| 1. |
- Borges, João Batista, et al.
(författare)
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Early inflammation mainly affects normally and poorly aerated lung in experimental ventilator-induced lung injury
- 2014
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Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 42:4, s. e279-e287
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The common denominator in most forms of ventilator-induced lung injury is an intense inflammatory response mediated by neutrophils. PET with [F]fluoro-2-deoxy-D-glucose can be used to image cellular metabolism, which, during lung inflammatory processes, mainly reflects neutrophil activity, allowing the study of regional lung inflammation in vivo. The aim of this study was to assess the location and magnitude of lung inflammation using PET imaging of [F]fluoro-2-deoxy-D-glucose in a porcine experimental model of early acute respiratory distress syndrome.DESIGN: Prospective laboratory investigation.SETTING: A university animal research laboratory.SUBJECTS: Seven piglets submitted to experimental ventilator-induced lung injury and five healthy controls.INTERVENTIONS: Lung injury was induced by lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. All animals were subsequently studied with dynamic PET imaging of [F]fluoro-2-deoxy-D-glucose. CT scans were acquired at end expiration and end inspiration.MEASUREMENTS AND MAIN RESULTS: [F]fluoro-2-deoxy-D-glucose uptake rate was computed for the whole lung, four isogravitational regions, and regions grouping voxels with similar density. Global and intermediate gravitational zones [F]fluoro-2-deoxy-D-glucose uptakes were higher in ventilator-induced lung injury piglets compared with controls animals. Uptake of normally and poorly aerated regions was also higher in ventilator-induced lung injury piglets compared with control piglets, whereas regions suffering tidal recruitment or tidal hyperinflation had [F]fluoro-2-deoxy-D-glucose uptakes similar to controls.CONCLUSIONS: The present findings suggest that normally and poorly aerated regions-corresponding to intermediate gravitational zones-are the primary targets of the inflammatory process accompanying early experimental ventilator-induced lung injury. This may be attributed to the small volume of the aerated lung, which receives most of ventilation.
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| 2. |
- Borges, João Batista, et al.
(författare)
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Ventilation Distribution Studies Comparing Technegas and "Gallgas" Using (GaCl3)-Ga-68 as the Label
- 2011
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:2, s. 206-209
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Tidskriftsartikel (refereegranskat)abstract
- Ventilation distribution can be assessed by SPECT with Technegas. This study was undertaken in piglets with different degrees of ventilation inhomogeneity to compare PET using Ga-68-labeled pseudogas or "Gallgas" with Technegas. Methods: Twelve piglets were studied in 3 groups: control, lobar obstruction, and diffuse airway obstruction. Two more piglets were assessed for lung volume (functional residual capacity). Results: In controls, SPECT and PET images showed an even distribution of radioactivity. With lobar obstruction, the absence of ventilation of the obstructed lobe was visible with both techniques. In diffuse airway obstruction, SPECT images showed an even distribution of radioactivity, and PET images showed more varied radioactivity over the lung. Conclusion: PET provides detailed ventilation distribution images and a better appreciation of ventilation heterogeneity. Gallgas with PET is a promising new diagnostic tool for the assessment of ventilation distribution.
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| 3. |
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| 4. |
- Sandström, Mattias, et al.
(författare)
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Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment
- 2013
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 54:1, s. 33-41
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Tidskriftsartikel (refereegranskat)abstract
- The organs at risk in radionuclide therapy with 177Lu-octreotate are the bone marrow and the kidneys. The primary aim of this study was to develop an individualized dosimetry protocol for the bone marrow. The secondary aim was to identify those patients, undergoing fractionated therapy with 7.4 GBq/cycle, who first reached an accumulated dose of either 2 Gy to the bone marrow or 23 Gy to the kidneys. Methods: Two hundred patients with metastatic neuroendocrine tumors with high somatostatin receptor expression were included. After the administration of 7.4 GBq of 177Lu-octreotate, blood samples were drawn 6 times within the first 24 h. In 50 patients, additional blood samples were obtained at 96 and 168 h. Moreover, urine was collected from 30 patients during the first 24 h. Planar whole-body and SPECT/CT images over the abdomen were acquired at 24, 96, and 168 h after the infusion. Calculation of the absorbed radiation dose to the bone marrow was based on blood and urinary activity curves combined with organ-based analysis of the whole-body images. The absorbed dose to the kidney was calculated from the pharmacokinetic data obtained from SPECT/CT. Results: For a single cycle of 7.4 GBq, the absorbed dose to the bone marrow and the kidney ranged from 0.05 to 0.4 Gy and from 2 to 10 Gy, respectively. In 197 of 200 patients, the kidneys accumulated an absorbed dose of 23 Gy before the bone marrow reached 2 Gy. Between 2 and 10 cycles of 177Lu-octreotate could be administered before the upper dose limit for the individual patient was reached. Conclusion: A method based on repeated whole-body imaging in combination with blood and urinary activity data over time was developed to determine the absorbed dose to the bone marrow. The dose-limiting organ was the kidney in 197 of 200 patients. In 50% of the patients, more than 4 cycles of 7.4 GBq of 177Lu-octreotate could be administered, whereas 20% of the subjects were treated with fewer than 4 cycles. Individualized absorbed dose calculation is essential to optimize the therapy.
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| 5. |
- Wållberg, H, et al.
(författare)
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Engineering of C-terminal cysteine-containing peptide-based chelators improves biodistribution of HER2-targeting 99mTc-labeled Affibody molecules
- 2011
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:3, s. 461-469
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules are a recently developed class of targeting proteins based on a nonimmunoglobulin scaffold. The small size (7 kDa) and subnanomolar affinity of Affibody molecules enables high-contrast imaging of tumor-associated molecular targets, particularly human epidermal growth factor receptor type 2 (HER2). 99mTc as a label offers advantages in clinical practice, and earlier studies demonstrated that 99mTc-labeled recombinant Affibody molecules with a C-terminal cysteine could be used for HER2 imaging. However, the renal retention of radioactivity exceeded tumor uptake, which might complicate imaging of metastases in the lumbar region. The aim of this study was to develop an agent with low renal uptake and preserved tumor targeting. Methods: A series of recombinant derivatives of the HER2-binding ZHER2:342 Affibody molecule with a C-terminal chelating sequence, –GXXC (X denoting glycine, serine, lysine, or glutamate), was designed. The constructs were labeled with 99mTc and evaluated in vitro and in vivo. Results: All variants were stably labeled with 99mTc, with preserved capacity to bind specifically to HER2-expressing cells in vitro and in vivo. The composition of the chelating sequence had a clear influence on the cellular processing and biodistribution properties of the Affibody molecules. The best variant, 99mTc-ZHER2:V2, with the C-terminal chelating sequence –GGGC, provided the lowest radioactivity retention in all normal organs and tissues including the kidneys. 99mTc-ZHER2:V2 displayed high uptake of radioactivity in HER2-expressing xenografts, 22.6 ± 4.0 and 7.7 ± 1.5 percentage injected activity per gram of tissue at 4 h after injection in SKOV-3 (high HER2 expression) and DU-145 (low HER2 expression) tumors, respectively. In both models, the tumor uptake exceeded the renal uptake. Conclusion: These results demonstrate that the biodistribution properties of recombinant 99mTc-labeled Affibody molecules can be optimized by modification of the C-terminal cysteine-containing chelating sequence. 99mTc-ZHER2:V2 is a promising candidate for further development as a diagnostic radiopharmaceutical for imaging of HER2-expressing tumors. These results may be useful for the development of imaging agents based on other Affibody molecules and, hopefully, other scaffolds.
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| 6. |
- Wållberg, Helena, et al.
(författare)
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Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
- 2010
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Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 12:1, s. 54-62
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Imaging using positron emission tomography (PET) in the field of nuclear medicine is becoming increasingly important. The aim of this study was to develop a method for labeling of affibody molecules with radiocobalt for PET applications. PROCEDURES: The human epidermal growth factor receptors type 2 (HER2) binding affibody molecule DOTA-Z(2395)-C was radiolabeled with (57)Co (used as a surrogate of (55)Co). The binding specificity and cellular processing of the labeled compound was studied in vitro followed by in vivo characterization in normal and tumor-bearing mice. Furthermore, a comparative biodistribution study was performed with a (111)In-labeled counterpart. RESULTS: DOTA-Z(2395)-C was successfully labeled with radiocobalt with nearly quantitative yield. The compound displayed good retention on cells over time and high tumor accumulation of radioactivity in animal studies. Imaging studies showed clear visualization of HER2-positive tumors. Furthermore, the radiocobalt label provided better tumor-to-organ ratios than (111)In. CONCLUSIONS: Radiocobalt is a promising label for affibody molecules for future PET applications.
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| 7. |
- Wållberg, Helena, et al.
(författare)
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Molecular Design and Optimization of Tc-99m-Labeled Recombinant Affibody Molecules Improves Their Biodistribution and Imaging Properties
- 2011
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:3, s. 461-469
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules are a recently developed class of targeting proteins based on a nonimmunoglobulin scaffold. The small size (7 kDa) and subnanomolar affinity of Affibody molecules enables high-contrast imaging of tumor-associated molecular targets, particularly human epidermal growth factor receptor type 2 (HER2). Tc-99m as a label offers advantages in clinical practice, and earlier studies demonstrated that Tc-99m-labeled recombinant Affibody molecules with a C-terminal cysteine could be used for HER2 imaging. However, the renal retention of radioactivity exceeded tumor uptake, which might complicate imaging of metastases in the lumbar region. The aim of this study was to develop an agent with low renal uptake and preserved tumor targeting. Methods: A series of recombinant derivatives of the HER2-binding Z(HER2:342) Affibody molecule with a C-terminal chelating sequence, -GXXC (X denoting glycine, serine, lysine, or glutamate), was designed. The constructs were labeled with Tc-99m and evaluated in vitro and in vivo. Results: All variants were stably labeled with Tc-99m, with preserved capacity to bind specifically to HER2-expressing cells in vitro and in vivo. The composition of the chelating sequence had a clear influence on the cellular processing and biodistribution properties of the Affibody molecules. The best variant, Tc-99m-Z(HER2:V2), with the C-terminal chelating sequence -GGGC, provided the lowest radioactivity retention in all normal organs and tissues including the kidneys. Tc-99m-Z(HER2:V2) displayed high uptake of radioactivity in HER2-expressing xenografts, 22.6 +/- 4.0 and 7.7 +/- 1.5 percentage injected activity per gram of tissue at 4 h after injection in SKOV-3 (high HER2 expression) and DU-145 (low HER2 expression) tumors, respectively. In both models, the tumor uptake exceeded the renal uptake. Conclusion: These results demonstrate that the biodistribution properties of recombinant Tc-99m-labeled Affibody molecules can be optimized by modification of the C-terminal cysteine-containing chelating sequence. Tc-99m-Z(HER2:V2) is a promising candidate for further development as a diagnostic radiopharmaceutical for imaging of HER2-expressing tumors. These results may be useful for the development of imaging agents based on other Affibody molecules and, hopefully, other scaffolds.
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