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Article ; Online: BF 2 -Azadipyrromethene Fluorophores for Intraoperative Vital Structure Identification

Cathal Caulfield / Dan Wu / Ian S. Miller / Annette T. Byrne / Pól Mac Aonghusa / Sergiy Zhuk / Lorenzo Cinelli / Elisa Bannone / Jacques Marescaux / Sylvain Gioux / Michele Diana / Taryn L. March / Alexander L. Vahrmeijer / Ronan Cahill / Donal F. O’Shea

Molecules, Vol 28, Iss 2167, p

2023 Volume 2167

Abstract: A series of mono- and bis-polyethylene glycol (PEG)-substituted BF 2 -azadipyrromethene fluorophores have been synthesized with emissions in the near-infrared region (700–800 nm) for the purpose of fluorescence guided intraoperative imaging; chiefly ... ...

Abstract	A series of mono- and bis-polyethylene glycol (PEG)-substituted BF 2 -azadipyrromethene fluorophores have been synthesized with emissions in the near-infrared region (700–800 nm) for the purpose of fluorescence guided intraoperative imaging; chiefly ureter imaging. The Bis-PEGylation of fluorophores resulted in higher aqueous fluorescence quantum yields, with PEG chain lengths of 2.9 to 4.6 kDa being optimal. Fluorescence ureter identification was possible in a rodent model with the preference for renal excretion notable through comparative fluorescence intensities from the ureters, kidneys and liver. Ureteral identification was also successfully performed in a larger animal porcine model under abdominal surgical conditions. Three tested doses of 0.5, 0.25 and 0.1 mg/kg all successfully identified fluorescent ureters within 20 min of administration which was sustained up to 120 min. 3-D emission heat map imaging allowed the spatial and temporal changes in intensity due to the distinctive peristaltic waves of urine being transferred from the kidneys to the bladder to be identified. As the emission of these fluorophores could be spectrally distinguished from the clinically-used perfusion dye indocyanine green, it is envisaged that their combined use could be a step towards intraoperative colour coding of different tissues.
Keywords	BF 2 -azadipyrromethene ; pegylation ; NIR-fluorescence ; ureter identification ; fluorescence guided surgery ; Organic chemistry ; QD241-441
Subject code	500
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Refining Glioblastoma Surgery through the Use of Intra-Operative Fluorescence Imaging Agents

Oluwakanyinsolami Netufo / Kate Connor / Liam P. Shiels / Kieron J. Sweeney / Dan Wu / Donal F. O’Shea / Annette T. Byrne / Ian S. Miller

Pharmaceuticals, Vol 15, Iss 550, p

2022 Volume 550

Abstract: Glioblastoma (GBM) is the most aggressive adult brain tumour with a dismal 2-year survival rate of 26–33%. Maximal safe resection plays a crucial role in improving patient progression-free survival (PFS). Neurosurgeons have the significant challenge of ... ...

Abstract	Glioblastoma (GBM) is the most aggressive adult brain tumour with a dismal 2-year survival rate of 26–33%. Maximal safe resection plays a crucial role in improving patient progression-free survival (PFS). Neurosurgeons have the significant challenge of delineating normal tissue from brain tumour to achieve the optimal extent of resection (EOR), with 5-Aminolevulinic Acid (5-ALA) the only clinically approved intra-operative fluorophore for GBM. This review aims to highlight the requirement for improved intra-operative imaging techniques, focusing on fluorescence-guided imaging (FGS) and the use of novel dyes with the potential to overcome the limitations of current FGS. The review was performed based on articles found in PubMed an.d Google Scholar, as well as articles identified in searched bibliographies between 2001 and 2022. Key words for searches included ‘Glioblastoma’ + ‘Fluorophore’+ ‘Novel’ + ‘Fluorescence Guided Surgery’. Current literature has favoured the approach of using targeted fluorophores to achieve specific accumulation in the tumour microenvironment, with biological conjugates leading the way. These conjugates target specific parts overexpressed in the tumour. The positive results in breast, ovarian and colorectal tissue are promising and may, therefore, be applied to intracranial neoplasms. Therefore, this design has the potential to produce favourable results in GBM by reducing the residual tumour, which translates to decreased tumour recurrence, morbidity and ultimately, mortality in GBM patients. Several preclinical studies have shown positive results with targeted dyes in distinguishing GBM cells from normal brain parenchyma, and targeted dyes in the Near-Infrared (NIR) emission range offer promising results, which may be valuable future alternatives.
Keywords	glioblastoma ; fluorescence guided surgery ; 5-ALA ; fluorescein ; NIR-AZA ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	616
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genomic Exploration of Distinct Molecular Phenotypes Steering Temozolomide Resistance Development in Patient-Derived Glioblastoma Cells

International Journal of Molecular Sciences, Vol 24, Iss 21, p

2023 Volume 15678

Abstract: Chemotherapy using temozolomide is the standard treatment for patients with glioblastoma. Despite treatment, prognosis is still poor largely due to the emergence of temozolomide resistance. This resistance is closely linked to the widely recognized inter- ...

Abstract	Chemotherapy using temozolomide is the standard treatment for patients with glioblastoma. Despite treatment, prognosis is still poor largely due to the emergence of temozolomide resistance. This resistance is closely linked to the widely recognized inter- and intra-tumoral heterogeneity in glioblastoma, although the underlying mechanisms are not yet fully understood. To induce temozolomide resistance, we subjected 21 patient-derived glioblastoma cell cultures to Temozolomide treatment for a period of up to 90 days. Prior to treatment, the cells’ molecular characteristics were analyzed using bulk RNA sequencing. Additionally, we performed single-cell RNA sequencing on four of the cell cultures to track the evolution of temozolomide resistance. The induced temozolomide resistance was associated with two distinct phenotypic behaviors, classified as “adaptive” (ADA) or “non-adaptive” (N-ADA) to temozolomide. The ADA phenotype displayed neurodevelopmental and metabolic gene signatures, whereas the N-ADA phenotype expressed genes related to cell cycle regulation, DNA repair, and protein synthesis. Single-cell RNA sequencing revealed that in ADA cell cultures, one or more subpopulations emerged as dominant in the resistant samples, whereas N-ADA cell cultures remained relatively stable. The adaptability and heterogeneity of glioblastoma cells play pivotal roles in temozolomide treatment and contribute to the tumor’s ability to survive. Depending on the tumor’s adaptability potential, subpopulations with acquired resistance mechanisms may arise.
Keywords	glioblastoma ; temozolomide resistance ; tumor heterogeneity ; single-cell RNA sequencing ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Integrating Colon Cancer Microarray Data

Ana Barat / Heather J. Ruskin / Annette T. Byrne / Jochen H. M. Prehn

Microarrays, Vol 4, Iss 4, Pp 630-

Associating Locus-Specific Methylation Groups to Gene Expression-Based Classifications

2015 Volume 646

Abstract: Recently, considerable attention has been paid to gene expression-based classifications of colorectal cancers (CRC) and their association with patient prognosis. In addition to changes in gene expression, abnormal DNA-methylation is known to play an ... ...

Abstract	Recently, considerable attention has been paid to gene expression-based classifications of colorectal cancers (CRC) and their association with patient prognosis. In addition to changes in gene expression, abnormal DNA-methylation is known to play an important role in cancer onset and development, and colon cancer is no exception to this rule. Large-scale technologies, such as methylation microarray assays and specific sequencing of methylated DNA, have been used to determine whole genome profiles of CpG island methylation in tissue samples. In this article, publicly available microarray-based gene expression and methylation data sets are used to characterize expression subtypes with respect to locus-specific methylation. A major objective was to determine whether integration of these data types improves previously characterized subtypes, or provides evidence for additional subtypes. We used unsupervised clustering techniques to determine methylation-based subgroups, which are subsequently annotated with three published expression-based classifications, comprising from three to six subtypes. Our results showed that, while methylation profiles provide a further basis for segregation of certain (Inflammatory and Goblet-like) finer-grained expression-based subtypes, they also suggest that other finer-grained subtypes are not distinctive and can be considered as a single subtype.
Keywords	colorectal cancer ; gene expression ; locus specific methylation ; colorectal cancer subtypes ; microarrays ; data integration ; Analytical chemistry ; QD71-142 ; Chemistry ; QD1-999 ; Science ; Q
Subject code	570
Language	English
Publishing date	2015-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Durability of cell line xenograft resection models to interrogate tumor micro-environment targeting agents

Ian S. Miller / Liam P. Shiels / Emer Conroy / Kate Connor / Patrick Dicker / William M. Gallagher / Norma O’ Donovan / Robert S. Kerbel / John Crown / Annette T. Byrne

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 10

Abstract: Abstract Angiogenesis is a key tumor microenvironment (TME) event underpinning tumor growth and metastasis. Nevertheless, the relatively poor performance of anti-angiogenic therapies in clinical trials compared to pre-clinical studies implies that ... ...

Abstract	Abstract Angiogenesis is a key tumor microenvironment (TME) event underpinning tumor growth and metastasis. Nevertheless, the relatively poor performance of anti-angiogenic therapies in clinical trials compared to pre-clinical studies implies that classical subcutaneous xenograft models have limited predictive potential in this setting. To address this issue, we established orthotopic surgical resection models of breast cancer, which replicate the phenotype of clinical post-resection micro-metastasis. To demonstrate the power and precision of these models, we recapitulated the BETH adjuvant trial (NCT00625898) where the addition of bevacizumab (BVZ) to chemotherapy plus trastuzumab (Trast) failed to provide additional benefit. SCID mice were orthotopically implanted with bioluminescent Her2+ MDA-MB-231 or HCC1954 cells and tumors resected c.5 weeks later. Following resection, mice were treated with 10 mg/kg Trast +5 mg/kg paclitaxel (PAC) IP once weekly for 6 cycles +/− weekly BVZ (5 mg/kg IP). Metastasis was monitored by imaging. Using these models our data confirms that the addition of the anti-angiogenic antibody BVZ to adjuvant Trast + chemotherapy provides no additional benefit compared with Trast + chemotherapy alone. Previous studies using non-resection subcutaneously engrafted xenografts failed to predict this outcome. Our results provide compelling evidence for the utility of cell line xenograft resection models to predict clinical outcome for TME targeting agents.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer.

Monika A Jarzabek / William R Proctor / Jennifer Vogt / Rupal Desai / Patrick Dicker / Gary Cain / Rajiv Raja / Jens Brodbeck / Dale Stevens / Eric P van der Stok / John W M Martens / Cornelis Verhoef / Priti S Hegde / Annette T Byrne / Jacqueline M Tarrant

PLoS ONE, Vol 13, Iss 6, p e

2018 Volume 0198099

Abstract: Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 ( ...

Abstract	Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab')2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 570
Language	English
Publishing date	2018-01-01T00:00:00Z
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: Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor AResearch in context

Elke Burgermeister / Francesca Battaglin / Fagr Eladly / Wen Wu / Frank Herweck / Nadine Schulte / Johannes Betge / Nicolai Härtel / Jakob N. Kather / Cleo-Aron Weis / Timo Gaiser / Alexander Marx / Christel Weiss / Ralf Hofheinz / Ian S. Miller / Fotios Loupakis / Heinz-Josef Lenz / Annette T. Byrne / Matthias P. Ebert

EBioMedicine, Vol 45, Iss , Pp 139-

2019 Volume 154

Abstract: Background: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like ( ... ...

Abstract	Background: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA. Methods: PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J Apcmin/+; BALB/c nu/nu xenografts) and CRC patients under combination chemotherapy with Beva. BMAL1 single nucleotide gene polymorphisms (SNPs) were analysed by DNA-microarray in clinical samples. BMAL1 functions were studied in human CRC cell lines using colorimetric growth, DNA-binding and reporter assays. Findings: In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (p = .0061) and reduced progression-free survival (PFS) [p = .0223, Hazard Ratio (HR) = 1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound a − 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines. Interpretation: BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy. Fund: This work was in part supported by the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]). Keywords: BMAL1, ARNTL, REVERBA, Bevacizumab, Colorectal cancer, VEGFA
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In Vivo Bioluminescence Imaging Validation of a Human Biopsy–Derived Orthotopic Mouse Model of Glioblastoma Multiforme

Monika A. Jarzabek / Peter C. Huszthy / Kai O. Skaftnesmo / Emmet McCormack / Patrick Dicker / Jochen H.M. Prehn / Rolf Bjerkvig / Annette T. Byrne

Molecular Imaging, Vol

2013 Volume 12

Abstract: Glioblastoma multiforme (GBM), the most aggressive brain malignancy, is characterized by extensive cellular proliferation, angiogenesis, and single-cell infiltration into the brain. We have previously shown that a xenograft model based on serial ... ...

Abstract	Glioblastoma multiforme (GBM), the most aggressive brain malignancy, is characterized by extensive cellular proliferation, angiogenesis, and single-cell infiltration into the brain. We have previously shown that a xenograft model based on serial xenotransplantation of human biopsy spheroids in immunodeficient rodents maintains the genotype and phenotype of the original patient tumor. The present work further extends this model for optical assessment of tumor engraftment and growth using bioluminescence imaging (BLI). A method for successful lentiviral transduction of the firefly luciferase gene into multicellular spheroids was developed and implemented to generate optically active patient tumor cells. Luciferase-expressing spheroids were injected into the brains of immunodeficient mice. BLI photon counts and tumor volumes from magnetic resonance imaging (MRI) were correlated. Luciferase-expressing tumors recapitulated the histopathologic hallmarks of human GBMs and showed proliferation rates and microvessel density counts similar to those of wild-type xenografts. Moreover, we detected widespread invasion of luciferase-positive tumor cells in the mouse brains. Herein we describe a novel optically active model of GBM that closely mimics human pathology with respect to invasion, angiogenesis, and proliferation indices. The model may thus be routinely used for the assessment of novel anti-GBM therapeutic approaches implementing well-established and cost-effective optical imaging strategies.
Keywords	Biology (General) ; QH301-705.5 ; Medical technology ; R855-855.5
Subject code	610
Language	English
Publishing date	2013-05-01T00:00:00Z
Publisher	Hindawi - SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.

Alice C O'Farrell / Rhys Evans / Johanna M U Silvola / Ian S Miller / Emer Conroy / Suzanne Hector / Maurice Cary / David W Murray / Monika A Jarzabek / Ashwini Maratha / Marina Alamanou / Girish Mallya Udupi / Liam Shiels / Celine Pallaud / Antti Saraste / Heidi Liljenbäck / Matti Jauhiainen / Vesa Oikonen / Axel Ducret /

Paul Cutler / Fionnuala M McAuliffe / Jacques A Rousseau / Roger Lecomte / Suzanne Gascon / Zoltan Arany / Bonnie Ky / Thomas Force / Juhani Knuuti / William M Gallagher / Anne Roivainen / Annette T Byrne

PLoS ONE, Vol 12, Iss 1, p e

2017 Volume 0169964

Abstract: Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We ...

Abstract	Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2017-01-01T00:00:00Z
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: Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy

Dominiek Smeets / Ian S. Miller / Darran P. O’Connor / Sudipto Das / Bruce Moran / Bram Boeckx / Timo Gaiser / Johannes Betge / Ana Barat / Rut Klinger / Nicole C. T. van Grieken / Chiara Cremolini / Hans Prenen / Massimiliano Mazzone / Jeroen Depreeuw / Orna Bacon / Bozena Fender / Joseph Brady / Bryan T. Hennessy /

Deborah A. McNamara / Elaine Kay / Henk M. Verheul / Neerincx Maarten / William M. Gallagher / Verena Murphy / Jochen H. M. Prehn / Miriam Koopman / Cornelis J. A. Punt / Fotios Loupakis / Matthias P. A. Ebert / Bauke Ylstra / Diether Lambrechts / Annette T. Byrne

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 16

Abstract: Increased copy number alterations, indicative of chromosomal instability, is associated with poor cancer outcome. Here, metastatic colorectal cancer patients displaying intermediate-high CIN associate with improved outcome following chemotherapy and ... ...

Abstract	Increased copy number alterations, indicative of chromosomal instability, is associated with poor cancer outcome. Here, metastatic colorectal cancer patients displaying intermediate-high CIN associate with improved outcome following chemotherapy and bevacizumab treatment, suggesting CIN as a predictive biomarker.
Keywords	Science ; Q
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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