351 results found
Przystal J, Waramit S, Pranjol MZI, et al., 2019, Efficacy of systemic temozolomide-activated phage-targeted gene therapy in human glioblastoma, EMBO Molecular Medicine, Vol: 11, ISSN: 1757-4676
Glioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno‐associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the αvβ3 integrin receptor. Second, genes are expressed from a tumor‐activated and temozolomide (TMZ)‐induced promoter of the glucose‐regulated protein, Grp78. Here, we investigated systemic combination therapy using TMZ and targeted suicide gene therapy by the RGD4C/AAVP‐Grp78. Firstly, in vitro we showed that TMZ increases endogenous Grp78 gene expression and boosts transgene expression from the RGD4C/AAVP‐Grp78 in human GBM cells. Next, RGD4C/AAVP‐Grp78 targets intracranial tumors in mice following intravenous administration. Finally, combination of TMZ and RGD4C/AAVP‐Grp78 targeted gene therapy exerts a synergistic effect to suppress growth of orthotopic glioblastoma.
Hau Leow C, Bush NL, Stanziola A, et al., 2019, High-contrast 3D in vivo microvascular imaging using scanning 2D ultrasound and acoutic sub-aperture processing (ASAP), IEEE International Ultrasonics Symposium, IUS. 2018, Publisher: IEEE, ISSN: 1948-5719
Non-invasive techniques for microvascular environment assessment are invaluable for clinical diagnosis and treatment monitoring. We recently developed a super contrast processing to suppress noise background in ultrafast Power Doppler, known an acoustic sub-aperture processing (ASAP), and demonstrate using 2D contrast enhance ultrasound. However, 2D imaging is insufficient to represent the 3D complex vascular environment. We therefore extend our study to demonstrate the feasibility of our technique for volumetric imaging. A pseudo-3D imaging technique was developed and demonstrated using a research system and preclinical transducer. A mouse liver was scanned using 2D ultrafast ultrasound and a mechanical translation stage. Initial results not only demonstrated a substantial noise reduction in 2D vascular images using ASAP, but also a high contrast volumetric rendering of a mouse liver. Our technique is ready for clinical use to provide better evaluation of angiogenesis.
Leow CH, Braga M, Bush NL, et al., 2019, Contrast vs non-contrast enhanced microvascular imaging using acoustic sub-aperture processing (ASAP): in vivo demonstration, IEEE International Ultrasonics Symposium, IUS. 2018, Publisher: IEEE, ISSN: 1948-5719
Angiogenesis plays a vital role in the progression of cancer. Non-invasive imaging techniques capable of assessing the microenvironment are therefore of clinical interest. Although highly sensitive vascular mapping has been demonstrated using ultrafast Power Doppler (PD), the detectability of microvasculature from the background noise may be hindered by the low signal-to-noise ratio (SNR) in deeper region and without the use of contrast agents. We recently developed acoustic sub-aperture processing (ASAP) processing for super-contrast vasculature imaging. This technique relies on the spatial coherence of the backscattered echoes over different acquisitions to substantially reduce the noise floor compared to the power Doppler (PD) technique. In this study, we demonstrate the feasibility of applying ASAP processing for non-contrast enhanced microvascular imaging in preclinical condition, and compare it with contrast enhanced ASAP as well as ultrafast PD. Comparing to PD, ASAP exhibit SNR improvement up to 12 dB. Higher SNR and extra visibility of smaller vessel are also demonstrated in contrast enhanced images in comparison to the non-contrast images. In conclusion, we have demonstrated the feasibility of using ASAP in vivo for non-contrast microvascular imaging, and the added benefit of using contrast agents in microvascular imaging.
Vassileva V, Stribbling S, Barnes C, et al., 2019, Evaluation of apoptosis imaging biomarkers in a genetic model of cell death, EJNMMI Research, Vol: 9, ISSN: 2191-219X
PurposeWe have previously developed the caspase-based radiotracer, 18F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18F-ICMT-11 specificity in a murine melanoma death-switch tumour model with conditional activation of caspase-3 induced by doxycycline.MethodsCaspase-3/7 activity and cellular uptake of 18F-ICMT-11, 18F-ML-10 and 18F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction.Death-switch induction was confirmed in vivo in xenograft tumours, and 18F-ICMT-11 and 18F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18F-ICMT-11, 18F-ML-10 and 18F-FDG. Caspase-3 activation was confirmed by immunohistochemistry.ResultsSignificantly increased caspase-3/7 activity was observed only in B16ovaRevC3 cells after death-switch induction, accompanied by significantly increased 18F-ICMT-11 (p < 0.001) and 18F-ML-10 (p < 0.05) and decreased 18F-FDG (p < 0.001) uptake compared with controls.B16ova and B16ovaRevC3 tumours had similar growth in vivo; however, B16ovaRevC3 growth was significantly reduced with death-switch induction (p < 0.01). Biodistribution studies showed significantly increased 18F-ICMT-11 tumour uptake following death-switch induction (p < 0.01), but not for 18F-ML-10. Tumour uptake of 18F-ICMT-11 was higher than that of 18F-ML-10 after death-switch induction. PET imaging studies showed that 18F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18F-FDG signal decreased in tumours after death-switch induction.ConclusionsWe demonstrate that 18F-ICMT-11 can be used to detect caspase-3 activation in a death-switch tumour model, independent of the confounding effects of cancer therapeutics, thus confirming its specificity and supporting the development of this r
Lu H, Arshad M, Thornton A, et al., 2019, A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic and molecular-phenotypes of epithelial ovarian cancer, Nature Communications, Vol: 10, ISSN: 2041-1723
The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35–40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name “Radiomic Prognostic Vector” (RPV). RPV reliably identifies the 5% of patients with median overall survival less than 2 years, significantly improves established prognostic methods, and is validated in two independent, multi-center cohorts. Furthermore, genetic, transcriptomic and proteomic analysis from two independent datasets elucidate that stromal phenotype and DNA damage response pathways are activated in RPV-stratified tumors. RPV and its associated analysis platform could be exploited to guide personalized therapy of EOC and is potentially transferrable to other cancer types.
Jones DT, Valli A, Haider S, et al., 2019, 3D Growth of Cancer Cells Elicits Sensitivity to Kinase Inhibitors but Not Lipid Metabolism Modifiers, MOLECULAR CANCER THERAPEUTICS, Vol: 18, Pages: 376-388, ISSN: 1535-7163
Arshad MA, Thornton A, Lu H, et al., 2019, Discovery of pre-therapy 2-deoxy-2-F-18-fluoro-D-glucose positron emission tomography-based radiomics classifiers of survival outcome in non-small-cell lung cancer patients, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 46, Pages: 455-466, ISSN: 0340-6997
PurposeThe aim of this multi-center study was to discover and validate radiomics classifiers as image-derived biomarkers for risk stratification of non-small-cell lung cancer (NSCLC).Patients and methodsPre-therapy PET scans from a total of 358 Stage I–III NSCLC patients scheduled for radiotherapy/chemo-radiotherapy acquired between October 2008 and December 2013 were included in this seven-institution study. A semi-automatic threshold method was used to segment the primary tumors. Radiomics predictive classifiers were derived from a training set of 133 scans using TexLAB v2. Least absolute shrinkage and selection operator (LASSO) regression analysis was used for data dimension reduction and radiomics feature vector (FV) discovery. Multivariable analysis was performed to establish the relationship between FV, stage and overall survival (OS). Performance of the optimal FV was tested in an independent validation set of 204 patients, and a further independent set of 21 (TESTI) patients.ResultsOf 358 patients, 249 died within the follow-up period [median 22 (range 0–85) months]. From each primary tumor, 665 three-dimensional radiomics features from each of seven gray levels were extracted. The most predictive feature vector discovered (FVX) was independent of known prognostic factors, such as stage and tumor volume, and of interest to multi-center studies, invariant to the type of PET/CT manufacturer. Using the median cut-off, FVX predicted a 14-month survival difference in the validation cohort (N = 204, p = 0.00465; HR = 1.61, 95% CI 1.16–2.24). In the TESTI cohort, a smaller cohort that presented with unusually poor survival of stage I cancers, FVX correctly indicated a lack of survival difference (N = 21, p = 0.501). In contrast to the radiomics classifier, clinically routine PET variables including SUVmax, SUVmean and SUVpeak lacked any prognostic information.ConclusionPET-based radiomics classifiers deriv
Theodorou I, Ruenraroengsak P, Carter D, et al., 2019, Towards multiplexed near-infrared cellular imaging using gold nanostar arrays with tunable fluorescence enhancement, Nanoscale, Vol: 11, Pages: 2079-2088, ISSN: 2040-3364
Sensitive detection of disease biomarkers expressed by human cells is critical to the development of novel diagnostic and therapeutic methods. Here we report that plasmonic arrays based on gold nanostar (AuNS) monolayers enable up to 19-fold fluorescence enhancement for cellular imaging in the near-infrared (NIR) biological window, allowing the application of low quantum yield fluorophores for sensitive cellular imaging. The high fluorescence enhancement together with low autofluorescence interference in this wavelength range enable higher signal-to-noise ratio compared to other diagnostic modalities. Using AuNSs of different geometries and therefore controllable electric field enhancement, cellular imaging with tunable enhancement factors is achieved, which may be useful for the development of multicolour and multiplexed platforms for a panel of biomarkers, allowing to distinguish different subcell populations at the single cell level. Finally, the uptake of AuNSs within HeLa cells and their high biocompatibility, pave the way for novel high-performance in vitro and in vivo diagnostic platforms.
Fu R, Carroll L, Yahioglu GK, et al., 2018, Antibody fragment and affibody immunoPET imaging agents: radiolabelling strategies and applications, ChemMedChem, Vol: 13, Pages: 2466-2478, ISSN: 1860-7187
Antibodies have long been recognised as potent vectors for carrying diagnostic medical radionuclides, contrast agents and optical probes to diseased tissue for imaging. The area of ImmunoPET combines the use of positron emission tomography (PET) imaging with antibodies to improve the diagnosis, staging and monitoring of diseases. Recent developments in antibody engineering and PET radiochemistry have led to a new wave of experimental ImmunoPET imaging agents that are based on a range of antibody fragments and affibodies. In contrast to full antibodies, engineered affibody proteins and antibody fragments such as minibodies, diabodies, single‐chain variable region fragments (scFvs), and nanobodies are much smaller but retain the essential specificities and affinities of full antibodies in addition to more desirable pharmacokinetics for imaging. Herein, recent key developments in the PET radiolabelling strategies of antibody fragments and related affibody molecules are highlighted, along with the main PET imaging applications of overexpressed antigen‐associated tumours and immune cells.
Dubash SR, Merchant S, Heinzmann K, et al., 2018, Clinical translation of [F-18]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 2285-2299, ISSN: 1619-7070
BackgroundEffective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy.ResultsBreast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes.ConclusionThis study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.
Kaliszczak M, Hechanova E, Alsadah H, et al., 2018, The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death, British Journal of Cancer, Vol: 119, Pages: 1278-1287, ISSN: 0007-0920
BACKGROUND: Cytosolic Deacetylase HDAC6 is involved in the autophagy degradationpathway of malformed proteins, an important survival mechanism in cancer cells. Weevaluated modulation of autophagy-related proteins and cell death by the HDAC6-selectiveinhibitor C1A.METHODS: Autophagy substrates (LC3 and p62 proteins) and endoplasmic reticulum (ER)stress phenotype were determined. Caspase 3/7 activation and cellular proliferation assayswere used to assess consequences of autophagy modulation.RESULTS: C1A potently resolved autophagy substrates induced by 3-MA and chloroquine.The mechanism of autophagy inhibition by HDAC6 genetic knockout or C1A treatmentwas consistent with abrogation of autophagosome-lysosome fusion, and decrease of Mycprotein. C1A alone or combined with the proteasome inhibitor, bortezomib, enhanced celldeath in malignant cells demonstrating the complementary roles of the proteasome andautophagy pathways for clearing malformed proteins. Myc positive neuroblastoma, KRASpositive colorectal cancer and multiple myeloma cells showed marked cell growthinhibition in response to HDAC6 inhibitors. Finally, growth of neuroblastoma xenograftswas arrested in vivo by single agent C1A, while combination with bortezomib slowed thegrowth of colorectal cancer xenografts.CONCLUSIONS: C1A resolves autophagy substrates in malignant cells and induces celldeath, warranting its use for in vivo pre-clinical autophagy research.
Heinzmann K, Nguyen Q-D, Honess D, et al., 2018, Depicting changes in tumor biology in response to cetuximab mono- or combination therapy by apoptosis and proliferation imaging using 18F-ICMT-11 and 3’-Deoxy-3’-[18F]Fluorothymidine (18F-FLT) PET, Journal of Nuclear Medicine, Vol: 59, Pages: 1558-1565, ISSN: 1535-5667
Imaging biomarkers must demonstrate their value in monitoring treatment. Two PET tracers, the caspase-3/7–specific isatin-5-sulfonamide 18F-ICMT-11 (18F-(S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluoro-phenoxymethyl)-pyrrolidine-1-sulfonyl)isatin) and 18F-FLT (3′-deoxy-3′-18F-fluorothymidine), were used to detect early treatment-induced changes in tumor biology and determine whether any of these changes indicate a response to cetuximab, administered as monotherapy or combination therapy with gemcitabine. Methods: In mice bearing cetuximab-sensitive H1975 tumors (non–small lung cancer), the effects of single or repeated doses of the antiepidermal growth factor receptor antibody cetuximab (10 mg/kg on day 1 only or on days 1 and 2) or a single dose of gemcitabine (125 mg/kg on day 2) were investigated by 18F-ICMT-11 or 18F-FLT on day 3. Imaging was also performed after 2 doses of cetuximab (days 1 and 2) in mice bearing cetuximab-insensitive HCT116 tumors (colorectal cancer). For imaging–histology comparison, tumors were evaluated for proliferation (Ki-67 and thymidine kinase 1 [TK1]), cell death (cleaved caspase-3 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling [TUNEL]), and target engagement (epidermal growth factor receptor expression) by immunohistochemistry, immunofluorescence, and immunoblotting, respectively. Tumor and plasma were analyzed for thymidine and gemcitabine metabolites by liquid chromatography–mass spectrometry. Results: Retention of both tracers was sensitive to cetuximab in H1975 tumors. 18F-ICMT-11 uptake and ex vivo cleaved caspase-3 staining notably increased in tumors treated with repeated doses of cetuximab (75%) and combination treatment (46%). Although a single dose of cetuximab was insufficient to induce apoptosis, it did affect proliferation. Significant reductions in tumor 18F-FLT uptake (44%–50%; P < 0.001) induce
Valindria V, Lavdas I, Cerrolaza J, et al., 2018, Small organ segmentation in whole-body MRI using a two-stage FCN and weighting schemes, International Workshop on Machine Learning in Medical Imaging (MLMI) 2018, Publisher: Springer Verlag, Pages: 346-354, ISSN: 0302-9743
Accurate and robust segmentation of small organs in whole-body MRI is difficult due to anatomical variation and class imbalance. Recent deep network based approaches have demonstrated promising performance on abdominal multi-organ segmentations. However, the performance on small organs is still suboptimal as these occupy only small regions of the whole-body volumes with unclear boundaries and variable shapes. A coarse-to-fine, hierarchical strategy is a common approach to alleviate this problem, however, this might miss useful contextual information. We propose a two-stage approach with weighting schemes based on auto-context and spatial atlas priors. Our experiments show that the proposed approach can boost the segmentation accuracy of multiple small organs in whole-body MRI scans.
Theodorou I, Jiang Q, Malms L, et al., 2018, Fluorescence enhancement from single gold nanostars: towards ultra-bright emission in the first and second near-infrared biological windows, Nanoscale, Vol: 10, Pages: 15854-15864, ISSN: 2040-3364
Gold nanostars (AuNSs) are promising agents for the development of high-performance diagnostic devices, by enabling metal enhanced fluorescence (MEF) in the physiological near-infrared (NIR) and second near-infrared (NIR-II) windows. The local electric field near their sharp tips and between their branches can be enhanced by several orders of magnitude, holding great promise for large fluorescence enhancements from single AuNS particles, rather than relying on interparticle coupling in nanoparticle substrates. Here, guided by electric field simulations, two different types of AuNSs with controlled morphologies and plasmonic responses in the NIR and NIR-II regions are used to investigate the mechanism of MEF from colloidal AuNSs. Fluorophore conjugation to AuNSs allows significant fluorescence enhancement of up to 30 times in the NIR window, and up to 4-fold enhancement in the NIR-II region. Together with other inherent advantages of AuNSs, including their multispike morphology offering easy access to cell membranes and their large surface area providing flexible multifunctionality, AuNS are promising for the development of in vivo imaging applications. Using time-resolved fluorescence measurements to deconvolute semi-quantitatively excitation enhancement from emission enhancement, we show that a combination of enhanced excitation and an increased radiative decay rate, both contribute to the observed large enhancement. In accordance to our electric field modelling, however, excitation enhancement is the component that varies most with particle morphology. These findings provide important insights into the mechanism of MEF from AuNSs, and can be used to further guide particle design for high contrast enhancement, enabling the development of MEF biodetection technologies.
Lavdas I, Rockall AG, Daulton E, et al., 2018, Histogram analysis of apparent diffusion coefficient from whole-body diffusion-weighted MRI to predict early response to chemotherapy in patients with metastatic colorectal cancer: preliminary results, Clinical Radiology, Vol: 73, Pages: 832.e9-832.e16, ISSN: 0009-9260
AimTo evaluate apparent diffusion coefficient (ADC) histogram analysis parameters, acquired from whole-body diffusion-weighted magnetic resonance imaging (DW-MRI), as very early predictors of response to chemotherapy in patients with metastatic colorectal cancer (mCRC).Materials and methodsThis was a single-institution prospective study, approved by the West Midlands-South Birmingham research ethics committee. All patients gave fully informed consent prior to imaging. Sixteen patients with histologically confirmed mCRC were enrolled to the study and 11 were successfully scanned with whole-body DW-MRI before (baseline) and 10.8±2.7 days after commencing chemotherapy (follow-up). Therapy response was assessed by RECIST 1.1. Mean ADC and histogram parameters (skewness, kurtosis, 25th, 50th, and 75th percentiles) were compared between progressors and non-progressors at baseline and follow-up. Receiver operating characteristics (ROC) analysis was performed for the statistically significant parameters. Data from metastases were also compared to normative tissue data acquired from healthy volunteers.ResultsThree patients had progressive disease (progressors) and eight had partial response/stable disease (non-progressors). Mean, 25th, 50th, and 75th percentiles were significantly lower for progressors at baseline (p=0.012, 0.012, 0.012 and 0.025 respectively) with areas under the ROC curves (AUC)=0.58, 0.50, 0.58 and 0.63, respectively. Skewness and kurtosis were significantly lower for non-progressors at follow-up (p=0.001 and 0.003 respectively) with AUC=0.67 and 0.79 respectively.ConclusionADC histogram analysis shows potential in discriminating progressive from non-progressive disease in patients with mCRC, who underwent whole-body DW-MRI. The technique can potentially be tested as a response assessment methodology in larger trials.
Li H, Stokes WB, Chater E, et al., 2018, Resistance to tyrosine kinase-targeted therapy in lung cancer: Autophagy and metabolic changes, Meta Gene
© 2018 Lung cancer is the commonest cancer killer worldwide. Tyrosine-kinase inhibitors (TKI) are novel agents in the treatment of this cancer. However, their efficacy is impaired by the rapid development of drug-resistance through a variety of mechanisms. Here, we will discuss resistance to the first-generation EGFR inhibitors (e.g. Erlotinib) and SRC inhibitors (e.g. Dasatinib). The principal mechanism of resistance to first-generation EGFR inhibitors is the appearance of the T790M receptor mutation. While the reason for resistance was proposed to be changes in affinity of the receptor for ATP, our metabolomics analysis additionally revealed that resistance is associated with decreased cellular levels of glutathione (GSH), a direct consequence of the T790M mutation. This occurred because of decreased SQSTM1/NRF2-mediated transcription of GSH synthesising enzymes in cell lines and clinical samples with T790M-EGFR. We demonstrate that increasing GSH levels in resistant cells re-sensitises these to first-generation EGFR inhibitors in vitro and in vivo. As compounds exist in the clinic to achieve this, our finding may have profound therapeutic and economic consequences. Src family kinases (SFK) are commonly overexpressed or hyperactivated in lung cancer cell lines and clinical samples. However, despite their on-target efficacy, SRC inhibitors have failed to prevent tumour growth and improve patients’ survival in multiple clinical trial. Here we show that this failure is associated with the induction of autophagy in treated cells that prevents these compounds from triggering apoptosis cell death. Targeting autophagy, either genetically or using our novel small-molecule inhibitor, C1A, sensitises lung cancer cell lines to Dasatinib both in vitro and in vivo by unlocking the apoptotic response. These findings propose new combinational therapeutic strategies that could resurrect the use of SRC inhibitors in the treatment of lung cancer.
Heinzmann K, Schelhaas S, Wachsmuth L, et al., 2018, Thymidine metabolism as confounding factor of 3’-Deoxy-3’-[18F]Fluorothymidine uptake after therapy in a colorectal cancer model, Journal of Nuclear Medicine, Vol: 59, Pages: 1063-1069, ISSN: 1535-5667
Non-invasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer (CRC) xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods: Tumor bearing CD1 nude mice, engrafted with FOLFOX-sensitive Colo205 CRC xenografts, were treated with FOLFOX (5 fluorouracil, leucovorin and oxaliplatin) in weekly intervals. On d1, d2, d6, d9 and d13 of therapy, tumors were assessed by in vivo imaging and ex vivo analyses. In addition, HCT116 xenografts, which did not respond to the FOLFOX treatment, were imaged on d1 of therapy. Results: In Colo205 xenografts, FOLFOX induced a profound increase in uptake of the proliferation PET tracer 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT), which was accompanied by increases in markers for proliferation (Ki67, TK1) and for activated DNA damage response (DDR; γH2AX), whereas the effect on cell death was minimal. As tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrate that [18F]FLT PET can non-invasively monitor molecular alterations induced by a cancer treatment, including thymidine metabolism and DDR. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements.
Pardo OE, Rupniewska E, Roy R, et al., 2018, Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors, Oncotarget, Vol: 9, Pages: 27346-27362, ISSN: 1949-2553
Lung cancer is the main cancer killer in both men and women, mostly due to the rapid development of drug resistant metastatic disease. Here, we evaluate the potential involvement of SRC family kinases (SFK) in lung cancer biology and assess the possible benefits of their inhibition as a therapeutic approach. We demonstrated that various SRC family members, including LYN and LCK, normally expressed solely in hematopoietic cells and neural tissues, are overexpressed and activated in a panel of SCLC and NSCLC cell lines. This was clinically relevant as LYN and FYN are also overexpressed in lung cancer clinical specimens. Moreover, LYN overexpression correlated with decreased patient survival on univariate and multivariate analysis. Dasatinib (BMS-354825), a SRC/ABL inhibitor, effectively blocked SFK activation at nanomolar concentrations which correlated with a significant decrease in cell numbers of multiple lung cancer cell lines. This effect was matched by a decrease in DNA synthesis, but only moderate induction of apoptosis. Indeed, dasatinib as well as PP2, another SFK inhibitor, strongly induced autophagy that likely prevented apoptosis. However, inhibition of this autophagic response induced robust apoptosis and sensitised lung cancer cells to dasatinib in vitro and in vivo. Our results provide an explanation for why dasatinib failed in NSCLC clinical trials. Furthermore, our data suggest that combining SFK inhibitors with autophagy inhibitors could provide a novel therapeutic approach in this disease.
Inglese M, Grech-Sollars M, Ordidge K, et al., 2018, Association between pharmacokinetic parameters from DCE-MRI and metabolic parameters from dynamic 18F-fluoromethylcholine PET in human brain glioma, 27th International Society for Magnetic Resonance in Medicine
Inglese M, Honeyfield L, Aboagye E, et al., 2018, Comparison of the Tofts and the Shutter Speed Model for DCE-MRI in patients with Brain Glioma, 27th International Society for Magnetic Resonance in Medicine
Kramer GM, Liu Y, de Langen AJ, et al., 2018, Repeatability of quantitative18F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 951-961, ISSN: 1619-7070
INTRODUCTION: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative18F-FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of18F-FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. METHODS: A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five18F-FLT repeatability cohorts in solid tumors.18F-FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUVmax, SUVmean, SUVpeak, proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test-retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. RESULTS: Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test-retest data for all18F-FLT uptake metrics (R2 ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUVpeak(RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUVmax ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26-28%), but did not affect the repe
Valindria V, Pawlowski N, Rajchl M, et al., 2018, Multi-modal learning from unpaired images: Application to multi-organ segmentation in CT and MRI, IEEE Winter Conference on Applications of Computer Vision, Publisher: IEEE
Convolutional neural networks have been widely used in medical image segmentation. The amount of training data strongly determines the overall performance. Most approaches are applied for a single imaging modality, e.g., brain MRI. In practice, it is often difficult to acquire sufficient training data of a certain imaging modality. The same anatomical structures, however, may be visible in different modalities such as major organs on abdominal CT and MRI. In this work, we investigate the effectiveness of learning from multiple modalities to improve the segmentation accuracy on each individual modality. We study the feasibility of using a dual-stream encoder-decoder architecture to learn modality-independent, and thus, generalisable and robust features. All of our MRI and CT data are unpaired, which means they are obtained from different subjects and not registered to each other. Experiments show that multi-modal learning can improve overall accuracy over modality-specific training. Results demonstrate that information across modalities can in particular improve performance on varying structures such as the spleen.
Hajitou A, Campbell S, Suwan K, et al., 2018, Selective inhibition of histone deacetylation in melanoma increases targeted gene delivery by a bacteriophage viral vector, Cancers, Vol: 10, ISSN: 2072-6694
The previously developed adeno-associated virus/phage (AAVP) vector, a hybrid between M13 bacteriophage (phage) viruses that infect bacteria only and human Adeno-Associated Virus (AAV), is a promising tool in targeted gene therapy against cancer. AAVP can be administered systemically and made tissue specific through the use of ligand-directed targeting. Cancer cells and tumor-associated blood vessels overexpress the αν integrin receptors, which are involved in tumor angiogenesis and tumor invasion. AAVP is targeted to these integrins via a double cyclic RGD4C ligand displayed on the phage capsid. Nevertheless, there remain significant host-defense hurdles to the use of AAVP in targeted gene delivery and subsequently in gene therapy. We previously reported that histone deacetylation in cancer constitutes a barrier to AAVP. Herein, to improve AAVP-mediated gene delivery to cancer cells, we combined the vector with selective adjuvant chemicals that inhibit specific histone deacetylases (HDAC). We examined the effects of the HDAC inhibitor C1A that mainly targets HDAC6 and compared this to sodium butyrate, a pan-HDAC inhibitor with broad spectrum HDAC inhibition. We tested the effects on melanoma, known for HDAC6 up-regulation, and compared this side by side with a normal human kidney HEK293 cell line. Varying concentrations were tested to determine cytotoxic levels as well as effects on AAVP gene delivery. We report that the HDAC inhibitor C1A increased AAVP-mediated transgene expression by up to ~9-fold. These findings indicate that selective HDAC inhibition is a promising adjuvant treatment for increasing the therapeutic value of AAVP.
Lledos M, Mirabello V, Sarpaki S, et al., 2018, Synthesis, radiolabelling and in vitro imaging of multifunctional nanoceramics, ChemNanoMat, Vol: 4, Pages: 361-372, ISSN: 2199-692X
Molecular imaging has become a powerful technique in preclinical and clinical research aiming towards the diagnosis of many diseases. In this work, we address the synthetic challenges in achieving lab‐scale, batch‐to‐batch reproducible copper‐64‐ and gallium‐68‐radiolabelled metal nanoparticles (MNPs) for cellular imaging purposes. Composite NPs incorporating magnetic iron oxide cores with luminescent quantum dots were simultaneously encapsulated within a thin silica shell, yielding water‐dispersible, biocompatible and luminescent NPs. Scalable surface modification protocols to attach the radioisotopes 64Cu (t1/2=12.7 h) and 68Ga (t1/2=68 min) in high yields are reported, and are compatible with the time frame of radiolabelling. Confocal and fluorescence lifetime imaging studies confirm the uptake of the encapsulated imaging agents and their cytoplasmic localisation in prostate cancer (PC‐3) cells. Cellular viability assays show that the biocompatibility of the system is improved when the fluorophores are encapsulated within a silica shell. The functional and biocompatible SiO2 matrix represents an ideal platform for the incorporation of 64Cu and 68Ga radioisotopes with high radiolabelling incorporation.
Schelhaas S, Heinzmann K, Honess DJ, et al., 2018, 3'-Deoxy-3'-[(18)F]Fluorothymidine uptake is related to thymidine phosphorylase expression in various experimental tumor models, Molecular Imaging and Biology, Vol: 20, Pages: 194-199, ISSN: 1536-1632
PURPOSE: We recently reported that high thymidine phosphorylase (TP) expression is accompanied by low tumor thymidine concentration and high 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake in four untreated lung cancer xenografts. Here, we investigated whether this relationship also holds true for a broader range of tumor models. PROCEDURES: Lysates from n = 15 different tumor models originating from n = 6 institutions were tested for TP and thymidylate synthase (TS) expression using western blots. Results were correlated to [(18)F]FLT accumulation in the tumors as determined by positron emission tomography (PET) measurements in the different institutions and to previously published thymidine concentrations. RESULTS: Expression of TP correlated positively with [(18)F]FLT SUVmax (ρ = 0.549, P < 0.05). Furthermore, tumors with high TP levels possessed lower levels of thymidine (ρ = - 0.939, P < 0.001). CONCLUSIONS: In a broad range of tumors, [(18)F]FLT uptake as measured by PET is substantially influenced by TP expression and tumor thymidine concentrations. These data strengthen the role of TP as factor confounding [(18)F]FLT uptake.
Ali S, Patel H, Periyasamy M, et al., 2018, ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment, Molecular Cancer Therapeutics, ISSN: 1535-7163
Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.
Khan RU, Zhang X, Kumar R, et al., 2018, Evaluating the Performance of ResNet Model Based on Image Recognition, International Conference on Computing and Artificial Intelligence (ICCAI), Publisher: ASSOC COMPUTING MACHINERY, Pages: 86-90
Aboagye EO, James GC, Gao J, et al., 2018, Probabilistic Time Context Framework for Big Data Collaborative Recommendation, International Conference on Computing and Artificial Intelligence (ICCAI), Publisher: ASSOC COMPUTING MACHINERY, Pages: 118-121
Heinzmann K, Honess DJ, Lewis DY, et al., 2017, The relationship between endogenous thymidine concentrations and [F-18]FLT uptake in a range of preclinical tumour models (vol 6, 63, 2016), EJNMMI Research, Vol: 7, ISSN: 2191-219X
Cowell S, Carroll L, Lavdas I, et al., 2017, Towards an MMP-2-activated molecular agent for cancer imaging, Dalton Transactions, Vol: 47, Pages: 1530-1534, ISSN: 1477-9234
Matrix metalloproteinases (MMPs) have been identified as biomarkers for cancer, offering prognostic potential; however, non-invasive detection protocols are currently lacking. Herein, we describe the synthesis of a DOTA-containing peptide sequence that can be radiolabelled easily with 68Gallium or can be incorporated with gadolinium for possible MRI applications with clear selectivity for MMP-2 over other members of the MMP family, giving MMP-2 selective cleavage of the labelled peptides.
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