| 1. |
- Altai, Mohamed, et al.
(author)
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188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors : preclinical assessment
- 2014
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In: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:11, s. 8-1842
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Journal article (peer-reviewed)abstract
- UNLABELLED: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors.METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.RESULTS: Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.CONCLUSION: (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.
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| 2. |
- Kristiansson, Amanda, et al.
(author)
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177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging
- 2021
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In: Biomolecules. - : MDPI AG. - 2218-273X. ; 11:2
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Journal article (peer-reviewed)abstract
- Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α1-microglobulin (A1M) together with 177-Lutetium (177Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [177Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3-4 days and 3-4 weeks after injections). In a parallel set of experiments, mice were given [177Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [177Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [99mTc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [177Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [99mTc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [177Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.
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| 3. |
- Alattar, Abdul Ghani, et al.
(author)
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Recombinant alpha(1)-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a Lu-177-DOTATATE Mouse Radiation Model
- 2023
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In: Biomolecules. - 2218-273X. ; 13:6
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Journal article (peer-reviewed)abstract
- Lu-177-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although Lu-177-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. alpha (1)-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M's renal protective effect in a mouse Lu-177-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-Lu-177-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with Lu-177-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with Lu-177-DOTATATE.
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| 4. |
- Altai, Mohamed, et al.
(author)
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Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with (188)Re.
- 2014
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 87, s. 519-28
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Journal article (peer-reviewed)abstract
- Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of (188)Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all (188)Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The (188)Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of (188)Re-ZHER2:V2 (3.1 ± 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental (188)Re-ZHER2:2395 (172 ± 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of (188)Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.
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| 5. |
- Altai, Mohamed, et al.
(author)
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Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re
- 2013
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 40:Suppl. 2, s. S219-S220
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Journal article (other academic/artistic)abstract
- Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1±0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172±32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.
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| 6. |
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| 7. |
- Brodd, Katarina Strand, et al.
(author)
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Development of Smooth Pursuit Eye Movements in very preterm born infants : 3. Association to perinatal risk factors
- 2012
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In: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 101:2, s. 164-171
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Journal article (peer-reviewed)abstract
- Aim: To investigate the association between perinatal risk factors and neonatal complications and early oculo-motor development in very preterm infants. Methods: Perinatal risk factors were identified, and the potential association with early oculo-motor development was evaluated by measuring smooth pursuit eye movements (SP) at 2 and 4 months' corrected age (CA) in a population of very preterm infants born in Uppsala County 2004-2007 (n = 113). Results: Among the 15 tested factors, eight showed significant association in univariate analysis with lower levels of SP at 4 months' CA, namely administration of prenatal corticosteroids, gestational age, birthweight, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, intraventricular haemorrhage >grade 2, and persistent ductus arteriosus. At 2 months' CA, only retinopathy of prematurity >stage 2 was associated with lower levels of SP. When all factors significant in the univariate tests were included in multiple regressions aimed to assess each factor's independent relation to SP, periventricular leukomalacia was the only significant independent factor. When adding 2-5 of the significant factors using multiple regression analysis, the levels of SP became lower. Conclusion: Perinatal risk factors were associated with lower levels of SP. This could be interpreted as delayed or disturbed development of normal oculomotor ability.
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| 8. |
- Brodd, Katarina Strand, et al.
(author)
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Development of smooth pursuit eye movements in very preterm infants : 1. General aspects
- 2011
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In: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 100:7, s. 983-991
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Journal article (peer-reviewed)abstract
- Aim: To investigate early oculo-motor development in a population-based cohort of very preterm infants.Methods: Early oculo-motor development was prospectively studied by measuring smooth pursuit eye movements at 2 and 4 months corrected age in a population of very preterm infants born in Uppsala County 2004–2007. Eighty-one preterm infants were studied, and 32 healthy term infants constituted the control group.Results: The study group consisted of infants with a mean gestational age of28 + 5 weeks. At 2 and 4 months corrected age, infants born very preterm showed lower gain (p < 0.001) and proportion of smooth pursuit eyemovements (p < 0.001) compared to the control group. The boys showed higher gain of smooth pursuit eye movements at both 2 and 4 months corrected age, compared to girls.Conclusions: Oculo-motor development measured by smooth pursuit eye movements is delayed in very preterm infants at 2 and 4 months corrected age. This might be a risk factor or early indicator of later perceptual and behavioural impairment.
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| 9. |
- de Morais Lima, Priscila, et al.
(author)
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Farmers’ perceptions on organic fertilisers towards circularity–a case study in Sweden
- 2024
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In: Acta Agriculturae Scandinavica - Section B. - : Taylor and Francis Ltd.. - 0906-4710 .- 1651-1913. ; 74:1
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Journal article (peer-reviewed)abstract
- Adequate treatment of organic manures and digestates from livestock production should reduce environmental impacts and provide well-defined and attractive biofertlisers for a crop production market, which can promote the closure of the nutrient cycle in agriculture. In this sense, a survey was conducted during the autumn of 2021 to investigate Swedish farmers’ perspectives on organic fertilisers use. The survey consisted of an online questionnaire, which was distributed broadly in the social media, homepages, different types of networks and at course events in order to reach all types of farms. There were 22 questions focused on current use, reasons for current use and preferences for future use. The analysis of the 99 fully responded surveys, demonstrated that 43% of the respondents think that they will increase their use of organic fertilisers in the coming 5–10 years and 60% think that they will use manure digestate in different forms (both solid and liquid fractions). Soil improvement was the main reason to use organic fertilisers, but there were also preferences for organic fertilisers with fast release of nutrients. The risk of soil compaction was the main reason not to use organic fertilisers and based on the responses, pellets and granulates seem to be more interesting than liquids and solids in general. Animal manures dominate the current use of organic fertilisers in Sweden however, other types of organic waste such as digestate and digestate derived fertilisers seems appealing to Swedish farmers. In conclusion, from this survey with 62% of the respondees in crop production, we found several indications of that there is a potential for increased use of organic fertilisers in Sweden on farms with limited use today. We found an openness, a broad interest and a demand for different types of products of different forms and origin. Since this demand in the end will almost always depend on the price of products in relation to the price of mineral fertilisers, which are fluctuating, we see the need of policy incentives in order to stimulate initiatives for the development towards increased circularity of nutrients.
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| 10. |
- Gee, Kira, et al.
(author)
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BONUS BALTSPACE Deliverable 3.3: Addressing MSP integration challenges: The role of tools and approaches. Geesthacht.
- 2018
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Reports (other academic/artistic)abstract
- This report discusses seven different tools and approaches to address important integration challenges in marine and coastal spatial planning and management, namely in relation to sectors and policies, boundaries, stakeholders and different types of knowledge. BONUS BALTSPACE (2015-2018) was conceived against the background of the EU MSP Directive and the need for Member States to produce marine spatial plans by 2021. MSP is an integrative concept that requires integration of sectors and stakeholders, of different types of knowledge, as well as integration across administrative borders. BALTSPACE was the first transnational, interdisciplinary MSP research project in the BSR to focus on four key integration challenges in MSP, namely policy and sector integration, multi-level and transboundary integration, stakeholder integration and knowledge integration. Work Package 3 was tasked with developing and assessing practitioner-oriented approaches and tools for MSP to help deal with the integration challenges identified (www.baltspace.eu). The capacity of seven problem- and process-specific techniques and approaches (subsequently termed tools) was assessed in different case study settings: •Bowtie •Culturally Significant Areas •Governance Baselines •Integrated Indicator System for monitoring the spatial, economic and environmental effects of MSP solutions •Marxan •Open Standards for the Practice of Conservation •Spatial Economic Benefit Analysis (SEBA) Each tool was applied once in a particular country context in a format determined by the tool user. Some applications were desktop exercises, others were more participative, although most had some form of verification by stakeholders. Tool selection reflected both the variety of available methods and the diverse range of tasks in MSP, leading to the inclusion of product- and process-oriented tools, descriptive and analytical tools, as well as data and forecasting tools. One of the tools (SEBA) was specifically developed for MSP as part of BALTSPACE. An overview of academic literature revealed that “tools” in MSP are mostly understood as technical instruments that provide decision support. To a large part, the tools described in the literature rely on scientific data and information, in line with a view of MSP as an evidence-based exercise requiring data collection and analysis as a basis for planning. There is little mention of the role of process in MSP and the learning that might result from tool-supported processes. Also, most assessments do not focus on the indirect or ‘soft’ impacts of tool use, which are often related to the persons or groups engaging with the tool – and which could have positive integration effects by and for themselves. Examples of such impacts include greater mutual understanding or an improved sense of trust, both of which could arise from improved stakeholder and knowledge integration facilitated by a tool. Integration effects may therefore manifest themselves when the tool is being used - e.g. to generate a particular output such as a map – or when the results are being fed back into the MSP process. After a short overview of the purpose of each tool and where it fits in the MSP cycle, an analytical template is set out. This breaks down the four integration challenges into a series of sub-challenges, so as to enable a comparative evaluation of the seven tools against the same set of challenges. It also sets out some more general contributions the tools could make with respect to MSP, such as contributing to the efficiency of the MSP process or to improved decision-making. The assessment is based on the retrospective evaluation of the BALTSPACE researchers and largely descriptive, focusing also on the direct outputs and indirect outcomes of tool use. Throughout, the assessment focuses on the capacity of each tool, taking account of the fact that tool use is context-dependent and that a range of external factors comes into play when it comes to the actual integration results. The assessment shows that the integration challenges most readily addressed are stakeholder and knowledge integration. Conversely, policy integration is difficult to achieve as a direct result, although some tools are well suited to analysing the existing policy landscape and potential integration gaps. Multi-level (transboundary) integration depends on the scale of tool use and is potentially achievable as all tools can be up-scaled if necessary. Some tools are also well-placed to contribute to land-sea integration. An important difference is noted between the inherent capacity of the tools and their application. Some tools are better at certain tasks than others but ultimately, it is the application that is make or break. For example, some tools (such as OS or CSA) are specifically designed to support stakeholder and knowledge integration, in the sense that they would not deliver a result without them. Other tools that are less specifically designed for this purpose can also contribute to stakeholder integration, but this then happens as a result of how the tool is applied – in this case in a participative setting. To some degree, the capacity to facilitate stakeholder and knowledge integration depends on whether a tool is process- or product-oriented or analytical or experimental. Generally, process-oriented tools, especially complex ones such as OS require active stakeholder involvement and input, but there are also product-oriented tools (such as CSA or SEBA) that rely on the integration of various stakeholders and their knowledge. Analytical tools such as Bowtie or Governance Baselines could in theory be conducted as mere desktop exercises, which would restrict their impact on knowledge integration; if applied as participatory tools they would also make an indirect contribution to stakeholder integration. The mere fact that a tool requires stakeholder involvement does not automatically lead to integration benefits, although involvement is certainly a prerequisite. Especially with respect to process-oriented tools, much depends on the skill of the tool user and the quality of the application process, including for example facilitation skills, timing and resources, also on the part of the participating stakeholders. Much also depends on the quality of the (surrounding) MSP process and whether this is capable of absorbing the benefits that may be generated from tool use. The seven tools are unable to contribute to increasing national/transnational policy coherence and resolving institutional compatibilities, and less well placed to help evaluate the consequences of planned action. Only the most comprehensive process-oriented tool (OS) is able to create a forum for deliberation. A key aspect for applying the seven BALTSPACE tools in practice is to know the precise challenge to be addressed, the capacity of the tool (its potential outcomes) including any soft benefits to be achieved, and the capacity of those using the tool (time, timing, resources). It is also important to consider which role the tool is expected to play in the MSP process: Will it be used as a free-standing, independent entity and process, feeding results into the MSP process? Will it be used as a trigger of the MSP process and “way in” or door-opener, for example to motivate stakeholders? Or is the tool to be intimately linked to the entire MSP process, effectively running large parts of it? Insights and practical tips for using the tools are provided in a separate Tools Handbook which is available for download on the BALTSPACE website (www.baltspace.eu). The website also contains short video tutorials on selected tools, as well as a briefing note and short summary of the opportunities and challenges in using tools to support integration in MSP.
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