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- El Fakiri, Mohamed, et al.
(författare)
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Development and Preclinical Evaluation of [211At]PSAt-3-Ga: An Inhibitor for Targeted a-Therapy of Prostate Cancer
- 2024
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Ingår i: JOURNAL OF NUCLEAR MEDICINE. - 0161-5505 .- 1535-5667. ; 65:4, s. 593-599
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Tidskriftsartikel (refereegranskat)abstract
- The application of prostate -specific membrane antigen (PSMA)- targeted a -therapy is a promising alternative to b 2 -particle-based treatments. 211 At is among the potential a -emitters that are favorable for this concept. Herein, 211 At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. Methods: To identify a 211 At-labeled lead, a surrogate strategy was applied. Because astatine does not exist as a stable nuclide, it is commonly replaced with iodine to mimic the pharmacokinetic behavior of the corresponding 211 At-labeled compounds. To facilitate the process of structural design, iodine -based candidates were radiolabeled with the PET radionuclide 68 Ga to study their preliminary in vitro and in vivo properties before the desired 211 At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be 211 At-labeled and tested in biodistribution studies. Results: All 68 Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified [ 68 Ga]PSGa- 3 as the lead compound. Subsequently, [ 211 At]PSAt- 3 -Ga was synthesized in a radiochemical yield of 35% and showed tumor uptake of 19 +/- 8 percentage injected dose per gram of tissue (%ID/g) at 1 h after injection and 7.6 +/- 2.9 %ID/g after 24 h. Uptake in off -target tissues such as the thyroid (2.0 +/- 1.1 %ID/g), spleen (3.0 +/- 0.6 %ID/g), or stomach (2.0 +/- 0.4 %ID/g) was low, indicating low in vivo deastatination of [ 211 At]PSAt- 3 -Ga. Conclusion: The reported findings support the use of iodine -based and 68 Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm [ 211 At]PSAt- 3 as a promising radiopharmaceutical for targeted a -therapy.
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- D’Agrella-Filho, Manoel S., et al.
(författare)
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A new 1.42 GA paleomagnetic pole from the Amazonian craton : implications for the Columbia supercontinent configuration
- 2011
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Ingår i: Proceedings of Second Biennial Meeting of Latinmag.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Paleomagnetic studies carried out on the 1.42 Ga Indiavaí mafic intrusive rocks, that crop out in the SW Mato Grosso State provides a great opportunity to test the proposed paleogeographic models for Columbia. Paleomagnetic AF and thermal treatment revealed south/southwest magnetic directions with downward inclinations for sixteen analyzed sites. These directions are probably carried by SD/PSD magnetite with high coercivities and high unblocking temperatures as indicated by additional magnetic tests, including thermomagnetic curves, hysteresis loops and the IRM acquisition curves. A different magnetization obtained for host mafic rocks from the basement ca. 10 km NW away from the Indiavaí intrusive, further attests to the primary origin of the characteristic magnetic component. A mean site direction was calculated at Dm=209.8°, Im=50.7° (α95=8.0°, K=22.1), which yielded a paleomagnetic pole located at 249.7°E, -57.0°N (A95=8.6°). Comparison of this pole with other paleomagnetic poles of similar age from Baltica and Laurentia provides evidence for a link of north-northeastern Amazonian craton, southwestern Baltica and Laurentia, as previously suggested from the similar Mesoproterozoic geological evolution of their margins.
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- Heinzel, Andreas, et al.
(författare)
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Validation of Plasma Biomarker Candidates for the Prediction of eGFR Decline in Patients With Type 2 Diabetes
- 2018
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 41:9, s. 1947-1954
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Tidskriftsartikel (refereegranskat)abstract
- RESEARCH DESIGN AND METHODS: We studied participants in PROVALID (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers), a prospective multinational cohort study of patients with type 2 diabetes and a follow-up of more than 24 months (n = 2,560; baseline median eGFR, 84 mL/min/1.73 m2; urine albumin-to-creatinine ratio, 8.1 mg/g). The 17 biomarkers were measured at baseline in 481 samples using Luminex and ELISA. The prediction of eGFR decline was evaluated by linear mixed modeling.RESULTS: In univariable analyses, 9 of the 17 markers showed significant differences in median concentration between stable and fast-progressing patients. A linear mixed model for eGFR obtained by variable selection exhibited an adjusted R2 of 62%. A panel of 12 biomarkers was selected by the procedure and accounted for 34% of the total explained variability, of which 32% was due to 5 markers. The individual contribution of each biomarker to the prediction of eGFR decline on top of clinical predictors was generally low. When included into the model, baseline eGFR exhibited the largest explained variability of eGFR decline (R2 of 79%), and the contribution of each biomarker dropped below 1%.CONCLUSIONS: In this longitudinal study of patients with type 2 diabetes and maintained eGFR at baseline, 12 of the 17 candidate biomarkers were associated with eGFR decline, but their predictive power was low.OBJECTIVE: The decline of estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes is variable, and early interventions would likely be cost-effective. We elucidated the contribution of 17 plasma biomarkers to the prediction of eGFR loss on top of clinical risk factors.
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- Kammer, Michael, et al.
(författare)
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Integrative analysis of prognostic biomarkers derived from multiomics panels helps discrimination of chronic kidney disease trajectories in people with type 2 diabetes
- 2019
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 96:6, s. 1381-1388
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Tidskriftsartikel (refereegranskat)abstract
- Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73 m2, urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor.
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- Martin, S, et al.
(författare)
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Pre-validation of a reporter gene assay for oxidative stress for the rapid screening of nanobiomaterials
- 2022
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Ingår i: Frontiers in toxicology. - : Frontiers Media SA. - 2673-3080. ; 4, s. 974429-
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Tidskriftsartikel (refereegranskat)abstract
- Engineered nanomaterials have been found to induce oxidative stress. Cellular oxidative stress, in turn, can result in the induction of antioxidant and detoxification enzymes which are controlled by the nuclear erythroid 2-related factor 2 (NRF2) transcription factor. Here, we present the results of a pre-validation study which was conducted within the frame of BIORIMA (“biomaterial risk management”) an EU-funded research and innovation project. For this we used an NRF2 specific chemically activated luciferase expression reporter gene assay derived from the human U2OS osteosarcoma cell line to screen for the induction of the NRF2 mediated gene expression following exposure to biomedically relevant nanobiomaterials. Specifically, we investigated Fe3O4-PEG-PLGA nanomaterials while Ag and TiO2 “benchmark” nanomaterials from the Joint Research Center were used as reference materials. The viability of the cells was determined by using the Alamar blue assay. We performed an interlaboratory study involving seven different laboratories to assess the applicability of the NRF2 reporter gene assay for the screening of nanobiomaterials. The latter work was preceded by online tutorials to ensure that the procedures were harmonized across the different participating laboratories. Fe3O4-PEG-PLGA nanomaterials were found to induce very limited NRF2 mediated gene expression, whereas exposure to Ag nanomaterials induced NRF2 mediated gene expression. TiO2 nanomaterials did not induce NRF2 mediated gene expression. The variability in the results obtained by the participating laboratories was small with mean intra-laboratory standard deviation of 0.16 and mean inter laboratory standard deviation of 0.28 across all NRF2 reporter gene assay results. We conclude that the NRF2 reporter gene assay is a suitable assay for the screening of nanobiomaterial-induced oxidative stress responses.
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