Edward George Robins
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medegr@nus.edu.sg
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Publication Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson's disease(BioMed Central Ltd, 2020-08-08) Goggi, J.L.; Qiu, L.; Liao, M.C.; Khanapur, S.; Jiang, L.; Boominathan, R.; Hartimath, S.V.; Cheng, P.; Yong, F.F.; Soh, V.; Deng, X.; Lin, Y.M.; Haslop, A.; Tan, P.W.; Zeng, X.; Lee, J.W.L.; Zhang, Z.; Sadasivam, P.; Tan, E.K.; Luthra, S.K.; Shingleton, W.D.; Oh, S.K.W.; Zeng, L.; Robins, E.G.; DEAN'S OFFICE (MEDICINE)Background: Significant developments in stem cell therapy for Parkinson's disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies will be critical for future regulatory approval and application. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cell-derived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD. Methods: Female NIH RNu rats received a unilateral stereotaxic injection of 6-OHDA into the left medial forebrain bundle to create the PD lesion. hESC-mDA cell and sham transplantations were carried out 1 month post-lesion, with treated animals receiving approximately 4 × 105 cells per transplantation. Behavioural analysis, [18F]FBCTT and [18F]fallypride microPET/CT, was conducted at 1, 3 and 6 months post-transplantation and compared with histological characterisation at 6 months. Results: PET imaging revealed transplant survival and maturation into functional dopaminergic neurons. [18F]FBCTT-PET/CT dopamine transporter (DAT) imaging demonstrated pre-synaptic restoration and [18F]fallypride-PET/CT indicated functional dopamine release, whilst amphetamine-induced rotation showed significant behavioural recovery. Moreover, histology revealed that the grafted cells matured differently in vivo producing high- and low-tyrosine hydroxylase (TH) expressing cohorts, and only [18F]FBCTT uptake was well correlated with differentiation. Conclusions: This study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of DAT imaging for the determination of early post-transplant cell maturation and differentiation of hESC-mDAs. © 2020 The Author(s).Publication Improved amyloid burden quantification with nonspecific estimates using deep learning(SPRINGER, 2021-01-07) Liu, Haohui; Nai, Ying-Hwey; Saridin, Francis; Tanaka, Tomotaka; O' Doherty, Jim; Hilal, Saima; Gyanwali, Bibek; Chen, Christopher P; Robins, Edward G; Reilhac, Anthonin; Assoc Prof Li Hsian Christopher Chen; PHARMACOLOGY; DEAN'S OFFICE (MEDICINE); SOLAR ENERGY RESEARCH INST OF S'PORE; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; BIOCHEMISTRYPurpose: Standardized uptake value ratio (SUVr) used to quantify amyloid-β burden from amyloid-PET scans can be biased by variations in the tracer’s nonspecific (NS) binding caused by the presence of cerebrovascular disease (CeVD). In this work, we propose a novel amyloid-PET quantification approach that harnesses the intermodal image translation capability of convolutional networks to remove this undesirable source of variability. Methods: Paired MR and PET images exhibiting very low specific uptake were selected from a Singaporean amyloid-PET study involving 172 participants with different severities of CeVD. Two convolutional neural networks (CNN), ScaleNet and HighRes3DNet, and one conditional generative adversarial network (cGAN) were trained to map structural MR to NS PET images. NS estimates generated for all subjects using the most promising network were then subtracted from SUVr images to determine specific amyloid load only (SAβL). Associations of SAβL with various cognitive and functional test scores were then computed and compared to results using conventional SUVr. Results: Multimodal ScaleNet outperformed other networks in predicting the NS content in cortical gray matter with a mean relative error below 2%. Compared to SUVr, SAβL showed increased association with cognitive and functional test scores by up to 67%. Conclusion: Removing the undesirable NS uptake from the amyloid load measurement is possible using deep learning and substantially improves its accuracy. This novel analysis approach opens a new window of opportunity for improved data modeling in Alzheimer’s disease and for other neurodegenerative diseases that utilize PET imaging.Publication Imaging the proangiogenic effects of cardiovascular drugs in a diabetic model of limb ischemia(Hindawi Limited, 2019) Goggi, J.L.; Haslop, A.; Boominathan, R.; Chan, K.; Soh, V.; Cheng, P.; Robins, E.G.; Bhakoo, K.K.; DEAN'S OFFICE (MEDICINE); PHYSIOLOGYPurpose. Peripheral artery disease (PAD) causes narrowing of arteries in the limbs, leading to tissue ischemia, gangrene, and eventually limb amputation. The presence of diabetes greatly exacerbates the course of PAD, accounting for the majority of lower limb amputations. Therapeutic strategies focussing on macrovascular repair are less effective in diabetic patients where smaller vessels are affected, and proangiogenic therapies offer a viable adjunct to improve vascularisation in these at risk individuals. The purpose of the current study was to assess the proangiogenic effects of drugs routinely used to treat cardiovascular disease in a diabetic murine model of hind limb ischemia longitudinally using multimodal imaging. Procedures. Diabetic mice underwent surgical intervention to induce hind limb ischemia and were treated with simvastatin, metformin, or a combination orally for 28 days and compared to diabetic and nondiabetic mice. Neovascularisation was assessed using [ 18 F]FtRGD PET imaging, and macrovascular volume was assessed by quantitative time of flight MRI. At each imaging time point, VEGF expression and capillary vessel density were quantified using immunohistochemical analysis, and functional recovery and disease progression were assessed. Results. Combined use of simvastatin and metformin significantly increased neovascularisation above levels measured with either treatment alone. Early angiogenic events were accurately assessed using PET [ 18 F]FtRGD, showing maximal retention in the ischemic hind limb by day 8, which translated to a sustained increase in vascular volume at later time points. Immunohistochemical analysis shows that combined therapy significantly increased VEGF expression and capillary density (CD31 + ) in a similar time course and also slowed disease progression while simultaneously improving functional foot use. Conclusions. Combined treatment with simvastatin and metformin led to a significant improvement in limb angiogenesis, vascular volume, and sustained functional recovery in a diabetic murine model of HLI. PET imaging with [ 18 F]FtRGD provides a robust method for early detection of these proangiogenic effects preclinically and may be useful for the assessment of proangiogenic therapies used clinically to treat diabetic PAD patients. © 2019 J. L. Goggi et al.Publication Granzyme B PET Imaging of Combined Chemotherapy and Immune Checkpoint Inhibitor Therapy in Colon Cancer(Springer Science and Business Media Deutschland GmbH, 2021-03-12) Goggi, Julian L.; Hartimath, Siddesh, V; Xuan, Tan Yun; Khanapur, Shivashankar; Jieu, Beverly; Chin, Hui Xian; Ramasamy, Boominathan; Cheng, Peter; Rong, Tang Jun; Fong, Yong Fui; Yuen, Tsz Ying; Msallam, Rasha; Chacko, Ann-Marie; Renia, Laurent; Johannes, Charles; Hwang, You Yi; Robins, Edward G.; DEAN'S OFFICE (MEDICINE); DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLPurpose: Chemotherapeutic adjuvants, such as oxaliplatin (OXA) and 5-fluorouracil (5-FU), that enhance the immune system, are being assessed as strategies to improve durable response rates when used in combination with immune checkpoint inhibitor (ICI) monotherapy in cancer patients. In this study, we explored granzyme B (GZB), released by tumor-associated immune cells, as a PET imaging-based stratification marker for successful combination therapy using a fluorine-18 (18F)-labelled GZB peptide ([18F]AlF-mNOTA-GZP). Methods: Using the immunocompetent CT26 syngeneic mouse model of colon cancer, we assessed the potential for [18F]AlF-mNOTA-GZP to stratify OXA/5-FU and ICI combination therapy response via GZB PET. In vivo tumor uptake of [18F]AlF-mNOTA-GZP in different treatment arms was quantified by PET, and linked to differences in tumor-associated immune cell populations defined by using multicolour flow cytometry. Results: [18F]AlF-mNOTA-GZP tumor uptake was able to clearly differentiate treatment responders from non-responders when stratified based on changes in tumor volume. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumor-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells and GZB+ NK+ cells. Conclusions: [18F]AlF-mNOTA-GZP tumor uptake, driven by changes in immune cell populations expressing GZB, is able to stratify tumor response to chemotherapeutics combined with ICIs. Our results show that, while the immunomodulatory mode of action of the chemotherapies may be different, the ultimate mechanism of tumor lysis through release of Granzyme B is an accurate biomarker for treatment response. © 2021, The Author(s).Publication Imaging adipose tissue browning using the TSPO-18kDa tracer [18F]FEPPA(Elsevier GmbH, 2019) Hartimath, S.V.; Khanapur, S.; Boominathan, R.; Jiang, L.; Cheng, P.; Yong, F.F.; Tan, P.W.; Robins, E.G.; Goggi, J.L.; DIAGNOSTIC RADIOLOGYObjectives: The browning of white adipose tissue (WAT) into beige has been proposed as a strategy to enhance energy expenditure to combat the growing epidemic of obesity. Research into browning strategies are hampered by the lack of sensitive, translatable, imaging tools capable of detecting beige fat mass non-invasively. [18F]FDG is able to detect activated beige fat but provides little information on unstimulated beige fat mass. We have assessed the use of [18F]FEPPA, a tracer for the TSPO-18KDa found on the outer mitochondrial membrane, as an alternative imaging agent capable of detecting unstimulated brown fat (BAT) and beige fat. Methods: Female Balb/c mice (n = 5) were treated for 7 days with the β3 adrenergic agonist CL-316,243 to induce the browning of inguinal WAT (beige fat). Animals were imaged longitudinally with [18F]FDG and [18F]FEPPA and uptake in interscapular BAT and inguinal WAT assessed. The browning of inguinal WAT was confirmed using H&E and immunohistochemical detection of UCP-1 and TSPO. Results: Repeated dosing with β3-adrenergic agonist CL-316,243 caused a significant increase in [18F]FDG uptake in both interscapular BAT and inguinal WAT associated with the increased metabolic activity of brown and beige adipocytes respectively. [18F]FEPPA uptake was likewise increased in inguinal WAT but showed no increase in BAT uptake due to stimulation over the same time course. Furthermore, inguinal WAT uptake was unaffected by pharmacological blockade, indicating that [18F]FEPPA uptake is associated with the expression of mitochondria in BAT and beige adipocytes and independent of activation. Conclusion: These data show that [18F]FEPPA can detect BAT and newly formed beige fat under non-stimulated, thermoneutral conditions and that uptake after stimulation is linked to mitochondrial expression as opposed to activation. © 2019 The AuthorsPublication An improved synthesis of n-(4-[18 f]fluorobenzoyl)-interleukin-2 for the preclinical pet imaging of tumour-infiltrating t-cells in ct26 and mc38 colon cancer models(MDPI AG, 2021-03-19) Khanapur, Shivashankar; Yong, Fui Fong; Hartimath, Siddesh, V; Jiang, Lingfan; Ramasamy, Boominathan; Cheng, Peter; Narayanaswamy, Pradeep; Goggi, Julian L.; Robins, Edward George; DEAN'S OFFICE (MEDICINE)Positron emission tomography (PET) imaging of activated T-cells with N-(4-[18 F]fluorobenzoyl)-interleukin-2 ([18 F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [18 F]FB-IL-2, which reduces synthesis time and improves radiochem-ical yield. With this optimized approach, [18 F]FB-IL-2 was prepared with a non-decay-corrected radiochemical yield of 3.8 ± 0.7% from [18 F]fluoride, 3.8 times higher than previously reported methods. In vitro experiments showed that the radiotracer was stable with good radiochemical purity (>95%), confirmed its identity and showed preferential binding to activated mouse peripheral blood mononuclear cells. Dynamic PET imaging and ex vivo biodistribution studies in naïve Balb/c mice showed organ distribution and kinetics comparable to earlier published data on [18 F]FB-IL-2. Significant improvements in the radiochemical manufacture of [18 F]FB-IL-2 facilitates access to this promising PET imaging radiopharmaceutical, which may, in turn, provide useful insights into different tumour phenotypes and a greater understanding of the cellular nature and differential immune microenvironments that are critical to understand and develop new treatments for cancers. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Publication Imaging fibrogenesis in a diet-induced model of nonalcoholic steatohepatitis (NASH)(Hindawi Limited, 2019) Hartimath, S.V.; Boominathan, R.; Soh, V.; Cheng, P.; Deng, X.; Chong, Y.C.; Yong, F.F.; Tan, P.W.; Han, W.; Robins, E.G.; Goggi, J.L.; DEAN'S OFFICE (MEDICINE)Purpose. Liver fibrosis is the hallmark of chronic nonalcoholic steatohepatitis (NASH) and is characterised by the excessive deposition of extracellular matrix proteins. Early detection and accurate staging of liver fibrosis is critically important for patient management. One of the earliest pathological markers in NASH is the activation of hepatic stellate cells (HSCs) which may be exploited as a marker of fibrogenesis. Activated HSCs secreting factors such as integrin ?v?3 propagate fibrosis. The purpose of the current study was to assess the utility of the integrin ?v?3 imaging agent [18F]FtRGD for the early detection of fibrosis in a diet-induced model of NASH longitudinally using PET imaging. Procedures. Mice were fed with either standard chow diet (SD), high-fat diet (HFD), or a choline-deficient, L-amino acid-defined high-fat fibrogenic diet (CDAHFD) to mimic the clinical pathology of liver disease and followed longitudinally for 10 weeks to assess the development of liver fibrosis using [18F]FtRGD positron emission tomography (PET) imaging. Standard blood biochemistry, histological measures, and qPCR were used to quantify integrin ?v?3, smooth muscle actin, and collagen types 1 and 6 to assess the extent of NASH pathology and accurately stage liver fibrosis. Results. The CDAHFD fibrogenic diet predictably developed hepatic inflammation and steatosis over the 10 weeks studied with little NASH pathology detected in high fat diet-treated animals. Stage 1 fibrosis was detected early by histology at day 21 and progressed to stage 2 by day 35 and stage 3 by day 56 in mice fed with CDAHFD diet only. Noninvasive imaging with [18F]FtRGD correlated well with integrin ?v?3 and was able to distinguish early mild stage 2 fibrosis in CDAHFD animals compared with standard chow diet-fed animals at day 35. When compared with high fat diet-fed animals, [18F]FtRGD was only able to distinguish later moderate stage 2 fibrosis in CDAHFD animals at day 49. Conclusions. The diet-induced progression of liver fibrosis was confirmed using histology and correlated well with the mRNA of integrin ?v?3 and extracellular matrix protein expression. [18F]FtRGD showed very good correlation between liver uptake and integrin ?v?3 expression and similar detection sensitivity to the current clinical gold standard modalities for staging of liver fibrosis. © 2019 S. V. Hartimath et al.Publication Plasma P‐tau181 to Aβ42 ratio is associated with brain amyloid burden and hippocampal atrophy in an Asian cohort of Alzheimer's disease patients with concomitant cerebrovascular disease(Wiley, 2021-02-18) Chong, Joyce R; Ashton, Nicholas J; Karikari, Thomas K; Tanaka, Tomotaka; Saridin, Francis N; Reilhac, Anthonin; Robins, Edward G; Nai, Ying-Hwey; Vrooman, Henri; Hilal, Saima; Zetterberg, Henrik; Blennow, Kaj; Lai, Mitchell KP; Chen, Christopher P; Dr Kim Peng Mitchell Lai; PHARMACOLOGY; DEAN'S OFFICE (MEDICINE)Publication Granzyme B PET Imaging Stratifies Immune Checkpoint Inhibitor Response in Hepatocellular Carcinoma(Hindawi Limited, 2021-12-09) Goggi, Julian L.; Ramasamy, Boominathan; Tan, Yun Xuan; Hartimath, Siddesh V.; Tang, Jun Rong; Cheng, Peter; Msallam, Rasha; Chacko, Ann-Marie; Hwang, You Yi; Robins, Edward G.; DEAN'S OFFICE (MEDICINE); DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLHepatocellular carcinoma (HCC) is a notoriously difficult cancer to treat. The recent development of immune checkpoint inhibitors has revolutionised HCC therapy; however, successful response is only observed in a small percentage of patients. Biomarkers typically used to predict treatment response in other tumour types are ineffective in HCC, which arises in an immune-suppressive environment. However, imaging markers that measure changes in tumour infiltrating immune cells may supply information that can be used to determine which patients are responding to therapy posttreatment. We have evaluated [18F]AlF-mNOTA-GZP, a radiolabeled peptide targeting granzyme B, to stratify response to ICIs in a HEPA 1-tumours, a syngeneic model of HCC. Posttherapy, in vivo tumour retention of [18F]AlF-mNOTA-GZP was correlated to changes in tumour volume and tumour-infiltrating immune cells. [18F]AlF-mNOTA-GZP successfully stratified response to immune checkpoint inhibition in the syngeneic HEPA 1-6 model. FACS indicated significant changes in the immune environment including a decrease in immune suppressive CD4+ T regulatory cells and increases in tumour-associated GZB+ NK+ cells, which correlated well with tumour radiopharmaceutical uptake. While the immune response to ICI therapies differs in HCC compared to many other cancers, [18F]AlF-mNOTA-GZP retention is able to stratify response to ICI therapy associated with tumour infiltrating GZB+ NK+ cells in this complex tumour microenvironment. © 2021 Julian L. Goggi et al.Publication Longitudinal [18F]FB-IL-2 PET Imaging to Assess the Immunopathogenicity of O'nyong-nyong Virus Infection(Frontiers Media S.A., 2020) Chan, Y.-H.; Teo, T.-H.; Torres-Ruesta, A; Hartimath, S.V.; Chee, R.S.-L.; Khanapur, S.; Yong, F.F.; Ramasamy, B.; Cheng, P.; Rajarethinam, R.; Robins, E.G.; Goggi, J.L.; Lum, F.-M.; Carissimo, G.; Rénia, L.; Ng, L.F.P.; DEAN'S OFFICE (MEDICINE); MICROBIOLOGY AND IMMUNOLOGY; BIOCHEMISTRYO'nyong-nyong virus (ONNV) is an arthritogenic alphavirus that caused two large epidemics in 1959 and 1996, affecting millions of people in Africa. More recently, sero-surveillance of healthy blood donors conducted in 2019 revealed high rates of unreported ONNV infection in Uganda. Due to similar clinical symptoms with other endemic mosquito-borne pathogens in the region, including chikungunya virus, dengue virus and malaria, ONNV infections are often un- or misdiagnosed. Elucidating the immunopathogenic factors of this re-emerging arbovirus is critical with the expanding geographic distribution of competent vectors. This study reports the establishment of an immune competent C57BL6/J mouse model to mechanistically characterize ONNV infection and assess potential treatment efficacy. This mouse model successfully recapitulated arthralgia and viremia profiles seen in ONNV patients. Furthermore, longitudinal in-vivo PET imaging with [18F]FB-IL-2 (CD25+CD4+ binding probe) and histopathological assessment in this model demonstrated the pathogenic role of CD4+ T cells in driving joint pathology. Concordantly, in vivo CD4+ T cell depletion, or suppression with fingolimod, an FDA-approved immunomodulating drug, abrogated CD4+ T cell-mediated disease. This study demonstrates the importance of this immune competent ONNV model for future studies on factors influencing disease pathogenesis, which could shape the discovery of novel therapeutic strategies for arthritogenic alphaviruses. © Copyright © 2020 Chan, Teo, Torres-Ruesta, Hartimath, Chee, Khanapur, Yong, Ramasamy, Cheng, Rajarethinam, Robins, Goggi, Lum, Carissimo, Rénia and Ng.