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Impaired mobility is common in people with multiple sclerosis (MS). Changes in gait have different causes and require individualised gait rehabilitation. A common and often early cause of mobility impairment is footdrop, inability to lift the foot during the swing phase of gait, with increased risk of falls, effortful walking and fatigue. Using literature review, we have characterised published data on footdrop treatment in MS, specifically functional electrical stimulation (FES) to better understand the reported outcomes relevant to the user. We discuss the strengths and weaknesses of FES and how far it meets the needs of people with footdrop. Physiotherapy combined with FES may further enhance the benefits of FES. MS studies emphasise the value of maintaining activity levels in early MS but discussion on how to achieve this is lacking. We emphasise the value of qualitative measures to broaden our understanding and improve treatment and adherence and identify areas for further research. Supplementary video material illustrates key features of MS gait and its correction using FES and physiotherapy.

BACKGROUND Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS), experienced by more than 80% of people with MS. FACETS (Fatigue: Applying Cognitive Behavioral and Energy Effectiveness Techniques to Lifestyle) is an evidence-based, face-to-face, 6-session group fatigue management program for people with MS. Homework tasks are an integral part of FACETS and are currently undertaken in a paper-based form. Feedback from a consultation undertaken with FACETS attendees and health care professionals with experience in delivering the FACETS program suggested that being able to complete the homework tasks digitally would be desirable, potentially enhancing engagement and adherence and enabling on-the-go access to fit into busy lifestyles. Relative to other long-term conditions, there are few apps specifically for MS and, of those available, many have been developed with little or no input from people with MS. OBJECTIVE The purpose of this mixed methods study was to create a digital toolkit comprising the homework tasks (eg, activity diary, goal planner, thought diary) of the FACETS program for people with MS, considering end users’ unique requirements throughout the design, build, prototyping, and testing stages. METHODS Phase 1 involved the elicitation of detailed user requirements for the toolkit via 2 focus groups with previous attendees of FACETS (n=3 and n=6) and wireframing. Phase 2 involved supervised usability testing with people with MS (n=11) with iterative prototyping. The usability sessions involved going through test scenarios using the FACETS toolkit on an Android test phone with video capture and concurrent think-aloud followed by completion of the System Usability Scale (SUS) and a semistructured interview collecting feedback about design, content, and functionality. RESULTS The mean SUS score for the digital toolkit was 74.3 (SD 16.8, 95% CI 63.2-85.6; range 37.5-95), which equates to an adjective rating of good and a B grade (70th-79th percentile range) on the Sauro-Lewis curved grading scale. A number of usability and design issues (such as simplifying overall screen flow to better meet users’ needs) and suggestions for improvements (such as using location-based services and displaying personalized information and progress via a central dashboard) were addressed and implemented during the usability testing cycle. CONCLUSIONS This work highlights the importance of the participation of people with MS across the entire development cycle, working to a human-centered design methodology to enable a considered and MS-centered solution to be developed. Continued horizon scanning for emergent technological enhancements will enable us to identify opportunities for further improvements to the FACETS toolkit prior to launch. The toolkit supports self-monitoring and management of fatigue and has potential applicability to other long-term conditions where fatigue is a significant issue.

Purpose Glycogen synthase kinase 3 (GSK3) is a key controlling element of many cellular processes including cell-cycle progression and recent studies suggest that GSK3 is a potential anticancer target. Changes in glucose metabolism associated with GSK3 inhibition may impact on lipid synthesis, whilst lipid metabolites can act as molecular response markers. Methods Here, SKBr3 breast and HCT8 colorectal cancer cells were treated with the GSK3 inhibitor SB216763, and [14C (U)] glucose and [3H] choline incorporation into lipids was determined. Cell extracts from treated cells were subject to 31P NMR spectroscopy. Results SB216763 treatment decreased choline incorporation into lipids and caused an accumulation of CDP-choline which was accompanied by decreased conversion of glucose into lipid components. Conclusion SB216763 profoundly inhibits phospholipid synthesis in cancer cells which demonstrate accumulation of CDP-choline detectable by 31P NMR spectroscopy. Metabolic changes in lipid metabolism present potential response markers to drugs targeting GSK3.

Targeted radiotherapy is proving to be an effective alternative to external beam radiotherapy for cancer treatment. Gold nanoparticles are biocompatible, commercially available, and readily functionalized, which makes them perfect candidates for the delivery of cytotoxic radionuclides labeled with antibodies to proteins abnormally expressed on cancer tissue. However, there is a lack of information regarding the efficacy of the successive modification steps involved in the functionalization process, as well as of the actual final state of the nanoparticles prior to preclinical tests, which results in a very inefficient screening and that will further impact on biological barriers, such as half-life interactions with serum proteins. Here, gold nanoparticles (15 nm diameter) were functionalized with linkers for antibody and radionuclide conjugation, following a well-stablished method. Successful coating of the gold nanoparticles was demonstrated using state-of-the-art physicochemical techniques, which include AF4-UV-ICPMS-MALS, Raman spectroscopy, and force-distance spectroscopy, which have led to an accurate description of the hydrodynamic diameter of the functionalized NPs and also about the adhesion energy and elastic properties of the modified NPs. Successive steps involved in the coating led to an organic shell of 12 nm diameter and no nanoparticle aggregation was observed. This may be a consequence of a decrease (or even the total absence) in water adsorption on the metal surface and/or of the organic labeling, that decreases the surface tension of the particles as estimated from the atomic force microscopy force-distance curves. Radiolabeling of gold nanoparticles prescreened using these physicochemical tools with

Summary Signal transduction pathways, which regulate cell growth and survival, are up-regulated in many cancers and there is considerable interest in their pharmaceutical modulation for cancer treatment. However inhibitors of single pathway components induce feedback mechanisms that overcome the growth moderating effect of the inhibitor. Combination treatments have been proposed to provide a more complete pathway inhibition. Here the effect of dual treatment of cancer cells with a pan-Akt and a pan-mTOR inhibitor was explored. Breast (SKBr3 and MDA-MB-468) and colorectal (HCT8) cancer cells were treated with the pan-Akt inhibitor MK2206 and pan-mTOR inhibitor AZD8055. Cytotoxic effect of the two drugs were determined using the MTT assay and the Combination Index and isobolomic analysis used to determine the nature of the interaction of the two drugs. Flow cytometry and western blot were employed to demonstrate drug effects on cell cycle distribution and phosph-Aktser473 expression. Radiolabelled ([methyl-3H]) Choline uptake was measured in control and drug-treated cells to determine the modulatory effects of the drugs on choline incorporation. The two drugs acted synergistically to inhibit the growth rate of each cancer cell line. Flow cytometry demonstrated G0/G1 blockade with MK2206 and AZD8055 which was greater when cells were treated with both drugs. The incorporation of [methyl-3H] choline was found be decreased to a greater extent in cells treated with both drugs compared with cells treated with either drug alone. Conclusions Pan-mTOR and pan-Akt inhibition may be highly effective in cancer treatment and measuring changes in choline uptake could be useful in detecting efficacious drug combinations.

Colony counting by eye is time consuming and subjective. Here comparison between the measurements of proliferative growth inhibition in plates of radiation-treated cells by an imaging station correlated highly significantly with counts determined by eye. This would suggest that an imaging station could be a viable alternative for colony counting for doses over 200KBq.

The article describes the design, manufacturing, modelling and testing of a hybrid composite support made from auxetic open cell foam liners and curved thermoplastic plates with rhomboidal perforations for human body support. Both the foam and the curved perforated plate have in-plane negative Poisson's ratio behaviour. The static bending stiffness of the hybrid auxetic composite support is modelled using an analytical and Finite Element approach benchmarked against experimental results from three-point bending tests. The benchmarked Finite Element models are used to develop a map of optimised static stiffness versus the geometry of the rhomboidal perforations. A Design of Experiment testing campaign is also carried out on 16 hybrid auxetic composite plates to understand the interaction and correlation of the static bending versus the geometry of the perforations and the contribution given by the auxetic foam liner.

9 pags. 6 figs., Cu0(core)-Au0(shell) (Cu@Au) bimetallic nanoparticles (NPs) synthesized under microwave-assisted heating were interrogated for surface enhanced Raman scattering (SERS)-active substrates. NPs characterization, by XRD, XPS and UV/vis spectroscopy, showed the formation of self-assembled particles with the occurrence of electron transfer from Cu to Au and the absence of CuxO. TEM and AF4 demonstrated NPs with a mean diameter of 4.7 nm. Despite the low LSPR shown by small nanoparticles (, Funded by Chief Scientists Office (TCS/16/07), Tenovus Scotland(G15-03) and the University of Aberdeen Development Trust. KCNgratefully acknowledges the University of Aberdeen for theElphinstone PhD scholarship (RG13451-10) and to Postnova Ana-lytics UK for the loan of the AF4 system together with training,support, and advice on the technique. AM Mendez gratefully ac-knowledges CONICYT (National Commission of Scientific andTechnological Research, Chile) for scholarship (21160174). Micro-scopy was performed in the Microscopy and Histology Core Facilityat the University of Aberdeen.

BACKGROUND Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS) and is the main reason why people with MS stop working early. The MS Society in the United Kingdom funded a randomized controlled trial of FACETS—a face-to-face group-based fatigue management program for people with multiple sclerosis (pwMS)—developed by members of the research team. Given the favorable trial results and to help with implementation, the MS Society supported the design and printing of the FACETS manual and materials and the national delivery of FACETS training courses (designed by the research team) for health care professionals (HCPs). By 2015 more than 1500 pwMS had received the FACETS program, but it is not available in all areas and a face-to-face format may not be suitable for, or appeal to, everyone. For these reasons, the MS Society funded a consultation to explore an alternative Web-based model of service delivery. OBJECTIVE The aim of this study was to gather views about a Web-based model of service delivery from HCPs who had delivered FACETS and from pwMS who had attended FACETS. METHODS Telephone consultations were undertaken with FACETS-trained HCPs who had experience of delivering FACETS (n=8). Three face-to-face consultation groups were held with pwMS who had attended the FACETS program: London (n=4), Liverpool (n=4), and Bristol (n=7). The interviews and consultation groups were digitally recorded and transcribed. A thematic analysis was undertaken to identify key themes. Toward the end of the study, a roundtable meeting was held to discuss outcomes from the consultation with representatives from the MS Society, HCPs, and pwMS. RESULTS Key challenges and opportunities of designing and delivering an integrated Web-based version of FACETS and maintaining user engagement were identified across 7 themes (delivery, online delivery, design, group, engagement, interactivity, and HCP relationships). Particularly of interest were themes related to replicating the group dynamics and the lack of high-quality solutions that would support the FACETS’ weekly homework tasks and symptom monitoring and management. CONCLUSIONS A minimum viable Web-based version of FACETS was suggested as the best starting point for a phased implementation, enabling a solution that could then be added to over time. It was also proposed that a separate study should look to create a free stand-alone digital toolkit focusing on the homework elements of FACETS. This study has commenced with a first version of the toolkit in development involving pwMS throughout the design and build stages to ensure a user-centered solution.

Background: Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS) and is the main reason why people with MS stop working early. The MS Society in the United Kingdom funded a randomized controlled trial of FACETS—a face-to-face group-based fatigue management program for people with multiple sclerosis (pwMS)—developed by members of the research team. Given the favorable trial results and to help with implementation, the MS Society supported the design and printing of the FACETS manual and materials and the national delivery of FACETS training courses (designed by the research team) for health care professionals (HCPs). By 2015 more than 1500 pwMS had received the FACETS program, but it is not available in all areas and a face-to-face format may not be suitable for, or appeal to, everyone. For these reasons, the MS Society funded a consultation to explore an alternative Web-based model of service delivery. Objective: The aim of this study was to gather views about a Web-based model of service delivery from HCPs who had delivered FACETS and from pwMS who had attended FACETS. Methods: Telephone consultations were undertaken with FACETS-trained HCPs who had experience of delivering FACETS (n=8). Three face-to-face consultation groups were held with pwMS who had attended the FACETS program: London (n=4), Liverpool (n=4), and Bristol (n=7). The interviews and consultation groups were digitally recorded and transcribed. A thematic analysis was undertaken to identify key themes. Toward the end of the study, a roundtable meeting was held to discuss outcomes from the consultation with representatives from the MS Society, HCPs, and pwMS. Results: Key challenges and opportunities of designing and delivering an integrated Web-based version of FACETS and maintaining user engagement were identified across 7 themes (delivery, online delivery, design, group, engagement, interactivity, and HCP relationships). Particularly of interest were themes related to replicating the group dynamics and the lack of high-quality solutions that would support the FACETS’ weekly homework tasks and symptom monitoring and management. Conclusions: A minimum viable Web-based version of FACETS was suggested as the best starting point for a phased implementation, enabling a solution that could then be added to over time. It was also proposed that a separate study should look to create a free stand-alone digital toolkit focusing on the homework elements of FACETS. This study has commenced with a first version of the toolkit in development involving pwMS throughout the design and build stages to ensure a user-centered solution.

Metformin, currently undergoing clinical trials as an adjuvant for the treatment of breast cancer, modulates the activity of key intracellular signalling molecules which affect 2-[(18)F]Fluoro-2-deoxy-D-glucose ([(18)F]FDG) incorporation. Here, we investigate the effect of drugs used in the treatment of breast cancer combined with metformin on [(18)F]FDG incorporation in HER2- or HER1-overexpressing breast cancer cells to determine whether or not metformin may obscure changes in [(18)F]FDG incorporation induced by clinically utilised anticancer drugs in the treatment of breast cancer.Three breast cancer cell lines expressing HER2 and one HER2 negative but HER1 positive were exposed to metformin, doxorubicin and trastuzumab or cetuximab. Cytotoxicity was measured by the MTT assay. Expression of active (phospho-) AMPK, PKB (Akt) and ERK was determined by Western blotting. [(18)F]FDG incorporation by cells exposed to drug combinations with metformin was determined. Glucose transport was assessed by measuring the initial rate of uptake of [(3)H]O-methyl-D-glucose ([(3)H]OMG). Phosphorylation of [(18)F]FDG was determined in intact cells after exposure to [(18)F]FDG.Phospho-AMPK was increased by metformin in all cell lines whilst phospho-Akt and phospho-ERK expressions were decreased in two. Metformin treatment increased [(18)F]FDG incorporation in all cell lines, and treatment with anti-HER antibodies or doxorubicin only produced minor modulations in the increase induced by metformin alone. Glucose transport was increased in BT474 cells and decreased in SKBr3 and MDA-MB-468 cells after treatment with metformin. The fraction of phosphorylated [(18)F]FDG was increased in metformin-treated cells compared with controls, suggesting that hexokinase efficiency was increased by metformin.This is the first study to show that increased [(18)F]FDG incorporation by breast cancer cells induced by metformin overwhelms the effect of doxorubicin and anti-HER treatments on [(18)F]FDG incorporation. Metformin-induced increased [(18)F]FDG incorporation was consistently associated with enhanced [(18)F]FDG phosphorylation.

A method to characterise upper-limb tremor using inverse dynamics modelling in combination with cross-correlation analyses is presented. A 15 degree-of-freedom inverse dynamics model is used to estimate the joint torques required to produce the measured limb motion, given a set of estimated inertial properties for the body segments. The magnitudes of the estimated torques are useful when assessing patients or evaluating possible intervention methods. The cross-correlation of the estimated joint torques is proposed to gain insight into how tremor in one limb segment interacts with tremor in another. The method is demonstrated using data from a single patient presenting intention tremor because of multiple sclerosis. It is shown that the inertial properties of the body segments can be estimated with sufficient accuracy using only the patient's height and weight as a priori knowledge, which ensures the method's practicality and transferability to clinical use. By providing a more detailed, objective characterisation of patient-specific tremor properties, the method is expected to improve the selection, design and assessment of treatment options on an individual basis.

HER-2 overexpression does not guarantee response to HER2-targeting drugs such as trastuzumab, which is cardiotoxic and expensive, so early detection of response status is crucial. Factors influencing [(18)F]FDG incorporation in the timeframe of cell signalling down-regulation subsequent to trastuzumab treatment are investigated to provide a better understanding of the relationship between growth response and modulation of [(18)F]FDG incorporation. HER-2-overexpressing breast tumour cell lines, MDA-MB-453, SKBr3 and BT474 and MDA-MB-468 (HER2 non-over-expressor) were treated with trastuzumab (4 h) and probed for AKT, pAKT, ERK1/2, pERK1/2 and HIF-1α to determine early signalling pathway inhibitory effects of trastuzumab. Cells incubated with trastuzumab and/or PI3K inhibitor LY294002 and ERK1/2 inhibitor U0126 and glucose transport and [(18)F]FDG incorporation measured. Cell lines expressed AKT, pAKT, ERK1/2 and pERK1/2 but not HIF-1α. Trastuzumab treatment decreased pAkt but not pERK1/2 levels. Trastuzumab did not further inhibit AKT when maximally inhibited with LY294002. Treatment with LY294002 and trastuzumab for 4 h decreased [(18)F]FDG incorporation in BT474 and MDA-MB-453 but not SKBr3 cells. LY294002 inhibited glucose transport by each cell line, but the glucose transport rate was tenfold higher by SKBr3 cells than BT474 and MDA-MB-453 cells. AKT-induced uptake of [(18)F]FDG was found to be HIF-1α independent in breast cancer cell lines. AKT inhibition level and tumour cell glucose transport rate can influence whether or not PI3K inhibitors affect [(18)F]FDG incorporation which may account for the variation in preclinical and clinical findings associated with [(18)F]FDG-PET in response to trastuzumab and other HER-2 targeting drugs.

Hypoxia can stimulate (18)F-fluorodeoxyglucose (FDG) uptake in cultured cells. A better understanding of the underlying molecular mechanism is required to determine the value of FDG for studying tumour hypoxia.The effect of hypoxia on FDG uptake, and key proteins involved in glucose transport and glycolysis, was studied in MCF7 and MDA231 breast cancer cell lines.Hypoxia induced a dose- and time-dependent increase in FDG uptake. The FDG increase was transient, suggesting that FDG uptake is only likely to be increased by acute hypoxia (24 h). Molecular analysis indicated that hypoxia upregulated glut1 and 6-phosphofructo-2-kinase, key proteins involved in regulating glucose transport and glycolysis, and that these changes were induced by Hypoxia-Inducible factor 1 (HIF1) upregulation and/or AMP-activated protein kinase activation.FDG may provide useful information about the oxygenation status of cells in hypoxic regions where HIF1 upregulation is hypoxia-driven.

Androgen receptor (AR) activation is the primary driving factor in prostate cancer which is initially responsive to castration but then becomes resistant (castration-resistant prostate cancer (CRPC)). CRPC cells still retain the functioning AR which can be targeted by other therapies. A recent promising development is the use of inhibitors (Epi-1) of protein-protein interaction to inhibit AR-activated signalling. Translating novel therapies into the clinic requires sensitive early response indicators. Here potential response markers are explored. Growth inhibition of prostate cancer cells with flutamide, paclitaxel, and Epi-1 was measured using the MTT assay. To simulate choline-PET scans, pulse-chase experiments were carried out with [H3-methyl]choline and proportion of phosphorylated activity was determined after treatment with growth inhibitory concentrations of each drug. Extracts from treated cells were also subject to 31P-NMR spectroscopy. Cells treated with flutamide demonstrated decreased [H3-methyl]choline phosphorylation, whilst the proportion of phosphorylated [H3-methyl]choline that was present in the lipid fraction was increased in Epi-1-treated cells. Phospholipid breakdown products, glycerophosphorylcholine and glycerophosphoethanolamine levels, were shown by 31P-NMR spectroscopy to be decreased to undetectable levels in cells treated with Epi-1. LNCaP cells responding to treatment with novel protein-protein interaction inhibitors suggest that 31P-NMR spectroscopy may be useful in detecting response to this promising therapy.

Akt is an intracellular signalling pathway that serves as an essential link between cell surface receptors and cellular processes including proliferation, development and survival. The pathway has many downstream targets including glycogen synthase kinase3 which is a major regulatory kinase for cell cycle transit as well as controlling glycogen synthase activity. The Akt pathway is frequently up-regulated in cancer due to overexpression of receptors such as the epidermal growth factor receptor, or mutation of signalling pathway kinases resulting in inappropriate survival and proliferation. Consequently anticancer drugs have been developed that target this pathway. MDA-MB-468 breast and HCT8 colorectal cancer cells were treated with inhibitors including LY294002, MK2206, rapamycin, AZD8055 targeting key kinases in/associated with Akt pathway and the consistency of changes in 31P-NMR-detecatable metabolite content of tumour cells was examined. Treatment with the Akt inhibitor MK2206 reduced phosphocholine levels in MDA-MB-468 cells. Treatment with either the phosphoinositide-3-kinase inhibitor, LY294002 and pan-mTOR inhibitor, AZD8055 but not pan-Akt inhibitor MK2206 increased uridine-5′-diphosphate-hexose cell content which was suppressed by co-treatment with glycogen synthase kinase 3 inhibitor SB216763. This suggests that there is an Akt-independent link between phosphoinositol-3-kinase and glycogen synthase kinase3 and demonstrates the potential of 31P-NMR to probe intracellular signalling pathways.

[18F]Fluorination is usually carried out by nucleophilic substitution reactions entailing the use of stringent conditions. A number of novel techniques including silicon and boron-based fluoride acceptor molecules, [18F]fluoro-2-deoxy- d-glucose and chelation of the Al18F complex have been employed recently to achieve [18F]radiolabelling of macromolecules. These approaches are reviewed herein. Copyright © 2012 John Wiley & Sons, Ltd.

Breast tumours responding to chemotherapy exhibit decreased []fluoro-2-deoxy-D-glucose ([]FDG) incorporation. Underlying mechanisms of these changes is poorly understood. Here, in MCF-7 cells, responding to chemotherapy drugs commonly utilised in the treatment of breast cancer, []FDG incorporation and several pivotal factors associated with []FDG incorporation investigated. Methods. IC50 and subclinical doxorubicin, docetaxel, and tamoxifen doses determined using MTT assay. []FDG incorporation by cells treated with IC50 drug doses for 48 hours and 72 hours were determined and FDG dephosphorylation estimated by measuring loss of 18F from []FDG-preincubated cells (pulse-chase). Glucose transport determined by measuring initial uptake rate of non-metabolised glucose analogue omethylglucose; hexokinase activity and ATP content measured in cell homogenates; Cell cycle distribution determined using flow cytometry of propidium iodide stained nuclei. Results. []FDG incorporation and ATP content decreased in cells after 72 hours treatment with IC50 doses of tamoxifen, doxorubicin, and docetaxel compared with untreated controls. Decreased glucose transport and/or hexokinase activity accompanied decreased []FDG incorporation by MCF-7 cells treated with tamoxifen or doxorubicin but not docetaxel. Conclusions. Tumour cell []FDG incorporation along with ATP content decreased by treatment with tamoxifen, doxorubicin and docetaxel paralleling clinical observations for solid tumours. Effect of each treatment on glucose transport and hexokinase activity was chemotherapy-drug dependent.

In terms of nuclear decay 18F is the most ideal PET nuclide but its short t1/2 precludes its use for directly labelling whole antibodies due to their long blood residence times. Pre-targeted imaging using affinity systems such as Neutravidin™–biotin facilitates the application of short-lived nuclides by their attachment to biotin for imaging cell surface proteins targeted with Neutravidin™-conjugated antibodies. Methods Boroaryl functionalised biotin was prepared with a PEG linker and radiolabelled by incubation with 18F in acidified aqueous solution. Cells expressing high (SKBr3), medium (MDA-MB-453) and low (MDA-MB-468) levels of HER-2 were pre-incubated with Neutravidin™-conjugated trastuzumab, washed, and then incubated with 18F-PEG-biotin. Results The 18F-fluorination of boroaryl-PEG-biotin was much more efficient than reported for other versions of boroaryl-biotin. The novel 18F-PEG-biotin was demonstrated to bind to HER-2-expressing cells in-vitro pre-incubated with Neutravidin™-conjugated trastuzumab. Conclusion Biotin can be functionalised with boroaryl and readily 18F-radiolabelled in aqueous solution and will bind to cells pre-incubated with Neutravidin™–antibody conjugates.

The biotin–avidin affinity system is exploited in pre-targeted imaging using avidin-conjugated antibodies. 18F-FDG is available at all PET centres. 18F-FDG forms oximes by reaction with oxyamine. Herein we describe the synthesis of oxyamine—funtionalised biotin, its 18F-labelling by conjugation with 18F-FDG and confirm its ability to interact with avidin.

Cetuximab, an anti-HER1 (EGFR) antibody, is currently under trial for the treatment of breast cancer. HER1 expression is not necessarily a predictor of response to cetuximab as mutant components of the pathways activated by HER1 which include PI3K/Akt can lead to resistance. Techniques that monitor events downstream of HER1 are more likely to provide an accurate measure of the efficacy of an anti-HER1 treatment. Glucose metabolism has been shown to be strongly influenced by the state of activation of PI3K/Akt. Here, the association between [18F]-FDG incorporation in breast cancer cells during response to cetuximab is investigated. The study also reviews the development of medical imaging probes that target HER1 The sensitivity to cetuximab of three breast tumour cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing HER1 at low and high levels, are determined using an MTT assay over a six-day period and a clonogenic assay carried out after seven- and 10-day exposures. Incorporation of FDG by cells treated with growth inhibitory doses of cetuximab were carried out after 4 hand two, four and six days of treatment. Glucose transport (rate of uptake of the non-metabolisable analogue [3H]o-methyl-D-glucose), hexokinase activity and lactate production were measured on cells treated with inhibitory doses of cetuximab for six days. The IC50, dose for MDA-MB-468 cells and the IC10 (maximum achievable inhibition) doses for MDA-MB-543 and SKBr3 treated with cetuximab for six days were 2.6, 5 and 148 microg/mL, respectively. Incorporation of FDG by SKBr3 and MDA-MB-453 cells was found to be decreased by MDA-MB468 cells using IC50, and IC20, doses of cetuximab for six days. Lactate production was found to be increased by MDA-MB-468 cells responding to cetuximab. Incorporation of FDG at the tumour cell level is modulated by treatment with growth inhibitory doses of cetuximab in cells sensitive to cetuximab due to modulation of HK activity.

HER-2/neu (a receptor for human epidermal growth factor) is involved in cell survival, proliferation, angiogenesis and invasiveness. It is overexpressed in about 25% of breast cancers. Overexpression of HER-2 is associated with response to the anti-HER-2 antibody trastuzumab (herceptin). However, HER-2 expression can be heterogeneous within the primary tumour and can also exhibit discordant expression between a primary tumour and its metastases, bringing into question the practice of HER-2 screening to determine whether a patient is a candidate for trastuzumab using material obtained only from the primary tumour. Medical imaging modalities using HER-2-targeted tracers (or contrast agents) facilitate a global approach to the determination of HER-2 expression across all detectable tumour lesions, and could provide a more reliable indication of the patient's likely response to trastuzumab treatment. Here, I review the development and pre-clinical (and occasional clinical) assessment of HER-2-targeted tracers. I discuss studies in which established imaging tracers, such as (11)C-choline, have been used to determine response to trastuzumab in a range of medical imaging modalities, including positron emission tomography (PET), single photon emission tomography (SPECT), MRI and optical imaging.

Both mutant p53 and chemoresistance are poor prognostic factors in cancer. Many studies have examined the influence of these factors on fluoro-2-deoxy-D-glucose (FDG) incorporation. Whilst mutant p53 is associated with increased FDG incorporation, chemoresistance, especially when associated with P-glycoprotein, is associated with decreased FDG incorporation.

Introduction: Tumor refractoriness to chemotherapy is frequently due to the acquisition of resistance. Resistant cells selected by exposure to chemotherapy agents may exhibit differences in [ 18 F]fluoro-2-deoxy-D-glucose (FDG) incorporation, as compared with sensitive cells. Methods: FDG incorporation, hexokinase (HK) activity, glucose transport and ATP content were determined in clones of 5-fluorouracil (5FU)-resistant MCF7 cells, established by long-term exposure to increasing 5FU concentrations, and in parental MCF7 cells. Results: FDG incorporation was decreased in MCF7 cells resistant to 5FU; HK activity was similar in the resistant and sensitive cells, while glucose transport was increased, as compared with sensitive cells. Treatment of cells with the glucose efflux inhibitor phloretin increased FDG incorporation to similar levels in the resistant and sensitive cells. Analysis of microarray data demonstrated the expression of GLUT1, 8 and 10 transporters in MCF7 cells. GLUT8 and 10 expression was decreased in the resistant cells, while GLUT1 was only increased in cells resistant to the lowest 5FU concentration. Conclusion: FDG incorporation in 5FU-resistant MCF7 cells is decreased, as compared with sensitive cells. Our findings also suggest that this may be due to high rates of membrane glucose transport in the resistant cells resulting in enhanced efflux of FDG. We believe that this is the first demonstration that facilitative glucose transporters can actually decrease the incorporation of FDG.

Decreased tumour [(18)F]2-fluoro-2-deoxy-D-glucose ((18)FDG) incorporation is related to response however its significance at the cell level in gastro-oesophageal cancer and how it relates to cell death is unknown. Here human gastric adenocarcinoma (AGS) cells were treated with lethal dose 10 and 50 (LD(10) and LD(50)), determined by using the MTT assay, of the three drugs, epirubicin, 5-fluorouracil and cisplatin, commonly used in the treatment of patients with gastro-oesophageal cancer. (18)FDG incorporation was determined after 48 and 72 h of treatment with each drug and related to drug-induced changes in glucose transport, hexokinase activity, cell cycle distribution and annexin V-PE binding (a measure of apoptosis). Treatment of cells for 48 and 72 h with LD(50) doses of cisplatin resulted in reductions in (18)FDG incorporation of 27 and 25% respectively and of 5-fluorouracil reduced (18)FDG incorporation by 34 and 33% respectively: epirubicin treatment reduced incorporation by 30 and 69% respectively. Cells that had been treated for 72 h with each drug were incubated in drug-free media for a further 6 days to determine their ability to recover. Comparison of the ability to recover from the chemotherapy agent, with (18)FDG incorporation before the recovery period allowed an assessment of the predictive ability of (18)FDG incorporation. Cells treated with either 5-fluorouracil or cisplatin demonstrated recovery on removal of the drug. In contrast, cells treated with epirubicin did not recover corresponding with the greatest 72 h treatment decrease in (18)FDG incorporation. In contrast to adherent cells treated with cisplatin or 5-fluorouracil, adherent epirubicin-treated cells also exhibited very high levels of apoptosis. Glucose transport was decreased after each treatment whilst hexokinase activity was only decreased after 72 h of treatment with each drug. There was no consistent relationship observed between (18)FDG incorporation and cell cycle distribution. Our results show that at the tumour cell level in gastric tumour cells, decreased (18)FDG incorporation and glucose transport, accompanies therapeutic growth inhibition. (18)FDG incorporation is particularly diminished in cells exhibiting apoptosis.

In this paper, we describe the radiosynthesis of the compound (E)-2,3′,4,5′-tetramethoxy[2-11C]stilbene, a potential, universal tumour positron emission tomography imaging agent. The production of (E)-2,3′,4,5′-tetramethoxy[2-11C]stilbene was carried out via 11C-methylation of (E)-2-(hydroxy)-3′,4,5′-trimethoxystilbene by using [11C]methyl trifluoromethanesulfonate ([11C]methyl triflate). (E)-2,3′,4,5′-tetramethoxy[2-11C]stilbene was obtained with a radiochemical purity greater than 95% in a 20 ± 2% decay-corrected radiochemical yield, based upon [11C]carbon dioxide. Synthesis, purification and formulation were completed on an average of 30 min following the end of bombardment (EOB). The specific radioactivity obtained was 1.9 ± 0.6 GBq/µmol at EOB. Copyright © 2007 John Wiley & Sons, Ltd.

This pilot study reports the uptake of 99mTc-transferrin by MCF7 cells and the biodistribution of the complex in mice bearing MCF7 tumours. Human serum holo-transferrin was labelled with 99mTc using pre-reduction with 2-mercaptoethanol. The uptake of the complex by MCF7 breast tumour cells, which was found to be competitively inhibited by the presence of unlabelled transferrin, reached a plateau within 30 min. Two groups of xenografted mice with small and large tumours, respectively, were injected with the complex, and the uptake was followed for up to 24 h post-administration using a dedicated gamma camera. The mean tumour uptake values, determined after dissection, in the two groups of mice were 6% (small tumours) and 1.7% (large tumours) of the injected dose per gram of tissue, with mean tumour/blood ratios of 2.7 and 1.7, respectively.

Clinical scales based on visual observation are routinely used to assess pathological tremors, informing diagnoses and treatment selection. Because these scales incorporate elements that are subjective and limited in accuracy, sensor-based measurements of tremor are increasingly being considered as a means of improving on current practice. The translational potential of such measurement systems can be limited by their complexity and insufficient characterisation of how the new measures relate to the established scales and the prior literature that is based on those scales. In this study, we considered two simple sensor-based measures of tremor amplitude and compared them against an established clinical scale, the Fahn-Tolosa-Marin Tremor Rating Scale, among a cohort of 21 people with multiple sclerosis. Both metrics were found to be strongly correlated with the clinical scores (Pearson's r = 0.83 in both cases). Sources of discrepancy are discussed, suggesting avenues for further refinement of tremor assessment methods.

Purpose: Positron emission tomography, using the glucose analogue fluorodeoxy-d-glucose (FDG), is proving to be useful in the early response detection of head and neck tumors. Presently mechanisms underlying changes in FDG uptake after therapy are poorly understood. Response of tumors to therapy is often accompanied by a decrease in tumor cell proliferation. The purpose of this study was to assess whether or not changes in the uptake of deoxyglucose (DG) may reflect differences in proliferative fraction independent of other metabolic changes induced by using therapeutic agents. Methods and Materials: HN5 head and neck tumor cells were grown to different cell densities producing populations of cells with different proliferative indices without the need for exogenous agents to manipulate cell-cycle kinetics. 3 H-DG uptake, S-phase fraction (Spf), and lactate production were determined in each population of cells. Results: Large differences in Spf between populations of cells were associated with differences in DG incorporation. Lactate production was also found to correlate strongly with DG uptake. Conclusion: Therapy-induced changes in FDG uptake by tumors may be partly due to changes in proliferation.