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- Kalhori, S, et al.
(author)
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A re-entrant cavity for microwave-enhanced chemistry
- 2003
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In: The Journal of microwave power and electromagnetic energy : a publication of the International Microwave Power Institute. - : Informa UK Limited. - 0832-7823. ; 38:2, s. 125-135
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Journal article (peer-reviewed)
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- Buentke, E, et al.
(author)
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Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells
- 2011
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In: Blood Cancer Journal. - : Macmillan Publishers Limited. - 2044-5385. ; 1:e31, s. 9-
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Journal article (peer-reviewed)abstract
- Malignant cells are known to have increased glucose uptake and accelerated glucose metabolism. Using liquid chromatography and mass spectrometry, we found that treatment of acute lymphoblastic leukemia (ALL) cells with the glucocorticoid (GC) dexamethasone (Dex) resulted in profound inhibition of glycolysis. We thus demonstrate that Dex reduced glucose consumption, glucose utilization and glucose uptake by leukemic cells. Furthermore, Dex treatment decreased the levels of the plasma membrane-associated glucose transporter GLUT1, thus revealing the mechanism for the inhibition of glucose uptake. Inhibition of glucose uptake correlated with induction of cell death in ALL cell lines and in leukemic blasts from ALL patients cultured ex vivo. Addition of di-methyl succinate could partially overcome cell death induced by Dex in RS4;11 cells, thereby further supporting the notion that inhibition of glycolysis contributes to the induction of apoptosis. Finally, Dex killed RS4;11 cells significantly more efficiently when cultured in lower glucose concentrations suggesting that modulation of glucose levels might influence the effectiveness of GC treatment in ALL. In summary, our data show that GC treatment blocks glucose uptake by leukemic cells leading to inhibition of glycolysis and that these effects play an important role in the induction of cell death by these drugs.
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- Elander, N, et al.
(author)
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Microwave-enhanced radiochemistry
- 2000
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In: CHEMICAL SOCIETY REVIEWS. - : Royal Society of Chemistry (RSC). - 0306-0012 .- 1460-4744. ; 29:4, s. 239-249
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Research review (other academic/artistic)
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- Lundberg, J., et al.
(author)
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Endovascular Method for Transplantation of Insulin-Producing Cells to the Pancreas Parenchyma in Swine
- 2014
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In: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 14:3, s. 694-700
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Journal article (peer-reviewed)abstract
- Insulin-producing cells are transplanted by portal vein injection as an alternative to pancreas transplantation in both clinical and preclinical trials. Two of the main limitations of portal vein transplantation are the prompt activation of the innate immunity and concomitant loss of islets and a small but significant risk of portal vein thrombosis. Furthermore, to mimic physiological release, the insulin-producing cells should instead be located in the pancreas. The trans-vessel wall approach is an endovascular method for penetrating the vessel wall from the inside. In essence, a working channel is established to the parenchyma of organs that are difficult to access by percutaneous technique. In this experiment, we accessed the extra-vascular pancreatic parenchyma in swine by microendovascular technique and injected methylene blue, contrast fluids and insulin-producing cells without acute adverse events. Further, we evaluated the procedure itself by a 1-year angiographical follow-up, without adverse events. This study shows that the novel approach utilizing endovascular minimal invasiveness coupled to accurate trans-vessel wall placement of an injection in the pancreatic parenchyma with insulin-producing cells is possible. In clinical practice, the potential benefits compared to portal vein cell transplantation should significantly improve endocrine function of the graft and potentially reduce adverse events. This study presents one-year follow-up safety data on the microendovascular trans-vessel wall technique and shows that the technique can be used to transplant insulin-producing cells to the swine pancreas parenchyma.
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- Stafford, William C., et al.
(author)
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Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy
- 2018
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In: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 10:428
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Journal article (peer-reviewed)abstract
- Cancer cells adapt to their inherently increased oxidative stress through activation of the glutathione (GSH) and thioredoxin (TXN) systems. Inhibition of both of these systems effectively kills cancer cells, but such broad inhibition of antioxidant activity also kills normal cells, which is highly unwanted in a clinical setting. We therefore evaluated targeting of the TXN pathway alone and, more specifically, selective inhibition of the cytosolic selenocysteine-containing enzyme TXN reductase 1 (TXNRD1). TXNRD1 inhibitors were discovered in a large screening effort and displayed increased specificity compared to pan-TXNRD inhibitors, such as auranofin, that also inhibit the mitochondrial enzyme TXNRD2 and additional targets. For our lead compounds, TXNRD1 inhibition correlated with cancer cell cytotoxicity, and inhibitor-triggered conversion of TXNRD1 from an antioxidant to a pro-oxidant enzyme correlated with corresponding increases in cellular production of H2O2. In mice, the most specific TXNRD1 inhibitor, here described as TXNRD1 inhibitor 1 (TRi-1), impaired growth and viability of human tumor xenografts and syngeneic mouse tumors while having little mitochondrial toxicity and being better tolerated than auranofin. These results display the therapeutic anticancer potential of irreversibly targeting cytosolic TXNRD1 using small molecules and present potent and selective TXNRD1 inhibitors. Given the pronounced up-regulation of TXNRD1 in several metastatic malignancies, it seems worthwhile to further explore the potential benefit of specific irreversible TXNRD1 inhibitors for anticancer therapy.
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- Cheng, Qing, et al.
(author)
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Preclinical PET imaging of EGFR levels : pairing a targeting with a non-targeting Sel-tagged Affibody-based tracer to estimate the specific uptake
- 2016
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In: EJNMMI Research. - : Springer. - 2191-219X. ; 6
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Journal article (peer-reviewed)abstract
- Background: Though overexpression of epidermal growth factor receptor (EGFR) in several forms of cancer is considered to be an important prognostic biomarker related to poor prognosis, clear correlations between biomarker assays and patient management have been difficult to establish. Here, we utilize a targeting directly followed by a non-targeting tracer-based positron emission tomography (PET) method to examine some of the aspects of determining specific EGFR binding in tumors. Methods: The EGFR-binding Affibody molecule Z(EGFR:2377) and its size-matched non-binding control Z(Taq:3638) were recombinantly fused with a C-terminal selenocysteine-containing Sel-tag (Z(EGFR:2377)-ST and Z(Taq:3638)-ST). The proteins were site-specifically labeled with DyLight488 for flow cytometry and ex vivo tissue analyses or with C-11 for in vivo PET studies. Kinetic scans with the C-11-labeled proteins were performed in healthy mice and in mice bearing xenografts from human FaDu (squamous cell carcinoma) and A431 (epidermoid carcinoma) cell lines. Changes in tracer uptake in A431 xenografts over time were also monitored, followed by ex vivo proximity ligation assays (PLA) of EGFR expressions. Results: Flow cytometry and ex vivo tissue analyses confirmed EGFR targeting by ZE(GFR:2377)-ST-DyLight488. [Methyl-C-11]-labeled Z(EGFR:2377)-ST-CH3 and Z(Taq:3638)-ST-CH3 showed similar distributions in vivo, except for notably higher concentrations of the former in particularly the liver and the blood. [Methyl-C-11]-Z(EGFR:2377)-ST-CH3 successfully visualized FaDu and A431 xenografts with moderate and high EGFR expression levels, respectively. However, in FaDu tumors, the non-specific uptake was large and sometimes equally large, illustrating the importance of proper controls. In the A431 group observed longitudinally, non-specific uptake remained at same level over the observation period. Specific uptake increased with tumor size, but changes varied widely over time in individual tumors. Total (membranous and cytoplasmic) EGFR in excised sections increased with tumor growth. There was no positive correlation between total EGFR and specific tracer uptake, which, since Z(EGFR:2377) binds extracellularly and is slowly internalized, indicates a discordance between available membranous and total EGFR expression levels. Conclusions: Same-day in vivo dual tracer imaging enabled by the Sel-tag technology and C-11-labeling provides a method to non-invasively monitor membrane-localized EGFR as well as factors affecting non-specific uptake of the PET ligand.
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| 32. |
- Fredriksson, A., et al.
(author)
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Labeling of human C-peptide by conjugation with N-succinimidyl-4- F-18 fluorobenzoate
- 2001
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In: Journal of labelled compounds & radiopharmaceuticals. - : Wiley. - 0362-4803 .- 1099-1344. ; 44:7, s. 509-519
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Journal article (peer-reviewed)abstract
- We have labeled proinsulin connecting peptide (C-peptide) with fluorine-18 (t(1/2) = 109.7min) in order to perform in vivo biodistribution and pharmacokinetic studies with position emission tomography (PET). This study reports the optimization of the conjugation labeling in the N-terminal with N-succinimidyl-4-[F-18]fluorobenzoate ([F-18]SFB). In preparative runs N-4-[F-18]fluorobenzoyl-C-peptide ([F-18]FB-C-peptide) was produced in 8-12% decay-corrected yields, counted from resolubilized [F-18]F-, in less than 5h. The specific radioactivity of [F-18]FB-C-peptide, determined using ELISA for one of the preparations, was around 70 GBq/mu mol at end of synthesis.
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