Publications by authors named "Julie Foster"

38 Publications

Bioconjugated technetium carbonyls by transmetalation reaction with zinc derivatives.

Bioorg Med Chem Lett 2021 Feb 5;37:127840. Epub 2021 Feb 5.

Departament de Química, Edifici C, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain. Electronic address:

The transmetalation reaction between zinc dithiocarbamates functionalized with organic groups and the cation fac-[Tc(HO)(CO)] has been studied as a new strategy to bind biomolecules to this radionuclide for preparing radiopharmaceuticals with high molar activity. All complexes were obtained in high yields by heating at moderate temperatures and without subsequent purification. The chemical identity was ascertained by HPLC comparison with the homologous rhenium complexes. Stability studies in cysteine solution and serum have shown a good stability of the coordination set fac-[Tc(CO)(SS)(P)]. Preliminary biological studies of the radiocomplex functionalized with D-(+)-glucosamine with carcinoma cells have been performed.
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http://dx.doi.org/10.1016/j.bmcl.2021.127840DOI Listing
February 2021

Cancer associated fibroblast FAK regulates malignant cell metabolism.

Nat Commun 2020 03 10;11(1):1290. Epub 2020 Mar 10.

Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.

Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.
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http://dx.doi.org/10.1038/s41467-020-15104-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064590PMC
March 2020

Systemic delivery and SPECT/CT in vivo imaging of I-labelled oncolytic adenoviral mutants in models of pancreatic cancer.

Sci Rep 2019 09 6;9(1):12840. Epub 2019 Sep 6.

Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

Early phase clinical trials have demonstrated good therapeutic index for oncolytic adenoviruses in patients with solid tumours when administered intratumorally, resulting in local tumour elimination. Entrapment and binding of adenovirus to erythrocytes, blood factors, and neutralising antibodies have prevented efficient systemic delivery and targeting of distant lesions in the clinic. We previously generated the novel replication-selective Ad-3∆-A20T to improve tumour targeting by increasing the viral dose at distant sites. Here, we developed a protocol to directly radiolabel the virus for rapid and sensitive detection by single-photon emitted computed tomography (SPECT/CT) providing a convenient method for determining biodistribution following intravenous administration in murine models. Longitudinal whole-body scans, demonstrated efficient viral uptake in pancreatic Suit-2 and Panc04.03 xenografts with trace amounts of I-Ad-3∆-A20T up to 48 h after tail vein delivery. Hepatic and splenic radioactivity decreased over time. Analysis of tissues harvested at the end of the study, confirmed potency and selectivity of mutant viruses. Ad-3∆-A20T-treated animals showed higher viral genome copy numbers and E1A gene expression in tumors than in liver and spleen compared to Ad5wt. Our direct radiolabeling approach, allows for immediate screening of novel oncolytic adenoviruses and selection of optimal viral genome alterations to generate improved mutants.
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http://dx.doi.org/10.1038/s41598-019-49150-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731255PMC
September 2019

Erratum: Site-specific stabilization of minigastrin analogs against enzymatic degradation for enhanced cholecystokinin-2 receptor targeting: Erratum.

Theranostics 2019;9(16):4595-4596. Epub 2019 Jun 19.

Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria.

[This corrects the article DOI: 10.7150/thno.24378.].
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http://dx.doi.org/10.7150/thno.36746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643442PMC
June 2019

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting.

Oncotarget 2019 Jul 2;10(42):4276-4289. Epub 2019 Jul 2.

Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

Anterior gradient 2 (AGR2), a protein disulfide isomerase, shows two subcellular localizations: intracellular (iAGR2) and extracellular (eAGR2). In healthy cells that express AGR2, the predominant form is iAGR2, which resides in the endoplasmic reticulum. In contrast, cancer cells secrete and express eAGR2 on the cell surface. We wanted to test if AGR2 is a cancer-specific tumor-associated antigen. We utilized two AGR2 antibodies, P3A5 and P1G4, for tumor localization and tumor growth inhibition. The monoclonal antibodies recognized both human AGR2 and mouse Agr2. Biodistribution experiments using a syngeneic mouse model showed high uptake of P3A5 AGR2 antibody in xenografted eAgr2 pancreatic tumors, with limited uptake in normal tissues. In implanted human patient-derived eAGR2 pancreatic cancer xenografts, tumor growth inhibition was evaluated with antibodies and Gemcitabine (Gem). Inhibition was more potent by P1G4 + Gem combination than Gem alone or P3A5 + Gem. We converted these two antibodies to human:mouse chimeric forms: the constructed P3A5 and P1G4 chimeric mVhC and mVhC (γ1, γ2, γ4) genes were inserted in a single mammalian expression plasmid vector, and transfected into human 293F cells. Expressed human:mouse chimeric IgG1, IgG2 and IgG4 antibodies retained AGR2 binding. Increase in IgG yield by transfected cells could be obtained with serial transfection of vectors with different drug resistance. These chimeric antibodies, when incubated with human blood, effectively lysed eAGR2 PC3 prostate cancer cells. We have, thus, produced humanized anti-AGR2 antibodies that, after further testing, might be suitable for treatment against a variety of eAGR2 solid tumors.
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http://dx.doi.org/10.18632/oncotarget.26945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611513PMC
July 2019

Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89.

Biomolecules 2019 03 6;9(3). Epub 2019 Mar 6.

Department of Nuclear Medicine, Medical University Innsbruck, 6020 Innsbruck, Austria.

Fusarinine C (FSC) has recently been shown to be a promising and novel chelator for Zr. Here, FSC has been further derivatized to optimize the complexation properties of FSC-based chelators for Zr-labeling by introducing additional carboxylic groups. These were expected to improve the stability of Zr-complexes by saturating the 8-coordination sphere of [Zr] Zr, and also to introduce functionalities suitable for conjugation to targeting vectors such as monoclonal antibodies. For proof of concept, succinic acid derivatization at the amine groups of FSC was carried out, resulting in FSC(succ)₂ and FSC(succ)₃. FSC(succ)₂ was further derivatized to FSC(succ)₂ AA by reacting with acetic anhydride (AA). The Zr complexation properties of these chelators were studied by reacting with ZrCl₄. Partition coefficient, protein binding, serum stability, acid dissociation, and transchelation studies of Zr-complexes were carried out in vitro and the results were compared with those for Zr-desferrioxamine B ([Zr]Zr-DFO) and Zr-triacetylfusarinine C ([Zr]Zr-TAFC). The in vivo properties of [Zr]Zr-FSC(succ)₃ were further compared with [Zr]Zr-TAFC in BALB/c mice using micro-positron emission tomography/computer tomography (microPET/CT) imaging. Fusarinine C (succ)₂AA and FSC(succ)₃ were synthesized with satisfactory yields. Complexation with ZrCl₄ was achieved using a simple strategy resulting in high-purity Zr-FSC(succ)₂AA and Zr-FSC(succ)₃ with 1:1 stoichiometry. Distribution coefficients of Zr-complexes revealed increased hydrophilic character compared to [Zr]Zr-TAFC. All radioligands showed high stability in phosphate buffered saline (PBS) and human serum and low protein-bound activity over a period of seven days. Acid dissociation and transchelation studies exhibited a range of in vitro stabilities following the order: [Zr]Zr-FSC(succ)₃ > [Zr]Zr-TAFC > [Zr]Zr-FSC(succ)₂AA > [Zr]Zr-DFO. Biodistribution studies of [Zr]Zr-FSC(succ)₃ revealed a slower excretion pattern compared to [Zr]Zr-TAFC. In conclusion, [Zr]Zr-FSC(succ)₃ showed the best stability and inertness. The promising results obtained with [Zr]Zr-FSC(succ)₂AA highlight the potential of FSC(succ)₂ as a monovalent chelator for conjugation to targeted biomolecules, in particular, monoclonal antibodies.
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http://dx.doi.org/10.3390/biom9030091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468543PMC
March 2019

DOTA-MGS5, a New Cholecystokinin-2 Receptor-Targeting Peptide Analog with an Optimized Targeting Profile for Theranostic Use.

J Nucl Med 2019 07 7;60(7):1010-1016. Epub 2018 Dec 7.

Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria; and

Molecular imaging and targeted radiotherapy with radiolabeled cholecystokinin-2 receptor (CCK2R) targeting peptide probes holds high promise to improve the clinical management of patients with metastatic medullary thyroid carcinoma and other CCK2R-expressing malignancies. Low stability and suboptimal targeting of currently available radiolabeled peptide analogs has prompted us to seek new stabilization strategies. In this study, we present a new minigastrin analog with site-specific C-terminal modifications showing a highly optimized targeting profile. DOTA-D-Glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-NH (DOTA-MGS5) radiolabeled with In, Ga, and Lu was evaluated in extensive in vitro stability studies. For Lu-DOTA-MGS5, additional metabolic studies were performed on BALB/c mice. Receptor affinity and cell uptake were studied in A431 human epidermoid carcinoma cells transfected with human CCK2R (A431-CCK2R), as well as the same cell line transfected with the empty vector (A431-mock). A431-CCK2R/A431-mock xenografted athymic BALB/c nude mice were used for biodistribution studies and small-animal SPECT/CT. DOTA-MGS5 radiolabeled with In and Lu showed a highly increased stability against enzymatic degradation in different media up to 24 h of incubation. Similar results were observed for Ga-DOTA-MGS5 incubated up to 4 h. In the blood of mice injected with Lu-DOTA-MGS5, at least 70% intact radiopeptide was detected up to 1 h after injection. The unlabeled peptide and the complexes with the natural isotopes showed retained receptor affinity, and the radiopeptides showed unexpectedly high cell uptake in A431-CCK2R cells (>60% at 4 h). Regardless of the radiometal used for labeling, impressively high uptake in A431-CCK2R xenografts was found (∼20% injected activity/g 1-4 h after injection), whereas the uptake in A431-mock xenografts was negligible. Low background activity and favorable tumor-to-kidney ratios (4-6) allowed for high image contrast in small-animal SPECT/CT. The excellent targeting properties of DOTA-MGS5 support future clinical studies evaluating the diagnostic and therapeutic potential in patients with progressive or metastatic medullary thyroid carcinoma, as well as other advanced-stage CCK2R-expressing malignancies.
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http://dx.doi.org/10.2967/jnumed.118.221283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604694PMC
July 2019

Second round results from the Manchester 'Lung Health Check' community-based targeted lung cancer screening pilot.

Thorax 2019 07 12;74(7):700-704. Epub 2018 Nov 12.

Manchester Thoracic Oncology Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

We report results from the second annual screening round (T1) of Manchester's 'Lung Health Check' pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.
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http://dx.doi.org/10.1136/thoraxjnl-2018-212547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585285PMC
July 2019

Site-specific stabilization of minigastrin analogs against enzymatic degradation for enhanced cholecystokinin-2 receptor targeting.

Theranostics 2018 16;8(11):2896-2908. Epub 2018 Apr 16.

Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria.

Minigastrin (MG) analogs show high affinity to the cholecystokinin-2 receptor (CCK2R) and have therefore been intensively studied to find a suitable analog for imaging and treatment of CCK2R-expressing tumors. The clinical translation of the radioligands developed thus far has been hampered by high kidney uptake or low enzymatic stability. In this study, we aimed to develop new MG analogs with improved targeting properties stabilized against degradation through site-specific amino acid modifications. Based on the lead structure of a truncated MG analog, four new MG derivatives with substitutions in the -terminal part of the peptide (Trp-Met-Asp-Phe-NH) were synthesized and derivatized with DOTA at the -terminus for radiolabeling with trivalent radiometals. The properties of the new analogs were characterized by analyzing the lipophilicity, the protein binding, and the stability of the Indium-111 (In)-labeled analogs in different media. Two different cell lines, AR42J cells physiologically expressing the rat CCK2R and A431 cells transfected with human CCK2R (A431-CCK2R), were used to study the receptor affinity and cell uptake. For the two most promising MG analogs, metabolic studies in normal BALB/c mice were carried out as well as biodistribution and imaging studies in tumor xenografted athymic BALB/c nude mice. Two out of four synthesized peptide analogs (DOTA-MGS1 and DOTA-MGS4) showed retained receptor affinity and cell uptake when radiolabeled with In. These two peptide analogs, however, showed a different stability against enzymatic degradation and When injected to normal BALB/c mice, for In-DOTA-MGS1 at 10 min post injection (p.i.) no intact radiopeptide was found in the blood, whereas for In-DOTA-MGS4 more than 75% was still intact. In-DOTA-MGS4 showed a clear increase in injected activity per gram tissue (IA/g) for A431-CCK2R xenografts (10.40±2.21% IA/g 4 h p.i.) when compared to In-DOTA-MGS1 (1.23±0.15% IA/g 4 h p.i.). The tumor uptake of In-DOTA-MGS4 was also combined with a low uptake in stomach and kidney leading to high-contrast NanoSPECT/CT images. Of the four new MG analogs developed, the best results in terms of enzymatic stability and increased tumor targeting were obtained with In-DOTA-MGS4 showing two substitutions with -methylated amino acids. In-DOTA-MGS4 was also superior to other MG analogs reported thus far and seems therefore an extremely promising targeting molecule for theranostic use with alternative radiometals.
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http://dx.doi.org/10.7150/thno.24378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996369PMC
July 2019

Radiolabeled Antibodies Against Müllerian-Inhibiting Substance Receptor, Type II: New Tools for a Theranostic Approach in Ovarian Cancer.

J Nucl Med 2018 08 19;59(8):1234-1242. Epub 2018 Apr 19.

Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France

We have developed the 16F12 mouse monoclonal antibody (mAb), which targets the Müllerian-inhibiting substance receptor, type II (MISRII), expressed by ovarian tumors. Here, we assessed in preclinical models the possibility of using radiolabeled 16F12 in a theranostic approach for small-volume ovarian peritoneal carcinomatosis, such as after cytoreductive surgery. DOTA-, DTPA- or deferoxamine mesylate-conjugated 16F12 mAb was radiolabeled with β-particle (Lu) or α-particle (Bi) emitters for therapeutic use and with Zr for PET imaging. On the 13th postxenograft day, mice bearing intraperitoneal MISRII-positive AN3CA endometrial carcinoma cell xenografts were treated by conventional intraperitoneal radioimmunotherapy (IP-RIT) with 10 MBq of Lu-16F12 or 12.9 MBq of Bi-16F12 or by brief intraperitoneal radioimmunotherapy (BIP-RIT) using 50 MBq of Lu-16F12 or 37 MBq of Bi-16F12. For BIP-RIT, 30 min after injection of the radiolabeled mAbs, the peritoneal cavity was washed to remove the unbound radioactivity. The biodistribution of Lu- and Bi-16F12 mAbs was determined and then used for dose assessment. Hematologic toxicity was also monitored. The 16F12 mAb was satisfactorily radiolabeled for both therapy and imaging. IP-RIT with Lu-16F12 was slightly more efficient in delaying tumor growth than IP-RIT with Bi-16F12. Conversely, Bi-16F12 was more efficient than Lu-16F12 in BIP-RIT. The biodistribution analysis showed that the tumor-to-blood uptake ratio was significantly higher with BIP-RIT than with IP-RIT for both Bi- and Lu-16F12. Hematologic toxicity was more pronounced with Lu-16F12 than with Bi-16F12. SPECT/CT images (after BIP-RIT with Lu-16F12) and PET/CT images (after injection of Zr-16F12 in the tail vein) showed focal uptake at the tumor site. Radiolabeled 16F12 could represent a new theranostic tool for small-volume ovarian peritoneal carcinomatosis. Specifically, Bi-16F12-based BIP-RIT could be proposed to selected patients as an alternative adjuvant treatment immediately after cytoreductive surgery. An anti-MISRII mAb is currently being used in a first-in-human study, thus making radiolabeled anti-MISRII mAbs a realistic theranostic option for the clinic.
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http://dx.doi.org/10.2967/jnumed.118.208611DOI Listing
August 2018

Clinically compliant spatial and temporal imaging of chimeric antigen receptor T-cells.

Nat Commun 2018 03 14;9(1):1081. Epub 2018 Mar 14.

ImmunoEngineering Group, King's College London, Division of Cancer Studies, 3rd Floor Bermondsey Wing, King's Health Partners Integrated Cancer Centre, Great Maze Pond, Guy's Hospital, London, SE1 9RT, UK.

The unprecedented efficacy of chimeric antigen receptor (CAR) T-cell immunotherapy of CD19 B-cell malignancy has established a new therapeutic pillar of hematology-oncology. Nonetheless, formidable challenges remain for the attainment of comparable success in patients with solid tumors. To accelerate progress and rapidly characterize emerging toxicities, systems that permit the repeated and non-invasive assessment of CAR T-cell bio-distribution would be invaluable. An ideal solution would entail the use of a non-immunogenic reporter that mediates specific uptake of an inexpensive, non-toxic and clinically established imaging tracer by CAR T cells. Here we show the utility of the human sodium iodide symporter (hNIS) for the temporal and spatial monitoring of CAR T-cell behavior in a cancer-bearing host. This system provides a clinically compliant toolkit for high-resolution serial imaging of CAR T cells in vivo, addressing a fundamental unmet need for future clinical development in the field.
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http://dx.doi.org/10.1038/s41467-018-03524-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852048PMC
March 2018

Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester.

Thorax 2019 04 13;74(4):405-409. Epub 2018 Feb 13.

Manchester Thoracic Oncology Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCO calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.
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http://dx.doi.org/10.1136/thoraxjnl-2017-211377DOI Listing
April 2019

Targeting of Tumor-Associated Glycoforms of MUC1 with CAR T Cells.

Immunity 2016 11;45(5):945-946

King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.

We read with interest the manuscript by June and colleagues published recently in Immunity in which they describe targeting of aberrantly glycosylated tumor-associated cell membrane mucin MUC1 using chimeric antigen receptor-engineered human T cells (Posey et al., 2016). In that study, the authors used a second generation 4-1BB costimulatory-molecule-based chimeric antigen receptor (CAR) (Imai et al., 2004) in which targeting was achieved using a single-chain variable fragment (scFv) derived from the 5E5 antibody. This CAR selectively binds MUC1 that carries the Tn or sialyl (S)Tn glycan. Both of these truncated glycans are aberrantly expressed on the MUC1 glycoprotein in a spectrum of malignancies and consequently represent attractive targets for immunotherapeutic exploitation.
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http://dx.doi.org/10.1016/j.immuni.2016.10.014DOI Listing
November 2016

Student midwives and paramedic students' experiences of shared learning in pre-hospital childbirth.

Nurse Educ Today 2016 Jun 31;41:73-8. Epub 2016 Mar 31.

University of Cumbria, United Kingdom.

Aim: To explore the experiences of midwifery and paramedic students undertaking interprofessional learning.

Method: A one day interprofessional learning workshop incorporating peer assisted learning for undergraduate pre-registration midwifery and paramedic students was developed based on collaborative practice theory and simulation based learning. Twenty-five student midwives and thirty-one paramedic students participated in one of two identical workshops conducted over separate days. Videoed focus group sessions were held following the workshop sessions in order to obtain qualitative data around student experience. Qualitative data analysis software (ATLAS.ti) was used to collate the transcriptions from the focus group sessions and the video recordings were scrutinised. Thematic analysis was adopted.

Results: Four main themes were identified around the understanding of each other's roles and responsibilities, the value of interprofessional learning, organisation and future learning. Students appeared to benefit from a variety of learning opportunities including interprofessional learning and peer assisted learning through the adoption of both formal and informal teaching methods, including simulation based learning. A positive regard for each other's profession including professional practice, professional governing bodies, professional codes and scope of practice was apparent. Students expressed a desire to undertake similar workshops with other professional students.

Conclusion: Interprofessional learning workshops were found to be a positive experience for the students involved. Consideration needs to be given to developing interprofessional learning with other student groups aligned with midwifery at appropriate times in relation to stage of education.
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http://dx.doi.org/10.1016/j.nedt.2016.03.020DOI Listing
June 2016

Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

Sci Transl Med 2016 Mar;8(332):332ra43

UCL Cancer Institute, University College London, London WC1E 6BT, UK.

Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.
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http://dx.doi.org/10.1126/scitranslmed.aad9982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973268PMC
March 2016

Evaluation and comparison of a new DOTA and DTPA-bombesin agonist in vitro and in vivo in low and high GRPR expressing prostate and breast tumor models.

Appl Radiat Isot 2015 Feb 11;96:91-101. Epub 2014 Nov 11.

Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.

We evaluated and compared a new bombesin analog [Tyr-Gly5, Nle(14)]-BBN(6-14) conjugated to DOTA or DTPA and radiolabeled with In-111 in low and high GRPR expressing tumor models. Both peptides were radiolabeled with high radiochemical purity and specific activity. In vitro assays on T-47D, LNCaP and PC-3 cells showed that the affinity of peptides is similar and a higher binding and internalization of DOTA-peptide to PC-3 cells was observed. Both peptides could target PC-3 and LNCaP tumors in vivo and both tumor types could be visualized by microSPECT/CT.
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http://dx.doi.org/10.1016/j.apradiso.2014.11.006DOI Listing
February 2015

Adoptive immunotherapy of epithelial ovarian cancer with Vγ9Vδ2 T cells, potentiated by liposomal alendronic acid.

J Immunol 2014 Dec 22;193(11):5557-66. Epub 2014 Oct 22.

King's College London, King's Health Partners Integrated Cancer Centre, London SE1 9RT, United Kingdom; Department of Immunology, Barnet Hospital, Barnet, Hertfordshire EN5 3DJ, United Kingdom; and Department of Clinical Immunology and Allergy, King's College Hospital National Health Service Foundation Trust, London SE5 9RS, United Kingdom

Adoptive immunotherapy using γδ T cells harnesses their natural role in tumor immunosurveillance. The efficacy of this approach is enhanced by aminobisphosphonates such as zoledronic acid and alendronic acid, both of which promote the accumulation of stimulatory phosphoantigens in target cells. However, the inefficient and nonselective uptake of these agents by tumor cells compromises the effective clinical exploitation of this principle. To overcome this, we have encapsulated aminobisphosphonates within liposomes. Expanded Vγ9Vδ2 T cells from patients and healthy donors displayed similar phenotype and destroyed autologous and immortalized ovarian tumor cells, following earlier pulsing with either free or liposome-encapsulated aminobisphosphonates. However, liposomal zoledronic acid proved highly toxic to SCID Beige mice. By contrast, the maximum tolerated dose of liposomal alendronic acid was 150-fold higher, rendering it much more suited to in vivo use. When injected into the peritoneal cavity, free and liposomal alendronic acid were both highly effective as sensitizing agents, enabling infused γδ T cells to promote the regression of established ovarian tumors by over one order of magnitude. Importantly however, liposomal alendronic acid proved markedly superior compared with free drug following i.v. delivery, exploiting the "enhanced permeability and retention effect" to render advanced tumors susceptible to γδ T cell-mediated shrinkage. Although folate targeting of liposomes enhanced the sensitization of folate receptor-α(+) ovarian tumor cells in vitro, this did not confer further therapeutic advantage in vivo. These findings support the development of an immunotherapeutic approach for ovarian and other tumors in which adoptively infused γδ T cells are targeted using liposomal alendronic acid.
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http://dx.doi.org/10.4049/jimmunol.1402200DOI Listing
December 2014

Identification of ZDHHC14 as a novel human tumour suppressor gene.

J Pathol 2014 Apr 8;232(5):566-77. Epub 2014 Feb 8.

Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene, ZDHHC14. The expression of ZDHHC14, a putative protein palmitoyltransferase with unknown cellular function, was decreased at both RNA and protein levels in testicular germ cell tumours. ZDHHC14 expression was also significantly decreased in a panel of prostate cancer samples and cell lines. In addition to our findings of genetic and protein expression changes in clinical samples, inducible overexpression of ZDHHC14 led to reduced cell viability and increased apoptosis through the classic caspase-dependent apoptotic pathway and heterozygous knockout of ZDHHC14 increased [CORRECTED] cell colony formation ability. Finally, we confirmed our in vitro findings of the tumour suppressor role of ZDHHC14 in a mouse xenograft model, showing that overexpression of ZDHHC14 inhibits tumourigenesis. Thus, we have identified a novel tumour suppressor gene that is commonly down-regulated in testicular germ cell tumours and prostate cancer, as well as given insight into the cellular functional role of ZDHHC14, a potential protein palmitoyltransferase that may play a key protective role in cancer.
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http://dx.doi.org/10.1002/path.4327DOI Listing
April 2014

Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging.

Cancer Res 2014 Feb 27;74(3):896-907. Epub 2013 Nov 27.

Authors' Affiliations: Barts Cancer Institute-a Cancer Research UK Center of Excellence, John Vane Science Center, Queen Mary University of London; Department of Medicine, Imperial College, Charing Cross Campus; St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London; Wellcome Trust Center for Human Genetics, Oxford; Cancer Research UK Cambridge Research Institute, Li Ka Shing Center; Hutchison/MRC Research Center, University of Cambridge, Medical Research Council Cancer Unit; Pharmacometrics Ltd., Cambridge; Dundee Cancer Center, University of Dundee, Ninewells Hospital, Dundee, United Kingdom; Laboratory of Cancer Genetics and Translational Oncology, S Croce General Hospital, Cuneo, Italy; Department of Structural Biology, Medical University of Lodz, Lodz, Poland; Polaris Group, San Diego, California; Department of Pathology, Chi-Mei Medical Center; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan; and National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-1702DOI Listing
February 2014

Latency can be conferred to a variety of cytokines by fusion with latency-associated peptide from TGF-β.

Expert Opin Drug Deliv 2014 Jan 27;11(1):5-16. Epub 2013 Sep 27.

William Harvey Research Institute Barts and The London Medical School, Bone and Joint Research Unit , Charterhouse Square, London WC1M 6BQ , UK +44 207 882 2352; +44 207 882 6121;

Objectives: Targeting cytokines to sites of disease has clear advantages because it increases their therapeutic index. We designed fusion proteins of the latent-associated peptide (LAP) derived from TGF-β with various cytokines via a matrix metalloproteinase (MMP) cleavage site. This design confers latency, increased half-life and targeting to sites of inflammation. The aim of this study is to determine whether this approach can be applied to cytokines of different molecular structures and sizes.

Methods: Mature cytokines cloned downstream of LAP and a MMP cleavage site were expressed in 293T cells and assessed for latency and biological activity by Western blotting and bioassay.

Results: We demonstrate here that fusion proteins of TGF-β, erythropoietin, IL-1ra, IL-10, IL-4, BMP-7, IGF1 and IL-17 were rendered latent by fusion to LAP, requiring cleavage to become active in respective bioassays. As further proof of principle, we also show that delivery of engineered TGF-β can inhibit experimental autoimmune encephalomyelitis and that this approach can be used to efficiently deliver cytokines to the brain and spinal cord in mice with this disease.

Conclusions: The latent cytokine approach can be successfully applied to a range of molecules, including cytokines of different molecular structure and mass, growth factors and a cytokine antagonist.
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http://dx.doi.org/10.1517/17425247.2013.839655DOI Listing
January 2014

Preclinical in vivo modeling of cytokine release syndrome induced by ErbB-retargeted human T cells: identifying a window of therapeutic opportunity?

J Immunol 2013 Nov 23;191(9):4589-98. Epub 2013 Sep 23.

Department of Research Oncology, King's Health Partners Integrated Cancer Centre, King's College London, London SE1 9RT, United Kingdom;

The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4(+) T cells exhibit antitumor activity against several ErbB(+) cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB(+) cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4(+) T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4(+) T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.
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http://dx.doi.org/10.4049/jimmunol.1301523DOI Listing
November 2013

Generation and characterization of a diabody targeting the αvβ6 integrin.

PLoS One 2013 4;8(9):e73260. Epub 2013 Sep 4.

UCL Cancer Institute, University College London, London, United Kingdom.

The αvβ6 integrin is up-regulated in cancer and wound healing but it is not generally expressed in healthy adult tissue. There is increasing evidence that it has a role in cancer progression and will be a useful target for antibody-directed cancer therapies. We report a novel recombinant diabody antibody fragment that targets specifically αvβ6 and blocks its function. The diabody was engineered with a C-terminal hexahistidine tag (His tag), expressed in Pichia pastoris and purified by IMAC. Surface plasmon resonance (SPR) analysis of the purified diabody showed affinity in the nanomolar range. Pre-treatment of αvβ6-expressing cells with the diabody resulted in a reduction of cell migration and adhesion to LAP, demonstrating biological function-blocking activity. After radio-labeling, using the His-tag for site-specific attachment of (99m)Tc, the diabody retained affinity and targeted specifically to αvβ6-expressing tumors in mice bearing isogenic αvβ6 +/- xenografts. Furthermore, the diabody was specifically internalized into αvβ6-expressing cells, indicating warhead targeting potential. Our results indicate that the new αvβ6 diabody has a range of potential applications in imaging, function blocking or targeted delivery/internalization of therapeutic agents.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073260PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762766PMC
April 2014

A comparative study of matrix metalloproteinase and aggrecanase mediated release of latent cytokines at arthritic joints.

Ann Rheum Dis 2014 Sep 27;73(9):1728-36. Epub 2013 Jun 27.

Bone and Joint Research Unit, William Harvey Research Institute, Queen Mary University of London, London, UK.

Background: Latent cytokines are engineered by fusing the latency associated peptide (LAP) derived from transforming growth factor-β (TGF-β) with the therapeutic cytokine, in this case interferon-β (IFN-β), via an inflammation-specific matrix metalloproteinase (MMP) cleavage site.

Objectives: To demonstrate latency and specific delivery in vivo and to compare therapeutic efficacy of aggrecanase-mediated release of latent IFN-β in arthritic joints to the original MMP-specific release.

Methods: Recombinant fusion proteins with MMP, aggrecanase or devoid of cleavage site were expressed in CHO cells, purified and characterised in vitro by Western blotting and anti-viral protection assays. Therapeutic efficacy and half-life were assessed in vivo using the mouse collagen-induced arthritis model (CIA) of rheumatoid arthritis and a model of acute paw inflammation, respectively. Transgenic mice with an IFN-regulated luciferase gene were used to assess latency in vivo and targeted delivery to sites of disease.

Results: Efficient localised delivery of IFN-β to inflamed paws, with low levels of systemic delivery, was demonstrated in transgenic mice using latent IFN-β. Engineering of latent IFN-β with an aggrecanase-sensitive cleavage site resulted in efficient cleavage by ADAMTS-4, ADAMTS-5 and synovial fluid from arthritic patients, with an extended half-life similar to the MMP-specific molecule and greater therapeutic efficacy in the CIA model.

Conclusions: Latent cytokines require cleavage in vivo for therapeutic efficacy, and they are delivered in a dose dependent fashion only to arthritic joints. The aggrecanase-specific cleavage site is a viable alternative to the MMP cleavage site for the targeting of latent cytokines to arthritic joints.
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http://dx.doi.org/10.1136/annrheumdis-2013-203513DOI Listing
September 2014

Liver-targeting of interferon-alpha with tissue-specific domain antibodies.

PLoS One 2013 25;8(2):e57263. Epub 2013 Feb 25.

Innovation Biopharm Discovery Unit, Biopharm R&D, GlaxoSmithKline, Cambridge, United Kingdom.

Interferon alpha (IFNα) is used for the treatment of hepatitis C infection and whilst efficacious it is associated with multiple adverse events including reduced leukocyte, erythrocyte, and platelet counts, fatigue, and depression. These events are most likely caused by systemic exposure to interferon. We therefore hypothesise that targeting the therapeutic directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. We genetically fused IFN to a domain antibody (dAb) specific to a hepatocyte restricted antigen, asialoglycoprotein receptor (ASGPR). Our results show that the murine IFNα2 homolog (mIFNα2) fused to an ASGPR specific dAb, termed DOM26h-196-61, could be expressed in mammalian tissue culture systems and retains the desirable biophysical properties and activity of both fusion partners when measured in vitro. Furthermore a clear increase in in vivo targeting of the liver by mIFNα2-ASGPR dAb fusion protein, compared to that observed with either unfused mIFNα2 or mIFNα2 fused to an isotype control dAb VHD2 (which does not bind ASGPR) was demonstrated using microSPECT imaging. We suggest that these findings may be applicable in the development of a liver-targeted human IFN molecule with improved safety and patient compliance in comparison to the current standard of care, which could ultimately be used as a treatment for human hepatitis virus infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057263PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581439PMC
September 2013

Contrasting effects of sunitinib within in vivo models of metastasis.

Angiogenesis 2012 Dec 28;15(4):623-41. Epub 2012 Jul 28.

Tumour Biology Team, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK.

Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose-dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients.
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http://dx.doi.org/10.1007/s10456-012-9291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496518PMC
December 2012

Degree of chemical functionalization of carbon nanotubes determines tissue distribution and excretion profile.

Angew Chem Int Ed Engl 2012 Jun 23;51(26):6389-93. Epub 2012 May 23.

Nanomedicine Laboratory, Centre for Drug Delivery Research, UCL School of Pharmacy, University College London, London WC1N 1AX, UK.

Getting rid of the tubes: An assessment of the retention of functionalized multi-walled carbon nanotubes (MWNTs) in the organs of mice was carried out using single photon emission computed tomography and quantitative scintigraphy (see scheme). Increasing the degree of functionalization on MWNTs enhanced renal clearance, while lower functionalization promoted reticuloendethelial system accumulation.
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http://dx.doi.org/10.1002/anie.201201991DOI Listing
June 2012

Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells.

Mol Med 2012 May 9;18:565-76. Epub 2012 May 9.

King's College London, King's Health Partners Integrated Cancer Center, Department of Research Oncology, Guy's Hospital Campus, London, UK.

Pharmacological targeting of individual ErbB receptors elicits antitumor activity, but is frequently compromised by resistance leading to therapeutic failure. Here, we describe an immunotherapeutic approach that exploits prevalent and fundamental mechanisms by which aberrant upregulation of the ErbB network drives tumorigenesis. A chimeric antigen receptor named T1E28z was engineered, in which the promiscuous ErbB ligand, T1E, is fused to a CD28 + CD3ζ endodomain. Using a panel of ErbB-engineered 32D hematopoietic cells, we found that human T1E28z⁺ T cells are selectively activated by all ErbB1-based homodimers and heterodimers and by the potently mitogenic ErbB2/3 heterodimer. Owing to this flexible targeting capability, recognition and destruction of several tumor cell lines was achieved by T1E28⁺ T cells in vitro, comprising a wide diversity of ErbB receptor profiles and tumor origins. Furthermore, compelling antitumor activity was observed in mice bearing established xenografts, characterized either by ErbB1/2 or ErbB2/3 overexpression and representative of insidious or rapidly progressive tumor types. Together, these findings support the clinical development of a broadly applicable immunotherapeutic approach in which the propensity of solid tumors to dysregulate the extended ErbB network is targeted for therapeutic gain.
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http://dx.doi.org/10.2119/molmed.2011.00493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388141PMC
May 2012

Quantitative Accuracy of Low-Count SPECT Imaging in Phantom and In Vivo Mouse Studies.

Int J Mol Imaging 2011 16;2011:197381. Epub 2011 Mar 16.

Centre for Molecular Oncology and Imaging, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.

We investigated the accuracy of a single photon emission computed tomography (SPECT) system in quantifying a wide range of radioactivity concentrations using different scan times in both phantom and animal models. A phantom containing various amounts of In-111 or Tc-99m was imaged until the activity had decayed close to background levels. Scans were acquired for different durations, employing different collimator pinhole sizes. VOI analysis was performed to quantify uptake in the images and the values compared to the true activity. The phantom results were then validated in tumour-bearing mice. The use of an appropriate calibration phantom and disabling of a background subtraction feature meant that absolute errors were within 12% of the true activity. Furthermore, a comparison of in vivo imaging and biodistribution studies in mice showed a correlation of 0.99 for activities over the 200 kBq to 5 MBq range. We conclude that the quantitative information provided by the NanoSPECT camera is accurate and allows replacement of dissection studies for assessment of radiotracer biodistribution in mouse models.
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http://dx.doi.org/10.1155/2011/197381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094821PMC
July 2011

Bioluminescence imaging of the brain response to acute inflammation in living C/EBP reporter mice.

Neurosci Lett 2011 Jun 27;497(2):134-8. Epub 2011 Apr 27.

Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel, London E12AT, UK.

The transcription factor CCAAT enhancer binding protein (C/EBP) is a key regulator of inflammation and immune responses, and recent studies suggest it is involved in inflammatory processes in the nervous system. We generated a transgenic reporter mouse model, carrying the luciferase (luc) gene under the transcriptional control of C/EBP, for visualising C/EBP activity in vivo. Real-time bioluminescence imaging reflecting C/EBP activity was performed in an acute inflammation model, after systemic administration of lipopolysaccharides (LPS), in C/EBP-luc mice. A striking activity of C/EBP was imaged predominantly in the brain of living C/EBP-luc mice in response to LPS, showing for the first time in vivo that C/EBP mediates the brain response to inflammation. Furthermore, dexamethasone, a potent anti-inflammatory agent, diminished the LPS-induced C/EBP activity demonstrating the physiological regulation of bioluminescence intensity in the brain of C/EBP-luc mice. Our results implicate that C/EBP reporter mice have the potential to be a valuable tool for studies on the mechanisms of brain inflammation in vivo and for the noninvasive preclinical evaluation of therapeutic agents targeting neuroinflammatory diseases.
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http://dx.doi.org/10.1016/j.neulet.2011.04.046DOI Listing
June 2011

Trafficking of CAR-engineered human T cells following regional or systemic adoptive transfer in SCID beige mice.

J Clin Immunol 2011 Aug 20;31(4):710-8. Epub 2011 Apr 20.

The CAR Mechanics Group, King's College London School of Medicine, Guy's Hospital Campus, St Thomas Street, London, SE1 9RT, UK.

Adoptive immunotherapy using chimeric antigen receptor-engrafted T cells is a promising emerging therapy for cancer. Prior to clinical testing, it is mandatory to evaluate human therapeutic cell products in meaningful in vivo pre-clinical models. Here, we describe the use of fused single-photon emission CT-CT imaging to monitor real-time migration of chimeric antigen receptor-engineered T cells in immune compromised (SCID Beige) mice. Following intravenous administration, human T cells migrate in a highly similar manner to that reported in man, but penetrate poorly into established tumors. By contrast, when delivered via intraperitoneal or subcutaneous routes, T cells remain at the site of inoculation with minimal systemic absorption-irrespective of the presence or absence of tumor. Together, these data support the validity of pre-clinical testing of human T-cell immunotherapy in SCID Beige mice. In light of their established efficacy, regional administration of engineered human T cells represents an attractive therapeutic option to minimize toxicity in the treatment of selected malignancies.
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http://dx.doi.org/10.1007/s10875-011-9532-8DOI Listing
August 2011