| 1. |
- Abouzayed, Ayman, et al.
(författare)
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The GRPR Antagonist [Tc-99m]Tc-maSSS-PEG(2)-RM26 towards Phase I Clinical Trial : Kit Preparation, Characterization and Toxicity
- 2023
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Ingår i: Diagnostics. - : MDPI AG. - 2075-4418. ; 13:9, s. 1611-
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Tidskriftsartikel (refereegranskat)abstract
- Gastrin-releasing peptide receptors (GRPRs) are overexpressed in the majority of primary prostate tumors and in prostatic lymph node and bone metastases. Several GRPR antagonists were developed for SPECT and PET imaging of prostate cancer. We previously reported a preclinical evaluation of the GRPR antagonist [Tc-99m]Tc-maSSS-PEG2-RM26 (based on [D-Phe(6), Sta(13), Leu(14)-NH2]BBN(6-14)) which bound to GRPR with high affinity and had a favorable biodistribution profile in tumor-bearing animal models. In this study, we aimed to prepare and test kits for prospective use in an early-phase clinical study. The kits were prepared to allow for a one-pot single-step radiolabeling with technetium-99m pertechnetate. The kit vials were tested for sterility and labeling efficacy. The radiolabeled by using the kit GRPR antagonist was evaluated in vitro for binding specificity to GRPR on PC-3 cells (GRPR-positive). In vivo, the toxicity of the kit constituents was evaluated in rats. The labeling efficacy of the kits stored at 4 degrees C was monitored for 18 months. The biological properties of [Tc-99m]Tc-maSSS-PEG2-RM26, which were obtained after this period, were examined both in vitro and in vivo. The one-pot (gluconic acid, ethylenediaminetetraacetic acid, stannous chloride, and maSSS-PEG(2)-RM26) single-step radiolabeling with technetium-99m was successful with high radiochemical yields (>97%) and high molar activities (16-24 MBq/nmol). The radiolabeled peptide maintained its binding properties to GRPR. The kit constituents were sterile and non-toxic when tested in living subjects. In conclusion, the prepared kit is considered safe in animal models and can be further evaluated for use in clinics.
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| 2. |
- Aquilante, Francesco, et al.
(författare)
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Modern quantum chemistry with [Open]Molcas
- 2020
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 152:21
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Tidskriftsartikel (refereegranskat)abstract
- MOLCAS/OpenMolcas is an ab initio electronic structure program providing a large set of computational methods from Hartree-Fock and density functional theory to various implementations of multiconfigurational theory. This article provides a comprehensive overview of the main features of the code, specifically reviewing the use of the code in previously reported chemical applications as well as more recent applications including the calculation of magnetic properties from optimized density matrix renormalization group wave functions.
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| 3. |
- Borin, Lars, et al.
(författare)
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Swe-Clarin : Language Resources and Technology for Digital Humanities
- 2016
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Ingår i: <em>Extended Papers of the International Symposium on Digital Humanities</em>. - : CEUR. ; , s. 29-51, s. 29-51
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Konferensbidrag (refereegranskat)abstract
- CLARIN is a European Research Infrastructure Consortium (ERIC), which aims at (a) making extensive language-based materials available as primary research data to the humanities and social sciences (HSS); and (b) offering state-of-the-art language technology (LT) as an eresearch tool for this purpose, positioning CLARIN centrally in what is often referred to as the digital humanities (DH). The Swedish CLARIN node Swe-Clarin was established in 2015 with funding from the Swedish Research Council.In this paper, we describe the composition and activities of Swe-Clarin, aiming at meeting the requirements of all HSS and other researchers whose research involves using text and speech as primary research data, and spreading the awareness of what Swe-Clarin can offer these research communities. We focus on one of the central means for doing this: pilot projects conducted in collaboration between HSS researchers and Swe-Clarin, together formulating a research question, the addressing of which requires working with large language-based materials. Four such pilot projects are described in more detail, illustrating research on rhetorical history, second-language acquisition, literature, and political science. A common thread to these projects is an aspiration to meet the challenge of conducting research on the basis of very large amounts of textual data in a consistent way without losing sight of the individual cases making up the mass of data, i.e., to be able to move between Moretti’s “distant” and “close reading” modes.While the pilot projects clearly make substantial contributions to DH, they also reveal some needs for more development, and in particular a need for document-level access to the text materials. As a consequence of this, work has now been initiated in Swe-Clarin to meet this need, so that Swe-Clarin together with HSS scholars investigating intricate research questions can take on the methodological challenges of big-data language-based digital humanities.
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| 4. |
- Borin, Lars, 1957, et al.
(författare)
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Swe-Clarin: Language resources and technology for Digital Humanities
- 2017
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Ingår i: Digital Humanities 2016. Extended Papers of the International Symposium on Digital Humanities (DH 2016) Växjö, Sweden, November, 7-8, 2016. Edited by Koraljka Golub, Marcelo Milra. Vol-2021. - Aachen : M. Jeusfeld c/o Redaktion Sun SITE, Informatik V, RWTH Aachen.. - 1613-0073.
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Konferensbidrag (refereegranskat)abstract
- CLARIN is a European Research Infrastructure Consortium (ERIC), which aims at (a) making extensive language-based materials available as primary research data to the humanities and social sciences (HSS); and (b) offering state-of-the-art language technology (LT) as an e-research tool for this purpose, positioning CLARIN centrally in what is often referred to as the digital humanities (DH). The Swedish CLARIN node Swe-Clarin was established in 2015 with funding from the Swedish Research Council. In this paper, we describe the composition and activities of Swe-Clarin, aiming at meeting the requirements of all HSS and other researchers whose research involves using text and speech as primary research data, and spreading the awareness of what Swe-Clarin can offer these research communities. We focus on one of the central means for doing this: pilot projects conducted in collaboration between HSS researchers and Swe-Clarin, together formulating a research question, the addressing of which requires working with large language-based materials. Four such pilot projects are described in more detail, illustrating research on rhetorical history, second-language acquisition, literature, and political science. A common thread to these projects is an aspiration to meet the challenge of conducting research on the basis of very large amounts of textual data in a consistent way without losing sight of the individual cases making up the mass of data, i.e., to be able to move between Moretti’s “distant” and “close reading” modes. While the pilot projects clearly make substantial contributions to DH, they also reveal some needs for more development, and in particular a need for document-level access to the text materials. As a consequence of this, work has now been initiated in Swe-Clarin to meet this need, so that Swe-Clarin together with HSS scholars investigating intricate research questions can take on the methodological challenges of big-data language-based digital humanities.
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| 5. |
- Borin, Lars, 1957, et al.
(författare)
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Swe-Clarin: Language resources and technology for digital humanities
- 2016
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Ingår i: CEUR Workshop Proceedings. - 1613-0073. ; 2021, s. 29-51
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Konferensbidrag (refereegranskat)abstract
- CLARIN is a European Research Infrastructure Consortium (ERIC), which aims at (a) making extensive language-based materials available as primary research data to the humanities and social sciences (HSS); and (b) offering state-of-the-art language technology (LT) as an e-research tool for this purpose, positioning CLARIN centrally in what is often referred to as the digital humanities (DH). The Swedish CLARIN node Swe-Clarin was established in 2015 with funding from the Swedish Research Council. In this paper, we describe the composition and activities of Swe-Clarin, aiming at meeting the requirements of all HSS and other researchers whose research involves using text and speech as primary research data, and spreading the awareness of what Swe-Clarin can offer these research communities. We focus on one of the central means for doing this: pilot projects conducted in collaboration between HSS researchers and Swe-Clarin, together formulating a research question, the addressing of which requires working with large language-based materials. Four such pilot projects are described in more detail, illustrating research on rhetorical history, second-language acquisition, literature, and political science. A common thread to these projects is an aspiration to meet the challenge of conducting research on the basis of very large amounts of textual data in a consistent way without losing sight of the individual cases making up the mass of data, i.e., to be able to move between Moretti’s “distant” and “close reading” modes.
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| 6. |
- Bragina, Olga, et al.
(författare)
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Phase I study of 99mTc-ADAPT6, a scaffold protein-based probe for visualization of HER2 expression in breast cancer
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Radionuclide molecular imaging of human epidermal growth factor (HER2) expression may be helpful to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. ADAPTs (albumin-binding domain derived affinity proteins) are a new type of small (46-59 amino acids) proteins useful as probes for molecular imaging. The aim of this first in-human study was to evaluate biodistribution, dosimetry, and safety of HER2-specific 99mTc-ADAPT6.METHODS. Twenty-two patients with HER2-positive (n=11) or HER2-negative (n=11) primary breast cancer were intravenously injected with 385125 MBq. The injected amount of protein was either 500 μg (n=11) or 1000 μg (n=11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6 and 24 h. An additional cohort received a dose of 250 μg, and the planar scintigraphy followed by SPECT imaging was performed after 2 h only.RESULTS. Injection of 99mTc-ADAPT6 was well tolerated for all doses evaluated in the study, and was not associated with any adverse effects. 99mTc-ADAPT6 cleared rapidly from the blood and the majority of tissues. The normal organs with the highest accumulation were kidney, liver and lung. The effective doses were determined to 0.0090.002 and 0.0100.003 mSv/MBq when injecting protein amounts of 500 and 1000 μg, respectively. Injection of 500 μg resulted in excellent discrimination between HER2-positive and HER2-negative tumors already 2 h after injection (tumor-to-contralateral breast ratio was 3719 vs 52, p < 0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (p < 0.5) higher for the injected mass of 500 μg than for both 250 and 1000 μg. In one patient, the imaging using 99mTc-ADAPT6 revealed three bone metastases, which were not found at the time of diagnosis by CT or 99mTcpyrophosphate bone scan. MRI imaging confirmed this finding.CONCLUSION. Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. A protein dose of 500 μg is preferable for discrimination between tumors with high and low expression of HER2. 99mTc-ADAPT6 is a promising imaging probe for the stratification of patients for HER2-targeting therapy.
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| 7. |
- Bragina, Olga, et al.
(författare)
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Phase I study of 99mTc-ADAPT6, a scaffold protein-based probe for visualization of HER2 expression in breast cancer
- 2021
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 62:4, s. 493-499
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Tidskriftsartikel (refereegranskat)abstract
- Radionuclide molecular imaging of human epidermal growth factor (HER2) expression may be helpful to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. ADAPTs (albumin-binding domain derived affinity proteins) are a new type of small (46-59 amino acids) proteins useful as probes for molecular imaging. The aim of this first-in-human study was to evaluate biodistribution, dosimetry, and safety of the HER2-specific 99mTc-ADAPT6.METHODS: Twenty-nine patients with primary breast cancerwere included. In 22 patients with HER2-positive (n = 11) or HER2-negative (n = 11) histopathology an intravenous injection with 385±125 MBq 99mTc-ADAPT6 was performed, randomized to an injected protein mass of either 500 µg (n = 11) or 1000 µg (n = 11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6 and 24 h. An additional cohort (n = 7) was injected with 165±29 MBq (injected protein mass 250 µg) and imaging was performed after 2 h only.RESULTS: Injections of 99mTc-ADAPT6 at all injected mass levels were well tolerated and not associated with adverse effects. 99mTc-ADAPT6 cleared rapidly from blood and most other tissues. The normal organs with the highest accumulation were kidney, liver and lung. Effective doses were 0.009±0.002 and 0.010±0.003 mSv/MBq for injected protein masses of 500 and 1000 µg, respectively. Injection of 500 µg resulted in excellent discrimination between HER2-positive and HER2-negative tumors already 2 h after injection (tumor-to-contralateral breast ratio was 37±19 vs 5±2, p<0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (p<0.05) higher for injected mass of 500 µg than for both 250 and 1000 µg.CONCLUSION: Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. Protein dose of 500 µg is preferable for discrimination between tumors with high and low expression of HER2. Further studies are justified to evaluate if 99mTc-ADAPT6 can be used as an imaging probe for stratification of patients for HER2-targeting therapy in the areas where PET imaging is not readily available.
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| 8. |
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| 9. |
- Garousi, Javad, et al.
(författare)
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Comparative evaluation of dimeric and monomeric forms of ADAPT scaffold protein for targeting of HER2-expressing tumours
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER SCIENCE BV. - 0939-6411 .- 1873-3441. ; 134, s. 37-48
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Tidskriftsartikel (refereegranskat)abstract
- ADAPTs are small engineered non-immunoglobulin scaffold proteins, which have demonstrated very promising features as vectors for radionuclide tumour targeting. Radionuclide imaging of human epidermal growth factor 2 (HER2) expression in vivo might be used for stratification of patients for HER2-targeting therapies. ADAPT6, which specifically binds to HER2, has earlier been shown to have very promising features for in vivo targeting of HER2 expressing tumours. In this study we tested the hypothesis that dimerization of ADAPT6 would increase the apparent affinity to HER2 and accordingly improve tumour targeting. To find an optimal molecular design of dimers, a series of ADAPT dimers with different linkers, -SSSG- (DiADAPT6L1), -(SSSG)(2)- (DiADAPT6L2), and -(SSSG)(3)- (DiADAPT6L3) was evaluated. Dimers in combination with optimal linker lengths demonstrated increased apparent affinity to HER2. The best variants, DiADAPT6L2 and DiADAPT6L3 were site-specifically labelled with In-111 and I-125, and compared with a monomeric ADAPT6 in mice bearing HER2-expressing tumours. Despite higher affinity, both dimers had lower tumour uptake and lower tumour-to-organ ratios compared to the monomer. We conclude that improved affinity of a dimeric form of ADAPT does not compensate the disadvantage of increased size. Therefore, increase of affinity should be obtained by affinity maturation and not by dimerization.
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| 10. |
- Garousi, Javad, et al.
(författare)
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Radionuclide therapy using ABD-fused ADAPT scaffold protein : Proof of Principle
- 2021
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Ingår i: Biomaterials. - : Elsevier. - 0142-9612 .- 1878-5905. ; 266
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Tidskriftsartikel (refereegranskat)abstract
- Molecular recognition in targeted therapeutics is typically based on immunoglobulins. Development of engineered scaffold proteins (ESPs) has provided additional opportunities for the development of targeted therapies. ESPs offer inexpensive production in prokaryotic hosts, high stability and convenient approaches to modify their biodistribution. In this study, we demonstrated successful modification of the biodistribution of an ESP known as ADAPT (Albumin-binding domain Derived Affinity ProTein). ADAPTs are selected from a library based on the scaffold of ABD (Albumin Binding Domain) of protein G. A particular ADAPT, the ADAPT6, binds to human epidermal growth factor receptor type 2 (HER2) with high affinity. Preclinical and early clinical studies have demonstrated that radiolabeled ADAPT6 can image HER2-expression in tumors with high contrast. However, its rapid glomerular filtration and high renal reabsorption have prevented its use in radionuclide therapy. To modify the biodistribution, ADAPT6 was genetically fused to an ABD. The non-covalent binding to the host's albumin resulted in a 14-fold reduction of renal uptake and appreciable increase of tumor uptake for the best variant, 177Lu-DOTA-ADAPT6-ABD035. Experimental therapy in mice bearing HER2-expressing xenografts demonstrated more than two-fold increase of median survival even after a single injection of 18 MBq 177Lu-DOTA-ADAPT6-ABD035. Thus, a fusion with ABD and optimization of the molecular design provides ADAPT derivatives with attractive targeting properties for radionuclide therapy.
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