoxicity and tumor concentration of RIC. Methods: Rats were injected with (177)tumor Y-90-labeled antibody conjugate (mAb-DOTA-biotin) (mAb is monoclonal antibody; DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid) and subjected to removal of the conjugate from the circulation by extracorporeal affinity adsorption treatment (ECAT) 12, 24, or 48 h after injection. Myelotoxicity was assessed by analysis of blood parameters for 10 wk. The effect of ECAT on the tumor concentration of RIC was evaluated in parallel by scintillation camera imaging in rats injected with In-111-labeled RIC. Results: ECAT reduced the blood content of RIC by 95%. Thus, myelotoxicity was significantly milder in animals subjected to ECAT than that in controls. The timing of ECAT influenced the rate and level of bone marrow recovery, with an earlier recovery in animals subjected to ECAT early after injection. The toxicity-reducing effect of ECAT was more distinct in animals injected with Lu-177-labeled RIC than in animals injected with 90Y-labeled RIC. Scintillation camera imaging of tumors before and after ECAT revealed that subjecting animals to ECAT at 12 h after injection considerably reduced the total activity in tumors (34%), whereas the effect was lower at both 24 h (18%) and 48 h (18%) after injection. Conclusion: ECAT can efficiently reduce myelotoxicity associated with RIT, and the concentration of RIC in tumor can be sustained, provided ECAT is performed at an optimal time after antibody administration. The choice of radionuclide for RIT in combination with ECAT is important, as the physical half-life is crucial for the toxicity-reducing potential of ECAT at a specific time.
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| 24. |
- Nilsson, Greger, et al.
(författare)
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Distribution of Coronary Artery Stenosis After Radiation for Breast Cancer
- 2012
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:4, s. 380-386
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To study distribution of coronary artery stenosis among patients with breast cancer (BC) and to assess correlation between radiotherapy (RT) and location of stenosis. PATIENTS AND METHODS A Swedish BC cohort diagnosed from 1970 to 2003 was linked to registers of coronary angiography from 1990 to 2004, which yielded 199 patients. Stenoses of the coronary arteries were graded from 0 to 5, where 0 indicated a normal vessel and 5 indicated occlusion. Two hotspot areas for radiation were defined: proximal right coronary artery (prox RCA), mid and distal left anterior descending artery and distal diagonal (mdLAD + dD). RT regimens were categorized as high or low risk of irradiating the hotspot areas. Left breast/chest wall was considered high risk for mdLAD + dD; left internal mammary chain (IMC), high risk for prox RCA and mdLAD + dD from 1970 to 1995 and thereafter solely for mdLAD + dD; and right IMC, high risk for prox RCA. Other RT targets and no RT were considered low risk. Results were expressed in odds ratios (ORs) and 95% CIs. RESULTS For irradiated left- versus right-sided BC, the OR for grade 3 to 5 stenosis in mdLAD + dD was 4.38 (95% CI, 1.64 to 11.7), and for grade 4 to 5 stenosis, the OR was 7.22 (95% CI, 1.64 to 31.8). For high-risk RT versus low-risk or no RT, the OR for grade 3 to 5 stenosis in hotspot areas was 1.90 (95% CI, 1.11 to 3.24). CONCLUSION An increase of stenosis in mdLAD + dD in irradiated left-sided BC and an association between high-risk RT and stenosis in hotspot areas for radiation indicate a direct link between radiation and location of coronary stenoses.
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| 25. |
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| 26. |
- Nilsson, Greger, et al.
(författare)
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Radiation dose distribution in coronary arteries in breast cancer radiotherapy
- 2016
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 55:8, s. 959-963
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Tidskriftsartikel (refereegranskat)abstract
- Background: Women irradiated for left-sided breast cancer (BC) have an increased risk of coronary artery disease compared to women with right-sided BC. We describe the distribution of radiation dose in segments of coronary arteries in women receiving adjuvant radiotherapy (RT) for left- or right-sided BC.Material and methods: Fifteen women with BC, seven left-sided and eight right-sided, who had received three-dimensional conformal radiotherapy (3DCRT), constituted the study base. The heart and the segments of the coronary arteries were defined as separate organs at risk (OAR), and the mean and maximum radiation doses were calculated for each OAR.Results: In women with left-sided BC, irrespective of if regional lymph node RT was given or not, maximum dose in mid and distal left anterior descending artery (mdLAD) was approximately 50Gy in 6/7 patients, whereas women with right-sided BC mainly received low doses of radiation. In women with left-sided BC, 6/7 patients had substantially higher mean dose to the distal LAD than to the heart, ranging from 30 to 55Gy and 3 to13Gy, respectively.Conclusion: We found a pronounced difference of radiation dose distribution in the coronary arteries between women with left- and right-sided BC. Women with left-sided BC had almost full treatment dose in parts of mdLAD, regardless of if regional lymph node irradiation was given or not, while women with right-sided BC mainly received low doses to the coronary arteries.
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| 27. |
- Nilsson, Rune, et al.
(författare)
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Antigen-independent binding of rat immunoglobulins in a radioimmunoassay. Solutions to an unusual background problem
- 1984
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Ingår i: Journal of Immunological Methods. - : Elsevier BV. - 1872-7905 .- 0022-1759. ; 66:1, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- A high non-specific binding of immunoglobulins to plastic surfaces was noted with a number of rat sera, when tested in an indirect 125I-labeled protein-A assay for detection of cell-surface-bound rat immunoglobulins of various classes and IgG subclasses. This type of non-specific binding was found with all types of Ig. The degree of binding varied with the type of test plate used and fluctuated with time among sera drawn sequentially from the same donors. Coating test wells with fetal calf serum supplemented with BSA, gelatin or fibrinogen did not eliminate the reactions. The immunoglobulins bind directly to the polystyrene, and not to antigens present in fetal calf serum or autoantigens in rat serum. Two different approaches were used to eliminate the nonspecific reaction. When living cells were used as target antigens, exclusively cell-bound radioactivity was eluted with the non-ionic detergent Nonidet P40, which solubilizes the cell membrane without breaking the protein-A/rabbit IgG, rabbit IgG/rat Ig, or rat Ig/plastic interactions. When rat serum antibodies are tested on target antigens adsorbed on non-tissue culture grade plates, non-specific binding may be avoided by including 0.05% Tween 20 in the incubation mixture.
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| 28. |
- Nilsson, Rune, et al.
(författare)
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Fractionation of rat IgG subclasses and screening for IgG Fc-binding to bacteria
- 1982
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Ingår i: Molecular Immunology. - 1872-9142. ; 19:1, s. 119-126
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Tidskriftsartikel (refereegranskat)abstract
- The four IgG subclasses of the rat, IgGl, IgG2a, IgG2b and IgG2c, were purified from normal serum by a combination of protein A-affinity chromatography and DEAE-cellulose chromatography. Purified, radiolabelled preparations of IgG were tested for binding to Gram-positive bacteria representing five different Fc-receptor (FcR) types. Distinct rat subclass-specific Fc-binding was noted to bacterial species belonging to different Fc-receptor types. Staphylococcus aureus (FcR I) strains bind IgGl and IgG2c as shown by others. Group C and G Streptococci (FcR III) bind all four subclasses of rat IgG. Streptococcus zooepidemicus strains (FcR V) also bind all four subclases but only to a lower degree. Human group A Streptococci (FcR II) and bovine group G Streptococci (FcR IV) do not bind any of the rat IgG subclasses. Elution studies on two strains. Staphylococcus aureus, Cowan I, and human group G Streptococcus, G 148, showed that both thiocyanate and pH-elution might be useful for the fractionation of IgG subclasses bound to bacterial cells. The present work indicates the possible use of bacterial cells as solid-phase absorbents in immunological studies of rat IgG.
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| 29. |
- Nilsson, Rune, et al.
(författare)
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Quantitative analysis of rat Ig (sub) classes binding to cell surface antigens
- 1982
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Ingår i: Journal of Immunological Methods. - : Elsevier BV. - 1872-7905 .- 0022-1759. ; 55:2, s. 179-191
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Tidskriftsartikel (refereegranskat)abstract
- An indirect 125I-labeled protein A assay for detection of cell surface-bound rat immunoglobulins is presented. The assay is quantitative and rapid and detects as little as 1 ng of cell surface-bound Ig. It discriminates between antibodies belonging to different IgG subclasses, IgM and IgA. We describe the production and specificity control of the reagents used and show that the test can be used for quantitative analysis. A large number of sera from untreated rats are tested to evaluate the frequency of falsely positive responses and variation due to age, sex and strain of rat. With this test it is relatively easy to quantitate the binding of classes and subclasses of rat immunoglobulins in a small volume (6 μl) of untreated serum.
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| 30. |
- Nilsson, Rune, et al.
(författare)
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Toxicity-Reducing Potential of Extracorporeal Affinity Adsorption Treatment in Combination With the Auristatin-Conjugated Monoclonal Antibody BR96 in a Syngeneic Rat Tumor Model
- 2010
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 116:Suppl. 4, s. 1033-1042
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Antibody-drug conjugates, comprising monoclonal antibodies (MoAbs) that bind to tumor-associated antigens, display different toxicity profiles compared with radiolabeled MoAbs. Dose-limiting toxicities may include damage to the liver and myelotoxicity. The drug component is the antimitotic agent auristatin, which is 1001000 times more potent than doxorubicin. Consequently, auristatin antibody-drug conjugates require a high selectivity in tumor targeting to display pronounced activity at well-tolerated doses. We have evaluated the possibility of increasing the therapeutic index of BR96-auristatin by combining the administration of conjugates with subsequent extracorporeal affinity adsorption treatment. METHODS: Rats were injected with biotinylated, monomethyl auristatin F (MMAF)-conjugated monoclonal antibody BR96. The conjugate was then removed from the circulation by extracorporeal affinity adsorption treatment, 24 hours postinjection using an avidin affinity column. By analyzing blood parameters for 100 days, myelotoxicity, hepatotoxicity, and nephrotoxicity were assessed. Body weight, general status, and tumor size were also recorded. The toxicity-reducing effect of extracorporeal affinity adsorption treatment was evaluated. RESULTS: Extracorporeal affinity adsorption treatment removed 85%-90% of BR96-MMAF from the circulation. Early toxicity-related death was seen in nontumor-bearing animals that were given MMAF-conjugated BR96, in contrast to animals that were given a higher amount of BR96-MMAF with subsequent extracorporeal affinity adsorption treatment, in which all survived 100 days postinjection. Extracorporeal affinity adsorption treatment reduced the loss of body weight, myelotoxicity, and hepatotoxicity. CONCLUSIONS: Extracorporeal affinity adsorption treatment can be used to reduce the toxicity associated with administration of BR96-MMAF conjugates, making it possible to increase the amount of conjugates administered. The combined treatment will be further optimized in future studies. (C) 2010 American Cancer Society.
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| 31. |
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| 32. |
- Paulsson, Kajsa M, et al.
(författare)
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Association of tapasin and COPI provides a mechanism for the retrograde transport of major histocompatibility complex (MHC) class I molecules from the Golgi complex to the endoplasmic reticulum
- 2002
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 277:21, s. 18266-18271
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Tidskriftsartikel (refereegranskat)abstract
- Tapasin is a subunit of the transporter associated with antigen processing (TAP). It associates with the major histocompatibility complex (MHC) class I. We show that tapasin interacts with beta- and gamma-subunits of COPI coatomer. COPI retrieves membrane proteins from the Golgi network back to the endoplasmic reticulum (ER). The COPI subunit-associated tapasin also interacts with MHC class I molecules suggesting that tapasin acts as the cargo receptor for packing MHC class I molecules as cargo proteins into COPI-coated vesicles. In tapasin mutant cells, neither TAP nor MHC class I are detected in association with the COPI coatomer. Interestingly, tapasin-associated MHC class I molecules are antigenic peptide-receptive and detected in both the ER and the Golgi. Our data suggest that tapasin is required for the COPI vesicle-mediated retrograde transport of immature MHC class I molecules from the Golgi network to the ER.
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| 33. |
- 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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| 34. |
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| 35. |
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| 36. |
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| 37. |
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Sun, Yingyu, et al.
(författare)
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A glioma classification scheme based on coexpression modules of EGFR and PDGFRA
- 2014
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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. ; 111:9, s. 3538-3543
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EMlowPMlow gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EMlowPMlow gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EMlowPMlow gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtypespecific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.
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| 42. |
- Thorén, Sven A., et al.
(författare)
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A microcalorimetric vessel for monitoring cytotoxic reactions in the micro-submicrowatt region
- 1990
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Ingår i: Journal of Biochemical and Biophysical Methods. - 0165-022X. ; 20:3, s. 217-225
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Tidskriftsartikel (refereegranskat)abstract
- A microcalorimetric vessel for monitoring the initial phases of cytotoxic reactions in the micro-submicrowatt region has been designed and tested. The vessel is intended to be used witha multichannel microcalorimetric system from Thermometric, Järfälla, Sweden and can be built up stepwise in a modular way. The different functions of perfusion, stirring and addition of small amounts of soluble immune reactants can be used separately but also in combination. This is accomplished by the use of a vertical stirring mechanism and a reaction vessel of low volume, 200 μl. The simplcity of the vessel permits an identical vessel to be used on the reference side, handled in parallel with the measuring vessel. No gas phase is present.
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| 43. |
- Tranberg, Karl-Göran, et al.
(författare)
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Interstitial laser hyperthermia of a rat liver adenocarcinoma
- 2002
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Ingår i: Journal of X-Ray Science and Technology. - 0895-3996. ; 10:3-4, s. 177-185
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare interstitial laser thermotherapy with excision of a liver tumour. A dimethylhydrazine-induced adenocarcinoma was implanted into the left lateral lobe of the rat liver, and treatment was performed 8 days later. Rats were treated with resection of the tumour-bearing lobe or underwent interstitial laser thermotherapy, which was performed at a steady-state temperature of 46°C for 30 min, 3 mm from the tumour margin. The incidence and extent of intraperitoneal spread was smaller after laser thermotherapy than after resection, with no difference in local control. Using inoculation of tumour cell suspensions into the lateral and the median lobes of the liver simultaneously and treating the lateral lobe tumour only, we found that laser thermotherapy reduced take and growth of the untreated tumour in the median lobe indicating that laser thermotherapy may induce immunologic effects. It is concluded that interstitial laser thermotherapy reduces spread of liver tumour as compared to resection. It is suggested that this can be at least partly explained by a laser-induced immunologic effect.
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| 44. |
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| 45. |
- Wang, Zhongmin, et al.
(författare)
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Application of extracorporeal immunoadsorption to reduce circulating blood radioactivity after intraperitoneal administration of indium-111-HMFG1-biotin.
- 2002
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 94:4 Suppl, s. 1287-1292
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Extracorporeal immunoadsorption (ECAT) is a method of reducing activity in radiosensitive organs by removing excess monoclonal antibodies (MAbs) from the blood. Previously, the authors experimentally evaluated ECAT based on the avidin-biotin concept after intravenous administration of radioimmunoconjugates. The aim of the current study was to determine whether ECAT could be used to reduce activity after intraperitoneal (i.p.) administration of indium-111((111)In)-HMFG1-biotin in rats, and to compare the pharmacokinetics of (111)In-HMFG1 with or without attached biotin after i.p. injection. METHODS: HMFG1, a murine immunoglobulin G(1) MAb that recognizes an epitope on the polymorphic epithelial mucin (PEM) antigen, was labeled with (111)In and then biotinylated. ECAT was explored from unseparated blood using an avidin-agarose adsorption column. Thirty rats were used as controls and 13 underwent ECAT. The whole-body (WB), blood, and organ activity were monitored. RESULTS: The binding capacity of (111)In-HMFG1-biotin to avidin was high. Biotinylation did not enhance the excretion of HMFG1. When ECAT was employed, the WB and blood radioactivity were reduced by 35-40% (P < 0.05) and 75--86% (P < 0.01), respectively. After the completion of ECAT, the activity uptake in organs was significantly decreased. CONCLUSIONS: ECAT was successfully applied after i.p. injection of the (111)In-HMFG-biotin MAb to reduce the radioactivity in the WB, blood, and radiosensitive organs. Due to redistribution of the radiolabeled MAbs during and after the completion of ECAT, the adsorption may have been prolonged or repeated. Biotinylation did not significantly change the biodistribution of the (111)In-HMFG1 in rats after intraperitoneal injection.
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| 46. |
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| 47. |
- Wang, Zhongmin, et al.
(författare)
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Blood pharmacokinetics of various monoclonal antibodies labeled with a new trifunctional chelating reagent for simultaneous conjugation with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid and biotin before radiolabeling.
- 2005
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 11:19 Pt 2, s. 7171-7177
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Knowledge of the blood pharmacokinetics of monoclonal antibodies is crucial in deciding the optimal time for starting the administration of a "clearing agent"or using a "clearing device." The primary purpose was to investigate whether the pharmacokinetics of various antibodies labeled with the same chelator and In-111 differed significantly after i.v. injection in immunocompetent rats. A new trifunctional chelator called "1033" containing a biotin and a radiometal chelation moiety is introduced, making it possible to use only one conjugation procedure for the antibody. Experimental Design: Sixty-five non - tumor-bearing rats were included and divided into four groups (I-IV). The blood pharmacokinetics was investigated for rituximab, BR96, and trastuzumab labeled with 1033 and In-111 (I-III). The whole-body activity and activity uptake in muscle, liver, and kidney, which might explain differences in the early pharmacokinetics in blood, were also measured. hMN14 labeled with another chelator [1,4,7,10 -tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)], but with the same radionuclide ((111) In-biotin-DOTA-hMN14), was studied (IV).The blood pharmacokinetics from another 15 tumor-bearing rats was compared with those of non-tumor-bearing rats (III) by injection of In-111-1033-BR96. Results: No statistical difference was detected between the groups regarding the blood pharmacokinetics of rituximab, BR96, or trastuzumab. The pharmacokinetics and biodistribution of In-111-biotin-DOTA-hMN14 exhibited a clear difference compared with others. There were no significant differences in the blood pharmacokinetics of In-111-1033-BR96 between tumor-bearing rats and non-tumor-bearing rats. Conclusions: Different antibodies labeled with the trifunctional chelator 1033 and In-111 did not exhibit different blood pharmacokinetics, which means that the pharmacokinetics could be predicted irrespective of the IgG1 antibody chosen. A small tumor burden did not change the pharmacokinetics of the radioimmunoconjugates.
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| 48. |
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| 49. |
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