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Article ; Online: Huntington’s Disease

Klaudia Cybulska / Lars Perk / Jan Booij / Peter Laverman / Mark Rijpkema

Molecules, Vol 25, Iss 3, p

A Review of the Known PET Imaging Biomarkers and Targeting Radiotracers

2020 Volume 482

Abstract: Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A ... ...

Abstract	Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.
Keywords	huntington’s disease ; mutant huntingtin ; positron emission tomography ; radiochemistry ; fluorine-18 ; carbon-11 ; radiopharmaceuticals ; [ 11 c]raclopride ; [ 18 f]mni-659 ; Organic chemistry ; QD241-441
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Carbonic Anhydrase IX-Targeted α-Radionuclide Therapy with 225Ac Inhibits Tumor Growth in a Renal Cell Carcinoma Model

Robin I. J. Merkx / Mark Rijpkema / Gerben M. Franssen / Annemarie Kip / Bart Smeets / Alfred Morgenstern / Frank Bruchertseifer / Eddie Yan / Michael P. Wheatcroft / Egbert Oosterwijk / Peter F. A. Mulders / Sandra Heskamp

Pharmaceuticals, Vol 15, Iss 570, p

2022 Volume 570

Abstract: In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 ( 225 Ac) or the β - -emitter lutetium-177 ( 177 Lu) in mice. ... ...

Abstract	In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 ( 225 Ac) or the β - -emitter lutetium-177 ( 177 Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [ 225 Ac] Ac-DOTA-hG250 ( 225 Ac-hG250) or 30 µg [ 177 Lu] Lu-DOTA-hG250 ( 177 Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of 225 Ac-hG250; 13 MBq of 177 Lu-hG250; or no treatment. Tolerability was evaluated in non-tumor-bearing animals. High tumor uptake of both radioimmunoconjugates was observed and increased up to day 7 (212.8 ± 50.2 %IA/g vs. 101.0 ± 18.4 %IA/g for 225 Ac-hG250 and 177 Lu-hG250, respectively). Survival was significantly prolonged in mice treated with 15 kBq 225 Ac-hG250, 25 kBq 225 Ac-hG250, and 13 MBq 177 Lu-hG250 compared to untreated control ( p < 0.05). Non-tumor-bearing mice that received single-dose treatment with 15 or 25 kBq 225 Ac-hG250 showed weight loss at the end of the experiment (day 126), and immunohistochemical analysis suggested radiation-induced nephrotoxicity. These results demonstrate the therapeutic potential of CAIX-targeted α-therapy in renal cell carcinoma. Future studies are required to find an optimal balance between therapeutic efficacy and toxicity.
Keywords	radioimmunotherapy ; RCC ; actinium-225 ; CAIX ; G250 ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multimodal CEA-targeted fluorescence and radioguided cytoreductive surgery for peritoneal metastases of colorectal origin

Jan Marie de Gooyer / Fortuné M. K. Elekonawo / Andreas J. A. Bremers / Otto C. Boerman / Erik H. J. G. Aarntzen / Philip R. de Reuver / Iris. D. Nagtegaal / Mark Rijpkema / Johannes H. W. de Wilt

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 10

Abstract: Imaging of tumor burden during surgery can lead to better tumor resection. Here, the authors develop a fluorescent probe that binds to carcinoembryonic antigen, expressed on colorectal cancer cells, and describe the results of their phase I clinical ... ...

Abstract	Imaging of tumor burden during surgery can lead to better tumor resection. Here, the authors develop a fluorescent probe that binds to carcinoembryonic antigen, expressed on colorectal cancer cells, and describe the results of their phase I clinical trial.
Keywords	Science ; Q
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A pretargeted multimodal approach for image-guided resection in a xenograft model of colorectal cancer

Fortuné M. K. Elekonawo / Susanne Lütje / Gerben M. Franssen / Desirée L. Bos / David M. Goldenberg / Otto C. Boerman / Mark Rijpkema

EJNMMI Research, Vol 9, Iss 1, Pp 1-

2019 Volume 8

Abstract: Abstract Background Image-guided surgery may improve surgical outcome for colorectal cancer patients. Here, we evaluated the feasibility of a pretargeting strategy for multimodal imaging in colorectal cancer using an anti-carcinoembryonic antigen (CEA) x ...

Abstract	Abstract Background Image-guided surgery may improve surgical outcome for colorectal cancer patients. Here, we evaluated the feasibility of a pretargeting strategy for multimodal imaging in colorectal cancer using an anti-carcinoembryonic antigen (CEA) x anti-histamine-succinyl-glycine (HSG) bispecific antibody (TF2) in conjunction with the dual-labeled diHSG peptide (RDC018), using both a fluorophore for near-infrared fluorescence imaging and a chelator for radiolabeling. Methods Nude mice with subcutaneous (s.c) CEA-expressing LS174T human colonic tumors and CEA-negative control tumors were injected with TF2. After 16 h, different doses of 111In-labeled IMP-288 (non-fluorescent) or its fluorescent derivative RDC018 were administered to compare biodistributions. MicroSPECT/CT and near-infrared fluorescence imaging were performed 2 and 24 h after injection. Next, the biodistribution of the dual-labeled humanized anti-CEA IgG antibody [111In]In-DTPA-hMN-14-IRDye800CW (direct targeting) was compared with the biodistribution of 111In-RDC018 in mice with TF2-pretargeted tumors, using fluorescence imaging and gamma counting. Lastly, mice with intraperitoneal LS174T tumors underwent near-infrared fluorescence image-guided resection combined with pre- and post-resection microSPECT/CT imaging. Results 111In-RDC018 showed specific tumor targeting in pretargeted CEA-positive tumors (21.9 ± 4.5 and 10.0 ± 4.7% injected activity per gram (mean ± SD %IA/g), at 2 and 24 hours post-injection (p.i.), respectively) and a biodistribution similar to 111In-IMP288. Both fluorescence and microSPECT/CT images confirmed preferential tumor accumulation. At post mortem dissection, intraperitoneal tumors were successfully identified and removed using pretargeting with TF2 and 111In-RDC018. Conclusion A pretargeted approach for multimodal image-guided resection of colorectal cancer in a preclinical xenograft model is feasible, enables preoperative SPECT/CT, and might facilitate intraoperative fluorescence imaging.
Keywords	Colorectal cancer ; Pretargeting ; Near-infrared fluorescence ; Image-guided ; Carcinoembryonic antigen ; Medical physics. Medical radiology. Nuclear medicine ; R895-920
Subject code	616
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	SpringerOpen
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Carcinoembryonic antigen-targeted photodynamic therapy in colorectal cancer models

Fortuné M. K. Elekonawo / Desirée L. Bos / David M. Goldenberg / Otto C. Boerman / Mark Rijpkema

EJNMMI Research, Vol 9, Iss 1, Pp 1-

2019 Volume 9

Abstract: Abstract Background In colorectal cancer, survival of patients is drastically reduced when complete resection is hampered by involvement of critical structures. Targeted photodynamic therapy (tPDT) is a local and targeted therapy which could play a role ... ...

Abstract	Abstract Background In colorectal cancer, survival of patients is drastically reduced when complete resection is hampered by involvement of critical structures. Targeted photodynamic therapy (tPDT) is a local and targeted therapy which could play a role in eradicating residual tumor cells after incomplete resection. Since carcinoembryonic antigen (CEA; CEACAM5) is abundantly overexpressed in colorectal cancer, it is a potential target for tPDT of colorectal cancer. Methods To address the potential of CEA-targeted PDT, we compared colorectal cancer cell lines with different CEA-expression levels (SW-48, SW-480, SW-620, SW-1222, WiDr, HT-29, DLD-1, LS174T, and LoVo) under identical experimental conditions. We evaluated the susceptibility to tPDT by varying radiant exposure and concentration of our antibody conjugate (DTPA-hMN-14-IRDye700DX). Finally, we assessed the efficacy of tPDT in vivo in 18 mice (BALB/cAnNRj-Foxn1 nu/nu ) with subcutaneously xenografted LoVo tumors. Results In vitro, the treatment effect of tPDT varied per cell line and was dependent on both radiant exposure and antibody concentration. Under standardized conditions (94.5 J/cm2 and 0.5 μg/μL antibody conjugate concentration), the effect of tPDT was higher in cells with higher CEA availability: SW-1222, LS174T, LoVo, and SW-48 (22.8%, 52.8%, 49.9%, and 51.9% reduction of viable cells, respectively) compared to cells with lower CEA availability. Compared to control groups (light or antibody conjugate only), tumor growth rate was reduced in mice with s.c. LoVo tumors receiving tPDT. Conclusion Our findings suggest cells (and tumors) have different levels of susceptibility for tPDT even though they all express CEA. Furthermore, tPDT can effectively reduce tumor growth in vivo.
Keywords	Colorectal cancer ; Targeted photodynamic therapy ; Carcinoembryonic antigen ; Targeted ; IRDye700DX ; Medical physics. Medical radiology. Nuclear medicine ; R895-920
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	SpringerOpen
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Targeting CD44v6 for fluorescence-guided surgery in head and neck squamous cell carcinoma

Julia Odenthal / Mark Rijpkema / Desirée Bos / Esther Wagena / Huib Croes / Reidar Grenman / Otto Boerman / Robert Takes / Peter Friedl

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 11

Abstract: Abstract Head and neck squamous cell carcinoma (HNSCC) is an often highly invasive tumor, infiltrating functionally important tissue areas. Achieving complete tumor resection and preserving functionally relevant tissue structures depends on precise ... ...

Abstract	Abstract Head and neck squamous cell carcinoma (HNSCC) is an often highly invasive tumor, infiltrating functionally important tissue areas. Achieving complete tumor resection and preserving functionally relevant tissue structures depends on precise identification of tumor-free resection margins during surgery. Fluorescence-guided surgery (FGS), by intraoperative detection of tumor cells using a fluorescent tracer, may guide surgical excision and identify tumor-positive resection margins. Using a literature survey on potential surface molecules followed by immunohistochemical validation, we identified CD44 variant 6 (CD44v6) as a constitutively expressed antigen in the invasion zone of HNSCC lesions. The monoclonal anti-CD44v6 antibody BIWA was labeled with both a near-infrared fluorescent dye (IRDye800CW) and a radioactive label (Indium-111) and dual-modality imaging was applied in a locally invasive tumor mouse model. BIWA accurately detected human HNSCC xenografts in mice with a tumor uptake of 54 ± 11% ID/g and invasion regions with an accuracy of 94%. When dissected under clinical-like conditions, tumor remnants approximately 0.7 mm in diameter consisting of a few thousand cells were identified by fluorescence imaging, resulting in reliable dissection of invasive microregions. These data indicate that CD44v6 is a suitable target for reliable near-infrared detection and FGS of invasive HNSCC lesions in vivo.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Ex Vivo Assessment of Tumor-Targeting Fluorescent Tracers for Image-Guided Surgery

Fortuné M.K. Elekonawo / Jan Marie de Gooyer / Desirée L. Bos / David M. Goldenberg / Otto C. Boerman / Lodewijk A.A. Brosens / Andreas J.A. Bremers / Johannes H.W. de Wilt / Mark Rijpkema

Cancers, Vol 12, Iss 987, p

2020 Volume 987

Abstract: Image-guided surgery can aid in achieving complete tumor resection. The development and assessment of tumor-targeted imaging probes for near-infrared fluorescence image-guided surgery relies mainly on preclinical models, but the translation to clinical ... ...

Abstract	Image-guided surgery can aid in achieving complete tumor resection. The development and assessment of tumor-targeted imaging probes for near-infrared fluorescence image-guided surgery relies mainly on preclinical models, but the translation to clinical use remains challenging. In the current study, we introduce and evaluate the application of a dual-labelled tumor-targeting antibody for ex vivo incubation of freshly resected human tumor specimens and assessed the tumor-to-adjacent tissue ratio of the detectable signals. Immediately after surgical resection, peritoneal tumors of colorectal origin were placed in cold medium. Subsequently, tumors were incubated with 111 In-DOTA-hMN-14-IRDye800CW, an anti-carcinoembryonic antigen (CEA) antibody with a fluorescent and radioactive label. Tumors were then washed, fixed, and analyzed for the presence and location of tumor cells, CEA expression, fluorescence, and radioactivity. Twenty-six of 29 tumor samples obtained from 10 patients contained malignant cells. Overall, fluorescence intensity was higher in tumor areas compared to adjacent non-tumor tissue parts ( p < 0.001). The average fluorescence tumor-to-background ratio was 11.8 ± 9.1:1. A similar ratio was found in the autoradiographic analyses. Incubation with a non-specific control antibody confirmed that tumor targeting of our tracer was CEA-specific. Our results demonstrate the feasibility of this tracer for multimodal image-guided surgery. Furthermore, this ex vivo incubation method may help to bridge the gap between preclinical research and clinical application of new agents for radioactive, near infrared fluorescence or multimodal imaging studies.
Keywords	image-guided surgery ; colorectal cancer ; translational medicine ; targeted imaging near infrared fluorescence ; antibody ; ex vivo ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	610 ; 616
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Neuroinflammation in cognitive decline post-cardiac surgery (the FOCUS study)

Peter Pickkers / Mark Rijpkema / Hendrik-Jan Dieker / Julia van Tuijl / Annemieke M Peters van Ton / Harmke B. Duindam / Wilson WL Li / Niels P Riksen / FJ Anton Meijer / Roy PC Kessels / Nils Kohn / Johannes G. van der Hoeven / Wilson F Abdo

BMJ Open, Vol 11, Iss

an observational study protocol

2021 Volume 5

Abstract: Introduction Postoperative cognitive dysfunction occurs frequently after coronary artery bypass grafting (CABG). The underlying mechanisms remain poorly understood, but neuroinflammation might play a pivotal role. We hypothesise that systemic ... ...

Abstract	Introduction Postoperative cognitive dysfunction occurs frequently after coronary artery bypass grafting (CABG). The underlying mechanisms remain poorly understood, but neuroinflammation might play a pivotal role. We hypothesise that systemic inflammation induced by the surgical trauma could activate the innate immune (glial) cells of the brain. This could lead to an exaggerated neuroinflammatory cascade, resulting in neuronal dysfunction and loss of neuronal cells. Therefore, the aims of this study are to assess neuroinflammation in vivo presurgery and postsurgery in patients undergoing major cardiac surgery and investigate whether there is a relationship of neuroinflammation to cognitive outcomes, changes to brain structure and function, and systemic inflammation.Methods and analysis The FOCUS study is a prospective, single-centre observational study, including 30 patients undergoing elective on-pump CABG. Translocator protein (TSPO) positron emission tomography neuroimaging will be performed preoperatively and postoperatively using the second generation tracer 18F-DPA-714 to assess the neuroinflammatory response. In addition, a comprehensive cerebral MRI will be performed presurgery and postsurgery, in order to discover newly developed brain and vascular wall lesions. Up to 6 months postoperatively, serial extensive neurocognitive assessments will be performed and blood will be obtained to quantify systemic inflammatory responses and peripheral immune cell activation.Ethics and dissemination Patients do not benefit directly from engaging in the study, but imaging neuroinflammation is considered safe and no side effects are expected. The study protocol obtained ethical approval by the Medical Research Ethics Committee region Arnhem-Nijmegen. This work will be published in peer-reviewed international medical journals and presented at medical conferences.Trial registration number NCT04520802.
Keywords	Medicine ; R
Subject code	610
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Consolidation differentially modulates schema effects on memory for items and associations.

Marlieke T R van Kesteren / Mark Rijpkema / Dirk J Ruiter / Guillén Fernández

PLoS ONE, Vol 8, Iss 2, p e

2013 Volume 56155

Abstract: Newly learned information that is congruent with a preexisting schema is often better remembered than information that is incongruent. This schema effect on memory has previously been associated to more efficient encoding and consolidation mechanisms. ... ...

Abstract	Newly learned information that is congruent with a preexisting schema is often better remembered than information that is incongruent. This schema effect on memory has previously been associated to more efficient encoding and consolidation mechanisms. However, this effect is not always consistently supported in the literature, with differential schema effects reported for different types of memory, different retrieval cues, and the possibility of time-dependent effects related to consolidation processes. To examine these effects more directly, we tested participants on two different types of memory (item recognition and associative memory) for newly encoded visuo-tactile associations at different study-test intervals, thus probing memory retrieval accuracy for schema-congruent and schema-incongruent items and associations at different time points (t = 0, t = 20, and t = 48 hours) after encoding. Results show that the schema effect on visual item recognition only arises after consolidation, while the schema effect on associative memory is already apparent immediately after encoding, persisting, but getting smaller over time. These findings give further insight into different factors influencing the schema effect on memory, and can inform future schema experiments by illustrating the value of considering effects of memory type and consolidation on schema-modulated retrieval.
Keywords	Medicine ; R ; Science ; Q
Subject code	005 ; 150
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Intermediate levels of hippocampal activity appear optimal for associative memory formation.

Xiao Liu / Shaozheng Qin / Mark Rijpkema / Jing Luo / Guillén Fernández

PLoS ONE, Vol 5, Iss 10, p e

2010 Volume 1000938

Abstract: BACKGROUND: It is well established that hippocampal activity is positively related to effective associative memory formation. However, in biological systems often optimal levels of activity are contrasted by both sub- and supra-optimal levels. Sub- ... ...

Abstract	BACKGROUND: It is well established that hippocampal activity is positively related to effective associative memory formation. However, in biological systems often optimal levels of activity are contrasted by both sub- and supra-optimal levels. Sub-optimal levels of hippocampal activity are commonly attributed to unsuccessful memory formation, whereas the supra-optimal levels of hippocampal activity related to unsuccessful memory formation have been rarely studied. It is still unclear under what circumstances such supra-optimal levels of hippocampal activity occur. To clarify this issue, we aimed at creating a condition, in which supra-optimal hippocampal activity is associated with encoding failure. We assumed that such supra-optimal activity occurs when task-relevant information is embedded in task-irrelevant, distracting information, which can be considered as noise. METHODOLOGY/PRINCIPAL FINDINGS: In the present fMRI study, we probed neural correlates of associative memory formation in a full-factorial design with associative memory (subsequently remembered versus forgotten) and noise (induced by high versus low distraction) as factors. Results showed that encoding failure was associated with supra-optimal activity in the high-distraction condition and with sub-optimal activity in the low distraction condition. Thus, we revealed evidence for a bell-shape function relating hippocampal activity with associative encoding success. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that intermediate levels of hippocampal activity are optimal while both too low and too high levels appear detrimental for associative memory formation. Supra-optimal levels of hippocampal activity seem to occur when task-irrelevant information is added to task-relevant signal. If such task-irrelevant noise is reduced adequately, hippocampal activity is lower and thus optimal for associative memory formation.
Keywords	Medicine ; R ; Science ; Q
Subject code	150
Language	English
Publishing date	2010-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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